Medicinal Chemistry 9789350432310, 9788184884746

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CHEMISTRY)

MEDICINAL CHEMISTRY

G.R. CHAlWAL MSc., Ph.D. Dayal Singh College Reader in Chtfmistry University of Delhi, New Delhi-11 0 003.

K4iJl GRiIIl:alaya GFublishing GRouse • Mumbai • Delhi • Bangalore • Hyderabad • Chennai • Ernakulam • Nagpur • Pune • Ahmedabad • Lucknow

C No part of this book shall be reproduced, rerpinted or translated for any purpose whatsoever without prior permission of the publisher in writing.

ISBN: 978-81-84884-74-6 REVISED EDITION : 2010

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Contents O. Concepts of Medicinal Chemistry ...................... (i}{xxix) I. Introduction to Pharmaceutical Chemistry. . . . . . . . . . . . . . . . .. 1-13 2 Classification and Nomenclature of Drugs ................ 14-36 3. 4. 5. 6. 7. 8. 9. 10. II. 12.

Theories of Drug Action and Factors Affecting Drug Action 37-78 Assay of Drugs and Metabolism of Drugs ............... 79-107 Relation of Chemical Structure and Chemical Activity ..... , lOS-lIS General Anaesthetics ............................... , 116-126 Local Anaesthetics ................................. , 127-133 Hypnotics and Sedatives ............................. 134-143 Anticonvulsant Drugs ............................... 144-148 Opioid Analgesics .................................. , 149-156 Antitussives ....................................... 157-161 Psychoactive Drugs ................................ , 162-174

13. Central Nervous System Stimulants ..................... 14.. Antiparkinsonism Drugs ............................. , 15. Adrenergic Drugs .................................. , 16. Cholinergic and Anticholinesterase Agents ............. , 17. Antispasmodic and Antiulcer Drugs .................... 18. Skeletal Muscle Relaxants ............................ 19. Antihistamines ...................................... 20. Nonsteroidal Antiinflammatory Agents and AnalgesiC-Antipyretics ............................... 21. Cardiovascular Agents ............................... 22. Diuretics .......................................... 23. Oxytocics .......................................... 24. Anthe1minitcs ......................................

175-179 180-186 187-196 197-201 202-208 209-213 214-224 225-238 239-263 264-271 272-275 276-282

25. Antimalarials....................................... 283-291 26. Antiamoebic Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 'l!J2-297 n. Miscellaneous Antiprotozoal Drugs. . . . . . . . . . . . . . . . . . . . . 298-302 28. Urimary Tract Antiseptics ............................ 303-304 29. Antifungal Drugs ................................... 305-312 30. Antiviral Agents .................................... 313-315 31. Antincoplastic Agents ............................... 316-333 32. Diagnostic Agents .................................. 334-341 33. Disinfectants and Antiseptics ......................... 342-358 34. Coagulants, Haemostatics and Anticoagulants ............ 359-363 35. Hypoglycaemic Agents ............................... 364-370 36. Thyroid Hormones and Antithyroid Drugs ............... 371-373 37. Steroids and Related Drugs . . . . . . . . . . . . . . . . . . . . . . . . . .. 374-391 38. Vitamins ........................................... 392-408 39. Sulphonamides ..................................... 409417 40. Antiboitics ......................................... 418447 41. Antimycobacterial Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448455 42. Insecticides and Insect Repellants ...................... 456-459 43. Organic Pharmaceuticals Aids ......................... 460486 44. Agents Affecting the Immune Response ................ 487495 45. Prostaglandins and Eicosanoids. . . . . . . . . . . . . . . . . . . . . . . . 496-504 46. Methylxanthines .................................... S05-512 47. Chemical Contraceptives .............................. 513-524 48. Sympathomimetic Drugs .............................. 525-559 49. Antifilarial Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 560-563 SO. Antidiabetic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 564-567 51. Anti-Inflammatory Drugs ............................. 568-571 52. Aids and HIV ...................................... 572-578 53. Vaccines and Antisera . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 579-584 Appendix-I Synthesis of Drugs .................................. 585-718

o Concepts of Medicinal Chemistry

0.1 Introduction Medicinal chemistry is considered to be an interdisciplinary science because it embraces all branches of chemistry and biology. However,

medicinal chemistry is concerned with the discovery, the development, the synthesis in the laboratory, the identification by physical and chemical methods, and the interpretation of the mode of action of biolOgically active compounds at the molecular level. Few authors have treated medicinal chemistry under pharmaceutical chemistry, molecular pharmacology, bio-organic chemistry and selectively toxicity. Sometimes the terms medicinal chemistry and pharmaceutical chemistry are being used interchangeably. However, there are various areas of overlap. For instance, the physiological aspects of drugs are of significance in both medicinal chemistry and pharmaceutical chemistry. In a limited sense pharmaceutical chemistry is concerned more with physical chemically oriented phases of drug action or availability like the pharmacokinetics, the thermodynamics and the assay of drugs in drug systems. In many advanced countries, the term pharmaceutical chemistry includes pharmaceutical technology. The medicinal chemistry deals mainly with organic medicinal substances which may be of natural or synthetic origin. The drugs obtained from natural sources are many alkaloids, glycosides, vitamins, hormones and antibiotics. Some of these are prepared synthetically, e.g., vitamins and· hormones. However, there are certain alkaloids such as morphine, reserpine and quinine, cardiac glycosides, many antibiotics, and some hormones like insulin can be obtained more economically from natural sources. Also, there are drugs

(ii)

Medicinal Chemistry

which can be prepared semi-synthetically by involving simple or more complex modifications of the structure of the natural drugs, e.g., semisynthetic penicillins. It has been now possible to prepare many new analgesics, local anaesthetics, sympathomimetics, antispasmodics, etc. by carrying out changes in the structures of natpral and synthetic drugs. However, there are drugs such as barbiturates, antihistamines, certaiu antihypertensives, many diuretics, some antinalarials, suphonamides, surface-active agents etc. which are of pure synthetic origin. The main aim of a medicinal chemist is to know the mode of action of drugs at molecular levels. He has to understand what a drug does to the biological system and what the body does to a drug molecule. He should acquire a knowledge about absorption, distribution, biotransformation and excretion of drugs. It is important to remember that the recent trends in molecular biology and computer science are exerting revolutionary influence on drug design and production. Recombinant DNA technology arid new cloning methods are exerting great impact. By these methods, it becomes possible to manufacture drugs such as human insulin, tissue plasminogen activator and growth hormone. Recombinant DNA techniques also play vital roles in studies of recaptors.

0.2 International Non-proprietary Names (INNs) During professional practice, it becomes essential to know about the propietary names. A propietary name is owned by a private party, firm or an individual. It can be only used by the consent of its owner. However, a nonpropietary name is the generic name for a drug and is a public property. The "World Health Organisation" has been authorised to select generic names for drugs. Such names for drugs have been called International Non-propietary Names (INNs). This system provides one name world-wide for a drug. Some countries accept the INNs and do not publish their own national generic names. Although the practice of publishing the respective national generic names continues in France, Japan, UK and USA, yet the experts from their respective national nomenclature committees participate in the meetings selecting INNs. The result of this has been that, with very rare exceptions, DCFs, BANs, JANs and USANs have been identical with INNs. The World Health Organization has published a cumulative list of _ International Nonproprietary Names (INN) for Pharmaceutical Substances. The latest list (no. 8) published in 1992 has grouped together 6085 INNs. The list has been featuring generic names presented in alphabetical order by Latin name. Each entry has been including equivalent nonproprietary names in English, French, Russian and Spanish; a reference to the INN list in which the name was originally proposed or recommended; and a reference to other

Concepts of Medicinal Chemistry

(iii)

generic names, like national nonproprietary names, pharmacological monographs, and names which are issued by the International Organisation for Standardization. New lists of proposed and recommended INNs are being published regularly throughout the year in the WHO Drug Information. For devising INNs, the following two primary principles are used: (i) INNs must be distinctive in sound and spelling. They should not be inconveniently long and should not be confused with names in common use.

(ii) The INN for a substance related to a group ofphannacologically related substances should, where necessary, exhibit this relationship. Names which may convey to the patient an anatomical, physiological, pathological or therapeutic suggestion should be avoided. If there is the group relationship, it is shown by a common stem. Some prominent stems and definitions for groups of substances have been outlined below. If there is no hyphen in a stem, it may be employed anywhere in the name.

-ac -adol or -adol-anserin -ase -ast -astine -azepam -azocine -azosin -bactam -cain-caine cef -cillin -conazole -curonium -cycline

anti-inflammatory agents, ibufenac derivatives analgesics serotonin receptor antagonists (mostly 5-HT2) enzymes antiasthmatics, antiallergics, not acting primarily as antihistaminics antihistaminics diazepam derivatives narcotic antogonists/agonists related to 6,7benzomorphan antihypertensive substances, prazosin derivatives beta-Iactamase inhibitors class I antiarrhythmics, procainamide and lidocaine derivatives local anaesthetics antibiotics, cephalosporanic acid derivaties antibiotics, 6-aminopenicillanic acid derivatives systemic antifungal agents, miconazole derivatives neuromuscular blockers, pancuronium related antibiotics, tetracycline derivatives

Medicinal Chemistry

(iv)

-dipine -fibrate -fylline gest g/i -ifene io-ium -mab

-metacin -mustine -mycin nalni-nidazole· -0101 -onide -oxacin -pramine -pride -pril -prilat -profen prost -racetam -relin rifa-

calcium channel blockers, nifedipine derivatives clofibrate derivatives N-methylate xanthine derivatives steroids, progestogens antihyperglycaemics, sulphonamide derivatives antioestrogens, clomifene and tamoxifen derivatives iodine-containing contrast media quaternary ammonium compounds monoclonal antibodies: rat origin -amab hamster origin -emab primate origin -imab mouse origin -omab human origin -umab chimeras origin -ximab antiinflammatory, indomethacin derivative antineoplastic, alkylating agents, (~-chloroethyl) amine derivatives antibiotics, produced by Streptomyces strains narcotic antagonists/agonists related to normorphine N0 2 derivatives and nicotinic acid derivatives antiprotozoals, metronidazole derivatives beta-adrenoreceptor antagonists steroids for topical use, acetal derivatives antibacterials, nalidixic acid derivatives substances of the imipramine group sulpiride derivatives angiotensin-converting enzyme inhibitors angiotensin-converting enzyme inhibitors antiinflammatory agent, ibuprofen derivatives prostagladins amide type nootrope agents, piracetam derivatives prehormones or hormone-release stimulating peptides antibiotics, rifamycin derivatives

Concepts of Medicinal Chemistry

(v)

som-statsulfa-tiazem -tide -tidine

growth honnone derivatives enzyme inhibitors / anti-infectives, sulfonamides calcium channel blockers, diltiazem derivatives peptides and glycopeptides histamine H 2-receptor antagonists, cimetidine derivatives .

-tizide vir

diuretics, chlorothiazide derivatives antivirals (undefined group)

At some places, the BAN (British Approved Names) and USAN (United States Approved Names) have been not identical to the INN. In order to understand this, the following are given. These should be compared with the relative INN stems and definitions listed above.

-ae -anserin -eaineel-eillin -dipine

glimethacin-oxacin sulpha-

anti-inflammatory agents (acetic acid derivatives) (USAN) serotonin receptor antagonists (undefined group) (USAN) antifibrillants with local anaesthetic activity (BAN) cephalosporins penicillins (USAN) phenylpyridine vasodilators (undefined group) (USAN) oral hypoglycemics (glipizide type) (USAN) anti-inflammatory substances (indomethacin type) (USAN) antibacterial agents of cinoxacin group (BAN) (BAN)

It has been agreed internationally that INNs cannot be registered as trade marks. However, there exists no protection against use of names which are similar to and manifestly derived from them.

This creates confusion and impedes the logical and orderly development of INNs, and this has made the World Health Assembly to adopt a resolution seeking better protection of INNs. Thus in resolution WHA 46.19 WHO Member States have been requested, amongst others, to encourage manufacturers to rely on their corporate names and the international nonproprietary names, rather than on trade marks, for promoting and marketing multisource products introduced after patent expiration.

(vi)

Medicinal Chemistry

Applications for INNs are submitted to the World Health Organtzation on a special form. Such applications are usually submitted by national nomenclature commissions; where these do not exist, the applications can be submitted directly by individual pharmaceutical manufacturers. All these requests are handled according to the well defined procedure. A suitable name so devised becomes the proposes INN, which would be publicised in the WHO Drug Information and elsewhere. When an objection is lodged against the proposed name, WHO uses its good offices to get withdrawal of the objection. In the absence of an objection, the proposed INN would become the recommended INN and is publicised in the same manner. One should not try to self-create a generic name but use a code until there is an assignment of a recommended INN. 0.3 Pharmacokinetics

It deals with different aspects of absorption, distribution, biotransformation and excretion of drugs. These vital processes and the amount of drug administered would ascertain the concentration of the drug which would get built up at the site of action. In pharmacokinetics, the processes are expressed mathematically. We will now outline the passage of drugs through cell membrane which forms a significant part of the processes enumerated above. The cell membrane (plasma membrane) is made up of a bilayer of amphipatbic lipids, with their fatty acid chains oriented inwards to yield a continuous hydrophobic . phase and their polar hydrophilic heads oriented outwards. The fluid-mosaic model of plasma membrane includes various membrane-associated proteins which are able to penetrate into either side of or entirely through a fluid phospholipid bilayer (Fig. 1). Lipid molecules in each layer can readily diffuse laterally. This is able to make the membrane fluid and flexible with high electrical resistance. It is also able to make the membrane relatively impermeable to highly polar molecules. The passage across the membrane by the drug molecule occurs either by passive process or by a mechanism which involves the active participation of the components of the membrane. In the passive process the drug molecule would be able to cross the membrane by passive diffusion along a concentration gradient due to its solubility in the lipid bilayer. Higher the concentration gradient across the membrane and higher the value of the lipid: water partition coefficient of the drug the greater would be its penetration. The membrane has been permeable to water which enters by diffusion or by flow resulting from hydrostatic or osmotic differences across the membrane. Along with-this bulk flow small water-soluble molecules are also carried. In active transport molecules would be carried against a concentration gradient and input of energy is needed.

Concepts of Medicinal Chemistry

(vii)

Fig. 1 : Fluid-mosaic model of plasma membrane

Absorption

In order to attain the desired effect, a drug molecule must first enter the blood stream and be carried to its site of action. The two common routes of administration of drugs include oral and parenteral. The extent to which a drug gets absorbed from its site of administration to the systemic circulation is termed as bioavailability. The absorption of a drug from the gastrointestinal tract has been involving the passage of the drug into the blood across the lipoid barrier of the cells of the gut lining. It occurs through passive diffusion ofnonionised molecules of the drug and depends upon the pKa of the drug and the pH gradient. Most drugs are weak acids or bases and are present in solution as both the ionised and non-ionised forms. The non-ionised molecules are able to diffuse across the cell membrane and the ionised molecules, due to their low lipid solubility, are unable to penetrate the lipid membrane. Absorption also depends on the concentration gradient between the gastrointestinal tract and blood. . It is possible to explain these points by taking example of absorption of aspirin which is an acid drug (pKa 3.5). The drug is absorbed in the stomach where the pH is around 2 and the drug is almost nonionised. In the plasma where pH is 7.4 the drug is ionised. It is unable to return to the stomach because there is a concentration gradient of 25000 to 1 (stomach to plasma) of the nonionised species. Basic drugs like ephedrine (pKa 9.6) get absorbed only slightly from stomach. The major region of drug absorption has been small intestine (pH 5 to 7) as it is long and is having a very large surface because of mucosal invaginations which are heavily vascularised. The number of active transport sites is also sufficiently high in small intestine. The large intestine (colon) is having a much smaller surface area. It happens to be the most alkaline part of the digestive tract (pH 7-8).

(viii)

Medicinal Chemistry

A drug which is absorbed from the stomach or intestine must pass through the liver before it enters the systemic circulation. In the liver the drug gets metabolised or excreted in the bile. If the drug gets extensively metabolised in the liver the bioavailability would be substantially decreased. It is called first-pass effect. Drugs would be removed from the liver as metabolised or unchanged drug either by biliary secretion or in hepatic vein. Drugs and metabolites eliminated from the liver into the bile would PilSS into the lumen of gastrointestinal tract. Here some of the drugs may get reabsorbed as such or after further metabolism. This recycling of drugs is called enterohepatic circulation. For example, morphine glucuronide gets excreted in the bile in higb concentration. Parenteral administration of drugs may occur through intravenous, subcutaneous or intramuscular routes. In intravenous route absorption has been circumvented. Absorption from subcutaneous or intramuscular sites takes place by simple diffusion. It may be important to mention the term bioequivalence to distinguish it from bioavailability. Two drug products, which are having the same ingredients and are identical in strength and concentration, dosage form and routes of administration, are regarded to be bioequivalent provided the rates and extent ofbioavailability of the active ingredient in the two products are not significantly different under suitable test conditions. .

Distribution A drug after taking is passed through the gastrointestinal tract, through the liver, and into the systemic circulation, or directly through intravenous route into the systemic circulation. Thus, it is distributed throughout the body. Drug distribution has been found to depend on certain physiological factors and physicochemical properties of drugs. The physiological factors may also cause the blood flow to various tissues. The physicochemical factors affecting the distribution include the partition coefficient of the drug between blood and the tissues, the degree of ionisation of the drug at the pH of plasma, the molecular size of the drug, and the extent of tissue and plasma protein binding. Usually a drug is accumulated in a given tissue which is able to prolong the drug action in the same tissue 0[ at a distant site For example, long-term therapy with antimalarial mepacrine causes the accumulation of the drug in liver. Many lipid-soluble drugs like .thiopentone, are stored by physical solution in the neutral fat. Many drug~ :ue bound to plasma proteins. Acidic drugs are mostly bound to albumin ,u:d basic drugs to aI-acid glycoprotein. Binding to other plasma proteins occurs to much iesser extent. As only the unbound drug has

Concepts of Medicinal Chemistry

(i.\)

been in equilibrium across membranes, binding of a drug with plasma proteins would limit its concentration in the tissue and at its site of action. Protein binding also influences the glomerular filtration of the drug, preventing rapid excretion of the drug. The protein binding is generally reversible, and depending upon the equilibrium constant. the drug can remain in systemic circulation bound to a protein for a considerable period, thus would not be available to the loci ofbiotransformations or to the pharmacologic receptors. Warfarin and other similar anticoagulants are known to bind with plasma proteins, their distribution gets restricted to plasma and extracellular fluid. Drugs bound to proteins can be displaced by other drugs. An example is that aspirin displaces orally active protein-bound hypoglycaemic agents and thus can increase the level of free antidiabetic drugs dangerously, thereby causing the hypoglycaemic shock. When the distribution of drug between blood and tissues occurs rapidly, or in other words the equilibrium between concentrations of the drug through the body and plasma gets attained instantaneously, the body is considered as a single homogeneous entity. The process is known as one compartment open model system (Fig. 2). It is seen that the rapid distribution and onset kf

Tissues ~Cl>S03H>NH2>CH3.>H. 2. When two or more substituents have first atoms of same kind, precedence is given to the substituent with a second atom of higher atomic number. Also, a carbon-oxygen double bond is considered equivalent to a carbon attached to two oxygens

o \I

-C-OH

o =

I

C-O

"-OH

o >

o

1\

-C-H

I =C-O

'"

H

A carbon nitrogen triple bond is considered equivalent to a carbon attached to three nitrogens. N N

-CaN

=

/ C-N > -C=N

'"

N

=

/ -C

"-N

33

Classification and Nomenclature of Drugs

CH A benzene ring is viewed as equivalent to C - CH.

Examples

The respective R or S descriptors are given in parentheses in the beginning of the chemical name. The (R)-(S) system is used for specifying configurations in chemical names of drugs. For example, adrenaline, an adrenergic drug, is

OH

Hovi-CH.NHCH. HO

H

.

named as (R)-l. (3,4-dihydroxyphenyl)-2-methylaminoethanol, and cycloserine, a tubercolostat, is named as (R)-aminoisoxyzolidine-3-one. (Z)-(E) Isomerism

The use of prefixes cis and trans to specify the geometric isomerism is common. In many cases the use of these notations poses problems. A system making use of descriptors Z and E is introduced. In specifying configuration about an ethylenic double bond, for example, first precedence of the groups attached to a double bond has been determined in accordance to the sequence

HO

34

Pharmaceutical Chemistry (Organic)

rule devised for (R)- (S) system. We try to look at the group of higher priority on the one carbon and the grofJp of higher priority on the other carbon and see whether they are on the same side of the molecule or on opposite sides. In order to specify the configuration we employ the letter Z (German: . zusammen together) to mean on the same side, and the letter E (German:entgegen, opposite) to mean on opposite sides. The respective notation Z or E, in parentheses, has been mentioned in the beginning of the chemical name. These descriptors are used for designating geometrical isomerism in the chemical names of drugs, For example, oleic acid, a pharmaceutical acid, has been (Z)-9 octadecenoic acid, and stilboestrol, and oestrogen, has been (E)-a, ~- diethylstilbene-4, 4'-diol.

Nomenclature of Drugs A. Names of Drugs Drugs may be having three or more names. These names are the following: code number or code designation; chemical name; proprietary, trivial, brand or trade name, or trademark; nonproprietary, generic official, or common name; synonym and other names. The code number usually is formed with the initials of the laboratory or the chemist or the research team that has prepared or tested the drug the first time, followed by a number. It does not identify the chemical nature or structure ofthe drug. It is discontinued as soon as an adequate name is chosen. , The chemical name should describe unambiguously the chemical structure of a drug. It is given according to rules of nomenclature of chemical compounds. As the chemical name is sometimes very elaborate, it not suitable for routine usage. The proprietary name is the individual name selected and used by manufactures. If a drug is manufactured by more than one company as frequently happens, each firm assigns its own proprietary name.!t should be written with capitalisation of the first letter of each word of the name. The nonproprietary name refers to the common, established name by which a drug is known as an isolated substance, irrespective of its manufacture. It should be simple, concise, and meaningful but often it is not. The first letter is not capitalised, It is chosen by official agencies. On a worldwide scale, however, the World Health Organisation has been the official agency to select, approve, and disseminate the generic names of drugs. Synonyms are names given by different manufactures to the same drug or old nonproprietary names. Some drugs may have several names. For instances, diphenhydramine has 13 different names; chlorpromazine, 61; phenobarbital 22; pethidine, 26; prednisone, 29; chloramphenicol, 45; sulfanilamide, 60; meprobamate, 64; vitamin Bl2 82.

B. Generic and Brand Names not Always Equivalent It is usually assumed that a drug bearing a generic name is equivalent to the same drug with a brand name. However, this is not always true. Although

Classification and Nomenclature of Drugs

35

chemically equivalent, drugs having the same nonproprietary name but different proprietary names, because they are manufactured by different laboratories, can markedly differ in their pharmacological action. Several factors, such as those pointed out by Sadove, account for this difference: size of crystal or particle, its forms, and isomers; form of the agent-solution vs. salt and type of salt; vehicle (primary and secondary), excipient, or binder; coatings, number, and types; degree of hydration of crystal or addition of dehydrating substances to package, or hydration of diluents, vehicles, and the like; diluent; purity-type and number of impurities. viscosity; pH; sustained-release f!Jrms; enteric coating; vehicle, base, or suspending agents; container-stopper, type of glass, whether or not glass is preheated or impervious; package, dating, type, literature enclosed, dehydration of cotton in package-amount of cotton; quality of active ingredient: relative and absolute; contaminants; allergenic substances (primary and secondary) in product; irritation; melting point; ionization of ingredients; surface tensionsurface active agents; storage factors; time, heat, light, vibration; flavouring and colouring agents; dose or quantity of drug, its distribution, and size of tablet or surface-to-tablet ratio; type and characteristics of gelatin capsules; antioxidant included in preparation; disolution and disintegration rate; buffer type and amount; air, mold, or bacterial contamination of product; antibacterial preservative; metallic contamination in process of manufacture or in packaging. The following among certainly many other drugs have been found to differ in pharmacological action when supplied by different manufacturers; chloramphenicol, prednisone, p-aminosalicylic acid, phenylbutazone, acetylsalicylic acid, sulfisoxazole, diphenydantoin, meprobamate, secobarbital, digitoxin, penicillin G, dextroamphetamine, chloral hydrate, heparin, dicumarol, diethylstibestrol, digoxin, oxytetracycline, acetaminophen, ampicillin, chlordiazepoxide, erythromycin, nitrofurantoin, riboflavin, sulfadiazine, warfarin.

Nomenclature of New Drugs by WHO New drugs are now named according to the general principles laid down by World Health Organisation (WHO), for the national pharmacopoeias. The principles are as follows. (I) Names should be free from any anatomical, physiological, pathological or therapeutic suggestions. (2) Indication of the presence of fundamental group in the drugs name should be made by the combination of syllables from the scientific chemical name. (3) More than four syllables should not be included in the name. It should be distinctive in sound and spelling. Name should not be confused with the names of the drugs already in use. They should not contain tenninal capital letter or number.

36

Phannaceutical Chemistry (Organic)

(4) The following termination should be used. Latin

English

1. 2

-alum . -anum

3. 4. 5.

6. 7.

-enum -inurn -inun -olum -onum

-al -ane -onium -inium -olium -ene -ine -in -01 -one

8.

-osidum

-osid.

Types of Compounds

Aldehyde saturated group Quaternary compounds

unsaturation Alkaloids, Organic bases Glycerides, neutral principles Alcohols phenols (-OH group) Ketones and other substances containing CO-group. Glycosides.

3 Theories of Drug Action and Factors Affecting Drug Action

Introduction to Theories of Drug Action The active microbial defenses of the body have been found to be both biological as well as chemical in nature. Biological defenses. When the infected organisms enter the body, they start manufacturing toxic antigens in the body. In order to combat the so formed specific antigens, the body starts manufacturing antibodies. The biological defense involves the engulfing of microbes by leucocytes. Similarly antitoxins which are seral antibodies neutralise toxins specific for a disease. Vaccines are devitalised disease organisms which, when administered have been found to stimulate the body for manufacturing antibodies in defense against the disease. Chemical defenses. As soon as chemotherapeutic agents enter our body, the body tries to get rid ofthese as early as possible by altering them chemically, either to make them less toxic or to make them more soluble and more easily excreted. Chemotherapeutic agents have been found to function in the following way:

(a) Surface active agents. Most antiseptics act by changing the surface characteristics of cell membranes, thus disrupting the cell so that cell constituents no longer have necessary organisation. Whenever there occurs change in structure of the hydroxy compounds, there occurs regular effects on bacteriostatic properties of these compounds. For example, phenols have been found to be more effective than alcohols. The effectiveness has been found to increase up to a certain point with increase in the length of alkyl chains. However, the effectiveness has been found to decrease with increasing number of hydroxyl groups.

Pharmaceutical Chemistry (Organic)

38

(b) Metabolite antagonism. When sulpha drugs were studied as antibacterial drugs, this gave rise to a principle of drug action. We know that paraaminobenzoic acid (PABA) is a normal cellular constituent or metabolite of the bacteria (micro-organism). When bacteria take up sulphonamide (the structurally similar compound to that of PABA), this (sulphonamide) can't fulfil the function of PABA, the essential metabolite and hence the growth and reproduction of bacteria would stop.

NH.

NH.

I

I

/,

/,

,/, I

\I

'/

I

"

I

SO.NHR

sulphonamide (PABA antagonist)

COOH

PABA (A normal cellular constituent i.e., normal metablite)

The inhibition or antagonism of the essential metabolite (e.g., PABA) by similar compound such as sulphonamides is called metaboliteantagonism while the inhibitors are called metabolite-antagonists. In the above example of metabolite-antagonism, the antagonist and metabolite resemble structurally. However, there are certain examples of metabolite-anatagonisms in which antagonists do not resemble the corresponding metabolite structurally. Some important examples of such metabolite-antagonisms are as follows: (i) Histamines and anti-histamines. Histamine, which is an essential amino acid, has been found to be antagonised by all the antihistamines, many of which possess the phenylbenzylalkylamine structure. structur~ly

N---CH

n

II

II

HC

II

C.CH.CH.NH.

'\./ N' H

histamine

/,

I

II CH.CeBs

'/'1 . N

I

CH.CH.NR.

antihistamines (histamine antagonists)

(ii) Aneurine (Vitamin B j ) pyrithiamine. Aneurine, which is an essential 0-13 growth factor, has been antagonised by pyrithiamine.

N::ri~'" N~1N"CH,oH H3C~ H2 ls HlCH2.0KK,C~N~NHz V t-I

Aueurine

PyrithJamine

39

Theories of Drug Action and Factors Affecting Drug Action

(iii) Biotin-desthiodiotin. Biotin has been anatagonised by desthiobiotin and nordesthiobiotin.

co

co

/" I I

HN

A

HN

NH

I

HC-.CH

I

I

HC-·CH I 1 Jil CH•. (CHI ), COOH

I

H~C

NH

CH.(CR.),.COOH

"/ S

desthiobiotin when a-CHi nordestbiobiotin when a ... H

biotioD

(iv) Some vitamin B complex antagonists. Pyridine-3-sulphonic acid has been found to be antagonistic to nicotinic acid or to nicotinamide, panytoyltaurine to pantothenic acid and pteroylaspartic acid to pterolygulatmic acid.

SO,H

COOH

/,,/ I

/,,/

N ,/

g

I

U

V

V

N

N

"pyridine-3-nlpbonic acfc.t

ni~ttnic

CONH,

N

aeid

nicotinamfde

CH,

I

CH,OH.C.CHOH.CONH.CH,CH,COOH

I

CHi

pantothenic .old

CHi

I

C",OH.C CHOH.CONH.CH•.CU•.SO,H ( CHi p&nloyltaarm.

OR

J

C

COOH

N

/=\.

CH.NH-,

N/"~/ I n I

/

}-CONH.CH

-,

"(CHa).COOB

A/"/

H,N

N

N

n-l pteron,lupartIa acid n-2 J)Ctro,lat1ltaadc acI4

From the above examples it may be seen that in some cases the structure of antagonist is identical to that of the metabolite. This led to the search for

Pharmaceutical Chemistry (Organic)

40

structurally analogous inhibitors (antagonists ).It is to be remembered that all the effective drugs neither act as direct inhibitors (antagonists) of some structurally identical natural metabolite nor all the structural analogues are effective drugs. This principle is still used in the studies of drugs. (c) Enzyme neutralisers. There are many compounds that have been found to interfere with enzyme activity by blocking their reactive groups. Some compounds have been so powerful in their effects that they act as poisons and thus considered as valueless for chemotherapeutic use. For example, heavy metal ions tie up mercapto groups in coenzyme A and similar coenzymes which do participate in redox. On the similar basis, arsenic compounds have been used as war gases. Similarly, carbon monoxide, cyanide ions and azide ions or binding ions in porphyrins block the activity of cytochromes as well haemoglobin. However, this type of drug action can be counteracted by an antidote which takes up the poison more effectively than the enzyme. For example, BAL (British Anti-Lewisite) has been used as an antidote to poisoning by lewisite which is a war gas. In actual practice, the antidote possesses mercapto groups which are able to prevent the arsenic of Lewisite from affecting enzymes with sensitive groups.

CICH=CHAsCl.

HS.CHa·CH.CH.OH

\

SH dlchlorochlorovinylarsme Lewisite

1. 2-c11tbio,lJC8l'ol BAI.

Absorption of Drugs The main factor affecting the performance of a drug is its ability to reach the site where it is required; this is generally achieved by the process of absorption. But most of the drugs are either weakly acidic or weakly basic compounds. Therefore, their absorption in the gastrointestinal tract has been found to depend upon their acidic or basic strength, i.e. pka values. The more dissociated a given drug into ions at a given pH, the more it is water soluble. On the other hand if the dissociation of a drug is poor at a given pH, then it is generally insoluble in water and most of it is lipid soluble (lipophilic). The weakly acidic drugs have been found to be absorbed more readily in the stomach because in the acidic environment they are almost undissociated. Hence the more lipophilic (lipid soluble) is the acid drug, the faster is its absorption in the stomach. On the other hand, the weakly basic drugs have been found to be readily absorbed in the intestine because due to the intestine alkalinity they are slightly dissociated there. Hence the more lipophilic (lipid soluble) is the basic drug, the faster is its absorption in the intestine.

Theories of Drug Action and Factors Affecting Drug Action

41

The lowest pKa value of an acid drug for absorption in the stomach has been found to be about 3 whereas the highestpKa value of a basic drug for rapid absorption in the intestine has been found to be about 7.8.

Isosterism Two molecules or ions which have an identical number and arrangement of electrons are known asisosteres and the phenomenon is known asisosterism. Most of the physical and chemical properties of the isosteres are almost similar. An important example of isosteri$m is benzene and thiophene. These are two isosteres and even their corresponding derivatives such as nitro, aldehyde, etc., have been found to be boiling at temperatures within very close range. As benzene and thiophene have much similarity in their physical properties and odour, they and their corresponding derivatives possess similar physiological activity, e.g., nitrothiophene and nitrobenzene have the same degree of toxicity. It is also found in that benzene ring may be replaced by thiophene in many compounds without altering their physiological action. However, this is not true in all cases because many exceptions are found,e.g., thienylalanine can't take the place of phenyalanine in nutrition. Friedman introduced the term biosterism to describe those isosteres which have the same type of biological activity also. Some other examples of bio-isosterism are as follows: (i) The 2-thineyl analogue of cocaine possesses strong local anaesthetic activity. (ii) 2-Methyltheinylcinchonic acid and phenylcinchonic acid both have been found to increase almost equally the urinary secretion of uric acid. (iii) Antergan and its 2-thiophene analogues have been found to be active

antihistamines.

Ferguson Principle By observing in a homologous series that certain physical properties like solubility in water, vapour pressure, capacity, and distribution between immiscible phases, alter in accordance to the geometric progression. Ferguson concluded that "molartoxic concentrations ... are largely determined by a distribution equilibrium between heterogeneous phases - the external circumambient phase where the concentration is measured and a biophase which is the primary seat of the toxic action."

42

Pharmaceutical Chemistry (Organic)

According to Ferguson, it is neither necessary to define the nature of biophase nor to measure the concentration of the drug at this site. If equilibrium conditions occur between the drug in the molecular biophase and in exobiophase, that is, in extracellular fluids the tendency for the drug to escape from each phase remains the same, even though the concentrations in the two phases have been different. This tendency has been assigned the name ofthermodynamic activity. It is equivalent approximately to the degree of saturation of each phase. Therefore, thermodynamic activity in the external phase (exobiophase) corresponds to thermodynamic activity in the molecular biophase; in practice it is the first that is measured, because it is not possible to measure the latter. In the case of volatile drugs their thermodynamic activity has been calculated from the expression Pt/Ps• where P, is the partial pressure of the substance at the experimental temperature. When the drug is nonvolatile, its thermodynamic activity has been calculated by using the ratio St/So where S, is the drug's molar concentration and So its corresponding solubility.

Structure and Activity Based on the mode of pharmacological action, drugs are divided into two main classes: structurally nonspecific and structurally specific. 1. Structurally Nonspecific Drugs. Structurally nonspecific drugs are those drugs in which pharmacological action is not directly subordinated to chemical structure, except to the extent that structure influences physicochemical properties. Among these properties may be cited absorption, solubility,pka, and oxidation-reduction potential, which affect permeability, depolarization of the membrane, protein coagulation, and complex formation. It is assumed that structurally nonspecific drugs act by physicochemical processes for the following reasons: (i) Their biological action is directly related to thermodynamic activity, which is usually high, with values from 1 to 0.0. It implies that such drugs act in relatiyely large doses. (ii) Although they vary in chemical structure they bring about similar biological responses.

(iii) Slight modifications in their chemical structure do not cause pronounced changes in biological action.

2. Structurally Specific Drugs. Structurally specific drugs are those drugs whose biological action has been resulted essentially from their chemical structure, which should adapt itself to the three-dimensional structure of receptors in the organism by forming a complex with them. Thus, in these drugs chemical reactivity, shape, size, stereochemical arrangement ofthe molecule, and distribution of functional groups, as well as resonance, inductive, effects, electronic distribution, and possible binding with receptors, besides other factors, play decisive roles. Many considerations suggest that the pharmacological effect produced by these drugs arises from complexation with a chemically reactive minuscule area

Theories of Drug Action and Factors Affecting Drug Action

43

of certain body cells whose topography and functional groups have been usually complementary to those of the drugs: 1. Their biological action is not dependent solely on thermodynamic activity, which is usually low (less than 0.(01). It implies that structurally specific drugs have been found to be effective in lesser concentration than the structurally nonspecific ones. 2. They possess some structural characteristics in common, and the fundamental structure present in all of them, by orienting functional groups into a similar spatial arrangement, is responsible for the analogous biological response they cause. 3. Slight modifications in their chemical structure may give rise to substantial changes in pharmacological acti vity , so that substances thus obtained may have actions which range from antagonistic to similar to that of the parent compound. Hansch's Mathematical Method of Studying Structure-Activity Relationships The method of correlating biological activity with chemical structure by mathematical models involves the expressing of the biological activity as a function of parameters attributed to each substituent group or parent of the molecule. This empirical model has been based on an additive mathematical model in which it is assumed that a certain substituent in a specific position contributes additively and constantly to the biological activity of a molecule in a series of chemically related compounds. Studies with this model started with Free and Wilson. They are now being pursued by Purcell, Craig, and other researchers. More perfect mathematical models are based on physicochemical parameters. These parameters have been more adequately correlated with biological activity, because biological processes have been of a physiochemical natur~. These models, called linearfree energy models, consider mainly the electronic, steric, and hydrophobic effect of the substituent groups introduced into the parent molecule upon formation of a drug-receptor complex. One of the most active investigators in this field has been Hansch. With the purpose of correlating the chemical structure with the physical properties and biological activity of drugs, Hansch is studying two complex processes: 1. Movement of the drug from the point of application in the biological system to the sites of action. 2. Occurrence of a rate-limiting chemical or physical reaction in receptor sites. Both these processes are often distant (in time and space) from the observed biological response, because the drug, before producing an effect, must cross a series of compartments made up essentially of aqueous or organic phases. Because of the success of Overton and Meyer and their disciples in

44

Pharmaceutical Chemistry (Organic)

correlating biological activity with partition coefficients, Hansch has used a model analogous to the one used by those authors. Hansch starts from a chemical substance of known biological action and compares its activity with that of compounds of analogous structure, differing from it only in substituent groups. He finds out the distribution coefficients of the parent compound and its derivatives between water, a polar solvent, and normal octanol, a nonpolar solvent. The difference between the respective logarithms of the distribution coefficients' is known as 1t 1t COOH

= log P CooH -

log PH

In the foregoing equation It represents the hydrophobicity constant and is the measure of contribution of the substituent to solubility in a series of portions. PCooH represents the partition coefficient of the carboxylic deerivative; PH represeents the partition coefficient of the parent compound. If 1t is carrying a position value, it means that the substitutent group increases the solubility of the compound in nonpolar solvents. If it is carrying a negative value, the substituent group will increase the solubility of the compound in polar solvents. Furthermore in his studies Hansch also considers Hammett's equation, which relates chemical structure both to equilibrium constants and to rate constants. Two parameters come in this equation: a; characteristic only of the substituent it represents the ability of the group to attract or repel electrons through a combination of inductive and resonance effects: p,characteristic of the reaction considered - it measures the sensitivity of this type of reaction to substitution in the parent compound. Hammett's equation may be put by the formula log

k

--=pa ko

where k and ko represent the rate constants for reaction of the derivative and the parent compound, respectively; such constants can be substituted by the equilibrium constants k and ~; in this case the equation becomes as follows: K log = pa ~ The value of a can be found out almost directly by measuring the effect ,of the substituent in the ionization constant of the parent compound, because a=log in which KCOOH and ~ represent the ionization constants of the substituted and nonsubstituted compounds, respectively. If a substituent presents a positive a value, it implies that it attracts electrons; if it has a negative a value, it implies that it donates electrons.

Theories of Drug Action and Factors Affecting Drug Action

45

On using the parameters n, cr, and p and not taking into account steric factors, which were assumed to be constant, Hansch and his coworkers were able to derive the following equation: log -

I C

=- k n2 + k'n + crp + k"

where C represents the drug concentration necessary to produce the biological effects, and k, k', k", represent constants for the system being studied, determined through regression analysis of the equations corresponding to the derivative biologically tested in the series. When this equation, with slight adaptations in some cases, was applied to various groups of drugs such as chloramphenicol derivatives penicillins, cephalosporins, fungicides, lincomycin and related antibiotics, sulfamidic diuretics, hemolytic agents, narcotic agents acetylcholine and histamine antagonists, anticonvulsants, spasmolytics, barbiturates, sulfonamides, a series of monoamine oxidase inhibitors, antihistaminics, ~-haloalkylamines, analgesics of the imidazoline series, and several antibacterial agents, correlations obtained between the observed and calculated activities were good, about 0.8 to 0.9 in most cases. In few cases, a better correlation was reported by certain authors (e.g., Cammarata) who employed an equation that regarded the volume of the substituent and separated its electronic influence into inductive and resonance effects. Another use of Hansch' s equation and its variants can be seen in proposals of mechanisms of action of several types of drugs, for example, the antibacterial tetracyclines and the antimalarial chloroquine. Drug Receptors

A. Nature of Drug Recepto~ Some drugs exhibit biological activity in minute concentrations. Because of this reason they are termed as structurally specific. The effect produced by them is ascribed to interaction with a specific celfular component called a receptor. As a result of this interaction the drug forms a complex with the receptor. (A chemist refers to the receptor in terms of chemical structural component, but the biologists prefers to treat it in microanatomical terms.) The hypothesis of existence of receptors was postulated because of three remarkable characteristics of drug action: 1. High potency. Many drugs are known which act at very low concentrations: 10-9 M and even 10-11 M. 2. Chemical specificity. Evidence for this comes from the diff~rences in effects produced by optical isomers. Thus, only one of the four isomers of chloramphenicol has been active. . 3. Biological specificity. Exemplified by epinephrine, which is having marked effect on heart muscles but very weak action on striated muscle.

Pharmaceutical Chemistry (Organic)

46

Experimental evidence indicates that receptors are localised in macromolecules most of which have protein-like properties and exhibit the specific ability to interact at least with natural substrates at their active sites. Their nature has been probably similar to that of the active site of enzymes, and they approximate in size the drug molecule which is able to form a complex with them. Complexation of a drug with special chemical groups on the receptor gives rise to a sequence of chemical or conformational changes that either cause or inhibit biological reactions. Nowadays such changes in biopolymers actually occur as an effect of the action of small molecules. A drug's ability to adapt itself to a receptor has been found to depend on the structural, configurational, and conformational characteristics of both drug and receptor.

B. Isolation of Drug Receptors Many attempts have been made to isolate drug receptor, but success as yet has been equivocal. Difficulties in separating the receptor from tissue proteins are great, because during the process of extraction the forces that unite both entities - drug and receptor - get broken. Concomitantly, because of changes in the structural shape of the macromolecule of which the receptor has been an integral part the functionality of this macromolecule can be destroyed. Further more in the isolation process the receptor undergoes changes in its natural spatial arrangement and charge distribution, and both of these factors have been essential to its interaction with the drug. Two basic methods - direct and indirect have been used in the isolation of receptors. 1. Direct Method. In the direct method, attempts have been made to label the functional groups of a receptor with substance able to bind irreversibly, that is, by covalent bonding, and then to isolate the resultant drug-receptor complex. Among the chemical reagents used to form covalent bonds have been those that can react with the serine hydroxyl group: phosphorylating agents, sulphonyl fluorides, carbamylating agents, alkylating agent, and N - alkylamaleimides, whose general structures have been given, respectively, as foHows:

R,O

"-UP-F /

R'

°n

R-S-F

n

°

H.C-CH.-CI

/

R-N

"-

H.C-CH.-Cl

° 11

R-C-CH.-Q

Theories o/Drug Action and Factors Affecting Drug Action

47

Applied to tissues, the direct method has been found to be nonspecific. Recent attempts with promising results to isolate cholinergic receptors were carried out by Changeux and colleagues, and Miledi and coworkers. 2. Indirect Method. In the indirect method one attempts to identify the macromolecule that has the receptor through the use of substances able to complex with it reversibly; that is, through weak bond, and then to isolate the macromolecule and characterise it. The first attempt to identify the cholinergic receptor by this method was made by Chagas in 1958. Later O'Brien and colleagues, Changeux and coworkers, Meunier and collaborators, and De Robertis have tried to reach the same goal with better success. In 1967, by X-ray diffraction methods, Fridborg and colleagues found out the three-dimensional structure of the complex formed between human carbonic anhydrase C and acetoxymercurisulphonamide, which is a modified inhibitor of the enzyme. Their work provided factual evidence of drug-receptor complexation.

c. Modification of Drug Receptors Studies are being conducted with the aim of modifying receptors in situ, through physical and chemical means so as to characterise them. Among the former are changes in temperature. Among the latter are alterations in pH, chelating agents, lipid solvents, enzymes, protein denaturating agents, and thiolic reagents.

D. Localisation of Drug Receptors Notwithstanding the great efforts made, accurate and complete topography of receptors is not yet known. This has not prevented however, the formulation of hypotheses about their structure and stereochemistry. The hypothetical maps of receptors serve very useful purposes, especially the rational explanation of how drugs act and the design of new potential drugs. Localisation of some drug receptors or acceptors has been the determined. Most of them have been either the active sites or allosteric sites of parts of DNA or RNA in the case of certain drugs, it is believed that they act either by intercalation between DNA base pairs, as in the case of chloroquine, or by alkylating and cross-linking of DNA strands, as in the case ofmitomycine (Fig. 3.1)

48

-,~

l

,

0.---__.

D \-

/~I

G

Pharmaceutical Chemistry (Organic)

--'- C

ACRIDINE

z u > ~ o .....

CHlOROOutN£

Fig. 3.1

~

Examples of drugs that act by intercalation between base pairs of DNA or by apposition, that is, by alkylating and cross linking of DNA strands: D = deoxyribose P = phosphodiester group . G = guanine C = cytosine

A = adenine T=thymine

E. Structure In spite of the little that is known about the subject, it is generally accepted that a receptor is an elastic three-dimensional entity, having perhaps in most

Theories of Drug Action and Factors Affecting Drug Action

49

cases of protein-constituent amino acids, whose stereochemical structure has been often complementary to that of the drug and which, sometimes after undergoing conformational change, is able to interact with it, usually in its preferred conformation in order to form a complex held together by various binding forces. As result of this drug-receptor complexation a stimulus gets generated and, in turn, brings about a biological action or effect. Theories of Drug Action 1. Nature ofPharmacoiogicai Action. The action of drugs is either from their physicochemical properties, as in the case of structurall y nonspecific drugs, or from their chemical structure, as in structurally specific drugs. The former which is exemplified by general anesthetics and certain hypnotics (e.g., aliphatic alcohols), act in relatively large doses, by forming a monomolecular layer over the whole area of certain cells of the organism. The structurally specific drugs, however, act in very small doses, and it is concluded that their activity arises from complexation with specific receptorf. localised in certain molecules of the organism. 2. Occupancy Theory. This theory was formulated by Clark and Gaddum.This theory (also called template theory) states that the intensity of pharmacological effect has been directly-proportional to the number of receptors occupied by the drug. According to this theory, drug-receptor interaction, which comply with the law of mass action, may be put by the equation where R represents a receptor, D a molecule

k2 of the drug. RD the drug-receptor complex, E the pharmacological effect, and Kl and ~ the rate constants of adsorption and desorption, respectively. The number of occupied receptors has been found to depend on the concentration of the drug in the compartment of the receptor and on the total number of receptors in the unity of area or of volume. The drug effect gets much more intense as the number of occupied receptors increases: hence maximal action is corresponding to the occupation of all receptors. (a) Affinity and Intrinsic Activity. In contradiction to the occupancy theory, not all agonists of a given class of drugs - an example is the alkyltrimethylammonium series of acetylcholine congeners - elicit the same maximal response. Furthermore, this theory fails to explain why some drug's act as agonists and other drugs with similar structures act as antagonists. With the purpose of offering an explanation for this and other incongruences, Ariens and Stephen sony made some modifications to the theory of occupancy. According to these authors, drug-receptor interactions involve two stages: (a) complexation of the drug with its receptor and (b) production of effect. For a chemical compound to manifest biological activity it becomes

50

Pharmaceutical Chemistry (Organic)

necessary not only that it hasaffinityfor the receptor, because of complementary structural characteristics. but also another property called intrinsic activity by Ariens and efficacy by Stephenson. This latter property, intrinsic activity or efficacy, wouid be a measure of the ability of the drug-receptor complex to produce the biological effects. According to the Ariens-Stephenson theory, agonists as well as antagonists possess strong affinity for the receptor, and this makes them to form the drug, receptor complex However. only agonists possess the ability, of giving urigin to the stimulus - that is, have intrinsic activity, or efficacy, while antagonists have been the drugs that are able to bind strongly to the receptor, i. e.. they possess great affinity for it hut are devoid of activity. It becomes possible to transform an agonist into an antagonist through appropriate structural modification, like the addition or removal of certain chemical groups. Antagonists, in comparison with 3gomsts. usually have more nonpolar, bulky groups that help to establish a stronger interaction with receptors. Rang and Ritter have revealed that agonists I\Iay alter the molecular structure of the receptor and that this change increases the affinity of the receptor toward some antagonists. To this phenomenon they assigned the namemetaphilic effect. In spite of its appeal, the occupancy theory, even with the additions introduced by Ariens and Stephenson, fails to explain satisfactorily why drugs have been found to vary in their type of action that is why one acts as an agonist and another as an antagonist, although both can occupy the same receptor, as the theory assumes. Its failure to elucidate the mechanism of drug action at the molecular level in terms of chemical structure has been the chief deficiency of the theory of occupancy. Furthermore, mathematical analysis has revealed that drug action cannot be explained by simple receptor-occupation models. (b) Charniere Theory. In order to explain why an agonist although not being able to remove an antagonist from the receptor site, can compete with it according to the law of mass action, Rocha deSilva postulated the so-called Charniere theory. It is based on Ariens and Simonis's hypothesis that in the pharmacoiogical receptor there are two sites (a) specific or critical site, which interacts with the pharmacophoric groups of the agonist; (b) nonspecific or noncritical site, which complexes with the nonpolar groups of the antagonist. According to the Charniere theory, both agonist and antagonist get fixed to the specific site through weak reversible bonds, but the antagonist binds also, and strongly, through hydrophobic and Van der Waals interactions, as well as charge transfer, to the nonspecific site. Competition between agonist and antagonist takes place at the specific site of the receptor. As antagoinst get" complexed steadily with the nonspecific site of the receptor, even an excess of agonist is not able to dislodge it from there. After removal of the excess agonist, blockade caused by the antagonist returns to the same level as berore the addition ,Jf the agonist. To this Charniere theory Rocha deSilva gave a thermodynamic

Theories of Drug Action and Factors Affecting Drug Action

51

approach. The phenomenon he described is general. It takes place for example in the competition between diphenhydramine and histamine, atropine and histamine, (+) tubocurarine and neostigmine, and methantheline and acetylcholine (Figure 3.2).

3. Rate Theory On the basis of the postulate of Croxatto and Huldobro that a drug is efficient only at the moment of encounter with its receptor, Paton and coworkers gave a rate theory.

Fig. 3.2 Competition between methanthe1ine and acetylcholine for specific site of muscarinic receptor. Bonds involved in the interactions are W, van der Waals and hydrophobic; CT, charge transfer; D-D, dipole-dipole; E, electrostatic. Although firmly bound by a nonpolar part of the nonspecific site, antagonist can compete with agonist for specific site of receptor.

According to Paton, activation of receptors has been proportional not to the number of occupied receptors but to the total number of encounters of tht: drug with its receptor per unit time. Unlike previous theories, the rate theory does not need formation of a stable Michaelis-Menten complex for activation of the receptor by a drug. In accordance with the theory, pharmacological activity has been a function only of the rate of association and dissociation between molecules of drug and receptor and not of formation of a stable drug-receptor complex. Each association constitutes a quantum of stimulus for the biological interaction.

52

Pharmaceutical Chemistry (Organic)

In the case of agonistics, the rates of both of association and dissociation have been fast (the latter faster than the former) and give rise to several impulses in unity oftime. When we consider antagonists, however, the rate of association is fast but that of dissociation is slow, which explains their pharmacological action. This has some experimental basis, because it has been shown that, before causing blockade, antagonists produce a short stimulating effect. In brief agonists have been characterised by high (and variable) dissociation rates, partial agonists by intermediate dislocation rates, and antagonists by low dissociation rates as a consequence of stronger adherence to the receptor and of greater difficulty in being withdrawn from it because they are larger in size when compared with agonists and partial agonists. As in the case of the occupancy theories, the rate theory has been widely criticised because it provides several inconsistencies, it fails to give interpretation of various experimentally observed facts. For instance, contrary to what Paton assumes, the agonist has characteristics that favour the formation of a complex that does not rapidly dissociate. Further, the rate theory, as well as the occupancy theory, fails to explain through interpretation of phenomena that occur at the molecular level, why one drug acts as an agonist whereas another structurally similar one acts as an antagonist. Both theories, as well as many . others that have been proposed, do not have a plausible physicochemical basis for the interpretation of phenomena involving receptors at the molecule level. In an effort to avoid criticism of the rate theory, Paton and Rang gave as an alternative to the dissociation theory. In this new theory the dissociation rate constant has been a function not of the intensity of the binding forces but of the extent to which the drug molecule disturbs the secondary protein structure. Relating stimulus to rate of dissociation, and this rate being proportional to the occupation of receptors, the dissociation theory has been not formally different from the occupancy theory.

4. Induced Fit Theory As itis applie.d to drug.receptorinteraction, the induced-fittheory has been based on the hypothesis, for which recent evidence is being accumulated, of induced conformational changes in enzymes. The hypothesis has been developed by a number of authors. For example, Koshland postulated that the active site of an isolated, crystalline enzyme does not necessarily need to have a morphology that is complementary to that of the substrate as a kind of negative to it, but that it acquires such morphology only after interacting with the substrate, which induces such a conformational change. He postulated that the active site of the enzyme is flexible, or, better, plastic or elastic, and not rigid: that is, not only can it be deformed or altered but it also possesses the ability to return to the original form after being deformed (Figure 3.3).

Theories of Drug Action and Factors Affecting Drug Action

53

(n

Fig. 3.3. The effect of inhibitors and activating agents on the elastic active site of the enzyme. In diagram I the inhibitor I attracts binding group C and prevents proper alignment of a catalytic group B, causing inhibition, which may be competitive, if the B chain is involved in complexation or non-competitive if it is not involved. In diagram II reagent R prevents juxtaposition of group C with inhibitor, I nullifying its effects without changing its affinity for the active site. In diagram m the hormone H stabilises the active conformation by attracting chains containing A and B.1n diagram N the hormone H overcomes the effect of the inhibitor I by attracting chains containing catalytic groups A and B.

According to the induced-fit theory the biological effect produced by drugs arises due to the activation or deactivation of enzymes. or even of noncatalytic proteins. through a reversible perturbution or change in tertiary structure enzymes or proteins. Conformational change does not get restricted. however. to proteins. Drugs having flexible structure can also undergo conformational change as they approach the site of action or the receptor site. Drugreceptor interaction therefore, can be seen as a dynamic and in most cases reversible. topographical and electronic compromise or accommodation between drug and receptor that triggers the stimulus which gives rise to the biological effect (Figure 3.4).

54

Pharmaceutical Chemistry (Organic)

drug-receptor complex Fig. 3.4. Schematic representation of the morphological and change induced fit in drugreceptor interaction

Recently Koshland and coworkers have modified the induced-fit theory so as to explain cooperative effects: the phenomenon that binding of one ligand molecule somehow accelerates binding of subsequent ones. Hence, binding of the first ligand to a polymeric protein, which may be an enzyme containing a receptor, induces a conformational change in one of its subunits. A change in the shape of this subunit influences the stability of the remaining subunit. The resulting energy of stabilisation makes possible stronger binding of the next molecules. Analogous theories are advanced by Changeux and colleagues, Wyman and Noble.

5. Macromolecular Perturbation Theory Very similar to the induced-fit theory, the macromolecular perturbation theory was postulated by Belleau in 1964. It may be regarded as an application of that theory to some classes of drugs. Taking into account the conformational adaptability of enzymes (and the receptors would be enzymes of a particular sort), Belleau argued that in the interaction of a drug with the protein component two general types of perturbation can take place in the complex: (i) Specific conformational perturbation, or specific ordering, which makes possible the adsorption of certain molecules related to the substrate it is the case of an agonist.

Theories of Drug Action and Factors Affecting Drug Action

55

(ii) Nonspecific conformational perturbation, or nonspecific disordering, which may serve to accommodate other classes of extraneous molecules; it is the case of an antagonist. If the drug pofosesses both characteristics - that is, if it contributes to specific as well as to nonspecific macromolecular perturbation - a mixture of two complexes will be formed. This explains the partial stimulating action of the drug or the case of the partial agonist or antagonist.

Belleau's hypothesis does not assume the existence of affinity and intrinsic activity, and it is incomplete agreement with several subsequent experimental data and results because it provides a plausible physicochemical basis for explaining the phenomena that involve a receptor at the molecular level.

Mechanism of Drug Action Many attempts have been made to postulate a general theory of mechanism of drug action. Most drugs act at the molecular level by one ofthe following mechanisms: activation or inhibition of enzymes; suppression of gene function; metabolic antagonism; chelation; alteration of biological membrane permeability; and nonspecific action. Several drugs act by various mechanisms. There are also many drugs whose mechanism of action can be categorised in two or three of tbe foregoing classes; a typical example has been the sulphonamides or antifolics: they can be regarded either as inhibitors of enzymes or as metabolic inhibitors.

1.

Action of Drugs on Enzymes Drugs acting on enzymes can either activate or inhibit them.

(a) Activation of Enzymes. Drugs that can supply inorganic ions act by activation of enzymatic systems. This process can take place in two ways: the ion can undergo interaction with an enzyme inhibitor preventing enzyme deactivation, or it can undergo interaction with an enzyme directly altering its conformation and charge. Other types of drugs increase enzymic activity through an induced adaptation mechanism. This phenomenon acquires special relevance in microbial systems. A classical example has been the activation of penicillinase induced by penicillin itself.

(b) Inhibition of Enzymes. In biochemistry the effect produced by an inhibitor is known as a biochemical lesion. It refers to any disturbance of metabolism by agents acting directly on metabolism systems. The inhibition caused by drugs may be reversible or irreversible. It is reversible when it gets characterised by an equilibrium between the enzyme and the inhibitory drug. It is irreversible when it increases with time, provided that the inhibitory drug is present in excess. There are two main types of inhibitions called competitive and noncompetitive.

56

Pharmaceutical Chemistry (Organic)

Competitive Inhibition. In competitive inhibition the drug tends to compete with the substrate for the same site of the enzyme and combines with it reversibly. In this process, therefore, the relative concentrations ofthe substrate and of the drug has been of fundamental importance, because they determine the degree of inhibition. Actually, in the presence of excess substrate the drug gets displaced from the receptor. which is then occupied by the substrate. Noncompetitive Inhibitor. In noncompetitive inhibition the drug undergoes combination with the enzyme or with an enzyme substrate complex with equal ease but at a site different from that to which the substrate gets attracted. This reveals that the inhibitor binds itself to different sites on the enzyme, and not to the catalytic centre, that is, the active site. Such inhibition, which is usually reversible and not influenced by substrate concentration, depends solely on drug concentrations and on the dissociation costant Kl of this inhibitor; a substrate never displaces the inhibitor even at high concentrations. Though purely noncompetitive inhibition has been very unusual, the effect of isofluorophate on cholinesterase action is an example. Presently noncompetitive inhibition is regarded as being related to allosteric phenomena. (c) Allosteric Inhibition. The classical concept of enzyme inhibition by an antimetabolite can be depicted by the following scheme: antimetabolite A inhibition

I

...

enzyme A

metabolite A - - - -.... metabolite B The antimetabolite is similar in structure to a given metabolite, and this characteristic of complementary allows it to combine with the active site ofthe enzyme, changing the enzyme substrate complex dissociation. This mechanism is true for the enzymes in general with the exception of allosteric enzymes, so called for having a binding site other than the active site. Because of the unusual kinetic and structural characteristics of allosteric enzymes, Monod and coworkers gave the following model for them: 1. All are polymers. As they are made up of one or more identical subunits, they can exist in at least two different conformational states. 2. Each one of the identical subunits possesses a single catalytic site for the substrate, and a separate allosteric site for each allosteric effector (inhibitor or activator). 3. For each conformational state the catalytic and allosteric sites possess equal affinities for their respective ligands. 4. The various conformational states of the enzyme have been in mutual dynamic equilibrium.

57

Theories of Drug Action and Factors Affecting Drug Action

5. The transition from one state to another takes place with simultaneous alternations in all the identical subunits within a particular molecule. Based on this model. a new concept of inhibition has come into existence recently. It was shown that the enzyme can also be inhibited by chemical substances that do not possess structural similarity with the substrate. These substances are known as allosteric inhibitors. They exert their action either by competing directly with activator substances for regulatory sites or by causing conformational changes, which result in decreased affinity for the substrates by catalytic sites. An example of allosteric called feedback or terminal product inhibition is given by the following diagram:

i

enzyme A

metabolite A----... metabolite B

I

enzyme C

~enzyme B

---metabolite O.-----nietabolite C In a series of reactions catalyzed by enzymes only the first enzyme A gets inhibited, due to the accumulation ofterminal metabolite D. The interaction of the inhibitor, the metabolite D, with the enzyme A is not necessarily at the same site that gets interacted with the substrate, that is, with its active site; in fact it usually is with another, the regulatory site, to which the name allosteric site has been assigned. Hence, the allosteric inhibitor does not need to possess any chemical resemblance to the substrate, because the allosteric site and the catalytic site are located in different portions of the enzyme. Interaction of the inhibitory drug with the allosteric site gives rise to an alteration in the conformational state ofthe enzyme, which adapts a form in which its affinity, at the catalytic site, for the substrates gets decreased. Hence, with the purpose of getting antagonists of the enzyme A, derivatives of the metabolite D can be synthesized instead of structural analogues of the metabolite A. (d) Examples of Enzyme Inhibitors. Many other types of drugs that act as enzyme inhibitors may be given as follows: (a) some anticholinesterase agents - inhibitors of acetylcholinesterase; (b) certain antidepressants - inhibitors of monoamine oxidase; (c) a number of diuretics inhibitors of carbonic anhydrase; (d) the salicylates; (e) several antibiotics. Pharmacodynamic Agents. Various pharmacodynamic agents inhibit biochemical processes offundamental importance. Among many others are the following: inhibitors of biosynthesis and metabolism of epinephrine, inhibitors of biosynthesis and metabolism of serotonin, inhibitors of biosynthesis of histamine, inhibitor of biosynthesis of uric acid. Chemotherapeutic Agents. Penicillins and cephalosporins are known to owe their action becauseofthe inhibition of transpeptidase, an enzyme catcalysing

58

Pharmaceutical Chemistry (Organic)

the cross-linking reaction oflinear polymers that comprise the bacterial cellular wall. The action of cycloserine is also on the bacterial wall, but through the inhibition of alanine recemase and D-alanyl-D-alanine synthetase, enzymes involved in the formation of dipeptide to complete the pentapeptide side chain of the cellular wall. Antimoinals having schistosomicidal action tend to inhibit the phosphofructokinase of the parasites. Heavy metals like Hg2+, Cu 2+, NF+, Pb2+, Zn 2+, C02+, Cd 2+, Mn2+, Mg2+, Ca 2+ and Ba2+ can bring about inhibition of enzymes, often with highly toxic effects to the human or animal body. The poisoning subsequent to interaction of metallic ions with enzymes results from their complexation with one or more of the following groups existing in any living cell and in most enzymes: -OH COOH, - P03H2, - SH, - NH2, imidazole ring.

2.

Drugs Acting as Suppressors of Gene Function

Many drugs are known to act as suppressors of gene function. Most of them have been chemotherapeutic agents, which are found among antibiotics, fungicides, antimalarials, trypanocides, antineoplastics, antivirals. Gene function can be suppressed in several steps of protein biosynthesis (Figure 3.5). Suppressors of gene function can act as (a) inhibitors ofbiosynthesis of nucleic acids; (b) inhibitors of protein synthesis.

(a) Inhibitors of Biosynthesis of Nucleic Acids. Many substances exhibit strong activity as inhibitors of biosynthesis of nucleic acids. Most of them have been exceedingly toxic, because they lack selectivity. They interact with biochemical processes both of parasite and host. Some of them, however, find use as chemotherapeutic agents.

gt.j1\

AMtl)~5 ~

~; t

,/RNA

~rA

_~r. . _ _...

A.MINOACVl t-RNA - -....t...

RI80S;:)MES

r=:=;>l PROT/ENS Fig. 3.5 Phases of protein biosynthesis liable to inhibition. The short arrows indicate the possible sites of attack by chemotherapeutic agents, mainly antibiotics

Theories of Drug Action and Factors Affecting Drug Action

59

Inhibitors of biosynthesis of nucleic acids have been divided into two groups: (i) those that interfere with the biosynthesis of nucleotide precursors; (ii) those that interfere with the polymerisation of nucleotides in nucleic

acids. In the first group can be included certain analogues of amino acids, folic acid, purines, and pyrimidines and their respective nucleotides. For example azaserine, DON, azotomycin, fluorouracil azauracil, fluorouridine, idoxuridine, azauridine, cytarabine, mercaptopurine, azathioprine, thioguanine, azaguanine, psicofuranine, aminopterin, and methotrexate. They act by metabolic antagonism. In the second group can be included several antibiotics and other chemotherapeutic agents, like certain antineoplastics, antibacterials, antimalarials, trypanocides, and schistosomicides, which act (a) either by interaction or apposition in the nucleic acids or (b) by inhibition of enzymes involved in nucleic acid synthesis. Daunomycin, dactinomycin, ethidium, proflavine, quinacrine, chloroq uine, lucan thone, hycanthone, and several other chemotherapeutic agents complex intercalation between pairs of DNA bases (Figure. 3.1). Alkylating agents, like nitrogen mustards, aziridines, methanesulfonate esters, epoxides, mitomycins, and several other substances complex with nucleic acids by apposition, by forming a crossed linkage with the DNA double strand (Figures 3.1 and 3.6). Rifamycins act by inhibition of RNA synthesis, interfering specifically with RNA polymerase function of sensitive bacterial cells. Nalidixic acid inhibits selectively DNA synthesis of pathogenic microorganisms. (b) Inhibitors of Protein Synthesis. Several chemotherapeutic agents are known to owe their activity to inhibition of protein biosynthesis of parasites, interfering in this way with the translation of genetic message. A well-studied case has been that of puromycin.

60

Pharmaceutical Chemistry (Organic)

Fig. 3.6 Crossed linkage of guanine bases of DNA twin strands by a bifunctional alkylating agent followed by depurination and excision of a bis (guanin-7-yl) derivative of the alkalating agent.

Because of its structural resemblance to the terminal aminoacyl adenosine moiety oftRNA, itcan interrupt the translation of the genetic code. Unfortunately, it has been toxic for use in therapeutics. Among many other antibiotics that inhibit protein biosynthesis may be mentioned streptomycin, neomycin, kanamycin, tetracylines, chlorampliIenicol, linomycin, erythromycin, fusidic acid and cycloheximide. The site of action of these and other antibiotics is depicted in Figure 3.7.

61

Theories of Drug Action and Factors Affecting Drug Action

ONA'~ (g~\~¢/MYCOPHENOLICACIO

I\3

CT~ l

PSICOFURANINE

GRISEOfULVINJ REPUCATIOW MITOMYCIN C c:::¢ DNA NALIDIXIC ACI. POLYMERASE' PORFIROMYCI ~

~ , \rri) TRANSCRlPTION "CTIONMYCINsf¢ RNA

~IFAMY{;INS

... / " ' - . . -lpOLYMER'ASV _, ~

nsLIl tRNA

~ rRNA

+

mRNA

~

ATP CTP

~ -ACCr-u:-n

aa-AccrLrlIl

I

+

~f

~

I

·~+ATP+En ... AMP-en

~

J"'VIV

t if

GTP T

+

BINDING ENZYME

~ ~HLORAMPHENICOL

TeRACYCLJN~ \EV:,/'

,.

I: TRANSLATION aENTAMYCIN

PEPTIDE SYNTHETASE CYCLOHEXIMloe FUSIOIC ACID

~

'+-rRANSLOCATION

0

KANAMYCIN ~ NEOMYCIN STREPTOMYCINS

Y"-~_j

H

R~

Fig. 3.7 Site of action of some antibiotics and other drugs. The arrows indicate inhibition of specific reactions in replication, translation, and translocation in molecular biology processes.

62

3.

Pharmaceutical Chemistry (Organic)

Drugs Acting on Biological Membranes

(a) Action of Drugs on Membranes. Many drugs are known to act on cellular membranes, modifying their physiological role and producing, in consequence, pharmacological effects. To this group some drugs of topical use, like antiseptics and polyene antibiotics belong. Antisepetics. Many antiseptics do not kill bacteria but only prevent their multiplication: organic defenses represented by antibodies and phagocytes eliminate the focus of infection. They act primarily on cytoplasmic membrane. Examples include phenols (hexachllorophene, used until recently but now restricted), cationic antiseptics (chlrohexidine), and polypeptide antibiotics (polymyxin, gramicidin S, tyroeidins, colistin). Polyene Antibiotics. These antibiotics, such as nystatin and amphotericin B tend to increase membrane permeability. They do not act on bacteria but on fungi (Candida albicans, for example), apparently because they possess affinity for sterols, which are present in the membranes of fungi and other higher organisms but not in bacterial membranes. (b) Action ofDrugs on Transport Systems. There are many mechanisms of transport of substances across cellular membranes: passive diffusion, active transport, facilitated diffusion. Some drugs owe their action to interference with one or more of these mechanisms. For example, insulin facilitates the diffusion ofhexoses and amino acids in some tissues. Copper ions decrease the facilitated diffusion of glucose.

4. Nonspecific Action of Drugs The action of structurally nonspecific drugs, like biological depressors, a class to which certain hypnotics, the general anaesthetics, and the volatile insecticides belong does not derive from their interaction with specific receptors but iesults from their physicochemical properties. It appears that their action gets originated from the accumulation of such drugs at some point of vi tal importance to the cell, with consequent disorganisation of a chain of metabolic processes.

Drug Binding Extensive drug binding in the body occurs in the blood. Blood contains 6.5% of protein of which 50% is albumin. It is mainly involved in drug binding. Its molecular weight is 69000 and its has net negative charge at blood pH 7.4. It can interact with anions and cations also. The drug-protein binding may be due to ion-ion interactions, hydrogen bonding and hydrophobic and van der walls forces. This protein drug binding is usually reversible reaction. (P) + (D) ~ (PD) where

(P) (D) (PD)

=

is free protein concentration is free drug concentration is drug-protein complex.

The drug binding resembles salt formation. This protein binding acts as a transport system for the drug, which while bound is hindered in its access to the site of metabolic action and excretion.

Theories of Drug Action and Factors Affecting Drug Action

63

Drug toxicity: Drug administration is always followed by the expected reaction. It is many a times associated with other side reactions; considered to be toxic reactions. This may range from a mild skin rash though more serious complications like blooddyscrasias (abnormaIiIty in the blood picture) and liver damage may occur. Drugs show short term (acute) and long term (chronic) toxicity.

Pro-drug A biologically active drug by latentiation gets converted into an inactive carrier form, is called a pro-drug. Pro-drug on reacting with enzyme or nonenzyme compound, releases the active compound (drug) Latentiation of drug produces: (i) prolongation of action (ii) shortening of action (Iii) drug localisation (iv) transport regulation

(v) adjuncts to phamlaceutical formulation. (vi) lessening of toxicity and side effects.

Drug addiction. After discontinuation of drug administration, the tolerance acquired by the individual disappears at a rate varying for each individual and each drug. The body cells readjust to the absence of drug unnoticeably. In some cases after the drugs withdrawal, a psychic craving for the drugs is observed. Which leads to physical disturbances. This syndrome is called "addiction". Certain drugs, for example morphine related compounds, cocaine, and under certain conditions barbiturates have a notable potentiality for causing addiction.

Biotransformation of drugs The drugs are converted into pharmacologically active metabolite by biotransformation. These metabolites are highly active. This activity contributes to pharmacological effect ascribed to the parent drug. In some cases inactive parent drug gets converted to biologically active metabolite. Since all the metabolites are not toxic, many toxic side effects like tissue mercrosis, carcinogencity are observed. The formation of water soluble metabolite enhances drug elimination and pharmacologically inactive, non toxic and polar compound formation. Most of the drugs under-go metabolic transformation in the body. The main site of metabolism is liver. Genetic differences, species differences, age, sex, nutritional and hormonal factors, pathological states and stress influence the rate and extent of drug biotransformation. and thus, influence the duration and extent of pharmacological activity.

Phannaceutical Chemistry (Organic)

64

Routes of drug administration: and dosage forms The rate of drug absorption in the body is decided by the route of administration. The common routes in the increasing order of rapidity of absorption in man are oral, subcutaneous, intramuscular, inhalation and intravenous. The speed of absorption of drug can be altered by a number of pharmacological and chemical manipulations. The injected drug is IspreDlliae

~

HN '-':

Prepranolol

NH Z

\::

Diphenylpyraline

Antagonists with strong receptor binding properties have high rate of association but low rate of dissociation. Occupancy of the receptor site by the antagonist is non-stimulant and non-productive; it prevents the productive events by the other molecules. This is blocking action and hence the name occupancy theory. The most important factor determining the drug action is the rate at which drug ,eceptor combination takes place.

Rate Theory The drug is efficient only at the moment of encounter with its receptor. Receptor's activation is proportional to the number of encounters of the drug with its receptor per unit time. According to this theory pharmacological activity

Pharmaceutical Chl'ml,I/tY (lhgllltl< )

78

is a function of the rate of association and dissociation between molecules of the drug and the receptor and not of a stable drug receptor complex. At equilibrium the rates of combination and dissociation of drug receptor reactions are same and equation can be written as. K l [A] [r] - [RA]

= _~ [RA~

[r]

[r]

Hence above equation can illustrate that Rate of receptor occupation =

~ [A]

Each association constitutes a quantum of stimulus for the biological interaction. Rate theory proposes high rates of association but low rates of dissociation for antagonists, while agonists are characterised by high (and variable) dissociation rates and high association rates. As a consequence, antagonist shows stronger adherence to the receptor and greater difficulty in withdrawal from it (as they are larger in size). The rate theory as well as occupancy theory lacks a plausible physico-chemical basis for the interpretation of phenomenon involving receptors at the molecular level.

4 Assay of Drugs and Metabolism of Drugs

ASSAY OF DRUGS

Introduction The measure ofthe biological activity of a drug is called its potency. Assay is the estimation of a potency of the active principle in the unit quantity of medicinal preparation. There are three types of assays: 1. Chemical assay, 2. Biological assay, and 3. Immunological assay. Let us discuss these one by one.

1. Chemical assay. In this case, the potency ofthe active principle in the drug preparation is determined by chemical methods. The choice of chemical method depends upon the nature of the functional group present in the drugs and its chemical properties. For instance the drug having hydroxyl group can be estimated by acetylation, the drug having ester or amide group can be estimated by hydrolysis, the drug having carboxylic group can be estimated by direct titration with an alkali; the drug having amino group can be estimated by acetylation or ifthe drug has aromatic amino group, it is estimated by diazotisation, and so on. Certain special methods have been developed for the estimation of individual drugs, e.g., penicillin is estimated by iodometry. More recently instrumental methods of analysis such as various spectroscopic, chromatographic and photometric techniques have been advantageously employed for drug assay. These methods are rapid, require smaller quantities

80

Pharmaceutical Chemistry (Organic)

of substance, can be readily compared with standards if available and the assay reports can be preserved. 2. Biological assay (Bioassay). It is the method of the estimation of concentration of the active principle present in the unit weight of the drug in terms ofhiological response in the treated organisms. The main idea ofhioassay is to establish the reliability of its potency. Units of biological activity. Previously, the potency of the drug was expressed only in absolute terms, e.g., lethal dose which may be defined as the minimum concentration of the active principle of the drug sufficient to produce fatal effect on animal. However, this was found to be unsatisfactory because hiological effects might vary from animal to animal and also from laboratory to lahoratory. Therefore, nowadays a reference of standard preparation of the drug is compared with the drug which is under investigation for biological a~tivity.

If a drug is a mixture of number of ingredients of variable activities from which the substance to be biossayed cannot be isolated in pure form, a stahle standard preparation is to be employed for comparison. These reference standards can be obtained from various pharmacopoeias such as LP., U.S.P. or B.P. These can also be obtained from W.H.O. This may be illustrated hy taking example of digitalis, a drug used as cardiotonic. This drug is not a single compound but a mixture of several active digitalis compounds whose proportions vary from plant to plant. Therefore, this drug is assayed against standard such as U.S.P. in which the biological response produced by a specified weight, say O.lg, is listed. If it is found that O.lg of the sample under investigation is more potent than O.lg of the standard, the sample is diluted with biologically inert material so as to make its potency equal to that of the U.S.P. staitdard. Principles of bioassay. The bioassay has been found to be hased on the following broad-based principles: (i) The specific effect produced by the drug under test must be the same in all the animal species. However, it is not applicable to liver preparations used for the treatment of pernicious anaemia because it occurs only in human beings. (ii) When conditions are identical, the same animals or animals of the same species must show the same degree of pharmocological response for a given quantity of the drug. (iii) The reference standard must be highly pure and previously hioas-

sayed. (iv) The activity of the reference standard must be due to the same active principle w~ich is being assayed in the sample. (v) Whenever problems arise out of individual variations, they must be kept to the minimum.

Assay of Drugs and Metabolism of Drugs

81

(vi) The bioassay must be carried out under rigid experimental conditions so as to provide high precision, reliability, reproductibility and ease of computation. (vii) The true relative potencies (as compared to the standard taken as 100 per cent) must be established at a certain level to probability, generally the 95 per cent level. Method ofbioassay. As bioassay involves the measurement of the concentration of the specific active ingredient present in the crude sample of a drug, it is done by studying the effect of the drug on animals, either singly or in groups, or on tissues. The various methods of bioassay are as follows: (a) Direct comparison on the same tissues. In this method, the sample under test is compared with the standard for its effect on the same tissues under identical conditions. It may be done either of the following methods: (i) Interpolation. In this method, the degree of effect produced by increasing doses of the standard drug is determined. Then, the log dose-response curve is plotted. Finally, the concentration of the unknown is read out from this graph by studying the response it is showing. (ii) Matching. In this method, the effect produced by a given amount of the drug to be bioassayed is bracketed by changing the dose of the standard till the effect produced by the latter becomes equal to that of the former. However, the difficulty in estimating the margin of error makes this method inaccurate. (iii) Four-point assay. It is a more accurate method because it involves the principles of both interpolation and matching .. (b) Direct assay on several animals. This method involves the treatment of a group of animals with several doses in incerasing amounts of standard preparation. Then, the minimum concentration required to have positive response from 50 per cent of animals is determined. This is known as ED'(50) i.e., the effective dose for 50 per cent with standard. Similarly, the effecti ve dose for positive response from 50 per cent animals for the unknown is also determined. This is known as ED u(50). The concentration of the unknown can be found by applying the following formula: C

=

ED S(50)

x conc. of standard

EDu(SO)

The minimum dose to cause death of 50 per cent animals is called LD50. This dose in general is known as tolerance or threshold dose.

(c) Indirect assay. In this method, the potency of a drug is determined b.y comparing the log dose-response curve of the unknown sample with that of the standard. The bioassay procedures must satisfy the following requirements: (i) The biological system should be sensitive to the drug. (ii) The standard substance should be uniform, stable and permanent. .

Pharmaceutical Chemistry (Organic)

82

(iii) The pharmacological response with the same dose should remain the same under identical conditions. (iv) The animals or tissues must remain 'bioassay fit' for a sufficiently long

time. (v) Animals or tissues selected for bioassay must be easily available.

Types of biological systems used (i) Isolated animal tissues or muscles are used for bioassay. For example, insulin is analysed for its blood sugar lowering effect on rabbits of the same weight and species. (ii) Histamine like drugs are bioassayed on the ileum of the Guinea pig. (iii) Folic acid, vitamins, and antibiotics are bioassayed by using different developing media such as agar-agar, and the growth of becteria and their response on either way are studied from the culture obtained.

Comparison of bioassay and chemical assay Although the chemical assays are more accurate than the biological assays, yet the latter methods are generally used for the standardisation of a large number of drugs. This is due to the following reasons: (i) The active principle present in the sample need not be known. (ii) If active principle is known, its chemical composition need not be

known. (iii) The active principle need not be isolated in pure state.

(iv) The drugs which are chemically pure but unstable can be bioassayed without loss of activity. (v) As the sensitivity of bioassay in number of cases has been found to be much greater than the chemical methods, a small quantity is sufficient to carry out bioassay, e.g., the assay ofB12 indicates that bioassay is about 2,50,000 times more sensitive than the chemical method. Thus, the bioassay method is more useful when the drug is scarce or very costly. (vi) Bioassay has been used to differentiate between the isomers of a drug which exist in active forms.

Inspite of above mentioned advantages, bioassay is less precise and sometimes costly in terms of time and animals, and hence chemical assay, wherever possible, is preferred. 3. Immunological assay. This method has been developed recently for estimating certain hormones. The principle underlying this method is that a hormone is an antigen and can react with its specific antibody. If labelled hormone is taken along with unlabelled (natural) hormone, there occurs competition between labelled and unlabelled hormones to react with the antigen. It is found that the unlabelled hormone inhibits the reaction of the labelled hormone and hence the ratio of bound and free (BIF ratio) hormone gradually decreases

Assay of Drugs and Metabolism of Drugs

83

as the concentration of unlabelled honnone increases. Now a group of BIP ratio to hormone concentration is plotted for the standard preparation. Again, the unknown quantity of unlabelled honnone is made to react with a mixture oflabelled honnone and the antibody under the same conditions as the standard. The BIF ratio is obtained and the concentration of the unknown labelled honnone is read out from the graph. However, the results of the immunological assay are, however, less reliable than the bioassay. METABOLISM OF DRUGS

Meaning of Metabolism. Drugs and other foreign compounds which enter a living organism are stored in the body or removed from it after a period of time. While inside the body, they may remain intact or undergo chemical transfonnation, giving compounds (a) less active, or (b) more active, or (c) having similar or different activity. This process of chemical alteration of drug inside the living organism is called drug metabolism. Drugs such as analogues of biogenic amines, steroids, purines, pyrimidines, and amino acids resemble closely substances nonnally present in animals, including man. For this reason, they may undergo the same specific interactions with enzymes, carrier proteins, and transport system as their endogenous counterparts. Most drugs, however, have no relationship whatsoever with nonnal body substrates. Hence their metabolism involves non-specific enzymes, and their movement across membranes and barriers is carried out by either passive diffusion or non-specific transport systems. In recent years it has been recognised that specific infonnation on the metabolism of a drug is essential for its safe and proper use. Thus, metabolic data have become an increasing requirement in the pre-clinical and clinical testing and evaluation of new drugs. The metabolic infonnation required may vary but for the following examples will illustrate:

1. (a) Rates and sites of absorption of both the drug and its metabolities; (b) plasma and tissue levels; (c) plasma protein binding; (d) rates of metabolism and half-life of the drug in blood and tissue; and(e) rates and routes of excretion. 2. Ascertain that the animal species used for toxicity testing, mutagenesis, teratogenesis, carcinogenesis, etc., metabolises the drug approximately the same as man. 3. A separate study of the known metabolities of the drug to detennine the molecular species responsible for its useful pharmacologic properties or for its undesirable side effects. The metabolism of a drug may have a profound effect on its pharmacological, and hence clinical activity and this frequently varies in different animal species. Rapid metabolism to inactive metabolities frequently results in a drug which has shown significant in vitro activity being either inactive or only poorly

84

Pharmaceutical Chemistry (Organic)

active in man. Moreover, the degree of metabolism, and this will change even from patient to patient, can influence the rate of elimination of a drug and thus its duration of action. The biological activity and toxicity of a drug is therefore, greatly dependent upon and is governed by its metabolic profile. The metabolic changes drugs undergo have been of considerable interest and frequently of great practical value in the search for new and improved medicines. The discovery by French workers that the azo dye Prontosil, which is inactive in vitro, is converted by reduction in the body to the active sulphanilamide, led to the rapid development of the sulfonamides as therapeutic

o

NH.

t \._~ -,H,N-S-( )-N=N-< /-NH. ~

o

- ...

=

prootosil 4-lu)pbonamldo-2'. 4'.diamiooazobenzeno

I

~

o -

t

NH.

'-

~H'N-

I

'/

guaiacol

veratrole

COOH I OCB.

COOH I OH

/"-./ i n

'/

.alicylic acid

II

/'-/

,/\I

I

methoxy benzoic acid

(b) In some compounds, the toxicity is increased on alkylation. For

example, (i) Some simple alkylamines have been found to be more toxic than ammonia, (U) Ethers (R-O-R) have been found to be more toxic than alcohols (R-O-

H), (iii) Resorcinol dimethylether has been found to have much more toxicity than resorcinol, and (iv) Theobromine (N-dimethyl derivative of xanthine), and caffeine (Ntrimethyl derivative of xanthine) have been found to be much more toxic than the parent compound, xanthine.

(c) In some compounds, the alkylation of a carboxyl, hydroxy and amino group causes the full appearance of certain masked properties. For example, cocaine is a strong anaesthetic while its analogue acid is inert; antipyrine is a strong antipyretic while its analogue having only one methyl group is inert.

Pharmaceutical Chemistry (Organicj

110

CH.-CH.--CH.COOH

I

,

I

CH.-CH--CHCOOCH.

I

N.CH. CHOCOC,H,

I

I

I

I

I

I

I

J

N.CH, CHOCOC.H,

I

J

CHa-CH--CH.

CH.-CH---CH.

cocaine (active)

analogue acid of cocaine (inert)

CHi

CHi

:-===/

=/

o

I

~H

I

/'-.N/

k.cH,

/'N/

o

J

,

PIl

Ph

phenyl-methy)-pyrazo)one (inert)

antipyrine (active)

The size of alkyl group also shows marked effect on the pharmacological activity, e.g., the ethyl group has more marked influence as compared to that of methyl group. It is evident from the following example: (i) Diethyl ketone is a stronger hypnotic than acetone.

(ii) When methyl group of acetophenone (hypnone)

C6 HSCOCH J is replaced by ethyl group, the resulting compound C 6HsCOC 2Hs has more hypnotic activity. (iii) Sulphones form the most important example of the comparative influence of methyl and ethyl groups. '"

C CH J

S02CH J

C2HS

S02C2HS

CH,

"\. C02C2Hs

C 2HS

S02CH 3

CH J

C

C CH 3

S02CH 3

reversed sulphonal. active

Sulponal, active

S02CH 3 inactive

(v) Dulcin having an ethyl group is about 200 times as sweet as its methyl analogue which is tasteless.

OCH.

OCaR,

I

I

/" ,/

U

I

J

NHCONH. dulcin (sweet)

/'-.

,/ I

II

I

NHCONH. (testele~s)

Relation of Chemical Structure and Chemical Activity

111

(vi) It was shown by Ehrlich and Michaelis that certain dyes having NEt2 grouping possess the property of dyeing the nerve fibre while the corresponding dyes having NMe 2 group do not show this property.

2. EtTect of hydroxyl group. The introduction of hydroxyl group into an aliphatic compound weakens its physiological action. This weakening has been found roughly proportional to the number of hydroxyl groups introduced into the aliphatic compound. It is evident from the following examples: (i) n-Propanol is more active than glycerol. (ii) Hexanol is more active than sorbitol.

(iii) Butyraldehyde is more active than ~-hydroxy derivative-(aldol), etc. Sometimes the presence of a hydroxy group makes the compound to lose its particular physiological activity. For example, hydroxycaffeine has none of the physiological activity present in caffeine. Similarly, the toxic hexaldehyde gives medicinally, inert glucose on the introduction of the hydroxyl groups. The isomeric alcohols having the same number of carbon atoms show a drop of activity from the primary to secondary to tertiary. For example, the phenol coefficient of I-propanol against Staph.aures is 0.082 as compared to that of 0.054 for 2 propanol. In homologous series, generally the member& having side chains are more active. The physiological activity is generally decreased by etherification, esterification and the conditions unfavourable to ester hydrolysis. It has been proved beyond doubt that the hydroxyl group itself, in such compounds, does not have physiological action of its own but it simply anchors the molecule on a reactive position of cell chemical. In the case of aromatic compound, the introduction of a hydroxyl group increases the physiological activity of the compound. This is completely reverse to that in the aliphatic compounds. For example, phenol is more toxic and a strong antiseptic than benzene; salicylic acid is not only a stronger antifungal agent but is also an antirheumatic agent, a property missing in the inert parent compound, the benzoic acid. Introduction of more hydroxyl groups in aromatic nucleus increases the toxicity. For example, resorcinol and pyrogyllol are more toxic than phenol. 3. EtTect of aldehyde and ketone groups. Aldehydes are more reactive than ketones and thus also exhibit a more intense biological acti vity. Formaldehyde, the simplest aldehyde, has a strong anti-septic property and a hardening effect on the tissues, a property for which it is used by taxidermist. The higher members have the combined property of the aldehydic and alkyl groups. The introduction of hydroxyl groups in the aldehyde molecule decreases the physiological activity of the compound which may even cause the compound to be medically inert, viz., glucose. However, on the whole the physiological effect produced by aldehydes cannot be generalised.

Pharmaceutical Chemistry (Organic)

112

In general, the pharmacological properties of ketones have been found to be similar to that of the corresponding secondary alcohols, i.e. ketones, in general, possess narcotic action. In aliphatic ketones, due to the presence of alkyl groups, the hypnotic action is fairly well marked but the mixed ketone, acetophenone C 6H sCOCH2 is a strong hypnotic (used under the namehypnone). ~-Unsaturated ketones are found to possess diuretic activity. 4. Effect of acidic groups. The introduction of an acidic group such as S03H or - COOH in a molecule either decreases or completely destroys the physiological activity of the parent compound. For example, phenol is poisonous but benzene suI phonic acid is harmless. From this it may appear that this is because of the disappearance of OH group. However, the introduction of acidic groups without altering the active or anchoring groups also makes compound less toxic. It is evident from the following examples: (i) Nitrobenzene is poisonous but nitrobenzoic acids are harmless.

(ii) Amines are toxic but amino acids are food stuffs. (iii) Aniline is toxic but m-aminobenzoic acid is harmless. (iv) Martius yellow (dinitronaphthol) is markedly toxic but its sulphonic

acid (naphthol yellow S) is harmless. However, the physiological properties of the compounds which have disappeared due to the introduction of acidic groups can be restored by esterification. For example, tyrosine, a phenolic amino acid, is harmless while its ethyl ester is poisonous.

OH

/,I

,/ I

II

I CH•. CH.COOH

I

NB. tyrosine

p-aminobenzoic esters

Similarly, p-aminobenzoic acid has no anaesthetic property but its alkyl esters are used as local anaesthetics. The acylation of basic compounds by means of organic acids reduces the basicity and physiological action of the compounds. The benzoylation has been found to increase the physiological activity of the various compounds. For example, ecgonine methy I ester is inactive while its benzoyl derivative, cocaine, is an important local anaesthetic.

113

Relation of Chemical Structure and Chemical Activity

CH.-CH--CH.COOCH s I I I I N.CHa CHOH

CH.-CH--CH.COOCHs

CH.-CH--CH.

CH.-CH--CH2

I

!

\

I I I

i

I

!

I

N.CH. CH.OCOC 6Hr,

cocaine (active)

ecgonine methyl ester (inactive)

5. EtTectofhalogens. The introduction ofnegative halogens. i.e. when the halogen is present in non-conjugated positions, has been found to increase the useful as well as the toxic properties but at different rates. However, the halogenation increases the toxicity only to a limited extent but increases the useful properties appreciabiy. Hence halogenation is used for increasing activity and widening the margin of safety in the given series. On the other hand, the introduction ofpositive halogens as in acid halides, halogenocarbonyl compounds decreases the toxicity of the compounds. Compounds having available halogens such as chloramines are strongly antiseptic, depending upon the percentage of hypohalous acid liberated on hydrolysis. Among halogens Cl, Br and 1, hypnotic properties generally decrease with increase in atomic weight but the antiseptic properties increase. This can be seen from the comparison of hypnotic and antiseptic properties of CHCl ,. CHBr, and CHI, in which the hypnotic activity decreases whereas antiseptic activity increases from chloroform to Iodoform. It is to be noted that fluorine compounds are comparatively much less physiologically active than the corresponding other halogens. The less activity of fluorinated compounds may be due to their stability. 6. EtTect of nitro (NO z) and nitrite (ONO) group. The introduction of a nitro group into aromatic compounds increases their toxicity. For example. nitrobenzene, nitronaphthol and nitrothiophene have been found to be more toxic than the parent hydrocarbons. However, if a readily oxidisable group such as -CH, or - CHO group is introduced, then the toxicity decreases. For example, p-nitrotoluene is less poisonous than nitrobenzene and also nitro-aldehydes are somewhat little poisonous.

o

R-N/ "'0 nitro compound

R-O-N=O nitrite

Nitrite group, which is isomeric with nitro group differs in their action. For example, aliphatic nitrites have dilating effect on blood vessels whereas

Pharmacelllical Chemistry (Organic)

114

nitrocompounds have no action. Thus, aliphatic nitrites are used to lower blood pressure. The strength of this effect increases from methyl nitrite to amyl nitrite. The secondary and tertiary nitrites are easily hydrolysed to alcohol and nitrites. Therefore, they are more powerful than the corresponding primary nitrites. 7. Effect of amino group. In general, the amino group is toxic. Successive alkylation of the amino group decreases toxicity. In general, the acylation of amino group decreases the physiological activity, e.g., aniline is toxic while acetanilide is used as a febrifuge. Sulphonation and carboxylation decrease the physiological effect of the amino compounds,e.g., aniline is poisonous whilep-aminobenzoic acid (PABH) is actually a vitamin of B group. The introduction of a second amino group increases the toxicity. For example, all the three phenylenediamines are more poisonous than aniline. It is to be remembered that aromatic amines and hydrazines are used as antipyretics and analgesics. 8. Effect of nitrile (.eN) group. The parent compound of nitrile group is HCN which is a well known strong poison. The introduction of nitrile group may give rise to two series of compounds, the nitriles RCN and isonitriles RNC. Both are poisonous. Nitriles produce coma. In aliphatic series, the lower nitriles have been found to be more poisonous than the higher nitriles. Isonitriles are also very poisonous. They paralyse the respiratory system. The cyanide ion in some inorganic compounds also exerts more poisonous effect. For example, potassium thiocyanate is a weak poison and sodium nitroprusside, Na2Fe (CN)~ NO is a strong poison which causes death. However, the cyanide ion in the sodium ferrocyanide Na4 Fe (CN)6 does not have any physiological action. 9. Effect of unsaturation. In general, the unsaturated compounds have been found to be more toxic than their corresponding saturated compounds. For example, propanol-l CH 3 CH 2 -OH has mild narcotic property but is nonpoisonous while allyl alcohol CH, = CH.CH,OH has strong poisonous properties. Also, unsaturated compounds-such as acrolein, crotonaldehyde and carvone have been found to be more toxic than that of the corresponding saturated compounds. I CH,=CH.CHO

/,\

-acrolein

I

'v~~

CH,.CH = CH.CHO crotonaldehyde

I

carvone (more toxic)

0

/"'

menthone (less toxic)

It is to be noted that the toxicity of acornpound increases with unsaturation.

,, I

Relation ojChemical Structure and Chemical Activity

115

Unsaturation has also been found to produce toxicity in the compounds other than carbon. For example, trivalent arsenic compounds have been found to be more toxic than those of quinquevalent arsenic. Also, mustard gas (CICH2CH2)2S is poisonous which on oxidation is converted into almost harmless and non-toxic substance, the sulphone (CICH2C~)2S02 (oxidation increases the valency of sulphur).

10. Effect of isomerism. (a) Structural isomerism. Structural isomers often show marked differences in their physiological properties. This can be seen in ortho, meta and para derivatives in the aromatic series. For example, 0hydroxybenzoic acid is physiological active while both p- and m-isomers are inactive. Similarl y, it can be explained that ordinary cocaine is a local anaesthertic while a-cocaine does into have this property. p-aminobenzene-sulphonic acid is an active drug whereas its two other isomers are inactive. (b) Stereoisomerism. Both geometrical and optical isomers show different physiological activity, e.g., maletic acid is poisonous while fumaric acid is harmless. (-) - Adrenaline is about 12 times as active as the (+)-form. Similarly. (-)-nicotine is twice as active as (+) form.

6 General Anaesthetics 6.1

Introduction to Anaesthetks

The term 'anaesthetic' is derived from the Greek word anaesthesia which means insensibility and hence anaesthetics may be defined as those drugs which produce insensibility to the vital functions of all types of cells, especially those of the nervous system. The effect produced by an anaesthetic is reversible which means that the effected organs return to the normal state as soon as the concentration of the anaesthetic is decreased. Thus, an anaesthetic produces temporary insensibility to pain or feeling in the whole body or a particular organ which has to undergo the surgical operation. Under anesthesia the patient has no agony during the operation, and the surgeon works carefully, patiently anci effectively. The advent of anaesthetics has revolutionised the surgery. In summary, an anaesthetic should provide: (a) A safe and pleasant anaesthesia for the patient. (b) Sufficient relaxation so that surgery can be readily achieved, and (c) Prompt recovery of the patient to preoperative physiologic norm.

Even though we do not have the ideal anaesthetic agent, with the combinations of anaesthetic dnd ancillary drugs now available it does appear that in skilled hands these objectives can be achieved. An ideal anaesthetic agent should have the following characteristics: (i) It should be inert (e&sentially non-metabolised). (ii) It should be porent and nonflammable. (iii) It should produce rapid and smooth induction.

(iv) It should be non-irritating to mucous membranes.

General Anaesthetics

117

(v) It should produce not only anaes~hesia but also analgesia and muscle

relaxation. (vi) It should not produce severe hypotension. (vi) It should be non-toxic to brain, liver, heart and kidney tissues.

(viii) It should not produce nausea or vomiting. (ix) It should be compatible with ancillary drugs used in anaesthesia. (x) It should be economical and usable with existing anaesthetic equip-

ment. (xi) It should be stable to soda lime, light and heat.

In a general way, the action of volatile anaesthetics may be di vided into the following four stages: (i) Preanesthesia, the induction stage, (ii) Delirium or dream stage, (iii) Surgical anaesthesia, the operative stage, and

(iv) Stage of medullary paralysis.

Classification. As anaesthetic!; may produce unconsciousness all overthe body or in a particular organ, they may be classified into two groups on the basis of their applications. (a) General or central anaesthetics. These depress the central nervous system to such an extent that all sensitivity to pain or feeling is lost, i.e., they produce unconsciousness all over the body. ( b) Local anaesthetics. These do not affect the whole body but make only a part of the body insensitive to pain or feeling. In this chapter, we shall discuss general or central anaesthetics. However, we shall discuss local anaesthetics in the next chapter.

6.2

Introduction to General Anaesthetics

General anaesthetics have been the central nervous system depressant dfllgs which are able to bring about a partial or total loss of the sense of pain accompanied by loss of consciousness. This state of insensibility is called anaesthesia. General anaesthetics are used for producing anaesthesia before carrying out a surgical operation, or in obstetrics. It is possible to di vide general anaesthetics into two categories depending on their mode of administration: volatile and gaseous anaesthetics which may get administered by inhalation, and intravenous anaesthetics.

6.3

Volatile and Gaseous Anaesthetics

Volatile anaesthetics include liquids of volatile nature which are used by inhalation. Examples of these anaesthetics are chemical classes of ethers and halogenated hydrocarbons. Among the gaseous substances used to produce anaesthesia have been cyclopropane and nitrous oxide.

118

Phannaceutical Chemistry (Organic)

1. Ether. It was the first compound to be used as an anaesthetic by American doctor Crawford Long but his results remain unpublished. In 1846, Morton demonstrated its use as an anaesthetic in surgery. However, it was Sir James Simpson who popularised the use of ether as an anaesthetic in surgical operations. Anaesthetic ether is diethyl ether (CH3CHPC~CH3) which is having a suitable non-volatile stabiliser in a proportion which should not be grt:ater than 0.002 per cent w/w. Ether is prepared preferably by Williamson's synthesis or from an alcohol in the presence of dehydrating agents. C 2HSBr + NaOC 2H s ~ C 2H sOC 2Hs + NaBr 2C 2HPH ~ C 2H sOC 2Hs + Hp It occurs as a clear colourless, volatile, highly flammable liquid, having a sweet burning taste and a characteristic odour. It is soluble 1 in 10 of water. It is miscible with alcohol, chloroform, benzene and with fixed and volatile oils. It finds use as a volatile anaesthetic, usually as a mixture with other anaesthetics like nitrous oxide. It is having irritant action on the mucous membrane and brings about the secretion of saliva and mucus from bronchial tissues. Atropine or hyoscine have to be given before induction of anaesthesia. Anaesthetic ether has to be stored in well-closed, light resistant containers in a cool place. Ether remaining in a partly used container should not be used because it may deteriorate rapidly. On the label on the container it should be stated "Very flammable; Do not use near a naked flame"; and the name and proportion of any stabiliser added. The stabilisers like sodium pyrogallate, hydroquinone, or propyl gallate are added in anaesthetic ether unless the anaesthetic ether is kept in a copper container or in a container which is copperplated internally. Advantages. Ether is a safe anaesthetic. Its principal site action is the central nervous system. It is inexpensive, and when stored properly it is comparatively stable. Disadvantages. Ether boils at a low temperature and is difficult to administer in tropical temperatures. Its vapours are flammable and somewhat irritating to mucous membrane. The blood solubility of ether is high and induction period is slow and often stormy. 2. Methyl n-propyl ether (methopryl). It was introduced in 1946. It has been found to be more powerful and less irritating than ethyl ether. Further, it has less objectionable after-effects than the ether. 3. Vinyl ether (vinthene). In 1930 Leake suggested that it would be of interest to prepare a hybrid molecule between ethyl ether and vinyl ether i.e., a molecule which contained the essential features of these anaesthetics. Following this suggestion, Major and Ruigh (1936) prepared divinyl ether from ethylene chlorobydrin in the following manner:

119

General Anaesthetics

CICHI.CHI

. HISO, 2CICH, CH.OR - - - _

'\,.

/

ethylene chlorobydrin

o

CICRI.CHI

2. 2'-d chloro-diethyl ether

CIHIIOH +KOH

--------+-

CHI-CH '\. 0

/

CHI=CH vinyl ether

=

=

Vinyl ether' (CH2 CHOCH CH2) occurs as a clear, colourless liquid having a characteristic odour. It is having nearly 4% v/v of absolute alcohol but not more than 0.01 % w/v of N-phenyl-I-naphthylamine or other suitable stabiliser.1t has been found to be miscible with alcohol, ether and chloroform. It should be stored in a well-closed container of capacity not more than 200 ml. These bottles must be kept in a cool place protected from light. If the container is opened it has to be used within forty-eight hours. It has been found to be more potent anesthetic than ether. It finds use in minor operative procedures of short duration. It also finds use as general anaesthetic when mixed with anaesthetic ether. Advantage. It is nearly seven times more potent than ether with a speedy recovery. Its use is confined to minor operations of short duration when rapid induction and recovery are required. It is especially useful for dental procedures.

Disadvantages. The main disadvantage of divinyl ether is its deterious effect on the liver. Repeated short administrations or prolonged anaesthesias with the agent lead to hepatio damage. Another disadvantage of divinyl ether is its flammability. 4. Methoxyflurane. It is a halogenated ether which is chemically 2, 2dichloro-l, I-diftuoroethyl methyl ether (CI2CHCF2OC~). It occurs as a clear, non-flammable liquid having a characteristic fruity odour. It is having om % w/w ofbutylated hydroxytoluene as an antioxidant. It must be kept in bottles in cool place. These bottles should be protected from light. It is a volatile anaesthetic which is less irritant to mucous membranes than ether. It is also exerting a good analgesic effect.

Official Anaesthetic Ether, B.P., J.P. Vinyl Ether, B.P. Gaseous Substances

Pharmaceutical Chemistry (Organic)

120

1. Ethylene. In 1923, it was used as a general anaesthetic. It causes a rapid and pleasant induction of unconsciousness with quick recovery. Ethylene anaesthesia has little effect upon respiration, circulation, liver, kidneys, or other systems or organs of the body. The use of ethylene has declined markedly over recent years. It is used for minor surgery which does not require deep anaesthesia and for analgesia in obstetrics. With oxygen it forms explosive mixtures. Therefore, it does not have to be a good general anaesthetic. 2. Cyclopropane. It is prepared by the action of metal such as sodium, magnesium or zinc on 1,3 di-chloropropane which is prepared by the careful chlorination of propane. CH 2

i \

Cl-CH2CH2CH2• Cl + Zn - - - ... + ZnCI 2 CH2 -CH2 Among the hydrocarbons, cyclopropane is the most potent and its use does not result disagreeable after effects as does ether. In many other respects it closely approaches the ideal anaesthetic agent. Cyclopropane occurs as a colourless gas at atmospheric pressure having a characteristic odour. It is flammable, and its mixture with oxygen or air at certain concentrations is explosive. Cyclopropane is widely used in poor-risk and elderly patie.nts, in those in shock owing to trauma or haemorrhage, for all types of major surgery relaxation of large muscles, in thoracic surgery, in patients with respiratory diseases, and in patients with severe metabolic disturbances. The disadvantages of cylopropane are as follows: (i) It does not profound degrees of abdominal relaxation which are afforded by ether. (ii) The sensitisation of the automatic tissue of the heart to epinephrine

and certain other sympathomimetic amines is a distinct danger. (iii) The explosiveness of mixtures of cyclopropane and oxygen has been

the cause of many serious anaesthetic accidents. It is av~lable in metal cylinders in compressed form. The cylinder having this must be painted orange bearing the name or chemical symbol of the gas and must by kept in a cool place. The gas is soluble in alcohol, chloroform and ether. It has been used as a non-irritant anaesthetic having rapid induction and recovery.

3. Nitrous oxide. It was the first anaesthetic. It is prepared by heating ammonium nitrite up to 2000c. It is purified and liquefied. NH4N02 ----+

Np + Hp

121

General Anaesthetics

Nitrous oxide (NP) occurs as a colourless gas, odourless and tasteless. It is soluble in water, alcohol and ether. It is available in metal cylinders which are painted blue and carry a label giving the name of the gas. In addition the shoulder of the cylinder must be labelled with the name of the gas or the symbol N,D stencilled in paint. The cylinders must be kept at a temperature which should,-in no case, not exceed 37°C. It is a weak anaesthetic but is exerting strong analgesic properties. It is nonirritant. For general anaesthesia it is generally used along with other anaesthetics. Nitrous oxide 50% with oxygen finds use for analgesia in obstetrics.

Nitrous oxide is administered in a circuit mixed with oxygen by the semiclosed technique. This induction period is short and not unpleasant. Recovery occurs almost immediately when anaesthetic mask is removed. The principal uses of nitrous oxide as an anaesthetic are as follows: (i) To induce anaesthesia to. be followed by ether, halothane or

methoxyflurane. (ii) For short dental operations. (iii) To supplement anaesthesia with thiopental sodium. (iv) To provide a state of unconsciousness due to surgery under spinal

anaesthesia. The light anaesthesia produced by nitrous oxide limits its field of usefulness and is its principal disadvantage.

Official Cylcopropane B.P., LP. Nitrous Oxide, B.P., LP.

Halogenated Hydrocarbons The halogenated hydrocarbons such as chloroform, halothane, trichloroethylene and ethyl chloride are used as anaesthetic substances. 1. Chloroform. It is among the most widely used general anaesthetics. II may be prepared from bleaching powder and ethyl alcohol or acetone as follows: CaOCl2 + ~O C 2HpH + Cl 2

~ ~

Ca(OH)2 + Cl2 CH3CHO + 2 HCl

CH3CHO + C~ ~ CCI 3CHO + 3HCI 2CCI)CHO + Ca(OH)3 ~ CHCl 3 + (HCOO)2Ca Chloroform occurs as a colourless, volatile liquid having a characteristic odour and sweet burning taste. It is having 1 to 2% v/v of ethyl alcohol which does not allow the formation of poisonous carbonyl chloride (phosgene) in chloroform, and also reacts with any carbonyl choride which might have been formed. It is not flammable but is freely miscible with ether and ethyl alcohol. It is having slight solubility in water. Chloroform has been a potent inhalation

122

Phannaceutical Chemistry (Organic)

anaesthetic. As chlorofonn is toxic to liver and kidney, other safer agents are preferred over it. It also finds use as a canninative, as a flavouring agent and as a preservative. It also finds use externally as rubefacient. Chlorofonn for anaesthetic purposes must be kept protected from light and air, otherwise decomposition will occur, fonning the toxic phosgene. Anaesthesia with chlorofonn may be induced using the open drop method or rebreathing in a closed circuit. As new safer agents have been prepared, the use of chlorofonn has markedly declined. However, it is still used for obstetrical anaesthesia as it produces good analgesia in a light phase of anaesthesia. Its introduction is prompt, the vapours are not flammable and the syndrome is not too unpleasant to the patient. Its various disadvantages are that it is cardiotoxic, hepatotoxic and its rapid decomposition by air, light or moisture into phosgene (COCI 2), a poisonous gas. Due to its decomposition, it is kept full in amber-coloured bottles. 2. Halothane. Chemically, it is 2-bromo-2chloro-I,I,1-trifluorothane (CHBr-CICF 3) F Br F"- C-CH I

F/,

'tl

It occurs as a colourless, non-tlammable liquid having odour resembling chlorofonn. It has been miscible with chlorofonn, ether, trichloroethylene and with fixed and volatile oils. It must be stored in air-tight containers at a temperature not exceeding 25° which are protected from light. It finds use an inhalation anaesthetic and has been more potent than chlorofonn and ether. It has been non-irritant to the skin and mucous membranes and does not give rise to necrosis when spilt on tissues. It is the most widely used anaesthetic agent at present. It is used in almost every type of surgical procedure. Anaesthesiologists like it because of the ease with which they can lighten or deepen the anaesthetic level. The main advantage of halothane is its lack of flammability and effectiveness. It is nearly four times more active than ether with a therapeutic index twice that of ether.

The main disadvantages of halothane are respiratory and cardiovascular depression, incomplete muscle relaxation, poor analgesia, potential hepatotoxicity, low margin of safety, etc. 3. Trichloroethylene. Chemically, it is as follows:

H,

/CI

Cl/

'CI

c=c

123

General Anaesthetics

It may be prepared by the alkaline decomposition of tetrachloroethane.

CHCI2.CHCI 2 + NaOH ~ CCI 2

=CHCI + NaCI + ~O

It may also be prepared by the controlled addition of chlorine to acetylene diluted with carbon dioxide and cooled at - 60°C. CH == CH + 2CI 2 ~ CCI 2 =CHCI + Hel

=

Trichloroethylene (CICH CCI) occurs as a clear, colourless or blue liquid having chloroform-like odour and taste. It is having not less than 0.008 per cent but not more than 0.012 per cent of thymol as a preserative. It is also having not more than 0.001 per cent w/w of a blue colour allowed under the Drugs and Cosmetic Rules, 1945 to distinguish it from chloroform.

It is almost insoluble in water but is miscible with alcohol, chloroform and ether. It must be kept in a tightly-closed, light resistant containers in a cool place. The label on the container must state in a prominent place: Caution - Repeated use may bring about liver damage; Warning - It should not be used in any cIosecircuit rebreathing system using soda lime or other alkali as phosgene or other toxic products may be produced. It has been found to be a weak volatile anaesthetic having potent analgesic action. It finds use mainly in short surgical procedures or in obstetrics. It also finds use for the relief of pain in trigeminal neuralgia. It also finds use for the prevention and treatment of angina of effort. Its anaesthatic use is specially recommended for dental extractions, orthopedic manipulations, cytoscopy, and similar short surgical procedures. Its anaesthetic use is also for inducing an analgesic state in the relief of pain in migraine, angina pectoris and I.!hild birth.

It is not a satisfactory agent for use as a general anaesthetic. It cannot be used in a closed system because it reacts with soda lime. It produces poor muscle relaxation, disturbances in cardiac rhythm, may l::e hepatotoxic and is difficult to vapourise.

4. Ethyl Chloride (CH3 CH1 CI). It is a gas at ordinary temperature and pressure. However, it is available, in compressed form, as a very volatile liquid having a pleasant ethereal odour, and a burning taste. It is having slight solubility in water but is miscible with alcohol and ether. It should be kept at a temperature below 15° in containers which are to be protected from light. When it is sprayed on the body surface it brings about intense cold by evaporation causing local anaesthesia. This effect is used for minor surgery. As a general anaesthetic it has been now superseded by other available safer anaesthetics. Official Chloroform, B.P., I.P. Ethyl Chloride, B.P., J.P. Halothane, B.P. Trichloroethylene, B.P., J.P.

- 124

Pharmaceutical Chemistry (Organic)

6.4

Intravenous Anaesthetics Intravenous anaesthetics are able to produce unconsciousness when they are allowed to administer parenterally. The intravenous drugs offer flexibility and allow the administration oflower doses of inhalation agents. These also find use to induce anaesthesia rapidly. The duration of effect has been found to depend on the amount of drug administered.

There are some ultrashort acting barbiturates like thiopentone sodium and methohexitone which are widely used as anaesthetics and given intravenousiy. ,A general discussion of barbiturates has been outlined under Hypnotics and Sedatives. The other intravenous anaesthetics are propanidid and steroidal compounds alphadolone acetate and, alphaxalone. 1. Thiopentone or Thiopental Sodium. It is a mixture of sodium 5-ethyl5-(l-methylbutyl)-2-thiobarbiturate and anhydrous sodium carbonate. It occurs as a yellowish-white hygroscopic powder. It is having characteristic alliaceous odour and a bitter taste. It is having solubility in water. Its solutions for injection could be obtained by dissolving, immediately before use, the sterile contents of a sealed container in the specific amount of water for injection. When it is administered intravenously as a 2.5% or occasionally as a 5% solution, it produces complete anaesthesia of short duration or the induction of general anaesthesia. It is also administered rectally as a solution or suppositories for basal anaesthesia. It also finds use for the control of conVUlsions, including drug-induced convulsions.

Thiopentone Sodium

Methohexitone

2. Methohexitone (methohexital). Chemically, it is 5-allyl-I-methyl-5 (l-methylpent-2-ynyl) barbituric acid. It occurs as a white or faintly yellowishwhite crystalline powder. It is very slightly soluble in water. Its sodium salt occurs as a white crystalline powder which is having solubility in water. It has been about thrice as potent as thiopentone sodium. It finds use as methohexitone injection which is a sterile solution obtained from a mixture of 100 parts by weight of methohexitone sodium and 6 parts by weight of dried sodium carbonate in water for injection which is free from carbon dioxide.

125

General Anaesthetics

It must be freshly prepared and has to be used within 24 hours. If the solutions are cloudy, they should not be used. It may be given either intravenousIy or administered by intramuscular injection and rectally. 3. Propanidid. It is a non-barbiturate intravenous anaesthetic which is chemically propyl4-diethylcarbamoylmethoxy 3-methoxyphenylacetate.

It occurs as a colourless or pale greenish-yellow hygroscopic liquid having a faint odour. It is having very slightly solubility in water but is miscible with alcohol, chloroform and ether. It has been acting as a short-acting anaesthetic. It is also having local anaesthetic activity.

CH.COOCH.CH.CH.

I

/' ,,,, I

\I

lOCH. I /C.Hs OCH.CON, Propanidld C.H,

4. Alphadolone and alphaxalone. Alphadolone acetate and alphaxalone arc steroids which find use as intravenous anaesthetic drugs. Chemically alphadolone acetate is 3a, 21-dihydroxy-5a-preganane-ll, 20-dione 21-acetate which occurs as a white to c:eamy white powder. It is almost insoluble in water. Chemically alphaxalone is 3a-hydroxy. 5a-pregnane-ll, 20-dione which also occurs as white to creamy white powder. It is almost insoluble in water. Both the drugs find use as anaesthetics. CH"OCOCH 3

I

CO

CH3

, H

Alphadolone Acetate

Alphaxalone

Alphadolone acetate has been found to he about half as potent as alphaxalone. It finds use for increasing the solubility of alphaxalone. Both the compounds may be administered intravenously in a solution having 3 mg of alphadolone acetate and 9 mg of alphaxalone per ml for the causing of anaesthesia. Official Alphadolone Acetate, B.P. Alphaxalone. B.P.

126

Pharmaceutical Chemistry (Organic)

Methohexitone Injection, B.P. Propanidid, B.P. Thiopentone Sodium, B.P., I.P. Thiopentone Injection, B.P.I.P.

7 Local Anaesthetics

7.1

Introduction Any substance applied topically or by localised injection or infiltration to dull or block pain sensation may be regarded as a local anaesthetic. This, when applied directly to the peripheral nervous tissue, blocks nerve conduction and abolishes all sensations in the part supplied by the nerves. It tends to block both the generation and the conduction of the nerve impulses. They are mainly used in dental and surgical procedures to prevent pain. The requisites of a local anaesthetic are as follows: (i) It should not be irritant. (U) It should not be painful. (iii) It should produce anaesthesia without causing the damage of nerve cells. (iv) Its toxicity should be low. (v) The duration of anaesthetic effect should be sufficient for carrying

out the operation. (vi) It should be stable. (vii) It should be sterilised without difficulty.

It is possible to induce local anaesthesia in many different ways depending on the route of administration. Surface or topical anaesthesia act by blocking the sensory nerve endings in the skin or mucous membranes. The drug should possess good penetration power. The main examples of surface anaesthetics are amethocaine, benzocaine, cocaine, lignocaine and prilocaine. It is possible to produce local or infiltration anaesthesia by injection directly into the area which is subjected to surgical operation. Local anaesthetic preparations used for this

Pharmaceutical Chemistry (Organic)

128

purpose should be having a small amount of adrenaline which acts as a vasoconstdctor. In dentistry, local anaesthesia is extensively used. Lignocaine, mepivacaine, prilocaine and procaine are common compounds which are used for infiltration anaesthesia. It is possible to induce regional nerve block anaesthesia by injection into or around the nelve trunks or ganglia that supply the parts to get operated. The agents mainly used for this purpose include bupivacain, lignocaine, mepivacaine and procaine. It is possible to produce spinal anaesthesia by injecting the drug within the dual membrane which is surrounding the spinal cord and the nerve coats. One should avoid the addition of adrenaline in them. Anaesthetic compounds used for spinal anaesthesia are amethocaine, cinchocaine and prilocaine. Chemically the local anaesthetics can be categorised into two main classes, esters (Ar-COO-R) and amides (Ar-CONH-R). In these, R generally refers to an aminoalkyl or alkyl substituted aminoalkyl group.

7.2. The Esters 1. Cocaine. It is an alkaloid which is isolated from the leavesofErythroxylum coca (Erythroxylon coca). It was the first chemical substance which was found to be having local anaesthetic properties. Cocaine is having tropane, skeleton. It is a levorotatory base. Chemically, cocaine is benzoylmethylecgonine. But ecgonine is a derivative of tropane which is having carboxylic group at position 2 and hydroxy group at position 3. Therefore, cocaine is an ester of benzoic acid having a nitrogenous alcohol. It is a white crystalline powder having bitter numbing teste. It is slightly soluble in water. Its hydrochloride salt forms hygroscopic crystals or white crystalline powder and is soluble in water. It is incompatible with alkali hydroxides and carbonates. It is to be protected from light. Cocaine acts as a surface anaesthetic.

Cocaine

Ecgonine

Due to its systemic toxic effects and the danger of bringing about addictional its use is now somewhat restricted to eye surgery and surgery of ear, nose and throat. 2. Benzocaine. From the structure of cocaine it follows that the structural feature responsible for local anaesthetic activity may be represented as ArCOO-(CH2), NRRI. By keeping this structure in view several esters ofthe type were prepared and tested. The simplest compound prepared was ethyl

129

Local Anaesthetics

.NHZ

4-aminobenzoate (benzocaine) which is having surface anaesthetic activity. It possesses low systemic toxicity and is used orally for relieving the pain of gastric ulcer or gastric carcinoma. Benzocaine occurs as a white crystalline powder having bitter taste followed by local anaesthesia of the tongue. It is having slight solubility in water. It is to be .stored in wellclosed, light-resistant containers.

Benzocaine 3 Procaine. It is a synthetic agent which is superior to cocaine. Chemically, it is 2-diethylaminoethyl p-aminobenzoate. Its CIBa hydrochloride is used. The salt forms colourless, / odourless crystals or a white crystalline powder fOOCBtCBIN" having slightly bitter saline numbing taste. This salt A C.B is soluble in water and alcohol. II II I Its solutions may be sterilised either by autoclaving ,/ or by filtration. Procaine hydrochloride is useless as I surface anaesthetic due to its poor penetration powN B. er. It is mainly used by inJ·ections. Its action gets Procaine prolonged by adding adrenaline to the solution. 4. Amethocaine. When a butyl substituent is introduced into thep-amino group of dimethylaminoethyl benzoate, it gives rise to a longer acting. rather

Amethocaine

Cyciomethycaine

toxic drug, amethocaine hydrochlore (tetracaine hydrocloride). It is especially used as surface anaesthetic. It is to be stored protected from light. Its solutions could be sterilised by maintaining at 98° to 100" for 30 minutes with a bactericide or by filtration. 5. Butacaine. Another compound related to procaine is butacaine sulphate which is the sulphate of the base 3-dibutyl amino-propyl p-aminobenzoate. It finds use as a surface anaesthetic having effects similar to those of cocaine. 6. Cyclomethycaine Sulphate. It is another example of ester type local anaesthetic which is having bulkier cyclohxy\oxy substitution at paraposition of

130

Pharmaceutical Chemistry (Organic)

the benezine ring. The ester group is having a 3-(2-methyl piperidino) propyl group. It exists as a white, crystalline powder. It is sparingly soluble in water. It finds use as surface anaesthetic. However, it is not suitable for injection or for use in ear, nose and throat.

7. Proxymetacaine. This compound is chemically related to procaine. It is having an amino group in meta position and a propoxy group atpara postion.

Proxymetacaine Chemically proxymetacaine is therefore 2-diethylaminoethyl 3-amino-4propoxybenzoate. Its hydrochloride salt is official which is a white or faintly buff-coloured powder and is soluble in water. It is a surface anaesthetic which finds use in ophthalmology. It has been found to be slightly more potent than amethocaine in equal concentrations.

Official Amethocaine Hydrochloride, B.P. Amethocaine Eye Drops, B.P. Benzocaine, B.P .. J.P. Cocaine, B ,Po Cocaine Hydmchloride, B.P. Cyclomethycaine Sulphate, B.P. Procaine Hydrochloride, B.P., J.P. Procaine and Adrenaline Injection, I.P. Proxymetacaine Hydrochloride, B.P. Proxymetacaine Eye Drops, B.P.

7.3

Amides

1. Lignocaine (Lidocaine). Among a number of anilides synthesised, lignocaine (lidocaine). N-diethylaminoacetyl-2, 6-xylidine, was reported to be an effective local anae~thetic. Its main advantage over procaine and other ester typ.e agents is its extreme resistance to hydrolysis. No appreciable decomposition oflignocaine takes place even ifit is heated with 50% sulphuric acid or 20% ethanolic potassium hydroxide for five hours.

131

Local Anaesthetics

The freebase occurs as a crystalline solid having a characteristic odour. It is almost insoluble in water. Lignocaine hydrochloride occurs as a white crystalline odourless powder having a slightly bitter numbing taste. It is very soluble in water. Its solution may be sterilised either by autoclaving or by filtration. Lignocaine has been widely used by injection and for local application to mucous membranes. It is having a rapid onset of action and the effects have been fouJ!Cl to be more prolonged than those of procaine. It is possible to increase its onset and duration of action by the addition of adrenaline. In dentistry its 2% solution with adrenaline or noradrenaline is generally used. It is also given intramuscularly in cardiac arrhythmias. 2. Prilocaine. Another compound which is related to lignocaine is prilocaine hydrochloride (2-propylaminopropio-o-toludide hydrochloride). It finds use in a similar way as lignocaine, and is some-what 40% less toxic. Its solutions may be sterilised by autoclaving or by filtration.

Lignocaine

Prilocaine

3. Bupivacaine. It is the lignocaine analogue in which the amino nitrogen is forming a part of a ring system. It is having N-butylpiperidine ring which gets attached to the carbon of amide group through position 2. Its hydrochloride is used. Its solutions are sterilised either by autoclaving or by filtration. It is exerting clinical usefulness which is similar to that of lignocaine and is having the same degree of stability; and is somewhat 2-4 times more potent and longer acting.

Bupivacaine 4. Cinchocaine hydrochloride. It is a non-anilide amide type of local anaesthetic. It is having quinoline as the basic skeleton with a butoxy group at position 2 and and N-(2-diethylaminoethyl) carboxamide group at position 4. It

Pharmaceutical Chemistry (Organic)

132

I

occurs as white hygroscopic crystalline salt having slightly bitter taste. It is soluble in water. It is stable. Its solutions can be sterilised either by autoclaving or by filtration. It gets darkened on exposure to light and should be kept protected from light. Cinchocaine has been reported to b~ several times more toxic than lignocaine by injection or cocaine by local application. However, its local anaesthetic action has been found to be greater and therefore it might be used in lower concentration.

Cinchocaine

5. Oxethazine.1t is another amide-type surface anaesthetic which is stated to have a prolonged action. Chemically it is 2,2'-(2-hydroxyethylimino)-bis [N-a-a-dimethylphenethyl)-N-methylacetamide]. Oxethazine occurs as a white CHI CH J 0

0:\ I.

V~

I

I,

I

I

11

CHI -C -N-C -CHl

I

I

~~3 ~ I

CH z -

~ I

J

-

CH I C H 1 0H

C - N - C - CHI

I

I

1\

CH1CH,O

Oxethazine

or almost white powder. It is practically insoluble in water. It is administered by mouth in conjunction with antacids for the symptomatic relief of oesophagitis. Official Bupivacaine Hydrochloride, B.P., I.P. Bupivacaine Injection, B.P., I.P. Bupivacaine and Adrenaline Injection, B.P. Cinchocaine Hydrochloride, B.P., Lignocaine, B.P. Lignocaine Hydrochloride, B.P., I.P. Lignocaine Gel, B.P. Lignocaine and Adrenaline Injection, B.P., I.P. Lignocaine and Chlorhexidine Gel, B.P.

Local Anaesthetics

133

Lignocaine Hydrochloride Injection, I.P. Lignocaine Injection, B.P. Oxethazine, B.P. Prilocaine Hydrochloride, B.P. Ethyl chloride (B.P.). CHFH2Cl, because of its low boiling point and the intense cold produced by evaporation, it is used as a local anaesthetic in minor surgery. This procedure, however, is not generally recommended. Ethyl chloride is gaseous at ambient temperatures and pressures, but usually compressed to a colourless, mobile, flammabile and very volatile liquid. It is having ethereal odour. Other drugs which are exerting local anaesthetic action have been benzyl alcohol, chlorbutol (described under Organic Pharmaceutical Aids) and clove oil. Further there are some antihistamines, beta-adrenocepter blocking agents, anticholinergic agents and anti-arrhythmic agents which are also having local anaesthetic property.

8 Hypnotics and Sedatives 8.1

Introduction

Hypnotics are central nervous system depressants that produce sleep to reduce restlessness and emotional tension. The patient cannot be easily awakened until the effect of the hypnotic wears out. Sedatives are also central nervous system depressants that reduce restlessness and emotional tension without producing sleep. From the above definitions, one cannot draw a definite line among the various groups of hypnotics and sedatives. Usually, their action varies with the dosage. For instance phenobarbital administered in dosages of 25-30 mg is considered a mild sedative, while in a 100 mg dose it is a hypnotic. Furthermore alone or in combination with hydantoin derivatives, phenobarbital is a potent anticon vulsant. When its large doses are taken, it may cause a state of anaesthesia from which the patient cannot be awakened until the drug has been metabolised. Generally, hypnotics when used in very large amounts may produce anaesthesia poisoning and even death in some cases. These progressive effects may be depicted as follows: Sedation ~ Hypnosis

~

Anaesthesia? Coma ~ Death

Hypnotics find use in cases of insomnia. Some of the compounds act slowly and if given in smaller doses bring about calming effect; these have been of value in the treatment of anxiety and restlessness. The hypnotic and sedative drugs generally bring about widespread depression of the central nervous system. There are certain CNS functions, in addition to the state of wakefulness, which are usually depressed by these drugs. Many of the drugs of this category are used as anticonvulsants and muscle relaxants and others may be employed for producing general anaesthesia.

135

Hypnotics and Sedatives

Chemically, it is possible to classify hypnotics and sedatives as barbiturates and non-barbiturates. 8.2

Barbiturates This is the general term which is used for the derivatives ofbarbituric acid.

Barbituric acid is 2,4,6-tioxo-hexa hydropyrimidine which is a cyclic ureide and formed by the condensation of urea with malonic acid ester. Barbituric acid itself has no central nervous system depressant activity. However, the substitution by alkyl or aryl group at its position 5 confers hypnoticsedative activity. The acidic character of barbituric acid arises through lactam-lactim (enol) tautomerisation through carbonyl at position 2 which gets favoured by the presence of two electronegative amido nitrogens flanking it. The lactim form gets favoured in alkaline solution, and salts are formed. Barbiturates are crystalline solids. These are having very poor solubility in water. However, if they are converted into sodium salts, their solubility increases tremendously. The solutions of these sodium ~alts have been found to be incompatible with ammonium salts and acidic substances. H

01ii~~O '''0'' _ o~r"" s .. • I 2r

3NH

o Barbituric Acid

o Sodium Barbiturate

The early drugs used to prevent epileptic seizures were barbiturates. As these are general central nervous system depressants whose anticonvulsant action is a part of their hypnotic effect. many researchers concentrated their efforts on preparing ante-ipileptic drugs that had no depressant action on the sensory cortex. The mechanism by which the barbiturates reduce the excitability of the motor cortex is unknown. The parent compound of barbiturates is barbituric acid and the majority of these barbiturates are obtained by making substitution in position 5 of the molecule. Therapeutically the barbiturate~ are exerting many disadvantages as hypnotics which include tolerance, abuse and dependence, hang-over and other prolonged effects. They have been replaced by much safer and less toxic drugs such as benzodiazepines. Some official barbiturates are as follows: 1. Phenobarbitone. Chemically, it is 5-ethyl-5-phenylbarbituric acid. It is a white crystalline solid having a slight bitter taste. It is having a slight solubility in water.

136

Pharmaceutical Chemistry (Organic)

Phenobarbitone sodium occurs as a hygroscopic white powder or crystalline granules. It is having very much solubility in water. Phenobarbitone has been used orally, while its sodium salt has been used as injections. Both are stored in well-closed containers. Phenobarbitone and phenobarbitone sodium are having hypnotic, sedative and anticonvulsant actions. They are especially used in the treatment of grand mal seizures or CH psychomotor attacks.

I

3

o~yo CzH, Ca H ,

Phenobarbitone

NW

o

Methylphenobarbitone

2. Methylphenobarbitone. It is obtained by the substitution of methyl group on nitrogen at position I of barbituric acid. It forms colourless crystals or whitecrystalline powder. It is almost insoluble in water. It finds use as anticonvulsant and sedative. 3. Amylobarbitone. Chemically, it is 5-ethyl-5-isopentylbarbituric acid. Its sodium salt i.e., amylobarbitone sodium is having much solubility in water. Its solutions for injections should be prepared aseptically in water for injection free from carbon dioxide. Such solutions should be used immediately after their preparation. It finds use in insomnia and as a pre-operative sedative. For the treatment of convulsion, it is given intravenously.

CH 3 ,

o~~yo

CzH,

++

Co

NH

/CHCHzCH z

CH3

0 2 Amylobarbitone

Cyclobarbitone

4. Butobarbitone. It is having butyl and ethyl groups at position 5. It occurs as colourless crystals or a white crystalline powder, having slight solubility in water. 5. Cyclobiritone.Chemically, it is 5-cyclohex-l', enyl-5-ethyl-barbituric acid. It has to be protected from light. Its calcium salt, cyclobarbitone calcium occurs as a white or slightly yellowish powder. It is slightly soluble in water. It is milder in action and finds use in insomnia and anxiety states. 6. Hexobarbitone. Chemically itis 5-cyclohexenyl-l, 5-dimethylbarbituric acid. It is a white crystalline powder; odourless.

137

Hypnotics and Sedatives

CH,

~'f0

°

fft CH,

NH

°

J

Hexobarbitone

Pentobarbitone

It is very slightly soluble in water. 7. Pentobarbitone Sodium. Chemically, it is sodium 5-ethyl-5-(lmethylbutyl) barbiturate. It is very soluble in water. It finds use in the treatment ofinsomnia.1t is also used as a sedative. It also finds use as basal narcotic before general anaesthesia, and in the production of obstetric amnesia. It also finds use intravenously for the treatment of convulsions.

0t:;yONQ H

CzH, CH,CHzCHzCH

I

N 0

CH, Pentobarbitone' 'Sodium

Quinalbarbitone Sodium

8. Quinalbarbitone Sodium. Chemically it is sodium 5-allyl-5-(1methylbutyl) barbiturate. Its uses are similar to those of pentobarbitone sodium. 9. Secbutobarbitone.1t is having an ethyl and a secondary butyl group at position 5. It occurs as fine white microcrystalline powder having bitter taste. It is having slight solubility in water. Official Amylobarbitone, B.P., I.P. Arnylobarbitone Tablets, I.P. Amylobarbitone Sodium, B.P., I.P. Arnylobarbitone Sodium Tablets, I.P. Butobarbitone, B.P. Cyclobarbitone Calcium, B.P., I.P. Cyclobarbitone Tablets, I.P. Hexobarbitone, B.P. Methylphenobarbitone, B.P. Pentobarbitone, B.P. Pentobarbitone Sodium, B.P., I.P. Pentobarbitone Capsules, B.P. Pentobarbitone Sodium Tablets, I.P.

Pharmaceutical Chemistry (Organic)

138

(pentobarbitone Tablets, B.P.) Phenobarbitone, B.P.I.P. Phenobarbitone, Elixir, B.P., Phenobarbitone, Tablets, B.P., I.P. Phenobarbitone Sodium, B.P.,I.P. Phenobarbitone Sodium Injection, I.P. (Phenobarbitone Injection, B.P.) Phenobarbitone Sodium Tablets, B.P., I.P. Quinalbarbitone Sodium, B.P.,I.P. Quinalbarbitone Tablets, I.P. 8.3

Non-barbiturates

Several compounds are known which do not have barbiturate structure but have hypnotic-sedative activity. They are having different structural groups, and may be grouped as benzodiazepines; other heterocyclics; and alcohols, aldehydes and ami des. Benzoliazepines Benzodiazepine is a system composed of a benzene ring which is fused to a seven-membered heterocycle having two nitrogens and three double bonds. As the positions of nitrogens have been I and 4, the system has been termed as I, 4-benzodiazepine. Many modifications in the structure of the ring system give rise to compounds which are having similar activities. These are collectively termed as benzodiazepines. These find use, in preference to barbiturates, as sedative-hypnotics and anticonvulsants. Benzodiazepines also find use as antianxiety agents and muscle relaxants. Examples of benzodiazepines are diazepam, flurazepam, oxazepam,lorazepam and nitrazepam which are used primarily as hypnotics and sedatives. Diazepam. It is having I, 3-dihydro-2H-l, 4-benzodiaepin-2, one skeleton which is having substitutions of methyl at position I, phenyl at position 5 and chloro at position 7. It occurs as a white or almost white to pale yellow crystalline powder having bitter after taste. It is sparingly soluble in water. It is kept in tightly closed, light resistant containers. It is either given orally or parenterally. Flurazepam. It is different from diazepam in having a 2-(diethylamino) ethyl group at position 1 and O-fluorophenyl group at position 5. It is used as CH a CH 2 N

CI~~ I :)0 '1 ~

Diazepam

....... C2 H,

'C,H,

F F1urazepam

139

Hypnotics and Sedatives

official as the monohydrochloride which is having much solubility in water. The salt is stored in a well-closed container in a cool place. Oxazepam and Lorazepam. These occur as white or almost white crystalline powders. These are practically insoluble in water. These are having a hydroxy group attached to position 3. Both the drugs are bearing no substituent at position -I. Lorazepam is different from oxazepam in having ao-chlorophenyl substituent at position 5 instead of phenyl of oxazepam. The drugs should be kept in well-closed containers which are protected from light.

c'11~ ~}OH ,.. ,

O'N~/, ~-f

I

~

I

;..--

~

X

Oxazepam (X =H) Lorazepam (X = el)

Nitrazepam.

Nitrazepam. It is having 1. 3-dihydro-2H-I, 4-benzodiazpin -2-one system with a nitro group at position 7 and a phenyl at position 5. It occurs as a yellow crystalline powder. It is almost insoluble in water. Itis kept in well-closed containers which are protected from light. Flunitrazepam. Chemically, it is 5-(2-fluorophenyl)-I, 3-dihydro-lmethyl-7-nitro-l, 4-benzodiazepin-2-one. It is a white or yellowish powder; practically insoluble in water. It should be kept in a well-closed container and protected from light. It is given by mouth in the short-term management of insomnia. Loprazolam.1t is an example of a benzodiazepine in which the carbonyl and nitrogen atoms of the azepine ring are involved in the formation of a third fused ring. Loprazolam is used in the form of its salt with methane sulphonic

Ok" H

.t.:

N

NH

N-CH,

'--.j

• CH,SO,H

OJN~~I~) ~I ~

Flunitrazepam

CI

Loprazolam Mesylate

acid, that is as loprazolam mesylate. The salt is a yellow crystalline powder; slightly soluble in water. Official Diazepam, B.P., J.P. Diazepam Capsules, B.P., J.P. Diazepam Injection, B.P., J.P.

Pharmaceutical Chemistry (Organic)

140

Diazepam Oral Solution, B.P Diazepam Tablets, B.P., J.P. Flunitrazepam, B.P. Flurazepam Monohydrochloride, B.P. Flurazepam Capsules, B.P. Loprazolam Mesylate, B.P. Loprazolam Tablets, B.P. Lorazepam, B.P. Lorazepam Tablets, B.P. Nitrazepam, B.P., I.P. Nitrazepam Capsules, B.P., I.P. Nitrazepam Oral Solution, B.P. Nitrazepam Tablets, B.P. Oxazepam, B.P. Oxazepam Capsules, B.P. Oxazepam Tabkts, B.P. Temazepam, B.P. Temazepam Oral Solution, B.P.

Other Heterocyclics Methaqualone, methyprylone, glutethimide and chlormethiazole are having heterocyclic systems of different types. Methaqualone is having partly saturated quinzoline system. Chemically, it has been 2-methyl-3-o-tolyquinazolin4-one. It occurs as a white crystalline powder. It is insoluble in water. It is kept in well-closed container which is protected from light. It is resembling barbiturates in its hypnotic action. When we give an anti-histamine, like diphenhydramine, along with it. the hypnotic effect gets increased. In lower doses it finds use as a sedative. In addition to sedative-hypnotic properties, methaqualone is having anticonvulsant, local anaesthetic, antitussive and weak antihistaminic properties.

Methaqualone

Methyprylone has been a piperidine -2A-dione having substitution oftwo ethyl groups at position 3 and a methyl at position 5. It is a water soluble white crystalline powder having a slight characteristic odour. It is stored in air-tight containers which are protected from light.

141

Hypl'/O.tics and Sedatives

H

O~N"f0 ~CzH, CIIH, Methyprylone

Glutethimide

Glutethimide. Chemically, it is 2-ethyl-2-phenylglutarimide. It is also named as 3-ethyl-3-phenyl-piperidine-2, 6 dione.1t occurs as a white crystalline powder. It is almost insoluble in water. It is exerting hypnotic and sedative actions. The drug should be kept in air-tight containers which are protected from light. Chlormethiazole. It is having thiazole as the heterocyclic system which is substituted at position 5 by 2-chloroethyl group and at position 4 by methyl group. Its salt with ethane-I, 2-disulphonic lIcid has been also official under the name of chlormethiazole edislyate. The salt occurs as a white crystalline powder having a characteristic odour. It becomes more distinct and rather unpleasant when exposed to heat. It is freely soluble in water. It is preserved in a cool place. Chlormethiazole acts as a hypnotic and sedative having anticonvulsant effects. It finds use in confusion, agitation and restlessness and in sleep disorders in elderly. It also finds use in epilepsy.

[

C,CH&CHair.]

CH Z-

I

SO~tt

CHa-SO.. H

CH, a

Chlormethiazole Edisylate

Official Chlormethiazole, B.P. Chlormethiazole Capsules, B.P. Chlormethiazole Edisylate, B.P. Glutethimide, B.P. Glutethimide Tablets, B.P. Methaqualone, B.P. Methyprylone, B.P. Methyprylone Tablets, B.P. Alcohols, Aldehydes and Amides Although ethyl alcohol is having a depressant action on central nervous system, its use in clinical practice is not recommended. The hypnotic activity of

Pharmaceutical Chemistry (Organic)

142

alcohols tends to increase as the molecular weight increases going maximum up to n-hexanol or n-octanol. Chlorination or bromination of alcohols also tends {O increase the activity, 2,2,2-Trichloroethanol finds use as monosodium salt of its dihydrogen phosphate under the trade name of trichlofos sodium. It occurs as a white hygroscopic powder having a saline taste. It has been found to be freely soluble in water. It has been found to be incompatible with salts of heavy metals and alkaloids.

o II Cl C CH 20-P- ONa. 3

I

OH Triclofos Sodium

Paraldehyde is a trimer of acetaldehyde. It is a powerful and quick acting hypnotic. Chemically it is 2,4,6-trimethyl-l ,3,5-trioxane.1t is having a suitable amount of an antioxidant. It occurs as a clear, colourless or slightly yellow liquid having a strong characteristic odour. It is freely soluble in water.

Its solution is sterilised by filtration; contact with rubber should be avoided. It is stored in air-tight containers in a dark and cool place. When it gets solidified, the whole of the contents of the container be liquified by warming before use. The label on the container should be pas led which should state: the nature and the proportion of the antioxidant; and that it may decompose on standing, to form potentially harmful substance. It also finds use by intramuscular injection for the treatment of convulsions. As in case of alcohols chlorination of aldehydes tends to increase the hypnotic activity. Chloral hydrate, Cl,CCH(OH)2 is chemically (2,2,2-trichloroethane-l, 1diol). It occurs as a colourless, crystalline solid having pungent odour and a bitter caustic taste. It volatalises slowly when exposed to air. It is very soluble in water. It should be kept in a cool place protected from light, in airtight containers. It is taken in diluted form as mixture or elixir because the concentrated forms have been found to damage the mucous membrane of the alimentary canal.

Dichloralphenazone is a combination of chloral hydrate and phenazone. It occurs as a white microcrystalline powder having a slight odour of chloral hydrate. It is soluble in water. It finds use as hypnotic and sedative with less gastric discomfort effect. For children it is given in tablet or elixir form.

Hypnotics and Sedatives

143

The monoacyl derivatives of urea are known as monoureides. An example is carbromal which is (2-bromo-2-ethylbutyryl) urea, (CH 3CH 2)2 BrCCONHCONH2.1t is a monoureide. It occurs as white crystalline powder. It is slightly soluble in water. It finds use orally as a hypnotic in mild insomnia.

Official Carbromal, B.P. Chloral Hydrate, B.P., I.P. Chloral Mixture, B.P. Paediatric Chloral Elixir, B.P. Dichloralphenazone, B.P. Dlchloralphenazone Elixir, B.P. Dichloraphenazone Tablets, B.P. Paraldehyde, B.P., I.P. Paralydehyde Injection, B.P. Triclofos Sodium, B.P. Triclofos Elixir, B.P. Triclofos Tablets, B.P.

In addition to the drugs described above. there are many other compounds which have sedative and hypnotic effects or side effects. Such drugs have been general anaesthetics, opioid analgesics, scopolamine (hyoscine) and antihistamines.

9 Anticonvulsant Drugs 9.1

Introduction

The drugs used in the treatment of various types of epilepsy are called anticonvulsant drugs. Epilepsy is a disease which arises due to the disorders of central nervous system. This disease is characterised by somewhat more or less frequent recurrence of seizures in which there occur convulsions or other abnormal body movements which are accompanied by loss or disturbance in consciousness. It is probable that the seizures may be correlated with abnormal and excessive discharges in the electroencephalogram (EEG). It is possible to classify the epileptic seizures into generalised and partial. Generalised seizures have been including absences (petit mal), tonicclonic (grand mal) and myoclonic seizures. The partial (focal, local) seizures have been including those with motor, sensory or autonomic symptoms and those of complex symptoms (pscyhomotor seizures). The anticonvulsant drugs, maybe classified into the chemical classes of barbiturates; hydantoins; oxazolidinediones; and succinirnides. There are many drugs with different chemical structures which cannot be included in any ofthese classes; such drugs have been included into the miscellaneous category. 9.2

Barbiturates

Barbiturates have been already described under Hypnotics and Sedatives. The barbiturates which selectively find use in the control of epilepsy include phenobarbitone, phenobarbitone sodium, and methyl phenobarbitone. Thiopentone sodium (discussed under General Anaesthetics) also finds use for the control of convulsions.

Anticonvulsant Drugs

145

9.3

Hydantoins Hydantoins are having an imidazoline-2,4-dione heterocyclic system. There are many substituted hydantoins which have been prepared and tested pharmacologically. Among these 5, 5-diphenyhydantoin (phenytoin) has been least hypnotic and most strongly anticonvulsant. Phenytoin occurs as a white powder. It is almost insoluble in water. Its sodium salt, phenytoin sodium, is soluble in water and is a hygroscopic powder which when exposed to air absorbs carbon dioxide with the liberation of phenytoin. The solutions may be sterilised by filtration. Phenytoin and its sodium salt have been employed successfuIly in controIling grand mal and psychomotor epilepsy but have been of insignificant value in petit mal attacks. They find use alone or in conjunction with phenobarbitone and/or primidone. Phentoin sodium also finds use in the treatment of cardiac arrhythmias.

Omcial

Pheytoln

Phenytoin sodium

Phenytoin, B.P. Pheyntoin Oral Suspension, B.P. Phenytoin Sodium, B.P., I.P. Phenytoin Capsules, B.P., I.P. Phenytoin Injection, B.P., I.P. Phenytoin Sodium Tablets, I.P. (Phenytoin Tablets, B.P.)

9.4 Oxazolidinediones Oxazolidine -2, 4-dione system has been more or less related to hydantoin, with the difference only in that an oxygen atom replaces the NH group at position 1. Chemically troxidone is 3,5,5-trimethyloxazoline-2,4-dione. It occurs as a colourless or white granular substance having a weak camphor-like odour. It is soluble in water and alcohol. It is to be stored in tightly-closed containers, in a cool place. A related compound is paramethadione which is having an ethyl group at position 5 in place of one of the methy I. It occurs as a clear, colourless liquid having characteristic odour. It is sparingly soluble in water and freely soluble in alcohol. Both troxidone and paramethadione find use in the treatment of epileptic seizures of petit mal type.

146

Pharmaceutical Chemistry (Organic)

Troxidone

Paramethadione

Official Paramethadione,I.P. Troxidone, B.P., I.P. Troxidone Capsules, B.P., I.P.

9.5

Succinimides H

o~NyO

~CH3 CzH,

Ethosuximide

Many derivatives of succinimide are known which are having high anticonvulsant activity. Ethosuximide is 2-ethyl-2-methylsuccinimide. Itoccurs as a white odourless powder or waxy solid having a slightly bitter taste. It is freely soluble in water. It finds use in the treatment of petit mal epilepsy (absence seizures).

Official Etho:mximide, B.P., I.P. Ethosuximide Capsules, B.P.. I.P. Ethosuximide Oral Solution, B.P. Ethosuximide Syrup, I.P. 9.6

Miscellaneous Drugs

There are other compounds of miscellaneous chemical structures which show anticonvulsant activities. Primidone is a 2-deoxy analogue of phenobarbitone which finds use in the treatment of grand mal and psychomotor epilepsy. It is usually given in conjunction with phenobarbitone and phenytoin.

Primidone

Carbamazepine

147

Anticonvulsant Drugs

Primidone occurs as a white odourless crystalline powder; very slightly soluble in water. Chemically, primidone is 5-ethyl-5-phenyl perhydropyrimidine-4,6-dione. Carbamazepine possesses dibenzazepine ring system which is having a carbamoyl group at nitrogen. It is a white or yellowish white crystalline powder. It is almost insoluble in water. It finds use in the treatment of grand mal and psychomotor epilepsy. It also finds use as an, analgesic in the treatment of trigeminal neuralgia. Chemically, it gets related to tricyclic antidepressants. Beclamide is N-benzyl-3-chloropropionamide.ltoccurs as white, crystaline powder; sparingly soluble in water. It finds use for the control of tonic-clonic (grand mal) seizures and psychomotor epilepsy. It is also used for the treatment of behavioural disorders.

Beclamide

Sulthiame occurs as a white crystalline powder. It is very slightly soluble in water. It is a benzenesulphoamide derivative. It is usually administered along with other anticonvulsants for treating all types of epilepsy except petit mal. It occurs as a carbonic anhydrase inhibitor. Another carbonic anhydrase inhibitor is acetazolamide (described under Diuretics) which is also used in the treatment of epilepsy.

o

0

'O-o-S02 ~q

NH

2

Suithiame

Valproic acid (2-propylpentanoic acid) has been a simple branched-chain carboxylic acid. Its sodium salt, sodium valproate is official which is having anticonvulsant activity against different types of seizures. It brings about only minimal sedation and other central nervous systel1l side effects. Sodium valproate occurs as a deliquescent white crystalline powder. It should be stored in wellclosed containers.

Sodium Valporate

---

148

Pharmaceutical Chemistry (Organic)

Official Beclamide, B.P. Beclamide Tablets, B.P. Carbamazepine, B.P., I.P. Carbamazepine Tablets, B.P., I.P. Primidone, B.P., I.P. Primidone Oral Suspension, B.P. Primidone Tablets, B.P., I.P. Sodium Valproate, B.P. Sodium Valproate Oral Solution, B.P. Sodium Valproate Tablets, B.P. Sulthiame, B.P. Sulthiame Tablets, RP. Besides these there are many compounds, benzodiazepines, such as diazepam and nitrazepam; chlormethiazole; and paraldehyde which have been described under Hypnotics and Sedatives and are also used as anticonvulsants.

10 Opioid Analgesics

10.1 Introduction The word 'opioid' refers, in a generic sense to all the drugs which are, natural and synthetic and having action such as morphine which is an analgesic alkaloid from opium. Opioid analgesics are the drugs which are mainly used in the relief of moderate to severe pain. Opioid analgesics give rise to dependence and most of the compounds cause stupor (narcosis) along with analgesia. Opioid analgesics are also known as narcotic analgesics. Non-opioid (non-narcotic) analgesics are generally having anti-inflammatory and antipyretic properties. They are used for the relief ofless severe pain and are discussed under Nonsteroidal Antiinflammatory Agents and AnalgesicAntipyretics. Opioid analgesics may be classified chemically into two main groups such as morphine and related compounds, and totally synthetic analgesics. 10.2 Morphine and Related Compounds Opium is sun-dried latex of unripe seed capsules of Papaver somniferum. It finds use for the relief of pain since ancient times. It is baving over two dozen alkaloids which constitute about 25 per cent by weight of opium. The alkaloids of opium can be grouped into phenanthrene and benzylisoquinoline related chemical classes. The phenanthrene type alkaloids include morphine (10 per cent of opium), codeine (0.5 per cent) and thebaine (0.2 per cent). The main benzylisoquinoline type alkaloids include papaverine (1 per cent), which finds use as a smooth muscle relaxant, and noscapine (6.0 per cent), which finds uses as an antitussive. Morphine and codeine have been the two most useful analgesics.

Pharmaceutical Chemistry (Organic)

150

Morphine is the main alkaloid of opium. It is used officially as morphine hydrochloride and morphine sulphate. Both the salts occur as white crystalline solids having bitter taste. They are soluble in water. Their solutions may be sterilised by maintaining at 98° to 1000 for 30 minutes with a bactericide or by filtration. Morphine salts are stored in well-closed, light-resistant containers. Morphine finds use as a powerful analgesic and narcotic. It is able to depress the central nervous system so that there occurs increased tolerance to pain. It finds use for the symptomatic relief of moderate to severe pain which is especially associated with cancer and for post-operative pain.

It finds use as hypnotic when sleeplessness occurs due to pain. It reduces intestinal motility and is used in the treatment of diarrhoea; and is also used for suppression of cough and relief of anxiety. It has been found to be more effective when it has been administered parenterally than when given by mouth. The two undesirable properties which morphine has are: respiratory depression and dependence liability.

Morphine

Codeine

Codeine exists as colourless crystals or a white crystalline powder; slightly soluble in water. Codeine is generally used as codeine hydrochloride (soluble in water), codeine phosphate (freely soluble in water) and codeine phosphate sesquihydrate (freely soluble in water). All the three salts exist as small crystals or white crystalline powder. Codeine and its salts are to be kept in well-closed containers and protected from light. The solutions have to be sterilised by autoclaving or by filtration. Structurally codeine is different from morphine in having a methoxyl (OCH 3) group at position 3 in place of phenolic hydroxyl. It is much less potent as analgesic than morphine and has weak sedative effects. It 'finds use for the relief of mild to moderate pain, given orally or through injections. It also finds use to suppress unproductive cough. There are some semi-synthetic derivatives which are prepared by structural modification of morphine and codeine. The 3-ethyl ether of morphine is called ethylmorphine. It finds use as the hydrochloride which occurs as water soluble . dihydrate. It is kept in well-closed, light-resistant containers. It finds use as analgesic and cough suppressant, but it is less effective than codeine. Diamorphin (heroin) is obtained by the acetylation of both the hydroxy groups at position 3 and 6 in morphine. It is official as the hydrochloride salt. It occurs as an almost white crystalline powder having bitter taste. It is freely soluble in water. Its solutions for injection are obtained by dissolving immediately before use the sterile contents of a sealed container in water for injection.

Opioid Analgesics

151

Diamorphine has been found to be more potent analgesic than morphine but has shorter duration of action. It finds use orally or parenterally for the relief of severe pain. It has been found to be effective for the relief of cough. Due to its addictive properties it should be used with discrimination. The double bond present in 7.8 position of codeine has been saturated to yield dihydrocodeine which is official as the tartrate. It is a water-soluble crystalline powder having bitter taste. The salt should be protected from light. Its solutions are sterilised by autoclaving or by filtration. It finds use orally or by injection for the relief of mild to moderate pain and for suppression of cough. Official

Codeine, B.P. Codeine Hydrochloride, B.P. Codeine Phosphate, B.P., I.P . Co-codamol Tablets, B.P. Co-codaprin Tablets, B.P. Codeine Linctus, B.P. Codeine Phosphate Oral Solution, B.P. Codeine Phosphate Syrup, I.P. Codeine Phosphate Tablets, B.P. Dispersible Co-codaprin Tablets, B.P. Paediatric Codeine Linctus, B.P. Codeline Phosphate Sesquihydrate, B.P. Codeine Linctus, B.P. Codeine Phosphate Oral Solution, B.P. Codeine Phosphate Tablets, B.P. Paediatric Codeine Linctus, B.P. Diamorphine Hydrochloride, B.P. Diamorphine Injection, B.P. Dihydrocodeine Tartrate, B.P. Co-dydramol Tablets, B.P. Dihydrocodeine Injection, B.P. Dihydrocodeine Oral Solution, B.P. Dihydrocodeine Tablets, B.P. Ethylmorphine Hydrochloride, B.P., I.P. Morphine Hydrochloride, B.P., I.P. Morphine Suppositories, B.P. Morphine Sulphate, B.P., I.P. Morphine Injection, I.P.

152

Pharmaceutical Chemistry (Organic)

(Morphine Sulphate Injection, B.P.) Morphine Suppositories, B.P. Morphine Tablets, B.P. Morphine and Atropine Injection, B.P., I.P. Totally Synthetic Analgesics It is possible to prepare a large number of synthetic analgesics by considering morphine as the model. The synthetic analgesics have been described under morphinans and benzomorphans; pethidine and analogues; and methadone and analogues.

Morphinans and Benzomorphans Levorphanol tartrate is the synthetic analgesic which is most closely resembling morphine in its structure. Chemically, levorphanol is (-)-3-hydroxy-N-methylmorphinan hydrogen tartrate dihydrate. It is different from morphine in the absence of ether bridge between positions 4 and 5 and lack alcoholic hydroxyl group at position 6 and the 7, 8-double band gets saturated. Levorphanol tartrate occurs as a white crystalline powder having a bitter taste. It is soluble in water. It is kept in air-tight containers. Its solutions can be sterilised by autoclaving or by filtration. Its actions are similar to morphine but differ from it in respect that it is found to be as effective by mouth as by injection.

Levorphanol

Pentazocine

The structure of morphine is further simplified in compounds such as pentazocine. The pentazocine is tricyclic and is a derivative of6, 7-benzomorphan. But benzomorphan is named as 1,2,3,4,5,6-hexahydro-2, 6-methano-3benzazocine. Therefore pentazocine is (2R, 6R, llR)-1,2,3,4,5,6,-hexahydro8-hydroxy-6, Il-dimethyl-(3-methylbut-2-enyl) 2,6-methano-3-benzazocine. Pentazocine occurs as a white or creamy white crystalline powder. It is practically insoluble in water. Its hydrochloride salt is water-soluble. This salt is white to pale cream coloured powder. Both the base and the salt must be stored in air-tight containers which are protected from light. Pentazocine finds use for the relief of moderate to severe pain, both orally and parenterally. It is having low dependence-producing properties compared with morphine. It is also exerting weak narcotic antagonist action. It is employed as pentazocine lactate injection. The injection is a sterile solution in water for

153

Opioid Analgesics

injection which is obtained from pentazocine and lactic acids. It is sterilised by autoclaving.

Official Levorphanol Tartrate. B.P. Levorphanol Injection. B.P. Levorphanol Tablets. B.P. Pentazocine. B.P. Pentazocine Lactate Injection. B.P. Pentazocine Hydrochloride. B.P .• I.P. Pentazocine Tablets. B.P. Pethidine and Analogues Pethidine is a synthetic compound which is a derivative of piperidine. Chemically it is 4-ethoxycarbonyl-I-methyl-4-phenyl piperidine. Its hydrochloride is official compound. Its salt is a white crystalline powder having slightly acid bitter taste. It is freely soluble in water. It is kept in well-closed. light-resistant containers. Its solutions can be sterilised by autoclaving or by filtration. It finds use as a substitute of morphine for the relief of most types of moderate to severe pains. It is also exerting a mild sedative action. Its analgesic action is not as prolonged as that of morphine. It also finds use in combination with chlorpromazine and promethazine for producing a special ty~of narcosis. It also produces mild euphoria. It has been used orally and parenterally. CH,

I

if-. cR ~

H'

eN I

m

CH

•

•

~ I Di:h::o~y~a:e

Pethidine

It is necessary to mention here diphenoxylate. a derivative of pethidine. which is having 3-cyano-3.3-diphenylpropyl group attached to the nitrogen of piperidine ring. It is used as the hydrochloride (B.P.) which is a white or almost

CH2CH2~

~

I

Y

r'l'Y, CH V N'CCH II

23

o

Fentanyl

154

Pharmaceutical Chemistry (Organic)

white powder; sparingly soluble in water. Diphenoxylate is having no analgesic activity. It reduces intestinal motility and is used in the symptomatic treatment of acute and chronic diarrhoea. Another pethidine related analgesic is fentanyl citrate which is chemically l-phenethyl-4-N-phenlpropionamidopiperidine dihydrogen citrate. It occurs as white granules or glistening crystalline powder. It is sparingly soluble in water. It is a potent analgesic whose actions are similar to those of morphine. The respiratory depressant effect of fentanl has been of shorter duration than that of pethidine. It is usually used for producing surgical analgesia.

Official Fentanyl Citrate, B.P. Pethidine Hydrochloride, B.P., I.P. Pethidine Injection, B.P., I.P. Pethidine Tablets, B.P., I.P.

Methadone and Analogues It is important to note that the structure of methadone has no resemblance with that of morphine but it displays remarkable opioid activity. Methadone is racemic 6-dimethylamine-4, 4 diphenyl heptane-3 one. Its activity is attributed mainly to its leva isomer which is somewhat 8 to 50 times more potent than the dextra isomer. Methadone was first of all synthesised by German chemists and was brought into. clinical use at the end of World War II. The official methadone is its hydrochloride which occurs as a white crystalline powder having bitter taste. It is soluble in water. The solutions maybe sterilised either by autoclaving or by filtration and distributed in ampOUles. These solutions must be having chlorocresol which acts as bacteriostatic. Methadone hydrochloride acts as a potent analgesic having less marked sedative action. It is also used for controlling non-productive cough. Its dependence liability is similar to that of morphine. It is also used for controlling withdrawal effects of morphine and other related narcotic drugs.

Methadone

Dipipanone

155

Opioid Analgesics

It is possible to prepare dipipanone, dextromoramide and dextropropoxyphene by structural changes in methadone. Dipipanone is having piperidino group in place of dimethylamino group of methadone. It is official as the hydrochloride. It occurs as a white crystalline powder having a bitter numbing and burning taste. It is sparingly soluble in water. Its solutions are sterilised by autoclaving or by filtration. The compound finds use as racemic mixture. It finds use orally or intramuscularly.

Chemically dextromoramide is (+ )-I-(3-methyl-4-morpholino-2, 2diphenylbutyryl)pyrrolidine. It is official as the tartrate. It occurs as a white crystalline or amorphous powder. It is soluble in water. It finds use in the treatment of moderate to severe pain. However, it is not recommended for use for obstetric analgesia. . Chemically dextropropoxyphene is 2-methyl-3,4-diphenyl-3propionyloxybutyl-N, N-dimethylamine.1t has been the dextrorotatory isomer. The official salts have been dextropropoxyphene hydrochloride (very soluble in water) and dextropropoxyphene napsylate (practically insoluble in water). These are kept in well-closed containers. The hydrochloride salt occurs as a white or slightly yellow powder, while the salt with naphthalene-2-sulphonic acid (napsylate) occurs as a white pOWder. Both the salts are having bitter taste. Dextropropoxyphene salts may be administered by mouth for alleviating mild to moderate pain. These are having little antitussive activity. These are especially used in conjunction with other analgesics with antiinflammatory activity like aspirin and paracetamol.

Q~~o -

/C-N

C

d 'I ~

I

3

CH /

~

/ OCCI-lP-l3

C

d

c'H2'CH-CH;

'CH-CH

-

Q~ _

1

N

Co) ' Dextromoramide

'I

\

~

CH~ /

-

N

0/ "cH 3 3

Dextropropoxyphene

Official Dextromoramide Tartrate, B.P. Dextromoramide Injection, B.P. Dextromoramide Tablets, B.P. Dextropropoxyphene Hydrochloride, B.P., J.P. Dextropropoxyphene Capsules, J.P. Dextropropoxyphene Napsylate, B.P., J.P. Dextropropoxyphene Capsules, B.P., I.P.

156

Pharmaceutical Chemistry (Organic)

Dipipanone Hydrochloride, B.P. Dipipanone and Cyclizine Tablets, B.P. Mathadone Hydrochloride, B.P., J.P. Methadone Injection B.P., J.P. Methadone Linctus, B.P. Methadone Tablets, B.P., LP. It is appropriate to describe certain narcotic antagonists here.

Narcotic Antagonists Narcotic antagonists maybe defined as those drugs which are able to counteract the effects of morphine and other morphine-like narcotic analgesics. They are mainly employed in the treatment of overdosage with narcotic ... analgesics. Narcotic dependence is also treated with these agents. Nalorphine and levallorphan have been found to be clinically useful narcotic antagonists. Nalorphine is N-allylnormorphine.1t is a structure in which methyl group attached to nitrogen in morphine gets replaced with an allyl ( CH2CH=CH2)group. It finds use as the hydrobromide and hydrochloride salts. Its hydrochloride occurs as a white or almost white crystalline powder which is slowly darkening on exposure to air and light. It should be kept in tightly-closed, light-resistant containers. Its hydrobromide occurs as a white to creamy white powder. Its storage requirements have been similar to the hydrochloride. /CH 2CH=CH 2

"O~OH Nalorphine

/CHtCH:::CH J

~ ~

HO

0

0

Naloxone

The solutions maybe sterilised either by autoclaving or by filtration. Nalorphine is administered by intravenous injection for treating the overdosage by morphine and other synthetic analgesics like pethidine, methadone and levorphanol. Though it is having analgesic action .also yet it is not used for this property due to unpleasant side effects. Naloxone is a derivative of7, 8-dihydro-14-hydroxymorphinone having an allyl group at the nitrogen. It finds use as the hydrochloride which occurs as a white or almost white crystalline powder; hygroscopic in nature. It is freely soluble in water. The salt is to be kept in an air tight container protected from light. Naloxone is usually given intravenously for a rapid onset of action which takes place within two minutes.

Official Nalorphine Hydrochloride, LP. Nalorphine Injection, J.P. Naloxone Hydrochloride, B.P.

11 Antitussives and Expectorants

11.1 Introduction Cough may be defined as a nonnal physiological response to irritation in larynx, trachea or in bronchi, the function of which is to expel irritating materials or mucus secretions from the respiratory tract. Although a useful physiological function, cough is needed to be controlled if it becomes too severe or too frequent or is nonproductive with pain and fatigue. The drugs used in the control of cough are being discussed under two categories: antitussives and expectorants. The drugs of the two categories are usually used in conjunction with each other.

ANTITUSSIVES An antitussive may be defined as a drug that is able to raise the threshold of the cough centre and suppresses the irritant non-productive cough. It is also known as cough suppressant. Antitussives can act either by raising the threshold of the cough centre that is situated in the medulla oblogata or by reducing the number of impulses transmitted to the cough centre from the peripheral receptors. Thus, a cough is a reflex phenomenon and potent antitussive acts centrally by depressing or suppressing by a reflex mechanism. However, some antitussives can act by both mechanisms. Accordingly, antitussives are divided into two groups: centrally acting antitussives and peripherally acting antitussives. The first group includes opium alkaloids, their semisynthetic derivatives and synthetic antitussives. The second group is comprised of demulcents, expectorants, mucolytic agents, and other agents, which, in general, are not used individually but incorporated into antitussive pharmaceutical preparations. Several of the narcotic analgesics like codeine, ethylmorphine, diamorphine and methadone also find use as antitussive agents. Some of the rdated com-

158

Phamwceutical Chemistry (Organic)

pounds for specific use as cough suppressants include noscapine, pholcodine, and dextromethorphan. Compounds that are having an antitussive activity, can be broadly divided into two categories viz. (i) Narcotic antitussives and (ii) Synthetic non-narcotic antitussives. 11.2 Narcotic Antitussives Morphine and codeine and the important alkaloids of opium are potent analgesics as well as well-known antitussive agents. These and ethyl morphine, diarnorphine, methadone, meperidine (pethidine) have been potent antitussive agents. As all these drugs are narcotic in nature, they are known as narcotic antitussives. The~e have been covered under the topic on analgesics. 11.3 Synthetic Non-narcotic Antitussives Some clinically useful compounds have been described as below: 1.

Noscapine (norcotine) (B.P.) It is an alkaloid ofbenzylisoquinoline group which is occurring in opium. It is a white crystalline powder having no taste. It is practically insoluble in water. It is having antitussive action but not having analgesic or sedative effects. It is also used as the hydrochloride salt which is freely soluble in water. Both the base and its salts have to be stored in well-closed containers and protected from light.

Noscapine

Noscapine Linctus has been official in B.P. and noscapine hydrochloride which is its water soluble salt, has been an ingredient of various cough preparations. Pholcodine (B.P.) .It is a semisynthetic derivative of the alkaloid morphine in which hydrogen of the hydroxy group at position 3 in morphine has been replaced by 2morpholinoetilyl group. Its monohydrate is in the form of colourless crystals or a white crystallin~ powder. It is having a very bitter taste. It is sparingly soluble in water. It finds use orally for the relief of unproductive cough. It is having mild sedative action also. The compound is stored in well-closed containers. 2.

159

Antitussives and Expectorants

Pholcodine

It is given in the form of linctus up to 60 mg in divided doses to control unproductive cough.

3.

Dextromethorphan

It is a synthetic compound having morphinan skeleton. The hydrobromide of the dextrorotatory of isomer 3-methoxy-N-methyl-morphinan occurs as monohydrate. Dextromethorphan hydrobromide is a white crystalline powder , ~~

~

c~o

Dextromethorphan

having bitter taste. It is sparingly soluble in water, but freely soluble in alcohol and chloroform. It is not having analgesic or sedative properties. It finds use as a cough suppressant. Its usual dose has been 15-30 mg. 1 to 4 times a day.

4.

Levopropoxyphene (N.F.)

(-) 4- (dimethyl-amino)-3-methyl-l, 2-diphenyI2-butanol propionate

The naphthalene sulphonate salt is also called napsylate. It occurs as'a white powder, which is almost tasteless. It has been sparingly soluble in water but more soluble in alcohol and chloroform. It is given in the form of suspension in a 50 mg dose.

160

Phannaceutical Chemistry (Organic)

Omcial Dextromethorphan Hydrobromide, B.P. Noscapine, B.P., I.P. Noscapine Linctus, B.P Noscapine Hydrochloride, B.P. Pholcodine, B.P., I.P. Pholcodine Linctus, B.P. Strong Pholcodine Linctus, B.P. EXPECTORANTS Expectorants may be defined as those drugs which are able to increase the volume of the sputum and promote the expulsion of secretions or exudates from respiratory tract. They are also able to reduce the viscosity of the temlf'eous sputum. Bromhexine and guaiphenesin are two of the drugs used as ex,tctorants. Bromhexine: It is a benzylamine derivative which is named as 2-amino3, 5-dibromobenzyl(cyc1ohexyl) methylamine. It finds use as the hydrochloride, which occurs as a white or almost white crystalline powder. It is practically

·'~eH,l~ ,Hel Br

NH z

Bromhexine Hydrochloride

insoluble in water. The drug is to be protected from light. Bromhexine is able to reduce the viscosity of the mucus and finds use in the treatment of respiratory disorders associated with viscid mucus. Guaiphenesin: It is a a-glyceryl ether of guaicol (2-methoxyphenol). It is named chemically as 3-(2-methoxyphenoxy)propane-I, 2-diol. It is able to OH

I OCHl CH CHzOH

&oeH,

Guaiphenesin

reduce the viscosity of tenacious sputum and finds use as an expectorant. Guaiphenesin exists as white crystals or crystalline aggregates. It is sparingly soluble in water.

Antitussives and Expectorants

Official

Bromhexine Hydrochloride, B.P. Bromhexine Tablets, B.P. Guaiphenesin, B.P.

161

12 Psychoactive Drugs

12.1 Introduction Several drugs are known which are used in the treatment of psychiatric disorders. Such drugs are known as psychoactive drugs. These drugs are also known as psychotropic drugs. The main aim of these drugs is to treat abnormalities of mental function. It is possible to classify psychoactive drugs as antipsychotic drugs, antidepressant drugs and antianxiety drugs. 12.2 Anti.Psychotic Drugs Several chemical classes of drugs are available which are found to be effective in the symptomatic treatment of psychoses. They are employed especially for treating psychoses like schizophrenia, mania and senile dementia, and behavioural disorder in children. Their occasional use may be indicated in depression or in severe anxiety. These drugs are termed as antipsychotic agents or drugs. In fact this expression is not true in the strict sense because they are used for symptomatic treatment of psychoses without curing the underlying disease states. There are tricyclic compounds like phenothiazine derivatives, butyrophenones, and lithium carbonate which find use as neuroleptics. The rauwolfia alkaloids also find use in the treatment of psychotic states, and these have been described in the chapter on Cardiovascular Agents. Phenothiazine Derivatives The chlorpromazine is a prominent antipsyhotic agent. The discovery of this drug was an outgrowth of research on antihistamines of the phenothiazine group.

163

Psychoactive Drugs

Phenothiazine heterocycle of which chlorpromazine has been a derivative, has been a three-ring structure. The central ring is having the hetero-atoms, sulphur and nitrogen. In chlorpromazine a chloro group gets attached to position 2 and 3-dimethylaminopropyl side chain gets attached to nitrogen (position 10). According to IUPAC nomenclature the systematic name of chlorpromazine hydrochloride has been 2-chloro-lO (3-dimethyJaminopropyl) phenothiazine hydrochloride. ......CH, CHaCHaCHaN I 'CH

.h ~~CI l 7~!I~1 e S 4

' ,HCI

Chlorpromazine Hydrochloride

Chlorpromazine base occurs as a creamy white powder or waxy solid or oily liquid. It is almost insoluble in water. Its hydrochloride salt occurs as a white or creamy white crystalline powder which is very soluble in water. Its solutions may be sterilised by autoclaving after distributing into containers in which the air is replaced by nitrogen or other suitable gas. In aqueous solution, chlorpromazine hydrochloride has been incompatible with sodium salts of barbiturates, and other alkaline solutions. It is kept in well-closed, light-resistant containers. Chlorpromazine is commonly recommended for the management of psychotic conditions. It is mainly used to control hyperkinetic states and aggression. In some cases, it is given in other psychiatric conditions for the control of anxiety and tension. It is also anti-emetic and is therefore used to control the nausea and vomiting of a variety of diseases and that caused by various drugs. It is also used in the alleviation of intractable hiccup. It is generally given alone or in combination with pethidine and sometimes promethazine as premedication for surgical or diagnostic procedures. It also finds use as an adj1mct in the treatment of tetanus and is given for controlling acute intermittent porphyria. Chlorpromazine hydrochloride is given by mouth or by injection. For parenteral use, it is administered by deep intramuscular injection. If the oral and parenteral routes have been found to be not suitable chlorpromazine base has to be administered reactally by suppository. When chlorpromazine was reported to be successful, an attempt was made to study the drug properties of other phenothiazines and tricyclic systems. Several phenothiazines having chlorpromazine relations with changes in substitutions at position 2 and aminoalkyl side chain at position 10 have been prepared. However, some of these have been found to be useful drugs.

164

Pharmaceutical Chemistry (Organic)

Apart from promazine which is having unsubstituted position 2, the official drugs are having at position 2 a chloro group (chlorpromazine, prochlorperazine, perphenazine, thiopropazate), a trifluoromethyl group (trifluperazine, fluphenazine, trioflupromazine), or a methylthio group (thiroidazine). The basic side chain which has been attached to position 10 has been 3-dimethylaminorpropyl (chlorpromazine, promazine, triflupromazine), 3-(4-methylpiperazin- J-yl) propyl (prochlorphrazine, trifluoperazine), 3-(4-(2hydroxyethyl) piperazin-I-yl)propyl (perphenazine, fluphenazine), 3-(4-(2acetyoxythyl) ethyl (thioridazine). Promazine is chemically 1O-(3-dimethylaminopropyl) phenothiazine. It is different from chlorpromazine in lacking chloro group at position. 2. It has been found to be less potent than chlorpromazine. Promazine hydrochloride is freely soluble in water. Its actions and uses have been reported to be similar to chlorpromazine hydrochloride and may be administered either by mouth or by injection (intramuscular and intravenous). Triflupromazine (flupromazine) is chemically 1O-(3-dimethylaminopropyl) 2-trifluoromethylphenothiazine.1t has been found to be different from chlorpromazine in having trifluorometyl group in place of chloro at position 2. The hydrochloride salt (soluble in water) is administered either by mouth or by injection (intramuscular). Chemically prochlorperazine, is 2-chloro-1O-[3-(4-methylpiperazin-lyl) propyl]-phenothiazine. It occurs as a pale-yellow viscous liquid, It is very slightly soluble in water. It is usually administered rectally as suppositories. Prochlorperazine may be administered by mouth as the maleate which occurs as white or pale-yellow crystalline powder and is almost insoluble in water and the mesylate (salt with methanesulphonic acid, 2CH 3S0 3H which is very soluble in water), by intravenous or deep intramuscular injection. Prochlorperazine is having quite powerful anti-emetic properties.

CHCOOH I

211

CHCOOH

Prochlotperazine Maleate

Chemically trifluoperazine is 10 [3-(4-methylpiperazin-I-yl)propyl]-2trifluoromethylphenothiazine. It is found to be different from prochlorperazine in having trifluoromethyl (F3C-) group at position 2 in stead of chloro group. Its hydrochloride (2HCI) is freely soluble in water. This r,altis having rapid onset of action and its effects are somewhat long lasting. It is having potent antiemetic properties. During the treatment of psychotic patients it has been found to be stimulating rather than sedating. It maybe given orally and by intramuscular injection.

165

Psychoactive Drugs

When given along with tranylcypromine it finds use in the treatment of anxiety and depression. Chemically, perphenazine is 2-chloro-1 0-{3-[4-(2-hydroxyethyl) piperazine-I-yl} phenothiazine. It occurs as a white or creamy white powder which is almost insoluble in water. It is having marked anti-emetic properties. It finds use especially in the treatment of severe anxiety and tension, in nausea and vomitting, and in psychotic states. It maybe given either by mouth or by intramuscular injection.

Prephenazine

Chemically, fluphenazine is 10-[3-{4-(2-hydroxyethyl)piperazin-lyl]propyl }-2-trifluoromethylphenothiazine. It is different from perphenazine in possessing trifluoromethyl group at position 2 in place of chloro group. It is very potent and it is exerting a longer duration of action. It is possible to administer fluphenazine as the hydrochloride (2HCI) generally by mouth or as the longer-acting decanoate or enanthate esters by intramuscular or sometimes subcutaneous injection. The esters have been insoluble in water but soluble in fixed oils. The oily solutions may be sterilised by filtration. Chemically thiopropazate is 10-[3-[4-2(2-acetoxyethyl) piperazin-lyl]propy]-2-chlorophenothiazine. Its structure has been similar to perphenazine but for the alcoholic group in the side chain being acetylated. Its dihydrochloride salt (freely soluble in water) occurs as a white or pale yellow, crystalline powder. It may be given orally.

c,'

jHZCHz-Q

~N~SCH3

~s~

,Hel

Thioridazine HydrochlOride

Chemically-thioridazine hydrochloride is lQ..[2-(1-methylpiperid-2-yl) ethyl] - 2 - methylthiophenothiazine hydrochloride. It occurs as a white or cream coloured crystalline powder which is freely soluble in water. It is having little anti-emetic action. It finds use especially for the treatment of schizophrenia and for the control of mania and agitation. It is also employed in the management of

166

Pharmaceutical Chemistry (Organic)

anxiety states and in children who are suffering from behavioural disorders. It is usually given orally. Omcial Chlorpromazine, B.P. Chlorpromazine Suppositories, B.P. Chlorpromazine Hydrochloride, B.P., I.P. Chlorpromazine Oral Solution, B.P. Chlorpromazine Injection, B.P.. I.P. Chlorpromazine Tablets, B.P., I.P. Fluphenazine Decanote, B.P. Fluphenazine Decanote Injection, B.P. Fluphenazine Enanthate, B.P. Fluphenazine Enanthate Injection, B.P., I.P. Fluphenazine Hydrochloride, B.P., I.P. Fluphenazine Hydrochloride Injection, I.P. Fluphenazine Tablets, B.P., I.P. ,Methotrimeprazine Hydrochloride, B.P. Perphenazine, B.P. Prephenazine Injection, B.P. Perphenazine Tablets, B.P. Prochlorperazine Maleate, B.P., I.P. Prochlorperazine Tablets, B.P., I.P. Prochlorperazine Mesylate, B.P., I.P. Prochlorperazine Injection, B.P., I.P. Prochlorperazine Hydrochloride, B.P. Promazine Hydrochloride, B.P. Promazine Injection, B.P. Promazine Tablets, B.P. Thioridazine Hydrochloride, B.P. Thioridazine Tablets, B.P. Trifluoperazine Hydrochloride. B.P., I.P. Trifluoperazine Tablets, B.P., I.P. Triflupromazine Hydrochloride, B.P., I.P. Triflupromazine Tablets, I.P.

Butyrophenones Next to phenothiazines the most important group of anti-psychotic agents include the derivatives of butyrophenone, C6H5COCH2CH2CH~. Haloperidol has been the representative of this group. This agent got developed druing the attempt to increase the analgesic potency of a series of 4-phenylpiperidines

Psychoactive Drugs

167

which are related to pethidine. Though they are structurally different from the phenothiazines, many of the butyrophenones share many of their pharmacological properties. Numerous butyrophenone derivatives have been of clinical interest. Haloperidol is official. Chemically; haloperidol is 4-(4-4-chlorophenyl-4-hydroxypiperidino)p-fluorobutyrophenone which occurs as a white to faintly yellowish amorphous or microcrystalline powder. It is insoluble in water. Haloperidol finds use for treating psychotic disorders, espcially when acute, and in behavioural disorders. It is administered either by mouth or by intramuscular or intravenous injection.

Haloperidol

Official Haloperidol, B.P. Haloperidol Injection, B.P.,I.P. Haloperidol Oral Solution, B.P. Haloperidol Tablets, B.P., I.P. Strong Haloperidol Oral Solution, B.P.

Lithium Carbonate Lithium carbonate, Li2CO~, occurs as a white crystalline powder. It is having slight solubility in water. The mechanism of its action in effective disorders is not known with certainty. It finds use in the prophylaxis and treatment of mania and in the prophylaxis of manic depression and depression. It may be administered by mouth.

Official Lithium Carbonate, B.P., I.P. Lithium Carbonate Tablets, B.P., I.P. Slow Lithium Carbonate Tablets, B.P.

12.3 Antidepressant Drugs It is possible to categorise the drugs as antidepressants under two classes: tricyclic antidepressants and monoamine oxidase inhibitors.

Tricyclic Antidepressants These are able to bring about the changes in the electroencephalogram which are similar to those caused by the phenothiazines. Their mode of action

Pharmaceutical Chemistry (Organic)

168

as antidepressants could not be understood completely. Some ofthem are having marked sedative actions and some are having tranquillising properties. The examples of these drugs are mainly dibenzazepine or dibenzocycloheptene and related deri vati ves. Due to their structures they are commonly called the tricyclic antidepressants. Before we discuss the antidepressant drugs we must describe the drugs made of heterocycles azepine, oxepin and thirpin. All these are seven membered rings having one nitrogen, oxygen or sulphur, respectively. Each of the systems is also having three double bonds.

o o o H

N

Arepine

s

o

Thiepin

Oxepin

Imipramine happened to be the first drug of the series which was prepared while looking for antihistamines that may be having sedative properties. Imipramine is adibenzazepine derivative. Dibenzazepine is having two benzene

COO I ~

l

I

N

"I:::

~

• crHCOOH

~HCOOH

/CH, CH CHCH-N, 2\ 2 'CH

eti 3

Imipramine Hydrochloride

3

Trimipramine Maleate

rings which are fused to the azepine system. The tricyclic system present in imipramine is having the central azepine ring which is partly satured (dihydro). The 3-dimethylaminopropyl side chain is attached to nitrogen (position 5 of the 10, II-dihy~rodibenzazepine). Imipramine has been official as the hydrochloride. Imipramine hydrochloride occurs as a white or slightly yellow crystalline powder having a burning taste. It has ~en freely soll!ble in water. It finds use in the treatment of patients suffering from endogenous depression. However, it is somewhat less effective in the treatment of neurotic or reactive depression. It is having less marked sedative properties than the antidepressant amitriptyline. For the treatment of depression, imipramine hydrochloride is generally given by mouth.

The structure of desipramine is similar to imipramine with the difference that 3-methylaminopropyl (CH 3NHCH 2CH 2CH 2) group is attached to position 5 instead of 3-dimethylaminopropyl. Desipramine hydrochloride is soluble in water. Its actions and uses have been similar to imipramine hydrochloride. It has been the main active metabolite of imipramine hydrochloride. It has been the

169

Psychoactive Drugs

main active metabolite of imipramine. Similar. to impramine. desipramine is having less marked sedative properties than amitriptyline. The structure of trimipramine is different from imipramine in possessing 3-dimethylamino-2-methylpropyl group attached to position 5. Trimipramine maleate occurs as white crystalline powder. It is having slight solubility in water. It maybe administered by mouth. Clomipramine is having structure like imipramine which is having a '3Its hydrochloride salt occurs as a white or slightly yellow crystalline powder. It is freely soluble in water. For the treatment of depression clomipramine hydrochloride is generally administered by mouth as capsules. c~lorosubstituent.

Amitriptyline is having tricyclic system but the central ring is not having nitrogen. It belongs to the class of dibenzocycloheptenes in which 3dimethylaminopropylidene side chain gets attached to the central ring. The structure of nortriptyline is similar to amitriptyline but the side chain which is attached to the central ring is 3-methylaminopropylidine (CH 1NHCH 2CH 2CH=). The amitriptyline hydrochloride is freely soluble in water while nortriptyline hydrochloride is sparingly soluble in water. Both these compounds are official and are given by mouth. Amitriptyline embonate is the salt having embonic acid. It occurs as a pale-yellow to brownish-yellow powder. It is insoluble in water and is somewhat tasteless. It may be given by mouth a flavoured aqueous suspension.

as

~ ~-HCl CHpif~NHCHJ

Amitriptyline Hydrochloride

Protriptyline Hydrochloride

Protriptyline has been adifferent modification of amitriptyline. Protriptyline hydrochloride is administered orally. Doxepin and dothiepin have been antidepressants which have been structurally related to amitriptyline but one of the methylene groups of the central ring has been replaced by oxygen and sulphur, respectively. Doxepin and

cx;o ~ I

SS

11

~

I~

-HCI

/CH CHCHCHN... :I 2 2 'CH :I

Doxepin Hydrochloride

Dothiepin Hydrochloride

Phannaceutical Chemistry (Organic)

170

dothiepin have been the derivatives of dihydrodibenzoxepin and dihydrodibenzothiepin, respectively. Both doxepin hydrochloride and dothiepin hydrochloride may be administered orally as capsules. Mianserin has been a tetracyclic antidepressant. A part of its structure has corresponding to heterocycle piperazine. Its hydrochloride salt occurs as white or almost white crystals or crystalline powder. Its salt is sparingly soluble ill water. In the treatment of depression this salt is given by mouth.

b~en

, Hel Mianserin Hydrochloride

Official Amitriptyline Embonate, B.P. Amitriptyline Embonate Mixture, B.P. Amitriptyline Hydrochloride, B.P., J.P. Amitriptyline Tablets, B.P., J.P. Clomipramine Hydrochloride, B.P. Clomipramine Hydrochloride Capsules, B.P. Desipramine Hydrochloride, B.P. Desipramine Tablets, B.P. Dothiepin Hydrochloride, B.P. Dothiepin Capsules, B.P. Doxepin Hydrochloride, B.P. Doxepin Capsules, B.P. Imipramine Hydrochloride, B.P., I.P. Imipramine Tablets, B.P., J.P. Mianserin Hydrochloride, B.P. Mianserin Hydrochloride Tablets, B.P. Nortriptyline Hydrochloride, B.P. Nortriptyline Capsules, B.P. Nortriptyline Tablets, B.P. Protriptyline Hydrochloride, B.P. Protriptyline Tablets, B.P.

171

Psychoactive Drugs

Trimipramine Maleate, B.P. Trimipramine Tablets B.P. Monoamine Oxidase Inhibitors Monoamine oxidase (MAO) is an enzyme which is mainly responsible for metabolising monoamines such as noradrenaline. The action of monoamine oxidase inhibitors is attributed to increasing the concentration of amines like noradrenaline in the brain. However. the mechanism of their action as antidepressants is not understood completely. Three of the official drugs have been described as follows: Phenelzine. It is a MAO inhibitor. ChemicaIJy, it is a derivative of hydrazine (H2NNH 2) and is named as phenethylhydrazine. Phenelzine sulphate (freely soluble in water) is usuaIJy administered as tablets for treating both reactive and endogenous depression. Isocarboxazid.lt is a hydrazine derivative and is named as N-benzyl-N'(5-methylisoxazol-3-yJcarbonyl) hydrazine. It occurs as a white or creamywhite crystalline powder having slight solubility in water. Its uses are similar to those of phenelzine sulphate. 1

o

H3C~-:~Z

54~ 4

'

CONHNHCHz--Q Isocarboxazid

Phenelzine Sulphate

Tranylcypromine. Chemically it is (±)-trans-phenyJcyclopropyl amine. It is a non-hydrazine monoamine oxidase inhibitor which is exerting some direct stimulating activity and a rapid onset of action. Tranylcypromine sulphate finds

Tranylcypromine Sulphate

use in the treatment of patients who are suffering from severe mental depression and who are not able to respond satisfactorily to other antidepressant drugs. Official Isocarboxazid, I.P. Isocarboxazid Tablets, I.P. Phenelzine Sulphate, B.P. Phenelzine-Tablets, B.P.

172

Pharmaceutical Chemistry (Organic)

Tranylcypromine Sulphate, B.P. Tranylcypromine Tablets, B.P. Lithium Salts Lithium salts have been found to be of great significance in the prophylaxis of manic depression and recurrent depression. and also in the prophylaxis and treatment of mania. The mechanism by which they exert their effect in effective disorders is not known with certainty. The lithium ions may act by competing with sodium ions at various sites in the body. Among the salts used include lithium carbonate and lithium citrate. Lithium carbonate, Li 2C0 3, exists as a white powder and is slightly soluble in water. Lithium citrate is a white or almost white, fine crystalline powder, and is freely soluble in water. The salts are given by mouth. CHz COOLi

I

HOCCOOLi J CHz (OOli Lithium Citrate

Official Lithium Carbonate, B.P., I.P. Lithium Carbonate Tablets, B.P., I.P. Lithium Citrate, B.P. Miscellaneous Agents There are other drugs which were formerly used in the treatment of depression and these include some of the directly acting stimulants like amphetamines (described under Adrenergic Drugs). However, these are exerting a short duration of action and their use has been generally restricted to mild depression. 12.4 Antianxiety Drugs There are chemically simple drugs meprobamate and benzodiazepine derivatives such as chlordiazepoxide, diazepam and oxazepam which find use in the treatment of psychoneuroses for reducing pathological anxiety, agitation and tension. They cannot be called accurately as antianxiety drugs. However, some use the term minor tranquillisers for them. These have been prescribed more frequently than any other group of therapeutic agents. Meprobamate is 2, 2-di(carbamoyloxymethyl) pentane which occurs as a white crystalline powder. It is slightly soluble in water. Meprobamate acts as a mild tranquillising drug having some anticonvulsant and muscle relaxant properties. It finds use in the treatment of anxiety and tension but it is found to be less effective than the benzodiazepines.

Psychoactive Drugs

173

o

II NH CO CH 2 2

I

CH,CH2~H2CI CH 3

/I

NH C OCH 2

2

Meprobamate Diazepine is a seven-membered heterocycle which is having two nitrogens and three double bonds. 1,4-Benzodiazepine is having benzene ring which is fused to 1, 4-diazepine. In this the numbers 1 and 4 refer to the positions of nitrogens. Chlordiazepoxide is a derivative of 1, 4-benzodiazepine which is almost insoluble in water. Chlordiazepoxide hydrochloride occurs as a white or slightly yellowish crystalline powder having a very bitter taste. It is soluble in water and is less potent than the related drug diazepam and is having less anticonvulsant, muscle relaxant and sedative properties. They find use in the treatment of anxiety and tension states, for premedication, and for relieving the acute symptoms of alcohol withdrawal. Chlordiazepoxide and its hydrochloride are usually administered by mouth. Diazepam occurs as a white crystalline powder having bitter after taste. It is very slightly soluble in water. It is administered orally but may also be given by deep intramuscular or slow intravenous injection. CHI

~I \)0

N::::lHCH3

Cl

I '~~'"CL

..... I

~

Chlordiazepoxide Hydrochloride

CL

'"

",-_

~

I

Diazepam

Oxazepam and lorazepam have been also structurally related compounds. These occur as white or almost white, crystalline powders. They are almost insoluble in water. Their action and uses have been similar to these of diazepam. They are usually given by oral administration. Discussion about diazepam, oxazepam and lorazepam is also gi ven under the chapter Hypnotics and Sedatives. I

Although chlordiazepoxide and diazepam have been chemically different from meprobamate, yet their pharmacological actions are close. Medazepam (a yellowish crystalline powder; practically insoluble in water) is not having carbonyl function at position 2. Otherwise it has structure, action and uses similar to diazepam. Chemically it is 7-chloro-2,3-dihydro-lmethyl-5-phenyl-1 H-l , 4-benzodiazepine. Flurazepam has general properties similar to those of diazepam. Flurazepam monohydrochloride (a white or almost white crystalline powder; very soluble in water) finds use as a hypnotic in the

Pharmaceutical Chemistry (Organic)

17'4

Oxazepam (X Lorazepam (X

= H) = CI)

short-term management of insomnia. The salt is kept in a well-closed container and stored at a temperature of go to 15°. A mention is also made regarding diazepam, oxazepam and lorazepam under the chapter Hypnotics and Sedatives. Chlordiazepoxide and diazepam have been chemically so different from meprobamate but the pharmacological actions have been close. Official Chlordiazepoxide, B.P., I.P. Chlordiazepoxide Tablets, B.P., I.P. Chlordiazepoxide Hydrochloride, B.P. Chlordiazepoxide Capsules, B.P. Chlordiazepoxide Hydrochloride Tablets, B.P. Diazepam, B.P., I.P. Diazepam Capsules, B.P., I.P. Diazepam Injection, B.P. Diazepam Oral Solution, B.P. Diazepam Tablets, B.P., I.P. F1urazepam Monohydrochloride, B.P. F1urazepam Capsules, B.P. Lorazepam, B.P. Lorazepam Injection, B.P. Lorazepam Tablets, B.P. Medazepam, B.P. Medazepam Capsules, B.P. Meprobamate, B.P., I.P. Meprobamate Tablets, J.P. Oxazepam, B.P. Oxazepam Capsules, B.P. Oxazepam Tablets, B.P.

13 Central Nervous System Stimulants

13.1

In~uction

Drugs which have in common the property of increasing the activity of various portions of the central nervous system are called nervous system stimulants. Many forms of illness, both mental and physical, involve a depression of mood or of mental activity. In such circumstances, a drug which stimulates central nervous activity maybe helpful. Most of the early nervous system stimulants are respiratory stimulants and analeptics (restoratives). Respiratory stimulation may be brought about not only by the action of drugs directly upon the respiratory centre of the medulla but by pH changes in the blood which supplies the centre. On the other hand, analeptics often stimulate a variety of other centres as well. The vasomotor centre, which maintains the constriction of the blood vessel walls, is frequently affected. There are some analeptic agents which increase vasoconstrictions. These result in increased peripheral resistance to the flow of blood, thereby causing an elevation of blood pressure. Central nervous system stimulants maybe divided into two groups: central stimulants proper and antidepressant drugs. However, whether there is a true division between them is a contentious point which cannot be so far resolved because of the present limited understanding of the workings of the brain. The drugs which are able to increase the acti vity of some parts of brain or spinal cord are known as central nervous system stimulants. They are also known as analeptics. They find use in the treatment ofintoxication because ofoverdosage of central nervous system depressant drugs. The drugs acting on the sensory areas of the brain tend to increase mental alertness and give rise to a condition of wakefulness. The drugs which are acting

Pharmaceutical Chemistry (Organic)

176

directly and stimulating the respiratory centre in the medulla find use as respiratory stimulants. They find use to increase the rate and depth of respiration in the conditions such as carbon dioxide accumulation brought about by chronic respiratory disease; drug induced post-anaesthetic respiratory depression. The xanthine derivatives are the naturally occurring drugs which find use as central nervous system stimulants. Among the synthetic drugs have been leptazol, nikethamide and ethamivan. There are some sympathomimetic drugs which also find use for their central stimulant effect.

Purines or Xanthine Derivatives Purines occur widely distributed among natural products (e.g. in uric acid, coffee, tea, cocoa, nucleic acids and enzymes). The 2, 6-dihydroxylated purines or xanthine derivatives are caffeine, theobromine and theophylline. These have stimulating action on the central nervous system. This stimulating action is almost physiologic in nature and helps to combat fatigue and sleepiness. However, there is a tendency to build up little tolerance. Among purines, caffeine is the most important. A cup of tea or coffee contains about 60 mg of caffeine. Caffeine is employed in headaches of certain kinds, such as in neuralgia, rheumatism, migraine and in those due to fatigue, frequently combined with other analgesics such as phenacetin and aspirin. However, large doses cause insomnia, restlessness, excitement, tinnitus, and diuresis.

0

X:0 '('

~_oommo_u_rc_en_-l

t-c_o_m_p_O_und ___R_ _ _R_'___R_"___ Caffeine Theophylline Theobromine

CH 3 CH 3 H

CH 3 CH 3 CH 3

CH 3 H CH 2

'"

Tea, Coffee Tea Cocoa

R=R' =R"=H Xanthine

Caffeine, theophylline and theobromine have been the methyl derivatives of xanthine. They are found in tea, coffee and other plants. Chemically, caffeine is 1,3, 7-trimethylaxanthine; theophylline 1, 3-dimethyl-xanthine and theobromine 3, 7-dimethylxanthine. These compounds are exerting stimulant effect on central nervous system; both caffeine and theophylline have been especially

Xanthine

Caffeine

Central Nervous System Stimulants

177

important in this respect. The methylxanthines are able to stimulate cardiac muscle, and relax smooth muscles, especially the bronchial muscle. Theophylline has been found to be most effective and therefore, finds use in the treatment of bronchial asthma. Methylxanthines are also able to stimulate the medullary respiratory centre. They are also acting on kidneys for producing diuresis and theophylline is having maximum activity in this respect (also described under Diuretics). As a central nervous system stimulant, caffeine, is generally regarded to be the most potent ofthe methylxanthines; though theophylline is having more profound stimulant than caffeine. Theobromide is almost inactive in this respect. Caffeine occurs as a white crystalline powder having a bitter taste. It sublimes on heating. It has been found to be sparingly soluble in water, but very soluble in boiling water. On crystallisation from alcohol, chloroform or ether anhydrous base is obtained while on crystallisation from water a monohydrate base is obtained. With sodium benzoate caffeine forms a water-soluble complex which finds use in the form of injection. Caffeine is especially used for its effects on central nervous system for producing a state of wakefulness and for enhancing mental activity. It also brings about the stimulation of respiratory centre. We shall discuss here theophylline and related products which find use in the treatment of bronchial asthma and diseases of cardiovascular system. Theophylline and theophylline hydrate (having one molecule of water) are having slight solubility in water. The aqueous solubility can be appreciably increased by making complex of theophylline with ethylenediamine (H2NCH2CH2NH2); the complex is called aminophylline. Choline theophylline is the salt with choline, (CH 3)3 WCH2CHPH. It is very soluble in water. Aminophylline finds use in the treatment of bronchial asthma and diseases of cardiovascular system. It has been found to be less effective by mouth than by intravenous injection, and often brings about gastric irritation. Choline theophyllinate is administered orally. Many 7 -substituted derivati ves of theophylline have been prepared which find use for the same purposes as aminophylline. Some examples of these derivatives have been diprophylline, 7-(2,3-dihydroxypropyl)-I, 3dimethylxanthine; hydroxyethyltheophylline (etofyline), 7-(2-hydroxyethyl)1, 3-dimethylxanihine; proxyphylline, 7-(-2-hydroxypropyl)-1 ,3-dimethyl-xanthine; and etamiphylline camsylate, 7-(2-diethylaminoethyl)-1, 3dimethylxanthine comphor-IO-sulphonate. Official Aminophylline, B.P., I.P. Aminophylline Injection, B.P.; I.P. Aminophylline Suppositories, B.P. Aminophylline Tablets, B.P., I.P.

178

Pharmaceutical Chemistry (Organic)

Caffeine, B.P., I.P. Aspirin and Caffeine Tablets, B.P. Caffeine Hydrate, B.P. Choline Theophyllinate, B.P. Choline Theophyllinate Tablets, B.P. Diprophylline, B.P. Etamiphylline Camsylate, B.P. Etamiphylline Camsylate Injection, B.P. Etamiphylline Camsylate Suppositories, B.P. Etamiphylline Camsylate, Tablets, B.P. Etofylline, B.P. Hydroxyethlytheophylline, I.P. (Etofylline, B.P.) Proxyphylline, B.P. Theobromine, B.P. Theophylline, B.P., I.P. Theophylline Hydrate B.P.

Some Synthetic Compounds The synthetic drugs such as leptazol (pentetrazol), nikethamide and ethamivan have been described here. Tetrazole is a five-membered heterocycle having four nitrogen atoms in the ring. Leptazol refers to a tetrazole derivative in which positions 1 and 5 have been bridged by a pentamethylene chain. Chemically, it is named as 1, 5pentamethylenetetrazole. Leptazol occurs as a crystalline solid having a bitter taste. It is very soluble in water. Its solutions could be sterilised either by autoclaving or by filtration. It is especially useful parenterally for its stimulant effect for the treatment of respiratory depression. It is also used for screening anticonvulsants in laboratory. N

a ••

A!....AI

1/

"-AI

Leptazol

([A

/CzHs

CON ........

CzHs Nikethamide

Chemically nikethamide is N, N-diethylpyridine-3-carboxamide. It occurs as a colourless or slightly pale oily liquid having a characteristic odour and Abitter taste. It is miscible with water. Its solutions maybe sterilised either by atuoclaving or by filtration. Nikethamide is administered either orally or by injection as a 25% solution as a respiratory stimulant. It also finds use in circulatory failures. However, it is replaced by more effective treatments. The ?rug should be kept in tightly closed light-resistant containers.

Central Nervous System Stimulants

179

Chemically ethamivan is N, N-diethylvanillamide. It is having a common amide feature with nikethamide. It

occurs as a white crystalline powder. It is sparingly soluble in water. Ethamivan is administered either intravenously or orally as a respiratory stimulant. Doxapram is l-ethyl-4-(2-morpholinoethyl)-3, 3diphenyl-2-pyrrolidone. It finds use as the hydrochloride which is a monohydrate salt. Doxapram hydrochloride Ethamivan occurs as a white or almost white, crystalline powder; soluble in water. Doxapram has been reported to be a central and respiratory C,HI I

("'f0 ~

o

"- CHaCHa

'-J

~Ph Ph

Doxapram

stimulant of brief duration of action. It is given intravenously in respiration depression following anaesthesia.

Official Doxapram Hydrochloride, B.P. Doxapram Injection, B.P. Ethamivan, B.P. Ethamivan Oral Solution, B.P. Leptazol, J.P. Leptazol Injection, J.P. Nikethamide, B.P., I.P. Nikethamide Injection, B.P., I.P. Many drugs having sympathomimetic and anorectic actions (described under the chapter on Adrenergic Drugs) also exert stimulant effect on the central nervous system. The adrenergic drugs used for this purpose include amphetamine sulphate, dexamphetamine sulphate, methylamphetamine hydrochloride and fenfluramine hydrochloride.

i

The respiratory depression caused by the overdosage of morphine and similarly. acting narcotics can be treated with narcotic antagonists such as levallorphan and nalorphine (described under the chapter on Analgesics). Dichlorphenamide (described under Diuretics) finds use in treating respiratory insufficiency which is associated with chronic bronchitis and emphysema.

14 Antiparkinsonism Drugs

14.1. Introduction Parkinson's disease is named after James Parkinson, who first described it in 1917. Various types of Parkinson's disease are known as idiopathic paralysis agitans, postencephalitic and arteriosclerotic parkinsonism. It is characterised by tremor, rigidity, akinesia or bradykinesia, and postural instability. Treatment of this disease involves not only drug therapy but also physiotherapy, exercises, activities, and psychological support. Drugs seen in this section only alleviate the symptoms, allowing a number of patients to live normal lives. Assays used to disclose useful antiparkinosnism drugs are numerous. Some are based on blockade of tremors of central origin induced in animals by chemical agents, such as tremorine and oxotremorine. Others are based on the ability of potential agents to antagonize the activating effects of physostigmine and similar drugs on the electroencephalogram of laboratory animals. A third group of assays involves the induction of tremors in primates by localised lesions in the midbrain and blocking them by potential anti parkinsonism drugs. Drugs used in Parkinson's disease are not highly toxic. Usually they may be administered for long periods of time. Nevertheless, they cause some minor untoward effects, such as dryness of the mouth, constipation, blurred vision, and gastrointestinal disturbances. Doses should be adjusted individually. Since Parkinson's disease requires continuous medication, from time to time it is necessary to change drugs and adjusted gradually the dosage of the new drug; The drugs used for the treatment of this disease are known as antiparkinsonism drugs. These drugs are divided into two categories on the basis

181

Anliparkinsonism Drugs

of their mode of action, dopaminergic agents, for example levodopa; and anticholinergic antiparkinsonian agents. 14.2. Levodopa and some other Dopaminergic Agents 1. Dopamine. Dopamine (3, 4-dihydroxyphenylethylarnine) has been a key neurotransmitter in the central nervous system. Its depletion has been considered to get associated with the clinical condition of parkinsonism. Accordingly, agents which are able to replenish central dopamine or which themselves act as stimulants of dopamine receptors may be able to alleviate the symptoms of parkinsonism. 2. Levodopa: Levodopa is the levorotatory isomer of 3-(3,4dihydroxyphenly)-L-alanine.1t is converted into dopamine by decarboxylation after penetrating the blood-brain barrier. Thus it acts by replacing depleted brain dopamine in patients of parkinsonism. It is a white crystalline powder. It darkens on exposure to light and air. It is slightl y soluble in water. It is administered orally

Levodopa

for the treatment of parkinsonism. It also finds use to control neurologic symptoms of chronic manganese poisoning which resemble those of parkinsonism. It has to be stored in well-closed, light resistant containers in a dry place. 3.Carhidopa:Chemically,carbidopais(-)-L-2-(3,4-dihydroxybenzyl)2-hydrazinopropionic acid. It does not have antiparkinosnian action of its own but increases the action oflevodopa by inhibiting its peripheral decarboxylation. Unlike levodopa it fails to cross blood-brain barrier. It also helps in reducing side effects like nausea, vomiting and cardiac arrhythmias. Itis generally given in the

Carbidopa

ratio of I part of carbidopa to 10 parts of levodopa. Carbiodopa is a white to creamy-white powder. It is slightly soluble in water. It should be protected from light. 4. Other Dopaminergic Agents. There are many agents which have been structurally related to dopamine and hence act as dopaminergic agonists, i.e., as stimulants of dopamine receptors. Apomorphine has been one of them. It is mainly used to control symptoms of parkinsonism. Its chief effect is emesis. It

Pharmaceutical Chemistry (Organic)

182

is given subcutaneously for inducing emesis in acute non-corrosive poisoning. If it is administered by mouth, its emetic action is not dependable. Apomorphine hydrochloride is usually used. It occurs as white or greyish-white crystals or microcrystalline powder. When it is exposed to air and light, it rapidl) takes up a greenish tint. It is kept in well-closed containers which are protected from light. It is sparingly soluble in water. Its aqueous solutions decompose on storage. CH3

\

~'HC' HO

OH

Apomorphine Hydrochloride

Under dopaminergic agents we may also describe amantadine which may be able to provoke release of dopamine from nerve endings. Amantadine is an amino derivative of the hydrocarbon adamantane. The systematic name given in the I.P. for amantadine hydrochloride has been tricyclo [3.3.1 3.7] dec-lylammonium chloride. The salt occurs as a white or nearly white, crystalline powder. It is having a bitter taste. It is freely soluble in water. It finds use in the

+

Adamantane

iJ

CI

Amantadine Hydrochloride

treatment of parkinsonism, generally in combination with other therapy. Amantadine hydrochloride also finds use as an antiviral drug (see under Antiviral Agents). It gets readily absorbed from the gastrointestinal tract.

Official Amantadine Hydrochloride, I.P. Amantadine Hydrochloride Capsules, I.P. Amantadine Hydrochloride Syrup, I.P. Apomorphine Hydrochloride, B.P. Carbidopa, B.P. Co-careldopa Tablets, B.P. Levodopa, B.P., I.P. Co-careldopa Tablets, B.P.

183

Antiparkinsonism Drugs Levodopa Capsules, B.P., I.P. Levodopa Tablets, B.P., I.P.

An Ergoline Ergot alkaloids and derivatives with the same basic tetracyclic structure may all be tenned as ergolines, but in practice the tenn is restricted to compounds CHI

CHI CH HO CONH..yu,.

'''''tP o .

N

o.J-N~ . 0 I

CH a CHtCH"2

Bromocriptine

used for the dopaminergic activity. Bromocriptine is a derivative ofa-ergocryptine which is one of the ergolines with dopaminergic activity. It is a dopamine agonist acting at receptors in the central nervous system. It is administered by mouth as bromocriptine mesylate which occurs as a white or greyish-white to pale yellow, crystalline powder; practically insoluble in water. The salt is kept in an air-right container which is protected from light and stored at a temperature not exceeding

-18°. Official Bromocriptine Mesylate, B.P. Bromocriptine Capsules, B.P. Bromocriptine Tablets, B.P.

11.3. Anticholinergic Antiparkinsonian Agents Many drugs which exert anticholinergic effects find use in the treatment of Parkinson's disease and related disorders. The belladona alkaloids such as atropine and hyoscine (described under Antispasmodic and Antiulcer Drugs) had been the first compounds of value in the symptomatic treatment of the disease. Many synthetic anticholinergics find use in clinical practice. These drugs belong to chemical classes of aminoalcohols and ethers. Ethopropazine, an antiparkinsonian drug, has been a phenothiazine derivative.

Aminoalcohols Examples of aminoalcohols are benzhexol biperiden and procyclidine. These are having a piperidine or pyrrolidine ring which is separated from hydroxyl carrying carbon by two methylenes. The carbon which is carrying hydroxyl group has been substituted by bulky cyclic moieties.

Pharmaceutical Chemistry (Organic)

/84 •

Chemically benzhexol hydrochloride is l-cyc1ohexyl-l-phenyl-3piperidinopropan-I-ol hydrochloride. It is a crystalline solid having bitter numbing taste. It is sparingly soluble in water. It is administered orally for the treatment of parkinsonism and related disorders.

,_/

/-"

/-"

-, /

C(OH)CH2CHaN" /

-

/-" ,,_/ Benzhexol

It can be given along with other antiparkinsonism drugs.

Chemically, biperiden, is 1-(bicyclo[2.2.1] hept-5-en-lyl)-I-phenyl-3piperidinopropan-I-ol. It is almost insoluble in water.

Biperiden

It finds use as biperiden lactate injection.

Procyclidine hydrochloride has been found to be structurally similar to benzhexol differing only in possessing a pyrrolidine ring instead of piperidine.

Q O(OH) CH.CH.{J oHCI Procyclidine Hydrochloride

Chemically it is l-cyclohexyl-I-phenyl-3-pyrrolidinopropan-I-ol hydrochloride. It occurs as a white powder having slight odour and a bitter taste. It is a sparingly soluble in water. Its solutions may be sterilised either by autoclaving or by filtration. Official Benzhexol Hydrochloride, B.P. Benzhexol Tablets. B.P.

185

Antiparkinsonism Drugs

Biperiden, B.P. Biperiden Lactate Injection, B.P. Procyclidine Hydrochloride, B.P. Procyclidine Tablets, B.P.

Ethers Chemically orphenadrine is N, N-dimethyl-2-(o-tolylbenzyloxy) ethylamine. It has been a weak anticholinergic and antihistaminic.lts citrate and

f\

~_

/,CH,

Cj.-{CHOCH 2 CH 2N,

U

(.H 3

Orphenadrine

hydrochloride salts are mainly used. Its citrate salt is sparingly soluble in water, whereas the hydrochloride salt is very soluble. The citrate also finds use to relieve pain because of spasm of voluntary muscles. Chemically benztropine mesylate is 3-(diphenylmethoxy) tropane methylsulphonate. It occurs as a white, slightly hygroscopic powder having

Benztropine Mesylate

bitter taste. It is freely soluble in water. Its solutions could be sterilised either by autoclaving or by filtration. It is administered either oral1y or by injection for the symptomatic treatment of parkinsonism. Official

Benztropine Mesylate, B.P. Benztropine Injection, B.P. Benztropine Tablets, B.P. Orphenadrine Citrate, B.P. Slow Orphenadrine Citrate Tablets, B.P. Orphenadrine Hydrochloride, B.P. Orphenadrine Hydrochloride Tablets, B.P.

Pharmaceutical Chemistry (Organic)

186

A Phenothiazine Derivative Ethopropazine is a phenothiazine derivative. It is having anticholinergic, adrenergic-blocking, slightantihistaminic, local anaesthetic and ganglion blocking properties. Chemically, it has been 1O-(2-diethylaminopropyl) phenothiazine. Its hydrochloride, occurs as a white or creamy white powder having bitter taste. This salt is mainly used. The salt has slight solubility in water. It is stored in well-closed, light resistant containers. It finds use in the symptomatic treatment of parkinsonism.

Ethopropazine Hydrochloride

Official

Ethopropazine Hydrochloride, I.P. Ethopropazine Tablets, I.P.

15 Adrenergic Drugs IS.1 Introduction Adrenaline is a hormone which gets secreted by adrenal medulla and is known to exert numerous pharmacological actions like cardiac stimulation, rise in blood pressure, constriction of smaller arterioles and precapillary sphincters, relaxation of bronchial muscles and central nervous system stimulation. These actions are able to stimulate the effects which get produced by the stimulation of postganglionic sympatqetic (adrenergic) nerves. Although the term adrenergic is used, yet it is noradrenaline which is the endogenous neurotransmitter at the postganglionic sympathetic nerves and within the central nervous system. The drugs exerting similar actions are termed as adrenergic or sympathomimetic agents. Clinically these agents find use for treating asthma and similar conditions for their bronchodilatory effects; heart block and similar conditions; nasal congestion; and hypotension. These are also used in the prevention of premature labour. Many sympathomimetic agents find use for their central stimulant effect and for their anoretic action. The effect of the sympathomimetic agents is largely due to their direct action on adrenergic receptors (adrenoceptors) which can be categorised into two types, alpha adrenergic receptors and beta adrenergic receptors. The physiologic effects exerted due to the stimulation of alpha or beta receptors have been different. Stimulation of the alpha receptors is largely due to the predominant effect of noradrenaline. This causes vasoconstriction of arterioles of skin and splanchnic area, giving rise to an increase in blood pressure, dilatation of the pupil, and relaxation of the gut.

Pharmaceutical Chemistry (Organic)

188

Stimulation of the beta receptors is largely due to the predominant effect of isoprenaline. This causes an increased cardiac output, excitability, and rate, dilatation of arterioles supplying skeletal muscles, and relaxation of the uterus, intestine, and bronchial muscle. Adrenaline is having both alpha and beta adrenoceptors stimulating property. Some sympathomimetic agents such as amphetamines, are known to act indirectly by releasing noradrenaline from storage in adrenergic nerve endings. It is possible to discuss the adrenergic drugs under the chemical groups such as catecholamines, non-catecholamilles, and imidazoline derivatives. Catecholamines Chemically catechol is I, 2-dihydroxybenzene. Catechalomines are the smypathomimetic agents having similar hydroxy substitution in the benzene ring and amine functions as part of the side chain. Adrenaline (epinephrine).Chemically, it is 1-(3,4-dihydroxyphenyl)-2methylaminoethanol. It is isolated from the adrenal glands of mammals or prepared synthetically. Adrenaline is a levorotatory base. It is a white crystalline powder having a slightly bitter numbing taste. It is sp&.ringly soluble in water. It is oxidised readily. It darkens slowly when exposed to air. It is, thus, stored in airtight containers which are protected from light; the container should preferably be filled with nitrogen. The acid tartrate salt is also used which is water soluble. Its solutions are sterilised either by autoclaving or by filtration and should be having 0.1 % of sodium metabisulphite as an antioxidant. Adrenaline is administered subcutaneously for relieving bronchial spasm in acute attacks of asthma. HO

n

CH(OH)COOH • HO~-CHCH2NHCH3 ., I CH(OH)COOH OH Adrenaline Acid Tartrate

Noradrenaline

It also finds use in the treatment of heart block with syncope. Its aqueous solution can be applied to the nasal mucous membrane in the fonn of spray in acute coryza, allergic rhinitis, hay fever and sinusitis. Adrenaline is generally added to local anaesthetic for prolonging the duration of effect. Noradrenaline

It is the primary amine which corresponds to adrenaline which does not have methyl attached to nitrogen. It finds use as the water-soluble acid tartrate salt of the levorotatory ispmer of the base. The solutions are sterilised by autoclaving or by filtration land should possess 0.1 % of sodium metabisulphite.

189

Adrenergic Drugs

Noradrenaline finds use in the treatment of peripheral vasomotor collapse, in hypotensive states, and in acute cardiac infarction. It is generally administered as intravenous infusion. It is also applied locally for the control of capillary bleeding. Noradrenaline is also official as the hydrochloride which occurs as a white or brownish white crystalline powder, very soluble in water. It becomes coloured on exposure to air and light. Therefore, it is required to be kept in an air-tight container or preferably in a sealed tube under vacuum or under an inert gas and protected from light. When applied locally, it is used for the control of capillary bleeding. Isoprenaline. Chemicaliy, it is (±)-I-(3,4-dihydroxyphenyl)-2 isopropylamino-ethanol.lt is a synthetic analogue of adrenaline possessing an isopropyl group in place of methyl. Its hydrochloride and sulphate salts are freely soluble in water. The solutions of the hydrochloride salt can be sterilised by filtration and the solution of the sulphate can be sterilised by auloc!aving or filtration. The solutions should have sodium metabisulphite. Isoprenaline has been found to be a more powerful bronchodilator than adrenaline and finds use in the symptomatic relief of bronchial asthma and pulmonary emphysema. It also finds use in the treatment of bradycardia. It is used as a stimulant following heart attack. It is more effective when given orally. The drug is kept in well-closed, light-resistant containers.

-0-"

HO HO

-

CH CH NH CH

I

2

OH

/CH3

.HCl

"-

CH 3

Isoprenaline Hydrochloride

Dopamine. Chemically it is 3,4-dihydroxyphenylethylamine, it is a biogenetic precursor of noradrenaline and is a neurotransmitter in its own right. Concentrations of dopamine get reduced in the brains of patients with Parkinson's

Dopamine

disease; increased brain-doparnine concentrations are accordingly beneficial in this condition. In practice, as dopamine has been found to be not active by mouth and does not readily cross blood-brain, barrier, its precursor, levodopa (see Antiparkinsonism Drugs) has been given for treatment. Dopamine finds use as the hydrochloride in the treatment of shock unresponsi ve to replacement of fluid loss and especially where renal function is impaired. It also finds use in the

Pharmaceutical Chemistry (Organic)

190

management of congestive heart failure. Dopamine hydrochloride occurs as a white or almost white crystalline powder; freely soluble in water. It should be kept in well-closed container and protected from light.

Official Adrenaline, B.P., I.P. (Adrenaline Eye Drops, B.P. ) Adrenaline Bitartrate, I.P. (Adrenaline Acid Tartrate, B.P.) Adrenaline Tartrate Injection, I.P. (Adrenaline Injection, B.P.) Adrenaline Solution, B.P. Bupivacaine and Adrenaline Injection, B.P. Lignocaine and Adrenaline Injection, B.P. Dopamine Hydrochloride, B.P. Dopamine Intravenous Infusion, B.P. Isoprenaline Hydrochloride, B.P., I.P. Isoprenaline Hydrochloride Injection, I.P. (Isoprenaline Injection, B.P.) Isoprenaline Sulphate, B.P., I.P. Noradrenaline Acid Tartrate, B.P., I.P. Noradrenaline Injection, B.P.

Non-catecholamine The sympathomimetic drugs of the non-catecholamine group are not having 1,2-dihydroxy groups in the phenyl ring but are having differently substituted or unsubstituted phenyl ring. Orciprenaline and terbutaline have been related drugs. Orciprenaline sulphate. Chemically, it is (±)-1(3,5~dihydroxyphenyl)2-isopropylaminoethanol sulphate and is soluble in water. Its solutions could be sterilised either by autoclaving or by filtration. It finds use orally or parenterally to treat bronchial asthma. It also finds use in the treatment of premature labour. Terbutaline. Chemically terbutaline is 2-tert-butylamino-I-(3,5dihydroxyphenyl)-ethanol. It is different from orciprenaline in possessing a tertiary butyl group attached to nitrogen in place of isopropyl group. Its sulphate salt is official. It occurs as white to greyish-white powder having a bitter taste. It is freely soluble in water. HO

0-

/CH3

~ ~ CHCH NHCH _ I 2 "-

HO

OH"

Orciprenaline

CH

3

191

Adrenergic Drugs

Its uses are similar to those of orci:prenaline. It should be kept in a wellclosed container protected from light. Fenoterol: In fenoterol the nitrogen has been substituted by a 4-hydroxya-methylphenethyl group, and the rest of the structure has been the same as in orciprenaline. Fenoterol, thus, is a racemic mixture of 1-(3,5-dihydroxyphenyl)2-(4-hydroxy-a-methyl-phenethylamino) ethanol. It is used as the hydrobromide

~HJ--.J='L

HO

h

~

HO

~HCH1NHCHCH1~OH

OH Fenoterol

which occurs as white crystalline powder; soluble in water. It is to be kept in a well-closed container and protected from light. It finds use in the treatment of bronchial asthma by inhalation or as a nebulised solution. It also finds use in the management of premature labour.

Salbutamol (a1buterol). Chemically salbutamol (albuterol) is 1-(4-hydroxy-3-hydroxymetyl-phenyl)-2-t-butylaminoethanol. It is having a hydroxymethyl at meta position and a hydroxy at para position of the phenyl ring. It is sparingly soluble in water. Its sulphate salt is also official. This salt is freely soluble in water. It finds use as a bronchodilator and is having more prolonged and selective action than isoprenaline. Salbutmol is administered as an aerosol (inhalation) for the chronic management and prophy latic therapy of bronchial asthma. Infusions having salbutamol (5 mg in 500 ml) are also administered for arresting premature labour. HOCbHO

CH

'I ~ CHC~NHC/ C~3 -

I OH

"

CM3

Salbutamol

Methoxamine hydrochloride. Chemically, the methoxamine hydrochlorid~ is 2-amino-l-(2,5-dimethoxyphenyl)-propan-l-ol hydrochloride. It is a whi~ crys~l1ine powder; and is soluble in water. Its solutions are usually stenhsed eIther by autoclaving or by filtration. It is a~ministe~ed intram~scularl~ for maintaining or restoring the blood pressure dunng surgIcal operations and In hypotensive states like postoperative shock or after ganglionic blockagep=OCH 3

'I,~ ,eH 0 J

CH CH NH

I I

:I

OH eH

'Hel

J

Methoxamine Hydrochloride

192

Pharmaceutical Chemistry (Organic)

Phenylephrine and metaraminol The compounds having only one hydroxyl group at meta position of the phenyl ring include phenylephrine hydrochloride, which is (-)-1-(3hydroxyphenyl) 2-methylaminoethanol hydrochloride, and metaraminol tartrate which is chemically (-)-2, amino. 1-(3-hydroxyphenyl) propan-l-ol hydrogen tartrate. Both the salts occur as white crystalline powders. Both these are freely soluble in water. Its solutions could be sterilised by filtration. Phenylephrine finds use in the treatment of various hypotensive states. It is given intravenously for arresting paroxysmal auricular tachycardia. It also finds use as nasal decongestant and for allergic conditions. In ophthalmology it finds use to ilate the pupil. Metaraminol is administered to the patients subcutaneously or intramuscularly for its pressor action in hypotensive states. HO

h

~II

CH CH NH2

OH CH

Phenylephrine

3

Metaraminol

Oxedrine. Oxedrine has been isometric with phenylephrine in which the phenolic hydroxyl is atpara position rather than meta. Its tartrate is official. The base is a racemic mixture. Oxerdrine is recommended in hypotensive states and finds use as an ocular decongestant. Ephedrine. It is an alkaloid which is isolated from Ephedra species. It is having a close resemblance in structure with adrenaline. It does not have phenolic hydroxyl groups. Chemically ephedrine has been (-)-2-methylaminoI-phenylpropan-l-01 and has been one of the four possible optical isomers. It occurs as a white crystalline hemihydrate base which is water-soluble. Anhydrous ephedrine also finds use as official. Its hydrochloride salt is freely soluble in water. Its solutions are sterlised either by autoclaving or by filtration. Ephedrine is given orally or subcutaneously for the prevention of bronchial spasms in asthma. It is also used orally to treat narcolepsy and catalepsy. It is administered by subcutaneous or intramuscular injection for maintaining the blood pressure during spinal anaesthesia which may fall during this. Its solutions can be applied locally for the treatment of nasal congestion. OH

~l

NHCH3

:

~!-f-CH3 H

H

Ephedrine

Ephedrine is also official as racephedrine hydrochloride (racemic ephedrine hydrochloride). It is a white crystalline powder; freely soluble in water.

193

Adrenergic Drugs

Pseudoephedrine. It is 'an optical isomer of ephedrine. Its hydrochloride is generally used. It is freely soluble in water. It is having less pressor action and central nervous system effects than ephedrine. It especially finds use as a nasal and bronchial decongestant.

OH

~I

NH,

I

~CH-CHCH,

Phenylpropanolamine

Pseudoephedrine

Phenylpropanolamine. Phenylpropanolamine hydrochloride is a: synthetic compound. Its structure is different from ephedrine in lack of methyl group attached to nitrogen. Chemically this is (±)-2-amino-I-phenylpropan-l01 hydrochloride. It is a white to creamy-white crystalline powder having a bitter taste. It is freely soluble in water. Its solutions can be sterilised either by atuocIaving or by filtration. Its actions have been similar to those of ephedrine, but has been found to be more active as vasoconstrictor and less active as a central nervous system stimulant. Many sympathomimetic drugs are known which lack hydroxy group at the carbon attached to the phenyl ring. They find use especially for their central nervous system stimulant action and also for their anorectic action.

Amphetamine. Chemically, it is (±)-a-methyJphenethylamine. It finds use as the sulphate which occurs as a white powder and has a slightly bitter numbing taste. It is freely soluble in water. Its solutions can be sterilised by autoclaving or filtration. Amphetamine finds use in the treatment of narcolepsy

_~ o-

CHCHNH

21

2

CH 3

Amphetamine

Methylamphetamine

and in depressive states. The dextrorotatory isomer of amphetamine has been official as dexamphet•.mine sulphate. It has been nearly twice as potent as amphetamine. I

Methylamphetamine. Methylamphetamine has been a secondary amine which corresponds to amphetamine having a methy J group attached to nitrogen. It finds use as the hydrochloride. It has been the salt of the dextrorotatory isomer of the base.

Pharmaceutical Chemistry (Organic)

194

Methylamphetamine is administered by intramuscular injection to combat falling blood pressure during spinal anaesthesia and ganglionic blockage. It also finds use in psychiatry for elevating mood and in the treatment of narcolepsy.

o 11

0- I ~!J

........ CzH,

CCHN ........ CzH,

CH 3

Fenfluramine

Diethylpropion

Fentluramine hydrochloride. It is a sympathomimetic agent which mainly finds use as anorectic agent. Chemically it is the hydrochloride of 2ethylamino-l-(3-trifluoromethylphenyl) propane. It is a white crystalline powderhaving a slightly bittertaste.ltis soluble in water.ltis lacking stimulant effect upon the central nervous system in the usual therapeutic doses. It finds use as an anoretic for the treatment of obesity. Diethylpropion hydrochloride. It is a sympathomimetic agent which finds useas appetite suppressant. Chemically, it is 2-diethyl-aminopropiophenone hydrochloride. The especial feature of this sympathomimetic agent is the presence of a keto group. It occurs as a white crystalline powder. It is very soluble in water. It should be kept in a well-closed container protected from light and stored at a temperature not exceeding 25°. Official Amphetamine Sulphate, B.P. Dexamphetamine Sulphate, B.P. Dexamphetamine Tablets, B.P. Diethylpropion Hydrochloride, B.P. Ephedrine, B.P.,I.P. Ephedrine, Anhydrous, B.P. Ephedrine Hydrochloride, B.P., I.P. Ephedrine Elixir, B.P. Ephedrine Nasal Drops, B.P. Ephedrine Tablets, I.P. (Ephedrine Hydrochloride Tablets, B.P.) Fentluramine Hydrochloride, B.P., I.P. Fentlilramine Tablets, B.P., I.P. Fenoterol Hydrobromide, B.P. Metaraminol Tartrate, B.P. Metaraminol Injection, B.P. Methoxamine Hydrochloride. B.P.

195

Adrenergic Drugs

Methoxamine Injection, B.P. Methylamphetamine Hydrochloride, I.P. Methylamphetamine Injection, I.P. Orciprenaline Sulphate, B.P. Orciprenaline Injection, B.P. Orciprenaline Oral Solution, B.P. Orciprenaline Tablets, B.P. Phenylephrine Hydrochloride, B.P., I.P. Pheylephrine Injection, B.P., I.P. Phenylpropanolamine Hydrochloride, B.P. Pseudoephedrine Hydrochloride, B.P. Pseudoephedrine Tablets, B.P. Pseudoephedrine Hydrochloride, B.P. Pseudoephedrine Hydrochloride, B.P. Racephedrine Hydrochloride, B.P. Pseudoephedrine Tablets, B.P. Racephedrine Hydrochloride, B.P. Salbutamol, B.P., I.P. Salbutamol Inhaler, I.P. Salbutamol Injection, I.P. Salbutamol Pressurised Inhalation, B.P. Imidazoline Derivatives Imidazole has been five-membered heterocycle which is having two double bonds and two nitrogen atoms at 1,3 positions. Chemically imidazoline is dihydromidazole. 2-lmidazoline is having a double bond between positions 2 and 3. There are many derivaties of2-imidazoline with substitution at position 2 with arylmethyl group which are sympathomimetic agents. Naphazoline nitrate which is chemically 2-(naphth-I-ylmethyl)-2-imidazoline nitrate, has been one of them. Naphazoline nitrate. It is a white crystalline powder having a bitter taste.

,HC\

Naphazoline Nitrate

Xylometazoline Hydrochloride

It is sparingly soluble in water. Its solutions may be sterilised by maintain~ ing at 98" to 100° for 30 minutes with a bactericide or by filtration. Naphazoline

Pharmaceutical Chemistry (Organic)

196

acts as a vasoconstrictor which is having a rapid and prolonged action. It finds use for the symptomatic relief of rhinitis and sinusitis.

Xylometazoline. It is another imidazoline derivative which finds use as sympathomimetic agent. Chemically, it is 2-(4-tert-butyl-2,6-dimethylbenzyl)2-imidazoline.lts hydrochloride is the official which occurs as a water-soluble white crystalline powder. Similar to naphazoline it finds use for the relief of nasal congestion which gets caused by rhinitis and sinusitis. . Official

Naphazoline Hydrochloride, B.P. Naphazoline Nitrate, B.P. Xylometazoline Hydrochloride, B.P. Xylometazoline Nasal Drops, B.P.

16 Cholinergic And Anticholinesterase Agents

16.1. Introduction

In the body. the nervous system is responsible for the transmission of information. In order for an organism to perform its transmission functions. the nervous system is composed of sub-units which function together or separately. The main divisions of the nervous system are: (i) Central nervous system (CNS) consisting of brain and spinal cord. (ii) Peripheral nervous system comprised of nerves and ganglia. The nerves represent a bundle of fibres which are used for conveying impulses of. sensation. motion. etc .• between the brain or spinal cord and other parts of the body. Peripheral nervous system is composed of somatic and autonomic nervous systems. The autonomic nervous system is further composed of two parts such as the sympathetic and parasympathetic nervous systems. The transmission of message along the nerves occurs through electric impulses. As the ends of the nerve fibres do not make direct contact with the effector neves (the junction is known as synapse). there is a very minute gap (l00-500A) which does not allow the transmission of the electric impulse. However. this transmission is accomplished by chemical mediators (which are sometimes known as neurohumoral agents) which are stored in a vesicle cell). As soon as the electric impulse reaches the vesicle. it releases these chemical mediators which are transmitted through the synapse. Then. these react with the receptor at the effector cell membrane and this leads to the initiation of the impulse at that cell.

Phamwceutical Chemistry (Organic)

198 I

SYNAPSE i

tELL BRAIN~

SPINAL '----2"'''---f--..J CORD

EFFECTOR NERVE

EFFECTOR

ORGAN RECEPTOR DENDRON

Many organs or tissues have been doubly innervated (supplied) by two sets of nerve fibres. One set is utilising one of the major chemical transmitters while the other the second. In general, the effect, produced by one agent is opposed to that produced by the other,i.e., if one increases activity then the other decreases activity. Those transmitters which mimic the stimulation of the sympathetic nerves are known asadrenergic agents, whereas those which mimic the parasympathetic system as cholinergic agents. The enzyme acetylcholinesterase hydrolyses acetylcholine to choline and acetic acid at or near the site of liberation. Drugs that are able to inhibit acetylcholinesterase are known as anticholinesterase agents. By their action they are able to prolong the life of acetylcholine ancl bring about accumulation of it at cholinergic receptor sites and give rise to effects which are similar to excitation of cholinergic system. Clinically cholinergic agents and anticholinesterases find use for treating cardiac arrhythmias; for the relief of atony of gut and urinary bladder; for decreasing the intraocular pressure in glaucoma; and for relieving muscular weakness in myasthenia gravis. 16.2. Cholinergic Agents Acetylcbloline: It gets destroyed enzymatically in the blood to be of any clinical value. There are several structural analogues of acetycholine which do not get rapidly inactivated in the body and are having prolonged action and are used medicinally. One of the drugs of this type has been methacholine chloride. 0

CH 3

1$

/I

CH 3-N-CH CHOCCH

I

2

2

Cl

e

3

CH 3

Acetylcholine Chloride

199

Cholinergic and Anticholinesterase Agents

Metbacholine chloride. Chemically, it is acetyl-~-methylcholine chloride.1t forms very deliquescent crystals or crystalline powder. It is very soluble in water. Its solutions can be sterilised by filtration. Methacholine finds use to terminate attacks of supraventricular paroxysmal techycardia. It is used in the treatment of Raynaud's syndrome, scleroderma and other vasospastic conditions of extremities. Eye drops having methacholine find use in the diagnosis of Adie's pupil.

Methacholine Chloride

Pilocarpine: It is an alkaloid which is extracted from leaflets ofPilocarpus microphyllus and other species ofPilocarpus. It acts as a parasympathomimetic agent having muscarinic effects of acetylcholine. Its nitrate salt is used which is a crystalline powder having a slightly bitter taste and is freely soluble in water and its hydrochloride is also used which is a hygroscopic powder very soluble in water. Its solutions can be sterilised by autoclaving or by filtration. They are kept protected from light. The 1 to 5% solutions of pilocarpine salts are used as miotic to constrict pupil and lowers the intraocular pressure in glaucoma. They also find use for counteracting the effects of shortacting mydriatics on the eye.

~N CH ) /

;1z

(Or:-o

~ CHz

,HNO)

C2 H5

Pilocarpine Nitrate

Official

Methacholine Chloride, I.P. Pilocarpine Hydrochloride, B.P. Pilocarpine Eye Drops, B.P. Pilocarpine Nitrate, B.P., I.P. 16.3. Anticholinestrase Agents

Physostigmine, an alkaloid, and many synthetic compounds are known to act by bringing about the inhibition of the enzyme acetylcholinesterase. Physostigmine (eserine). It can be extracted from the dried ripe seeds of Physostigma venenosum.1t finds use as physostigmine salicylate (which occurs as colourless or faintly yellow crystals having a slightly bitter taste; sparingly

200

Phannaceutical Chemistry (Organic)

soluble in water). It also finds use as sulphate (which is white deliquescent powder and very soluble in water). Its solutions can be sterilised either by maintaining at 98° to 100' for 30 minutes with a bactericide or by filtration. The saIts and their aqueous solutions become red when exposed to light and air. They must be protected from light. Physostigmine finds use especially as a miotic. It is also used to decrease intraocular pressure in glaucoma. It also finds use by injection for reversing the toxic effects of anticholinergics and for treating poisoning because of anticholinergics and tricyclic antidepressants. CHI CHI

I

I

H H : H

,(}Cp ~

CNa"MCOO

; C"I

COOH " O

& I" ~

Physostigmine Salicylate

Neostigmine bromide. It is a synthetic compound which is chemically dimethylcarbamic ester of 3-hydroxy-N,N,N-trimethylanilinium bromide. It occurs as a crystalline powder having bitter taste. It is very soluble in water. Its solutions are sterilised either by autoclaving or by filtration. Its methylsulphate salt is also used as official. Neostigmine bromide is given orally for treating myasthenia gravis, whereas the methylsulphate is given parenterally for carrying out the treatment and diagnosis of myasthenia gravis. It also finds use in the treatment of paralytic ileus and postoperative urinary retention. It is used to curtail muscular relaxation which gets produced by nondepolarising muscle relaxants. Its slats are kept in well-closed, light-resistant CH3 containers.

I®

CH 3

Ie

CH3-N-CH3

~

U

/CH,

OCON , ' - C H3

Neostigmine Bromide

.,"

C'H'~

CH,

Ci

ll,;l.

e

OH Edrophonium Chloride

Edrophonium chloride. Chemically, it is ethyl(m-hydroxyphenyl) dimethylammonium chloride which is structurally related to neostigmine and is exerting actions similar to it. It is soluble in water. Its solutions can be sterilised either by autoclaving or by filtration. Edrophonium is mainly used in the diagnosis of myasthenia gravis. Due to its brief action the drug cannot be used for the routine treatment of myasthenia gravis. It was originally used for reversing the effects of tubocurarine and other nondepolarising muscle relaxants. I Pyridostigmine bromide. Chemically, it is 3-dimethylcarbamoyloxy-lmethyl-pyridinium bromide. It is a white deliquescent crystalline powder having a bitter taste. It is very soluble in water. Its solutions are sterilised either by autoclaving or by filtration.

201

Cholinergic and Anticholinesterase Agents

It is given either orally or by subcutaneous or intramuscular injection for treating myasthenia gravis. The drug should be protected from light. CH 3

1$

ri'N~

~

e /CH 3

8r

OCON ......... CH 3 Pyridostigmine Bromide

Ecothiopate iodide

Ecothiopate iodide. It is an organophosphorus compound which is chemically S-2 dimethylaminoethyl diethyl phosphorothiolate methiodide. It occurs as a white crystalline power having an a\liaceous odour. It is freely soluble in water. It exerts miotic action and brings about reduction in intraocular pressure. It finds use especially to treat open-angle glaucoma by direct instillation into the affected eye. Ecothiopate iodide should be stored in a well-closed container which is protected from light, and maintained at a temperature between 2° and go. Official Ecothiopate Iodide, B.P. Edrophonium Chloride, B.P. Edrophonium Injection, B.P. Neostigmine Bromide, B.P., I.P. Neostigmine Tablets, B.P., I.P. Neostigmine Methylsulphate, B.P., I.P. Neostigmine Injection, B.P., I.P. Physostigmine Salicylate, B.P., I.P. Physostigmine Injection, I.P. Physostigmine Sulphate, B.P. Physostigmine Eye Drops, B.P. Pyridostigmine Bromide, B.P. Pyridostigmine Injection, B.P. Pyridostigmine Tablets, B.P. A mention should be made here of dichlorphenamide (discussed under diuretics) which also finds use in the treatment of glaucoma. It is a carbonic anhydrase inhibitor.

17 Antispasmodic and Antiulcer Drugs 17.1 Introduction

If acetylcholine is liberated in excessive amounts, it brings about some undesirable physiological effects such as spasms of the stomach, intestine, heart, blood vessels; excessive gastric and salivary secretion, sweating and miosis. The compounds which are able to block the action of acetylcholine at parasympathetic system (postganglionic cholinergic nerves which are able to innervate exocrine glands and smooth muscles) are known as anticholinergic drugs. These drugs are also called parasympatholytics. But these drugs mainly antagonise the muscarinic actions of acetylcholine. Therefore, they are also termed as antimuscarinic or muscarinic cholinergic blocking agents. As these drugs do not disallow the formation of acetylcholine yet they may compete with the liberated neurotransmitter for the cholinergic receptor. Clinically the anticholinergic drugs find use therapeutically for the relief of spasms of gastrointestinal, biliary, and urinary tracts. Their inhibitory effect on gastric secretions finds use for treating gastric and duodenal ulcers. These agents are known to exert a depressant effect on certain motor mechanism of central nervous system. Therefore, they also find use in symptomatic treatment of parkinsonism (Described under Antiparkinsonism Drugs). Anticholinergics also find use for their cycloplegic and mydriatic effects on eyes. The drugs which are used for their antispasmodic arid antiulcer effects have been described under the atropine and related drugs, and synthetic agents. 17.2 Atropine and Related Drugs Atropine.Itis an alkaloid which is extracted from solanaceous plants such as Duboisia, Atropa, and Hyoscyamus spp. It is a racemic compound. It is an ester of aromatic acid, (±)-tropic acid, with tropine which is an alcohol having

Antispasmodic and Antiulcer Drugs

203

a nitrogenous bicyclic system. Its levorotatory isomer is termed as hyoscyamine whose sulphate salt is official. From the latter it is possible to prepare atropine by racemisation. Atropine occurs as a white powder which is slightly soluble in water. It finds use as the methonitrate and sulphate salts which are appreciably soluble in water. Its solutions may be sterilised either by autoclaving or by filtration. Atropine behaves like an anticholinergic drug which is exerting both central and peripheral actions. First of all it stimulates and then depresses the central nervous system and is exerting antispasmodic action on smooth muscle. Atropine and its salts are used for treating gastric and duodenal ulcers and for the relief of renal and biliary colics. They are administered orally but atropine sulphate is also administered parenterally. They also find use in the symptomatic treatment of parkinsonism. Before inducing general anaesthesia atropine is administered for reducing salivary and bronchial secretions and also for diminishing risk of vagal inhibition of the heart. For premedication before carrying out anesthesia atropine sulphate (300 to 600 Jlg) usually in combination with morphine sulphate (10 to 15 mg) is given by subcutaneous or intramuscular injection. For the dilatation of pupil. atropine in the form of oily drops and the salts as aqueous solutions or ointments are used topically. The actions and use of hyoscyamine are similar to those of atropine. 1:2

a CHaH

7~"1~

6~ a-C-CH-U 5

• Atropine

Hyoscine Butylbromide

Hyoscine (scopolamine).It is an atropine-related alkaloid. It is having an oxido bridge between carbon atoms 6 and 7. The acid precursor of this ester has been levorotatory. Hyodscine finds use as the hydrobromide. butylbromide methobromide and methonitrate salts. The hydrobromide salt of hyoscine occurs as a crystalline trihydrate salt. It is freely soluble in water. Its solutions are sterilised either by autoclaving or filtration. Its pharmacological action is different from atropine in exerting a depressant effect on cerebral cortex and brings about drowsiness euphoria amnesia and dreamless sleep. It finds use in the treatment of acute mania and delirium and for calming the excitement. In conjunction with morphine or Pethidine it is used for producing amnesia and partial analgesia. a condition which is termed as ''twilight sleep" in obstetrical practice. '

Pharmaceutical Chemistry (Organic)

204

For preanaesthetic medication it is injected subcutaneously. It also finds use for the prevention and treatment of motion sickness. The mydriatic and cycloplegic effects of hyoscine on eye have been of rapid onset and of short duration than atropine. The butylbromide, methobromide and methonitrate salts of hyoscine find use in treating conditions which are associated with gastrointes. tinal spasms.

Homatropine: It is a semisynthetic derivative which is the ester of tropine with (±) mandelic acid. It finds use as the hydrobromide and the methy lbromide

Homatropine Hydrobromide

salts. Both the salts exist as colourless crystals or white crystalline powder; freely soluble in water. They should be stored in well-closed containers and protected from light. Homatropine is mainly used as mydriatic and is preferred to atropine due to its more mpid and less prolonged action. It is used as a 2% aqueous solution for ~ye drops. Its effect on eye can be readily controlled by physostigmine.

omcal Atropine Methobromide, B.P. Atropine Methonitrate, B.P., I.P. Atropine Sulphate, B.P., I.P. Atropine Eye Drops, B.P. Atropine Eye Ointment. B.P., J.P. Atropine Injection, B.P., J.P. Atropine Sulphate Tablets, J.P. (Atropine Tablets, B.P.) Morphine and Atropine Injection, B.P., J.P. Homatropine Eye Drops, B.P. Homatropine Methylbromide Injection, B.P. Homatropine Methylbromide, B.P. Hyoscine Butylbromide, B.P. Hyoscine Butylbromide Injection, B.P. Hyoscine Butylbromide Tablets, B.P. Hyoscyamine Sulphate, B.P. . Scopolamine Hydrobromide, J.P. (Hyoscine Hydrobromide, B.P.)

205

Antispasmodic and Antiulcer Drugs

Hoyscine Eye Drops, B.P. Scopolamine Injection, I.P. (Hysocine Injection, B.P.) Scopolamine Hydrobromide Tablets, I.P. (Hyoscine Tablets, B.P.)

17.3 Synthetic Agents During the design of synthetic anticholinergic agents the structure of atropine and acetylcholine form their basis. Compounds having bulky moieties, generally cyclic groups, linked by a chain of atoms of limited length to a quaternary nitrogen are synthesised and are used. Many compounds having an ester group are used. Further many compounds having an ester group in the main chain are also us~. Examples of these are cyclopentolate, dicycIomine, oxyphenonium tromide, poldine and propantheline. However, tropicamide is an amide derivative. Cyclopentolate. Chemically it is [2-dimethylaminoethyl a-(lhydroxycyclopentyl)-a-phenylacetate] hydrochlordide. It occurs as a crystalline solid and is very soluble in water. Its solutions can be sterilised by filtration. It acts as an anticholinergic agent having actions similar to atropine. It mainly finds use for its cycloplegic and mydriatic effects in eye.

Cyclopentoiate

Dicy(')omine

Dk:yclomine hydrochloride. It is having a diethylaminoethyl chain which is attached to oxygen and a bicyclohexyl group on the other side of the ester group. It occurs as a white solid having a bitter numbing taste. It is soluble in water. Its actions are somewhat weaker than those of atropine. It is having local anaesthetic action also. It finds use for the relief of spasms of biliary, intestinal and urinary tracts. It also finds use for treatment of gastric and duodP.nal ulcers. Oxyphenoninm bromide. It is an ester of substituted glycolic acid. Chemically it is 2-(a-cyclohexyl-a-phenylglycoloyloxy) ethyldiethylmethy-

.Q _ O

0 II

e

CHaCH,

I

8r

C(OH)COCHaCH1-0fIC~

'/ ~

CH

,

Oxyphenonium Bromide

206

Pharmaceutical Chemistry (Organic)

lammonium bromide. It occurs as white powder having bitter taste. It is freely soluble in water. Its solution can be sterilised by filtration. PoId.ine. Chemically, it is an ester of2-hydroxymethyl-I-methyepyolidine with benzilic acid. It finds use as the methylsulphate salt which is having bitter taste. It finds use Q'~oWC .rut antiulcer agent

' \/

C

d 'I '\

-

CH J

e

CH J

CH,S04

COCHa -aNf)

II o Poldine Methylsulphate

Propantheline bromide. It is an ester which is carrying xanthene heterocycle. Chemically, it has been N.N-di-isopropyl-N-methyl [2-(xanthen-9ylcarbonyloxy)ethyl] ammonium bromide. It is yellowish white in colour. It is having bitter taste. It finds use as an antispasmodic and antiulcer drug. CH(CH 3 )2

ceo l

~

@I

COOICH~"1::~l, .,"

o

h

Propantheline Bromide

It also finds use as an adjunct for carrying out x-ray examination of gastrointestinal and biliary tracts. It also finds use in the treatment of enuresis. Mebeverine. It is an ester of veratric acid (3,4-dimethoxybenzoic acid) with 4-[ethyl(4-methoxy-lets, B.P. Tolazoline Hydrochloride, B.P. Tolazoline Tablets, B.P. MisceUaneous Vasodilators These include isoxsuprine, papaverine, inositol nicotinate and methyl nicotinate which are described as follows: Isoxsuprine hydrochloride. It is known for its predominantly betaadrenegic stimulation effect. For its dilating action, it finds use in the treatment of central and peripheral vascular disease. It is either given by moth or by intramuscular or intra-arterial injection. It is also given by intravenous infusion .

.

OHCH,

HO-o-~ - ~H~H\ NH o-oc~~1 CH, Isoxsuprine

As it is able to inhibit contractions of the uterus, it finds use by intravenous injection for arresting premature labour. Chemically isoxsuprine hydrochloride is named as I-(4-hydroxyphenyl)-2-(I-methyl-2-phenoxyethylamino) propanI-ol-hydrochloride. It occurs as a white or almost white, crystalline powder. It is slightly soluble in water. Papaverine. It is an alkaloid which is extracted from opium. It is also prepared synthetically. Chemically, it is 6,7-dimethoxy-I-(3,4-dimethoxy-benOCH,

Papaverine

262

Pharmaceutical Chemistry (Organic)

zyl) isoquinoline. It is'able to relax smooth muscle directly. It is given for, relieving ischaemia. It is added to some cough preparations. However, there occurs no evidence to justify its clinical use. It is usually given as the hydrochloride. It can be administered orally or parenterally. Its hydrochloride salt exists as white or almost white crystals or crystalline powder. Its solutions can sterilised by autoclaving or filtration. Inositol nicotinate. Chemically, it is hexanicotinate ofhexahydric alcohol meso-inositol. It occurs as a crystalline solid. It is almost insoluble in water.

N

R=Gl

co-

Inositol Nicotinate

It acts as a vasodilator and slowly gets hydrolysed to nicotinic acid. It is given by mouth for treating peripheral vascular disorders and is also recommended for cerebral vascular disease. It is also exerting a fibrinolytic effect and is able to reduce hypercholesterolaemia. Methyl nicotinate. It is a vasodilator which finds use in ::reams and ointments for topical application as a rubefacient I .... for relieving of pain in muscular rheumatism, lumbago, and ~ COOCH fibrosis. Methyl nicotinate exists as white or almost white I crystals or crystalline powder having a characteristic odour. It Methyl Nicotinate is very soluble in water. On keeping it darknse in colour thereby, becoming reddish. Nicotinyl alcohol is a vasodilator having general properties similar to thoseofnucotinic acid. Nicotiinyl alcohol or its tartrate is given by mouth in the

~

.. ~ N

~ ~

.

CHzOH

"

CHIOH) COOH CHIOH) COOH

Nicotinyl Alcohol Tartrate

treatment of vascular disorders. It is recommended for the treatment of hypercholesterolaemia. Nicoitinyl alcohol tartrate occurs as a white or almost white crystalline powder. It is freely soluble in water.

Official Inositl Nicotinate, B.P.

Cardiovascular Agents

263

Inositls Nicotinate Tablets, B.P. Isoxsuprine Hydrochloride, B.P., I.P. Isoxsuprine Injection, B.P., I.P. lsoxsuprine Tablets, B.P., I.P. Methyl Nicotinate, B.P. Nicotinyl Alcohol Tartrate, B.P. Nicotinyl Alcohol Tablets, B.P. Papaverine Hydrochloride, B.P.

Lipid-lowering Agents The fatty deposits in the blood vessels of patients suffering from atherosclerosis are high in cholesterol, either free or as esters. It is assumed that the reduction of abnormally high lipid levels will be able to inhibit atherosclerosis. This assumption gave rise to the study of substances that are able to lower the levels of lipids (especially cholesterol) in human blood. An example of these agent is clofibrate, which is ethyl 2-( 4-chlorophenoxy)2-methylpropionate. It is able to decrease elevated plasma concentrations of triglycerides and, to a somewhat smaller extent, elevated plasma concentrations of chloesterol. It finds use in the long-term treatment and propylaxis of patients who are suffering from coronory heart disease. Clofibrate occurs as a clear

Clofibrate

colourless to pale yellow liquid having characteristic and faintly acrid odour. Its taste is acrid at first, becoming sweet. It is almost insoluble in water. It can be administered as capsules. Although nicotinic acid (pyridine-3-carboxylic acid) is also able to lower serum cholesterol concentrations when given in large doses, yet its side-effects at high dosage are able to limit its usefulness.

Official Clofibrate, B.P, I.P. Clofibrate Capsules, B.P., I.P.

22 Diuretics

22.1 Introduction The kidney tubules filter about 180 litres offluid each day. Most of this is reabsorbed into the blood, only about 1% being voided through the urinary bladder. The reabsorbed portion contains sodium and potassium salts, mainly as chlorides and bicarbonates, the excess of electrolytes with urea, uric acid and other substances being rejec!ed in the form of urine.

Substances that increase the output of urine by the kidneys are called diuretics. The major use of diuretics is for the purpose of increasing the excretion of sodium and chloride. Diuretics are generally employed for the treatment of all types of oedema, i.e., diseases which are associated with abnormal retention of salt and water in the extracellular parts of the body, and, therefore, may be properly regarded as life-saving drugs. The main diseases associated with oedema are congestive heart failure, premenstrual tension, oedema of pregnancy, renal oedema and cirrhosis with ascites. Diuretics are also employed for the treatment of oedema induced by the administration of ACTH and the other cortico steroids. Diuretics are given either alone, or in combination with other antihypertensive agents, in the treatment of raised blood pressure. Different kinds of the diuretics have been described under the heads: carbonic anhydrase inhibitors; thiazides and related agents; high-ceiling diuretics; spironolactone and other potassium - sparing diuretics; and miscellaneous agents.

265

Diuretics

22.2 Carbonic Anhydrase Inhibitors It was reported that the antibacterial drug sulphanilarnide brought about acidosis in patients using it. This occurred probably due to inhibition of enzyme carbonic anhydrase, which is responsible for the conversion of carbon dioxide and water to hydrogen ion and bicarbonate ion. CO2 + HP;! H + HC0 3The inhibition of carbonic anhydrase lowers hydrogen ion sodium exchange in the renal tubules, and so there occurs an increased excretion of sodium and bicarbonate ions in the urine and is able to explain the diuretic action which occurs as the result. These observations gave rise to the investigation of compounds having sulphamoyl group (H2NS02- ) for discovery of new diuretics. First of all the attention was directed towards the potential carbonic anhydrase inhibitors which were having natriuretic action (excretion of sodium ions) but later they discovered sulphonamides which are known to exert saluretic action (excretion of sodium and chloride ions). In 1953, acetazolamide was the first commercial sulphonamide diuretic which is a derivative of 1,3,4-thiadiazole. Chemically it is N-(5-sulphamoyl1,3,4-thiadiazol-2-yl) acetamide. It occurs as a white or a yellowish-white crystalline powder. It is having very slight solubility in water but is soluble in solutions of alkali hydroxides. It acts as an inhibitor of carbonic anhydrase. If administration of acetazolamide is continued, it gets associated with metabolic acidosis and associated loss of diuretic activity. Thus its effectiveness tends to decrease with continous use. As a diuretic it is mainly superseded by drugs like the thiazides and frusemide. By inhibiting carbonic anhydrase in the eye acetazolamide is able to decrease intra-ocular pressure and finds use in the treatment of glaucoma. It is also given, either alone or in combination with other

HzNO z

S S""", --......,...NHCOCH, 5\\ 1/ z

N-N 4

,

Actazolamide

anticonvulslmts, for treating various forms of epilepsy. Acteazolamide is generally administered orally. However, its sodium salt may be administered by intramuscular or preferably by intravenous injection. Prolonged treatment gives rise to hypokalaemia because of excess loss of potassium ions, and so it becomes necessary for the administration of potassium supplement. Chemically, dichlorphenamide is 4,5-dichlorobenzene-l,3disulphonamide. It is also an inhibitor of carbonic anhydrase and is known to exert actions which are similar to those of acetazolamide but it also brings about an increase in the excretion of chlorides. It finds use to reduce intra-ocular perssure in glaucoma. If treatment gets prolonged there occurs hypokalaemia.

Pharmaceutical Chemistry (Organic)

266

~NH' CIYSOZNH Z CI Dichlorphenamide

It is administered orally. Dichlorphenamide occurs as a white or almost white crystalline powder and is almost insoluble in water. Official Acetazolamide, B.P., I.P. Acetazolamide Tablets, B.P., I.P. Dichlorphenamide, B.P. Dichlorphenamide Tablets, B.P.

22.3 Thiazides and Related Agents The compounds of this group mo~tly belong to analgoues of 1.2,4,henzothiadizine I. I-dioxide. The first compound in the series had been chlorothiazide which is chemically, 6-chloro-2H-I,2,4,- benzothiadizine -7sulphonamide I, I-dioxide. Chlorothiazide and other thiazdies act as diuretics. They are known to reduce the reabsorption of electrolyte from the renal tubules, thus enhancing the excretion of sodium and chloride ions, and consequently of water. They also decrease carbonic anhydrase activity so that bicarbonate excretion gets increased, but this effect has been small. The thiazides are also known to exert a slight lowering effect on the blood pressure. Chlorathiazide and other thiazide diuretics also find use

Hydrochlorothiazide

in the treatment of oedema and hypertension. It can be a administered orally. Hydrochlorothiazide has been somewhat different from chlorothiazide in having 3,4-double bond saturated. Chemically it is 6-chloro-3, 4-dihydro-2H-l, 2, 4-benzothiadiazine -7-sulphonamide 1, 1- dioxide. It has been reported to be ten to fifteen times more potent than chlorothiazide. Both chlorothiazide and hydrochlorothiazide occur as white crystalline powders. Both are almost insoluble in water but are soluble in alkali hydroxides.

Diuretics

267

Bendrofluazide

Cyclopenthiazide

The structural modifications included in thiazides involve the replacement of chloro group at 6 with trifluoromethyl (F lC-) group and a substituent at position 3 is introduced. Hydroflumethiazide has been different from hydrochlorothiazide in having F3C-grouP in place of Cl at position 6. Bendrofluazide having F1C- at position 6 and benxyl group attached to position 3 and cyclopenthfazide 'whose structure is same as hydrochlorothiazide but having cyclopentylmethyl group attached to position 3 have been very potent diuretics and have been found to be effective in much smaller dosage. The structure of poly thiazide is similar to hydrochlorothiazide but is having 2-methyl and 3-(2,2,2,-tritluoreoethylthiomethyl) (F,CCH,SCH,) as additional substitutes. It has been reported to be much more ptllent -than hydrochlorothiazide. Chlorthalidone is obtained as a product during the studies on disulphonamides which are involving different structural modifications. It is primarily existing in a tautomeric form having structure related to isoindoide. It is chemically 2-chloro-5-(3-hydroxy-l-oxoisoindolin-3-yl) benzenesulphonamide. It occurs as a white to yellowish-white crystalline powder. It is

o

Ct Chlorthalidone

almost insoluble in water but soluble in solutions of alkali hydroxides. The actions and uses of chlorthalidone have been similar to those of chlorothiazide. It is administered orally. When treatment given by thiazides and related agents gets prolonged, or in susceptible patients, loss of potassium may occur thus producing hypokalaemia and as such administration of potassium supplements becomes necessary.

Official Bendrofluazide, B.P., I.P. Bendrofluazide Tablets, B.P.

268 ,

Phannaceutical Chemistry (Organic)

Chlorotbiazide, B.P. Chlorothiazide Tablets, B.P. Chlorthalidone, B.P.,I.P. Chlorthalidone Tablets, B.P.,I.P. Cyclopenthiazide, B.P. Cyclopenthiazide, Tablets, B.P. Hydrochlorothiazide, B.P., I.P. Hydrochlorothiazide Tablets, B.P., I.P. Co-amiloride Oral Solution, B.P. Co-amiloride Tablets, B.P. Hydrofiumethiazide, B.P. Hydrofiumetbiazide Tablets, B.P. Poly thiazide, B.P. Polythiazide Tablets, B.P.

22.4 High-Ceiling Diuretics These are known to exert a distincti ve action on renal tubular functipn. The peak diuresis has'been found to be appreciatively greater than that observed with other agents. The main site of action of high-ceiling diuretics is the thick ascending limb of the loop of Henle, and because of this these agents are sometimes termed as loop diuretics. They give rise to an intense diuresis of relatively short duration. Two drugs of the type such as frusemide and ethacrynic acid have been described. They are chemically not related. Chemically frusemide (furosemide) is 4-chloro-N-furfuryl-5sulphamoylanthranilic acid. It occurs as a white or almost white crystalline powder. It is almost insoluble in water. It should be stored in bottles which are to be protected from light. The us~ of frusemide is similar to that of Ii-

chlorothiazide and is effective in patients who are 'not responsive to thiazide diuretics. It is not exerting any effect on carbonic anhydrase in the kidney. It is administered either by mouth, or by injection as a solution of sterile solution of frusemide sodium. Solutions for injection are obtained by using sodium hydroxide, giving solutions having a pH of about 9 which can be

269

Diuretics

sterilised either by autoclaving or filtration. The main precaution is that such solutions should not be mixed or diluted with dextrose injection or other acidic solution. Ethacynic acid has been an a, (3-unsaturated ketone and has been ·a derivative of phenoxy acetic acid. Chemically it is [2,3-dichloro-4-(2ethylacryloyl)-phenoxyl]acetic acid, It occurs as a white or almost white, crystalline powder. It is having very slight solubility in water. It is stored in wellclosed container. Its actions and uses have been similar to those of frusemide. It is generally administered by mouth. In emergency it is given intravenously.

~~:OH

Y'CI C-C=CH II

o

2

I

C2 H,

Ethacrynic acid

Similar to thiazides and related agents, if treatment gets prolonged with frusemide or ethacrynic acid, or in susceptible patients, loss of potassium may occur for producing hypokalaemia. In such cases potassium supplements should be given.

Official Ethacnynic Acid, B.P., I.P. Ethacrynic Acid Tablets, B.P., I.P. Frusemide, B.P., I.P. Frusemide Injection, B.P., I.P. Frusemide Tablets, B.P., I.P. 22.S Spirolactone and other Potassium Sparing Diuretics Spironolactone Spironolactone is having a steroid structure. It has been an aldosterone antagonist which is known to act as a competitive inhibitor of the natural adrenocortical hormone aldosterone. Therefore, it is able to increase sodium and

o

c..,.t"f

::~~

OUJ.".S:CH3 Spironolactone

Pharmaceutical Chemistry (Organic)

270

water excretion and lowers potassium excretion. Chemically it is 7a-acetylthio3-oxo-17a-pregn-4-ene-21, 17~-carbolactone. It occurs as a buff coloured powder. It is either odourless or is having a slight odour of thioacetic acid. It is almost insoluble in water. It must be protected from light. Spironolactone has been used both as a diuretic and as a antihypertensive agent. It finds use in the treatment of hypertension and in the management of refractory oedema. It is usually given in combination with the thiazides, frusemide and similar diuretics. It is administered by mouth.

Official Spironolactone, B.P., I.P. Spironolactone Tablets, B.P. Amiloride and Triamterene Amiloride and triameterne have been also potassium-sparing diuretics. However, their mode of action has been somewhat different from spironolactone. Both are organic bases. Amiloride finds use as the hydrochloride. Chemically amiloride has been N-amidino-3, 5-diamino-6-chloropyrazine-2, carboxamide hydrochloride. It occurs as a pale yellow to "greenish-yellow powder, having slight solubility in water. The salt is to be stored in a well-closed container which is protected from light.

Amiloride Hydrochloride

Chemically, triamterene is 2,4,7-, triarnino-6-phenylpteridine.1t occurs as a yellow, crystalline powder and has very slight solubility in water. It is to be kept in well-closed containers.

.

,

H2N~Nr;;N~NH2 ., "I .... 12 .....

...,N

CeHs e N S

4

3

NH2 Triamterene

Similar to spironolactone both amiloride and triamterene are also able to increase the excretion of sodium and chloride but reduce the excretion of potassium.

Diuretics

271

Unlike spironolactone it is found that both amiloride and triamterene do not act by inhibiting aldosterone. They behave as mild diuretics which probably act mainly on distal renal tubules. They find main use as an adjunct to the thiazides, frusemide, and similar diuretics, for conserving potassium, in the treatment of refractory oedema. These are not much effective in the treatment of hypertension. These are administered orally.

Official Amiloride Hydrochloride, B.P. Amiloride Tablets, B.P. Co-amiloride Oral Solution, B.P. Co-amiloride Tablets, B.P. Triamterene, B.P., J.P. Triamterene Capsules, B.P., I.P.

Miscellaneous Agents Miscellaneous agents include mannitol, HOCH 2(CHOH)4 CHPH, and urea, HN,CONH,. which find use as osmotic diuretics. They can be administered by intravenous injections. It is possible to sterilise the solution of mannitol either by autoclaving or by filtration. Further, it is possible to sterilise urea solution by filtration.

Official Mannitol, B.P., J.P. Mannitol Intravenous Infusion, B.P. Mannitol Injection, J.P. Urea, B.P., J.P. The diuretic activity of certain xanthines has been explained in the chapter on Central Nervous System Stimulants.

23 Oxytocics 23.1 Introduction There are many drugs which are able to stimulate the smooth muscle of the uterus. These drugs are known as oxytocics. These also find use in obstetrical practice to induce labour, to control post-partum uterine atony and haemorrhage, to bring about uterine contraction after caesarean section or during other uterine surgery. Oxytocics also find use for inducing therapeutic abortion. The therapeutically useful drugs include oxytocin; and numerous ergot alkaloids and their semisynthetic deri vati ves. 23.2 Oxytocin It is a cyclic polypeptide hormone which is secreted by posterior lobe of pituitary body (neurohypophysis). It can be isolated from the glands of the oxen or other mammals or can be obtained synthetically. Oxytocin is termed as nonapeptide because it is made up-of nine amino acid units. It finds use as oxytocin injection which is a sterile aqueous solution having oxytocin. Its solutions can be sterilised by filtration and can get distributed aseptically in sterile containers which are then sealed. When oxytocin injection is stored at a temperature between 2° and go, it is able to retain its potency for at least three years from the date of manufacture. When it is stored at a temperature not exceeding 25°, it is able to retain its potency for at least two years. A label should be pasted on the oxytocin injection. This label should state the potency as the number of units (oxytocic) per ml; the date after which the contents must not be used; and storage conditions.

273

Oxylocics

Oxytocin has been found to stimulate both the frequency and force of contraction of uterine smooth muscle. It has been also able to stimulate the modified smooth muscle (myoepithelium) of mammary gland and brings about milk ejection. Oxytocin has been employed for the induction and maintenance of labour and has been also able for controlling post-partum haemorrhage. It also finds use in cases of faulty milk ejection. The oxytocin may also be given in the form of tablets which are needed to be allowed to dissolve slowly in the mouth. Official Oxytocin Injection, B.P.,I.P. Oxytocin Tablets, B.P.

23.3 Ergot Alkaloids and their Synthetic Derivatives Ergot is obtained from the dried sclerotium of the fungus Claviceps purpurea which gets developed in the ovary of the rye plant. It was first used by physicians as a uterine stimulant nearly 450 years ago. It is a mixture of several alkaloids. The alkaloids finding interest clinically are amide derivatives of (+)lysergic acid and are having a double bond between C-9 and C-lO. The main clinical uses of the ergot alkaloids can be divided into two categories: as oxytocics in obstetrics and in the treatment of migraine. H."

COOH

Lysegic Acid

Ergometrine (ergonovine) finds use as an oxytocic whereas ergotamine finds especial use for migraine. Many semisynthetic derivatives of the ergot alkaloids are prepared and many of them have been of therapeutic interest. Methlylergometrine (oxytocic), methysergide (for migraine) and dihydroergotamine (for migraine) have been such drugs.

~

CONH~HCH20J.f

I

I

~ ~

HN

CH3

N

eHeOOH

,,·1:

I-f ~

eHcoOH

I

Ergometrine Maleate

274/

Pharmaceutical Chemistry (Organic)

Ergometrine (ergonovine) finds use as ergometrine maleate. This salt occurs as a white or faintly yellow, slightly hygroscopic powder. It is darkened on keeping as well as on exposure to light. Chemically ergometrine has been an amide derivative of lysergic acid with 2-aminopropanol. It is dextrorotatory. It is having low solubility in water. Its solutions can be sterilised by autoclaving and stored in ampoules, the air of which has been replaced by nitrogen or other suitable gas. Ergometrine malerte occurs as a uterine stimulant which finds use Jl!ainly for the treatment of post-partum haemorrhage. Its action has been somewhat more prolonged than that of oxytocin. It is administered both orally and parenterally. It is also given in combination with oxytocin by injection. Methylergometrine has been a partially synthetic homologue of ergometrine. Chemically it is an amide oflysergic acid with 2-aminobutanol.lt finds use as maleate which occurs as a white or faintly yellow crystalline powder having a bitter test. It is having slight solubility in water. It is kept in an atmosphere of nitrogen, in sealed light-resistant tubes which are stored in a cool place. It is possible to sterilise the solutions by autoclaving or by filtration; before autoclaving or after filtration, the solution gets distributed into ampoules the air of which gets replaced by nitrogen or some other suitable gas. Methy lergometrine tinds use similar to ergometrine maleate. CO.,.H CHCH zOI1

I

R'

CHCOOH

, \I

CHCOOH

Methy1ergometrine Maleate Methysergide Maleate

R = H: R = CH);

R' = CH 2CH] R' = CH 2CH1

Methysergide has been a semisynthetic derivative of ergometrine which is having two extra methyl groups, one is present at ir.dolenitrogen and the other in amide side chain. It finds use as the maleate which occurs as a white or almost white crystalline powder. It is having slight solubility in water. It is having only slight oxytocic effect. It finds use as a prophylactic in the management of severe recurrent migraine.

Ergotamine tartrate is known to exert oxytocic action, but it especially finds use in the treatment of migraine for which it is preferably administered parenterally. It occurs as a white crystalline powder which is slightly soluble in water.

275

Oxytocics

It is kept in light-resistant, sealed tube, under nitrogen and in a cool place. It finds use orally or parenterally for the symptomatic relief of the pain of migraine. When given in combination with caffeine, it is believed to enhance its action. Chemically dihydroergotamine is 9,1 O-dihydro derivative of ergotamine. It finds use as the tartrate (very slightly soluble) and mesylate (slightly soluble). The mesylate salt is kept in a cool place in an atmosphere of nitrogen in hermeticaIly sealed containers. Both the salts should be protected from light. They are finding use orally or parenterally for treating migraine.

Official Dihydroergotamine Mesylate, B.P. Dihydroergotamine Injection, B.P. Dihydroergotamine Oral Solution, B.P. Dihydroergotamine Tablets, B.P. Dihydroergotamine Tartrate, B.P. Ergometrine Maleats, B.P., J.P. Ergometrine and Oxytocin Injection, B.P. Ergometrine Injection, B.P., J.P. Ergometrine Tablets, B.P., J.P. Ergotamine Tartrate, B.P., I.P. Ergotamine Injection, B.P., I.P. Ergotamine Tablets, B.P., I.P. Methylergometrine Maleate, I.P. Methylergometrine Injection. I.P. Methylergometrine Tablets, I.P. Methylsergide Maleate, B.P. Methysergide Tablets, B.P. Other derivatives of ergot alkaloids discussed elsewhere have been bromocriptine mesylate (Antiparkinsonism Drugs) and co-dergocrine me~ylate (Cardiovascular Agents).

24 Anthelminitics 24.1 Introduction to Helminthiasis The parasitic wonns are tenned as helminths. Helminthiasis is a disease caused by infestation with parasitic wonns living in the alimentary canal or in the other tissues of the host. This disease is one of the major prevalent diseases in the world, particularly in the tropical countries. The main reasons responsible for the widespread nature of this disease in the developing countries are the lack of adequate sanitary facilities and supply of pure water, coupled with poverty and illiteracy. The helminth infection can be acquired either by (i) contact with infected animals or (ii) by the ingestion of infected meat or (iii) by the animal or human excreta via ground or water or (iv) by means of certain mosquitoes, e.g., filarial wonns are transmitted via blood sucking mosquitoes. The wonns enter the body in the fonn of either larvae or the egg fonn. In some cases they produce disease immediately whereas in other cases they take weeks or months to produce disease. Thus, to take preventi ve measures against these wonns one should have exact understand~ng of the life cycle of helminths, i.e., womiS. The main danger of helminthiasis is that the wonns may burrow into the tissue, thus causing injuries to the vessels and organs. They may cause loss of blood, nutritional deficiency, utricaria and other allergic conditions. The main parasitic wonns found in India are roundwonns, hookwonns, threadwonns, tapewonns, guineawonns and filarial wonns.

24.2 Anthelmintics The anthelmintics are the drugs which are used to kill or remove the parasitic wonns such as hookwonns, roundwonns, tapewonns, etc. Those anthelmintics which kill the wonns are calledvennicidal while those which help

277

Anthelminitics

in expelling them by making the environment uncomfortable for living are called vermifuges. The term anthelmintic should not be restricted just to drugs acting locally to expel worms from the gastrointestinal tract. Various types of worms are able to penetrate tissues, and the drugs used to act against systemic infections should be included also under the general term anthelmintic. So the anthelmintics broadly have been the drugs which are used to combat any type ofhelminthiasis. An ideal anthelminitic should fulfil the following characteristics: (i) It should act either specifically or inimically to all worms. (ii) It should not be toxic when it is absorbed from gut or when administered parenterally. (iii) It should not necessitate elaborate preparation or precaution in the direction of dietetic restriction or choice of purgatives. (iv) It should be cheap. An anthelmintic may act by causing narcosis or paralysis of worm by either penetrating the cuticle or by the worm ingesting. It may damage the cuticle of the worm or partially lyse it. The specificity of anthelmintics reveals that they interfere with metabolism of the worm; each worm is having its own metabolic requirement. The human and animal parasitic worms zoologically belong to the classes Cestoda (tapeworms) Trematoda (flukes) and Nematoda (roundworms). The drugs active against the respective helminthiases have been described in the following articles.

24.3 Drugs used in Cestode Infections Chestodes (tapeworms) have been flat segmented worms. The most serious tapeworm infections have been caused by fish, pork, beef and dwarf tapeworms. DichIorophen and Niclosamide Dichlorophen, 2, 2' -methylenebis (4-chlorophenol), and niclosamide, 2', 5-dichloro-4' - nitrosalicylanilide, have been synthetic compounds which have been found to be effective against tapeworm. Dichlorophen occurs as a white or not more than slightly cream coloured powder, and niclosamide occurs as a cream-coloured powder. They are almost insoluble in water. They are usually administered as tablets. OH

OH

HO

Cl

~c~ ~CO.H~~ a

Cl

Dichlorophen

Cl

Niclosamide

The antimalarial mepacrine (see under Antimalarials) is also employed for expUlsion of tapeworms.

278

Pharmaceutical Chemistry (Organic)

Official Dichlorophen, B.P. Dichlorophen Tablets, B.P. Niclosamide,I.P. (Anhydrous Niclosamide, B.P.) Niclosamide Tablets, B. P., I.P. Niclosamide Monohydrate, B.P.

24.4 Drugs used in Trematode Infection Trematodes (flukes) have been usually flat, leaf-shaped, unsegmented worms. They have been animals of a low order of development. The most important flukes parasitic in man include three species of Schistosomas (S. mansoni. S. haematobium. and S. japonicum) that occur in the lumen of veins. The intermediate hosts have been aquatic or amphibious snails. The disease schistosomiasis has been the most common disease in tropical and subtropical regions. Nearly 200 to 300 million persons are known to suffer from it. The official schistosomicide has been trivalent antimony compound antimony sodium tartrate [NaOOC-CHOHCHOH-COO(SbO)] which forms a colourless and transparent or whitish hygroscopic scales or powder. It is freely soluble in water. Its solutions may be sterilised by autoclaving or by filtration. It has been found to be incompatible with acids and alkalis, salts of heavy metals, albumin soap and tannins. It may be administered intravenously. The pentavalent antimony compounds such as sodium stibogluconate and urea stibamine have been found to be of greater value in leishmaniasis (a protozoan infection) and these have been described under Miscellaneous Antiprotozoal Drugs. Official Antimony Sodium Tartrate, B.P. Antimony Sodium Tartrate Injection, B.P.

24.5 Drugs used in Nematode Infections The nematodes have been found to be of a higher organisation than the flatworms. They have been unsegmented worms. The nematodes parasitic to man have been roundworms, hookworms"whipworms, threadworms, and the pinworms. The drugs used in nematode infections have been described under the sub-heads such as antifilarial agents and drugs for intestinal nematode infections. Antif"darial Agents Filariasis is the name given to a group of diseases in man and other vertebrates which are produced by insect-transmitted round worms infections. Wuchereria bancrofti and W. malayi have been most important filarial organ-

Anthelminitics

279

isms which are effective in Africa, India, China, Japan and the East and West Indies. Antimony Compounds. The antimony compounds such as antimony sodium tartrate and urea sitbamine find use in filariasis. These are given intravenously, and remission usually takes place. Diethylcarbamazine is an effective metal free drug. ' Diethylcarbamazine citrate. Chemically, it is 4-diethylcarbamoyl-lmethylpiperazine dihydrogen citrate. It i~ a white crystalline powder. It is very slightly soluble in water. It finds use to treat filariasis particularly when caused CH eOOH

I

2

C (OH) eOOH

I

eH?eOOH

LJlethylcarbamazine Citrate

by W.bancrofti or Loa loa. It finds use in the treatment of tropical eosinophilia. It is generally administered by mouth as tablets. Official Diethylcarbamazine Citrate, B.P., I.P. Diethylcarbamazine Tablets, B.P., I.P. Drugs for Intestinal Nematode Infections Piperazine. It is a simple heterocycle and is effective against roundworms (Ascaris) and threadworms. Piperazine is generally administered orally as the adipate, citrate, or phosphate salts. Piperazine Hydrate Hexylresorcinol. It is a crystalline powder very slightly soluble in water. It has been found to be effective against roundworms (Ascaris) and dwarf tapeworms. It has been found to be also active against

o OH

YOH (CH 2\CH 3 Hexylresorcinol

Tetrachloroethylene

certain hookworms, thread worms, whipworms, and giant intestinal flukes. It has ~een largely replaced by newer drugs. It is administered by mouth. Tetrachloroethylene. It is a mobile liquid. It is insoluble in water and has been found to be effective against hookworms and intestinal flukes. It is administered as a draught or in gelatin capsules.

280

Pharmaceutical Chemistry (Organic)

,Heterocyclic compounds. The other anthelmintics of value have been the heterocyclic compounds such as thiabendazol, mebendazole, levamisole, and viprynium. Both thiabendazole and memben dazole are benzimidazole derivatives. Chemically thiabendazole is 2-(thiazole 4-yl) benzimidazole. It is a white

H

~N\.

M ~ I

liS

V':~N~

C.H,CO

H

0

,N

"

}-NHCOCH 3 N

Mebendazole

Thiabendazole

or almost white odourless powder. It is having a high degree, of activity against a wide range of nematodes. It is used in the treatment of the infections which are due to threadworms, strongyloid worms, hookworms, roundworms (Ascaris) and whipworms. Mebendazole (methyI5-benzoy lbenzimidazole-2-y1carbamate) has also been reported to be effective against thread worms, roundworm, whipworm~, and hookworms. It is a white to slightly yellow, almost odourless, amorphous powder. Thiabendazole and mebendazole have practically no solubility in water. They are administered as tablets. The hetrocyclic compound levamisole is used as the hydrochloride and it is the levo-isomer of tetramisole. The I isomer has been reported to be more active than the racemic mixture. Chemically, levamisole hydrochloride is (-)- (S-)2, 3,5, 6-tetrahydro6-phenylimidazo [2,I,b] thiazole hydrochloride. It has been found to be effective against roundworm (Ascaris) infestation moderately active against hookworms and stronglyoids. The hydrochloride is a white pale cream coloured crystalline

H~N~S\

CH ;'O\"'-N-/

.HCI

6 5

Levamisole Hydrochloride

powder. It is freely soluble in water, finds use as an anthelmintic and for its effects on the immune system. It is administered orally as a syrup or tablets. Viprynium (pyrvinium) is having quinoline and pyrrole moieties. It is official as the salt with embonic acid (parrnoic aCid), 4, 4', methylenebis (3hydroxy-2-naphthoic acid). Chemically, viprynium embonate is 6dimethylamino-2-[2-(2, 5-dimethyl-I-phenylpyrrol-3-yl) vinyl]-lmethylequinolinium 4, 4'-methylenebis (hydroxy-2- napthoate) Viprynium embonate is a bright orange red to almost black crystalline powder. It is practically insoluble in water, and is given orally in the treatment of threadworm

Anthelminitics

281

2

Viprynium Embonate

infection. It has also been reported to be of some value in some cases of strongyloidiasis. Chemically, bephenium hydroxynaphthoate is N-berizyl-N, N-dimethylN (2-phenoxyethyl) ammonium 3-hydroxy-2-naphthoate. It is a yellow crystalline powder and practically insoluble in water. CH)

o-OCHzC~CH~ CH

~

~I o:x

COO

e

A

OH

J

Bephenium Hydroxynaphthoate

It has been reported to be effective against hookworms, roundworms (Ascaris), and species of Trichostrongylus. It is administered orally as granules.

Official Bephenium Hydroxynaphthoate, B.P., l.P. Bephenium Hydroxynapthoate Granules, I.P. (Bephenium Granules, B.P.)' Hexylresorcinol, B.P . . Levamisole Hydrochloride, B.P. Mebendazole, I.P. Mebendazole Tablets, l.P. Piperazine Ad;pate, B.P., l.P. Piperazine Adipate Tablets, l.P. Piperazine Citrate, B.P., l.P. Piperazine Citrate Elixir, B.P. Piperazine Citrate Syrup, l.P. Piperazine Hydrate, B.P., I.P.

Pharmaceutical Chemistry (Organic)

282

Piperazine Phosphate, B.P., I.P. Piperazine Phosphate Tablets, B.P., I.P. Tetrachloroethylene, B.P., I.P. Tetramisole Hydrochloride, I.P. Thiabendazole, B.P., I.P. Thiabendazole Tablets, B.P., I.P.

25 Antimalarials

25.1 Introduction Malaria was and is still recognised as a disease of world-wide incidence. It is a highly wide spread infectious disease caused by sporozoa of genus plasmodium. It is characterised clinically by periodic fever, anaemia and enlargement of liver and spleen. It is the cause of higher sickness or death rate than any other disease, particularly in tropical and subtropical countries like Asia, Africa and South America. At one time, hundreds of millions of people were infected by this disease and millions died annually. However, due to the cooperation of all countries and WHO, this disease could be controlled to certain extent only in the last 20 years. However, there appears to be a return of the disease because the malarial organisms have developed resistance against synthetic agents which are being used to control them. Malarial Parasite and its life cycle The word, malaria, is derived from Italian words mal (bad) and aria (air). For long time it was believed that malaria was caused by a miasma which arises from stagnant water at night. Night air was, thus, regarded as bad. Ronald Ross in 1897 demonstrated the presence of malarial parasites in the wall of the stomach of female anopheles mosquito which lives in damp regions. Thus, a rational explanation was given for the earlier belief that malaria arises from swamps and stagnant waters. By the close of nineteenth century, the two cycles of malarial parasites, one in man and other in mosquito were clearly established. The genus anopheles is a large one. However, its four species, viz., Plasmodium vivax, Plasmodium malariae, PlasmJdium ovale and Plasmodium Jalciparum are responsible for malaria in man.

284

Pharmaceutical Chemistry (Organic)

All species of Plasmodium have two hosts, a vertebrate and a mosquito that acts as both vector and definitive host. The malarial parasite requires time in both hosts tc complete its multistage life cycle. The simplified representation of life cycle of malarial parasite (Plasmodia) is given in Table 25.1. Table 25.1 Simplified Representation of Life-cycle of Malarial Parasites (Plasmodia) Sequence of Events and Site of Action

Form of Parasite

Mosquito bite

t

Human blood stream Exo-erythrocytic schizogony

+ .t LIver cells

Blood stream

!

Sporozoites Pre-erythrocytic schizonts Pre-erythrocytic schizonts Pre-erythrocytic merozoites

Blood stream Erythrocytic schizogony

1 !

Trophozoites Erythrocytic schizonts Erythrocytic merzoites

Red blood cells Erythoryctic merozoites and gametocytes (Sexual)

Mosquito

~

Human blood stream

Sexual development Sporozoites

History of Development of Antimalarials In the search for antimalarials, a large number of alkaloid-bearing plants were investigated for their antimalarial activity. In the course of this search, the extract ofthe bark of cinchona tree was found to be highly active against malaria. Various forms of cinchona bark have been used for about 400 years. In 1820, Pelletier and Caventous succeeded in isolating quinine and cinchonine from this bark. During and after World War I, the quinine and its derivatives were not available' in sufficient quantities in Germany. Therefore, the chemists of this country attempted to synthesise antimalarials which were to be independent of quinine structure. They started with methylene blue which had some antimalarial activity. They found that dialkylamino-alkyl side chain was necessary for antimalarial activity and they ultimately were successful in synthesising first synthetic antimalarial,pamaquine However, it fo~.nd limited applications due to

Anfimalarials

285

Methylene blue

its toxicity and ineffectiveness against acute attack of malaria. Further researches led to other synthetic antimalarials, such as quinacrine, chloroquine, santoquine, etc. During the World War II, British chemists sythesised some biguanide derivatives, e.g., chloroguanide which is quite effective against non-resistant strains of plasmodist. It is to be administered daily till' a person remains in malaria infected area. In 1963, cycloguanil pamoate was synthesised which immunises man against P. vivax infections for 6-19 months. 25.4 Chemotherapy of Malaria For convenience, the antimalarial drugs may be classified as follows: (i) Prophylactic agents (Sparozontoscides): These are the drugs which ar~ capable of killing the sporozoites and/or the parasites of the tissue phase as soon as they enter the blood stream. However, very few drugs of such properties have been found. (ii) Suppressive agents (Erythrocytic schizontocides): These are the durgs which are capable of affecting primarily the asexual erythrocytic phase, i. e., they inhibit the development of schizonts. Thus, these agents are able to keep the blood forms of the organism to such a low level that the clinical symptoms (fever, etc.) would not be able to make their appearance. (iii) Curative agents (Exoerythrocytic schizontocides): These are the drugs which are capable of killing the parasites in the schizont stage, in either primary or in secondary exoerythrocytic form (common inP. Vivax). Only some drugs of this type are available. " (iv) Gametocidal agents (Gametocides): These are the drugs which are capable of destroying the parasites in the gametocyte state i.e., the sexual phase responsible for the disease, i. e., they help to prevent the spread of the disease. A few drugs of this type are available. (v) Sporontocidal agents (Sporontocides): These are the drugs which are capable of preventing sporongony in the mosquito. This is because they effect the gametocytes in blood of the host. All sporontocidal agents are also curative agents. . From the above classes of the antimalarials, it is evident that an ideal antimalarial should exhibit all the five types of activity against all the four species of plasmodium. However, no such single broad spectrum antimalarial is known so far, though the same drug may have an action on more than one phase. ".

286

Pharmaceutical Chemistry (Organic)

Chemically, the antimalarials can be classified as follows: 1. Quinine salts 2. 4-Aminoquinolines 3. 8-Aminoquinolines 4. 9-Aminoacridines 5. Diaminopyrimidines. Besides the above drugs there are some other drugs such as dapsome, certain sulphonamides and tetracyclines which are used in the treatment of malaria.

25.5 Quinine Salts Quinine is an alkaloid which occurs in Cinchona. The amounts of total alkaloids presen~ in different cinchona barks have been found to vary considerably, the average being about 6-10 per cent. Quinine generally forms about one quarter of the total, the remainder having quinidine, cinchonine, cinchonidine and other alkaloids. Quinine consists of a quinoline nucleus which is attached through a carbon carrying secondary alcohol group to a qQinuclidine system. A methoxy group gets attached to the quinoline ring and a vinyl group gets attached to the quinuclidine.

Quinine

Quinine occurs as a white, odouriess, slightly efflorescent, flaky granular or microcrystalline powder. It has very slight solubility in water. It is having an intensely bitter taste. It has been levorotatory. It has been adi-acid tertiary base. The mono-acid salts of quinine have been usually much less soluble in water than the di-acid salts. Quinine and its salts are kept in well-closed, light-resistant containers. Quinine sulphate is having slight solubility in water, while quinine bisulphate has been freely soluble; quinine hydrochloride has been soluble and quinine dihydrochloride has been very soluble in water. The quinine salts have been found to be incompatible with alkalis, iodides and tannic acid. Quinine acts as a highly active blood schizonticide and is able to suppress the asexual cycle of development of malarial parasites in the erythrocytes. It is regarded to be acting by interfering with DNA.

287

Antimalarials

Quinine has been generally administered as the sulphate, bisulphate, hydrochloride, or dihydrochloride. It now finds main use in the treatment of P. Jalciparum malaria which is resistant to chloroquine or other antimalarial drugs. When it is not possible to take quinine by mouth or there is an emergency, a soluble quinine salt, like the dihydrochloride, may be administered by slow intravenous injection or by slow intravenous infusion. The solutions for injection have to be sterilised by autoclaving or filtration.

Official Quinine Bisulphate, B.P., J.P. Quinine Bisulphate Tablets, B.P., J.P. Quinine Dihydrochloride, B.P., J.P. Quinine Dihydrochloride Injection, B.P., J.P. Quinine Hydrochloride, B.P. Quinine Sulphate, B.P., J.P. Quinine Sulphate Tablets, B.P., J.P. 25.6. 4-Aminoquinolines Quinoline heterocycle system occurs in quinine. Synthetic studies have given rise to several other quinoline derivatives which are having anti-malarial activity. Such quinoline compounds have been related to 4-aminoquinoline and 8-arninoquinoline. The main 4-aminoquinolines of interest have been c·hloroquine, amodiaquine and hydroxchloroquine. 1.

Chloroquine Chemically, it is 7-chloro-4-(4-diethylamino-I-methybutylamino} quinoline.1t occurs either as a white or slightly yellow odourless crystalling powder. It is having a bitter taste. It has very slight solubility in water. Chloroquine finds use as the phosphate and sulphate salts; both have been freely soluble in water. The salts occur as white or almost white crystalline powders. They are preserved in well-closed, light resistant containers. 8

"';CzHs NHCHCH 2 CH zCH z N

I

'CzH 5

CH,

Chloroquine

ChI Jroquine is having a rapid schizonticidal effect. Probably, it affects the cell growth by interfering with DNA. It is able to kill the erythrocytic forms of malarial parasites. It finds use for the suppression and treatment of tualaria. If the patient fails to swallow, the phosphate or sulphate may be administered by intramuscularorintravenous injection. The solutions should be sterilised

288

Pharmaceutical Chemistry (Organic)

by autoclaving or filtration. Chloroquine also finds use in the treatment of amoebic hepatitis. It also finds use in the treatment of discoid or subacute lupus erythmatosus and rheumatoid arthritis. It finds use in the treatment of giardiasis.

2.

Amodiaquine

ChemicaIly, it is 4( -7-chloro-4-quinolylamino)-2-(diethylaminomethyl) phenol. Its hydrochloride salt is used. This salt is a yellow crystalline powder which is odourless or almost odourless. Its taste is bitter. The salt is soluble in water. It is having an action which is similar to that of chloroquine and find use interchangeably for the same purpose. It is usually given by mouth.

3.

Hydroxychloroquine Its structure has been similar to chloroquine with the difference that the

Amodiaquine

substituent at position 4 has been 4-(N-ethyl-N-2-hydroxyethylamino)-Imethylbutylamino- (HOCH 2CH 2) (CH 3CH 2)- NC~ CH 2CH 2CH(CH 3) NH-. Hydroxychloroquine sulphate occurs as a white or almost white odourless crystalline powder. It is having a bittertaste.1t has been found to be freely soluble in water. It must be protected from light. It is having an antimalarial action which is similar to chloroquine but it finds main use in the treatment of systemic and discoid lupus erythematosus and rheumatoid arthritis.

Official Amodiaquine Hydrochloride, B.P., I.P. Amodiaquine Tablets, B.P., I.P. Chloroquine Phosphate B.P., I.P. Chloroquine Phosphate, Injection, B.P., I.P. Chloroquine Phosphate Tablets, B.P., I.P. Chloroquine Sulphate, B.P., LP. Chloroquine Sulphate Injection, B.P., I.P. Chloroquine Sulphate Tablets, B.P., I.P. Hydroxychloroquine Sulphate, B.P. Hydroxychloroquine Tablets, B.P.

25.7 8-Aminoquinolines There are many 8-aminoquinoline antimalarials but primaquine phosphate has been the official one. Chemically, it is has been 8-(4-amino-l-

Antimalarials

289

methylbutylamino)-6-methoxyquinoline diphosphate. It is an orange red crystalline powder. It is having a bitter taste and is preserved in well-closed light resistant containers. It has been found to be soluble in water. Its aqueous solutions should not be heated. Primaquine has been able to kill the primary exoerythrocytic stages of P. jalciparum, P. vivax, P. malariaeand P. ovale and the secondary exoerythrocytic form of all except P. jalciparum. It has been also able to kill gametocytes of all species, or has been able to render them incapable of development in the mosquito; but it has been exerting little action on other erythrocytic stages .

.Primaquine Phosphate

Primaquine has been mainly used for the radical cure of P. vivax infections. It is advisable to give primaquine in conjunction with a 4-aminoquinoline schizonticide. like chloroquine. Official Primaquine Phosphate. B.P.• I.P. Primaquine Tablets. B.P.. I.P. 25.8 9-Aminoacridines Attempts have been made to test a good number of 9-aminoacridines for antimalarial activity but mepacrine (quinacrine) has been found to be the best of all. Mepacrine hydrochloride is bright yellow crystalline powder. It is having a bitter taste. It must be protected from light. It has been found to be sparingly soluble in water. It has been incompatible with alkalis. nitrates. and oxidising

Mepacrine

290

Pharmaceutical Chemistry (Organic)

agents. It is having a rapid schizonticidal action. It finds use for suppression and treatment of malaria, but it is superseded by chloroquine and other newer antimalarials. If finds use in the treatment of giardiasis and expulsion of tapeworms.

omcial Mepacrine Hydrochloride, B.P. Mepacrine Tablets, B.P. 25.9 Biguanides Biguanide has been related to guanidine as biuret (NH2CONHCONH 2) has been to urea. Attempts have been made to prepare substituted biguanides in a search for new antimalarials. Proguanil (chloroguanide) has been one such drug which is chemically 1(-4-chlorophenyl)-5-isopropyl biguaunide.1t finds use as the hydrochloride. The salt is a white crystalline powder having a bitter taste. It is kept in well-closed, light-resistant containers. It has slight solubility in water. Proguanil acts as an antimalarial and dihydrofolate reductase inhibitor. It is having a slow schizonticidal effect in the blood and some schizonticidal activity in the tissues. It is having a marked sporonticidal action against some strains of P. Jalciparum. - CI

\, -0I

,

~H ~H / CH 3 NH-C-NH-'C -NHCH -HCI \

CH

3

Proguanil Hydrochloride

Official Proguanil Hydrochloride, B.P., LP. Proguanil Tablets, B.P., LP.

25.10 Diaminopyrimidines Pyrimethamine and trimethoprim have been the diaminopyrimidines. Pyrimethamine was used almost solely as an antimalarial agent. Trimethoprim was developed as an antibacterial but it was at a later stage found to have antimalarial properties. Pyrimethamine has been discussed here, and trimethoprim will be discussed along with sulphonamides. C H 2 5

ffiI

CI

I N~NH2

'-'::

....,N

~

NH2

Pyrimethamine

Chemically, pyrimethamine is 2, 4-diamino-5-(4-chloro-phenyl)-6ethylpyrimidine. It is white, crystalline powder. It is tasteless and is stored in tightly-closed, light-resistant containers. It is almost insoluble in water.

Antimalarials

291

The main value of pyrimethamine has been a ssuppressant. Pyrimethamine has been an antimalarial drug and dihydrofolate reductase inhibitor such as proguanil hydrochloride. It is used alone for the suppression of falciparum and sometimes of vivax malaria. Usually, it finds use in combination with other drugs for both suppression and treatment. Pyrimethamine in combination with sulphadoxine is used for the treatment of mild or uncomplicated falciparum malaria.

Official Pyrimethamine, B.P., I.P. Pyrimethamine Tablets, B.P. Pyrimethamine and Sulphadoxine Tablets, I.P.

26 Antiamoebic Drugs

26.1 Introduction Amoebiasis has been found to be a disease of world-wide occurrence. In human beings it occurs mainly due to infection by Entamoeba histolytica, which has been microscopic one-celled animal of the Phylum Protozoa. For practical purposes, it becomes possible to divide amoebic infections into two principal subdivisions: intestinal and extraintestinal. In the latter case, the liver, lung or other organs, may be infected. Many antiamoebic drugs have been of natural origin. The other has been the class of drugs which include synthetic preparations.

26.2. Drugs of Natural Origin Emetine hydrochloride, finds use an antiamoebic agent. Emetine has been an alkaloid which may be obtained from ipecacuanha, or it may be obtained by methylating cephaeline, which is another related alkaloid. Emetine hydrochloride occurs as a white or very slight yellowish crystalline powder having a bitler taste. It becomes fairly yellow when it is exposed to light. It is k~pt in well closed containers which are light resistant. It is freely soluble in water. Its solutions could be sterilised by heating with a bactericide or by filtration. Emetine is an amoebicide which is acting principally in the bowel wall and in the liver. It is administered by subcutaneous or intramuscular injection. In severe amoebic dysentery it is gi ven along with tetracycline and an amoebicide where this combination acts within the intestinal lumen like diloxanide furoate. In hepatic amoebiasis, emetine is given along with chloroquine and an ameobicide where lhis comhination acts within the intestinal lumen, but treat-

Antiamoebic Drugs

293

ment with metronidazole (see under Miscellaneous Antiprotozoal Drugs) is usually preferred.

Emetine Hydrochloride

Dehydroemetine' has been a close structural analogue or emetine. It is having a double bond between positions 2, 3. Dehydroemetine is having actions and uses similar to emetine but it is regarded to be less toxic. Dehydroemetine hydrochloride occurs as a white to yellowish-white, crystalline powder having a bitter taste. It is kept in well-closed, light resistant containers. It is having solubility in water. It may be administered by deep subcutaneous or deep intramuscular injection. It has been administered by mouth. The antibiotics such as erythromycin, paromomycin and some tetracyclines find use in the treatment of intestinal amoebiasis. Among these paromomycin refers to the only one that is directly amoebicidal; the other antibiotics have been not amoebicidal directly, but have been acting by interfering with the intestinal flora essential for the proliferation of the pathogenic amoebae. Paromomycin sulphate is a mixture of sulphates of the antimicrobial substances. It is produced by Streptomyces rimosus formaparomomycinus.1t is given by mouth in intestinal amoebiasis. Paromomycin is also effective in the treatment of tapeworm infestation. It is also used for treating acute bacillary dysentery.

Official Dehydroemetine Hydrochloride, J.P. Dehydroemetine Injection, J.P. Dehydroemetine Tablets, J.P. Emetine Hydrochloride, B'.P., J.P. Emetine Injection, B.P., J.P. Emetine Hydrochloride Pentahydrate, B.P. Emetine Injection, B.P.

Pharmaceutical Chemistry (Organic)

294 26.3 Synthetic Drugs

Quinoline Derivatives There are many quinoline derivatives which are found to be acting as antiamoebic agents. For example, chloroquine is used in the treatment of extraintestinal amoebiasis. Further chloroquine salts finds use in the treatment of amoebic hepatitis. There are certain halogenated 8-hydroxyquinoline which find use clinically as antiamoebic agents. Examples of such quinolines include quinodochlor, diiodohydroxyquinoline and halquinol which are effective in intestinal amoebiasis. Quiniodochlor. (clioquinol; idochlohydroxyquin iodochlorohydroxyquinoline). It has been chemically 5-chloro-7-iodoquinolin -8-01. It occurs as a yellowish-white to brownish-yellow powder having a slight-characteristic odour. It is tasteless. When exposed to light, it is darkened. It is kept in well-closed, light resistant containers. It is almost insoluble in water. It is incompatible with oxidising agents. Quiniodochlor is given by mouth for treating of intestinal amoebiasis. Quiniodochlor is having antibacterial and antifungal activities and is used in creams and ointments in the treatment of skin infections. Vaginal installations are used in the treatment of trichomonal vaginitis.

It¢o OH

....

"/

~I

..:

CI Quiniodochlor (Clioquinol)

It¢o OH

""

~I

...

...-:

1 Diiodohydroxyquinoline (lodoquinol)

Diiodohyxdroxyquinolne.(iodoquinol; diiodohydroxyquin). Chemically, it is 5,7 diiodoquinolin-8-01. It occurs as a light yellow to yellowish-brown microcrystaline powder. It is tasteless. It is kept in well-closed, light resistant containers. It is almost insoluble in water. It finds use alone or with metronidazole (see under Miscellaneous Antiprotozoal Drugs) for the treatment of intestinal amoebiasis. It also finds use in giardiasis, and finds use locally against Trichomonas vagina lis.

Halquinol.lt is prepared by chlorinating 8-hydroxyquinoline. Actually, it is a mixture having 57 to 74% of 5, 7-dichloroquinolin 8-01, 23 to 40% of 5chloroquinolin-8-01. and not more than 4% of7-chloroquinalin-8-01. Halquinol occurs as a yellowish white to yellowish grey voluminons powder having a faint cresol-like odour. It is almost insouble in water. It is incompatible with many metal ions. It is to be protected from light and kept free from contact with metal.

Antiamoebic Drugs

295

Halquinol has been found to be antiamoebic, antibacterial, and antifungal. It finds use in the treatment of amoebiasis and in some cases of bacillary dysentery. It finds use topically for the treatment of infected skin conditions.

Halquinol

Official Chloroquine Phosphate, B.P.,I.P. Chloroquine Phosphate Injection, B.P.,I.P. Chloroquine Phosphate Tablets, B.P.,I.P. Chloroquine Sulphate, B.P.,I.P. Chloroquine Sulphate Injection, B.P.,I.P. Chloroquine Sulphate Tablets, B.P.,I.P. Diiodohydrox yquinoline, I.P. Diiodohydroxyquinoline Tablets, I.P.. Quiniodochlor,I.P. (Clioquinol, B.P.) Clioquinol Cream, B.P. Hydrocortisone and Clioquinol Cream, B.P. Hydrocortisone and Clioquinol Ointment, B.P. Quiniodochlor Tablets, I.P.

Other Metal-free Substances Besides the quinoline derivatives there are the other metal-free antiamoebic agents official such as diloxanide furoate and metronidazole. Many halocetamides are investigated for antiamoebic activity. Diloxanide is acetanilide derivative and chemically it is 2, 2-dichloro 4-hydroxy-Nmethy lacetanilide. Its ester wi th 2-furoic acid (furan-2-carboxy lic acid) has been found to be more effective. Its provides higher intestinal concentrations. Diloxanide furoate is chemically 4-(N-methyl-2,2-dichloroacetamido) phenyl 2-furoate. It occurs as a white or almost white crystaline powder. It is tasteless. It is protected from light. It is very slightly soluble in water.

It finds use along with chloroquine and tetracycline for treating intestinal amoebiasis, and is given with chloroquine and dehydrogmetine or emetine fnr treating hepatic amoebiasis. Diloxanide furoate is used along with an amoebicide

Pharmaceutical Chemistry (Organic)

296

I[/-COO-Q-jCOCHCI2 CH, Diloxanide Furoate

that acts in the tissues, such as metronidazole or dehydroemetine in patients with symptomatic intestinal amoebiasis or with hepatic amoebiasis. It is administered as tablets. Metronidazole and tinidazole (see under Miscellaneous Antirprotozoal Drugs) are also used in the treatment of hepatic or intestinal amoebiasis. In the treatment of amoebic dysentery, they may be given along with a luminal amoebicide such as diiodohydroxyquinoline or diloxanide furoate. One should mention about metronidazole benzoate (benzoyl metronidazole) is 2-(2-methyl-5-nitroimidazol-I-yl )etbyl benzoate. It occurs as a white or cream-coloured crystalline powder. It is stored in well-closed, light resistant containers. It is sparingly soluble in water. Metronidazole is having a bitter and has slightly saline taste, but metronidazole benzroate is almost tasteless. Oral suspensions having metronidazole benzoate find use as an acceptable tasteless form.

Metronidazole Benzoate

Official DiIoxanide Furoate, B.P., I.P. Diloxanide Furoate Tablets, I.P. (Diloxanide Tablets, B.P.) Metronidazole, B.P., I.P. Metronidazole Injection, I.P. Metronidazole Suppositories, B.P. Metronidazole Tablets, B.P., I.P. Metronidazole Benzoate, I.P. Metronidazole Benzoate Oral Suspension, I.P.

Antiamoebic Drugs

297

Tinidazole I.P. Tinidazole Tablets, I.P. Organometallic Compounds Various organometallic compounds are used as amoebicides. Only one, namely acetarsol however remains official (see under Miscellaneous Antiprotozoal Drugs ).It is an organoarsenical. It was probably the first organometallic compound which is formally introduced in the chemotherapy of amoebiasis. Acetarsol finds use in the treatment of intestinal amoebiasis. It was being given orally along with other amoebicides.1t is now replaced by less toxic drugs. Local application of acetarsol are found in the treatment of trichomonal vaginitis. Official Acetarsol, B.P.

27 Miscellaenous Antiprotozoal Drugs

27.1 Introduction The serious protozoan diseases beings include malaria, amoebiasis, trypanosomiasis, and leishmaniasis. Trichomoniasis and giardiasis have been the other protozoan diseases. The antimalarials and anti amoebic drugs have been described in separate chapters. Here a brief coverage has been ascribed to the other antiprotozoal drugs.

27.2 Trypanocides Trypanosomiasis is a dangerous disease which is caused by infection of parasites of the genus Trypanosoma. The disease gets transmitted by certain insects. African trypanosomiasis (sleeping sickness) is caused by infection of T. gambiense arxl T. rhodesiense. South American trypanosomiasis (Chaga's disease) is caused by to T.oruzi. Among the drugs used as trypanocides, pentamidine is described here. Pentamidine has been a diarnidine. It has been official as the salt with isethionic acid (2-hydroxyethanesulphonic acid), HOC~-C~S03H. Chemically pentamidine isethionate is 4, 4'- (pentamethylenedioxy) dibenzamidine bis (2-hydroxyethanesulphonate). It occurs as white or almost white, crystals or powder. It is having a very bitter taste. It is freely soluble in water. The solutions for injection may be prepared aseptically. Aqueous solutions get deteriorated on storage and have to be used immediately after preparation.

Pentamidine Isthinoate

Miscellaenous Antiprotozoal Drugs

299

It finds use in the treatment of early stages of African trypanosomiasis, especially in T. gambiense infections. It also finds use in the treatment of leishmaniasis (kala azar). It is generally administered by intramuscular injection.

Official Pentamidine Isethionate, B.P., I.P. Pentamidine Injection, B.P.

27.3 Leishmanicides Leishmaniasis is caused by the infection of the protozoa of the genus Leishmania. The disease has been reported to be spread by sand-flies. Kala azar has been a generalised form ofleishmaniasis which is occurring in the tropics. It is caused by the parasiteL. donovani. The cutaneous leishmaniasis (oriental sore) occurs due to L. tropica. The pentavalent antimony compounds such as sodium antimony gluconate (sodium stibogluconate) and urea stibamine have been found to be of value as leishmanicides. Sodium antimony gluconate is obtained by action of antimony pentachloride on gluconic acid and sodium hydroxide. It occurs as a white, amorphous powder. It is very soluble in water. Its solutions are sterilised by autoclaving or by filtration. It is administered either by intravenous or intramuscular injection in the treatment of visceral leishmaniasis (kala azar).1t also finds use by infiltration in the treatment of cutaneous leishmaniasis (oriental sore). Urea stibamine is prepared by reacting p-aminophenylstibinic acid with urea. It has indefinite structure. It is a pale greyish, pale brownish, or pinkish amorphous powder. It is soluble in water. The solutions for injection are obtained aseptically immediately before use. It finds use in the treatment of leishmaniasis, especially in India. It finds use in filariasis and schistosomiasis. It is administered by intravenous injection. As described elsewhere (under Trypanocides) pentamidine also finds use in the treatment of leishmaniasis, especially kala azar. It is particularly valuable in patients who fail to respond to treatment with antimonial drugs.

Official Pentamidine Isethionate, B.P .• I.P. Pentamidine Injection, B.P. Sodium Antimony Gluconate. I.P. (Sodium Stibogluconate, B.P.) Sodium Antimony Gluconate Injection, I.P. (Sodium Stibogluconate Injection, B.P.)

Pharmaceutical Chemistry (Organic)

300

27.4 Trichomonacides Trichomoniasis is brought about by Trichomonas species T. vaginalis has been found to be a parasite of the human genito-urinary tract. The official trichomonacides metronidazole and acetarsol have been described here. Metronidazole. Chemically, it is 2-(2-methyl-5-nitroimidazol-I-yl) ehtanol. It occurs as a white or cream coloured crytalline powder. It is having a bitter and slightly saline taste. It darkens on exposure to light. It is stored in wellclosed, light-resistant containers. It is sparingly soluble in water. Metronidazole is having antiprotozoal and antibacterial actions. It has been found to be effective against T. vaginalis and other protozoa such as Entamoeba histolytica and Giardia lamblia, and against anaerobic bacteria.

Metronidazole

Tinidazole

It finds use in the treatment of trichomoniasis of the genito-urinary tract in males and females. It finds use in the treatment of amoebic dysentery and amoebic liver abscess, and also in the treatment of giardiasis. The drug also finds use in the treatment of infections with various anaerobic bacteria. Metronidazole is usually given as tablets. Suppositories are also used. Metronidazole benzoate has been described under Antiamoebic Drugs. Acetarsol. It is an organoarsenical which is chemically 3-acetamido-4hydroxyphenylarsonic acid. It occurs as a white crystalline powder which is almost insoluble in water. Trichomonal vaginitis may be treated by local application of acetarsol. It also finds use orally in the treatment of intestinal amoebiasis.

-

o II

HO-/ '-As-OH

)=/

CHaCONH

I

OH Acetarsol

Diiodohydroxyquinoline (see under Antiamoebic Drugs). It has been used locally against T. vaginalis. Tinidozole. It is 1-[2-(ethylsulphonyl) ethyl]-2-methyl-5-nitroimidazole. It forms pale yellow crystals or crystalline powder having a slight characteristic

301

Miscellaenous Antiprotozoal Drugs

odour. Itis stored in well-closed, light-resistant containers. It is sparingly soluble in water. It is having antimicrobial actions of metronidazole and finds use similarly in the treatment of amoebiasis, giardiasis, and trichomoniasis.

Official

Dii~ohydroxyquinoline, I.P. Metronidazole, B.P., I.P. Metronidazole Injection, I.P. Metronidazole Suppositories, B.P. Metronidazole Tablets, B.P., I.P. Tinidazol, I.P. Tinidazole Tablets, I.P.

Drugs Used in Giardiasis Giardiasis (lambliasis) is an infection which is caused by Giardia Lamblia (formerly called G. intestinalis). This infection gives rise to diarrhoeic or dysenteric symptoms. Some antimalarials have been reported to be active against giardiasis Mepacrine (see under Antimalarials) has been suggested for the treatment of giardiasis. This is the major indication for the administration of mepacrine. As an antimalarial it is replaced by other drugs and its use for the expUlsion of tapeworms is also regarded as obsolete. Diiodohydroxyquinoline (see under Antiamoebic Drugs) also finds use in the treatment of giardiasis. One should also mention about furazolidone, which is having antibacterial and anti protozoal actions. It finds use in the treatment of diarrhoea and gastroenteritis of bacterial origin. It also finds use in the treatment of giardiasis. Chemically furazolidone is 3-(5-nitrofurfurylideneamino) oxazolidin-2-one.1t occurs as a yellow, crystalline powder. It is testeless intially, followed by a bitter after-taste. It is kept in well-closed, light-resistant containers. It is having slight solubility in water.

Furazolidone

Official Diiodohydroxyquinoline, I.P. Diiodohydroxyquinoline Tablets, I.P. Furazolidone, B.P., I.P. Furazolidone Tablets, J.P.

302

Pharmaceutical Chemistry (Organic)

Metronidazole, B.P., I.P. Metronidazole Injection, I.P. Metronidazole Suppositories, B.P. Metronidazole Tablets, B.P., I.P.

28 Urinary Tract Antiseptics 28.1 Introduction There are many antibiotics or sulphonamides which are preferred in treating the infections of urinary tract. These have been discussed under, the respecti,.ve chapters. Many other urinary antimicrobial agents are known which find use in the treatment and prophylaxis ofinfections of the lower urinary track. Two of them, especially, nitrofurantoin and nalidixic acid have been described here because these have been found to be of value for treating infections which are resistant to other agents. 1. Nitrofurantoin. Chemically, it is 1-(5-nitrofurfurylidine amino) imidazolidine-2,4-dione. It is having furan and imidazolidine heterocycles.

o

O,M-frCH=N_NqH o Nitrofurantoin

It occurs as lemon-yellow crystals or a fine powder. It is having bitter taste. It is having slight solubility in water. It gets decolourised by alkalis and by exposure to light. Due to this reason, it has to be preserved in well-closed container which is protected from light and kept in a cool place. Nitrofurantoin has been found to be bactericidal in vitro to most Grampositive and Gram-negative urinary-tract pathogens. Pseudomonas aeruginosa has been generally resistant and most strains of Proteus spp have been found to be moderately resistant. Nitrofurantoin is regarded to act by interfering with bacterial enzymes which are involved in carbohydrate metabolism.

304

Phannaceutical Chemistry (Organic)

It readily gets absorbed from the gastrointestinal tract and gets concentrated in the urine, antimicrobial concentrations not being reached in blood. It has been widely used prophylactically and for long-term suppressive therapy. It is either given as tablets or a mixture. Nitrofurantoin sodium is given parenterally to patients when they fail to take the drug by mouth. 2. Nalidixic acid. It is a derivative of 1.8-naphthyridine. Chemically, it is l-ethyl-l, 4-dihydro-7 -methyl-4,oxo-l, 8-naphthyridine 3-carboxylic acid.

CH CH I H3CWN N '" I I 2

& N

1

N 7~"'rI"~2

1S~3 5

'"

1.8-Naphthyridine

~

3

COOH

o Nalidixic Acid

It occurs as a white to yellow crystalline powder. It is practic~lY insoluble in water. It has to be kept in well-closed, light-resistant containers. Nalidixic acid has been bactericidal and has been found to inhibit Gram-negative microorganisms. Pseudomonas aeruginosa is usually resistant. Unlike nitrofuratoin, Gram-positive urinary-tract pathogens have been found to be relatively resistant. Nalidixic acid is regarded to be acting by inhibiting the replication of bacterial DNA. Nalidixic acid readily gets absorbed from the gastrointestinal tract. It is either given as tablets or a mixture in the treatment of urinary-tract infections due to Gram-negative microorganisms other thanPseudomonasspp., which has been generally not susceptible. Its antibacterial activity does not get significantly affected by differences in urinary pH. It also finds use in the treatment of bacterial dysentery. The sodium salt of nalidixic acid is given by intravenous infusion. Official Nalidixic Acid, B.P., I.P. Nalidixic Acid Mixture, B.P. Nalidixic Acid Tablets, B.P., I.P. Nitrofurantoin. B.P., J.P. Nitrofurantoin Mixture, B.P. Nitrofurantoin Tablets, B.P., J.P.

29 Antifungal Drugs 29.1 Introduction Previously fungal infection was regarded as an uncommon disease. Now in recent years fungal infections are worldwide in nature and are systemic as well as local among individuals of all ages. Many remedies have been used against fungus infections, and research still continues which would lead one to conclude that the ideal topical anti-fungal agent has not yet been found. However, now practically the whole spectrum of fungus diseases can be successfully treated. Antifungal agents are used in the treatment of a variety of fungal infections. Some are active orally while others are mostly applied topically in the form of ointment, creams, lotions, suspensions. Fatty acids and some aromatic acids are having antifungal properties, Some of the newer synthetic drugs have been now of interest as antifungal agents. The other important category of antifungal substances belong to the antibiotics class. The antifungal agents have been generally used in the treatment of infections of the hair, mucous membranes, nail, or skin by the fungi of the genera Candida (candidiasis ),Epidermophyton, Microsporum, and Trichophyton(tinea; ringworm).

29.2 Antibiotics Several antibiotics are known which possess antifungal activity. These include griseofulvin, and certain antibiotics belonging to polyene macrolide class.

306

1.

Pharmaceutical Chemistry (Organic)

Griesofulvin

An antibiotic which is not polyene is griseofulvin (Fulvicin, Grisactin). It was first isolated from Penicillin griseofulvum Dierck in 1939 but in 1958 its use in the treatment of fungal infection was recommended. Chemically, it is having a spiro system (in such system a single atom has been common to two rings). It has been named as (2S,6'R)-7-chloro-2', 4, 6trimethoxy-6'-methylbenzofuran-2-spiro-1 '-cyclohex-2'-ene- 3,4' dione. It occurs as a white to pale cream powder whose panicles are generally up to 4 11m in maximum dimension with only a few larger panicles exceeding 3011m. It is tasteless. It is having very slight solubility in water. It is administered by mouth for doing the treatment of a variety offungal infections of the skin, nails and hair. Griseofulvin is irregularly absorbed over a prolonged period from the gastrointestinal tract. It has specific action against ringworm infection of the body, nails and the scalp and athlete's foot (tinea pendis).1t is used orally. However, the treatment has to be carried out for months because this antibiotic prevents the growth of the organism in new tissues, but the old tissues suppon the fungi already present, therefore, the treatment with griseofulvin has to be continued till the old tissues become completely exfoliated. The side effects of this drug are gastric discomfort, diarrhoea, and headache, urticaria and rash.

el CH,O

o Griseofulvin

Official Griseofulvin, B.P., I. P. Griseofulvin Tablets, B.P., I.P. 2.

Polyenes

Many polyene antibiotics having a conjugated system of double bonds show similar antifungal activity. They are macrocyclic lactones but are riifferent from the macrolide antibiotics of the erythromycin type by having a larger lactone ring in which conjugated polyene system is present. Many of them have a glycosidic ally linked aminosugar. Their antifungal action is perhaps by forming a complex with sterols which are present in the membrane. Three important macrocyc1ic antibiotics which are used as antifungal agents are nystatin (Mycostatin), amphotericin B (Fungizone) andcandicidin (Candeptin). (i) Amphotericin. Amphotericin isolated from the growth of the strain of the species Streptomyces nodosus is not one compound but consists of two closely related substances called amphotericin A and B. The compound B has been more active and has been found to be very effective against deep seated

Antifungal Drugs

307

mycotic infections and also effective in systematic infections which are caused by Candida aIbicans. The drug is dangerous because thrombophlebitis may be produced at the site of infection and some renal damage, skin rash and gastrointestinal upset may also occur. Still its use is recommended in severe systematic infection.

Amphotericin B

It is a yellow to orange powder. It is almost tasteless. It is kept in tightly closed, light resistant containers in a cold place. It is insoluble in water. It finds use for the treatment of severe mycotic infections. Its colloidal form in combination with sodium deoxycholate is used for injection and its crystalline form for topical or oral administration. It does not get absorbed from the gastrointestinal tract and is usually given by mouth for suppressing oral or intestinal candidiasis. (ii)Candicidin.Candicidin isolated from a strain ofStreptomyces griseus (1953) was used in the treatment of momlia infection of the vaginal tract after 1964. Candicidin is a mixture of antifungal heptaenes which are produced by Streptomyces griseus and other Streptomyces spp. It forms a yellow powder. It is very slightly soluble in water. It should be preserved in well-closed container which is protected from light. It is especially used for th~ local treatment of vaginal candidiasis. (iii) Nystatin. Nystatin which is isolated from the strain of Streptomyces nourseiis very useful in the treatment of gastrointestinal and local infections of Candida albicans. .

Nystatin

Nystatin is a mixture of antifungal polyenes which are produced by the growth of certain strains of Streptomyces noursei. It occurs as a yellow to light

308

Pharmaceutical Chemistry (Organic)

brown hygroscopic powder. It is very slightly soluble in water. It is kept in wellclosed, light-resistant containers at a temperature not exceeding 50. It finds use for the local treatment of candidiasis, especially that due to Candida albicans.1t also finds use in the treatment and prophylaxis of intestinal candidiasis. It gets absorbed poorly from the gastrointestinal tract. (iv) Hamycin: It is a polyene antibiotic substance which is produced by the growth of Streptomyces pimpriTUl. It is a yellow amorphous powder; almost insoluble in water. It is an amphoteric compound. Hamycin is reported to possess antifungal and antitichomonal properties. It is administered topically and by mouth in a variety of fungal infections. Official Amphotericin B.P., I.P. (Amphotericin, B.P.) Ampotericin Lozenges, B.P. Nystatin, B.P., J.P. Nystatin Ointment, B.P., I.P Nystatin Oral Suspension, B.P. Nystatin Tablets, B.P., I.P. Nystatin Vaginal Tablets, J.P. (Nystatin Pessaries, B.P.) 29.3 Synthetic Antifungal Drugs Micronazole, econazole, flucytosine, and Tolnaftate have been relatively recently discovered antifungal agents. The earlier known remedies have been miscellaneous agents such as some fatty and aromatic acids, dithranol, and chlorphenesin. Miconazole and Econazole Miconazole, econazole and clotrimazole are having imidazole heterocycle. Miconazole and econazole are related compounds. Miconazole is 1-[2,4dichloro-~-(2,4-dichlorobenzyloxy)phenethyl]imidazole, and econazole is I1.

N

~) N Cl

Cl

Cl

Miconazole (X = el) Econazole (X = H)

Antifungal Drugs

309

[2,4-dichloro-~(4-chlorobenzyloxy)phenethyl]imidazole. They are official as the nitrates. These occur as white or almost white crystalline powders; miconazole nitrate may be microcrystalline. They are having very slight solubility in water. They are stored in well-closed containers protected from light.

Miconazole nitrate and econazole nitrate have been applied topically for treating fungal infections like candidiasis, pityriasis versicolor and tinea. Creams and pessaries find use in vaginal candidiasis.

2.

Clotrimazole

It is 1-(2-chlorotrityl) imidazole. It occurs as white to pale yellow, crystalline powder. It is to be stored in a well closed container and protected from light. It is practically insoluble in water. Clotrimazole is applied locally in the treatment of candidiasis, tinea, and pityriasis versicolor. It is given as a vaginal cream or pessaries for treating candidal and trichomonal vaginitis. N~

~N' CI

O-6~-b I~

~

Clotrimazole

3.

Flucytosine

Flucytosine is a fluorinated pyrimidine analogue which is related to fluorouracil. Chemically it is 4-amino5-fluoropyrimidin-2(lH)-one. It occurs as a white or almost white, crystalline powder. It is sparingly soluble in water. It is kept in a well closed container, which is protected from light. Flucytosine gets absorbed from the gastrointestinal tract. It finds use in the treatment of severe Flucytosine systemic and urinary tract infections due to susceptible fungi including Candida and Crypococcus spp. It is adminstered by mouth, by intravenous infusion, or by intraperitoneal infusion.

4.

Tolnaftate

Tolnaftate is an ester of ~-naphthol Chemically it is 0-2-naphthyl Nmethyl-m-tolylthiocarbamate.1t occurs as a white to creamy white powder. It is CH 3

s

:\ /, N-C-0'OO V i 11-

:;.-'" I" ~

CH 3

Tolnaftate

~

Pharmaceutical Chemistry (Organic)

310

practically insoluble in water. Tolnaftate is an antifungal agent which is used topically as a solution, powder, or cream for treating various fonns oftinea and of pityriasis versicolor. It is used with nystatin when candidal infections are present.

S.

Acids and their Salts

Previously it was postulated that it was the pH of perspiration which was responsible for its fungicidal and fungistatic effect. However, Peck in 1939 showed that the presence of fatty acids and their salts was responsible for this property of perspiration. Chemical analysis of sweat reveals that it possesses about 0.0081 per cent of propionic acid. Later on, it was found that the propionic acid and its sodium, ammonium, calcium, copper, zinc, and potassium salts are active fungicides. Further the salts have been found to be active as the free acid. Other acids like caprylic and undecylenic acids also exhibit similar fungicidal properties. Many other fatty acids are known which also possess antifungal properties. However, the above acids are used because they are readily available. C~CH2COOH

Propionic acid

CH/CH2 )sCH2COOH Caprylic acid

CH2=CHCH2(CH2)7COOH Undecylenic acid Ofthese undecylenic acid is best fatty acid which is used as topical fungicidal agent. Aromatic acids such as benzoic acid and salicylic acid are having antibacterial and antifungal properties and are used externally. Compound benzoic acid ointment (bezoic acid and salicylic acid ointment; Whitfield's ointment) finds use for the treatment of funguos infections of the skin.

COOH

I

/,

,/

I

II

Benzoic acid

(i) Benzoic acid (I.P., B.P., U. s. P.). Benzoic acid contains not less than 99.5 per cent and not more than the equivalent of 100.5 cent of C 7HP2' which is calculated with reference to the anhydrous substance.

Itfonns colourless, light, crystals, scales or needles. Its odour is slight and characteristic. It is slightly soluble in water but freely soluble in chloroform and in solvent ether. Its melting range is 121° and 123°.

It gives buff coloured precipitate with ferric salt. Ii forms insoluble salts with heavy metals such as silver, lead, mercury, etc. Benzoic acid finds use externally as an antiseptic in lotions, ointments, mouth washes, etc. Benzoic acid in combination with salicylic acid finds use as antifungal agent. Benzoic acid and its sodium salt find use as effective food preservati ve. Benzoic acid is stored in well closed containers.

Antifungal Drugs

COOH I OH

CX

/311

(ii) Salicylic acid (J.P., B.P., U.S.P.). Salicylic acid is 2-hydroxybenzoic acid. It contains not less than 99.5 per cent and not more than the equivalent of 101.0 per cent of C7HP3 calculated with reference to the dried substance.

Salicylic acid forms colourless or almost colourless feathery crystals or a white powder. It is almost odourless. Its taste is sweetish and acrid. Salicylic acid

Salicylic acid is slightly soluble in water, but it is soluble in boiling water. It is freely soluble in alcohol and in solvent ether. It is sparingly soluble in chloroform. With ferric salts, it gives violet colour. With heavy metals, it forms salts. With oxidising agents, it forms coloured compounds. It is having antiseptic properties. It acts as antifungal in 3 to 5% in the form of iointment, cream, lotions. (iii) Undecylenic acid. An antifungal fatty acid official has been undecylenic (undecenoic) acid, CH2=CH(CH2)g-COOH (undec-l O-enoic acid). It is obtained by cracking castor oil. It occurs as a colourless to pale yellowish brown clear liquid or white to yellowish-white, crystalline mass. It is having a congealing range between 21° and 24°. It is having a characteristic odour. Its refractive index is between 1.447 and 1.450. It is preserved in tightly-closed, light-resistant containers. It finds use topically in the prophylaxis and treatment of dermatophytic infections of superficial areas. It is used as the acid or the zinc salt, which is also official. (iv) Zinc undecylenate (I. P., U. S. P.). Zinc undecy lenate (zinc udecenoate) occurs as a fine, white or pale yellowish white powder having a characteristic odour. It is practically insoluble in water. It is applied to the skin, generally in conjunction with undecylenic acid, in ointments and dusting powders. [CH2=CH (CH 2)gCOO]2 Zn Zinc undecylenate is stored in well-closed containers.

6.

Dithranol

It is a phenolic compound dithranol (deoxyanthranol; antralin) which finds use in the treatment of psoriasis. It acts as a fungicide and finds us in the treatment of ringworm infections and chronic dermatoses. Dithranol has been a mixture of 1,8,9- anthracentriol and its tautomers. In the B. P., it is regarded as a mixture of I, 8-dihydroxy-9-anthrone and its tautomers. It occurs as a

OH

OH

OH

OH ~ ~

10

~

Dithranol

0

OH

cill ...

/.

312

Pharmaceutical Chemistry (Organic)

yellowish-brown powder. It is practically insoluble in water. It is soluble in solution of alkali hydroxides. It is kept in well closed, light resistant containers.

7.

Chlorphenesin Chlorphenesin, having antibacterial and antifungal properties, have been official in the LP. Chemically it is 3-(4-chlorophenoxy)-1, 2-propanediol. It occurs as a white or pale cream-coloured powder. Its odour is slightly phenolic. OH

~I

CI\~OCH2CHCH20H

Chlorophenesin

It is having slight solubility in water. Chlorophenesin finds use mainly in the prophylaxis and treatment of dermatophytoses of the feet and other sites. It has been applied topically as an ointment and as a dusting powder. Official

Benzoic Acid, B.P.. LP. Compound Benzoic Acid Ointment, B.P., LP. Chlorphenesin, I.P. Clotrimazle, B.P., LP. Clotrimazole Cream, B.P. Clotrimazole Pessaries, B.P. Dithranol, B.P., I.P. Dithranol Ointment, B.P. Dithranol Paste, B.P. Econazole Nitrate, B.P. Econazole Nitrate Cream, B.P. Econazole Nitrate Pessaries, B.P. Flucytosine, B.P. F1ucytosine Tablets, B.P. Miconazole Nitrate, B.P., I.P. Miconazole Cream. B.P. Miconazole Ointment, I.P. Tolnaftate, B.P. Undecylenic Acid, I.P. (Udecenoic Acid, B.P.) Zinc Undecylenate, LP. (Zinc Undecylenate, B.P.) Zinc Undecylenate Ointment, I.P. *

* Contains Zinc Undecylenate and Undecylenic Acid.

30 Antiviral Agents

30.1 Introduction Viruses are obligate parasites that need the active participation of the metabolic processes of the invaded cell. Antiviral chemotherapy is confronted with two major obstacles which explain its slow progress and scanty achievements: (a) the intimate relationship that exists between mUltiplying viruses and mammal cells; thus, most antiviral agents lack selectivity, being equally toxic to both virus and host; (b) many viral diseases are diagnosed too late for effective treatment; usually, the first symptoms of viral diseases appear at the final stage of viral multiplkation. Despite the great effort toward discovering useful antiviral agents, only a few are presently available. None has broad-spectrum antiviral activity, although drugs ofthis sort are badly needed. Therefore, antiviral chemotherapy is at same stage as antibacterial chemotherapy before the introduction of sulfa drugs. For prophylaxis of most serious viral diseases, the only available and dependable resources are vaccines. For treatment of others, sera are the recommended preparations. The antiviral drugs idoxuridine and methisazone may be discussed first.

1.

Idoxuridine

It is 5-iodo-2'-deoxyuridine. It forms odourless crystals or white crystalline powder and has to be stored in well closed, light-resistant containers. It has slight solubility in water. Its aqueous solutions have been found to be most stable· at pH 2 to 6. Its aqueous solutions are freshly prepared and stored in a refrigerator. It finds use in the treatment of superficial herpes simplex keratitis

314

Pharmaceutical Chemistry (Organic)

, /

Idoxuridine

(dendritic keratitis) of recent origin. Idoxuridine is applied as eye drops or eye ointment in 0.1 and a 0.5% concentration respectively.

2. Acyclovir Chemically, it is 9-(2-hydroxyethoxymethyl) guanine. It occurs as a white or almost white, crystalline powder. It is slightly soluble in water. Acyclovir is used for the treatment of viral infections because of herpes simplex virus (types

o HN;JcN,

H2N~N

N

I CHzOCHzCHaOH Acyclovir

1 and 2) and varicella zoster virus (herpes zoster and chicken pox). It is given by intravenous (as the sodium salt), oral, or topical routes. The other antiviral agents levamisole (see under Anthelmintics), and cytarabine (see under Antineoplastic Agents~ have been discussed elsewhere. 3. Methisazone (metisazone) Chemically, it is 2-methylindoline-2,3-dione, 3-thiosemicarbazone. It is an orange yellow powder. It is particularly insoluble in water. Methisazone is protected from light. It has been reported to be active against the proxviruses and is being used in the prophylaxis of smallpox and alastrim (variola minor) although smallpox vaccination is regarded to/provide better long-term protection. It may be used for mass administration in conjunction with vaccination in the event of an epidemic of smallpox ever occurring again. It is also given to

/CH a

/'\./N I

II '=0

,/'\./

'NNHCNH.

II

s Methisazone

315

Antiviral Agents

prevent complications following vaccination and is used in the treatment of eczema vaccinatum and vaccinia gangrenosa. It is given by mouth. 4.

Amantadine hydrochloride

It is an antiviral agent which is used prophylactically against infection with influenza A 2 virus. It is not effective in preventing infection with other types of influenza virus. It has been tried in the treatment of herpes zoster. Amantadine

may increasedopaminergic activity and find use in the treatment of parkinsonism usually in conjunction with other therapy. Amantadine hydrochloride is given to patient by mouth.

JjUC

Amantadine hydrochloride

It is given in 200 mg daily dose in preventation of influenza virus A 2 strain. (Also, see under Antiparkinsonism Drugs)

S.

Levamisole hydrochloride It is an anthelmintic which affects immune response. It has been tried in a wide variety of disorders involving the immune response, including bacterial and viral infections.

6.

Cytarabine It is a pyrimidine nucleoside analogue which finds use as an antineoplastic agents mainly in the treatment ofleukaemia.1t has also been used as an anti viral drug. It is given by intravenous injection in the treatment of herpes infection. It given intrathecally for encephalitis. (Also, see under Antine