Pharmacology Review

Table of contents :
Cover
......Page 1
Contents
......Page 4
1- General pharmacology......Page 5
2- Autonomic nervous system......Page 12
3- Skeletal muscle relaxants......Page 24
4- Autacoids......Page 26
5- Eye......Page 30
6- Respiration......Page 32
7- Blood......Page 33
8- Diuretics......Page 36
9- Cardiovascular......Page 38
10- GIT......Page 44
11- CNS......Page 46
12- Hormones......Page 58
13- Chemotherapy......Page 65
14- Clinical topics......Page 74
15- List of abbreviations......Page 87

Citation preview

PHARMACOLOGY Dr.E ~

sayed MAhmo .d E okh Professor of Pharmacology

Faculty of Medicine - Cairo University

Content Subject

Page

1-General pharmacology 2-Autonomic nervous system 3-Skeletal muscle relaxants 4-Autacoids 5-Eye 6-Respiration 7-Blood 8-Diuretics 9-Cardiovascular

26

10- GIT

40

11-CNS 12-Hormones 13 -Chemotherapy 14-Clinical topics 15-List of aabbreviations

42 54 61

1 8 20 22

28 29 32 34

70

83

Sources of drugs Plant ori g in: atro pine, digox in ........... . Anima l o rig in: ins ulin , heparin . Micro organis ms - penici II in. Recom binant DN A technology as insulin and tPA . Synthe tic drugs: su lphonam ides.

Mechanisms of drug action

* Ph) ..,it:al : osmo ti c diuresis by ma nn itol, kaol in in di a rrhea to adsorb tox ins. * Chcmi~a l : Na HC03 in hyperacidity, d imercapro l (BA L) to c he late Hg. * \!h.:mbram: action: loca l anesthetics. * Enzyme activati on or inhibition (revers ible & irreversib le). metabo lic pathway e.g. '' ith * lnterl~ n.! s ulphonamides compete with PABA. * C)toto\.iWhy th iopentone has very short duration.

Biotransformation (metabolism)

Distribution is:

* Extracellular: quaternary amines, mannitol, a+, G- ..... * lntracelluar: te rtiary a mines, alcohol, morph ine ....

* Intravascul ar: -d rugs highly bound LO pl

sma proteins and hig

weig ht drugs as dextran. *Selective:- thiopentone in fats, bin th ro id g land.

Drugs are present in blood in:Free form Diffusib le, active, metabolized & excreted

' - - - - - -inert, not"avaiiable-for r------m 1 etabolisrn r-excr.etion (reserv ir for drugs)

l~ver):

' • Resgpn ib e for oxtdation (by cytochro 4so), g luc uro nide COl1Jugati on, reductio n and hydro lysis. ~ Act i v ity is low in ne born (esp. premantre), in e lderly and starvation. *The:t can be induced and inh ib ited by drugs.

N on microsomal en: rmes: * Present in li ver, gut, plasma, k idney, lungs ...... . * Responsible for other conjugations, ox idation, reduction & hydro lysis. * Acfvity is stable & a re not ind uced or inhibited.

*Phase 1 (11o n srnt!Jttid reactions:- inci\Jde oxidation, reduction and hydro lysis. T hey may resul t in drug inactivation or convert active drug into * Drugs are bound ma inl y to albumin. act ive metabolite or inacti ve drug into acrive o r convert drug into more toxic metabolite. * Binding to proteins is revers ible. *Phase 11 (srntheticJ r eactions :- conjugatio n of drug o r its metabo lite with *Drugs may displace each other from plas.[lla prote in bin ·ng ites ---4 drug glucuronic acicl(microsomal e nzymes) or acetic ac id , g lycine, sulphate or interactions. Salicylates, phe nybutazone-..and su lphonam ·des aJrtltsplace metnyl group non microsomal). They u~t1all y resu lt in drug inactivation but oral anticoagulants & ora l hypog lycet ics. S ul pho/i: es ca dis p1acc m rphine-6-g lucurqqide ts active. bi lirubin - ke rnictrus in newborn esp. prem tu ·e. ._. Enzyme a 13 - receptor stimulation => => a , -receptor stimul ation thro

Gs protein so j c mrcJuQn~ Gi protein so

*Stimulation of a 2 (a - presynaptic) * Stimulation o f~ presynaptic recepro,rs

insulin release.

cocaine, guanemioine. => Uptake I of noradrenaline is b b phenoxybenzaovne. => Uptake II of noradrenaline is bl by rese!:,Pine which decrease sym~athetic activity, -while ~i e which => Granular uptake of noradrenaline is blocks uptake I will j sympathetic actiVity. * s~ nthcsis of noradrena line:hy droxy lare

oraorenalin ins" de vesicles dopa Rate limiting step => Noradrenaline inhibits its own synthesis by inhibiting tyrosine by oxyl e el"\Z)' e rate limifmg step) ~ => a - methyl tyrosine inhibits tyrosine hydroxylase enzyme _j Bo1liinhibit noradrenaline synth esis => a- methyl dopa inhi bits dopa decarboxylase enzyme

Tyrosine

. . - - - Cholinergic Stimulants (Parasympathomimetics) Darect actmg ...---Stim ul ate muscarinic receptors

* Choline esters

+

(q uaternary am ine) A.ch., methacho line, carbacho l a nd bethanechol

-~-------..

-+ Indirect acting

.........- Canticholincsterascs~

Lholinomimetic alkaloi

* Revers ible

*-Muscarinic actions:

* Irreversible • DFP, pa ra thio n,

1- Eye: mi osis, contract ci li a ry muscle, accorn d ra inage, -!.. I.O.P. i lacrimation, co ·unc ·val 2 - Secre ti ons: - i sa liva ry, bronchia l 3- Bronchoconstricti on . 4- Bradycardia, l A.Y. conducti 5- i g ut moti lity. 6- contract wa ll of urina ry blad er, e lax s phincter

ma lath io n, metri fonate • Ecothiopate (water so luble)

release of adr. & notadr.

"'--A.ch L.D. I a nd a ll anticho linestrases

=> C holine esters:- quaterna ry A.Ch . -True chol ineste rase. - Pseudocho lineste rase. - Muscarinic actions. -N icoti n ic acti ons. - O ral absorptio n. - Selecti vity. -Adm ini stration. -Uses.

Carbachol

Bethanechol

+++

+++

Hydrolyzed Hydrol yzed

+++

comple te - urinary tract Oral o r S.C. (ca rbach o l ), para lytic ile us a nd no n o bstructi ve urine re tentio n ~ye-G IT.

=> Pilocarpine: Plant ori gi n, tertiary a mine (passes BBB). Acts iTeetly...on..muscarin' ecepto rs, selecti ve o n eye & secretions, used in ttt o f g la ucoma, to an tagoni ze mydriatics & a lternati vely wi th mydriatic to cut adhesions. A lso toisa li vation & increases sweat (d ia pho retic ) in fe ver. => Cev imcline is o ral muscari n ic agonist for ttt o f xero stomia

Ach. binds to the active site of the enzyme and hydrolyzed ----=----~ into free choline and acetylated enzyme in 150 microseconds

Acetyl Choline dctCic acld

1- Reversible anticholinesterases

* Edrophonium is alcohol with which binds to the active 5 minutes and then exc substrate for the

c:sterath::

* Carbamates

(physostif'>&U"""'""' hydrolysis as Ach. resistant to hydrati substrate for the Carbarnates

2- Irreversible anticholi They combine with phosphorylated en for hydrolysis). This p aging process which complete and permanent en have long duration until new

Orgunoph()~phorous

compounds

:~; -~"::_.· ~\:··.:-.?~' '

'

ible (organophosphorus compounds) They are non competitive

* Physostigmine • Natural, plant origin • Tertiary amine Actions 1- Muscarinic 2- Nicotinic. 3- C.N.S stimulati on => Uses: Local: o n eye in ttt antagonize mydriatics, between iris and lens. Systemic: in atropine poisoning.

y lipid soluble and can be absorbed from insoluble. : parathion , malathion ( inactive ion is safe r ), DFP, tabun, sarin . (long use

~

cataract).

horus poisoning:

l

H.R and

inducing skeletal muscle convulsions) then coma &

l

=> Physostigmine & neostig min => => Demecari urn eye drops

to respiratory fai lure.

* Edrophonium is a quaternary ami

antagonize muscarinic effects

rena l excretion. It is given I.V. => Used for diag nosis of myasthenia gra cholinergic and myasthenic weakness. antidote to curare. * Tacrine has anticholine esterase activity, used in A~lwc~triieF:.un~~·~· * Donepczil, Galantamine and rivastigminc are more se1ectnre o nce/day in Alzheimer's disease and are not hepatotoxic. N. B. : Mcmantine is used in tttt of Alzheimer's disease & acts by blocking NMDA rece

rs as pralidoxime, ( PAM) rn(Jifio:xin1e (DAM) l. V. as early as possible. (PAM) can not pass to C.N.S. but diacetyl

'incmax-tfi1e (DAM) crosses blood brain barri er. - Anticonvulsions as diazepam. -Gastric lavage (if oral) & skin wash (if through skin).

'

.". -~( .

~

Muscarinic antagonists (Parasympatholytics) Compete with Ach for muscarinic receptors

--------.

Synthetic d crivath cs Natuntl bclladona alkaloids Plant origin, include atropine, hyoscine = scopolam ine. * Antiasthmatic * Antisccrctory * Atropine: Antispasmodic um is pratropi I • mydriasis ive pass • Eye:amine, given quaternary and zepinc Pire - ve light reflex, cycloplegia, i lOP. by inhalation, dilates telenz pine l Lacrimation. 7-10 days local bronchi with no dryness 1 lockers). (M • l Secretions (salivary, gastri c, bronchial of secretions, used in • Proba theine. and sweat) bronchial asthma. • Bronchodilatation. • Tiotropium is similar, • i H.R. , T A. V conduction. Toxio dos longer duration and used flushing. in COPD. * U cd as atropine & • l gut motili ty and urinary retent'on. in glaucoma. p, fi Ted in preanaesthesia • T R.C. , TC.I.C. (in itial l H.R als diac and thyrotox io f block of pre-synapti c M recepto .) * Bcnzhc:xol and pati nts, in labour • l Vom iting center. (+analgesic) motion • l Basal ganglia. ~ic~q!-ess, Mini-ere's dtse~, • Large dose i cortex I pept c ulcer, col ics. Gano ion blockers * Uses • Depolarising : NLD. 1- Preanaesthet ic medication to d cr se salivary and bron hial secretions & • on Jepolarising (competitive) prevents bronchospasm, to prote t h art from bradyca dia to T R.C. & prevent Trityethaphan: release histamine, given by vomiting. I.V. infusion, no C.N.S. action. 2- Fundus exam ination, errors of re ~ cti n & iritis. ecamylamine (Secondary amine, affects yndromc. 3- Bradycardia, heart block & carotid ·n .N.S). 4- Bronchial asthma (ipratropium is bet r). Quaternary am ines: TEA, 5- Duodenal ulcer, co lics, diarrhea. hexamethonium, ecolid = .C reflexly, 6- Nocturnal enuresis. ine chlorisondam gut. 7- Antidote to parasympathomimetics (parathio ......). + orthostatic atropine as Actions: • T , 6acco smoking i 8- Parkinsoni sm. (postura l) hypotension + impotence. enzyme inducer. 9- Motion sickness (hyoscine is better & may be used a Uses: - Trimethaphan in ttt of emergency • Lobeline-is used in tl1 I0- Hyperhiderosis (excessive sweating). hypertension & to induce controlled * Toxicity:- dry mouth (xerostomia), blurred vision, T H.R., m)tdtia i .-~-~ neonatal asphyxia. hypotension during surgery. flushing, dry skin, hyperthermia, excitation. ttt by physostigmine, cold fomentations. * Contraindications:- glaucoma- prostatic enlargement.

Natural:- dopamine, noradrenaline, adrenaline ..,. Catecholamines Synthetic:- isoprenaline dobutamine, isoetharine. -+Non catecholamincs: ephedrine, amphetamin " pheuy.lep ··ne salbutamol. ......... . ..,. Mechani sm or action:I - Direct:- catecholamines, pheny: brine, salbutamol. 2- Indirect:- amphetamine, t r ine on · - 13 , no e f ·e and repeated use - tac yphy~ax is. 3- M ixed (dual):- e edri . ..,. Catecholamines are metabolised by COMT

Sympathomirneti~:

Adrenaline

-=:::::::::

Dobutaminc

* Receptors a - 13 13, * Admini stration. S.C. I.Y. infusion ...,. Local * Decongestant, hemostatic, chronotropic so i H.R. , contraction * Delay absorption of loca l anesth tics and CO. * l i.O.P., littl e effect on pupi l siz . Produces V'.D ...,. Systemic l P.R. * i H.R. contraction, C.O., prodL ces .__·~----~ or no V.C. (a) & Y.D. (132). * B.P: systolic i ( i C.O.) diastol'c ± So i B.P., reversed by a - blae r. Isoet harine * Dilates bronchi (132), .!. gut, u1 'ne retention. * Contracts uterus (a), relaxes hu man pregnant uterus (132). Fenoldopam *t glycogenolysis (132) and lipolys is 13 u . * , receptor agonist 11'hich decreases P.R. i blood glucose & blood lactate. by dilating arterioles. * Physiological antagonist to hi stamine *It is given by I. V. drip in emergency on bronchi & B.P. hypertension. * i K+ uptake ~ hypokalemia. Side effects: Used in: allergy (anaphylactic shock), Headache. flushing and tachycardia . ~-----~~~~~~~~~--+--+----~~~~~-~~----~ with local anesthetics, epistaxis (loca ll y), glaucoma (dipi vefrine is a Dopexamine * a- stimu lants prodrug), cardiac arrest It acts on D 1, D2, f32 receptors ..,. Renex bradycardia is bloc d-by at-mpine-o ~angli on blocker. (intracardiac), acute bronch ial It is given by l. Y. drip in shock & heart * Chronotropic= H. R. N.B. : * Inotropic= contraction. asthma. hypoglycem ia, failure

* Contraidications of adrenaline :- Hypertension - arrhythm ia- angin a pectoris- Thyrotoxicosis - with loca l anesthetics in fingers & toes digitali s and some general anesthetics as halothane

----4

----4

arrhythmias, & with non selective f3- blockers ----4 severe hypertension

lsopt·enalinc Receptors

H.R. Increased

Contractility COP

Skin & mm vessels ( Ske letal vessels (!32

Little effect or

Increased

v.c. V.D.

TPR Systolic B. P.

or no effect

Diastolic B.P. Bronch i (fl 2)

Relax

In testi ne (u- fl)

Decreases motility

Uterus (a - lh)

Relax

Administration

Inhalation, sublingual

gangrene, with

Non- Catecholamines fl- stimulants ..,.. Selective fh agonists:Salbutamol, terbutaline,(short duration = 12 h) orally or injection or inha lation, and salmetrol, formote•·ol inhalation ( long acting, 12 h) & bambuterol oral 24 h ). They are not affected by MAO or COMT ~ Produce bronchodi latation , 1 bronchia l secretions & l releas of a lle rg ic mediators from ma ce lls & jmucociliary activi ty. ~ Relax uterus & produce Y.D., mild tachycardia (reflex & weak ~~ effect). i g lycogenolysis & insu lin releas -Used in bronchia l asthma. Side e ffects: Tremors, j HR, nervousness, tolerance &lK+ ~

Ritodrine:- B:! agon ist, used in pre mature labour & constriction ring of uterus & dysmenorrhea. Non selective fl - agonists

* lsoxsuprine in vascular diseases & constriction ring of uterus.

* Orciprenaline orally or inhalation in bronchial asthma.

11--:::-::::==-:-=:":"'"l':='"--·.l:":':: m~1~ ss~1-':': n. ---1 0':':'

Amphetamine Synthetic, weak base, acidic urine i its excretio n. It acts indirectly and has marked action on C.N.S. Pro duces euphoria, a naleptic action, i synaptic transmi ss ion, ..!.appetite. It i B.P., produce mydriasis, urine rytention. tJ, ed in obesity - narcolepsy - rtention deficit hyperkinetic di order in ch ildren (ADHD) . LO g use ~ addiction. M thylphen idate is amphetamine v iant which is used in (ADHD). tomoxitine se lectively inhibits n radr. uptake & is used in ADHD. has clonidine like action on CNS so has little CVSeffects. S ibu tramine inhibits noradr. & 5HT uptake & is used as appetite suppressant, but may produce cardiovascular strokes. Duloxetine is a ntidepressant w hic h inhibits 5HT , noradr. uptake with no CVS risks. Modafi nil is a psychos timulant wh ich acts on central receptors (a, 5HT and g lutamate) and is used in narcolepsy .

Sympathetic Depressants (Sympatholytic Drugs)

1- Adrenoceptor blocker: a and

a2 and imidazoline receptors

yl noradrenaline has high affin ity fo r a2 receptors,

~-bl ockers .

r non adrenergic binding site (imidazo li ne

2- Adrenergic neuron blockers, which inhibit nn•~a~n ...,.r,a

clonidine and other imidazoline

(guanethidine, bretylium) or deplete n

to these non adrenergic binding sites.

3- Inhi bitors o f noradrenaline sythesis 4- Ganglion blockers.

inc act on imidazo line receptors

imidazo line receptor agonis

LILU,.........

e less sedation and less dry

N. B.:

Noradrenaline Limiting step in catecholam

is the rate nc are a 2 agonists used in

a-methy l-p-tyrosine inhibits tyrosine hydroxylase enzyme.

and reduces withdrawal (morphine and nicotine).

a!!12lmtsV. which is used as a central muscle spasti city.

a - adrenoceptor blockers

ta onists as prazos in, doxazosin.

* Phentolamine, tolazoline - lmidazoline derivatives. Block a1, a2 & 5HT receptors. Stimulate muscarinic, H 1 & H2 receptors. Stimulate heart & gut. ..,.. Phentolamine is used also in diagnosis of sustained pheochromocytoma (dangerous). Contraindicated in peptic ulcer & cardiac arrhythmia.

Labetalol blocks a1 - 13 receptors,

used in ttl of hypertension & in pheochromocytoma. * Carvedilol blocks a1 - 13, used in H.F. *Yohimbin e is selective a2 blocker.

noradrenalin e.

8- adrenoceptor blockers Uses :

*- ve chronotropic ( l H.R), 1 conduction, l automaticity 1 excitability antiarrhythm ic action (class II). * - ve ino tropic ( 1 contraction) So 1 C.O. * 1 B.P. on long use due to 1 C.O., 1 renin, resetting of baroreceptors & block of presynaptic B~ ! symp. tone. P.R. is T initi ally. * 1 myocardia l work & 1 0 2 requirements & demands. * Increase the hypertensive effect of adrenaline. *B lock the hypotensive effect of 13 agonists as isoprenaline. * Bronchospasm with 13 2 blockers. * 1 glycogenolysis, Teffect of insulin in diabetic patients. * 1 lipolysis. * 1 I. O.P. without affecting pupil size or cil iary muscle. * Antianx iety and antitremors. * Some have l.S.A. i.e. (partial agonist). * Some have local anaesthetic acti on = quinidine like action = membrane stabi lizing (MSA). * ! portal pressure.

• Prophylax is of angina pectoris but not in variant angina. • Myocardi al infarction. • ttl of arrhythmias (atrial, vcr1lri cular). • Lll of hypertcns!.9 . • Wi th a - blockers i

! heart. !\lcrnhrane

~tabiiLdn

• action

+ 0 0 0

0 0

'ide effects:._- .,..,..._,__. • If stopped sud .._. sy . overacti vity due to up cgulation of f3 receptors • Bra cardia & heart blo k (t eated by a ropinc). • acute dministration -7H .F. w en heart i dri ven by sympat~etic

+ 0

+ +

0

• Cold extremities. • Sedati on & fati gue. • Dryness of eye & ski n with practolol (not used now) • Sexua l dysfunction

• Esrnolol is ultrashort 01, bloker given by I. Y. infusion. It is rapidly metabolized by esterase enzyme in RBCs (t1 1 is I 0 minutes). Used in emergency arrhythmia.

Skeletal muscle relaxants _ _ _ _ __ _ __

~Pedpher _ ;u

~

C entral

Direct skeletal mu scle relaxa nt

Mephenesin -Gi ven orally, inhibit subcortical polysynaptic transm ission ~ muscle relaxation without hypnosis or anesthesia sed in muscle spasm & rigidity & ntidote to strychnine.

..,. Dantrolene:- hydantoin deri vati ve. Given orally, It inhibits ca++ release from sarcopla ic reticu lum by acting on rayanod ine recepto , U in muscle rigidity and to control mali gn t hyperthermi a induced by halothane or succinylcholi ne.

+Competitive neuromus ..,. They are quaternary amin aralysis. otentiated

his amine, blocks

T

~Spasmo l y t ic

drugs:- Dantrolenc (direct relaxant), ag nist & may inhibi t sudstance p release) izao.dine (a 2 a nis ) Idrocilamide& riluzole inhibit gtuta~~nat.... Progabide acts on GABA" & GABAu ~to Gabapentin ( antiepilepti c) Mephenesin , lorzoxa oe, n~ ~~

Renal (40%)

'

I ,_

Moderate bloc: k

\

''

~

Steroid derivatives

Pancu ronium

\.\

\ sttght

I

Elimination

Renal (80%)) Hepatic (75-90%) Hepatic

Renal Plasma Ch. E.

Histamine Fonned from histidine by dacarboxylatio n. Stored in mast cells & basophils. Released by trimethaphan, curare & morphine. -It can't pass B.B.B. & not effective ora lly. Metabol ized by methy lation mainl y and ox idation by diamine oxidase (histaminase), ac on H 1, H2 and HJ receptors. H, receptors in smooth muscles. Action is med'ate th rough PLC --. T Ca ~-+.

H 1 e ffect on BY -~ YO & increased cGMP

..,.

ses:-

..,. C im etid ine:- is enzyme inhibitor Other H2 antagon ists are less toxic & are not enzyme inhibitors . Serotonin (SliT) ormed in enterchromaffi n cells esp. in gut,

Stor d in p late lets & in nerve endings . It can't pass

.B.B. ~etabolised by MAO into SH IAA w hich is t in care· oid umour & by reserpine therapy, & ! by 1VIAO " *Acts o recepto

receptors (7 types in C.N.S), SHT2

i smooth muscles & platelets .

It pro Fe-+ so vit C T absorption. Absorption IS controlled by mucosal block mechanism. Ora l iron: ferrous sulphate, gluconate. Inj ection: iron dextran lM, I.V. iron sorbitol citric acid LM. side effects: gut irritation, pain at s~e inj ection, haemosiderosis. Acute tox icity is treated by desferrioxa1 Pernicious anemia Treated with cyanocoba lamin (81 2), 9r hydroxocoba lamin (also in cyanide l?ois 1ing) Not treated with folic acid alone (it Imp oves blood picture but worsen nervous lesio Megaloblastic anem a Due to fo li c acid deficiency in diet long use.of barbiturates, phenytoin. Proguanil, trimethoprim. Pyrimethamine which inhibit conv io of folic into folinic acid. Methaemoglobinemia Induced by nitrites, primaquine, p Treated with vit C or methyl ene blue.

etin .

Sclerosing agents as sodium tetradecylsulphate& ethanolamine are used in varicose ve ins & esophageal varices to induce irritation, thrombosis & fibrosis

Hemostatics (Stop Bleeding) Uses : Hypoprothrombinemia due to : * oral anticoagulant or sali cylate overdose.

reparations I.M. obulin I.V. in hemophi li a.

ions in severe bleeding. nt1-fi6riii01ysins as aminocaproic acid and 5-0 yc (oxidized cellul o e): urgical gauze treate w th nitrogen dioxide. It action is mech, ic blockage.

Diuretics A) Renal : * 1 N aC I reabsoptio n : thiazide & loop diuretics. * 1 Na+/ H+excha nge: C.A. inhibito rs. * l Na+/ K+ excha nge: K- retai ning diureti cs. * Osmotic diuretics : Ma nnito l.

·on ; Moderate d iure ti acti on ~ loss ofNa, Cl H20 , K, Mg, but l g lome rular fHterate. oduce hypoka lem 2 Anti-diure tic effect in ephrogeni c dia etes insipidus. 3 l B.P (see a ntihypert sive drugs). 4 H ~:r.:cemi a l ins lin re l eas~. 5- Hyperuricemia ( l uric acid secretion).

COH.TKX

MJo;DlJl.LA Thick~

loop

l

Ca++ in urine.

2- Loop diuretics ( High effi cacy= high ceiling) * Frusemide &bumetanid e.(sulphonami de derivative)-, ethacrynic acid, * They are given orall y or l. Y., highly bound to proteins, excreted by renal tubules. They NaCl & KC I reabsorption in ascending limb of loop of Hen le. They act from lu minal si * Action : 1- Diuretic action, rapid onset and short duratio n. Produce loss ofNa, C l, H20, K, g, a, H in unne. 2- T Renal blood flow (due toT PGs . 3- Venod ilator effect. 4 1 B. P. mainl y by decreasing bloo vo lume & C.O. 5- Hy perglycemia. 6- Hyperuricemia. * Uses: Severe edema, acute pulrtton ry edema resistant edema - oliguria - H ypertens"on (emergency, renal impairment)- ypercalcem ia and hyperkalem ia. * Adverse effects: - H ypokalemia, hypomagnesemi a. - Hypocalcemia, alka losis. -Hyponatremi a, hypovolemi a, dehydration hypotension. -Ototoxicity. - Hyperglycemia & hyperlipidemia. - Hyperuricem ia. -A llergy. - G ut upset. N.B.: Both thiazides & loop diuretics --> h ypokalem ia.

* Osmotic diuretics

3- K-retaining diuretics *They

1

Na£[( exchange · distalJ.ubul es ->Na los K retention. Als They ar

• Mannito l I.Y filtered in glo meruli no t reabsorbed _. water loss. Used to decrease I. O. P. in acute glaucoma & to 1 intra-crani al pressure.

* C.A. inhibitors

al osteronism.

Aiso tn primary hype I osteronism and resis ant hypertension. pironolactone & eplerenone in low d ses edtjce mortality in H.F.& reduce myocar ial perfusion derects after myocaroial mfarction. Th.e?' ar~ombined w ith ~tUret1cs.

iaziaes or loop

cet -olamide, di chlorophenamide. •T y C.A. enzyme --> loss ofNaH C03 in un e (a kaline diuresis). • Meta lie c idosis occurs --> self limiting diures's. • They pr duce hypokalemia. • T hey ! .O.P. ( 1 formation) & have antiepi leptic action (in petit mal). • Used in t of glaucoma (system ic), to alka linize urine, ttt of a kalosis and epilepsy. • Dorzola ide nd brinzolam ide are used locally in g lauco a.

HC I, which

kidne~

IS

orm N H3 & excrete CJ· w ith it as N H~C I

ss of diuretic action (sclflim iting). It is used to acidify urine & in ttt of alkalosis & as a nauseant expectorant.

Anti-hypertensive drugs 1- Diuretics

They l B.P. by * Direct action 1 P.R. (may t PGs) * 1 Blood volume &C.O. * 1 Na+ in vessel wall, so l sensitivity to adr.& noradr. They include: • Thiazides: Hydrochl orothiazide, chlorthali one • Loop diuretics: ora l & I. V. Frusemide E acrynic acid, Bumetanide. • K-sparing diuretics: Spironol acton Ami loride. - Loop diuretics are used in emergency ypcrtension & in renal impairment. produce: * Both thiazides & loop hypokalemia hyperglycemia. hyperuricem i hyper Iipidemia. There is no sedation ,effect ·'.l'ller{fise other drug'i. 2- Sympatholytic A) a2 stimulants: clonidine, guanfaci e, uanabenz & a -methyl dopa (see later) & imida lin agoni sts .. B) Gangl ion blockers: obsolete excep tri :1ethaphan is sed in I. V. drip. It re leases histamine emergency hypertension & to produc co roll ed hypotension. C) Adrenergic neuron blockers: (see later) D) Receptor blockers a-blockers are not effective except se lecti ve blockers as prazosin. • 13 blockers are effective, no postural hypotension. •Labetalol and carvedilol block a,-13, used in pheochromocytoma & in hypertension including emergencies.

accumulation (prevented by Na thiosulphate or hydroxycobalamine). 4- Ca++ Channel blockers They 1 PR by dilating arterioles • V.erapami l affects heart > BY • N1 ~dipine & nitrendipine affect BY > heart. se lso in ttt of angina pectoris & verapamil & · ti m in arrhythmias. • Ther is o postural hypotens ion, no Na retention, no se ti n, no sexual dysfunct ion .

5- Dr sa fccting renin/angiotcnsion system A) ACE in ibi rs (ACEis) Captopril, li ino ril. Enalapril, perindopril, fosinopril (prodrug) ... They inhibit CE & kininase II enzyme. angiotensin II --+ V.D.. 1 aldosterone .\-.....;.--'-.u'e .1-catecholamines, t ren in, angiotensin I & .bradykini ? V.D. • They di late art rioles & veins so decrease after & pre-l oad. e i glomerular filtrate. j C.O. in H.F. ension, H.F. myocardial infarction • Used in: diabet ic ep ropathy. • Side effi: cts: protei nuria, allergy, cough, decreased taste ens tion (dysgeusia), 1 B.P, hyperkalemia, an ·oneurotic edema, bone marrow depression, affect oetus • C:ontraindicated in: bi lateral renal artery stenosis, P. gnancy.Caition with K sparing diuretics Angiotensin receptor b lockers: (ARBs) Losartan and valsartan are orally effective angiotensin 11 -blocker for AT 1 receptors. _..._.,""'.uension, acute H. . & to Uses as ACEis. stopped Side effects: as ACE I but wi thout cough . hypotensio . to excess ive cyanide Saralasin is partial agonist on angiotensin II receptors, given I. V.

or

Adrenergic neuron blockers

Central sympathetic depressants (a2 agonists)

-They decrease sympathetic tone ~ used in ttt of hy pertens ion. - Receptors become supersensiti ve (upregulation) ~ direct actin g sympathomimetics produce exaggerated response .

* T hey include

I.Guanethidine - Incomplete ora l absorpti on and cum - It inhibits no radrenaline release fro n rves and depletes stores when used in large d ses. - It enters neuron by uptake I. - It has no e ffect on CNS or adrenal - Actions : - l BP and l HR more in standing position. -I gut motility, Mios is and l lOP. _~~~~

*Uses: - Hypertension (rare) . - Glauoma (locall y).

* Side effects : - Orthostatic (postural) hypotension -Fa ilure of ejacu lation. - Parotid pa in, sali vati o n and diarrhea . - Salt retention. -Nasal congestion. * Contt·:lindications: pheochromocytoma. * Interactions: -Drugs blocking uptake I as imi pram ine ~ antagoni ze its acti on. - Directly acting sympathomimetics ~ exaggerated response.

urine. • It blo s granular uptake.

* ct ons:

-!

P, HR and T gut m ti lity. - se atio n and antipsyohot c. - U es : mild and moderate hypertension (rare).

* S~!4!0f,UI.~-j - Sedati dep ession, night m es uicidal endency and parki sorli sm. - Sa ivati on, diarrhea, peptic ulc~r, hyperpro I ctinemia ~ galactor ea & impotence . - Sal retenti on, nasa l aon estion and weig

: a -methyl dopa, clonidine, guanfaci ne and guanabenz. * They stimul ate az receptors so l YMC., pathetic tone, l norad r, release and n. in hypertens ion especia lly in renal nrt. a -methyl dopa is used in hv1nPT-tPr1 art "ol s=afl:erload. So l venous return, heart i:ze B.P (systolic > diastolic) l myocardial wor & Q2 consumption. • Di late coronary vessels if not ath • T H.R. and contraction. T res pi • Relax other smooth muscles. by l\cs:- Angina pectoris (acute nitroglycerin or isosorbide dinitr te L. or oral spray & long acting nitrates for pr ph taxis. -Acute myocardial infarction by nitr ~ly r in I.V. drip (it i c.GMP ~ l aggregation) - H.F. to decrease pre-load & congestion. - N itrites in cyanide poisoning to pt methaemoglobinem ia . Side effects : Headache, flushing, postura l hypotension & syncope, dizziness, tachycardia, a llergy, tolerance (due to depletion of SH & is prevented by nitrate free intervals)) Methaemoglobinemia and cyanosis (\\ ith nitrites ). I ntcractions : not used with si ldenafil (Viagra) ~ severe hypotens ion.

Anti-anginal drugs

C) Potassium C hannel Activators. Nicorandil : venodilator as nitrates and opens ATP dependent K+channel which dilates arterioles and veins. It is used in tolerance to nitrates. 2- ll - blockers ey are either selective Pt or non-selective. ! H.R., contraction, C.O., BP, myocardial work & sumption. They can be combined with nitrates or ·n arrhythmia, hypertension & prophylaxis of migrat • • Not used · H art block, bronchial asthma (non selective PV , care in diabetics. not stopped suddenly.

decreases oxygen deman by jnhibiting fatty acid oxidation. 4-:.Ran,ojazine prevents abnormal opening of late Na +channel so !contraction, jcoronary

3-Trimetazidln

flow. 5- Inhibitors For l>latelet aggregation • Aspirin in mall dose (75-150 mglday). • Dipyrida leJ It T c.AMP by inhibiting phospho "esterase so ! B.P., T H.R. & CO. Inhibits thromboxane synthesis and is better ined with low dose of aspirin. • Titlopidine and Clopidogrel : inhibit ADP pathway of platelet aggregation. • Abciximab, eptifibatide and tirofiban, block GP llb/I II a receptor I. V .. N.B.- In H.F. ca•• blockers aiTecting heart > B.V. are contraindicated. - 13 blockers can be combined with nitrates or with Ca++ blockers which affect BY > heart

+ve inotropic drugs: Cardiac glycosides, Bipyridinc derivatives, Xanthincs, fl agonists 1- Cardiac glycosides Formed from glycone (sugar) part & aglycone part (active part, steroid unsaturated lactone ring at C11). It is of pl ant origin (digitalis root). Kinetics : -Oral bioavai lability. - Binding to proteins. - Metaboli sm. -Elimination. -t

I / 2.

-Vd (L/Kg). - Cumulation. - Administration.

digitox in 95% 90% 80% urine, bil e I 68 hrs (7 da:>l 0.6 most oral

l moderate oral, I.V .

least I. V.

• In renal impairment digitox in is pr ferr d. In emergency digoxin can be used. Mechanism : l Na+I K' ATPasc T intracellular Na ! intracellular K+. t intracellul ar Na ... ~ T intracellular ca+ (by l Ca t+ efflu ' TCa ' I influx, T ca++ release from sarcoplasmi c reticulum}- tiding of actin/m osi . T acti on by T Ca r&

1

K ...

Actions: I- +ve inotropic effect, not bl ocked by better emptying & fi lling, i mecha111 al efficiency. 2- TC.O. in H.F, little effect or l C. O. i no al. 3- T B.P. if low due H.F.

A.V. conduction), restore myocardial ey on't cure A. F. (auricle is still

l A,V. conduction. Convert flutter into A.F., cure m y occur when stoppe - Paroxysmal atria tac ycardia (PAT). ever used in ventri ul arrhythmia. Ad,·crsc & toxic effects (They have low theraP.t!utic index). •"Gl .""nausea, omiting coli , diarrhe .

C.N.S.: headache, confjlsion, hallucinati n, ~d convu lsions. Eye: blurred visio , diplopia, amblyopia affi ct colored vision -7 yellow or green ock. A.F., vent. extrasystole, pulsus

- If due to Ca++ injection give disodium edetate I. V. to chelate ca++. -Ventricu lar arrhythm ia with heart block by phenytoin (diphenylhydantoin). - Ventricu lar arrhythm ia without block by lidocaine xylocaine I. Y., or f3 blocker. - Cholestyram ine to bind digitoxin in gut- Digox in antibodies in acute toxicity. * Interactions: - j Absorption by atropine, probantheli 9 , bIt l absorption"Py cholestyramine, kaolin, charcoal, AI ~OH , metoclopram ·ae. -Enzyme activators & inhibitors affect dtgitoxin. - Drugs inducing hypokalemia - i xi ty. - Quinidine j di goxin in blood ( l ren excretion). -Quinine, verapam il, K-retaining diU~~ tics -1 digoxin excretion. * Contraindications : ventricular rrh m1a.

• It 1 phosphodiesterase -4 So i c.AMP. It is +ve inotropic, V.D., diuretic, bronchodilator. .G. for~ min. after Y. administration. Rapidly I.Y. - l B.P., arrhythmia, arrest.

drip. +ve inotropic > chronotropic, used in acute

2-Bipyridine d riv

- Inamrinone (amrinone), milrinone: +.ve inotropic, no blocked by f3 blockers, don't inhibi Na K '" ATPase but! phosphodiesterase- 3 so j c.AMP. t Ca influx. They have V.D. effect, little effect on B.P. & H. . - Used for short-term ttt of H.F., given I. - Long use of amrinone- thrombocyte enia hepatoto - Milrinone is more potent, less tox ic. 3-Xanthines

-Aminophyl line is theophylline derivative givens wly diluted I. Y. in a dose of250 mg in ttt of acute left ven. with pu lmonary edema (cardiac asthma).

i

tc support in acutely-

* Class I = membrane stabilizing= Na+

Antiarrhyt hmic drugs

channel blockers. • 1-A

* Quinidine, procainamide, di sopyramide. • l Automaticity & exc itability. • l Conduction, prolong R.P. , action pote duration. • -ve inotropic effect. • Atropine like action (more with di s yramide) so may T A.V. conduction so w~en used in ttt of atrial arrhythmias, give dig ita ~is before to l A. V. conduction. • Prolong PR interval, QT interval, widen QRS & inve11 T wave. * Used in atrial & ventricular arr ythm-ias. * Side effects: SA node depressiqn. -A V block, vent. fibrillation ifQRS is widened > 50%. - Allergy - gut upset. - Paradoxical tachycardia due to at opioe like action on A.V. conduction (# by "gitalis). -Embolism in old A.F. -Cinchonism with quinidine. - Lupus like with procainamide in slow acetylators. -Atropine like with di sopyramide. - Quin idine Tdigox in in blood. • 1-B

- Lidocaine - xylocai ne- li gnocaine LV. Mex ilitine, tocai nide, phenytoin = diphenylhydantoin. - l automati city in Purkinje fibers.

• tfsed in vent. arrh ythmias due to infarction, di "talis or cardiac su gery. • Phenytion ·s used in vent arr ythmia with heart block and al so in grand maJ..epi1epsy. • Xyl caine may induce convulsions (# by iaz pam), nausea, ] BP, all ergy, thrombophlebitis. • Cimetidine, /3 blocker blood. • Include encainide, necai id~ , lorcainide, propafenone. They prolong RP in A.V. node, pr long PR interva l, l conduction. Used in pre ature vent. contract"on & WPW syndro

Class Ill (K t - channel blockers) Amiodarone, sotalol, bretylium ( LV., I.M.) ibutilide (IV) & dofetilide -They prolong action potential duration. Brctylium :!automaticity in Purkinje fibers. • sed in vent, arrhythmia if D.C. shock cardioversion) & lidocaine fail. Amiodarone blocks also Na+, Ca,.... channels & blocks /3 receptors. • Used in atrial & vent, arrhythmias . - J~u~ili~ is ~iven I. V. to rest~re ~-A node aCtiVIty 111 tnal Outter and fibnllat10n. - Dofetilide is effective in maintaining sinus rhythm afte cardioversion of A.F. or a nutter

Class I\ (Ca+ channel blockers) ( erapamil, dilti~zem ). • l SA no e, l A V conduction, prolong RP. • -ve inotropic ffect. * Used in supravent (atrial) arrhythmias (AF, A. Ou er PAT) to l AV conduction. * Not used i H.F., heart block, l BP & not confuined with /3 blockers. • Sr. tylit m inhibits noradr, release. • erapamil i digoxin level in blood. • ectric cardioversion is used in ttt of fibrill ation, but it is dangerous with digitalis. • Atropine, pacemaker & isoprenaline can be used in ttt of heart block. • Adenos ine ( LV.) T K+ conductance .......; hyperpolarization, can be used in ttt of PAT.

Treatment of peptic ulcer 1- Antacids to neutralize excess HCL.

• Enzyme inhibitor ____, t e ffect o f warfari n,phenytoin. • Other H2 ~ lockers have no e ffect on cytochrome P450 & no·~nt.ianldr6jfCiljieelffectr"--.

1- Chemical antacids: A) Systemic (absorbed) : Na i iCOJ. It neutra li zes HC I rapid ly --. NaC I, C0 2, 1-bO. Used in heartburn , Itt o f ac idos is, di sso lve mucus & urine alka linizer. Side effects : C02 re lease-> diste nsio n & rebound T in HC I, sho rt duration, a lkalo & nuid retention. B) Local (non systemic) antacids : * Mg oxide, hydroxide, trisilicate long dlirati(fn re lease, no alkalosis. Mg trisil · diox ide (adsorbing & demul cent) onset. has but physical A ll Mg salts___, diarrhea ( laxative) * AI (OH)J acts physical and chemical} no a lkalosis, long duration. Used also n p os hate sto nes. It produces constipa tio n, l phosp ate absorption & ! ~-..,. digox in & tetracycline absorpti on. * CaCOJ rapid onset, long duration It produces constipati on, hypercalcemia, re leas s 0 2 & l oral tetracycline absorption . 2- Physical antacids & gastric mucin : demu lcents, adsorbents. • Best antacid contain Mg salt + A I or Cas It. • Ca, A I, Mg salts 1 oral tetracycline absorption. • A I, Mg antac ids L abso rption of theo phyllin , di gox in, warfarin, qu inolo nes, ketoconazo le.

ll.A nti., ecretory

tlru~-:s:

1- H 2 receptor antagonists: c imetidine 400 mg, ranitidine, ni zatidine ISO famo tidine 20 mg. Given twice/day fo r 6-8 weeks then o nce at night for 6 mo nths to prevent recurre nce. • C imetidine produces headac he, dizziness, nausea, myalg ia, rash, itc hing. Confusion, somme lence, antia ndrogenic effect.

Ill. M ucosal p rotcctives (t mu cosal r·csistancc): 1- Colloidal bismuth subcitrate : It promotes healing by coating the ulcer, inhibit pepsin, Tmucus & PGs, ant i microbial against H.pylori . Given 240 mg twice be fo re break fast & bedtime. It produces black colo ration o f o ra l cavity & feces. inhibit HC I secretion, T mucus & bicarbonate ,.... ,.,..,r,.,,,,.,, ve). M isoprosto l is PG E1, analog used to ulcer induced by NSAIDs. It may produce cramps. Not used in pregnancy. (Aluminum sucrose s ulphate) : binds to •n.. ua~;e o f ulcer so coats the ulcer & t PGs. bonate & promo tes healing of gastri c & It is given o n empty stomach no t with antacids ( it needs acidity for activation). of consti pation, L absorption cimetid ine,

CalrbtenOXIOIOtDt = Biogastrone : liquo rice derivative ling o f ul ce r by f mucus & T PG a retenti o n, edema, t B.P., H.F., pironolacto ne abol ishes its effect. ndica ted in p eptic ulcer: NSA IDs smoking, alcoho l, ethyl reserpine, gl ucocorticoids, racetamol), ~··-··~•·· .... ·ne, to lazol ine KC I oral preparations & mimet ics, a ga ldrate is mg hydroxide +AI hydroxide

Rehampitle increases prostaglandin generation

• Saline p urgatives (MgS04, Na2S04) ac t after 1-2 hrs. g iven

Antiemetic drugs I. H 1 blockers (dimenhydrinate, diphenhydramine, promethaz ine, mecl izine, cycli zine I vo miting center, so used in moti on s ickness. 2. ll yosci nc, atro pin e ! vo miting center. 3. Py rid ox ine (136) in vomiting o f pregnancy. 4. Pheno thiaz incs: c hl orp romaz ine. triflupcraz ine. 5. Butyrophcno nes : droperidol & ha loperido l. 6. Th ioxanthenes. 7. Mctoclopramide. 4,5.6 ,7 block D2 recepto rs in CTZ so no t c ffe tive in motion s ickness. • They can produce parkinson ism & tpro la in level. "pase enzym e in presence of • Mctoclopramidc I CTZ & T gut motili (prokineti c). e inoleic aci d whic otility. So it is ineftecti e Used as antiemet ic & in rc nux ocsopha itis, to empty sto mac h in emergency anesthesia & to acili ate intubatio n and in di abeti c gastroparesi . • Oomperidonc has lim ited abil ity to pass in ide C.N.S. 1 has lo ng duration due toe (less toxic). Anthrilccnc (senna, casca ra .. rei ase active conlpOllllds -+ 8-Aprepitant : antagonizes neurokin in receplOrs-.ilHlfe&--....• .1 pos tre ma & used in vomit ing due to T motility. che mot herapy xc ted in mil k and chang col r o urine. 8. Ondansctro n and grani setron (5 HT 3 a tagon ist), used in . • Bisacodyl. -r. Sodium pi osu).phate is moderate vomiting due to cancer chemotherapy. 9. Glucocorti coids. irritant urgative as bisacodyl . I 0. Dronabinol (acts on cannabino id rccc - Se ere ·rritant: croton o il. • Uses co stipat ion - drug & fi od o isoning -be fore

Prokinetic Agents I. Metoclopramide a nd Domperidone. 2. C isapride acts on 511T4 n.:ccpturs. 3 . Eryth romycin (acts o n moti lin receptors).

Treatment of Diarrhea 1- Rehydration therapy. 2- Specifi c treatment of cause by chemotheraputic agents. 3- Symptomat ic treatment by: a) Adsorbants & absorbants as cha lk, pectin, kaoli n, bi sthmus s ubsa l icy late o r subga ll ate. b) stringants to ppt s urface pro teins as tinctu re catechu o r kra ria whi ch release tannic ac id.

S ialagogue : stimulants (i did ·) and re flex st im ul ants (stomachi c and nauseant cxp ctor nts). Anti-sial agog ue: ! sa li vation by atropine and gang li on blockers. appeti e by stimulating taste buds e.g. ethyl a lcohol, spices and ittcrs. CflcnoCieoxyc o lc: a~id &urodcoxycholic acid arc used to d issolve cho lc tero gall blade r stones. C ho lagogucs : e acu tc gall bladder by MgS04 sm all dose to relax s phincter of ddi or by cho lecystok in in to contract wa ll of gall adder. C holorctic: s ·mu ate bile secre tio n by the li ver. Hydrocholotetlc:: increase water content in bile by sa licylate and enzoatcs.

Treatment of obesity

* ltopride is a prokinc tic drug w hic h acts o n 5 HT

4

receptors&d ompcrido ne.

Purgatives I. Bulk: e.g. bran, meth yl ce llul ose. psyllium (plan tago) seed a nd MgSO~. They increase content so T peri stalsis. • Sorbitol. lactulose.

3-13-blockers to reduce portal venous in now and portal venous pressure. on selective 13-blockers (propra nolol, nadolo arc more e flcctive than selecti ve blockers.

appetite by phenmetrazine, fen nuramine a nd s ibutraminc. * L fa t absorptio n by o rli stat whi ch inhibits pancrea ti c lipase enzy me. *T lossofenergy.

Centra l A na lgesics 0 ioid (narcotic) analgesics * Can relieve any type of pain except itching. * Act cortical and subcortical. * Produce e uphoria and stupor.

.-------------~----Q.!ch decrease feve r temperature to nonnal. They may ofii ver) or non specific (do not affect cause of

* Addicti ve. 1-0pioid (Narcotic) agonist )pium

alkaloids

contain: -

Pt n

threne(morphine,

ine,thebaine.),analgt

.mogenic- Benzylisoquinoline (P.apa erine, narcotine) without ana lgesic acti

- C.N.S. osi , euphoria . • Miosis due to s ·mulation of I II nerv nuc eus not local. ~DHrelease,

nanthrene alkaloids of opium :

.----:.--~-R.

J.

Ilea regUlating center

. ('SO't002 i 1Blood,

excitatory transmitter ( substa n modu late release of other neuro t

es p ess re),

l

cough center, VMC.,

scles & sphincters,

!

l

CTZ.

peristalsis,

ry pressure (contract wal l of gall bladder Opioid recptors are G-protein coupled transmitter release and postsynaptic T K inh ibit adenylcyclase -->

l

cAM P.

Opioid receptors: J.l (mu) inducing supraspinal a depression, miosis, e uphoria, gut spasm and sedation. k (Kappa) inducing spinal analgesia, sedation, less R.C. depress1 cr (sigma) inducing dysphoria & halluc ination.

*T

· r 14 days to depressant actions but not to miosis and constipation. G oss tolerance wi th other depressants. er

cur

*Uses: 1- Ana lgesic in severe pain (post-operati ve, cancer, myocardial infarcti 2- Cardiac asthma (acute LVF) T.V. 3- Neurogenic shock ( I. V.). 4- Pre-anaesthetic medi cation. 5- Insomnia due to pain . Dose I0 mg S.C., I.M ,, T oxicity : • Acute : coma, pinpoint pupils, and 1 Ill: Antidote (naloxone, naltrexone) wash & pwgative (MgS04) . • Chronic : Add iction. Treated by nn',""'" withdrawal , then methadone rep withdrawal. a2 agonists as cion· reactions. Oral naltrexone to nnP•VP1nl

------

* Contraindica ti ons I. Head inj ury & i CSF 3. Biliary coli c & pancreatiti 5. Lactation. 7. Extremes of age, 9. Myxedema. I I. Adrenal insuffic iency. 12.0pioid agoni st with mi xed "''"''"'·"' B) Cod eine (methyl morphin e): I central anti-tussive and anal gesic. 2. Semi-synthetic derivatives: Apo•nn'"'"' Di-acetylmorphine (Heroin) is hydro! addi ctive. 3. Synthetic non-phenantherene derivatives ! * Meperidine (pethidine) : oral, inj ection, ad dicti ve, shorter duration, less or no

depression, L.D. ~ tremors, excitation, has atropine like action, no miosis, less or no consti pation, no cough depressant action, i CTZ & local

antagonists Pentazocine, butog>h ol, nalbup hine, Bu renorphine. They are agonist on k receptors, antagonist or partial agonist on )..l. • Anal gesic actio as r more potent t an orphinc. • Can induce wit ra al syndrome in opi id addict. • They have ce ili g e feet on R.C.( a alg sia > R.C. depression) • Less liable for add"ction & are giv n p renterall y.

• Na loxone, nal exone are antagonists. • Nalorphi e levallo han are f}Jartial agonists. • In normal P.erson no e[ ct w"th antagonists but partial agon ist acts as morp, in t ut prgd ces anxiety & hallucination. • Thct.Y are antidote in,acute toxici ty & induce withdrawa l in add icts. Used tl r ttt of acute>-op ioid tox icity & diagnosis or opioid addiction. Oral .naltre one to prevent re-addiction. • N.B.: Diphenoxylate & loperamide have low so lubility, weak C.N.S. action, so used orall y in ttt of diarrhea.

Analgesic Antipyretic drugs (NSAIDs) Eicosanoid synthesis :

+ + of PLA 2 - release of arachidonic aciA---Cycl o-oxyge na~

COX (1 ,2,3)

Lipoxyge

enzyme

LO~

PGs

* Induce pain, fever, inflammation.

* Contract uterus, (PGF2a). * Prevent peptic ulcer (PGE2, l 2). * Maintain patency of ductus arterios

.

* T Renal blood fl ow.

* Thromboxane A2 (TXA2)

platelet aggregati - V. * Prostacyclin (PGb)- V.D., 1 plate t aggregation.

____ 8...I)ley have little effect on renal function in normal subj ects but may decrease enal flow and glomerular filtrate in heart failure, hepatic cirrhosi or reiial diseases. They may produce salt and water retention and hyperka emia. 9. Use ofaspirin like drugs in pregnant women is not recommended. If there is need ~irin may be he safest anti- inflammatory while paracetamol is ti yretic. ~spirin should be discontinued before the safes analgesi parturition to avoid pr61 onged labour, increased postpartum haemorrhage d...ffi ute 'ne c osure of ductus arteri osus. e.a 1-in ammatory of choice in ch il dren include aspirin, tolmetin and naproxen but .aspirin is avo ided in viral illness for fear of Reye's syndrome. I I . Most ofNSA IDs bind firml y to plasma proteins and can displace other drugs as warfarin, oral hypoglycem ics, inducing drug interactions. 1- alic lates : acetyl alicylic acicL(aspirin) sod salicylates. Absorbed orally, as irin can be absorbed from sto ach & sod salicylate is given

uos "NSAIDs" I. They are analges ic, antipyreti c · d anti -innammato , owever,

paracelamol (acetaminophen) h n anti -innamma o action. 2. They can be used in dysmenorrh a, P\ltent ductus arterio us and are tocolytic in premature labour. 3. They arc used in systemic mastocyfosislo antagonis V.D. induced by PGD2. Also used to 'nhibit Oushing dose of niac in. 4. Frequent use of aspiri n decreases the inci ence cancer colon and inhibits po lyp formati on mostl y due to CO - inhibition. 5. They affect platelet function and can be used as antithrom oti . 6. They can induce gastric or intestinal ulcerati ons with secondary anaemia. 7. They may induce bronchospasm, vasomotor rhinitis, rticaria susceptible patients due to lacking effect on lipoxygenase pathway.

enteric coated, highly bound to plasma P. oteins, excreted in urine partly unchanged, alkaline urine with Nafi.CO , wi ll Ttheir excretion. SO obey first order kinel!ics hile L.D obey zer order kinetics. Aclions : Local : s icylic acid is ketato yti c & anti-fungal. Methyl salicylate is coun -irritant.

-----

T heat

3- Large doses l R.C.~ washing of C0 2 ~ resp iratory alkalosis. Kidney excrete Uses: analgesic antipyretic in patients with haemophilia, peptic ulcer, NaHC0 3 ~ compensated respiratory alkalosis. Decreased NaHC0 3 in b l~o~od:::-~ --..;;. br;.,;o;.;.n;.:.c.:..:_ hi a l asthma, gout, pregnancy & virus in fection in ch ildren .

pl asma proteins. analgesic - antipyretic (0.3 2 gtday) - acute rheu ati fever ( I Og/day). Rheumatoid arthritis (8g/day) to inhi it platelet aggreoatio (75-1 50 ing/day) gout (4-5 g/day). Reduce cancer colon, catara ana eat eclampsia. * Toxicity: gut irritation - allergy - aemoly ~s ·n G-6-'Pt> defiGienGy-bleeding--du to hypoprothrombinemi a - salic is (tinn itus, deafne , vertigo, headache, sweating.... ). Acute toxicity :

* Uses:

ena fa ilure Uaund·ce, hypoglycemi coma, oliguria, hematuria and anuria). Admini strati on o N~ cetylcysteine wt in -8 hrs fo llowi ng acute overdose can protect agai nst to ici . - Indole dcri' a tiv s: indomethacin & s lin c (pro-drug). Indomethacin is potent inh ibitor or PG syn thesis, used in acute gout & in patent ductus a11eriosus.

2-

Actions : analgesic, antipyretic but Not anti -nflamrnatory. h central not periphera l. (Selective COXJ inhibitor) o effect on pepti c ulcer, no effect on platelets & no bronchospasm.

id, no

• ocnzyme is found in gut, kidney and platelets. COX 2 isoenzyme is induced at site of inflammation, selective COX 2 inhibitor as celecoxib, rofecox ib, valdicoxib, eterocox ib and meloxicam

have analgesic, antipyretic and anti-inflammatory e ffects as non selective COX inhibitors, but with fewer gastrointesti na l side effects and wi tho ut a ffecting platelets, however COX2 is acti ve within the kidney. So COX2 inhibitors prod tox ic ity as classic non-selective COX inhi b itor. Rofecoxib has cerebro-vascular thrombotic events . COX 3 in CNS is inhibited by paracetamo l.

&i

xanthines &

Gout Is increased uric acid in b lood due to i (e.g. due to drugs as thiazides). Uric acid is synthesized from purine bas precipitated in joints, cartilage & kid

ombinant form o f urate oxidase so • Colchicine, demicolcine . • NSA IDs as indomethacin, phe ny lb • ACT H, g lucocorticoids in resistan * IL l inh ibitors as a nakinra, cana · r•nn•An * Colc hic ine alkaloid w ith anti-1111 gouty arthritis w itho ut affecti ng leucocyte migrat ion so prevents I...........,a-... so inhibits uric precipitation. Uses: - Acute go ut (0.5 mg/2h rs). - Prophylaxis of gout (0.5 mg 2-3 time:sUIVef~K - Prophylaxis of Medetranean fever- li Cl ·hosis, psori asis Toxicity: nausea, vomiting, diarrhea - bon hae mo rrhag ic gastroenteritis - nephrotoxic toxici ty.

Uricosuric drugs • Probenicid (which l renal excreti on o f penicillin). • Su lphinpyrazone (which l aggregati on o f platelets). • Benzbromarone. They are uricosuric in L.D. but produce uri c acid retenti on in small dose. T hey have no analgesic or anti-inflammatory action & their action is anta on ized b sa lic lates

produce

.B. In gou t give nu ds a lka lini ze urine. Uric acid is i in blood by thiazides & loop diuretics, dia zoxide. pyrazinamide

& cancer them y.

Sedatives & Hypnotics Anti-anxiety = anxiolytic drugs

Mecha nism Benzodiazepines act on specific recepto GABAA receptors without directly act vafng on GABA rece tors or opemng the associated Cl- channel but increase the frequency of ch nel openm -Action ofbenzodiazepines could oe blocked by flum azen'l (specific benzod iazepine receptor antagonist). - Benzodiazepine receptors are tw t es (BZ, and B~). z, for anxiolytic, sedative and hypnotic effects. BZ fo muscle relaxan an anticonvul sant effects.

azepem, nordazepam, clorazepate.

- Zolpidem , Zaleplon & Zopiclone ct on sz, receptors and have minimal muscle relaxant effect. • Buspirone is anx iolytic drug, w ich acts as partial a oni ton SHT1A receptors in C.N.S. No muscle rela ati n or anticonvu l an action and no addi ction .It has delayed onset. • Choral hydrate (acti ve) ~ trichlor eili ol (active me conj ugated & excreted in urine as uroc lo lie acid. Toxic dose ~ vomiting, l R.C., pin-po' t p ils l ng !fu sed with a lcoho l ~ knock out.

n1sm, ce epi lepsy. • They have autonomic actions. • No addiction. I

•No parkinsonism. •Treat epilepsy. •No autonomic actions. •Addictive.

Barbiturates

Antipsychotic drugs (Neurolcptics) & Lithium P

~Ghos~

is due to increased dopamine in limbic system, it is treated by : omazi ne, promazine, thioridazine, tri nuoperazine . 3- Thioxanthenes. are)

._ -- ---''do haloperidol.

lorpromazine .._,.,_....,, anti-emetic (block D2 receptors in CTZ, so not enn·a ( T heat loss, ! heat production), may m. Produces sedation and t effect of other

tissues. depressants. Actions : - C.N.S. - Sedation & hypnosis. -t.V. anesthesia (Thiopentone). - Anti-convulsions & anti-epilepsy. -No analgesic action but potentiates an ges'cs. • Respiration : - ! R.C. (decrease sensi 'vity to C(h • C.V.S.: large dose ! BP. • Liver : Enzyme inducer (activator). • L.D. smooth musc le relaxation.

• C.V.S:

l

! B.P (!

H R (refl ex, atropine like).

C(h in bl

Uses: - Sedation by long acting. - Pre-anaesthetic medication. esthesia. -Convulsions & epilepsy esp. by phenobarbt ne. - Potentiate analgesia of pyrazolones. -ttl of neonatal jaundice. Side effects - Idiosyncrasy (excitation), - Allergy. -Amnesia & automatism. - Addiction. -Acute toxicity ( ! R.C., ! B.P., hypothermia, hyporenex' Artificial respiration with 02, stomach wash, forced diurest , haemodiaysis (long acting), correct hypotension, hypothermia i. Contraindications 1- Porphyria because they acti vate 1:!.- ALA synthetase enzyme. 2- Respiratory diseases. 3- Shock. 4- Head injury. 5- Li ver & renal diseases.

iting (not in motion sickness)ough) - To induce

ithium cartiiinate:

o6d stabilizer, used in manic depressive psychosis. It induces

abetcs insi · us--&: hypothyroidism.

- - - -- nrluum ,Carbamazepine, Valproate&lamotrigine are mood stabilizing antimanic drugs.

2) Tricyclic antidepressants (TCA)

Antidepressant drugs

Mono-amine oxidase inhibitors They have slow onset (2-3 weeks).

1)Selccti\C serotonin rCUJ1htke

inhibitors (SSRis)

non-competitive): (irreversible Hydrazine phenel zine, nialamide, isocarboxazid.

Fluoxetine, Fluvoxamine, paroxetinc, citalopram and sc1·traline:

hydrazine: tranylcypromine, pargyline and electi ve drugs as moclobemide and (MAO-A inhibitor) orgyline 0 ren~d = se legiline (MA0-8 inhibitor).

They block 5HT uptake wi th no effect noradrenalin e uptake. Oral bioavailabi l it~ s 7 % USes: depression - noot hi ghly bound to plasma protein s, con ert d into ofmigraine headache -'leu lgia. active metabolites and l1 12 is 24 hrs. hey are less Side effects: C.N.S. stimulatio jau dice - blood dysc iasis -atropine toxic than tricycli c antidepressants. depression, obsessive-compulsive ar'hythmia - postural hypotension. 111 Used teractions disorders, anxiety states (panic, phob as), bulimia With MAO inhi bitors.

and alcoholism. Side

effects:

like

Anxiety,

insomnia,

tremors,

seizures, gut upset, rash, decreased libido decreased sexual activity, weight lo s (regained

-Potentiate syrnpathomimetics. ---- Ahtagonize hypoten ive effect of guanethidine, clonidine.

- Pot ntiate effect of alcoh I. Interactions: With MAOis seroton'n syndrome is -No i teraction with oo(i containing tyra ine. induced (hyperthermia, muscle rigid 'ty and rapid Not use in.-glaucoma & enlarged prostate, epilepsy. changes in mental cond ition).

They T eve! of catecholamines & 51-IT in brain. * Uses: ttt of depression. MA0-8 inhibitors in ttl of parkin on ism. * Side effects Excessive C.N .S. stimulation Jaundic - Optic neuritis -Hypertensive crisis with food co taining tyramine.

tyramine of food (ttt

after 12 months).

* Bupropionl Na, dopamine uptake & deer · psychic craving for nicotine. Atomoxetine, reboxetinel NA uptake & are used in ADHD.

- Paten iate sympathomimetics. - Re rse action of reserpine. eptine (Survector): blocks dopamine u ake. ianserin blocks a2receptors

Sedative

Omg

Chlorpromazine Fluphenazine Butyrophenones Thioxanthenes Clozapine Resperidonc Olanzapine Qu itap [ne Z [pr·asidone Aripipt·azole

Hypotensive effect High very low very low Medium Medium Low Low Low to medium Very low Low

Comparison of antipsychotic drugs

Antimusca

++

SHT ++

amine 0 0 +

+ 0 0 0 ,+

Fluvoxamine Fluxetine Citato m

0 0 ,+ 0

0 Corn arison of d i ffcrent antidepressant drug

A n tiepilcptic drugs Genera lized toni c/c lo ni c seiz ures (grand mal) & p rtia l seizures Phenytoin . Phenobarbitone. Prim idone, Sod. Va lproate, carbamazepine, lamotrig ine, to iramate

Absence se izures (petit ma l)

to

. Lamotrigine : ~Joe s Na+ channels and g lutam ate receptors and is used in arti al se izures ancJ.gntjlld mal. Sicle.effects~ sedation, ata..x~a, clip!Gpia and stevens-Jo hnson syndrome. 2. Vi abatrin : is irreversible inhibitor of ABA transaminase which is esponsible for deg dation of GABA d i used in partial seizures. S ide effects : depre~sion, psychosis nd isual dysfunction. Na influx, given oral ly or I.V. , high y . Gabapentin : n. ;\litrous O\.idc : non-inflammable, non-trntant, very rapid induction & recovery, analgesic but weak anaesthetic, inadequate muscle relaxat ion & produces diffusion hypox ia in recovery. Ethyl chloride : local & general anaesthet ic. N.B. * Hypothct·mia by lytic cocktail (chlorpromazine + meperid ine+ promethazine). ;, Controlled hypotension by halothane, ide. trimetha han and sod ium

methotrexate

ents I. V. in acute rejection. Muromonab-CD3 : binds to CD3 glyco protein on T-

ocardial depression. -A llergy more with PABA es ers. .J>rilocaine - ethaemogiobinemia -Spinal ane esia -7hyp ten ion, hea res iratory~aralysi$, memngi~s. : hematom or ain at Loc

- A tf ymphocytic & anti thymocyt ic globulin (A LG, ATG) om horses, but produce allergy. Sulphasalazine in ulcerative colitis & rheumatoid arthritis. nerve

damage , tissue damage due to added adrenal in e.

*

lmmunomodulators (immunosti mulants in immune deficiency syndrome, chronic infection as hepatitis B, C Cancer). They include : thymosin, cytokines, lcvamizole, BCG, garlic & Nigella sati va.

Mechanism of action of hormones

* Peptide honnones & adrenaline act on membrane receptors---. i c.AMP. * Steroids act on cytoplasmic receptors ---> mRNA ~ protein synthesis. * Thyroxine & estrogen act on nuclear receptors mRNA & protein synthesis. Thyroid gland * Synth esis of thyroxin e - Iodide uptake (trapping), active. - Iodide ~ iodine (peroxidase ... n -·"' nlP - Organification of iodine (combinati tyrosine~ MIT, DIT. -Coupl ing of iodotyrosine to form stored in colloid and released bylor4:>te;ase All these steps are controlled by regulated, by feedback mechanism * Actions: i 0 2 consumption & metabolic ra l Cholesterol & fat and glycogen i Glucose absorption, uptake & ut1n~anr•n i H.R., C.O., up-regulation of p rec~pt.otp i Sweating & produce diarrhea. Essential for physical, mental deve Iopmen t. * Excess thyroxine : ~ i H.R, angina, 'r"''"""'"" sweating, weight loss with i appetite, intolerance to heat, tolerance to cold, myopa osteoporosis & -ve nitrogen balance. * Uses: - Hypothyroidism (myxoedema, creti nism myxedema coma).

- To 1 TSH in puberty goiter & to dependent - To

l growth of TSH

* Side effects : Agranulocytosis (blood dyscrasias). i size & vascularity of gland & i exophthalmos. All ergy (rash, fever, hepatitis, nephritis .. ) Joint pain, depigmentation of hair, pass through placenta & milk. nion inhibitors : k-perchlorate & thiocyanate compete with iodide for uptake ---> l ·ne, i TSH. Action is antagonized by did e. ---> aplastic anem ia. lugol's iodine, Kl. Inhibit action of t iodine binding & inhibit protease size & vascularity of gland ey act within 2-7 days. PllC:OD~ra ive to 1 size & vascularity. In with propranolol Prophylaxis to allergy, interfere with thyroid iodism (lacrimation, rh initis, , and diarrhea). 131 JOlllcmll.! iodine (1 ), which is concentrated destroys thyroid foil icles, acts after 3 in old age or in recurrence, of other therapy, metastatic cancer thyroid osi s of thyroid function (1 132 ). effect: hypothyroidi sm Not used in pregnancy, lactation. blockers without ISA are used to control symptoms pre-operative & with radioactive iodine & in t ic crisis.

Ins u lin

*

• Preparations:

Blood glucose is controlled hy insulin and antiinsulin (growth hormone, g lucagon, cortisol , thyroxine and adrenal ine). Lns ulin is fom1ed of 2 chains of amino acids, derived from animals human insulin is availab le. It is give n S .C.

* It is re leased from f3 cells of pancreas. j Release by- Gut hormones, e nzymes. glucose(oral > IV),amino acids & fatty ac· s ..stimulation.

* ttt: - Soluble insulin I. V ., S.C. - Saline (0.9% NaC l) to correct dehydration. - NaHC03, in se vere acidosis. - 5% g lucose to avo id hypoglycemia. - KCito correct hypoka le mia. Antibi otics. Oral Anti-d iabetic Drugs 11-N IDDM) (type onset adult in icatecl diabetes. A-Su lphonylurea * Sho : To butamide t.d .s., metabo li zed in liver.

non

J

excreted : glibenclamide* unchanged glyclaztde•,:glipizide*, gl imeperide* in urine acctohex tde • Long: c hi rpr amide (used also in ttl of diabetes insipidus) *Second g neratio n include g libenclamicle, glyclazicle, .___ _"'•Li iz ide gli beride.

• lnt cm1 ia

muscarinic stimul atio n.

*Mechanism:

adipose

tissue,

l

gluconeogenesis & g lycogenolysi - No effect on glucose trans port to & liver. • T Lipogenesis ( i lipoprotein lipase).

• l Lipolysis ( l tri glyceride lipase). • T Protein synthesis, -!.. prote in breakdown. • Decrease K, M g in b lood (ente r inside cell s). • Diabe tic kcl?nftt41~~~~~~~lUJ ~ hyperglycemia, osmotic diuresis, kelogenesis.

r----::-1'- in trlfn r leas rrom ~ Cells (act by blocking ATP - ! glucagon. nnel s). senslttve - T Activity f" ulin receptors. * Side effec : • 1-lypoglyc mia • T Appe te, /ut upset, ataxia, drows iness. • Terato nic a ll ergy. dilutional produce may chlrrro pamiclc tremia by potentiating the effect of AD II, ol tati c jaundice and into lerance to alcohol (d. · lfiram-li ke action so increase acetaldehyde ~ miting and hypotensio n). • udden death to acute myocardial infarction especially with first generation drugs. • Failure o f therapy. * Primary failure : within the first 4 weeks due to insuffic ie nt number of funct ioning beta cells. *Secondary failure : in 5-30% o f initia l responders due to T diminished number of f·unctioning beta cells.

* Interactions : • Salicylates, indomethacin, sulphonamides displace them from plasma proteins -7 hypoglycemia. 13 blockers inhibit glycogenolysis & mask hypoglycemic manifestations except sweating. Thiazides, loop diuretics, glucocorticoids and oral contraceptives antagonize their action. B-Biguanides - Metformin. - Phenformin (toxic). Mechanism : - i Glycolysis in peripheral tissue. - 1 Glucose absorption from gut. - 1 Glucagon. - 1 Gluconeogenesis. -Antagonize anti-insulin so I effect of i * Used in adult onset with refractory sulphonylurea if fai led & in polycystic ovary. * Side effects: - Lactic acidosis especially in renal fail - ! Appetite. - 1 8 12 absorption. • They are euglycemic drugs. * Contra indications - liver & renal disease. - Diseases inducing hypoxia as heart lung disease (they i liabi lity for lactic acidosis). C- Aca r bose & meglitol : a- glucodase -+slow carbohydrate absorption, used in prandial hyperglyce mia .They produce flatu 0 - Glitazo ncs (ThiaLOiidinedioncs) : increase tr ue sensitivity to insulin by acting on PPAR receptor.Rosiglitazone & pioglitazone ( less hepatotoxic than obsolete troglitazone.They produce fluid retention E-:\l eglitinides : Repaglinide and Nateglinide acts as sulphonylureas to i insulin release. Shorter duration and less CVS effects.

I 1- Inhibit antigen/ antibody reaction-+ anti-allergic & immunosuppressant. 12- Anti-stress & anti-shock. 13- Feed back mechanism --+ 1 ACTH --+ atrophy of adrenal cortex after long use. *Cortisone is inactive (prodrug), converted into hydrocortisone (cortisol). Peak level of cortisol is from 4-8 a. m.

Uses. I) 1-

shock and bronchial

organ

Anti-inflammatory I

0.8 one sone (inactive) • T · mcinolone

5 5 5

10 30 30

salt retaining I

0.8 0.3 0.3 0 0 0 0

J

- betamethasone FPD=Fiourinated prednisolone derivatives.

FPD

- Bcclo mcthasonc, budcsonidc , nuti casone and tri amcinolo ne arc inha lation ste ro ids used in asthma. - Fludrocorti sonc is o ra ll y acti ve mincralcorti coid & has g lucocorti coid actio ns.

• r ludrocortisonc ora ll y, it has mine ra lo & g lucocorticoid acti vity, used in c hroni c adrenal insuffic iency.

rn

* Sid e effects : ad renal 1- If stopped suddenly > acute insuffi ciency. 2- Salt retenti on, weig ht gain, edema, T B. P .. & al ka losis. 3- Diabetes me llitus. 4- Cushing's syndrome. 5- Myopathy. osteoporosis. 6-Psychosis. 1- Peptic ulceration. 8- De lay healing of wo unds & ulcers. 9- Hirsutism, irrigu lar menses. I 0- Inhibit immune system ___, li ab ility infection. II- T Blood coagul ati on. 12- G rowth inhibitio n. 13- Cataract & g la ucoma. * Precautions : • Notice body weig ht, B.P., glucose in • X-ray o n spim:/6 mo nths. • Observe for pe ptic ul cer & hi dden in • Diet ri ch in K. Ca, prote ins, low in Na, steroids. • Not stopped suddenly. * T the dose in stress. * C ontraindications : Peptic ulcer - viral infectio n- psychosis- acti ve acute in fec tion (give che motherapy be fo re) - osteoporosis -gla ucoma - hypertensio n - heart fail diabetes me llitus- pregnancy - Cushing's syndrome. M ineralocorticoids Aldosterone produces Na+ retention & K- loss. It is controlled by ren in I a ng io tensin syste m, Na and K-. • Preparations : • Desoxycorticosterone S.L., injection (destroyed in liver)

ethinyl estrad io l

norgestrel

From day 1-6

0 .03 mg

0.05 mg

From day 7- 11

0.04 mg

0.075mg

0.03mg

0.125mg

3 months.

following

LH so inhibit o f cervical mucus so impair its rms. I changes & interfere with tube contracti on. tenderness, headache, libido changes, rawal bleedi ng. gain, skin pigmentation, acne, break& infection vaginal bleeding

Fro m 0.5 mg). From day morethi ndrone lmg). C) Triphasic combination tablets :

0.035mg with

thromboembolism, myocardial infarction, cruf"ebrmlas,c l lar disca c. cho lcstatic jaundice. severe Aic:or~sion & impaired glucose tolerance. LODIJI:Hndications: bolic diseases - hypertension - H. F.-diabctes itus- migra ine- Fibroids & cancer breast - liver disease - above age of35 years.- undiagnosed vaginal bleeding. Interact ions : - Decreased effect may be due to : I. Enzyme inducers as rifampici n. 2. Antibiotics which kill gut nora as (ampicillin) responsible fo r entero-hcpatic recycling ___, 1 estrogen abso ion.

* They will decrease the effect of anticoagulants, hypotensive and hypoglycemic ?rugs. *Tobacco smoking and antifibrino lytics increase the incidence ofthro mboemboltsm. Hormonal Replacement Therapy (HRT) Conjugated estrogen + progestin are used after menopause.

Benefits: reducing risk of osteoporosis, angina pectons, h atrophy.

Contraimlicatious : endometrial carcino a, b ast carcinoma, disease and thromboembolic disease g. D T.

• Drugs inducing ovulation Clomiphene citrate( estrogen rece or odulator)&bromoc iptine in ga lactorrhea-amenorrhea syndrom .. Human menopausal gonadotrophins hormone. Metformin in polycystic ovary. Aromatase inhibitors as letrozole a rpstrozole (inhibi increases gonadotroph ins& can be useCl in estrogen dependent cancer breast.

* Anti-estrogens : I) Selective estrogen receptor modu ato (SERMs): th agonist action on endometrium, bone, h~ids & cq_agtllation through ERa and antagoni stic effect on breast & pi it y through E . T ey include clomiphene ( used in induction of ovul "on), ta 1oxifen alo ifene ( used in ttt of cancer breast & osteoporosis 2) Estrogen synthes is inhibitors: A- continued use of gonadotrophin releas ing 1onnone B-danazo l which inhibits both GnRH&gonadotrop in C-aromatase inhibitors(A Is) : steroidal A Is as cxemestane (sui cide inhibition) non-steroidal Als as letrozo le

Gonadotrophin s include FSH , LH which are glycoprotei ns, FSH i Calcium homeostasis foil icular growth and i release of estrogen induced by LH in fe males and i spermatogenesis in males. LH i maturatio n of fo llicle, i estrogen and pro esteron 'n i testosterone production by Leydig cells in males CtlVIty. Human postmenopausal gonadotropins (hMG ave SH and g iven are ey T activity. LH e ha (hCG) gonadotrophins Human chorionic o ad by injection to stimulate ovu lation (hMG) d to f ula steroidogenes is (hCG). • Prolactin is controll ed by inhi b ito r~ rete sing factor (do a · e through Ih receptors so it is i by phenothiaz i es, butyrophenones res rpine ... to induce ovul tio in amenorrheaBromocriptine is D2 agonis o lactation, l Galactorrhea syndrome, to i f parkinsonism in acromega ly & in - ~Vasop ress i n (ADU): Polypeptid whi h increases thew ter reabsorption in distal tubules. • sooium etidfonate an pamidronate which inhibit bone Vasopressin (A DH) acts on: -V 1a receptors in vascular smooth m oraHy in treatm,ent f Paget's di sease, hypercalcemia resoption and are -V ,b receptors-+ jACTH assoc iated with rna ign ncy and postme op usa! osteoporos is. -V2 receptors in renal tubules. 2 Estrogens preven the esorbing effect fparatho rmone in early menopause. It is released by t osmotic press ase ca++ absorp ion and increase bone resorption. 3 Glucocorticoids pressure and ethyl alcohol. educe rena l Ca e cretion and are used in idiopathic In high doses it contracts smooth us les ~ t B.P. an cohcs. u e portal venous Used in diabetes insipidus, in bleeding o sop ageal varices to I caries. It may decrease frequency of pressure and in paralyt ic ileus. Given by i 'ecbon or nasal spra (~cause al nuresis. ulcer).Desmopressin is given orally in noc reduces H20 reabsorption , j V2 recept *Conivaptan is antagonist of V ia & RF. plasma Na+ & produces VD.lt is given IV in h na *Tolvaptan blocks V2 receptors & is given orally · h ntracts 1 Oxytocin stimulates uterine contraction sing1e cha in polypeptide hormone produced by a-cells of gon • milk ejection. It is g iven by injectioA o nasal breast in an eas. Its secretion is inhibited by elevated blood glucose, insulin and ocol i . spray.. Atosiban b locks oxytocin receptors & used a somat s atin and stimulated by am inoacids and sympathomimetics. It creas, it - Glucagon : peptide hormone re leased from a.-cells ot: lates li ver glycogeno lys is, g luconeogenesis and lipolysis and large stimu e Jipa activates & stimulates liver g lycogeno lysis, g luconeogenesis enzymes and is +ve inotropic.

,.&

dose relaxes smooth muscles and has +ve inotropic effect on heart. N.B. : Hyperglycemic hyperosmolar non ketotic (HHNK) syndrome is Used in hypoglycemic coma (S.C. or I.M.) and in treatme nt of 1ealrt~b1(:•ek~&.:--!Ulw-f':re..-h,me:r P i yce mi a w ith profound dehydration , increased osmolarity , heart fai lure due to overdose of ~-blockers & to relax · w ithout ke tosis or acidosis. It occurs primari ly in type II radio logical examination rrent illness and drugs as thiazide diuretics,

Osteoporosis It is abnormal bone loss pred isposing post-menopausal women , chronic g l hyperparathyroidism, thyrotoxicos is, idtoprattlQe", syndrome, alcohol abuse and cigarette ......u ...... Treatment: - Post menopausal osteoporosis is &a..t~·rl progestins but it may · -Selective estrogen receptor avoid breast and uterine raloxifen e -Vitamin 0 with d ie tary ca lci -Fluoride slow release for menopausal osteoporosis -Teriparatide is a recombinan ..,....,~1'=""'~o:;:-----, new bone formation. -Calcitonin : injection or nasa l -Biphosphonates inhibit bone r_,.,.....,t etidronate, and alendrona used in renal impairment , disorder .. -RANK ligand (RANKL) inhibitor :VtP,flh.IOII which binds to RANKL receptors so osteoclasts differentiation & function • ttt of tetany : calcium g luconate 20% I. V. , inCa ~-+

& low in phosphate. loop diuretic (to i absorption), phosphate, calcitonin, di sodiurn edelate (chelati d ialysis. (A T 10), diet rich

ttt of hypercalcemia

* 1 a- hydroxyl vitamin D due to renal fai lure

2

is used for secondary hyperparathyroi

in methaemoglobinemia, anti-oxidant

itching,

teratogenicity,

der swelling m extremities &

of the code andinterefere with initiation of peptide formation. • Macrolides & Cli ndamycin affect 50S ribosomes ~ inhibit translocation step. • Ch lorampheniol affect 50S ribosomes ~ inhibit activity of peptidyl transferase.

Classification of antimicrobial drugs According to spectrum : -Narrow spectrum e.g. penicillin, aminoglycos ides. -Broad spectrum e.g. tetracycli ne, chl orampheni co l. According to whether they kill bacteria o inhibit growth: Bacteriostatic drugs: Chloramphenicol, tetracyclines, clindamyc in, macrolide and sulphonamides Bactericidal drugs:Am inoglycoside , B lacta m antibiotics , polymyxins, quinol nes , ri famp icin, vancomycin and metro id ole. Bactericidal drugs are selected w en tiost defense mechani sm is impaired a in .___ _ _ _~ _ _~..., endocard itis ,men ingitis and inca cer..!J_la_ti_e_nts with neutropenia Bactericidal drugs can be divide in o: -Concentration dependent ki llin dfpgs, e.g. quino lones and amin oglycosid s, Wpere the rate of kil ling effects increases ·th \ increase drug concentration and this 1 responsible for the efficacy of once dat' dosing of aminoglycosides -Time dependent kill ing drugs, e.g. ~-I a tam antibiotics and vancomycin where bactericida activities continues as long as serum concentration is greater than the mi nim al bactericidal concentration ( MBC). Drug concentration of time dependent kill ing drugs - Tetracycfin e that lack a post- antibiotic effect (PAE) should aminoacyl tRNA to mR be maintained above the minimal inhibitory - Aminoglycosides affect 30S

IV) Affection of nucleic acid metabolism: act by competition wi th PABA: so inhibit synthesis of folic acid, whtch ls essential for purine and DNA synthesis. Rifa 1picin acts by inhibiting DNA b) depen ent NA polymerase enzyme. c) Quina one acts by inhibiting DNA gyrase revent DNA rep lication. Penicillins

a)

ribosomes~

~ulphonamides

•Lon ac ng: penicillinase sensitive P. oca·ne penicil lin I.M I 12-24 hrs e ~athin e penicillin J.M. I 4 weeks. resistant penicillin: pen icill in V, Ac· penicillinase sensitive, given ora lly. penicillins resistant • Penicillinase cloxacillin, oxacillin, I.M llin Methici dicloxacil lin, flucloxaci lli n & nafcillin orally. of • Broad spectrum pcnidllins: ampicillin, Amoxicillin ( better absorption & not affected by food) ,orally, penicillinase sens iti ve misreading

pivampicillin, as esters Ampicillin talampicillin (pro-drug) convetted to ampicillin in gut or liver. • Antipscudomonas penicillin: Carbenicillin (oral)., ticarcillin piperacillin, Azloci llin, mezlocill in I. M. I. V. 1'-.B.: clavulanic acid, sulbactam tazobactam are penicillinase (p lactamase) ith inhi bitor so they are combined amox icillin or ampi cillin or ticarcillin o i their action .

Cephalosporins Bactericidal

Third generation w ith a ntipseudomonal activity : cefoperazone, ceftazidime. to pcicillinase to Moxalactam can produce bleeding ( antivitam in K effect), rarely used. Activ ity :decreased activity aga in st Gram +ve organisms.Gram-negative: further increased activity agai nst Gram-vc org~i sms .

They are also able to pen etrate CNS (ex pt ephoperazone & oral preparations) making the m usefu l against meningitis caused by P.neumococci, meningococci, H. injluenzae, and susceptible E. coli, Klebsiella, and penicillin-res istant N.

• Spectrum: +ve, -ve cocci, +v b cilli, Broad actinomyces. spirochaetes, (extended spectrum) affect also ve baci lli . • Mechanism of action: bactericiClal by 1 cell wall synthesis, bind to PBPs s inhibit cross li nkage between peptide ehains attached to muramic acid and i acti.rity_a autolysins. Affect growing bacteria not resting one. • low C.S.F. level except in meningitis. ses: strept., staph. , pneumo & on cocca l infection - meningitis, syphilis, Miph eria, ever, typhoid actinomyces,H.pylori , rheumatic urinary in fect ion. Prophylaxis of & fever by benzathine penicill i bact~rial subacute of prophylaxis endocarditis. reaction Hypersensitivity Toxicity: (anaphylax is) - diarrhea (oral penicillins), nephriti s (methicillin) - loca l pain (I.M .), platelet (I. V.) thrombophlebitis dysfu nction (carbenicillin) - epilepsy & seizures (high close or inside CS F).

2nd en ration (intermcdi te pectrum) -Ora : Cefac lor, Cefuroxi e ,Cefprozil . - Parenteral : Cefamandole,Cefuroxime, Cefonicid xitir r, "Cefmetazo . Cefote A tiv 'ty : gram +ve: Less 1an first-generation. Gram-negati ve: gre ter than first-generation+ HEN (Haerophil us influenza .Enterobacter aerogenes and some Neiss ria ) e can not pass o CNS except ce furoxime. *Used in sinus-iri , lower respiratory tracL iofectio,ns. Anaerob· c infect' !D a bactaroidCs fragifs in petotinitis & peivic i ect10ns.( Cefotetan, efoxitin , ce fmetazole) &... C rnmun ·D' acquired pneumoni a ( ccfuroximej.

Ceftri

one

gonorrho~ae.

*Used ·n a wide vari ety of serious infectiOns. . Meningitis caused by pneum ococci, H. influenza meJlingococci &susceptible enteric gram - ve bacilli ( cefotaxime & ce ftriaxone) .Pseudomo as infection ( cephoperazone, ceftazidime) .Emperical therapy of sepsis of unknown ca use i neutropeni c, febril e . nmu ocompromised patients (ceftazidime often with other antibiotic). . S. typh i ( ceftriaxone)

4th generation ( broad spectrum): -Parentwral :cefepime, Cefpirome . More resistant to ~- lactamases. Activity :gram+ve: similar activity as first-generation.Highly active against S.aureus & S. pneumoni ae Gramve: Pseudomonas, enterobacter, haemophi lus & neiseria . . They have good activity against most penicill in non-susceptible st ain of streptococci & enterobacter infeotio s. They penetrate the CNS NB. Ceftarolin e ( 51h ge nerati n) has activity aga inst meth icilli n resistan staphylococci & broad gram -ve spectrum Pharmacokinetics:

They are distributed to body flu id, adequate level in CS F with third generation (except cephoperazon ) fourth generation . Excreted by t ul and glomeru li (p robenecid reduces thet secretion) . Cefoperazo ne and ceftria on are excreted in bile and faeces.Ceftri a ne has long duration , so can be given once daily.

Toxicity:

. Used in infections caused by susceptible organisms res istant to other available drugs as pseudomonas .A lso for enterobacter infecti on and in mixed anaerobic & aerobic infections & in febrile neutropen ic patients. Ertapenem is not used in pseudomonas Side Effects: Nausea, vomiting, diarrhea, skin l, eosinophil ia, neutropenia and seizures with I rge ose of imipenem. C ross allergy with pe icil ·n.

2} Monobactam

Aztreonam is monocycl ic B-lactam ring and is res istant to B atamase. It is inactive aga inst gram +ve bact ria and anaerobes but highly acti.Ye..against am -ve bacill i (pseudomonas aeruginosa an serratia). It is g iven I.M. or I.V. , excreted ilJ uri e. Side ef{ecfs: P 1lebitis, skin rash, elevated transam inase nd superin fection with staphylo occi. No c ross allergy w ith pen icill ins

•fi-lactam antibiotics ill in , _-C phalosporins, arbapenems as imipenem and meropencm, 4-Monobactam (aztreonam).

Macrolide antibiotics Inc lude: Erythromycin, C la rithromycin a nd Azithro mycin (lo ng acting, no t e nzyme inh ibitor). • Erythromycin : affect gram + ve (staph, strept, pneumococci di phtheria, -ve (H. influenza, mycop lasma, legionella). It .!.protein syn thesis b binding to 50S subunit of bacte ri al ri bosomes. Bactericidal in la rge dose, bacteriostatic in low dose, can't pass to C , given orall y enteric coated, excre ted in 'n & bile. Erythromycin is concentrated in rost tic fl uid, macrophages &PMNL, it und ente ro hepatic circulatio n Uses: diphtheria, penic illin all erg i pa - mycop lasma infecti on - Chl amyd ia esp. in pregnane . A so in di abetic Gastro pares is & to pi cal in ac e .. Side effects: gut upset, cho lesta ic j una ice fever, rash. It inhibits cytochrome P4, of theophylline. Clindamycin O ral or l. V. Active again st +ve anaerobes concentrated in bones, Uses -Severe a naerobic infections as (usua lly w ith metro nidazole). -Prophylax is of endocardi tis in patients valvular heart diseases. -With primaqu ine in pne umocystis carni i pneumoniae as an alterna ti ve to cotrimoxazo le. -W ith cephalosporins or am inoglycosides in penetrating wounds a nd in fectio ns in fema le gen ita I tract. -Top icall y in acne. Side effects: Nausea, diarrhea, skin rash, ne utropenia, impaired liver fun ction . Severe

*Active against E.co li , Klebsiella, proteus, pseudo monas, yersi nia & some staphylo & streptococci. *Poorly absorbed ora ll y, can't pass to CSF, pass placenta l barrier, hig h level in renal cortex & inne r ear. hey are nephrotoxic, o totox ic (damage of 8'1' a nia l ne rve) & have curare like action. in T. B l. M . g iven is tr tomycin act riostatic), Plague, endocard itis & oral in· tes inal in fect ion. It ro uces dea fn ess & vertigo. *Genta y ·n l. M., I. V. in urinary & resp. meningitis endocard itis, infect1on, (intratheca ~ & locally on skin & eye. Nephro oxi , o totoxic. * Neomy n: ighly tox ic used only orally or locaUy i in estina l infection & hepatic coma.

Bac tcri os .ttic )y l pro tei n synthesis. 1-C hlor ph nicol: +ve, -ve bacteria & ric ke sia It binds to 50 S ribosome subun it orall o inj ection, passes to CSF, conjugated w i gl c uron ic acid. * U d i typhoid fever, H. lnnuenza meningitis & pneumonia, anaerobic in fections, local on eye &

s

ir;.

xicity: agranulocytosis (do blood count), gray baby synd rome in premature, gut upset, superin fection vit. B & K deficiency. Enzyme inhibitor -+ T e ffect or other drugs affect +ve & -ve bacteria, 2- Tetntcyclines: pallidum, treponema chlamyd ia, cho lera, mycoplasma, a nd amoebae. Bind to 30 S ribosome subunit.

*

Tetracycl ine, oxytetracycline: incomplete oral absorption, l absorptin by iron, ca··, AL "' , excreted in urine g iven 250 mg/6 hrs. * Doxycycl ine : complete oral absorption, long duration excreted in bile g iven once/day used in rena l fa ilure. Poor CSF level except minocycline. * Tigecrc/ine is a te tracycline re lated to minocycline wh ich is used in res istant inrec ions a s M RSA & e nte rococci & has large V d * Uses: myco plasma pneumonia, c_J;olera, brucellosis, chl amydia, syphilis, ~6no hea in pen ic illin a llergy - resp. infection - era "cation o f H. pylori , amoebic dysenter~ acne Demiclocyli ne in S IADH to inhibi acti n of AD H. *Tox icity: - C he lation w ith Ca · in bones --+ ena me l dysplasia and yellow discoloration. - Superinfection (monil ia or bacte rial). -Gut upset - teratogenic effect - vi B deficien_cy - ras h, photosensitivity - hepato oxic especia ll y in pregnancy - outdated tetracycli nes ar' nephrotox ic ( Fanconi syndrome). - Dem ic locycline ~ diabetes insipi vo miting & vertigo. -Benign ontracranial hypertension. Quinolones -Firs t generation ( nalidixic acid ) : in y tract in fect ion no t pseudom onas, not syste ic -Second general ion (ofloxacin, norflox in, ciprofloxacin ) :60 times more potent, affect gr am - vc on haemophi lus, p seud o m o nas, nc isscria gonorrhea & some + ve( not pne umococci or e nte rococc i) a nd a typ ica l orga ni s ms mycop las m a, ch lamydia, lcgionc lla a nd m yco bacteria inc luding T.B.( not M . avium)

-Third generation (levofloxacin, sparfloxacin, moxifloxacin ) : expand d gram - vc& im proved + ve,atyp.jcai organisms. -Faurth e ration( t v Sflodcin : They a ect gram e , + eo ga ni s n;as & anaer~be Flftoroquinolo es are done ntrated · p ·astatic tissue & re ·creted in uri~e. Probe1 eci l their ism: Bacte "cidal by

l

ON~ gyras

e nzme pn ver t D duplicatio & transcription. They have post-antibio · c e ec\. * ctivity: t-coti, ncisscri a gono hea, pse d o m o nas. prote us, k ebsicl la, sa lmone Ia, shi el la , H. Influe nza, lcgio nc lla, some ve inac ti ve against anae ob except 4 111 gene ration. Gi en orally in urinary in fec ti on, proslatiti s, gononhca, shigella..& sahnonella.infcction, resistant T.B and bone & soft tissue in ectio n. Levofloxac~n in in community ac ui11 d & bro d rn aL i a l

Sulphonamides 1-

Absorbed ora ll y. Short acting: sulphadiaz ine I 6 hrs . Intermediate: s ulphamethoxazol e I 12 hrs. Long acting: sulphamethoxpyridaz ine I 24 hrs. Poorly absorbed ora ll y: sulphaguanidine, ul phasa lazi ne. - Local on eye (sulphacetamide) & on skin ( aft ide, silver s ulphad iazine). * S •ctr rn : gram +ve, -ve cocci & some -ve bacilli (E-c li, !. infl uenza), chl amydia, noca rdiosis & toxop asm sis. * 1\ Jcch · is : bacteriostatic, compete w ith PABA so inhi it ~ lie acid synthesis. Antagonized by PABA 84 dni s releasing PABA as procaine. * s~ nc t·gis 1: ij trimethoprim. DHF reductase enzyme id Folinic acid (-)

le

trimethoprim DNA

'--l'----~---1

T

me. Uses : meningitis (sulphadiazine), respiratory & uri nary infect ion, typhoid fever (co-trimoxazole), bac illary dysentery, ulcerati ve co li tis by s ulphasalazine, trachoma, toxoplas mos is, nocardiosis, pneumocystis carini i - s kin, eye infection. Prophylaxis of meningitis & rh e umatic fever.

Vancomycin

• Adverse effects: •Crystallu ria {prevented by a lkaline urine, fluid intake), a ll ergy, blood dyscrasias, haemo lysis in G6-PD deficiency - kern ictrus, gut upset, he patic tox ic ity, T effect of oral hypoglycem ics & oral anticoagulants. Megaloblastic anemia wi th trimoxazole. Treatment of typhoid f e ver: Acute: fluoroquinolones, a mpic ill in, Co-tri o cepha lospori generation Jrd ch loramphenicol. Carrier: Ampic illi n, Co-trimoxazole .

It is bacte ricida wa ll.

y- inhibiting ynthes is of ce ll

[

140/90 on at least 3 read ings on difTerent

it may be primary (essent ial) or

seeond ary.Norrnal B .P .. 120 systolic & ,80 diastolic

C lassification : Prchy pcrtcnsion systolic 120-139/ dias tolic 80-89 S tage I hy pertension systolic 140-159 /diastoli c 90-99 tage hy pertension systolic > 160/ diastolic > 100

* Lines of treatment: sa lt restrictio n( less

J.

th~ n ~d iiy) !fat, jfruits & vegeta bles- reduce wc tglit 1 obese patient- stop a lcoho l, smoking.Contro l dial:5etes & atherosclerosis - physical exe rcise Prehypertension + diabetes or ch ronic re?al fail ure: ARBs prevent onset of' hypertension

*

Diabe mellitus: ACE inhi bitors or ARBs or Ca .. blockers .

Stage [ hl pertensi'on : Start by monotherapy •Thiazides (chlorothi azide, hyarochlo.,-othiazide, chl orthalidone) in elderly patient & in heart fa ilure. • ACE inhibitors (captopril, enal pri, lisinop•·il, pel'indopl'il....) in high ren in, heart fai lure, diabetic nephropathy. • AT 1 blocke•·s (ARBs) as losartan, valsartan, candesartan in intolerance to ACE it ibitor. blocker·s (nifedipine, • ca++ isradipine, amlodipine, verapamil, diltiazem) i pectoris and in arrhythmia (verapamil). • B blockers (selective Bro•· non selective) in y ung patient, angina pectori s (not vari ant), arrhyth anxiety, H.F. (not the first c ho ice) Stage II hypertension: 2 drugs or more Us ually thiazides + ( B blocker or ACE inhibitor or ARB o•· CCB) according to compelling indications.

Hypertensive urgency .P. P>-220/120 without t get organ damage is t ·eated wit oral therapy by p..bJocker, diuretic,V .D.,ACE)., clo idine, labetal ol o lo:wer pressure withir 24 hs. AvQid rapid lowering ofB P. to nvoid hypop

* Heat·t failure: Diuretics & ACE inhibitors, *

ARB) , p blockers, aldosterone antagonist. Cot·ona llcar·t disease : P-blockcr, CCB, ACE!, diuretic ???? m ocardial infarction : B-blocker wi out ISA, ACE is, eplerenone hypertrophy, hype.-Iipidemia: selecti ve a , blockers as prazosin or doxazosin

Jn diabetes mellitus & in •·cnal failut·e B.P. should be maintained less than 130 I 80. Aliskiren is a renin inhibitor g ive n orally to inh ibit angiotens in II formati on . It is used as a monothcrapy in mild hyperte ns ion .

Heart Failure (H.F.) Inability of heart to maintain sufficient output. Classification of H. F.: Class I : no limitation of ordinary physical activity. Class II : ordinary activity results in sympto ns (fatigue, dyspnea, palpitations) Class liT :symptoms appear on less than ordin ry physical activity. Class I V: Symptoms are present with any hysical activity & at rest.

Ireutm6lnt of chronic u,F.

1- Treat the cause and control predis~ mg factors (resp. infection, rh. fever. .. ). 2- Restriction of physical acti vity ~ rest -weight reduction in obese - restrict NaCI - low caloric intake- small light frequent me Is. 3- Drug treatment: Class I patients use ACEis or ARBs o P- oc er. Class II - IV patients ACE I (or AJill) & ~-b locker. Add diuretic (usually loop ) to ontrol fluid retention . IV add If fai led add digox in & in spironolactone or eplerenone. N.B. -~-blockers ( carvcdilol, bisoprolol , metopro ol or nebivolol) starting by very low dose & "trated slowly over a period of weeks or months a symptoms may deteriorate initially.They re u mortality. - ACEis reduce mortality, improve symptoms & reduce hospitali zation. - Diuretics & digoxin reduce symptoms but do not reduce mortality. -Angiotensin receptor antagonists may be used if ACE inhibitors are not tolerated because of cough.

6-+v inotropics as digoxin .Y., dopamine, dobutamine (I.V. drip). inophylline 25 0-500 g slowly I. V. +ve inotropic, .D., ronchodilator, diur tic). H.F. +Atrial fib illation (A.F.)

digi alis is used to restore efficiency, reduce vent:ricu ar ra e by decreasing A.V. onduction, pro longing .P .V. node (by vagal

•Loop diuretics oral or I.V.: most potent, rapid onset, short duration, frusemide Trenal flow, used in rena l impairment, severe H.F., acute pulmonary edema & emergency hypertension. -Frusemide 40-80 mg oral 20-40 mg I. V. thacrynic acid 50-200 mg oral 50 mg I. V. -B metanide 0.5-2 mg oral 0.5-1mg I.V. . "de effects: Hypoka lemia, hypomagnesemia, hyponatremia, alkalosis, h ocalcemia, dehydration, hypotension, hypovo mia, ototo ic, allergy, gut upset, hyperglycemia, hyperUric ia, Cross sensiti vity between frusemide, umetanide & sulphonanides. N.B. H)\Po lem ia Tdigital is toxicity. Corrected by dietl!ty I3

Total bilirubin, mgldl Serum albumin, gldl

2.8- 3.5

6

Encephalopathy Total score of 5-6 is grade A or Total score of7-9 is grade B or ...... .,...._.... Total score of 10--15 is grade C or