Pharmacology Practical Ain Shams

Table of contents :
Cover
Contents
Drug Sources And Administration
Sources Of Drugs
Biological Synthesis
Dosage Forms Of Drugs
Enteral Dosage Forms
Oral
Rectal
Parentral Dosage Forms
Inhalation Dosage Forms
External Dosage Forms
Routes Of Administration
Enteral Route
Parentral Route
Inhalation Route
Topical Route
Drug Discovery & Evaluation
Drug Discovery
Drug Screening
Experimental Safety & Toxicity Tests
Official Authorities For Drug Approval
Prescription Writing
Prescription For Controlled Drugs
Microlabs
I. Acetylcholine Concentration- Response Curve
Ii. Histamine Concentration- Response Curve
Iii. Ampicillin Plasma Concentration-time Curve
Iv. Propranolol Plasma Concentration-time Curve In Liver Cirrhosis
V- Effect Of Intravenous Iniection Of Adrenaline On Blood Pressure& Heart Rate Of Anaesthetized Rat
Vi. Effect Of I.v. Acetylcholine On Blood Pressure & Heart Rate Of Anaesthetized Rat
Vii- Effect Of I.v. Histamine On Blood Pressure & Heart Rate Of Anaesthetized Rat
Viii- Effect Of I.v. Tvramine. Prazosin And Propranolol On Blood Pressure &heart Rate Of Anaesthetized Rat
Dose Adjustment And Individualization
Clinical Pharmacology
Introduction
I. Evaluation And Selection Of Drugs
Ii. Applying Pharmacokinetic Principles
Iii. Prescribing To Patients-at-risk
Iv. Pharmacogenetics
Pharmacovigilance
Vi. Risk Factors And Effectiveness Markers
Vii. Therapeutic Drug Monitoring 'tdm'
Clinical Pharmacology Sheets
I. Searching The Literature For Clinical Evidence On Pharmacotherapy
Ii. Reporting And Assessing Adverse Drug Reactions
Iii. Pharmacotherapy Of Patients At Risk
Iv. Starting, Continuing And Ending Pharmacotherapy
V. Checking For Drug Interactions
Vi. Apply Your Skills
Problem Solving
Case Of Angina
Heart Failure
Hypertension
Blood
Diabetes
Chemotherapy
Peptic Ulcer
Bronchial Asthma
Epilepsy
Tutorial Sheets
Dosage Forms And Routes Of Administration
Pharmacokinetics
Pharmacodynamics
Adrenergic
Cholinergic
Autacoids
Renal Pharmacology
Drug Therapy Of Angina
Drug Therapy Of Heart Failure
Drug Therapy Of Hypertension
Drug Therapy Of Anemia
Drug Therapy Of Thrombosis
Respiration
Gastrointestinal Tract Pharmacology
Peptic Ulcer
Thyroid
Cns Cases
Epilepsy
Local Anesthetics
General Anesthesia
General Chemotherapy
Special Chemotherapy
Quiz Sheets
I. Concentration-response Curve In Guinea Pig Ileum
I. Concentration-response Curve In Guinea Pig Ileum
Ampicillin Plasma Concentration-time Curve
Propranolol Plasma Concentration-time Curve In Liver Cirrhosis
Regulation Of Blood Pressure & Heart Rate Of Anaesthetized Rat
Work Sheets
Adr Report Forms
Pharmacotherapy Of Patients At Risk
Semesters

Citation preview

CLINICAL PHARMACOLOGY

Practical Notes Third Year Medical Students • Drug Sources & Administration • Microlabs

• Clinical Pharmacology • Problem Solving and Sheets

""""**»»*£% .'*%

Clinical Pharmacology Department Faculty of Medicine Ain Shams University

2019/2020

CLINICAL PHARMACOLOGY

Practical Notes Third Year Medical Students • Drug Sources & Administration • Microlabs

• Clinical Pharmacology • Problem Solving and Sheets

Clinical Pharmacology Department Faculty of Medicine Ain Shams University

2019/2020

CONTENTS

Drug Sources and Administration

5 - 26

Microlabs

27-72

Clinical Pharmacology

73 - 90

Clinical Pharmacology Sheets

91 -142

Problem Solving

143-160

Tutorial Sheets

161 - 204

Quiz Sheets

205 - 234

Drug Sources and

Administration

INTRODUCTION

Pharmacopoeia

• An official book containing a list of widely used drugs introduced according to their

therapeutic usefulness. It includes information about physical properties & therapeutic doses (minimum effective dose, maximum tolerated dose). Each nation has its

pharmacopeia: Egyptian Pharmacopeia, USA Pharmacopeia...

Sources of Drugs I. Natural

• Plants; e.g. atropine, morphine, oil of tolu, clove oil and peppermint • Animals; e.g. hormones.

• Microorganisms; e.g. antibiotics as penicillin. • Minerals; e.g. iron, calcium. N.B.: Many natural products are now synthesized. Those whose synthesis is very expensive, or complex are still derived from natural sources. II. Synthetic

A. Chemical synthesis; e.g. aspirin.

B. Biological synthesis: by recombinant DNA technology. HI. Semisynthetic

Semisynthesis is used when a needed precursor molecule is too structurally complex,

too costly, or too difficult to produce by total synthesis; e.g. some penicillin preparations.

-6-

Biological Synthesis Definition

• It is the selective insertion of the desired DNA into another DNA of a living cell to form recombinant DNA, yielding large & complex polypeptide & protein compounds. Indications

1. Supply of large amounts of material (for human use) that cannot be obtained by conventional purification methods; e.g. - Human insulin.

- Interferons.

- Erythropoietin.

- Hepatitis B vaccine.

- Human growth hormone.

- Tissue plasminogen activator.

2. Gene therapy:

Gene therapy is a technique that uses genes to treat or prevent disease. It is still considered an investigational technique. In the future, this technique may allow treatment of disorders by inserting a gene into a patient's cells. Researchers are testing the following approaches:

• Replacing a mutated gene that causes disease with a healthycopy of the gene. • Inactivating a mutatedgene that is functioning improperly. • Introducing a new gene into the body to help fight a disease.

Although gene therapy is a promising treatment option for a number of diseases (including inherited disorders, some types of cancer, and certain viral infections), the technique remains risky and is still under study to make sure that it will be safe and

effective. Gene therapy is currently only being tested for the treatment of diseases that have no other cures.

-7-

DOSAGE FORMS OF DRUGS

I.

ENTERAL DOSAGE FORMS A. Oral

1. Liquids A. Solutions

1. Aqueous Solutions i. Syrup: sweetened aqueous solution of drug e.g. cough syrups. This is the most

common aqueous solution for oral administration.

ii. Other less common aqueous solutions of drugs include:

• Water1

• Aqueous extract2.

• Infusion3

2. Alcoholic Solutions

i. Elixir: sweetened hydroalcoholic solution of drug e.g. antihistaminic elixir. ii. Other less common alcoholic solutions of drugs include:

• Spirit4

• Tincture5

• Fluid extracts6

B. Suspensions & Emulsions

• Suspensions: insoluble solids suspended in water.

• Emulsions: insoluble liquids suspended in water, as oils suspended in water, with addition of an emulsifying agent as gum.

1Water: aqueous solution of volatile oil e.g. peppermint water.

2Aqueousextract: 100% concentrated drug extract in water e.g. ergot extract 3Infusion: aqueous solution obtained by soaking dried plants in hot or coldwater 4Spirit: alcoholic solution ofvolatile oil e.g. peppermint spirit. 5Tincture: hydroalcoholic solutions of non-volatile substances (10-20% alcohol) e.g. tincture belladonna.

6 Fluid extracts: concentratedtinctures; each 1 ml contains the therapeutic ingredients of 1 g of crude drug e.g. cascara -8-

2. SOLID

A. Tablets

1. Ordinary tablet: a small disc of medicated compressed powder mixed with inert binder as starch or lactose, e.g. aspirin. 2. Caplet: a smooth, coated, oval-shaped tablet. Many caplets have an indentation

running down the middle so they may be split in half easier. 3. Coated tablet: a sugar coat protects the drug & masks its bad taste. 4. Extended release tablet: with different coats and different disintegration times to

give rapid onset & long duration of action, thus allows reduction in dosing frequency. 5. Delayed release tablet: does not release the drug immediately after administration, e.g. Enteric-coated tablet, in which the coat dissolves in the intestine to avoid gastric irritation or inactivation. 6. Orally disintegrating tablet: friable, for rapid buccal disintegration. Also known as sublingual tablets.

7. Lozenges: flavoured tablets, which dissolve slowly when, put in mouth. A lollipop is a lozenge on a stick.

8. Chewable tablet: is chewed to ensure complete breaking up of tablet & diffusion of

active ingredient. It produces a pleasant tasting residue in the oral cavity that is easily swallowed and does not leave a bitter or unpleasant after-taste, e.g. Al (OH)3 antacid.

9. Effervescent tablet: contains mixtures of acids (e.g., citric acid, tartaric acid) and sodium bicarbonate, which release carbon dioxide when dissolved in water, to

mask the salty or bitter taste of drugs.

B. Capsules

A solid oral dosage form consisting of a shell and a filling. The shell is composed of a single sealedenclosure, or two halves that fit together. Capsule shells may be made

from gelatin, starch, or cellulose, or other suitable materials, may be soft or hard, and

are filled with solid or liquid ingredients that can be poured or squeezed. Usually

hard gelatin capsule contains powder and soft gelatin capsule contains liquids. Other forms of capsules include: 1. Extended release capsule: also known as spansule or sustained-release capsule.

2. Delayed release capsules: such as enteric-coated capsule to avoid gastric irritation.

N.B. Pills

Prior to the widespread use of the machine-compressed tablet, pills were very popular products that usually were prepared by a pharmacist as spherical masses of medical substances. Now "pills" is used by the public to refer to variants of tablets and capsules.

C. Powders

• Powder forms of drugs may be dispensed in small paper packets and may be

formulated as effervescent granules (Mg2* sulfate). • Effervescence is due to CO2 release which masks the salty or bitter taste of drugs.

B. Rectal

1. Liquid (Enema) a. Evacuant Enema

• Warm water 600 ml given rapidly under high pressure. • Intended to evacuate the lower GIT b. Retention Enema

• Warm water 100 ml given slowly by drip under low pressure.

• To administer drug through rectum (corticosteroid in ulcerative colitis). >

Precautions before Retention Enema

1. Rectum is first cleaned with evacuant enema.

2. Amount must not exceed 200 ml & level of solution must not be high.

3. Drug solution should not be irritant.

-10-

2. Solid (Suppository)

• Drug is incorporated in a waxy base. They include: - Glycerine suppositories: to evacuate the lower GIT.

- Medicated suppositories: to administer drugs through rectum (Theophylline).

II. PARENTRAL DOSAGE FORMS

A. Liquid (Injections) 1. Ampoules

• The ampoule is a single dose of sterile solution or suspension. 2. Vials

• The vial may be a multi-dose preparation. Unstable drugs are prepared as vials to which the solvent is added before use.

3. Pre-filled syringe: for drugs requiringaccurate dosing e.g. enoxaprin B. Solid (Implants): Pellets

III. INHALATION DOSAGE FORMS

A. Gases: Oxygen, some general anaesthetics.

B. Vapours: Highly-volatile liquids: e.g. amyl nitrite & diethyl ether.

C. Steam Inhalation: drugs vaporized by steaming e.g. tinct. benzoin inhalation. D. Aerosols

• Aerosols aresuspensions of a liquid or solid in a gas administered through: I. Nebulizers:

- It depends on the suction created by a jet of air(orO2) to spray the drug. - Amount of drug delivered is limited only by toxicity of drug.

-11-

II. Metered-Dose Inhalers (MDI):

- The drug is dissolved in a low boiling point liquid in a canister under pressure.

- Pressing the top of the canister opens a valve releasing a metered-dose of liquid which evaporates leaving an aerosol of the drug to be inhaled. Advantages

Portable and compact and available for most substances. Disadvantages

1. Difficult to use as it requires coordination between activation of canister, inspiration & a final holding of breath. This problem can be overcome by the use of a Spacer.

2. Depends on the presence of a propellant substance added to the contents of the inhaler. Thus the amount of the drug delivered is limited by toxicity of drug as well as the additives in inhaler.

E. Powders

•

Powders are administered through dry-powder inhalers (DPI), e.g. Sninhalers: e.g. sodium cromoglycate.

- The drug is formulated as a micronized powder.

- Suitable for patients who fail to use metered-dose inhalers. - May cause transient bronchoconstriction.

• Other examples of DPI include: Aerolizer, Turbuhaler and Diskus

-12-

IV. EXTERNAL DOSAGE FORMS A. Skin and Mucous Membranes

1. Liquids

'• ':

a. Lotion: aqueous solution for local application. b. Liniment: alcoholic solution for local application.

c. Astringents: substances with vasoconstrictor &protein denaturing effect. d. Antiseptics: substances used topically to kill microorganisms (too toxic for systemic use).

e. Emollients (moisturizers): soften & smoothen skin surface byoccluding it with an

oily film making it impervious towater. This prevents normal water loss from skin surface & leads to a build-up of moisture in stratum corneum.

f. Drops for ear, nose and eye. 2. Semiliquid

a. Cream: emulsion of oil in waterincorporates the drug e.g. corticosteroids, antibiotics and antifungal drugs.

b. Gel: contains a gelling agent to provide stiffness to a solution or a colloidal dispersion.

b. Ointment: the ointment base (Vaseline or lanoline) incorporates the drug e.g. corticosteroids, NSAIDs and antibiotics.

N.B.: Ointments are used for dry lesions, creams for semi-wet lesions & lotions for wet lesions 3. Semisolid

a. Paste: mixture of powder + ointment.

b. Patches: A patch impregnated with the drug, e.g. nitroglycerin patch. 4. Solid: Powder, e.g. antifungal powder. B. Vaginal Dosage Forms

1. Liquid: Douche. 2. Solid: Pessary.

13-

Metered dose inhaler

Nebulizer

Intradermal injection

-14-

IV infusion

ROUTES OF ADMINISTRATION

I. Enteral

A. Oral. B. Buccal. C. Rectal.

D. Gastric gavage. II. Parenteral

Systemic l.IV 2.IM

3.SC

4. Intradermal 5. Intracardiac

6. Intra-arterial

7. Intraperitoneal 8. Intramedullary (into bone marrow) Local

1. Intra-articular 2. Intrathecal

3. Intrapleural

4. Around sensory nerve endings or nerve trunks. III. Inhalation IV. Tonical

•

Mucous membrane- skin.

-15-

I. Enteral Route A. Oral Route Advantages

1. Easy {self-medication).

3. More convenient and acceptable.

2. Safe.

4. No need for sterilization.

Disadvantages

1. Delayed onset: gastric emptying time (2-3 h).

2. Variable bioavailability: absorption (drug factors & patient factors) & first-pass metabolism

3. Not suitable for some drugs: e.g. •

Drugs destroyed in GIT, e.g. insulin & catecholamines.

• Drugs with extensive first-pass metabolism: methyltestosterone. • Hydrophilic drugs, e.g. gentamycin (not absorbed). •

Drugs irritant to stomach.

Contraindications of oral route

1. In emergency.

2. In presence of convulsions or vomiting. 3. Coma.

B. Buccal Route

1. Sublingual e.g, nitroglycerin & nifedipine 2. In the buccal pouch e.g, lozenges. 3. Transbuccal patch e.g, fentanyl Advantages of Sublingual route

1. No first-pass metabolism. 2. Rapid onset: useful in emergency.

3. Tablet could be easily taken out in case of over dosage.

-16

C. Rectal Route Advantages

1. Less first pass metabolism. 2. Suitable for children and adults.

3. Suitable in presence of vomiting & in coma.

4. Suitable for drugs irritant to gastric mucosa or destroyed by GIT enzymes. Disadvantages

1. Irregular bioavailability. 2. Disagreeable. 3. Chronic use leads to proctitis. Examples: aminophylline, NSAIDs and paracetamol.

D. Gavage • Introduction of food or drugs into stomach by flexible tube. • Used in coma.

• It is opposite to lavage (washing out stomach in poisoning).

II. Parentral Route

A. Intravenous Route (IVI) Advantages

1. Immediate onset (emergency). 2. 100% bioavailability -> highly predictable blood levels.

3. Suitable for irritant drugs & for large volumes. Indications

1. Useful in emergency conditions.

2. Fluid therapy, e.g. blood transfusion, saline, glucose... 3. IV anesthetics & skeletal muscle relaxants.

4. Irritant drugs after dilution.

17-

Precautions

1. Be sure of the dose since the administered drug cannot be retrieved. 2. Strict aseptic technique.

3. Don't give oily solutions.

4. Exclude air from the syringe. Lower the head below the level of the heart during injection into the jugular vein to avoid air embolism. 5. Slow administration.

6. Aspirate some blood to ensure injection into vein to avoid tissue necrosis with drugs such as a-agonists. Disadvantages

1. Need trained person and aseptic conditions. 2. Risk of anaphylaxis. 3. Extravasation —> local necrosis with vasoconstriction.

4. Prolonged infusion —*• | risk of thrombophlebitis. 5. Risk of infection.

6. Wrong technique —»• air embolism.

B. Intramuscular Route (IMI) Advantages

1. Rapid absorption.

2. Suitable for depot and oily preparation. 3. High bioavailability. Disadvantages

1. Unsuitable for large volumes (> 5 ml) & irritant drugs.

2. Accidental IV injections. 3. May be painful. 4. Sterile/infected abscesses.

-18-

C. Subcutaneous Route (SCI) Advantages

1. Prolonged duration of action. 2. Allows somewhat large volumes (more than IM less than IV).

3. Acceptable for self-administration (insulin). Disadvantages

1. Irritant.

2. Erratic absorption - poor absorption in peripheral circulatory failure. 3. Lipoatrophy (repeated injection in the same site). Factors affecting Absorption from SC Tissues

1. Local blood supply:

- Delayed absorption: shock, epinephrine & cold. - Increased absorption: exercise, massage & heat

2. Drug factors: molecular weight, particle size, type of solvent. 3. Multiple sites —• | SC absorption. 4. Hyaluronidase enzyme—* facilitates absorption. Special Forms of SC Injection

• Implantation, e.g. levonorgestrel (contraceptive).

D. Intradermal Route

• Injection between dermis and epidermis. Indications

1. Allergic tests.

2. Vaccines.

-19-

E. Intrathecal Route

• Injection of drugs into subarachnoid space Indications

1. Spinal anesthesia.

2. X-ray contrast media. 3. Drugs which cannot cross BBB: some antibiotics in meningitis.

ill. Inhalation Route

Factors affecting deposition

1. Aerosol factors: particle size (1-5 micrometers; the optimum size that reaches the terminal bronchioles is 2 micrometers). 2. Patient factors

- Airwaypatency. - Proper technique. Advantages 1. Immediate onset.

2. High concentration in respiratory tract. 3. Minor (if any) first-pass effect. 4. Low incidence of systemic side effects.

5. Large surface area for delivery of absorbable drug. Disadvantages

1. Irregular absorption. 2. Needs intelligentcooperativepatient.

3. Respiratory irritation with some drugs (sodiumcromoglycate & acetyl cysteine). 4. Glucocorticoids —• candidal infection & hoarseness of voice

-20-

IV. Topical route

• Activedrugs not prodrugs are given by this route (in most cases). A. Mucous Membranes

•

Eye, ear or nasal drops containing drugs.

B.Skin

1. Ordinary topical administration

• Application of creams, ointments & other dosage forms on skin. 2. Transdermal patch

• The patch is attached to the skin by a sticking plaster. The drug is released from

the patch through a rate-controlling membrane & passes through the skin into systemic circulation.

• Examples of drugs used by Transdermal patch: 1. Nitroglycerine for angina. 2. Clonidine for hypertension.

3. Estradiol for menopausal symptoms. 4. Hyoscine for motion sickness. Advantages

1. Long duration of action. 2. No first pass metabolism. 3. Gradual onset of action. 4. No GIT irritation.

5. Not destroyed by GIT enzymes. Disadvantages

1. Variable absorption. 2. Local allergy.

3. The stickingplaster may drop off and stick to anotherperson. -21-

DRUG DISCOVERY & EVALUATION Drug Discovery

1. Chemical modification of a known molecule e.g. thiazides were developed by chemical modification of carbonic anhydrase inhibitors.

2. Screening of natural products whose biologic activity is unknown e.g. streptomycin from microorganisms.

3. Rational drug design basedon the understanding of biologic mechanisms e.g. identification of different types ofhistamine receptors led to the development ofH2 blockers.

4. Serendipity: accidental discovery e.g. penicillin from the penicillium mould by Alexander Fleming. Drug Screening

Animal studies (Experimental Evaluation) A. Pharmacokinetics studies

• Include studies on drug absorption, distribution, metabolism & excretion. B. Pharmacodynamics studies

• It includes studying the effects of drugs on different body systems: CNS, GIT, CVS ... using intact animals & isolated organs

• Mechanisms of action of drugs at the molecular level are investigated by receptor

binding studies using agonists and antagonists, studies on enzyme activity, on ion channels

Lead Compound:

The results of drug screening yield a leadingcandidate for a successful new drug which is known as the "Lead Compound"

-22-

Experimental Safety & Toxicity Tests 1. Acute Toxicity studies (24 hours up to 5 days) These studies are conducted to calculate:

A. Effective dose fifty (EDso):

• The dose that produces the desired therapeutic effect in 50% of experimental animals.

B. Lethal dose fifty (LDso):

• The dose that kills 50% of experimental animals (using at least 2 species and 2 routes) Importance of LDso

1. Indicates acute toxicity of drugs; the lower the LD50, the more toxic the drug.

2. Determination oftherapeutic index (TI) =

%£> •It indicates the safety margin

of drugs; the higher the TI, the safer the drug, & vice versa.

N.B.; The initial human dose = Vioo - V10 of"no effect" dose (maximum dose at which a specified toxic effect is not seen). 2. Subacute Toxicity studies

• Their duration depends on duration of expected clinical use (up to months). • Include: clinical chemistry, hematology, histology, autopsy studies 3. Chronic Toxicity studies

• Duration: up to 2 years (done concurrently with clinical evaluation).

• Required if drug is intended to be used for prolonged periods. Include: 1. Tests similar to subacute toxicity studies.

2. Studies to determine teratogenic, carcinogenic & mutagenic potentials as well as addiction liability.

-23

Official Authorities for Drug Approval

• Animal studies provide a general idea of the pharmacology and toxicity of new drugs. The results of animal studies are presented to an authorized committee to gain approval for conduction of clinical studies in humans.

• a New Drug Application; NDA is submitted to the FDA to permit marketing of the drug.

FDA (Food & Drug Administration)

• It is the administration responsible for drug evaluation in the USA and for granting approval to market new drug products.

MCA (Medicines Control Agency) • It is the equivalent authority in the United Kingdom.

-24

PRESCRIPTION WRITING A prescription is a paper written by a doctor to the patient to prescribe medicine for a disease.

Parts of Prescription

1. Prescriber's identity: name, qualification, address & telephone number. 2. Date.

3. Patient's identity: name, age & address. 4. Prescription elements: a. Superscription: R/ (latin: recipe = take)

b. Inscription: drug name, form, strength & quantity whether the drug is simple or compound. c. Subscription: instructions for the pharmacist. d. Signature: instructions for the patient (via pharmacist).

5. Prescriber's signature Patient Name: JQhn SmttQ

Address:

rv

4QO E 3rd Street>^^ Pulutn. MN S

Rx

Amoxicillin 250 mg

If

42

9 tablets px^jF@pX 7

i+

6

7

if

12.

'AMPICILLIN PLASMA CONCENTRATION-TIME CURVE'

-37-

TIME:

Date:

NUMBER:

NAME:

Use graph paperand the table, below, to plot plasma concentration-time curves for i.v. and oral ampicillin (500 mg) at pH 2 & 3.5 Time

6

18

30

42

60

2

4

6

12

min

min

min

min

min

hs

hs

hs

hs

Plasma cone, (ng/ml) [iv.J

Plasma cone, (ng/ml) [oral; pH 2] Plasma cone, (ng/ml) [oral; pH 3.5]

1. i.v. (500 mg) ampicillin Plasma concentration-time curve: •tVz =

• AUCo-i2hs=

2. Oral (500 mg) ampicillin Plasma concentration-time curve [pH = 2]: L-max

AUCo-i2hs =

Bioavailability F = tVi =

* ltnax —

3. Oral (500 mg) ampicillin Plasma concentration-time curve [pH = 3.5]: •Cmax=

AUCo-i2hs=

•Tmax=

Bioavailability F =.... AS=

4. Comments:

Compare between txA in all curves Relative Bioavailability of the two oral doses = Compare between Cmaxofboth oral doses = What is the relation of ampicillin pharmacokinetics to food intake?

-38-

,

39

Pharmacology Department/ Faculty of Medicine E-CLASS OF PRACTICAL PHARMACOLOGY

'AMPICILLIN PLASMA CONCENTRATION-TIME CURVE'

Learning Objectives: At the end of session, I was able to:

1. Identify the plan for drawing a plasma concentration-time curve. 2. Explain the reason for plotting the plasma concentration-time curve for an i.v. dose ofa

drug to determine the absolute oral bioavailability of the same dose of the drug. 3. Use the MICROLABS to determine the plasma concentrations at the different selected time intervals.

4. Plot the plasma concentration-time curves of the i.v. and orally administered same (500 mg) dose of ampicillin.

5. Calculate the pharmacokinetic parameters (Cma\, TmaxJ tV6; AUC0-12 and Bioavailability) from the plots.

6. Contrast between the effects of two gastric pHs (2.0 and 3.5) on the selected PK parameters.

7. Suggest the clinical implications of these findings on the oral administration of ampicillin and other weakly acidic dmgs.

Identify the learning objectives achieved 1

2

3

YES NO

-40-

4

5

6

7

IV. PROPRANOLOL PLASMA CONCENTRATION-TIME CURVE IN LIVER CIRRHOSIS

How to start: Open MICROLABS 1. Click on Kinetics.

2. Select Man, then click Run.

3. Click Case I, then, select Species Man.

4. Then, select propranolol-cirrhosis and press Confirm.

5. From the left-side panel, click on Plasma Concentration. 6. In the new window, notice the weight, then, select Route: p.o. 7. Write 40 in the mg box.

8. In the time after last dose: write 18 in the minutes pane, then click Start.

9. In the pane at the middle of the page youwill readand record the plasma concentration. 10.Repeat as step (8) with times: 24; 36; 48; 60 minutes. Then, write Zero in the minutes box, and continue using the hours box as follows: 2; 4; 6; 12 hours.

11.You will get the records of the plasma concentrations in the middlepane.

12.Plot the propranolol (40mg)-cirrhosis plasmaconcentration- time curveon the graph paper.

13. Press the 'red' button on the right below [*

Ji*ȣ Chtfe^) PLASMA CONCENTRATION-TIME CURVE

of propranolol 40mg in adult (without cirrhosis) -42-

PLASMA CONCENTRATION-TIME CURVE

of propranolol (40 & 20 mg) in Liver Cirrhosis

-43-

Date:

TIME:

NAME:

NUMBER:

Use graph paper and the table, below, to plot plasma concentration-time curves for both oral propranolol doses (40 & 20 mg) administered to liver cirrhosis.

Time

18

24

36

48

60

2

4

6

12

min

min

min

min

min

hrs

hrs

hrs

hrs

Plasma cone, (ng/ml) [liver cirrhosis 40mg] Plasma cone, (ng/ml) [liver cirrhosis 20mg]

1. Oral (40 mg) propranolol plasma concentration-time curve [liver cirrhosis]: • Cmax=

Tmax111

AUC 0-12hs =

2. Oral (20 mg) propranolol plasma concentration-time curve [liver cirrhosis]: Cmax —

AUC 0-12hs =

lmox —.

3. Comments:

Comment on Cmax ofboth doses in liver cirrhosis as compared to Cmax of propranolol 40 mg in normal adult

Comment on AUC of both doses in livercirrhosis as compared to AUC ofpropranolol 40 mg in normal adult

Clinical implications of using normal average dose of propranolol and similar drugs in liver cirrhosis:

44-

-45-

Ah Shams IMverdy

Pharmacology Department/ Faculty of Medicine E-CLASS OF PRACTICAL PHARMACOLOGY

PROPRANOLOL PLASMA CONCENTRATION-TIME CURVE IN LIVER CIRRHOSIS

Learning Objectives: At the end of this session, I was able to:

1. Recognize the possible effects of liver cirrhosis on the pharmacokinetic parameters of a high extraction-ratio drug like propranolol.

2. Identify the plan for plotting plasma concentration-time curves to compare the pharmacokinetic parameters of'propranolol' in an adult with advanced liver cirrhosis. 3. Use the MICROLABS to determine the plasma concentrations of orally administered 40 &20 mg of'propranolol' at the different selected time intervals in liver cirrhosis.

4. Plot the 2-plasma concentration-time curves of orally administered 40 &20 mg of 'propranolol' in liver cirrhosis.

5. Report the pharmacokinetic parameters (Cmax; TmaX; AUCo-i:) from the 2 plots. 6. Compare between the selected pharmacokinetic parameters in normal & in cirrhotic liver disease.

7. Specify the clinical implications of the findings of the study. Identify the learning objectives achieved 1

2

3

YES NO

-46-

4

5

6

7

EFFECTS OF SELECTED DRUGS ON THE AUTONOMIC REGtJLAflON OF BLOOD PRESSURE & HEART RATE OF ANAESTHBTI^fiDRAT V- Effect of intravenous iniection of adrenaline on blood pressure & heart rate of anaesthetized rat:

How to Start: Open MICROLABS 1. Click on PHARMACOLOGY.

2. Select rat blood pressure. 3. Click run, then, continue twice.

4. Choose the dose in weight unit. 5. Select normal anaesthetized animal.

6. Select drug or procedure: Select 1 ug /kg adrenaline.

7. Plot curve on graph paper& repeat this step each time you use a new dose. 8. Selectdrug or procedure: Select2 ug/kgadrenaline. 9. Selectdrug or procedure: Select 5 ug/kg adrenaline. 10.Selectdrug or procedure: Select 1 mg/kg prazosin (ai blocker).

. ...

11.Select drug or procedure: Select 5 ug/kg adrenaline. 12.Select drug or procedure: Select 5 mg/kg propranolol (non-selective B-blocker). 13.Select drug or procedure: Select 5 ug/kg adrenaline.

N.B.

• Small rise in blood pressure (Pi effect) may be noticed when adding adrenaline after prazosin. • Take care to draw the curves of heart rate and blood pressure with the same time scale to ensure that both effects happened in response to the same drug& dose. • Write the name of the drugused &thedose used on its corresponding effect.

•47-

* ——

—*-

•""In-

Figure 1: Effect of i.v. adrenaline on blood pressure & heart rate of anaesthetized rat

-48-

Adrenaline "AD" Curves

Effect of i.v. adrenaline on blood pressure & heart rate of anaesthetized rat

-49-

WORK SHEET Date:

TIME:

NAME:

NUMBER:

Effect of adrenaline 'AD' and adrenergic antagonists on 'BP' & 'HR' 1. Effect of 'AD' on 'BP' and 'HR'

2. Whatis the effect of AD on 'BP' & 'HR' after adding prazosin?

3. What is the effect of AD on 'BP' & 'HR' after adding 'propranolol'?

4. Explain the receptors that are responsible for AD effect on 'BP' & 'HR'.

5. Terminate the experiment and begin a new one with the Following steps: • Select drug or procedure: Select 5 ug/kg adrenaline. • Select drug or procedure: Select 2 mg/kg propranolol (non-selective B-blocker). • Select drug or procedure: Select 5 ug/kg adrenaline. • Plot curve on graph paper. Use your observations from both experiments to answer the following question:

A

51-years-old

female

was

admitted

to

the

hospital

and

diagnosed

as

pheochromocytoma (a tumor that results in excess secretion of catecholamines), the

physicians need to control her blood pressure before surgery which regimen is better and why?

a) Alpha blocker followed by beta blocker b) Beta blocker followed by alpha blocker

-50

-51-

VI. Effect of i.v. acetylcholine on blood pressure & heart rate of anaesthetized rat

How to Start: Open MICROLABS 1. Click on PHARMACOLOGY.

2. Select rat blood pressure. 3. Click run, then, continue twice.

4. Choose the dose in weight unit. 5. Select normal anaesthetized animal.

6. Select drug or procedure: Select 1 pg/kg dose acetylcholine. 7. Select drug or procedure: Select 2 ug/kg dose acetylcholine.

8. Record the concentration used and the effect you had on a separate paper. 9. Plot the curve ongraph paper & repeat this step each time you use a new dose. 10.Select drug or procedure: Select 1 mg/kg neostigmine (ChED.

11. Select drug orprocedure: Select acetylcholine 2 ug/kg. 12. Select drug or procedure: Select 1 mg/kg atropine (Muscarinic blocker).

13. Select drug or proscedure: Select acetylcholine 2 ug/kg dose. N.B.:

•

Write the name ofthe drag used &the dose used and its corresponding effect.

•

Take care to draw the curves of heart rate and blood pressure with the same time scale to ensure that both effects happened in response to the same drug and dose.

52-

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Normal preparation

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Clinical

Pharmacology Sheets

I. 'Searching the literature for clinical evidence on pharmacotherapy* CASE 1.1

A 54-year-old male presented to clinic with moderate pain (VAS 5/10) and swelling in

his left big toe. His semm uric acid level was 8.5 mg/dl and acute gouty arthritis was diagnosed. The physician decided to start colchicine as soon as possible to treat this acute attack.

1. Answer the following questions: • What are other alternatives for initiating pharmacological treatment in this patient?

• If the patient had a GI contraindication to NSAIDs, which anti-inflammatory agent can be used?

• What is the recommended dose of colchicine in acute gout that should be used in the first day?

2. The words I used for my 'GOOGLE' search were (exactly as entered):

3. Number of results (hits) I got from my 'GOOGLE' search was:

92-

SEARCH THE LITERA TURE ON THE PHARMACOTHERAPY OF THIS PARTICULAR PATIENT

I. 'SEARCHING THE LITERATURE FOR CLINICAL EVIDENCE ON PHARMACOTHERAPY'

STUDENTS' GUIDELINES

• This session is about using information technology 'IT' by the practicing physician when she/he needs to consult the literature on clinical research to help her/him in making clinical decisions about using drugs for patients, who are not exactly like the typical patients. • The following are the steps you may follow, to learn how to use the Internet-based databases cleverly.

Read the Case. You are required to answer the questions by searching the internet 1. Open'GOOGLE'.

2. Enter (in the search box) the words that you think are useful to let you retrieve the literature you want.

3. Notice how many results (hits) you got. Are you able to read all these results? If you decide to select the first few articles to read, are you sure they provide correct answers to your questions? If you think the answers are correct, don't you need to know whether there are better ways to treat your patient? Whom you will consult to help

you decide? (Your patient is waiting...!!). 4. Write in the 'Worksheet' the exact words you used, exactly in the same way you

googled them in the 'search box'. 5. Write in the worksheet the number of results (hits) you get. Now you have millions!!!

6. Read the case again, and try to figure out a clinical question for your search

7. Use the PICO components to help you develop a relevant question: P = patient' characteristics age, sex, disease, etc... I = intervention (treatment you need to ask about)

C = comparisons between different interventions O = outcome (the effect you need to have for your patient)

8. Write down in the worksheet what terms you selected in front of each of the PICO components.

-93-

9. Try to figure out a question that reflects what you need to search, using the terms you selected in your PICO exercise. This will always keep your mind aware of what you really want to search for. Write your search question in the worksheet. 10.Access 'PubMed': http://www.ncbi.nlm.nih.gov/pubmed. Click on the search box in

the upper left, select (MeSH) [Medical Subject Headings]. Enter the term you want to search. Click 'Search'.

11.You will get a list of options. Read them and select what you think is relevant to what you mean. Click on the small box to the left of your choice. Then, click [Add to search builder] on the upper right corner.

12.Repeat 10-11 with the other terms you need to add (Remember to select AND, OR or NOT to combine your search terms). 13.Now all your search terms are written in the search builder. Click [Search PubMed]. You will get a long list of publications. Definitely much less than you got in your 'google' search, but you still need to specify what you exactiy need.

14.Look to the filters on the left-hand panel. Choose the following filters: Species: (Humans); Language (English); Article Types (Practice guidelines). If these filters are

not seen in the left-hand panel, click on "show additional filters" at the top or bottom of the left-hand panel. A pop-up box will appear. Check the small box near to Language, Species and Article Types and then click "show". Now these filters are

shown in the filters panels. If "practice guidelines" is not shown under the "article

types filter" click on more. Check the small box near to practice guidelines and then

click "show". Now double click on the filters you chose so that a Vis seen next to each of them. Notice the number of results getting smaller with every filter you add. Using all the filters will greatly limit the results to those very much related to your patient.

15. Now you get very few articles. You can click on any one and retrieve the abstract.

Follow the link to full text at the upper right corner. Now you have some clue to what you want. Right?

16. Write down the Search strategy: Database (Medline); MeSH (the terms you used); Filters (the selected filters). 17.Complete your Worksheet.

-94-

CASE 1.1

A 54-year-old male presented to clinic with moderate pain (VAS 5/10) and swelling in his left big toe. His serum uric acid level was 8.5 mg/dl and acute gouty arthritis was

diagnosed. The physician decided to start colchicine as soon as possible to treat this acute attack.

Answer the following questions: 1. The words I selected for the PICO format: Patient: intervention:

Comparisons: Outcome:

2. My search question was:

3. My Search strategy on PubMed was: Database:

MeSH:

Filters:

4. The title of the article I selected is:

5. What is the type of the article you selected? Why did you choose this type? 6. From the article you chose, find answers to the following question and mention the class of recommendation and level of evidence to each answer.

• What are the acceptable combination therapy approaches in acute gouty arthritis?

If the patienthad a GI contraindication to NSAIDs, which anti-inflammatory agent can be used?

• What is the recommended dose of colchicine in acute gout that should be used in the first day?

95-

CASE 1.2

A 40-year-old female, who has undergone a major surgery 25 days ago, is traveling from the USA to Egypt. The flight duration is 12 hours. The physician considered her at high risk for developing travel related thrombosis and suggested pharmacological intervention. Answer the following questions: 1. The words I selected for the PICO format: Patient: intervention: Comparisons: Outcome:

2. My search question was:

3. My Search strategy on PubMed was: Database:

MeSH:

Filters: 4. The title of the article I selected is:

5. What is the type of the article you selected? Why did you choose this type? 6. From the article you chose, find answers to the following questions and mention the level of evidence to each answer.

• Is this patient (with recent major surgery) indeed at high risk for developing travelrelated thrombosis?

• What are other recommendations for travelers at the highest risk of travel-related thrombosis?

• Is there evidence for an association between dehydration and travel-associated VTE?

-96-

CASE 1.3

A 45-year-old woman with an advanced stage of cancer (neoplasms) was scheduled to

undergo a pelvic surgery. Following surgery, she developed venous thromboembolism. The doctor prescribed her LMWH (200 U/kg once daily, s.c). Six months later, the

doctor changed the regimen starting long-term treatment to prevent recurrence.

Answer the following questions: 1. The words I selected for the PICO format: Patient:

intervention:

Comparisons: Outcome:

2. My search question was:

3. My Search strategy on PubMed was: Database:

MeSH:

Filters:

4. The title of the article I selected is:

5. What is the type of the article you selected? Why did you choose this type?

6. From the article you chose, find answers to the following questions and mention the level of evidence to each answer.

•

Is prophylaxis against venous thromboembolism recommended in cancer patient undergoing pelvic surgery?

•

What should the doctor prescribe for initial treatment of venous thromboembolism in cancer patients?

-97-

CASE 1.4

A 67-year-old male patient who had undergone a surgery. He received IV heparin post operatively. One week later, the patient developed heparin induced thrombocytopenia (HIT) that was confirmed by investigations. The doctor started treatment.

Answer the following questions: 1. The words I selected for the PICO format: Patient:

intervention:. Comparisons: Outcome:

2. My search question was:

3. My Search strategy on PubMed was: Database:

MeSH:

Filters: 4. The title of the article I selected is:

5. What is the type of the article you selected? Why did you choose this type?

6. From the article you chose, find answers to the following questions and mention the level of evidence to each answer.

• List 3 drugs that can be used for this case (as an alternative to heparin)?

• How many days of overlap between vitamin K antagonist and non-heparin anticoagulants are required?

-98-

CASE 1.5

A 47-year-old man, who is a smoker, came to the clinic with ischemic lower limb symptoms, including intermittent claudication. He was diagnosed as peripheral arterial disease (PAD). The doctor prescribed him an antiplatelet.

Answer the following questions: 1. The words I selected for the PICO format: Patient:

intervention:

Comparisons: Outcome:

2. My search question was:

3. My Search strategy on PubMed was: Database:

MeSH:

Filters:

4. The title of the article I selected is:

5. What is the type of the article you selected? Why did you choose this type?

6. From the article you chose, find answers to the following questions and mention the level of evidence to each answer.

•

Is antiplatelet therapy indicated for this patient?

Should the patient be advised to stop smoking?

Should statins be prescribed in this patient? Why?

-99-

CASE 1.6

A 50-years-old man came to the clinic complaining of exertional dyspnea and chest pain. After clinical assessment, he was diagnosed as hypertrophic cardiomyopathy (HCM) with no left ventricular outflow tract obstruction. The physician started pharmacological management.

Answer the following questions. 1. The words I selected for the PICO format:

Patient: intervention:

Comparisons: Outcome:

2. My search question was:

3. My Search strategy on PubMed was: Database:

MeSH:

Filters: 4. The title of the article I selected is:

5. What is the type of the article you selected? Why did you choose this type?

6. From the article you chose, find answers to the following questions and mention the level of evidence to each answer.

•

What would the physician prescribe for this patient?

• If the patientdeveloped heart failure what would be your recommendation?

100-

I. 'SEARCHING THE LITERATURE FOR CLINICAL EVIDENCE ON PHARMACOTHERAPY'

Learning Objectives: By the end of these sessions, I was able to: 1. Explain the situations, in every day clinical practice, when it is needed to search the literature on clinical research.

2. Describe the limitations of using search engines like 'GOOGLE' to search the relevant clinical literature.

3. Recognize the importance of developing a 'clinical search question' with the 'PICO' format.

4. Define the 'key words' for performing the search depending on the 'PICO' format of the 'clinical search question'.

5. List the steps of accessing 'PubMed' and using the 'MeSH' and 'limits' tools. 6. Write a 'search strategy1. 7. Select the relevant literature to answer the question related to the case of this particular patient.

Identify the learning objectives achieved 1

2

3

YES

NO

101-

4

5

6

7

II. 'REPORTING AND ASSESSING ADVERSE DRUG REACTIONS

(ADR)' CASE 2.1

A 67 years-old-male (S.M.E) patient (90 kg) was admitted on 20/3/2008 to Ain Shams University Hospital. Diagnosis at admission was rapid atrial fibrillation 'AF' and deep venous thrombosis 'DVT'. He received Heparin IV ampoule 30,000 IU/day for DVT. Heparin was started on 20/3/2008 and was stopped on 31/3/2008 as the patient's investigations revealed thrombocytopenia (decrease in the platelet count to less than 150.000/cubic millimeter). On 1/4/2008 the patient's platelets count returned to normal, so the doctor decided to re-administrate heparin on 2/4/2008. Again, on 9/4/2008

the patient developed thrombocytopenia and died on 10/4/2008 from severe thrombocytopenia. Other Drugs Generic name

Ranitidine

Form

Ampoule

Dose

50mg

Prescribed For

Date started

stopped

Stress ulcer

20/3

Not stopped

AF

20/3

Not stopped

Route

IV

Date

1x3

Digoxin

Tablet

0.25 mg Nasogastric tube 0.5x1

Lab investigations:

Platelet count: •

On 31/3/2008: 120.000/ cubic millimeter

•

On 9/4/2008: 70.000/ cubic millimeter

YOU ARE REQUIRED TO:

1. Complete the ADR Report form. 2. Report the number of cases found on the "Medicines and Healthcare Products Regulatory Agency" (MHRA) website.

-102

II. 'REPORTING ADVERSE DRUG REACTIONS (ADR)' STUDENTS' GUIDE 1. Read the case.

2. Decide on the suspected reaction, suspected drug. 3. Decide on the possible other drugs.

4. Fill the information in the report form about dates of starting & ending the administration of the drugs. 5. Decide on how serious the reaction is.

6. Report on any lab investigations or otherillness in the comments 7. Access Medicines and Healthcare Products Regulatory Agency (MHRA) using any search engine.

8. Select Drug Analysis Prints 'DAPs* and click start now. You will find an alphabet list. Click on relevant letter (e.g. 'H' for heparin). Then click on the group of first letters

(e.g. He-Hh for heparin). A list of drugs will appear. Click on the drug about which you like to read information.

9. Apage will show up. Then search in System Organ Class (SOC) relevant to suspected reaction (e.g. Blood disorders), then choose (expand all) orclick on the + sign next to the title you would like to expand. Search the specific disorder (ADR). 10. Identify the number ofprevious reports on this reaction. 11. Repeat this with other drugs and Record your findings. 12.Submit your ADR report.

-103-

The Naranjo ADR Probability Scale

Questions

Yes

No

Don't Know

1) Are there previous conclusive reports on this

+1

0

0

+2

-1

0

+1

0

0

4) Did the ADR appear with re-challenge?

+2

-1

0

5) Are there alternative causes for the ADR?

-1

+2

0

6) Did the reaction appear when placebo was

-1

+1

0

+1

0

0

+1

0

0

+1

0

0

reaction?

2) Did the ADR appear after the suspected drug was administered?

3) Did the ADR improve when the drug was discontinued?

given?

7) Was the drug detected in blood at toxic levels?

8) Was the reaction more severe when the dose was increased or less severe when the dose was decreased?

9) Did the patient have a similar reaction to the same or similar drug in any previous exposure?

10) Was the ADR confirmed by any objective

+1

0

evidence?

•

Score =

SUM (points for all 10 questions) Interpretation

definite adverse reaction to drug probable possible doubtful that reaction due to drug

-104-

ADR-REPORT (case 2.1) A) PATIENT DETAILS INITIALS

AGE

Dm

SEX:

Df

Kg

WT.

B) S US P E CT E P D R11G (S) Generic name

Form

Dose

Date started

Date stopped

Indication

C) SUSPECTED REACTION(S) •

Please describe the reaction(s):

• Date reaction(s) started:

Date reaction(s) stopped:

• Did the Reaction Stop after stopping the drug?

DYes

D No

• Don't know

• Did the Reaction Reappear after retaking the drug? D Didn't retake the drug •

•

Yes

D No

Was the Reaction serious (based on the reasons below)? • Yes

•

Don't know

D No

D Don't know

If Yes (serious), specify one or more:

• Patient Died

• Life threatening

• Hospitalization

• Prolonged Hospitali/ation

• Congenital Anomaly

• Permanent Disability

• Required intervention to prevent Damage

• Other, specify

D) OTHER DRUGS (Please list any other drug/s taken during the last month prior to the reaction - other than the suspected drug/s)

Generic name

Form

Dose

Date started

E) REPORTER DETAILS; F) ANY COMMENTS: G) REPORTED CASES IN MHRA:

-105-

Date stopped

Indication

zYes a Yes

•Was die reaction serious (based on tbe reasons below)?

• Hospitalization • Permanent Disability

b Congenital Anomaly - Other, specify

• Prolonged Hospitalization

• Required intervention to prevent Damage

• Don't Know

b Don't Know

nDon't Know

-Life threatening

No

• No

- No

= Patient Died

Ifyes (serious), specify one or more :

aumbei

Did not retake the drug

Batch

Date

Mopped

Age age trap

started

-kg

Date

Wetfhr

afdnyfc. wsa ihnmU

Date reactions(s) stopped:

Koine

• Did the Reaction Reappear after retaking the drug?

:]

Dose

b Female

b Yes

Used for

Sex: s Male

•Did the Reaction Stop after stopping die drug?

• Date reaction(s) started:

•Please describe tbe reactioo(s):

C" —Suspected Renetion(s)

zn

B — Suspected Drug(s) Drag Name Concentration

Knt'1 initials:

A-Patient Details

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Drug Name

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p —IJst of other drags taken (Please hst anv other drugs taken durmg the last month priorto the reactton-

CASE 2.2

A 60-year-old female patient (N.M) weighing 87 kg was admitted to the

hospital for hysterectomy on 9/3/2014. After the operation, she received meropenem i.v. injection as post-operative antibiotic (500 mg /vial/8 hours) and

diclofenac ampule by i.v. infusion (75 mg/8 hours) for post-operative analgesia. After 20 min. from the start of the diclofenac infusion she complained of chest tightness, palpitation and shortness ofbreathing. Her pulse rate was 183 b/min. and blood pressure was 80/40 mmHg. She was diagnosed as anaphylactic shock and was admitted to thelCU. The physician stopped the infusion of diclofenac and the

patient was treated with adrenaline, IV fluids, dopamine and methyl prednisolone. On 15/3/2014, her general condition improved &was discharged from the ICU. Lab investigations:

:•

O2 saturation was 55%.

YOU ARE REQUIRED TO:

1. Complete the ADR Report form. 2. Report the number of cases found in MHRA.

•;

f *. • •

•

108

1

ADR - REPORT (case 2.2) I A) PATIENT DETAILS

INITIALS

AGE

SEX:

Dm

Df

WT.

•Kg

B) SUSPECTED DRUG(S) Generic name

Form

Dose

Date stopped

Date started

Indication

C) SUSPECTED REACTION(S) - Please describe the reaction(s):

- Date reaction(s) started:

Date reaction(s) stopped: ..

- Did the Reaction Stop after stopping the drug?

nYes

• No

• Don't know

• Yes

•

No

• Don't know

• No

• Don't know

- Did the Reaction Reappear after retaking the drug? • Didn't retake the drug

- Was the Reaction serious (based on the reasons below)? • Yes

If Yes (serious), specify one or more: • Patient Died

• Life threatening

• Hospitalization

• Prolonged Hospitalization

• Congenital Anomaly

• Permanent Disability

• Required intervention to prevent Damage

• Other, specify

D) OTHER DRUGS (Please list any other daig/s taken during the last month prior to the reaction - other than the suspected drug/s) Generic name

Form

Dose

Date started

E) REPORTER DETAILS: F) ANY COMMENTS:

G) REPORTED CASES IN MHRA:

-109

Date stopped

Indication

CASE 2.3

A 40-year-old male patient (A.S.H) weighing 80 kg was admitted to the

hospital on 19/1/2014. He complained of lack of muscle control during voluntary movements (mild), which started on 12/1/2014. On examination, it was diagnosed as ataxia. After history taking, it was found that the patient has started lithium (300 mg tab/8 hours) and risperidone (3 mg tab/12 hours) since 5/1/2014 to control his bipolar disorder. Serum electrolytes, renal function tests & ECG were normal. So, the doctor stopped lithium on 20/1/2014. On 27/1/2014, his condition was

markedly improved and was discharged from the hospital.

YOU ARE REQUIRED TO:

1. Complete the ADR Report form. 2. Report the number of cases found in MHRA.

-110

[ ADR -

REPORT (case 2.3)

A) PATIENT DETAILS

INITIALS

AGE

SEX:

Dm

Df

Kg

WT.

B) SUSPECTED DRUG(S) Form

Generic name

Dose

Date stopped

Date started

Indication

C) SUSPECTED REACTION(S) •

Please describe the reaction(s):

• Date reaction(s) started:

Date reaction(s) stopped:

• Did the Reaction Stop after stopping the drug?

DYes

DNo

• Don't know

• Did the Reaction Reappear after retaking the drug? •

Didn't retake the drug

• Yes

• No

• Was the Reaction serious (based on the reasons below)? n Yes

• Don't know

D No

D Don't know

If Yes (serious), specify one or more:

• Patient Died

• Life threatening

• Hospitalization

• Prolonged Hospitalization

• Congenital Anomaly

• Permanent Disability

•Required intervention to prevent Damage

• Other, specify

D)OTHER DRUGS (Please list any other drug/s taken during the last month prior to the reaction - other than the suspected drug/s) Generic name

Form

Dose

Date started

E) REPORTER DETAILS: F) ANY COMMENTS:

G) REPORTED CASES IN MHRA:

-Ill

Date stopped

Indication

CASE 2.4

A 5-years-old male child (20 Kg) admitted to Pediatric Hospital, Ain Shams

University, on 1/3/2016 suffering severe dyspnea, wheezes, fever and crepitation. He was diagnosed as a case of pneumonia. He received intravenous vancomycin vial (15 mg/kg/day) for pneumonia and paracetamol syrup for fever (5 ml/8 hr for

5 days) After 2 days, the child developed whole body eruptions with oral mucositis, ulcerative skin lesions and was diagnosed as a case of Stevens-Johnson

syndrome (S.J.S), which is a life-threatening condition. On the same day, the physician stopped vancomycin and gave him IV teicoplanin (10 mg/kg/day for 7 days) instead.

For S.J.S. the patient received IV fluids, azithromycin (10 mg/kg/day IV for 5 days), and topical corticosteroids, calamine lotion, gentian violate. He was discharged on 1/4/2016 after complete recovery.

Lab investigations;

Hb=10.5 g/dl, WBO 14 xlO3 (N=4-ll xlO3), Plat. =230 xl03/mm3 (N=150-400

xl03/mm3), ALT= 150 IU/L (N=5-35 IU/L), C-reactive protein =27 mg/dl (N< 10 mg/dl). Chest X-rav;

Lower right lung lobe pneumonia

YOU ARE REQUIRED TO:

1. Complete the ADR Report form. 2. Report the number of cases found in MHRA.

-112-

ADR - REPORT (case 2.4) A) PATIENT DETAILS

INITIALS

AGE

SEX:

Dm

Df

-Kg

WT.

B) SUSPECTED PRUG(S) Form

Generic name

Dose

Date stopped

Date started

Indication

C) SUSPECTED REACTION(S) Please describe the reaction(s):

Date reaction(s) started:

Date reaction(s) stopped: ...

Did the Reaction Stop after stopping the drug?

DYes

• No

• Don't know

Did the Reaction Reappear after retaking the drug? •

Didn't retake the drug

• Yes

•

• Was the Reaction serious (based on the reasons below)? • Yes

No

• Don't know • No

• Don't know

If Yes (serious), specify one or more:

• Patient Died

• Life threatening

• Hospitalization

•Prolonged Hospitalization

• Congenital Anomaly

• Permanent Disability

•Required intervention to prevent Damage

• Other, specify

D)OTHER DRUGS (Please list any other drug/s taken during the last month prior to the reaction

other than the suspected drug/s)

Generic name

Form

Dose

Date started

E) REPORTER DETAILS: F) ANY COMMENTS: G) REPORTED CASES IN MHRA:

-113

Date stopped

Indication

CASE 2.5

Mrs. S.S.H is a 31-year-old female weighing 78 kg. She was admitted to the

hospital on 6/8/2015 with an acute exacerbation of systemic lupus erythromatosis

(SLE). Her physician started treatment with methylprednisolone (500 mg vial /day) and mycophenolic acid (250 mg tab /12 hours) for control of SLE and omeprazole (40 mg vial /12 hours) for prophylaxis against peptic ulcer and she was discharged on the second day. On 9/8/2015, she was admitted to the hospital as she developed abnormal behavior, incoherent speech, hallucinations and delusions that was diagnosed as acute psychosis.

The doctor stopped methylprednisolone immediately and added the

antipsychotic agent risperidone (2 mg tablet /8 hours), while other drugs were not stopped. The patient psychiatric symptoms were completely recovered on

14/8/2015. So, the physician decided to re-administer methylprednisolone,

however, only one day later the patient developed acute psychosis symptoms again, and immediately the doctor stopped methylprednisolone and added the

antipsychotic agent risperidone (2 mg tablet / 8hours). One week later, the patient was completely recovered and discharged from the hospital.

YOU ARE REQUIRED TO:

1. Complete the ADR Report form. 2. Report the number of cases found in MHRA.

-114

ADR - REPORT (case 2.5) A) PATIENT DETAILS

INITIALS

AGE

SEX:

Dm

DF

-Kg

WT.

B) SUSPECTED DRUG(S) Generic name

Form

Dose

Date stopped

Date started

Indication

C) SUSPECTED REACTION(S) •

Please describe the reaction(s):

• Date reaction(s) started:

Date reaction(s) stopped:

• Did the Reaction Stop after stopping the drug?

DYes

• No

• Don't know

• Did the Reaction Reappear after retaking the drug? • Didn't retake the drug

• Yes

• No

• Was the Reaction serious (based on the reasons below)? • Yes

• Don't know

• No

• Don't know

If Yes (serious), specify one or more:

• Patient Died

• Life threatening

• Prolonged Hospitalization DCongcnital Anomaly • Required intervention to prevent Damage

•Hospitalization

• Permanent Disability • Other, specify

D) OTHER DRUGS (Please list any otherdrug/s taken during the last month prior to the reaction - other than the suspected drug/s) Generic name

Form

Dose

Date started

E) REPORTER DETAILS: F) ANY COMMENTS: G) REPORTED CASES IN MHRA:

-115

Date stopped

Indication

CASE 2.6

Mr. Z.A.H. a 65-year-old male patient was admitted to the hospital on 16/12/2013 with a diagnosis of acute on top of chronic bronchitis. His lab

investigations were within the normal ranges. His medical history revealed that he is hypertensive and has congestive heart failure, for which he has been prescribed captopril (25 mg tab/8h, 7 months ago) and isosorbide mononitrate (40 mg tablets 2 tab/day, 1year ago for ischemic heart disease).

The patient was prescribed Augmentin (amoxicillin + clavulanic acid) for his chest infection (started on 16/12/2013) 1.2 mg vial/12 h IV and was dismissed the following day.

On 22/12/2013, the patient came to the clinic complaining of right upper abdominal pain & nausea, his lab investigations revealed mild elevation in liver

enzyme, where ALT = 66 IU/L, AST = 50 IU/L, Total bilirubin = 2 mg/dl, Alk. Phosphatase = 160 U/L. So, a diagnosis of cholestasis was made. The physician stopped Augmentin on 23/12/2013. 7 days later the patient improved, and the liver enzymes were normal.

YOU ARE REQUIRED TO:

1. Complete the ADR Report form. 2. Report the number of cases found in MHRA.

-116-

ADR - REPORT (case 2.6) A) PATIENT DETAILS

INITIALS

AGE

SEX:

Dm

Df

•Kg

WT.

B) SUSPECTED DRUG(S) Form

Generic name

Dose

Date stopped

Date started

Indication

C) SUSPECTED REACTION(S) •

Please describe the reaction(s):

• Date reaction(s) started:

Date reaction(s) stopped:

• Did the Reaction Stop after stopping the drug?

DYes

• No

• Don't know

• Did the Reaction Reappear after retaking the drug?

•

Didn't retake the drug

• Yes

•

• Was the Reaction serious (based on the reasons below)?0 Yes

No

• Don't know

D No

D Don't know

If Yes (serious), specify one or more:

• Patient Died

• Life threatening

•Hospitalization

• Prolonged Hospitalization

•Congenital Anomaly

• Permanent Disability

•Required intervention to prevent Damage

• Other, specify

D)OTHER DRUGS (Please list any other drug/s taken during the last month prior to the reaction - other than the suspected drug/s) Generic name

Form

Dose

Date started

E) REPORTER DETAILS:

F) ANY COMMENTS: G) REPORTED CASES IN MHRA:

-117-

Date stopped

Indication

CASE 2.7

A 44-year-old woman presented at the emergency room on 2/5/2018 with

palpitations, shortness of breath and chest pain. Cardiac enzymes and thyroid function tests were normal, but ECG revealed atrial fibrillation. Her previous medical history included only migraine headaches for the past year. Since 2017, she was taking topiramate at daily dose of 200 mg (tab) for migraine headache prophylaxis, while during the attack, she received sumatriptan in the dose of 50 mg (tab). The patient reported having an attack a week ago needing sumatriptan. At the hospital in the same day she was admitted to the ICU and was given amiodarone for controlling her heart rhythm and her migraine treatments were stopped. 2 days later, the patient status improved and was discharged from the hospital.

YOU ARE REQUIRED TO:

1. Complete the ADR Report form. 2. Report the number of cases found in MHRA.

118-

ADR - REPORT (case 2.7) A) PATIENT DETAILS

INITIALS

AGE

SEX:

Dm

OF

WT.

•Kg

B) SUSPECTED DRUG(S) Generic name

Form

Dose

Date stopped

Date started

Indication

C) SUSPECTED REACTION(S) •

Please describe the reaction(s):

• Date reaction(s) started:

Date reaction(s) stopped:

• Did the Reaction Stop after stopping the drug?

DYes

• No

• Don't know

• Did the Reaction Reappear after retaking the drug? • Didn't retake the drug

• Yes

• No

• Was the Reaction serious (based on the reasons below)? ^Yes

• Don't know • No

• Don't know

If Yes (serious), specify one or more: • Patient Died

• Life threatening

• Hospitalization

• Prolonged Hospitalization

•Congenital Anomaly

• Permanent Disability

• Required intervention to prevent Damage

• Other, specify

D) OTHER DRUGS (Please list any other drug/s taken during the last month prior to the reaction - other than the suspected drug/s) Generic name

Form

Dose

Date started

E) REPORTER DETAILS: F) ANY COMMENTS: G) REPORTED CASES IN MHRA:

-119

Date stopped

Indication

II. 'REPORTING AND ASSESSING ADVERSE DRUG REACTIONS'

Learning objectives: By the end of these sessions you will be able to: 1. Define Pharmacovigilance.

2. Identify the types of reporting adverse drug reactions.

3. Realizethe clinical importance of reporting adverse drug reactions. 4. Define the components of the ADR report. 5. Fill the ADR report.

6. Categorize the severity and prognosis of the ADR.

7. Search the MHRA database on the previous reports of the ADR.

Identify the learning objectives achieved 1

2

3

4

YES NO

120

5

6

7

III. 'PHARMACOTHERAPY OF PATIENTS AT RISK' CASE 3.1

A 79-year-old white Caucasian woman, 165 cm height and 70 kg weight, presented to the physician with bouts of disorientation in time and space, restlessness, impaired memory and disrupted sleep-wake cycle that were all suddenly pronounced the last few days. She was diagnosed by the physician as being in a delirium state.

Laboratory investigations including urea, electrolytes, liver function tests, full blood count and thyroid function tests, were within normal range, for her age. However, serum creatinine level was 1.6 mg/dL (normal for female is 0.5-1.1 mg/dL). Previous annual tests revealed that her serum creatinine had slowly changed (was 1.3 mg/dL, 10 years

earlier). Currently, she is on digoxin (0.250 mg/ day) in combination with other drugs for treatment of congestive heart failure and never changed the dose in the last 10 years. The

physician suspected digoxin as a cause of her confusion problem and ordered a serum digoxin test. The test revealed that the serum digoxin concentration 'SDC* was 3.6 ug/L (therapeutic SDC range for management of heart failure is: 0.6 - 0.9 ug/L). Some Recommended Serum Levels for Digoxin: Serum Concentration

Response

0.5 ug/L

No response

0.6-0.9 ug/L

Optimum effect for heart failure

1.0-2.0 p.g/L

Optimum effect in atrial fibrillation

> 2.5 ug/L

Toxicity

POINTS TO BE TAKEN INTO CONSIDERATION:

1. Is there a relation between the increased serum digoxin concentration 'SDC and the change in serum creatinine level? 2. Is it needed that this patient re-adjusts her digoxin dose? 3. How to calculate the re-adjusted digoxin dose? 4. Is it needed that the SDC would be monitored after re-adjustment? 5. If YES, when should we do the first SDC monitoring after the dose readjustment? RESPOND TO THESE QUESTIONS BY FOLLOWING THE STEPS IN THE WORKSHEET'

-121-

III. 'PHARMACOTHERAPY OF PATIENTS AT RISK' STUDENTS' GUIDE 1. Read the case.

2. Listen to the tutor's presentation.

3. Access the site of [Modification of Diet in Renal Disease 'MDRD' Calculator]: http://mdrd.com/, to calculate GFR.

4. When using the MDRD calculator, check the box of the units used in measuring serum creatinine. MDRD adjusts for ethnic differences. Your patient is not an African American.

5. Creatimne methods recalibrated to be traceable to IDMS (IDMS stands for isotope dilution mass spectrometry, check YES.

6. Write down the parameters required in item 1 in the worksheet [age, sex, serum creatinine, GFR from CKD-EPI CREATININE (2009) equation.

7. Respond to item 2 in the worksheet. Use the following equation:

IF: tVi (to be calculated) /1'/2 (Normal) = GFR (Normal) / GFR (of this patient). THEN: t'/2 (to be calculated) = V/z (Normal) x GFR (Normal) / GFR (of this patient)

8. For responding to item 3 in the worksheet [for how long we should ask the patient to stop the administration of digoxin, to bring back her SDC from 3.6 ug/L to the safe 0.9 ug/L], you should expect that this needs to be two t'As (0.9 is 1/4 of 3.6). So, use the information in the previous step (elimination tl4 calculated) to estimate the time (in hours/days) that is needed to wait until the safe SDC (0.9 ug/L) is most probably reached.

9. Calculate the new dose of digoxin after readjustment according to the Digoxin calculator through accessing http://clincalc.com/digoxin/ to calculate the recommended dosing for the patient: fill the required fields in the digoxin calculator and notice that the indication is congestive heart failure (CHF) and then press calculate

10.We usually need 4 to 5 VA s to reach the steady state concentration after which we start to measure SDC. Calculate the time for steady state concentration of this patient

(using the estimated tVi you previously figured, see step (7) above). Then answer the question in item 5 in the worksheet.

-122-

III. 'PHARMACOTHERAPY OF PATIENTS AT RISK' (CASE 3.1)

1. Calculate the glomerular filtration rate *GFR' of this woman now from CKD-EPI CREATININE (2009) equation through accessing http://mdrd.com/ AGE:

GENDER:

SERUM CREATININE:

GFR (Now):

2. The elimination VA of digoxin in this patient is

(Normal' VA: 40 hrs;

GFR:90mL/min/1.73m2).

{VA (to be calculated) = VA (Normal) x GFR (Normal) / GFR (of this patient)}

3. Forhow long should we ask this patient to stop administering digoxin tobring back her serum digoxin concentration 'SDC from the current level (3.6 ug/L) to the desired (safe) level of 0.9 ug/L?

4. What is the newlycalculated digoxin dosing for this patient, from Digoxin calculator through accessing http://clincalc.com/digoxin/? AGE:

HEIGHT:

WEIGHT:

GENDER:

CREATININE:

INDICATION:

5. Measuring serum digoxin cone. 'SDC should be started after

123-

days?

CASE 3.2

A 74-year-old Caucasian woman, was diagnosed to have bipolar depression. Her serum creatinine level was 2.3 mg/dl. The doctor decided to start treatment with oral lithium

carbonate 300 mg/day. One month later, the patient started to develop diarrhea, vomiting, drowsiness, muscular weakness and polyuria. The doctor suspected lithium toxicity. He ordered serum lithium level which was 3.2 mmol/1 (normal level is 0.4-1 mmol/1). The doctor stopped the drug for few days to bring serum lithium back to normal (0.4 mmol/1), then he restarted lithium treatment guided by serum lithium level.

Provided that Lithium carbonate is excreted exclusively through the kidney, answer the following questions:

PHARMACOTHERAPY OF PATIENTS AT RISK (CASE 3.2)

1. Calculate the glomerular filtration rate 'GFR' of this woman using the Modification of Diet in Renal Disease 'MDRD* Calculator:

AGE:

GENDER:

SERUM CREATININE:

GFR:

2. The elimination VA of lithium in this patient is (normal VA: 12 hrs; GFR :100 mL/min/1.73 m2)

3. Forhow long should the doctor ask this patient to stop administering lithium to bring back her serum lithium concentration from the current level (3.2 mmol/1) to the desired (safe) level of 0.4 mmol/1?

4. Measuring serum Lithium cone, should be started after

-124-

Days?

t.

TIL 'PHARMACOTHERAPY OF PATIENTS AT RISK1

LEARNING OBJECTIVES: By the end of this session I was able to: 1. Calculate the GFR of a patient using the MDRD Calculator. 2. Estimate the elimination VA of digoxin in different GFR values.

3. Calculate the dose of digoxin re-adjusted for changes in GFR.

4. Explain why we should select the proper time to aspirate a blood sample for SDC measurement.

5. Discuss the importance of readjusting the doses of drugs according to changes in GFR.

6. Realize the characteristics of the clinical presentations of drug responsiveness in elderly patients.

7. Calculate the dose of gentamycin re-adjusted for changes in GFR.

Identify the learning objectives achieved 1

2

3

YES

NO

-125-

4

5

6

7

IV. 'STARTING, CONTINUING AND ENDING PHARMACOTHERAPY' CASE 4.1

• Mr. HA is a 52-year-old non-smoker non-diabetic white man. He came to your GP clinic for routine checkup. The following are the information you got: Physical and Laboratory findings:

• Body weight = 93 kg - height = 173 cm - BMI = 31 kg/m2 [Ideal: 20-25 kg/ kg/m2]. • Blood Pressure 'BP' = 145/95 mmHg. • Fasting glucose = 124 mg/dL.

• Total cholesterol = 170 mg/dl, HDL = 40 mg/dl. [Normal Total cholesterol 40mg/dL].

• Creatinine = 1.0 mg/dL [Normal: 0.8-1.0] - K= 5.1 mEq/L [Normal: 3.5-5.0].

, how would that affect your treatment decision? FILL THE REQUIRED ITEMS IN YOUR WORKSHEET

CASE 4.1 STUDENTS' GUIDE

1. Listen to the tutor's presentation 2. Read case 4.1

3. Respond to the first question in the worksheet of case 4.1: Search for how to calculate the patient 10-years risk for atherosclerotic cardiovascular disease at this

site: www.cvriskcalculator.com/. Enter the patient'sdata and calculate the risk.

4. Access the guidelines from JNC-8 for blood pressure management from the right panel. Check the guidelines to answer the questions.

5. Access the final guidelines from the USPSTF for initiating aspirin therapy from the right panel.. 6. Discuss your answers with the tutor

-126

CASE 4.1

1. What is Mr. HA's estimated 10-year risk for developing atherosclerotic cardiovascular disease 'ASCVD' in his first visit?

2. Would you begin cholesterol lowering agent for him and why;

3. Does this patient need low dose acetyl salicylic acid (ASA) for the primary prevention of cardiovascular disease?

4. Would you start antihypertensive pharmacotherapy for this patient? What is the targeted blood pressure for this patient? Mention the level of evidence.

5. Mention 3 classes of antihypertensive drugs that could be used in this patient, mention the level of evidence.

-127-

6. If Mr. HA came to your clinic after 6 months for follow-up with the same data but he mentioned that he is now on anti-diabetic treatment for hewas diagnosed with diabetes 4 monthsago, and his blood pressure is still 145/95, What wouldbe his new estimated 10-year risk for developing atherosclerotic cardiovascular disease 'ASCVD'?

7. Now, would you begin cholesterol lowering agent for him? If yes, what is the regimen?

8. Does this patient need low dose acetyl salicylic acid (ASA) for the primary prevention of cardiovascular disease? Mention the level of evidence.

9. Despite being under antihypertensive treatment, the patient's blood pressure isn't controlled, what will be your next step?

128-

CASE 4.2

Mr 'MA' is a 38 years old male, who volunteered to donate 500 mL of his blood to his mother when she was undergoing a surgical operation. On the routine HCV screening for blood donors in the blood bank of the hospital, 'MA' was found to be HCV sero-positive

and the hospital searched for another HCV sero-negative donor. This was the first time for MA to know that he was HCV infected. Mr. MA decided to seek the advice of his

physician. The physician asked for a qualitative HCV RNA test for MA, which proved to be positive.

Major findings on Lab investigations:

1. Liver enzymes: ALT 130 U (Normal: 40 U) - AST 38 U (Normal: 40 U) 2. Serum albumin: 4 g/dL (Normal: 3.5-5 g/dL) 3.INR: 1.2 (Normal: 1.1-1.3). 4. Quantitative HCV RNA (viral load): 400,000 IU/mL. 5. Genotype of virus: 4

6. Liverbiopsy: Moderate portal fibrosis = 2 Metavir score7 7. Serum creatinine: 0.9 mg/dL (0.8-1.0 mg/dL)

• The physician suggested starting antiviral treatment with daily fixed-dose combination of sofosbuvir (400 mg) / velpatasvir (100 mg) for 12 weeks and asked Mr 'MA' to do some tests after 4 weeks of treatment to monitor for adverse

events. The physician also asked him to do Quantitative HCV viral load testing after 4 and 6 weeks of therapy.

7Fibrosis Scoring: (http://www.hepatitiscentral.com/hcv/biopsy/charts/metavir) F0: No fibrosis, Fl: Portal fibrosis without septa, F2: Portal fibrosis with few septa, F3: Numerous septa without cirrhosis, F4: Cirrhosis. -129-

CASE 4.2 STUDENTS' GUIDE

1. Listen to the tutor's presentation as regarding case 4.2 2. Read case 4.2

3. Search for the site of the American Association for the Study of Liver Diseases

'AASLD' Practice Guidelines: [www.hcvguidelines.org], choose your patient carefully from the list at the top of the page. You may Download the PDF version of the full guidance from the left panel.

4. Search in the AASLD guidelines for the answer of questions 1-5. Discuss with your tutor and write down your response. 5. Discuss the implications of the total cost of antiviral treatment of HCV on the decision to treat the selected patients. 6. Submit your worksheet.

130

CASE 4.2

1. Does Mr. MA need to start HCV therapy?

2. What are the recommended & alternative antiviral regimens that can be used in Mr. MA's case?

3. What is the recommended follow-up for patients who achieve a sustained virologic response (SVR)?

4. How to monitor possible side effects of the drugs used?

5. When should the treatment be discontinued?

6. What is the direct cost of drug therapy through the 12 weeks for this patient? Sofosbuvir/ Velpatasvir (pack enough for 4 weeks) = 900 EP

• In 2011, a 48-week treatment course with peg-INF + RBV from Roche and Schering-Plough cost the government approximately EGP 25,000. • Unsubsidized treatment outside the national program would cost a patient

approximately EGP75,000 for a full course. -131-

Management of HCV

HCV antibody

Nonreactive

Reactive

HCV RNA

Not detected

Detected

,

No HCV antibody

Current HCV

No current HCV

detected

infection

infection •

Stop*

Link to care

Additional testing as appropriatet

Figure and tables are from:

The American Association for the Study of Liver Diseases and the Infectious Diseases

Society of America HCV. Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Last Updated: April 12, 2017, www.hcvguidelines. -132-

Recommended Monitoring During Antiviral Therapy RECOMMENDED

RATING

A 10-fold increase in alanine aminotransferase (ALT) activity at

week 4 should prompt discontinuation of therapy. Any increase in ALT of less than 10-fold at week 4 and accompanied by any

weakness, nausea, vomiting, jaundice, or significantly increased bilirubin, alkaline phosphatase, or international normalized ratio, should also prompt discontinuation of therapy. Asymptomatic

l,B

increases in ALT of less than 10-fold elevated at week 4 should be

closely monitored and repeated at week 6 and week 8. If levels remain persistently elevated, consideration should be given to discontinuation oftherapy. ^^^^ Quantitative HCV viral load testing is recommended after 4 weeks of therapy and at 12 weeks following completion of therapy. Antiviral drug therapy should NOT be interrupted or discontinued if HCV RNA levels are not performed or available during treatment. Quantitative HCV viral load testing can be considered at the end of treatment and 24 weeks or longer following the completion of therapy.

l,B

l,B

Recommendations for Discontinuation of Treatment Because of Lack of

Efficacy RECOMMENDED

RATING O

If HCV RNA is detectable at week 4 of treatment, repeat

quantitative HCV RNA viral load testing is recommended after 2 additional weeks of treatment (treatment week 6). If quantitative HCV viral load has increased by greater than 10-fold (>1

III, 0

logioIU/mL) on repeat testing at week 6 (or thereafter), then discontinuation of HCV treatment is recommended.

The significance of a positive HCV RNA test result at week 4 that remains positive, but lower, at week 6 or week 8 is unknown. No recommendation to stop therapy or extend therapy can be provided at this time.

-133-

III, 0

HBV diagnosis and follow up of antiviral therapy HBV

* HBVs Ag +ve

* PCR

Viral load

*\

Viral load

2000IU/mL

Indication for TTT

No treatment

Till HBVs Ag-> -ve

In Egypt, all patients should be treated -Moss of follow up Only indication for INF-a now is: (acute HBV infection)

HAV diagnosis and treatment

HAV Ab +ve

* TTT: supportive therapy, bed rest

-134-

IV. Starting. Continuing & Ending Pharmacotherapy

LEARNING OBJECTIVES: Bythe end of this session I was able to:

1. Describe the life cycle ofdrug prescribing (starting, continuing &ending).

2. Identify the role ofrisk factors in making decisions about starting pharmacotherapy. 3. Calculate the degree ofrisk ofcardiovascular disease 'CVD' in a patient with hypertension.

4. Identify the goal(s) ofthe prescribed pharmacotherapies in the individual patient. 5. Demonstrate how to use published therapeutic guidelines and how to choose the recommended regimen according to thedifferent situations. 6. Calculate the direct costs of a course of pharmacotherapy and compare with older regimens.

Identify the learning objectives achieved 1

2

3

YES NO

135-

4

5

6

V. CHECKING FOR DRUG INTERACTIONS

Case 5.1:

A55-year-old patient is newly diagnosed with hepatitis Cvirus. His past history indicates that he is on phenytoin treatment for epilepsy. The doctor decided to start sofosbuvir treatment for HCV.

Ql: Access the drug interaction checker to see possible interactions between phenytoin and sofosbuvir?

Q2: If you decide to replace phenytoin with another anti-epileptic drug, will you choose oxcarbazepine or lamotrigine? Check both antiepileptic drugs for possible interaction with sofosbuvir.

N.B. Check drug interaction classification for both phenytoin and oxcarbazepine.

-136-

'CHECKING FOR DRUG INTERACTIONS*

STUDENTS' GUIDELINES

• This session is about using information technology 'IT' by the practicing physician when she/he needs to check for drug-drug interactions or drug-food interactions to

help her/him in making clinical decisions about using multiple drugs for patients. 1- Listen to your tutor's presentation about drug-drug interactions andfood-drug interactions. 2- Read case 5.1

3- Type the following link in your search engine https://www.drugs.com/drug interactions, click "accept and continue to check for interactions".

4- Type the first drug in drug name then click"add" or click on the name of the drug that appeared in a drop-down list. Make sure the name of the drug is addedin "My Interactions List" below the search box.

5- Type the second drug in drug name then click "add" or click on the name of the

drug that appeared in a drop-down list. Make sure the nameof the drug is addedin "My Interactions List" below the search box. 6- Click on "check for interactions".

7- Choose "professionals" option.

8- Scroll down read possible drug-drug interactions and drug-food interactions.

9- You may also check the drug interaction classification down the page to assess the clinical significance of the interaction "Major, Moderate, Minor or Unknown" 10-Answer the sheet with your tutor.

11 -Follow the same steps for case 5.2 and 5.3 to apply your skills.

12-You may also use the following link https://www.drugbank.ca/. from the top list choose search, then choose "drug & food interactions", access the 'Biolnteractor'

from the top of the page, enter your drugs to know their mechanism of action and the mechanism behind the drug interaction.

-137-

Case 5.2:

A 45-year-old patient on verapamil for rate control of atrial fibrillation. His recent

investigations revealed dyslipidaemia, so the doctor is considering the use of statin hypolipidemic drugs. Q: Access the drug interaction checker to determine which is the best statin member

(simvastatin, lovastatin or pravastatin) that can be used in this patient? (check for drug interaction of each statin member with verapamil).

N.B. You may check the classification of the drug interaction and the food-drug interaction

Case 5.3:

A 50-year-old obese diabetic and hypertensive patient, on losartan for control of blood pressure, simvastatin as hypolipidemic drug and metformin to control his diabetes, he has been on these medications for two years. However, one week ago the patient started to develop muscle pain and weakness. His lab investigations revealed elevated creatine kinase level.

On asking the patient about any new habits, he reported daily intake of a glass of

grapefruitjuice in the morning for the last two weeks. Q: Access the drug interaction checker to check for possible interactions between drugs

of the patient's current regimen (metformin, simvastatin and losartan). Explain why the patient developed myopathy?

-138-

Case 5.4:

A 69-year-old male with history of paroxysmal atrial fibrillation, whose rhythm has been maintained chronically with propafenone (class IC antiarrhythmic drug)

225mg 3 times a day since 2017. One month later, he was referred to the psychiatry dept. suffering from insomnia and the physician prescribed him hydroxyzine (sedative antihistaminic) 50mg every 6hours as needed. Recently, he was admitted to the hospital and his ECG showed prolonged QT interval. Answer the following questions:

Ql: Do you think there is adrug interaction between hydroxyzine and propafenone?

Q2: Explain the mechanism behind the possible drug interaction?

Q3: Is there any food interaction with either drugs?

Q4: Ifthe doctor decided to replace hydroxyzine by Zolpidem (sedative hypnotic drug), do you think there will beany drug interaction?

139

V. 'CHECKING FOR DRUG INTERACTIONS'

Learning Objectives: By the endof these sessions, I was able to:

1. Recognize the importance of different drug interactions.

2. Explain some of the mechanisms behind drug interactions.

3. Search for possible drug interactions using different drug interactions checker. 4. Identify drug combinations that should be avoided.

5. Assess the clinical significance of different drug interactions. 6. Check for food-drug interactions.

7. Make a clinical decision based on my search and on available data.

Identify the learning objectives achieved 1

2

3

YES NO

-140-

4

5

6

7

VI. Apolv vour skills Case 6.1

A7-year- old boy was brought by his mother to the chest physician for evaluation of his case. His mother stated that he is having repeated attacks ofchest tightness, difficulty and shortness ofbreath and cough that occur almost weekly. He has been on low dose inhaled corticosteroids for the past 6 weeks. He also complains of waking up at night almost twice weekly. The physician examined the patient and excluded common problems as; incorrect inhaler technique, poor adherence or persistent exposure to allergens at home, such as tobacco smoke, indoor or outdoor air pollution. He didn't change the treatment and asked the mother to revisit him after two weeks. Two weeks later, the mother

revisited the clinic with her son, who was still complaining of the same symptoms. The physician decided to modify his prescription. Questions:

a) Rationalize the decision ofthe physician not to modify the patient's prescription in the first visit.

b) Identify the best drug modification the chest physician did for the patient.

c) Is low dose ICS/LABA recommended in this patient?

-141

Case 6.2

A 23-year-old asthmatic female came to the chest clinic seeking medical advice. She is

on low dose inhaled corticosteroids because of attacks of chest tightness, dyspnea and cough. Now she is pregnant, and she has concerns about her medication use in pregnancy. Questions:

a) What is the medical advice that the physician should give her concerning using her asthma medications?

b) What are the precautions to be considered during labor?

c) Can the doctor step down for this case, if she is controlled?

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Problem

Solving

Case of angina Case Study (1)

M.M., a 62-year-old, is hospitalized for evaluation of chest pain About 3 weeks before admission, he noted retrosternal crushing chest pain brought on by lifting heavy objects or walking uphill only. When he stops working, the pain

subsides mabout 5minutes. His mother and brother died ofa heart attack at ages

62 and 57, respectively; his father, who is alive at age 86, has survived one heart

attack and one stroke. Family history is negative for diabetes mellitus.

M.M.'s other medical problems include a 10-year history of hypertension diabetes for 4years. Until 3weeks ago, M.M. could perform all his daily activities

without difficulty.

He is on the following medications: bisoprolol 10 mg every day oral antidiabetic and ramipril (10 mg/day). He rarely uses over-the-counter drugs He is

allergic to sulfa drugs.

On admission, resting vital signs include supine blood pressure (BP), 164/98

mmHg; regular pulse, 73 beats/minute. Admitting laboratory values include the

following: random blood glucose, 152 mg/dL; blood urea nitrogen (BUN) 27

mg/dL (normal, 10-20); serum creatinine (SrCr), 1.4 mg/dL (normal, 0.5-1 2) '

1. From the previous case what are the symptoms and signs relevant to angina? Which type of angina describes the previous situation?

2. After consultation, his cardiologist elects to control his angina medically. What are the goals ofhis therapy and how can these goals be achieved?

3. What independent risk factors for Coronary artery disease (CAD) are present in M.M.? Which of these may be modified? 4. What are the dietary changes that could be made to benefit his cardiovascular disease?

5. What instructions should M.M. receive with regard to the use ofsublingual NTG? How rapidly will sublingual NTG relieve his chest pain? 6. Rationalize the use of ramipril and bisoprolol in this patient.

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M.M. is still bothered by occasional angina episodes, ranging from one to four

times per week. The attacks usually are precipitated by strenuous work and are relieved by rest and NTG. The quality and location of the pain are unchanged, although the duration has increased by 1 or 2 minutes. He follows a lowcholesterol, no-added-salt diet.

Physical examination is unchanged except for a 10-kg weight loss. Vital signs include the following: supine BP, 119/76 mmHg; heart.rate, 65 beats/minute; and respiratory rate, 12 breaths/minute. His cardiologist elected to start a long-acting prophylactic nitrate (isosorbide mononitrate) as well as continuing his p-blocker and ACE inhibitor therapy.

•

7. What therapeutic endpoints should be used to evaluate the efficacy of longacting nitrates?

8. Could calcium channel blockers be used in this case as an alternative to

long acting nitroglycerin or isosorbide mononitrate? 9. Can calcium channel blockers be used for all types of angina?

Later on, he experienced severe angina that ended up in ECG changes I suggestive ofextensive myocardial infarction. 10. What is the treatment that should be added, in this case?

A. Streptokinase within 6 hours of the attack. B. I.V. nitrate

C. Enoxaparin D. All of the above

11. M.M. is now admitted to the emergency room for ventricular tachycardia

precipitated by myocardial ischemia. This arrhythmia is life threatening and must be controlled immediately. Which of the following drugs would be best to quickly control this arrhythmia? A. Dobutamine

C. Quinidine

B. Digitalis

D. Lidocaine E. Atropine

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||

Heart Failure

Case Study (1)

A 56-year-old white male, was admitted to the coronary care unit with a three-day historyof severe dyspnea.

Physical examination reveals 3+ pitting edema of the legs and jugular venous

distension when sitting, hepatomegaly and hepatojugular reflux.

He has a central venous pressure of 28 mm Hg, is profoundly oligouric and has a serum creatinine of 2.9 mg / dL with a BUN of 60 mg /dL. Home medication includes

digoxin, KC1 supplement, and chlordiazepoxide. His physical examination reveals a

blood pressure of140/70 mm Hg, apulse of100 beats/min without murmurs, gallops, or rubs.

Chest X-ray indicates CHF.

1. What drug would be most likely appropriate to promote a rapid diuresis in this patient?

A. i.v. chlorthalidone

C. i.v. spironolactone

B. i.v. mannitol

D. i.v. furosemide

2. An 80 mg i.v. bolus of furosemide resulted in a urine output of 750 mL over the next two and one-half hours. Following diuresis, renal function worsened as

evidenced by an increase in BUN to 75 mg/dL and creatinine to 3.2 mg /dL. Provide a possible explanation for the decline in renal function following furosemide administration.

3. Despite a reduction in pulmonary and peripheral edema after diuresis, the

patient's congestive failure had not resolved adequately and hydralazine + isosorbide dinitrate were added to the patient's drug regimen, chlordiazepoxide was stopped and oral furosemide was started at 120 mg/day. Hydralazine is classified as a

A. ACE inhibitor

B. Calcium channel blocker

C. Vasodilator

D. Cardiac glycoside

E. Centrally-acting sympatholytic

4. Following hydralazine & isosorbide dinitrate the patient's congestive failure improved. Why? 5. What is an alternative drug to hydralazine + isosorbide dinitrate?

6. Which class of drug does isosorbide dinitrate belong to and what might be the rationale for its use in this patient?

7- If following addition of isosorbide dinitrate, congestive failure did not adequately improve, an additional inotropic drug might be added (the patient was still on digoxin). Select an appropriate inotropic agent. A. isoproterenol B. epinephrine C. phenylephrine D. dobutamine

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E. dopamine

Case Study (2)

A 78 years old man had anterior myocardial infarction, 3 years ago. Echocardiography revealed marked left ventricular systolic dysfunction with reduced ejection fraction. He presented with several symptoms, including fatigue and decreased exercise tolerance, shortness of breath and peripheral oedema. Examination demonstrated cardiomegaly, a raised jugular venous pressure and crackles in the lungs. The EEG showed that he was in sinus rhythm.

1. Can Digoxin, BB or dobutamine be considered as an initial treatment for the patient? Explain why.

2. What are the choices of diuretic open to you in this case?

3. Potassium loss produced by diuretics may lead to hypokalemia, which should be avoided in patient with heart failure, particularly those taking digoxin. What is an effective way ofreducing potassium loss?

4. The patient was then started on captopril. What are the precautions that should be taken and how would its effectiveness be assessed?

5. After 4 weeks of treatment with ACEI and diuretics, symptoms were much

improved. However, he developed a cough while taking the ACEI which became intolerable. What is thought to be the reason for the cough and what alternativetherapy could be given to avoid this?

6. At which stage of heart failure can p-blockers be started? 7. At which stage of heart failure can spironolactone be started?

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Case Study (3)

A64 years old male came to the physician's office because ofincreasing shortness

of breath and the development of peripheral oedema. He had a20-year history of non-insulin-dependent diabetes mellitus and had been treated with oral

hypoglycaemic drugs for the past 10 years. He had past history of two myocardial infarctions and had been treated with captopril 50 mg twice daily and occasionally

frusemide 40 mg as required. On this occasion he was found to have atrial fibrillation, which had not been present previously. Physical examination revealed

pitting edema of both legs up to the knees and fine rales at the bases ofboth lungs The patient was given digoxin in adose of0.25mg/day, and frusemide 40 mg twice daily and he was urged to reduce his salt intake.

1-Precautions before starting digoxin therapy are:

2-The possible adverse effects ofdigoxin and frusemide combination are-

Ten days after the original visit, the patient returned with a complaint of palpitations by which he meant periods ofirregular heart beat that he felt in the

chest several times a day. An ECG showed multiple ventricular premature beats with occasional self-runs of ventricular tachycardia. He was sent to cardiogist in the hospital emergency room, where his serum creatinine was found to be twice the upper limit of normal. Serum digoxin level was 3.2 nmol/L, the serum K was

normal. The cardiologist discontinued the digoxin and admitted the patient to hospital for ECG monitoring. After 6 days the ventricular arrhythmia were no longer present and the serum digoxin level was 1.8 nmol/L. The patient was discharged on 0.125 mg of digoxin daily.

3-Whatare the possible arrhythmogenic mechanisms of digitalis? 4-The normal serum digitalis range is—

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Hypertension

A 35-year old married male, weighing 97 kg, came to the clinic suffering from fatigue over the past few weeks with recurrent headache. His pulse was 80/min and BP was 190/105. He gave a history of bronchial asthma. The physician

prescribed him bisoprolol 5 mg/day as antihypertensive. Two weeks later the patient returned to the clinic reporting discontinuation oftreatment. The physician gave him a combination ofcaptopril/hydrochlorthiazide.

1. Do you think commencing drug treatment for this patient is mandatory? 2. All of the following are 1st -line drug treatments for uncomplicated hypertension EXCEPT: a. thiazide diuretics

b. alphal-adrenoceptor blockers c. calcium channel antagonists

d. angiotensin-converting-enzyme inhibitors 3. Give THREE possible reasons why the patient discontinued bisoprolol. 4. Do you recommend other beta blockers of better efficacy and/or adverse effect profile?

5. Is prescribing the captopril/hydrochlorthiazide combination a good choice? Explain why?

6. Do you think the physician should ask for laboratory investigations, with regards to thiazide prescription? 7. If the patient would suffer from captopril, would you recommend an alternative, with related mechanism, instead? Mention the benefits of your choice.

8. One month following the last visit, the patient was admitted to the E.R. with severe chest pain, headache, confusion and shortness of breath. His BP was 220/130 and symptoms and signs of encephalopathy were evident.

Enumerate the drugs that can be given in such case.

9. Mention the possible causes for such increase in blood pressure.

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Blood

Case Study (1)

J.S., a55-year-old, 120-kg man, experienced a rapidly progressive paralysis of his right arm and slurred speech yesterday. These symptoms lasted for 15 to

20 minutes and resolved rapidly. His neurologic examination is entirely normal, and he denies any feeling of weakness. The condition was diagnosed as transient ischemic attack (TIA). He smokes two packs of cigarettes daily. His blood pressure (BP) is 165/100 mmHg, and he has a long history of hypertension. His hemoglobin (Hgb) is 16.5 g/dL (normal, 12-16 g/dL), his hematocrit (Hct) is 51% (normal, 42%-52%), and his total serum cholesterol

concentration is 275 mg/dL (normal,