Block A - Medicine - Clinical Pharmacology I

Question 1

Main determinants of drug toxicity

Answer 1

Drug dose, timing and susceptibility (DoTS)

Question 2

Define pharmacokinetic and pharmacodynamic drug interactions

Answer 2

Pharmacokinetic: affecting absorption, plasma levels, biotransformation, excretion

Pharmacodynamic: synergism and antagonism

Question 3

Give one example of drug displacement

Answer 3

Drug displacement: protein bound drugs are liable to be displaced, e.g. warfarin by sulphonamide

Question 4

Examples of drugs that induce or suppress liver enzymes and drug metabolism

Answer 4

Induce metabolism: Phenytoin, rifampicin

Reduce metabolism: Diltiazem, amiodarone, cimetadine, metronidazole

Question 5

Describe the interaction between amiodarone and warfarin

Answer 5

Amiodarone decreases metabolism of warfarin

Amiodarone has long half-life and does not immediately suppress INR
Amiodarone stabilizes after 2 weeks and suppresses metabolism of warfarin&raquo_space; INR increases
Interactions between warfarin and amiodarone may continue after amiodarone has been withdrawn

Question 6

Examples of drug synergism and antagonism

Answer 6

Antagonism: warfarin and vitamin K

Synergism:
 Benzodiazepine and other sedatives (including alcohol)
 Beta-blocker (e.g. atenolol) and calcium channel blocker (e.g. diltiazem)
 Aspirin and warfarin

Question 7

Example of D-D interaction affecting electrolyte balance

Answer 7

Increase potassium:
Potassium chloride
ACE inhibitor
Angiotensin receptor blocker
Aldosterone antagonist (e.g. spironolactone)

Decrease potassium:
Thiazide
Loop diuretic (e.g. frusemide)

Question 8

Describe the excretion of polar and non-polar drugs

Answer 8

Polar drug: water-soluble and excreted in urine unchanged, won’t go to brain or liver

Non-polar drug:
o Enters brain, fat (need higher dose in obese patients)
o Converted by liver from lipid-soluble into water-soluble and excreted in urine or bile

Question 9

Describe the polarity and 2 formulations of psychoactive drugs

6 classes of psychoactive drugs with examples

Answer 9

Most psychoactive drugs are non-polar and lipid soluble

Two formulations:
 Clear like water: dissolved in less polar solvents, e.g. alcohol
 Turbid / milkier: emulsion

Classes and examples:
o SSRI: fluoxetine, paroxetine
o Tricyclic antidepressant: amitriptyline, imipramine
o Traditional antipsychotic: haloperidol, chlorpromazine
o New antipsychotic: quetiapine, ziprasidone, respiridone
o Benzodiazepine: diazepam, midazolam
o New hypnotic: zopiclone, zolpidem

Question 10

7 routes of drug elimination

Answer 10

o Hair: quantitatively unimportant
o Expired air: volatile compounds
o Saliva: very low molecular weight compounds
o Milk: water- and lipid-soluble compounds
o Urine: low molecular weight polar compounds
o Bile: conjugated high molecular weight compounds
o Faeces: compounds excreted in bile or not absorbed in gut

Question 11

Describe 2 phases of drug metabolism

Answer 11

Drugs are metabolised to more hydrophilic/polar compounds in the liver for excretion:

Phase I reaction = oxidation, reduction and hydrolysis:
- Oxidation is catalysed by cytochrome P450 enzymes in the endoplasmic reticulum in hepatocytes

Phase 2 metabolism = conjugation with chemical groups to increase water-solubility for excretion in urine/faeces:
- Inducible conjugation with:
 Glucuronic acid
 Glutathione (Glu-Gly-Cys, “biological hoover”)
 Amino acids
 Sulphation
 Acetylation

Question 12

Most important enzymes for drug metabolism

Most abundant subtype

Answer 12

Cytochrome P450 enzymes
- Subtypes e.g. 3A4, 2D6, 2C19

Most abundant subtype = CYP 3A4
Responsible for half of cytochrome P450 metabolism of drugs
Wide substrate specificity (i.e. metabolises a diverse range of drugs)

Question 13

Examples of CYP enzyme polymorphism

Effect of CYP enzyme polymorphism

Answer 13

2C19 has the highest polymorphism in Asians

Polymorphism of CYP enzyme isotypes = poor metabolizer, decrease metabolism of certain drugs, increase risk of toxicity

CYP3A4 almost never mutates due to it’s integral function in drug and toxin metabolism

Question 14

Drugs affected by CYP2C19 polymorphism (poor metabolizer)

Answer 14

Antidepressants:

• Amitriptyline, imipramine
• Fluoxetine
• Citalopram
• Diazepam

Antiplatelets:

• Warfarin
• Clopidogrel

Omeprazol
Phenytoin

Question 15

D-D interaction involving CYP-2C19

Answer 15

clopidogrel (= prodrug, activated by 2C19) and omeprazole (inhibits 2C19) together

> > results in decreased levels of clopidogrel’s active metabolite, reducing clopidogrel’s anti-clotting effect

> > recommend omeprazol + prasugrel, ticagrelor instead of clopidogrel

Question 16

Examples of CYP P450 2D6** substrates and effect of D-D interaction

Answer 16

2D6 substrates slow down each other’s metabolism, increase half-life, decrease drug effect and impair clearance:

B-blocker: Propranolol and metoprolol

Antipsychotics and antidepressants: 
 Amitriptyline, imipramine, nortriptyline, desipramine
 Fluoxetine, paroxetine
 Haloperidol, risperidone
 Venlafaxine

Sedative:
 Thioridazine
 Codeine

Question 17

Examples of CYP P450 3A3/4 substrates

Answer 17

Question 18

Inducers and Inhibitors of warfarin

Answer 18

Question 19

Describe the D-D reaction between clarithromycin and colchicine

Answer 19

Fatal interaction between clarithromycin and colchicine in patients with renal insufficiency:

• development of pancytopenia were associated with death
• Clarithromycin is frequently used to treat community-acquired pneumonia
• Clarithromycin interfere with CYP P450 and P-glycoprotein transporter system
• Colchicine metabolism severe affected and increased to toxic dose, causing bone marrow toxicity and pancytopenia

Question 20

Which class of drug predominantly suppresses CYP enzyme activity

Answer 20

Antidepressants:

Most are inhibitors of CYP P450 and causes increase drug action or toxic effects of other drug metabolites

Question 21

Examples of CYP P450 enzyme inducers

Effect of using CYP inducer with another drug

Answer 21

CYP subtypes:
1A2: Tobacco, omeprazole
2C19: Rifampin
2D6: Carbamazepine, phenytoin, prednisolone
3A4: Carbamazepine, Phenytoin, Prednisolone, Rifampin
Non-specific inducer: Alcohol

Inducers increase activity of CYP P450 enzyme and increase metabolism of other drugs
» Decrease drug action and need increase dosage for therapeutic effect

Question 22

List classes of CYP3A4 substrate

Answer 22

Calcium channel blockers

Statins

Immunosuppressant agents:
 Cyclosporin
 Tacrolimus

Benzodiazepines

Macrolide antibiotics

Anti-HIV agents

Question 23

List classes of CYP3A inhibitors

Answer 23

Calcium channel blockers:

Azole antifungal agents:

Macrolide antibiotics:

Anti-HIV agents:

Others:
 Grapefruit juice* (e.g. do not drink if on cyclosporine)
 Mifepristone
 Nefazodone

Question 24

List classes of CYP3A inducers

Answer 24

Rifamycins:

Anticonvulsant agents:

Anti-HIV agents:

Question 25

3 patient groups at high risk of D-D interactions

Answer 25

 Elderly (multiple drugs)
 Patients with co-morbid illness
 Substance abusers (alcoholics)

Question 26

Name one major molecular transport protein for drug excretion

Answer 26

P-glycoproteins

Membrane transporters that move a wide range of molecules across membranes using ATP as energy source

Functions include moving unwanted molecules into the gut, into urine, out of the brain

Part of the first-pass effect

Involved in multidrug resistance of cancers:

Question 27

Management of amlodipine and simvastatin interaction

Answer 27

Reducing simvastatin dose to 20mg

Staying on simvastatin 40mg – discuss risks and benefits

Change to an alternative statin, e.g. pravastatin

Change to an alternative calcium channel blocker (NOT verapamil and diltiazem)

Do not change therapy in patients who are well controlled with amlodipine.

Question 28

Spot the D-D interaction in this drug list

Mr A 75/M with angina:
 Glyceryl trinitrate
 Isosorbide mononitrate
 Diltiazem
 Atenolol
 Simvastatin
 Clopidogrel
 Pantoprazole

Answer 28

Glyceryl trinitrate and isosorbide mononitrate are both nitrates&raquo_space;> synergism

Beta-blocker (e.g. atenolol) and calcium channel blocker (e.g. diltiazem)&raquo_space;> bradycardia, hypotension

Question 29

Spot the D-D interaction in this drug list

Mrs C 80/F with congestive cardiac failure:
 Frusemide (loop diuretic)
 Losartan (angiotensin II receptor blocker)
 Carvedilol (alpha1 and beta blocker)
 Spironolactone (aldosterone antagonist)
 Simvastatin

Answer 29

Frusemide decreases potassium, spironolactone increases&raquo_space;> beneficial drug-drug interaction

Losartan increases potassium too, concomitantly used with spironolactone&raquo_space;> detrimental drug-drug interaction

Both carvedilol and losartan&raquo_space; Postural hypotension