Block A - Medicine - Clinical Pharmacology I Flashcards
Main determinants of drug toxicity
Drug dose, timing and susceptibility (DoTS)
Define pharmacokinetic and pharmacodynamic drug interactions
Pharmacokinetic: affecting absorption, plasma levels, biotransformation, excretion
Pharmacodynamic: synergism and antagonism
Give one example of drug displacement
Drug displacement: protein bound drugs are liable to be displaced, e.g. warfarin by sulphonamide
Examples of drugs that induce or suppress liver enzymes and drug metabolism
Induce metabolism: Phenytoin, rifampicin
Reduce metabolism: Diltiazem, amiodarone, cimetadine, metronidazole
Describe the interaction between amiodarone and warfarin
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»_space; INR increases
Interactions between warfarin and amiodarone may continue after amiodarone has been withdrawn
Examples of drug synergism and antagonism
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
Example of D-D interaction affecting electrolyte balance
Increase potassium: Potassium chloride ACE inhibitor Angiotensin receptor blocker Aldosterone antagonist (e.g. spironolactone)
Decrease potassium:
Thiazide
Loop diuretic (e.g. frusemide)
Describe the excretion of polar and non-polar drugs
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
Describe the polarity and 2 formulations of psychoactive drugs
6 classes of psychoactive drugs with examples
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
7 routes of drug elimination
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
Describe 2 phases of drug metabolism
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
Most important enzymes for drug metabolism
Most abundant subtype
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)
Examples of CYP enzyme polymorphism
Effect of CYP enzyme polymorphism
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
Drugs affected by CYP2C19 polymorphism (poor metabolizer)
Antidepressants:
- Amitriptyline, imipramine
- Fluoxetine
- Citalopram
- Diazepam
Antiplatelets:
- Warfarin
- Clopidogrel
Omeprazol
Phenytoin
D-D interaction involving CYP-2C19
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
Examples of CYP P450 2D6** substrates and effect of D-D interaction
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
Examples of CYP P450 3A3/4 substrates
Inducers and Inhibitors of warfarin
Describe the D-D reaction between clarithromycin and colchicine
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
Which class of drug predominantly suppresses CYP enzyme activity
Antidepressants:
Most are inhibitors of CYP P450 and causes increase drug action or toxic effects of other drug metabolites
Examples of CYP P450 enzyme inducers
Effect of using CYP inducer with another drug
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
List classes of CYP3A4 substrate
Calcium channel blockers
Statins
Immunosuppressant agents:
Cyclosporin
Tacrolimus
Benzodiazepines
Macrolide antibiotics
Anti-HIV agents
List classes of CYP3A inhibitors
Calcium channel blockers:
Azole antifungal agents:
Macrolide antibiotics:
Anti-HIV agents:
Others:
Grapefruit juice* (e.g. do not drink if on cyclosporine)
Mifepristone
Nefazodone
List classes of CYP3A inducers
Rifamycins:
Anticonvulsant agents:
Anti-HIV agents:
3 patient groups at high risk of D-D interactions
Elderly (multiple drugs)
Patients with co-morbid illness
Substance abusers (alcoholics)
Name one major molecular transport protein for drug excretion
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:
Management of amlodipine and simvastatin interaction
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.
Spot the D-D interaction in this drug list
Mr A 75/M with angina: Glyceryl trinitrate Isosorbide mononitrate Diltiazem Atenolol Simvastatin Clopidogrel Pantoprazole
Glyceryl trinitrate and isosorbide mononitrate are both nitrates»_space;> synergism
Beta-blocker (e.g. atenolol) and calcium channel blocker (e.g. diltiazem)»_space;> bradycardia, hypotension
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
Frusemide decreases potassium, spironolactone increases»_space;> beneficial drug-drug interaction
Losartan increases potassium too, concomitantly used with spironolactone»_space;> detrimental drug-drug interaction
Both carvedilol and losartan»_space; Postural hypotension
