Pharmacokinetics III: drug interactions and individual variation

Question 1

drug interactions

Answer 1

change in magnitude or duration of response of one drug due to the presence of a second drug

Question 2

additive effect

Answer 2

where addition of second drug increases initial drugs absorption and reduces its metabolism

Question 3

negating effect

Answer 3

where addition of second drug decreases initial drugs effect by increasing its absorption and/or increasing its metabolism and elimination

e.g. rebound hypertension

Question 4

therapeutic index (TI)

Answer 4

the range at which drug concentration can rise in the plasma before causing toxicity

TI = toxic dose in 50% of patients divided by effective dose in 50% of patients

Question 5

risky drugs

Answer 5

cause serious consequences when the drug plasma concentration changes suddenly

e.g. 
anti thrombotics = blood clot formation 
anti dysrhythmics = irregular heart beats
anti virals = anti viral ineffective
anti epileptics = rebound seizures

Question 6

antagonistic effect

Answer 6

e.g. beta antagonist for hypertension and arrhythmia
and beta agonist for asthma.
if an individual with heart complications was given beta agonist this could worsen condition

Question 7

competitive antagonist

Answer 7

e.g. warfarin competes with vitamin K in the synthesis of coagulation factors.

antibiotics reduce vitamin K synthesis meaning that there are now more binding sites available for warfarin to bind to potentially leading to haemorrhaging.

Question 8

additive effect

Answer 8

anti histamines and alcohol = drowsiness

Question 9

drug interactions affecting: absorption

Answer 9

gastrointestinal absorption 2 examples:

1. slowed by drugs which inhibit emptying
   e. g. opiates
2. accelerated by drugs which promote emptying
   e. g. metoclopramide

complex formation in the GI tract:
calcium and iron form insoluble complexes with tetracycline

warfarin and digoxin can bind to colestyramine (bile acid binding resin) and have a net effect of reducing absorption of drugs

Question 10

drug interactions affecting: distribution

Answer 10

displacement of drug from plasma binding proteins:
displacement can increase concentration of both drugs in the plasma. normally not a major concern for most drugs with a wide therapeutic index as increased plasma concentration = increased elimination

drugs with narrow therapeutic index and have a clinical effect as their displacement occurs with reduced elimination e.g. warfarin and NSAIDS
NSAIDS displace warfarin from albumin and inhibit warfarins metabolism

result: risk of bleeding

Question 11

enzyme induction

Answer 11

where taking a drug will induce the expression of more CYP 450 enzymes over time and will as a result cause accelerated metabolism of some other drugs.

e.g. anti-epileptic drugs are auto inducers
barbiturates will cause enhanced metabolism of:
barbiturates
estradiol
phenytoin
quinine

phenytoin will cause enhanced metabolism of:
dexamethasone
digitoxin
theophyline

rifampicin will cause enhance metabolism of:
anticoagulants
oral contraceptives

mood stabiliser carbamazepine is an auto inducer and dose needs to be adjusted over time

Question 12

enzyme inhibition

Answer 12

second drug can inhibit the metabolism of the first drug by inhibiting CYP 450 enzymes.

it can negate the effect of pro drug (because pro drug requires conversion into its metabolites for activation) but it will add to the effect of drugs which are already pharmacologically active.

inhibitor examples:
cimetidine (antihistamine) inhibiting the metabolism of diazepam and warfarin

disulfiram inhibiting antipyrine, ethanol, phenytoin, warfarin

ethanol inhibiting methanol

Question 13

grapefruit juice

Answer 13

inhibits CYP 3A4 and should not be taken in combination with calcium channel blockers.

should not be taken with:
nifedipine
verapamil
cyclosporin

Question 14

Non CYP enzymes = Xanthine Oxidase

Answer 14

Xanthine oxidase is a phase 1 drug metabolising enzyme and it metabolises mercaptopurine.

anti gout drug = allopurinol will have an inhibitory effect on xanthine oxidase causing increased plasma drug level of mercaptopurine and excessive immunosuppression

Question 15

drug interactions affecting: excretion

Answer 15

3 main mechanisms:
1. drugs not bound to plasma proteins are eliminated faster

2. inhibition of tubular secretion e.g. probenecid which inhibits penicillin secretion resulting in reduced elimination
3. alteration in urine flow via sodium bicarbonate or vitamin C

Question 16

drug interactions affecting: metabolism

Answer 16

enzyme induction and enzyme inhibition

Question 17

disease and pharmacokinetics

Answer 17

hepatic disease:
reduced metabolic activity clearance and protein synthesis = increased free plasma concentration

renal disease:
reduced filtration and reabsorption = higher and prolonged free plasma levels

cardiovascular disease:
reduced cardiac output, reduced metabolism, reduced renal clearance = higher and prolonged free plasma levels.

Question 18

pharmacogenetic polymorphisms Phase I enzymes

Answer 18

CYP 2D6 hydroxylation of bufuralol
bufuralol = anaesthetic

debrisoquine polymorphism (CYP 2D6) 
debrisoquine = antihypertensive
some individuals were reporting hypotension

Question 19

plasma cholinesterase deficiency

Answer 19

phase 1 enzyme plasma cholinesterase breaks off ester groups to reveal functional groups

suxamethonium is a neuromuscular blocking agent used as a muscle relaxant

a carrier with this deficiency will experience paralysis lasting hours vs 2 to 6 mins (normal duration)

Question 20

pharmacogenetic polymorphisms Phase 2 enzymes

Answer 20

acetylation polymorphism of n acetyltransferase 2

polymorphism results in 2 subpopulations:

1. increased metabolism of drug
2. decreased metabolism of drug

e.g. isoniazid which is TB drug
slow metabolisers: isoniazid accumulates causing peripheral neuropathy

fast metabolisers: by product of metabolising isoniazid accumulates causing hepatotoxicity