DRUG INTERACTIONA

Question 1

the coagulation cascade

Answer 1

• complex series of enzyme reactions which ultimately leads to the formation of insoluble fibrin from soluble fibrinogen.
• the system consists of proteolytic enzymes and cofactors

Question 2

intrinsic and extrinsic pathways of the coagulation cascade

Answer 2

intrinsic pathway start within the blood vessels.
extrinsic pathway- fewer enzymes, requires tissue factor released from damaged cells outside the blood flow.
both pathways meet at factor 10.

Question 3

warfarin

Answer 3

• has a similar has a similar structure to vitamin K and competitively competes with it.
• warfarin inhibits the enzymatic reduction of vitamin K to its active hydroquinone form.
• vitamin K-dependent glutamate carboxylation of precursor clotting factors II, VII, IX and X
• action takes several days to develop because of T1/2 of clotting factors in plasma
• action is reversed by vitamin K

Question 4

heparin

Answer 4

• measure in units and biologically assayed as from animal sources such as pigs/cows
• 2 types standard ‘unfractionated heparin’ with a short duration of action and LMWH low molecular weight heparins are fragments of heparin and have a longer duration of action.
• thrombin lla converts fibrinogen to fibrin and activates factor XIII which stabilises fibrin links
• enzyme inhibitor antithrombin III neutralises all serine proteases in the cascade

Question 5

mechanism of action of unfractionated heparin

Answer 5

antithrombin III (AT III) inactivates thrombin (lla). heparin interacts with AT III and IIa by binding to them and increasing the inactivation of IIa.
heparin also speeds up anticoagulatory effects of (AT III) on factor Xa by binding to AT III.

Question 6

mechanism of action of low molecular weight heparin (LMWH)

Answer 6

LMHW speeds up the anticoagulatory effects of (AT III) on factor Xa by binding to AT III
- examples are dalteparin, enoxaparin and tinzaparin
- londer duration of action measure can be given subcutaneously once daily post-surgery
- no need for monitoring
- more predictable pharmacokinetics
used in DVT/PE treatment
- dose based on weight

Question 7

interactions

Answer 7

an interaction is said to occur when the effects of one drug are changed by the presence of another drug, food, drink or an environmental chemical agent. result of interaction there is either increased toxicity or therapeutic failure.
may be harmful or benefitial

Question 8

resources of drug interactions

Answer 8

BNF.
Stockley’s Drug Interactions- indicates significance.
computer alerts- variable, a recent study indicated that the different systems were inconsistent.

Question 9

strategies to address interactions

Answer 9

• narrow therapeutic index NTI drugs are defined as those drugs where small differences in dose or blood concentration dependent, serious therapeutic failures or adverse drug reactions e.g. digoxin, methotrexane, lithium, gentamicin, warfarin.
• avoid concomitant prescription of the high-risk drugs
• choose non-interacting alternatives
• reduce dose
• monitor the patient

Question 10

pharmacokinetic mechanisms of interaction

Answer 10

absorption:
2 drugs may interact to alter rate uptake e.g. tetracycline (Doxycycline) and iron/calcium.
Fe2+, Ca2+ decreases the absorption of doxycycline, levothyroxine Tannins and iron
-> pH:
passive absorption of drugs, best in uncharged form, is governed by pKa value.
rises in pH (antacids, hydrogen, antagonists, PPIs) may influence absorption of other drugs.
magnesium carbonate (antacid) and tetracycline- separate administration by 2-3 hours
-> binding:
colestyramine ( bile acid sequestrant) bind drugs such as digoxin, methotrexate, vitamin A/D/K
take other drugs at least on hour drugs one hour before or 4-6 hours after

Question 11

absorption: MDR1

Answer 11

MDR1: multiple drug resistant transporter. it has other names:
P-glycoprotein or ATP binding cascade (ABC).
may be reduced e.g. rifampicin.
may be inhibited e.g. verapamil, amiodarone
Efflux: pumps drugs out into lumen
Digoxin is a substrate and induction of MDR1 reduces bioavailiability

Question 12

effect of induction of P-glycoprotein on absorption of digoxin

Answer 12

digoxin is used in treating heart failure and arrhythmias, and is a substrate for P-glycoprotein.
Rifampicin is an antibiotic that is an influencer of P-glycoprotein. rifampicin is an antibiotic that is an influencer of P-glycoprotein.
Pre-treatment with rifampicin for several days increases the efflux process from the enterocyte (intestinal epithelial cell) to the intestinal lumen and therefore decreases the absorption of digoxin

Question 13

displacement

Answer 13

many drugs are protein bound, but only act in free form. acidic drugs (phenytoin, warfarin, NSAIDs etc.)
drugs may compete for binding sites, resulting in displacement, transient increases in toxicity but then increased elimination.

Question 14

drug metabolism

Answer 14

• liver enzymes bulk of drug metabolism
• Phase 1 reactions (oxidation, reduction hydrolysis) makes molecules more reactive.
• phase 2 reactions involve combining with other molecules (e.g. glucuronic acid) to inactive form for excretion
• induction
• inhibition

Question 15

cytochrome P450-mediated metabolism

Answer 15

many drugs metabolised by multiple CYPs. some drugs metabolised by single CYPs- these are most likely to be involved in clinically-relevant interactions.
2 possible interaction mechanisms:
inhibition and induction

Question 16

enzyme inhibition

Answer 16

• more of an issue then induction because effects occur straight away and increase as dose increases.
• some classic inhibitors amiodarone, allopurinol, cimetidine, amlopidine, diltiazem, verapamil, ciprofloxacin, erithromycin, ketoconazole etc.
• drugs of NTR

Question 17

enzyme inhibition: cytochrome P450 inhibition

Answer 17

H2 receptor antagonists e.g., cimetidine (numerous). antifungal agents (miconazole) (CYP3A4).
macrolides e.g. erythromycin, clarithromycin (CYP3A4). rapid onset: 1-2 days. often reverse quickly on stopping. warfarin: increase in INR~ risk of bleeding

Question 18

warfarin and Quinolone antibiotics

Answer 18

severe
ciprofloxacin
may interfere with Cytochrome P450-dependent metabolism.
may alter gut flora and reduce vitamin K levels. patient is more likely to bleed.

Question 19

simvastatin interactions with macrolides and calcium channel blockers

Answer 19

contraindicated with macrolides (severe)
increases side effects
interaction with amlodipine, verapamil, diltiazem .
for amlodipine plus statin:
20mg simvastatin as maximum dose. the risk of an interaction with amlodipine is much lower with atorvastatin than simvastatin

Question 20

metabolism: induction

Answer 20

enzyme induction: increase activity of metabolising enzymes e.g.
rifampicin
carbamazepine
reduces plasma conc of warfarin.
may take a week or 2 for effect
effect may persist on stopping inducer

Question 21

NSAIDs and warfarin

Answer 21

significant interactions
aspirin is antiplatelet - enhanced bleeding effects.
NASIDs# associated with gastric bleeding, enhanced by warfarin
avoid NSAIDs and warfarin.
ensure patients on warfarin don’t self medicate with NSAIDs

Question 22

clopidogrel and proton pump inhibitors (PPIs)

Answer 22

• omeprazole makes clopidogrel less effective: avoid omeprazole or esomeprazole
• due to both being biotransformed by same cytochrome P450
• clopidogrel is no longer converted to active metabolite. pantoprazole does not affect those cytochrome P450 and evidence suggests that it does not interact

Question 23

pharmacodynamic interactions

Answer 23

• these are interactions where the effects of one drug are changes by the presence of another drug at its site of action.
• additive or synergistic interactions e.g. alcohol and CNS depressants, combining antihypertensives, QT prolonging drugs etc.
• antagonistic interactions e.g. propanolol and salbutamol, oxybutynin and donepezil, warfirin and chamomile tea

Question 24

cranberry juice interactions

Answer 24

possibility of interaction with warfarin. some research suggests cranberry juice inhibits the CYP2C6 enzyme, which would cause bleeding due to increased warfarin plasma concentrations. clinical studies failed to demonstrate interaction.

Question 25

warfarin and food rich in vitamin K

Answer 25

may reduce the activity of warfarin. avoid significant changes in diet

Question 26

grapefruit juice

Answer 26

atorvastatin, transplant drugs, calcium channel blockers, amiodarone.
furanocoumarins inhibit CYP3A4 and P-glycoprotein transport

Question 27

beneficial interactions

Answer 27

combinations of antihypertensive drugs
e.g. calcium channel blockers and ACE inhibitors (CCBs/ACEIs)
combinations of drugs to manage Parkinson’s disease e.g. carbidopa/levodopa

Question 28

some key interactions

Answer 28

warfarin and NSAIDs: leading to enhanced bleeding
warfarin and antibiotics (esp erythromycin and ciprofloxacin): leading to enhanced bleeding
simvastatin and macrolides: avoid
Slimvastatin and amlodipine: caution dose (max dose of simvastatin 20mg)

ENZYME INHIBITORS LEAD TO INCREASED BLEEDING.
ENZYME INDUCERS LEAD TO FAILURE OF THERAPY