Drug interactions

Question 1

Drug interactions definition

Answer 1

when the effects of one drug are changed by the presence of another drug, food, drink or an environmental chemical agent

it can increase toxicity or reduce activity

Question 2

points about drug interactions

Answer 2

increased by polypharmacy
increased by conditions such as renal impairment
problem for drugs with narrow TW
beware of current OTC therapy
pharmacist is the best place to spot interactions

Question 3

resources

Answer 3

BNF
stockley’s drug interactions
computer alerts- variation

Question 4

strategies of drug interactions

Answer 4

always check
avoid/ choose non-interacting alternatives
reduces dose
monitor patient

Question 5

pharmacokinetic mechanisms

Answer 5

absorption: 2 drugs may interact and alter rate of absorption
pH: passive absorption of drugs is best in uncharged form- pKa value
binding

Question 6

Absorption: MDR1

Answer 6

multiple drug resistance transporter
P-glycoprotein= ATP binding Cassette (ABC)
may be induced (rifampicin) - reduces bioavailability of drug
may be inhibited (verapamil)
psoralen inhibits? grapefruit
efflux: pumps drugs out into lumen

Question 7

Displacement

Answer 7

many drugs are protein bound and act in free form
drugs may compete for binding sites- displacement
transient increases in toxicity but then increased elimination.

Question 8

Cytochrome P450-dependent metabolism

Answer 8

many drugs metabolised by multiple CYPs

some drugs metabolised by single CYPs – these are most likely to be involved in clinically-relevant interactions

Question 9

Two possible interaction mechanisms of Cytochrome P450

Answer 9

• Inhibition- increased conc of drug

* Induction (CYP2D6 not inducible)

Question 10

enzyme inhibition of cytochrome p450

Answer 10

•	Cyt P450 inhibition – 
–	cimetidine (heartburn)
–	antifungal agents (ketoconazole) 
–	Macrolide eg erythromycin, clarithromycin 
•	Rapid onset: 1-2 days
•	Often reverse quickly on stopping
•	Warfarin: Increase in INR ~ risk of bleeding
-	Assume it happens in every patient

Question 11

warfarin interaction with macrolides

Answer 11

• BNF: severe
• Well known interaction
– Established but unpredictable
• Stockley “A marked increase in the effects of warfarin has been seen in small number of patient”
• Monitor INR and reduce dose if appropriate
• Find a non-interacting antibiotic, monitor INR

Question 12

warfarin interaction with quinolones

Answer 12

• Severe
• Ciprofloxacin ~ may interfere with Cyt P450-dependent metabolism
• May alter gut flora and reduce vitamin K levels

Question 13

Simvastatin and inhibition

Answer 13

• Contraindicated with macrolides (severe)
– Increases side effects (muscle pain)
• Interaction with amlodipine (calcium channel blocker), verapamil, diltiazem
– For amlodipine plus statin:
• Use 10 mg atorvastatin
• Pravastatin does not interact
• Use 20mg simvastatin as maximum dose (half)

Question 14

enzyme induction

Answer 14

•	Enzyme induction: increase activity of metabolising enzymes
•	e.g.
–	Rifampicin (TB)
–	Carbamazepine (anti-epileptic) can make oral contraceptive ineffective 
-	Produces more cytochrome P450
•	Reduces plasma conc of warfarin
–	Monitor INR and increase dose
•	May take a week or 2 for effect
•	Effect may persist on stopping inducer

Question 15

NSAIDs and warfarin

Answer 15

• Aspirin is antiplatelet ~ enhanced bleeding effects avoid with warfarin
• NSAIDs ~ associated with gastric bleeding, enhanced by warfarin
• Avoid NSAIDs and warfarin
• Ensure patients on warfarin don’t self medicate with NSAIDs
• Warfarin and ibuprofen can cause gastric bleed

Question 16

warfarin and diet

Answer 16

• Vitamin K rich foods may reduce activity of warfarin
• E.g. Greens such as Brussel’s sprouts
• Avoid significant changed in diet
• Cranberry juice shown to potentiate warfarin leading to fatalities

Question 17

grapefruit juice

Answer 17

• Grapefuit juice interacts with simvastatin and some Ca-antagonists
• Psoralen in grapefruit juice may interfere with Cyt P450-dependent metabolism (CYP3A4) and increase levels of simvastatin
– AVOID
• Psoralen may also inhibit P-glycoprotein transport

Question 18

Clopidogrel and proton pump inhibitors

Answer 18

• Omeprazole makes clopidogrel less effective: AVOID omeprazole or esomeprazole
• Due to both being biotransformed by same Cyt P450.
• Clopidogrel is no longer converted to active metabolite.
• Pantoprazole does not affect cytP450 and evidence suggests that it does not interact.
• Current advice (2010): Use another PPI or H2RA (not cimetidine)

Question 19

key interactions

Answer 19

• Warfarin and NSAIDs: leading to enhanced bleeding
• Warfarin and antibiotics (esp erythromycin and ciprofloxacin): leading to enhanced bleeding
• Simvastatin and macrolides: avoid
• Simvastatin and amlodipine: caution dose
grapefruit juice and simvastatin