Drug Interactions - Adverse Drug Reactions (ADR)

Drug Interactions

·        = Effects of one drug are increased or decreased by another

·        Lots of interactions: the key is their significance

·        Often caused by Polypharmacy:

o  = “Irrational concurrent use of several different drugs”

o  Common in:

§  Multiple medical problems

§  Long term care

§  “Standing orders”, sedatives, laxatives, antidiarrhoeals, cough medicine

·        Guide to potential drug interactions:

o  How commonly are interacting drugs used together? 

o  Does one of the drugs have a low TI? Eg probenecid reduces penicillin clearance, but who cares. Erythromycin reduces theophylline clearance – critical 

o  Has a potential interaction been validated in in-vivo studies?

o  Are there case reports of adverse effects?

o  Is there a reasonable mechanism for the interaction?

·        Risk factors for drug interactions: 

o   Low volume of distribution (Vd) ® ­ plasma concentration (esp if protein bound)

o   Narrow TI (toxicity with small changes)

o   Capacity limited hepatic clearance (cf blood flow limited), eg phenytoin 

o   Extensive Metabolisers (EM): those genetically predisposed to rapid metabolism. Add in an enzyme inhibitor ® more dramatic change

o   High protein binding (®­­ plasma concentration if protein binding disrupted)

o   Acidic drugs: readily displace basic drugs 

o   Active renal tubular excretion (other drugs can compete for excretion pathways ® ¯clearance)

o   IV administration (risk of mixing drugs that shouldn‟t be mixed)

·        Pharmacokinetic mechanisms:

o   Drug Inactivation:  Eg Cholestyramine (ion binding resin) binds oral anticoagulants 

o   Altered absorption: Metoclopramide (­gastric emptying) + digoxin (takes long time to breakdown in stomach) ® ¯ absorption. Metoclopramide + paracetamol ® faster absorption 

o   Protein binding: Adverse reactions do not occur purely because of displacement from protein 

o   binding sites: Eg phenytoin + hypoalbuminaemia ® ¯ binding ® ­clearance ® ¯total concentration ® ­free fraction but free concentration remains the same 

o   Drug excretion: Probenecid + Penicillin – competition for limited capacity of active tubular excretion. Diuretics ® ¯ Lithium clearance

o   Drug metabolism: Metabolic reactions are unpredictable and highly variable. 

§  Multiple Cytochrome P450 enzyme phenotypes, each with it‟s own selectivity for inhibitors (immediate effect) or inducers (takes weeks, requires transcription, etc). Eg sulphinpyrazone: inhibits tolbutamide, warfarin, and phenytoin. Induces theophylline and verapamil 

§  CYP450: Mixed function oxidase system.  Genetic polymorphism results in:

·        Extensive metabolisers (EM).  Inhibition reactions will convert these to PMs

·        Poor metabolisers (PM).  Inhibition reactions won‟t affect these 

·        Ultra-rapid metabolisers (eg CYP2D6). Marked differences in genetic polymorphism (eg CYP2D6 – 7 % Caucasian, 1% Asian) 

§  Inhibition of CYP450 ® ­risk of type A reaction to another drug metabolised by the same enzyme 

§  CYP3A4 is the most abundant P450 enzyme (metabolises over half of all drugs):

·        Induced by carbamazepine, rifampicin, dexamethasone

·        Inhibited by grapefruit juice, azole antifungals, erythromycin

§  Enzyme inducers: chronic ethanol, anticonvulsants, rifampicin, isoniazid (Tb antibiotic) 

§  Enzyme inhibitors: acute ethanol, ANTIBIOTICS: macrolides (eg erythromycin), metronidazole, sulphonamides, quinolones (eg ciprofloxacin), azole antifungals, cimitidine, MAOIs, SSRIs, amiodarone, verapamil, omeprazole, grapefruit juice (inhibits CYP3A4) 

§  Eg non-sedating anti-histamines (eg terfenadine / Teldane). Concentration dependent inhibition of K influx ® prolongs action potential ® ­QT interval ® torsade du pois ® sudden death (very rare). However, ­Cp due to CYP450 inhibitors (eg erythromycin, cimitidine) ® ­risk of sudden death

·        Pharmacodynamic mechanisms:

o   = Additive or opposing effects at the same or different receptors

o   Majority of drug effects

o   Examples: 

§  Combinations of agonists or antagonists at the same receptors: eg Anxiolytics (lorazepam) + hypnotic (triazolam) ® ­BDZ adverse effects 

§  Combinations of agonists and antagonists: eg phenothiazine + L-Dope = antagonism of anti-parkinsonian effect 

§  Combinations of agonists or antagonists at different receptors: eg ethanol + benzodiazepines ® ­sedation

·        Pharmaceutic mechanisms: the interaction occurs prior to systemic availability

·        Common examples:

o   Ethanol/drug interactions:

§  CNS depressants: alcoholics need more to sedate but stay under longer

§  Anticonvulsants: unpredictable

§  Metronidazole gives a disulfiram reaction (Antabuse)

§  Warfarin: acute ethanol inhibits metabolism, chronic ethanol induces metabolism

o   Antihypertensives have decreased effect

·        Oral contraceptives:

o   23% of OC failures associated with antibiotics 

o   Mid cycle breakthrough bleeding may indicate important antibiotic effect (¯oestrogen level) 

o   Should have alternative contraception for the antibiotic course and 7 days afterwards with no pill free period. No action required for stat antibiotic doses or POPs 

o   Other interactions: antacids, H2 antagonists, NSAIDs, cough and cold remedies (pseudoephedrine)