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)
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