Drug interactions are a leading cause of adverse drug events, particularly in polypharmacy patients. This skill covers the pharmacokinetic (what the body does to the drug) and pharmacodynamic (what the drug does to the body) mechanisms of interactions, the major enzyme and transporter systems involved, and clinical management strategies.
Pharmacokinetic Interactions
CYP450 System Overview
The cytochrome P450 (CYP) enzyme system is responsible for the Phase I metabolism of approximately 75% of clinically used drugs. Six enzymes account for the majority of drug metabolism:
Enzyme
% of Drug Metabolism
Key Features
CYP3A4
~50%
Most abundant CYP in liver and gut wall
CYP2D6
~25%
Highly polymorphic, no induction
CYP2C9
~10%
Warfarin S-isomer, NSAIDs, sulfonylureas
Verwandte Skills
CYP2C19
~5%
Clopidogrel activation, PPIs, some SSRIs
CYP1A2
~5%
Theophylline, caffeine, clozapine
CYP2E1
~3%
Acetaminophen (to toxic NAPQI), ethanol
CYP3A4 — The Major Player
Common inhibitors (increase levels of 3A4 substrates):
Strong: ketoconazole, itraconazole, clarithromycin, ritonavir, grapefruit juice (intestinal only), cobicistat
Inducers (decrease substrate levels): rifampicin, St. John's wort, carbamazepine
Substrates: digoxin, dabigatran, colchicine, some statins
Many CYP3A4 inhibitors also inhibit P-gp — dual interaction potential.
Other Pharmacokinetic Interactions
Absorption: Antacids, PPIs, and H2 blockers alter gastric pH affecting absorption of ketoconazole, iron, dasatinib. Chelation: tetracyclines/quinolones bind divalent cations (Ca, Mg, Fe, Al).
Protein binding displacement: Warfarin displaced by NSAIDs, valproate displaced by aspirin. Clinically significant mainly for highly protein-bound drugs with narrow therapeutic indices.
Renal elimination: Probenecid blocks tubular secretion of penicillins. Methotrexate toxicity with NSAIDs (reduced renal clearance). Lithium toxicity with thiazides/ACEi (increased reabsorption).
Pharmacodynamic Interactions
QT Prolongation and Torsades de Pointes
Multiple QT-prolonging drugs used concurrently amplify risk:
Risk factors for torsades: Female sex, hypokalemia, hypomagnesemia, bradycardia, structural heart disease, congenital long QT, renal/hepatic impairment (increased drug levels).
Management: Avoid combinations of ≥2 QT-prolonging drugs when possible. Monitor ECG (QTc). Correct electrolytes. Use CredibleMeds (www.crediblemeds.org) as a reference.
Serotonin Syndrome
Excessive serotonergic activity from combining serotonergic agents:
High-risk combinations:
MAOI + any serotonergic drug (most dangerous — potentially fatal)
SSRI/SNRI + tramadol, fentanyl, or linezolid (MAOI activity)
SSRI + triptans (lower risk than often perceived but caution warranted)
Multiple serotonergic agents at high doses
Clinical features (Hunter criteria): Clonus (spontaneous, inducible, or ocular) is the most discriminating feature, plus agitation, diaphoresis, tremor, hyperreflexia, hyperthermia, diarrhea.
Management: Remove offending agents. Benzodiazepines for agitation. Cyproheptadine (serotonin antagonist) for moderate-severe cases. ICU for hyperthermia.