Advanced Pharmacology · Topic 2 of 13

Drug Interactions, CYP450 & QT-Prolonging Drugs

Pharmacology · interactions & QT safety

Drug Interactions, CYP450 & QT-Prolonging Drugs

CYP3A4 inhibitors raise and inducers lower substrate levels; stacking QT-prolonging drugs multiplies torsades risk — act when QTc tops 500 ms.

Key numbers

Act on QTc above 500 msQTc > 500 ms

01 · AvoidCYP3A4 inhibitors raise substrate levels

Strong CYP3A inhibitors — clarithromycin, ketoconazole, itraconazole, posaconazole, voriconazole, ritonavir, cobicistat — raise levels of 3A4 substrates; moderate inhibitors include erythromycin, diltiazem, verapamil, fluconazole and grapefruit juice.

02 · AvoidInducers lower levels: rifampin, carbamazepine, phenytoin

Strong CYP3A inducers — rifampin, carbamazepine, phenytoin and St John's wort — lower levels of 3A4 substrates and cause treatment failure; induction effects may take 1 week or more to appear.

03 · WatchAct on QTc above 500 ms

After starting a QT-prolonging drug, a QTc above 500 ms or a rise of 60 ms or more from baseline calls for action: stop or replace the drug, correct potassium and magnesium, and review interactions.

What it is

Core idea

Pharmacokinetic versus pharmacodynamic interactionsPharmacokinetic interactions change absorption, binding, metabolism or excretion — the amount of drug at the target; pharmacodynamic interactions add or oppose effects at the target, such as two sedatives or two QT-prolonging drugs.

Causes & risk factors

Why it happens

Narrow-therapeutic-index drugs need level checks must knowInteractions matter most for narrow-margin drugs — warfarin, digoxin, lithium, theophylline, antiarrhythmics, antiepileptics, tacrolimus and cyclosporine: recheck levels or INR whenever an interacting drug is started, stopped or changed.

Avoid stacking QT-prolonging drugs must knowTorsades risk rises sharply with more than one QT-prolonging drug and with risk factors: older age, female sex, heart disease, hypokalemia, hypomagnesemia, bradycardia or pauses, and renal or hepatic dysfunction.

Diagnosis & monitoring

Work-up

ECG before and 8–12 h after startingDocument the QTc before and at least every 8–12 hours after starting or increasing a drug known to cause torsades, and after overdose of a proarrhythmic drug; keep potassium and magnesium normal throughout.

Management

Orders

Common QT-prolonging drugs in the hospitalQT-prolonging drugs include class Ia and III antiarrhythmics (procainamide, sotalol, dofetilide, ibutilide), haloperidol and other antipsychotics, methadone, macrolides, levofloxacin, ondansetron, tricyclics and some azoles — check CredibleMeds.

Red flags & don'ts

Avoid harm

Warfarin: CYP2C9 inhibitors raise the INR interactionS-warfarin is cleared by CYP2C9: amiodarone, fluconazole and sulfamethoxazole raise the INR, while rifampin and other inducers lower it; check the INR more often when any drug, including an antibiotic, starts or stops.

Amiodarone: halve digoxin, cut warfarin interactionWhen starting amiodarone, reduce digoxin by half (or stop it), reduce warfarin by one-third to one-half and follow the INR, and limit simvastatin to 20 mg and lovastatin to 40 mg daily.

Simvastatin plus CYP3A4 inhibitor: myopathy interactionSimvastatin and lovastatin are sensitive CYP3A4 substrates: macrolides, azole antifungals, ritonavir and cyclosporine raise their levels and the risk of myopathy and rhabdomyolysis — lower the dose, hold or switch the statin.

Calcineurin inhibitors: check levels with every new drug interactionTacrolimus and cyclosporine are CYP3A4 substrates: azoles, macrolides, diltiazem, verapamil and ritonavir-boosted nirmatrelvir raise levels (toxicity), while rifampin, carbamazepine and phenytoin lower them (rejection).

Clopidogrel: avoid omeprazole and esomeprazole interactionClopidogrel is a prodrug activated by CYP2C19; omeprazole and esomeprazole blunt its antiplatelet effect — avoid them (pantoprazole interacts less). Known CYP2C19 poor metabolizers should get another P2Y12 inhibitor.

Opioid plus benzodiazepine: boxed warning interactionCombining opioids with benzodiazepines or other CNS depressants can cause profound sedation, respiratory depression, coma and death (FDA boxed warning): prescribe together only when alternatives are inadequate, at the lowest doses and shortest duration.

Serotonergic combinations cause serotonin syndrome interactionSerotonin syndrome is usually a drug interaction — most often an SSRI plus tramadol; linezolid (an MAO inhibitor), SNRIs, fentanyl, meperidine, triptans and ondansetron also contribute (see Serotonin Syndrome).

Stacked potassium-raising drugs cause hyperkalemia interactionACE inhibitors or ARBs combined with potassium-sparing diuretics, NSAIDs, trimethoprim, heparin or calcineurin inhibitors impair renal potassium excretion — monitor potassium, especially with CKD or AKI.

Metabolic inhibition magnifies QT risk interactionAnything that raises the level of a QT-prolonging drug raises torsades risk: CYP3A4 inhibitors (erythromycin, ketoconazole), CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine), liver disease, or renal failure with renally cleared dofetilide.

Separate fluoroquinolones from antacids and iron interactionDivalent and trivalent cations chelate fluoroquinolones: give levofloxacin at least 2 hours before or 2 hours after magnesium- or aluminum-containing antacids, sucralfate, iron or zinc-containing multivitamins.

CYP inhibitor or CYP inducer?

Commonly confused

Substrate levels	Rise — toxicity
Classic examples	Clarithromycin, azoles, ritonavir, diltiazem, verapamil, grapefruit
Warfarin	INR rises — bleeding
Tacrolimus or cyclosporine	Toxicity
Time course	Check levels when starting or stopping

More detail

Reference

Show 6 reference facts

FDA strength categories: a strong CYP inhibitor raises a sensitive substrate's AUC at least 5-fold, a moderate one 2- to 5-fold; a strong inducer lowers it by 80% or more, a moderate one by 50–80%.

Ritonavir, including the booster in nirmatrelvir/ritonavir, is a strong CYP3A inhibitor — review tacrolimus, statins, antiarrhythmics and sedatives such as midazolam before prescribing it.

Strong CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine) raise levels of 2D6 substrates such as beta-blockers, tricyclics, antipsychotics, flecainide and tramadol.

Digoxin and dabigatran are P-glycoprotein substrates; P-gp inhibitors such as amiodarone, verapamil, clarithromycin, dronedarone and quinidine raise their levels.

Ondansetron prolongs the QT and has caused torsades: avoid it in congenital long QT syndrome and obtain ECGs when it is given with electrolyte abnormalities, heart failure, bradyarrhythmias or other QT-prolonging drugs.

Rapid IV infusion produces higher drug concentrations and is itself a listed risk factor for drug-induced torsades.

Pearl

Inhibitors push substrate levels up toward toxicity; inducers pull them down toward treatment failure.

Sources · Merck Manual Professional — Drug Interactions (table: medications with potentially serious drug-drug interactions) · Merck Manual Professional — Drug Metabolism (table: common substances that interact with cytochrome P-450 enzymes) · US FDA — For Healthcare Professionals: FDA's Examples of Drugs that Interact with CYP Enzymes and Transporter Systems (Tables 1–2) · Drew BJ et al. Prevention of torsade de pointes in hospital settings: AHA/ACCF scientific statement. Circulation 2010;121:1047–1060 · Merck Manual Professional — Torsades de Pointes Ventricular Tachycardia · Warfarin sodium tablets prescribing information — DailyMed (§7 drug interactions: CYP2C9, 1A2, 3A4) · Amiodarone hydrochloride tablets prescribing information — DailyMed (§7 drug interactions) · Clopidogrel tablets prescribing information — DailyMed (boxed warning; §5.1 CYP2C19 inhibitors) · US FDA — New safety measures announced for opioid analgesics, prescription opioid cough products, and benzodiazepines (Aug 31, 2016 boxed warnings) · Ondansetron prescribing information — DailyMed (§5.2 QT prolongation; §5.3 serotonin syndrome) · Levofloxacin tablets prescribing information — DailyMed (§2.4 chelation agents; §5.11 QT prolongation) · Merck Manual Professional — Serotonin Syndrome (table: medications that can cause serotonin syndrome) · Merck Manual Professional — Hyperkalemia · Merck Manual Professional — Dyslipidemia (statin adverse effects and interactions) · Care of Adult Heart Transplant Recipients by the Primary Care Provider: A Practical Roadmap (calcineurin inhibitor interactions) · Patient Safety Solutions — Torsade de Pointes: Are Your Patients at Risk? (summary of the 2010 AHA/ACCF statement; rapid IV infusion) · Starter sheet built from the verified AGACNP fact map (facts reviewed 2026-10-15).