Popular drug interactions I must remember
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High-Yield Drug Interactions to Remember
Organized by clinical category, with mechanism and clinical consequence for each.
1. CYP450-Mediated Interactions (Pharmacokinetic)
These are among the most common and dangerous interactions.
CYP3A4 Inhibitors + Narrow Therapeutic Index Drugs
| Inhibitor | Victim Drug | Consequence |
|---|---|---|
| Macrolides (clarithromycin, erythromycin) | Statins (simvastatin, lovastatin) | Rhabdomyolysis |
| Azole antifungals (ketoconazole, itraconazole) | Statins | Rhabdomyolysis |
| Azole antifungals | HIV protease inhibitors | Toxicity from elevated protease inhibitor levels |
| Cyclosporine | Statins | Rhabdomyolysis (inhibits CYP3A4 + OATP1B1) |
| Diltiazem | Statins (with tacrolimus) | Rhabdomyolysis |
| Grapefruit juice | Many oral drugs | Increased bioavailability - Goodman & Gilman's warns against taking many medications with grapefruit juice due to furanocoumarins inhibiting CYP3A4 |
Remember: Azithromycin is a much weaker CYP3A4 inhibitor than clarithromycin/erythromycin - interaction risk is lower. - Harrison's 22E
CYP Inducers (Reduce Drug Effect)
| Inducer | Affected Drug | Consequence |
|---|---|---|
| Rifampicin | Warfarin, OCP, many others | Therapeutic failure |
| St. John's Wort | Warfarin, cyclosporine, antiretrovirals | Therapeutic failure |
| Phenytoin/Carbamazepine | Warfarin, OCP | Therapeutic failure |
2. Warfarin Interactions (Critical - Narrow Therapeutic Index)
Mechanism matrix:
| Drug | Mechanism | Effect on INR |
|---|---|---|
| NSAIDs | GI bleeding risk + impaired hemostasis | INR may rise (meloxicam specifically increases INR) |
| Metronidazole, fluconazole | Inhibit CYP2C9 - blocks S-warfarin metabolism | INR increases - bleeding risk |
| Rifampicin, St. John's Wort | CYP induction | INR decreases - clot risk |
| Broad-spectrum antibiotics | Gut flora reduction - decreased vitamin K synthesis | INR increases |
| Vitamin K (foods, supplements) | Competitive pharmacodynamic antagonism | INR decreases |
| Coenzyme Q10 | Structural similarity to vitamin K | Decreases warfarin effect |
| SSRIs + warfarin | Added bleeding risk (esp. GI) | Combined antiplatelet effect |
Avoid chronic NSAIDs in any patient on warfarin or DOACs. If SSRIs are needed alongside anticoagulants, citalopram or escitalopram have the lowest interaction potential. - Maudsley Prescribing Guidelines 15th ed
3. MAOI Interactions (Life-Threatening)
Tyramine + MAOIs - Hypertensive Crisis
- MAOIs block GI and hepatic MAO, allowing intact tyramine from aged cheeses, cured meats, fermented foods to enter systemic circulation
- Tyramine causes massive norepinephrine release
- Presentation: occipital headache, neck stiffness, palpitations, diaphoresis, tachycardia, hypertension, arrhythmias, stroke, intracranial hemorrhage
MAOIs + Serotonergic Drugs - Serotonin Syndrome
| Drug Combo | Risk |
|---|---|
| MAOIs + SSRIs | Fatal serotonin syndrome - absolute contraindication |
| MAOIs + TCAs | Serotonin syndrome |
| MAOIs + meperidine (pethidine) | Specifically contraindicated - hyperpyrexia, seizures |
| MAOIs + triptans | Serotonin syndrome |
The combination of fluoxetine + MAOI is contraindicated due to risk of fatal serotonin syndrome. Meperidine is also specifically contraindicated with MAOIs. - Katzung 16th ed
- Serotonin syndrome signs: myoclonus, agitation, hyperpyrexia, hypertension, abdominal cramping - potentially fatal (Harrison's 22E)
4. Antibiotic-Specific Interactions
| Antibiotic | Interacting Drug | Mechanism | Consequence |
|---|---|---|---|
| Fluoroquinolones (ciprofloxacin) | Theophylline | CYP1A2 inhibition | Theophylline toxicity (seizures, arrhythmias) |
| Fluoroquinolones | Warfarin | CYP2C9 inhibition | Increased INR |
| Fluoroquinolones + macrolides | Other QT-prolonging drugs | Additive QT prolongation | Torsades de pointes |
| TMP-SMX | Warfarin | CYP2C9 inhibition | Increased INR |
| TMP-SMX | Methotrexate | Folate antagonism + renal competition | Bone marrow suppression |
| Rifampicin | Nearly everything | Potent CYP inducer | Treatment failure |
| Metronidazole | Warfarin | CYP2C9 inhibition (S-warfarin) | Increased bleeding risk |
5. NSAIDs Interactions
| Interacting Drug | Mechanism | Consequence |
|---|---|---|
| Aspirin + Ibuprofen | Competitive inhibition of thromboxane pathway | Ibuprofen blocks aspirin's cardioprotective effect - give aspirin 30 min before ibuprofen |
| NSAIDs + Warfarin | GI bleeding + impaired hemostasis | Increased GI bleeding |
| NSAIDs + Lithium | Reduced renal prostaglandins - decreased renal clearance | Lithium toxicity |
| NSAIDs + Methotrexate | Reduced renal clearance of MTX | MTX toxicity (myelosuppression, mucositis) |
| NSAIDs + Metformin | Reduced renal perfusion/clearance | Lactic acidosis risk |
| NSAIDs + Antihypertensives (ACEi, ARBs) | Inhibit prostaglandin-mediated vasodilation | Loss of BP control, worsened renal function |
Ketorolac and diclofenac, unlike other NSAIDs, do NOT alter aspirin's antiplatelet effect on thromboxane synthesis. - Tintinalli's Emergency Medicine
6. QT Prolongation - Additive Risk Combos to Avoid
Any combination of QT-prolonging drugs multiplies TdP (Torsades de Pointes) risk:
- Macrolides (azithromycin, erythromycin, clarithromycin)
- Fluoroquinolones (ciprofloxacin, moxifloxacin)
- Antipsychotics (haloperidol, quetiapine, ziprasidone)
- Antifungals (fluconazole, itraconazole)
- Methadone
- Antiarrhythmics (amiodarone, sotalol, quinidine)
- Antihistamines (terfenadine - withdrawn for this reason; interaction with erythromycin/grapefruit was fatal)
- SSRIs/TCAs
Terfenadine was withdrawn from the market because CYP3A4 inhibition (by erythromycin or grapefruit) elevated parent drug levels, causing fatal ventricular tachycardia. Its safer metabolite fexofenadine replaced it. - Goodman & Gilman's
7. Azathioprine + Allopurinol (Classic High-Yield)
- Allopurinol inhibits xanthine oxidase (XO), which is the enzyme that metabolizes azathioprine
- Result: toxic accumulation of 6-mercaptopurine (the active metabolite)
- Action: Reduce azathioprine dose by 75% if allopurinol must be co-prescribed
- Same applies to febuxostat (another XO inhibitor) - contraindicated with azathioprine, 6-MP, theophylline
8. Digoxin Interactions
| Drug | Effect | Mechanism |
|---|---|---|
| Amiodarone | Increases digoxin levels | Inhibits P-glycoprotein and renal elimination |
| Quinidine | Doubles digoxin level | Displaces from tissue binding + reduces renal clearance |
| Verapamil/diltiazem | Increases digoxin levels | P-gp inhibition |
| Hypokalaemia (furosemide, thiazides) | Enhances digoxin toxicity | Digoxin competes with K+ at Na/K-ATPase - low K+ worsens toxicity |
9. SSRIs and Triptans
- Co-administration may precipitate serotonin syndrome via pharmacodynamic summation
- Effect is mild at low SSRI doses but caution is needed, especially with stronger serotonergic SSRIs (paroxetine, fluoxetine) - Kaplan & Sadock's Synopsis
Quick-Reference Summary Card
| ⚠️ Pair to Remember | Danger |
|---|---|
| MAOI + SSRI / meperidine | Fatal serotonin syndrome |
| MAOI + tyramine foods | Hypertensive crisis |
| Azathioprine + allopurinol | 6-MP toxicity - reduce AZA by 75% |
| Statins + macrolides / azoles | Rhabdomyolysis |
| Warfarin + metronidazole / TMP-SMX | Bleeding (elevated INR) |
| NSAIDs + lithium | Lithium toxicity |
| NSAIDs + methotrexate | MTX toxicity |
| Ibuprofen + aspirin | Blocks cardioprotection |
| QT drugs + QT drugs | Torsades de Pointes |
| Digoxin + amiodarone/quinidine | Digoxin toxicity |
| St. John's Wort + warfarin/OCP/cyclosporine | Treatment failure |
| Rifampicin + almost anything | Treatment failure |
Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics | Harrison's Principles of Internal Medicine 22E | Katzung's Basic and Clinical Pharmacology 16th ed | Tintinalli's Emergency Medicine | Kaplan & Sadock's Synopsis of Psychiatry | Maudsley Prescribing Guidelines 15th ed | Stahl's Essential Psychopharmacology
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