Drug-drug interactions

Dual blockade of the renin-angiotensin-aldosterone system.

An early study by Lau et al.

Dual RAAS blockade at two levels: enalapril blocks angiotensin II formation, losartan blocks the binding of residual angiotensin II to the AT1 receptor.

Warfarin acts via two stereoisomers: S-warfarin (5-fold more active) and R-warfarin.

Atorvastatin weakly inhibits CYP3A4 and CYP2C9.

Additive CNS and respiratory depression.

Additive antithrombotic effect: warfarin in the coagulation cascade plus clopidogrel at the platelet P2Y12 receptor.

Same as morphine + gabapentin.

Both prolong QT interval.

Bupropion is potent CYP2D6 inhibitor.

Fluoxetine — potent CYP2D6 inhibitor.

Same as rivaroxaban + ketoconazole.

Same as citalopram + azithromycin.

Amiodarone inhibits CYP3A4, which partially metabolizes atorvastatin.

Additive antithrombotic action: apixaban + aspirin increases major bleeding risk roughly 1.

Additive antithrombotic effect on two levels: apixaban blocks factor Xa while clopidogrel inhibits platelet aggregation.

Tramadol — weak opioid + SNRI.

Dual mechanism.

Aspirin's NSAID effect reduces prostaglandin-dependent renal perfusion and blunts the diuretic and natriuretic action of spironolactone.

No direct pharmacokinetic interaction.

Additive AV conduction slowing and heart rate reduction.

Additive antithrombotic effect at two levels: warfarin inhibits clotting factors while aspirin blocks platelet aggregation and simultaneously damages gastric mucosa (antiprostaglandin effect).

Beta-blocker + non-DHP CCB (verapamil/diltiazem) = additive AV node block + negative inotropy.

Additive QT prolongation (tacrolimus on hypoMg).

Both drugs prolong the QT interval (amiodarone strongly via IKr potassium channel blockade; sertraline modestly).

Synergistic BP reduction, a target combination in hypertension (losartan/hydrochlorothiazide fixed-dose product).

Additive QT prolongation (tramadol weakly prolongs QT) + mild serotonergic risk.

Amlodipine weakly inhibits CYP3A4 – atorvastatin concentration rises by about 18 %.

Synergistic BP reduction, a target hypertension combination.

ACE inhibitors improve tissue insulin sensitivity and potentiate metformin's glucose-lowering effect.

Thyroid hormones accelerate catabolism of vitamin K-dependent clotting factors.

A target combination in HFrEF and hypertension – synergistic BP and pre/afterload reduction.

Opposing effects on potassium: furosemide depletes potassium, spironolactone retains it.

A target combination in HF and hypertension.

Sequential nephron blockade: furosemide acts in the loop of Henle, the thiazide in the distal tubule.

Both drugs can cause hyponatremia (furosemide via natriuresis, sertraline via an SIADH-like mechanism).

Omeprazole inhibits intestinal OCT1 – metformin absorption rises slightly.

Amoxicillin can interfere with intestinal absorption of levothyroxine when taken simultaneously – clinically insignificant when administration is separated.

Hypothyroidism by itself raises LDL.

Omeprazole weakly inhibits CYP3A4 – atorvastatin exposure rises modestly (10–20 %).

Dual mechanism: 1) additive AV conduction slowing and heart rate reduction (amiodarone non-competitively blocks β-receptors, metoprolol selectively blocks β1); 2) amiodarone inhibits CYP2D6, doubling metoprolol concentration.

Older experimental data suggested that NSAIDs combined with fluoroquinolones increase CNS excitability and seizure risk (via fluoroquinolone-mediated GABA-A receptor antagonism with possible NSAID potentiation).

Additive QT prolongation: sertraline modestly and ciprofloxacin modestly.

Ciprofloxacin is better absorbed in an acidic gastric environment.

A target combination in triple/quadruple Helicobacter pylori eradication regimens (Maastricht VI / Florence Consensus 2022, Kyoto Global Consensus, Russian Ministry of Health 2024 guidelines).

Same as naproxen + methotrexate.

Amiodarone inhibits intestinal and renal P-glycoprotein – plasma digoxin concentration rises 1.

Dual risk: serotonin syndrome + fluoxetine's CYP2D6 inhibition reduces tramadol activation to active O-desmethyl metabolite, paradoxically reducing analgesia.

Dual mechanism: 1) sertraline inhibits serotonin reuptake in platelets, depleting platelet serotonin and reducing aggregation; 2) moderate CYP2C9 inhibition raises warfarin concentration and INR.

Simvastatin inhibits CYP3A4 and to a lesser extent CYP2C9, raising warfarin concentration.

SSRIs deplete platelet serotonin and impair primary hemostasis.

Broad-spectrum antibiotics eliminate gut flora that synthesize vitamin K2 – reducing vitamin K availability for hepatic γ-carboxylation.

TCA + SSRI: dual risk.

Same as amitriptyline + sertraline, but fluoxetine is stronger CYP2D6 inhibitor with long T1/2 (1-2 weeks for norfluoxetine).

Same as the ACE-inhibitor/furosemide pair: in a hypovolemic patient the first sartan dose can cause an abrupt BP drop and acute kidney injury.

Aspirin's COX inhibition reduces renal prostaglandin-mediated vasodilation.

Sartans, like ACE inhibitors, improve tissue insulin sensitivity.

Synergistic BP reduction (a target combination in hypertension – even an enalapril/hydrochlorothiazide fixed-dose product exists).

A target combination in angina and hypertension.

Spironolactone moderately inhibits P-glycoprotein – digoxin concentration rises by 20–30 %.

Two effects: 1) clopidogrel blocks aggregation at the P2Y12 receptor while sertraline impairs primary hemostasis by inhibiting platelet serotonin reuptake; 2) sertraline weakly inhibits CYP2C19 – clopidogrel activation is slightly reduced.

Opposing effects on potassium: thiazide depletes, spironolactone retains.

Thiazides are one of the commonest drug causes of hyponatremia in older adults (via an SIADH-like mechanism plus natriuresis).

Same as the amiodarone/furosemide pair: thiazide-induced hypokalemia and hypomagnesemia raise amiodarone's arrhythmogenic potential.

Omeprazole inhibits CYP2C19 – sertraline concentration rises by roughly 40 %.

Additive QT prolongation: amiodarone strongly blocks IKr potassium channels and ciprofloxacin does the same more mildly.

In 10–15 % of patients, gut flora (mainly Eubacterium lentum) metabolize part of digoxin into inactive products.

Additive antithrombotic effect plus platelet aggregation inhibition.

Metronidazole stereospecifically inhibits CYP2C9, the enzyme that metabolizes S-warfarin (the more potent enantiomer).

Additive antiplatelet action: aspirin inhibits COX-1 → thromboxane, clopidogrel blocks the P2Y12 receptor.

Same as morphine+diazepam.

Levothyroxine sodium requires gastric acidity to dissolve.

Ketoconazole — potent CYP3A4 and P-gp inhibitor.

Ciprofloxacin is potent CYP1A2 inhibitor.

Same as citalopram + amiodarone.

Fluoroquinolones disrupt glucose homeostasis – they can cause both hypoglycemia (especially in older patients on glucose-lowering therapy) and hyperglycemia.

In patients with activated RAAS (significant hypovolemia from aggressive diuresis, severe HF), the first ACE-inhibitor dose can cause an abrupt BP drop with syncope and acute kidney injury.

Furosemide is a loop diuretic that increases urinary loss of potassium and magnesium.

Amlodipine moderately inhibits CYP3A4 – simvastatin exposure rises 30–80 %, and the risk of myopathy and rhabdomyolysis increases.

Synergistic BP reduction via two mechanisms: amlodipine causes vasodilation, enalapril blocks the RAAS.

Thiazides cause hypokalemia and hypomagnesemia.

Same as the aspirin/ACE-inhibitor pair: aspirin's NSAID effect blunts renal vasodilation, and patients with CKD or hypovolemia may develop acute kidney injury.

Thiazides cause dose-dependent hyperglycemia and insulin resistance (especially at doses ≥ 25 mg/day) via hypokalemia and reduced insulin secretion.

Furosemide causes hypokalemia and hypomagnesemia – increasing myocardial sensitivity to amiodarone's QT-prolonging effect.

Trimethoprim blocks epithelial Na channel in collecting ducts (amiloride-like) → hyperkalemia.

Same as naproxen + warfarin.

Same as ketorolac + ibuprofen.

Ketorolac is the strongest oral NSAID.

Additive QT prolongation (tacrolimus prolongs QT, especially with hypoMg).

Additive QT prolongation at high quetiapine doses.

IV methylene blue is a reversible MAO-A inhibitor.

IV methylene blue inhibits MAO-A.

IV methylene blue inhibits MAO-A.

Alprazolam — CYP3A4 substrate.

Ritonavir induces CYP1A2, CYP2C9, CYP2C19 (long-term).

Fluvoxamine inhibits CYP1A2 (minor venlafaxine pathway) + additive serotonin.

Linezolid is a reversible MAO inhibitor with antibacterial activity.

SSRI + SNRI — serotonin syndrome.

Dual CYP3A4 inhibitors + QT prolongation.

Paracetamol above 2 g/day for more than 7 days raises INR by 1–3 units.

Glucocorticoids alter coagulation factor levels and can affect warfarin metabolism through CYP3A4.

Additive GI ulcer and bleeding risk.

SNRIs reduce platelet aggregation (via platelet serotonin).

Fluvoxamine — potent CYP1A2 inhibitor.

Same as ibuprofen — additive GI bleeding risk.

Glucocorticoids induce steroid-induced diabetes via inhibition of muscle glucose uptake and gluconeogenesis stimulation.

Glucocorticoids cause sodium and water retention, reducing ACE inhibitor antihypertensive effect.

Both cause hypokalemia: GCs via mineralocorticoid effect, furosemide via direct renal K excretion.

Combination of GCs with fluoroquinolones significantly increases tendon rupture risk (especially Achilles).

Ketoconazole — potent CYP3A4 inhibitor.

Dexamethasone induces CYP3A4 and P-gp.

Gabapentin reduces morphine clearance and potentiates CNS depression.

Ciprofloxacin — potent CYP1A2 inhibitor.

Tramadol itself inhibits serotonin reuptake (minor) and metabolizes via CYP2D6 to O-desmethyltramadol.

Tramadol minorly affects CYP2C9 warfarin metabolism via CYP2D6 pathway.

TCAs metabolize through CYP2C9 (minor) — potential competition with warfarin.

Bupropion lowers seizure threshold (especially high doses or predisposed patients).

Ketoconazole — potent CYP3A4 inhibitor.

Carbamazepine — potent CYP3A4 inducer.

Serotonin syndrome + tramadol seizure risk amplified.

Ciprofloxacin inhibits CYP1A2 and CYP3A4 (minor).

Both trimethoprim and sulfamethoxazole inhibit CYP2C9 (main S-warfarin metabolizer).

Doxycycline forms non-absorbable chelates with calcium (and other polyvalent cations Mg, Fe, Al).

Same as doxycycline + calcium.

NSAIDs reduce renal blood flow via prostaglandin blockade.

ARB reduces lithium renal clearance by 25-40% (via reduced GFR).

Colchicine — CYP3A4 + P-gp substrate with narrow TI.

Dual NSAID — additive GI bleeding and nephrotoxicity risk.

Both raise potassium: ARB via RAAS inhibition, spironolactone via K-sparing mechanism.

Same as losartan + ibuprofen.

NSAID + warfarin — triple risk: (1) NSAID alone causes GI ulcer/bleeding, (2) inhibits platelet aggregation, (3) high plasma protein binding competes with warfarin, raising free fraction.

NSAIDs reduce lithium renal clearance via prostaglandin-dependent renal blood flow blockade.

NSAIDs reduce methotrexate renal clearance (via RBF) and may displace MTX from protein binding.

Same as naproxen + lithium.

Same as other NSAID + warfarin.

Clarithromycin (like other macrolides) inhibits CYP1A2 and CYP3A4.

Rifampicin is most potent CYP1A2 and CYP3A4 inducer.

Same as rifampicin.

Dual risk: (1) ritonavir inhibits CYP3A4 → amiodarone AUC increases.

Amiodarone — P-gp and CYP3A4 inhibitor.

Same as apixaban + amiodarone.

Amiodarone — P-gp inhibitor.

Fluconazole — potent CYP2C9 inhibitor.

Rifampicin — CYP3A4 and P-gp inducer.

Clarithromycin — potent CYP3A4 inhibitor.

Same as clarithromycin.

Rifampicin reduces tacrolimus levels by 60-80% → loss of immunosuppression, transplant rejection risk.

Both cause benign intracranial hypertension (pseudotumor cerebri).

Carbamazepine — CYP3A4 inducer.

Ritonavir is most potent CYP3A4 inhibitor.

Dual SSRI — serotonin syndrome, no therapeutic rationale.

Systemic budesonide exposure increases 8-10x via CYP3A4 inhibition.

Tacrolimus AUC increases 50+ fold via CYP3A4 inhibition.

Dual mechanism: CYP3A4 inhibition + P-gp inhibition.

Same as ritonavir + apixaban.

Dual QT prolongation risk.

Additive QT prolongation.

Dual serotonergic risk + citalopram QT prolongation.

SSRI + lithium — additive serotonergic risk.

QT prolongation from both + amiodarone — potent CYP2D6 inhibitor, raises venlafaxine levels.

SNRI + SSRI — additive serotonin syndrome.

NSAID + nephrotoxic CNI — additive AKI risk.

Diltiazem — moderate CYP3A4 inhibitor.

Same as simvastatin, but atorvastatin less CYP3A4-dependent.

Non-DHP CCB + beta-blocker = additive AV node block + negative inotropy.

Same as diltiazem + bisoprolol.

Diltiazem inhibits P-gp → digoxin levels increase 20-30%.

Diltiazem inhibits CYP3A4.

Diltiazem raises cyclosporine via CYP3A4 + P-gp.

Additive bradycardia + AV block.

Same as bisoprolol + verapamil.

Same as carvedilol + verapamil.

Abrupt clonidine withdrawal — rebound hypertension.

Fluoxetine — potent CYP2D6 inhibitor.

Beta-blockers mask adrenergic hypoglycemia symptoms (tachycardia, tremor, sweating).

TCAs block α2 receptors → antagonize clonidine.

Additive bradycardia + AV block.

Same as clonidine + diltiazem.

Additive hypotension.

Celecoxib — CYP2C9 substrate.

NSAID reduces lithium renal clearance.

NSAID reduces methotrexate renal clearance.

NSAID + ACE-I — reduced renal blood flow, AKI risk in elderly, CKD, dehydration.

Same as celecoxib + enalapril.

Fluvoxamine — most potent CYP1A2 inhibitor among SSRIs.

Fluvoxamine inhibits CYP2C19 and CYP1A2 (minor warfarin pathway).

Fluvoxamine inhibits CYP2C19 and CYP3A4 — both metabolize diazepam.

SSRI + tramadol — serotonin syndrome + tramadol seizure risk amplified.

Telmisartan — P-gp inhibitor.

ARB + NSAID — reduced renal blood flow, AKI risk.

Additive hyperkalemia (both raise K).

Amiodarone prolongs QT and weakly inhibits CYP3A4.

Amiodarone inhibits CYP3A4 and P-gp — both key tacrolimus pathways.

Bupropion is a strong CYP2D6 inhibitor, raising TCA levels 2-5x.

Fluvoxamine inhibits CYP1A2 and CYP2C19 — main amitriptyline demethylation pathways.

Both prolong QT and are serotonergic.

Duloxetine is a moderate CYP2D6 inhibitor, raising TCA levels.

Venlafaxine is an SNRI with serotonin-noradrenaline activity; TCAs act similarly.

Apixaban directly inhibits Xa; meloxicam impairs platelet function and damages GI mucosa.

Same as apixaban + meloxicam — additive GI bleeding risk on anticoagulation.

Abrupt clonidine withdrawal on beta-blocker triggers hypertensive crisis: loss of α2 agonism while β-blockade preserves α-adrenergic response.

Bupropion inhibits CYP2D6 — the pathway converting tramadol to active M1 metabolite.

Ciprofloxacin inhibits CYP1A2 and itself lowers seizure threshold.

Additive seizure-threshold lowering + potential serotonin syndrome (bupropion has weak serotonergic component).

Dexamethasone strongly induces CYP3A4 and weakly CYP2B6 (bupropion metabolism).

Additive seizure-threshold lowering + synaptic norepinephrine surge (bupropion NDRI, duloxetine SNRI) → tachycardia, hypertension.

Escitalopram is the citalopram enantiomer with the same effects.

Fluoxetine is a strong CYP2D6 inhibitor, raising bupropion active metabolite (hydroxybupropion).

Fluvoxamine weakly inhibits CYP2D6 but strongly CYP2C19 and CYP1A2.

Haloperidol is a CYP2D6 substrate; bupropion inhibits CYP2D6 → haloperidol levels rise 2-3x → EPS, QT prolongation.

Same as bupropion + dexamethasone: steroid lowers seizure threshold and induces CYP3A4.

Mirtazapine lowers seizure threshold less than bupropion, but the effect is additive.

High-dose morphine and opioid-induced myoclonic hyperactivity raise seizure risk; bupropion lowers seizure threshold.

Same as bupropion + methylprednisolone: steroid lowers seizure threshold; clinically significant on long-term use.

Quetiapine lowers seizure threshold (especially >300 mg); bupropion is a potent proconvulsant.

Additive seizure-threshold lowering.

Theophylline at toxic levels causes seizures; bupropion lowers seizure threshold.

Additive seizure-threshold lowering + norepinephrine surge.

Dual RAAS blockade (ACEi + ARB) — randomized ONTARGET showed increased hyperkalemia, hypotension, AKI with no outcome benefit.

Carbamazepine strongly induces CYP3A4 and P-gp.

Dual NSAID therapy — additive GI bleeding, nephrotoxicity, and CV event risk.

Contrast agent and NSAID — both nephrotoxic.

NSAIDs reduce renal blood flow via prostaglandin inhibition.

Fluoroquinolone + steroid — 3-4x cumulative risk of tendinitis and Achilles rupture, especially >60 years and transplant recipients.

Additive QT prolongation (both prolong QTc).

Omeprazole strongly inhibits CYP2C19.

Clarithromycin prolongs QT and strongly inhibits CYP3A4.

Esomeprazole is the S-isomer of omeprazole, with same CYP2C19 inhibition.

Dronedarone prolongs QT (FDA black box).

Fluconazole inhibits CYP2C19 and CYP3A4 (moderate), prolongs QT.

Ketoconazole strongly inhibits CYP3A4.

Tacrolimus prolongs QT, especially with hypomagnesemia (common on CNI).

Dual SSRI — serotonin syndrome (tachycardia, myoclonus, hyperthermia).

SSRI + SNRI — serotonergic load rises, serotonin syndrome risk.

Escitalopram is the S-enantiomer of citalopram.

Dual SSRI + fluoxetine is a strong CYP2D6 and weak CYP2C19 inhibitor → citalopram AUC may rise.

Additive QT prolongation.

Mirtazapine is serotonergic (via α2 block) and blocks 5HT2A/2C.

Quetiapine prolongs QT at high doses.

SSRI + SNRI — serotonin syndrome, additive QT risk at high venlafaxine doses.

Clarithromycin strongly inhibits CYP3A4.

Tamsulosin is a CYP3A4 substrate.

Same as clonidine + bisoprolol: hypertensive crisis on abrupt clonidine withdrawal, additive bradycardia.

Same as clonidine + metoprolol.

Clopidogrel is a prodrug activated by CYP2C19.

Ritonavir inhibits CYP3A4 and CYP2C19 → clopidogrel not activated.

Diltiazem is a moderate CYP3A4 and P-gp inhibitor.

Tacrolimus and colchicine are both P-gp substrates with nephrotoxicity.

Diclofenac reduces renal blood flow via PGE2 inhibition.

Dual RAAS blockade — increased hyperkalemia, hypotension, AKI with no outcome benefit (ONTARGET).

Non-DHP CCB + BB — pronounced additive bradycardia, AV block, negative inotropy.

Rifampicin is the strongest CYP3A4 inducer.

Additive QT prolongation (both prolong QTc).

Ritonavir is the strongest CYP3A4 inhibitor; dronedarone is a CYP3A4 substrate with QT effect.

Dronedarone inhibits P-gp; tacrolimus is a substrate.

Additive QT prolongation.

Linezolid is a reversible MAO inhibitor.

SSRI + SNRI — increased serotonergic load, serotonin syndrome risk.

Fluoxetine strongly inhibits CYP2D6; duloxetine is minorly CYP2D6-metabolized.

Mirtazapine + SNRI — augmentation for treatment-resistant depression ("California Rocket Fuel").

SSRI + SNRI — serotonin syndrome.

Dual SNRI — doubling the same pharmacology, risk of serotonin syndrome, hypertension, tachycardia with no therapeutic benefit.

Esomeprazole inhibits CYP2C19; tacrolimus is minorly CYP2C19-metabolized (main pathway in poor metabolizers).

Fluconazole moderately inhibits CYP3A4 and CYP2C19.

SSRI + SNRI — serotonin syndrome.

SSRI + MAO inhibitor (linezolid) — serotonin syndrome, fatal cases described.

Serotonergic load on combination.

Additive CNS depression + amplification of tramadol seizure risk (gabapentin doesn't lower threshold, but CNS effects sum).

Aminoglycoside + calcineurin inhibitor — additive nephrotoxicity via two mechanisms (tubular necrosis vs.

Additive QT prolongation.

Dual antipsychotic therapy — additive EPS, sedation, QT prolongation, metabolic side effects.

Additive QT prolongation.

DOAC + NSAID — additive GI bleeding risk (anticoagulation + mucosal injury + platelet dysfunction).

Ibuprofen reduces renal blood flow via PGE2 inhibition; tacrolimus is nephrotoxic.

Contrast + nephrotoxic immunosuppressant — high contrast-induced nephropathy risk.

Contrast + NSAID — additive nephrotoxicity, especially in CKD and dehydration.

Same as iopromide + naproxen.

Ketoconazole is the strongest CYP3A4 inhibitor.

Dual strong CYP3A4 inhibitors.

Ketoconazole inhibits CYP3A4 — main methylprednisolone pathway.

Carvedilol is a moderate P-gp inhibitor; colchicine is a P-gp substrate with narrow TI.

Carvedilol blocks β2 receptors → bronchoconstriction in asthma/COPD.

Ketorolac is the most nephrotoxic NSAID, capped at 5 days.

Dual NSAID — sharp increase in GI bleeding (3-5x), AKI, and CV events.

NSAIDs reduce methotrexate renal clearance.

Dual immunosuppression + additive nephrotoxicity.

Ritonavir is the strongest CYP3A4 inhibitor.

"California Rocket Fuel" augmentation — mirtazapine (5HT2/3 blocker) + venlafaxine (SNRI).

Additive CNS and respiratory depression.

DOAC + NSAID — additive GI bleeding risk.

NSAID + nephrotoxic CNI — additive AKI risk.

Omeprazole inhibits CYP2C19; in CYP2C19 PMs tacrolimus is mainly CYP2C19-metabolized.

Same as gabapentin + tramadol: additive CNS depression, seizure risk.

Quetiapine is a CYP3A4 substrate.

Rifampicin is the strongest CYP3A4 inducer.

Additive CNS depression + seizure-threshold lowering (tramadol lowers threshold, quetiapine at high doses).

Rifampicin induces CYP3A4 → ritonavir and PI AUC falls critically → HAART failure, HIV resistance risk.

Simvastatin is a CYP3A4 substrate.

Rosuvastatin is not a CYP3A4 substrate, but a substrate of OATP1B1 and BCRP transporters that ritonavir inhibits.

Tamsulosin is a CYP3A4 substrate.

Sildenafil is a CYP3A4 substrate.

Spironolactone retains potassium via aldosterone receptor block; tacrolimus reduces renal K secretion via distal tubular effects.

Trimethoprim in co-trimoxazole blocks epithelial Na channel (ENaC) like amiloride → K retention.

SNRI + tramadol — serotonin syndrome + additive seizure risk.

SSRIs block platelet serotonin reuptake → impaired platelet function.

Same as ASA + fluvoxamine — SSRI platelet dysfunction + ASA antiplatelet effect → bleeding risk.

Diltiazem impairs platelet function via Ca channel blockade; ASA is antiplatelet.

Same as ASA + SSRI — SNRIs also affect platelets via serotonin.

Steroids damage gastric mucosa and suppress protective prostaglandins.

Naproxen may block aspirin acetylation of platelet COX-1, reducing ASA cardioprotection.

Same as ASA + methylprednisolone — steroid + antiplatelet → GI bleeding.

High-dose ASA (>1 g) may blunt ARB antihypertensive effect via PG mechanism.

SNRI + antiplatelet — GI bleeding risk.

Celecoxib is a selective COX-2 inhibitor and doesn't displace ASA from COX-1 (unlike ibuprofen/naproxen).

Meloxicam is preferentially COX-2 selective, weakly displaces ASA from COX-1.

Additive hypotension and sedation.

Additive CNS depression and hypotension (clonidine is a centrally acting α2 agonist with sedative effect).

SSRI + DOAC — bleeding risk via platelet dysfunction.

Diltiazem is a moderate CYP3A4 inhibitor; alprazolam is a CYP3A4 substrate.

Additive hypotension (BZDs have mild hypotensive effect, ARB is primary).

Tacrolimus is a weak CYP3A4 inhibitor; alprazolam is a substrate.

Additive orthostatic hypotension.

Fluvoxamine inhibits CYP3A4 and CYP1A2; alprazolam is CYP3A4-metabolized.

Additive CNS depression — sedation, ataxia, fall risk in elderly.

Additive CNS depression.

Additive CNS depression.

Additive CNS depression — sedation, ataxia.

Additive CNS and respiratory depression.

Additive CNS depression (minimal for venlafaxine, primarily alprazolam).

Fluvoxamine strongly inhibits CYP1A2; amiodarone is partly CYP1A2-metabolized.

Additive bradycardia + amiodarone QT effect on top of carvedilol negative chronotropy.

Celecoxib is a CYP2C9 substrate; amiodarone weakly inhibits CYP2C9.

Dual statin therapy — additive myopathy and rhabdomyolysis risk.

Duloxetine is a CYP1A2 substrate; amiodarone weakly inhibits CYP1A2.

Amiodarone weakly inhibits CYP3A4; tamsulosin is a CYP3A4 substrate.

TCAs have α1-blocking effect — additive orthostatic hypotension with carvedilol (α/β blocker).

Additive anticholinergic effect — dry mouth, constipation.

Diltiazem weakly inhibits CYP2D6 and CYP3A4; amitriptyline is metabolized by both.

TCA α1 blockade + ARB — additive hypotension, especially orthostatic.

Tacrolimus prolongs QT; TCAs do the same via quinidine-like effect on Na/K channels.

Additive orthostatic hypotension (both have α1-blocking effect).

Ritonavir strongly inhibits CYP2D6 and CYP3A4; amitriptyline is metabolized by both.

Additive CNS depression — sedation, dizziness, fall risk in elderly.

Same as amitriptyline + gabapentin — additive CNS depression.

Additive anticholinergic and QT effects.

Bupropion inhibits CYP2D6; amlodipine is minorly CYP2D6-metabolized (main pathway CYP3A4).

Steroids retain sodium and water → antagonize amlodipine antihypertensive effect.

Additive hypotension and peripheral edema (amlodipine causes ankle edema, BBs may potentiate).

Dual CCB — DHP + non-DHP.

NSAIDs antagonize CCB antihypertensive effect via PG-dependent renal sodium handling.

Same as amlodipine + prednisolone — steroid-induced sodium retention reduces CCB effect.

Same as amlodipine + meloxicam — NSAIDs reduce antihypertensive effect.

Additive hypotension.

Ritonavir is the strongest CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate.

Tacrolimus and amlodipine are both CYP3A4 substrates competing for the enzyme.

SSRI platelet dysfunction + DOAC.

COX-2 inhibitor + DOAC — selective COX-2 has lower GI risk but bleeding possible.

SSRI + DOAC — bleeding risk via platelet dysfunction.

Diltiazem moderately inhibits CYP3A4 and P-gp; apixaban is a substrate of both.

SNRI + DOAC — bleeding risk.

Fluconazole moderately inhibits CYP3A4.

In CKD spironolactone causes hyperkalemia; DOAC has rising exposure in CKD.

Tacrolimus weakly inhibits CYP3A4 + P-gp substrate.

SNRI + DOAC — bleeding risk.

Verapamil moderately inhibits CYP3A4 and P-gp.

Dexamethasone induces CYP3A4.

Esomeprazole weakly affects CYP3A4 (via CYP2C19).

Metronidazole is not a CYP3A4 inhibitor but raises statin myopathy risk in combination (mechanism unclear, post-marketing reports).

Pantoprazole is the most CYP-neutral PPI.

Dual statin therapy — doubling the same class, additive myopathy risk with no therapeutic benefit.

Fluvoxamine inhibits CYP3A4.

Ciprofloxacin weakly inhibits CYP3A4.

Atorvastatin inhibits P-gp → digoxin AUC rises 20%.

Dronedarone inhibits CYP3A4.

Linezolid is linked to rhabdomyolysis with statins (rare cases).

Atorvastatin inhibits OATP1B1 → methotrexate AUC may rise.

Tacrolimus weakly inhibits CYP3A4; atorvastatin is a substrate.

Verapamil moderately inhibits CYP3A4.

Dual macrolide therapy — doubled QT effect, redundant antibacterial activity without rationale.

Azithromycin weakly inhibits P-gp; rivaroxaban is a P-gp substrate.

Azithromycin alters gut flora that synthesize vitamin K → INR may rise.

Macrolides suppress gut Eggerthella lenta that inactivates digoxin → digoxin AUC rises.

Additive QT prolongation — both prolong QTc.

Additive QT prolongation.

Dual antibiotics + additive QT prolongation.

Additive QT prolongation (fluoxetine weakly prolongs QT at high doses).

Antibiotics may affect methotrexate gut absorption.

Additive QT prolongation (mirtazapine weakly prolongs QT).

Additive QT prolongation.

Additive QT prolongation (sertraline minimally prolongs QT).

Azithromycin weakly inhibits CYP1A2; theophylline is a substrate.

Additive QT prolongation.

Bupropion inhibits CYP2D6; bisoprolol is metabolized by CYP3A4 (50%) and renal excretion (50%) → clinically minor.

Additive bradycardia and hypotension.

Steroid-induced sodium retention reduces BB antihypertensive effect.

Systemic budesonide (not inhaled) — steroid-induced sodium retention reduces BB effect.

Calcium carbonate may reduce bisoprolol absorption when taken together.

Empagliflozin causes osmotic diuresis → hypovolemia, orthostatic hypotension.

BB masks adrenergic hypoglycemia symptoms (tachycardia, tremor, sweating).

Steroid-induced sodium retention reduces antihypertensive effect.

NSAIDs reduce BB antihypertensive effect via PG-dependent renal regulation.

Same as bisoprolol + ketorolac.

Additive hypotension, hypokalemia (from furosemide).

Standard HTN combination — additive antihypertensive effect.

Additive CNS depression and mild hypotension.

NSAIDs reduce BB antihypertensive effect.

Additive bradycardia and AV block.

Additive bradycardia.

Additive hypotension (haloperidol blocks α1) + QT prolongation (haloperidol).

Standard HTN combination — additive antihypertensive effect.

BB may impair treatment of contrast anaphylaxis (epinephrine less effective).

Linezolid is a reversible MAO inhibitor.

NSAIDs reduce BB antihypertensive effect.

Steroid-induced sodium retention reduces BB effect.

Additive hypotension and sedation.

NSAIDs reduce BB antihypertensive effect.

Additive hypotension (quetiapine blocks α1) + additive bradycardia.

Rifampicin induces CYP3A4 → bisoprolol AUC may fall modestly (half of the metabolism pathway).

Additive hypotension.

Standard HFrEF combination — additive antihypertensive effect, spironolactone retains K.

Standard HFrEF combination — additive antihypertensive effect and complementary mechanisms (neurohormonal blockade).

Dual immune suppression.

Steroid + NSAID — additive GI ulcer and bleeding risk.

Same as budesonide + ketorolac — GI risk on systemic steroid use.

Estrogens raise corticosteroid-binding globulin → more bound budesonide, but clinically minor.

Fluvoxamine inhibits CYP3A4; budesonide is a substrate.

Same as budesonide + ethinyl-estradiol.

Systemic budesonide retains sodium → antagonizes ACEi antihypertensive effect.

Systemic steroid reduces BB antihypertensive effect.

Steroid + NSAID — GI risk on systemic steroid use.

Fluoroquinolone + systemic steroid — tendinitis and rupture risk.

Systemic steroid retains sodium → antagonizes clonidine antihypertensive effect.

Steroid + NSAID — GI risk on systemic use.

Simvastatin clearance is 98% dependent on hepatic CYP3A4.

Clopidogrel is a prodrug.

Amiodarone moderately inhibits hepatic CYP3A4 – the primary clearance route for simvastatin.

Atorvastatin clearance depends on hepatic CYP3A4, but unlike simvastatin only ~70% of the dose follows this route – the rest uses alternative pathways.

Ibuprofen and warfarin compete for plasma protein (albumin) binding.

Cyclosporine (an immunosuppressant used after solid-organ transplantation and in severe autoimmune disease) is cleared through hepatic CYP3A4 and actively transported by P-glycoprotein.

Linezolid is an oxazolidinone antibiotic that also reversibly inhibits monoamine oxidase (MAO).

Tramadol is an opioid with serotonin–norepinephrine reuptake inhibition.

Amitriptyline, a tricyclic antidepressant, blocks serotonin and norepinephrine reuptake.

Escitalopram (SSRI) raises synaptic serotonin.

Fluoxetine (SSRI) raises synaptic serotonin.

Mirtazapine increases serotonin release by blocking presynaptic α2-adrenergic autoreceptors.

Citalopram (SSRI) raises synaptic serotonin.

Venlafaxine is a serotonin–norepinephrine reuptake inhibitor (SNRI).

Bupropion inhibits dopamine and norepinephrine reuptake.

Methylene blue (methylthioninium chloride) given intravenously is a potent reversible MAO-A inhibitor.

IV methylene blue inhibits MAO-A.

IV methylene blue reversibly inhibits MAO-A.

IV methylene blue is a potent reversible MAO-A inhibitor.