Drug-drug interactions

Dual blockade of the renin-angiotensin-aldosterone system.

An early study by Lau et al.

Amiodarone potently inhibits CYP2C9 (the main enzyme metabolizing S-warfarin) and, to a lesser extent, CYP3A4 (R-warfarin metabolism).

Atorvastatin weakly inhibits CYP3A4 and CYP2C9.

Amiodarone inhibits CYP3A4 and P-glycoprotein – apixaban exposure rises by approximately 40–50 %.

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

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

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

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.

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

Additive AV conduction slowing and heart rate reduction.

Thiazides cause hypokalemia and hypomagnesemia.

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).

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

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

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.

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

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.

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.

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 the ACE-inhibitor/spironolactone pair: the ARB blocks AT1 receptors and lowers aldosterone synthesis, while spironolactone blocks the mineralocorticoid receptor.

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

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

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

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

SSRIs deplete platelet serotonin and impair primary hemostasis.

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

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

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.

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.

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

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

Sartans, like ACE inhibitors, improve tissue insulin sensitivity.

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.

Omeprazole is a potent CYP2C19 inhibitor, the key enzyme for clopidogrel bioactivation.

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

Levothyroxine sodium requires gastric acidity to dissolve.

Amiodarone inhibits CYP3A4, the enzyme responsible for simvastatin metabolism.

Furosemide causes potassium and magnesium loss.

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

Dual mechanism: 1) ciprofloxacin is a moderate CYP1A2 inhibitor and weak CYP3A4 inhibitor, raising R-warfarin concentration; 2) elimination of gut flora reduces vitamin K2 synthesis.