Warfarin

Mechanism

Aspirin irreversibly blocks platelet cyclooxygenase and reduces aggregation. Warfarin blocks vitamin K-dependent clotting factor synthesis. Two different antithrombotic mechanisms add up. Aspirin also injures the gastric mucosa.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

Combine only for strict indications: after coronary stenting, mechanical heart valves, acute coronary syndrome. Limit triple/dual antithrombotic therapy to 1–6 months based on risk. Aspirin 75–100 mg/day. Mandatory pantoprazole cover; check INR every 2–4 weeks.

Mechanism

Atorvastatin weakly inhibits CYP3A4 and CYP2C9 – the warfarin clearance route. Some patients show a 20–30% INR rise within 2–4 weeks; a small share experience clinically significant effects.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

The combination is acceptable. After starting atorvastatin, check INR at 2 and 4 weeks, then resume routine monitoring. If INR rises above target, reduce warfarin by 10–20%.

Mechanism

Carbamazepine strongly induces CYP2C9 and CYP3A4. Warfarin plasma levels fall by 50–70% over 2–4 weeks; anticoagulant effect weakens.

Symptoms

INR drops below target. Thromboembolic risk rises: deep vein thrombosis, pulmonary embolism, ischaemic stroke in atrial fibrillation.

Management

After starting carbamazepine, check INR every 1–2 weeks for the first month and titrate warfarin (usually 1.5- to 2-fold dose increase). On carbamazepine withdrawal, induction persists for 2–4 weeks – return warfarin gradually. Alternative anticonvulsants without induction: levetiracetam, lamotrigine.

Mechanism

Celecoxib is metabolised by CYP2C9 – the same route as S-warfarin (the more active form). Enzyme competition raises INR. Celecoxib also moderately injures the gastric mucosa.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

The combination is acceptable when chronic NSAID therapy is needed. Check INR at 1 and 2 weeks after starting celecoxib, then monthly. PPI cover with pantoprazole is mandatory.

Mechanism

Ciprofloxacin blocks CYP1A2 and, to a lesser extent, CYP3A4 – warfarin clearance routes. It also suppresses vitamin K-producing gut flora. INR rises 1.5- to 2-fold within 5–7 days of co-administration.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

During ciprofloxacin therapy, empirically reduce warfarin by 20%; check INR 3–5 days after starting and 7 days after stopping the antibiotic. Alternatives: cephalosporin or nitrofurantoin (minimal CYP impact).

Mechanism

Clarithromycin inhibits CYP3A4 and CYP2C9. INR rises 25-50%.

Symptoms

Gum and nose bleeding, petechiae, haematuria within 5-10 days.

Management

Check INR on days 3 and 7. Alternative – azithromycin (minimal INR effect).

Mechanism

Warfarin blocks vitamin K-dependent clotting factor synthesis; clopidogrel inhibits platelet aggregation via the P2Y12 receptor. The two antithrombotic mechanisms add up.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

Combine only for clear indications (e.g., atrial fibrillation plus coronary stent). Limit dual therapy to 1–6 months depending on risk. Keep INR at the lower end of the target range (2.0–2.5) and provide PPI cover with pantoprazole.

Mechanism

Warfarin blocks vitamin K-dependent clotting factor synthesis; clopidogrel inhibits platelet aggregation via the P2Y12 receptor. The two antithrombotic mechanisms add up.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

Combine only for clear indications. Limit dual therapy to 1–6 months depending on risk. Keep INR at the lower end of the target range (2.0–2.5) and provide PPI cover with pantoprazole.

Mechanism

Trimethoprim in co-trimoxazole inhibits CYP2C9. INR rises 50-100% within 3-5 days. High bleeding risk in elderly.

Symptoms

Gum and nose bleeding, petechiae, haematuria within 5-10 days.

Management

If possible – alternative antibiotic. If co-trimoxazole needed – cut warfarin by 30% and check INR on days 3 and 7.

Mechanism

Diclofenac (NSAID) inhibits platelet aggregation, injures the gastric mucosa, and weakly displaces warfarin from albumin binding. Additive GI bleeding risk independent of INR.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

Avoid chronic diclofenac on warfarin. For analgesia, choose paracetamol (up to 2 g/day for short courses). For chronic NSAID needs, use a selective COX-2 inhibitor (celecoxib) under pantoprazole cover.

Mechanism

Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI). It depletes the platelet serotonin pool, impairing primary haemostasis. On warfarin, upper GI bleeding risk roughly doubles.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

The combination is acceptable. PPI cover with pantoprazole is mandatory. Check INR at 2 and 4 weeks after starting duloxetine, then monthly. Alternative antidepressants with minimal platelet effect: mirtazapine or agomelatine.

Mechanism

Fluconazole inhibits CYP2C9, the main enzyme of S-warfarin (the more active isomer). INR rises to 8–12 with risk of major bleeding: gastrointestinal, intracranial, retroperitoneal.

Symptoms

By days 3–5: gum and nose bleeding, petechiae, haematuria, bloody stool. INR above 6 without clinical bleeding still requires action.

Management

If fluconazole is required, reduce warfarin by 25–50% from day 1 and check INR on days 3 and 7. Short courses (3 single doses) – INR check on day 5. After fluconazole withdrawal, retitrate warfarin upward.

Mechanism

Fluvoxamine inhibits CYP2C19 and CYP1A2 – minor warfarin clearance routes. INR rises within 1–2 weeks of co-administration. Fluvoxamine (an SSRI) also depletes the platelet serotonin pool, impairing primary haemostasis.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

After starting fluvoxamine, check INR at 1 and 2 weeks, then monthly. If INR rises above target, reduce warfarin by 10–20%. Alternative antidepressants without CYP1A2/CYP2C19 effect: sertraline or escitalopram with pantoprazole cover.

Mechanism

St. John's wort is a potent inducer of the CYP3A4 enzyme (and of CYP2C9 and P-glycoprotein). After 1–2 weeks it speeds up the breakdown of Warfarin and lowers its blood level, weakening its effect.

Symptoms

Drop in international normalized ratio (INR), weaker anticoagulation, risk of thrombosis and thromboembolism.

Management

Do not combine. If St. John's wort was already taken, stop it and monitor INR; the warfarin dose may need lowering after the herb is stopped.

Mechanism

Ibuprofen and warfarin compete for plasma protein (albumin) binding. The free warfarin fraction rises and its anticoagulant effect intensifies. In parallel, ibuprofen reversibly inhibits platelet aggregation and damages the gastric mucosa – two additional bleeding mechanisms. INR may rise modestly, but gastrointestinal bleeding risk increases independently of INR.

Symptoms

Black or tarry stools (melena), vomiting blood or coffee-ground material, epigastric pain. Less severe presentations: gum bleeding, epistaxis, bruising. Risk multiplies in patients with a history of peptic ulcer disease.

Management

For analgesia in a warfarinised patient, paracetamol is preferred (up to 2 g/day, short courses). If chronic NSAID therapy is needed, switch to a selective COX-2 inhibitor (celecoxib) with proton pump inhibitor cover and frequent INR monitoring. Topical NSAIDs (gels, creams) deliver minimal systemic absorption and are acceptable.

Mechanism

Ketorolac is the most potent available NSAID. It inhibits platelet aggregation and strongly injures the gastric mucosa. On warfarin, massive GI bleeding risk multiplies. FDA Toradol Section 4.3 lists anticoagulants as contraindications.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

The combination is not prescribed. For analgesia on warfarin, use paracetamol (up to 2 g/day), metamizole, or a short opioid course. Ketorolac courses never exceed 5 days under any circumstances.

Mechanism

Thyroid hormones accelerate catabolism of vitamin K-dependent clotting factors. When levothyroxine starts or its dose increases, warfarin sensitivity rises and INR climbs within 1–4 weeks.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool. Severe cases include gastrointestinal or intracranial haemorrhage.

Management

When levothyroxine starts or is escalated, check INR at 1, 2, and 4 weeks and titrate warfarin (typically a 10–25% dose reduction). Once thyroid function stabilises, warfarin requirements stabilise too.

Mechanism

Meloxicam (preferential COX-2 NSAID) inhibits platelet aggregation less than non-selective NSAIDs but still injures the gastric mucosa. On warfarin, bleeding risk rises moderately.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

When unavoidable, use the minimum effective meloxicam dose for short courses under pantoprazole cover. Check INR at 1 week. For chronic needs, celecoxib or paracetamol are preferable.

Mechanism

Metronidazole inhibits CYP2C9 – S-warfarin (more active isomer) accumulates. INR doubles within 5-7 days.

Symptoms

Gum and nose bleeding, petechiae, haematuria within 5-10 days.

Management

Reduce warfarin by 25-50% from day 1. Check INR on days 3 and 7. After metronidazole withdrawal – retitrate up.

Mechanism

Metronidazole stereospecifically inhibits CYP2C9, the clearance route for S-warfarin. INR may double within 3–7 days of co-administration.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

For short metronidazole courses, empirically reduce warfarin by 20–30% and check INR 3–4 days after starting and 7 days after stopping the antibiotic. For prolonged therapy, titrate warfarin to INR.

Mechanism

Naproxen (NSAID) inhibits platelet aggregation and injures the gastric mucosa. On warfarin, GI bleeding risk multiplies, particularly in older patients and with prior peptic ulcer disease.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

Avoid chronic naproxen on warfarin. For analgesia, choose paracetamol. For chronic NSAID needs, use a selective COX-2 inhibitor (celecoxib) under pantoprazole cover.

Mechanism

Prednisolone (a systemic glucocorticoid) raises fibrinogen and clotting factors but can also alter warfarin metabolism through liver enzymes. The effect is unpredictable: INR may either drop or rise.

Symptoms

If INR drops: thromboembolic risk (deep vein thrombosis, stroke in atrial fibrillation). If INR rises: gum bleeding, epistaxis, bruising, GI bleeding (amplified by glucocorticoid-induced gastric mucosa injury).

Management

When prednisolone starts, is escalated, or is withdrawn, check INR at 1 week, then every 2 weeks until stable. Titrate warfarin to INR. PPI cover with pantoprazole is mandatory.

Mechanism

Propafenone inhibits CYP2C9 (S-warfarin metabolism). INR rises 25-50%.

Symptoms

Gum and nose bleeding, petechiae, haematuria within 5-10 days.

Management

Check INR 5-7 days after propafenone start. Warfarin usually reduced by 25%.

Mechanism

Rifampicin induces CYP2C9, CYP3A4 and CYP1A2 – all main warfarin metabolism pathways. Warfarin requirement rises 2–3 fold. After rifampicin withdrawal sensitivity returns over 2–4 weeks, with bleeding risk if the dose is not titrated back down.

Symptoms

During use: subtherapeutic INR, thrombosis risk. After rifampicin withdrawal: sudden INR rise, bleeding risk.

Management

Monitor INR twice weekly for the first 4 weeks of rifampicin; increase warfarin by 25–100% as needed. After rifampicin withdrawal, frequent INR monitoring and downward titration.

Mechanism

Complex mechanism. Ritonavir inhibits CYP3A4 but simultaneously induces CYP1A2, CYP2C9, and CYP2C19 (long-term effect). The net effect on warfarin varies: in some patients INR rises, in others it falls.

Symptoms

If INR rises: gum bleeding, epistaxis, bruising without trauma, blood in urine or stool. If INR drops: thromboembolic risk (deep vein thrombosis, stroke in atrial fibrillation).

Management

When ritonavir starts, is escalated, or is withdrawn, check INR at 1, 2, and 4 weeks and titrate warfarin to effect. Alternative anticoagulant in HIV-positive patients: low molecular weight heparin for short courses (no CYP interactions).

Mechanism

Sertraline (SSRI) blocks serotonin reuptake into platelets, depleting the platelet serotonin pool and impairing primary haemostasis. Even with a stable INR, GI bleeding risk roughly doubles in warfarin-treated patients.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

The combination is acceptable. PPI cover with pantoprazole and more frequent INR checks (every 2–4 weeks in the first month) are advisable. Alternative antidepressants with minimal platelet effect: mirtazapine or agomelatine.