Pharmacology
Cardiovascular
An 80 year old man requires treatment with an antibiotic. He takes warfarin for atrial fibrillation. What antibiotic is the safest choice for this patient:
Answer:
Alterations in INR are common among patients who receive antibiotics, especially those prescribed antibiotics at high risk of interacting with warfarin. Cephalexin and clindamycin, which have minimal interactions with warfarin, are considered low-risk antibiotics. Antibiotics at high risk of interacting with warfarin, and enhancing its anticoagulant effects include:- Azithromycin
- Quinolones e.g. ciprofloxacin, levofloxacin
- Macrolides e.g. clarithromycin, erythromycin
- Metronidazole
- Sulfonamides e.g. co-trimoxazole
- Trimethoprim
- Tetracyclines e.g. doxycycline
Warfarin
Pharmacology / Cardiovascular
Last Updated: 6th December 2020
The main use of anticoagulants is to prevent thrombus formation or extension of an existing thrombus in the slower-moving venous side of the circulation, where the thrombus consists of a fibrin web enmeshed with platelets and red cells. Anticoagulants are of less use in preventing thrombus formation in arteries, for in faster-flowing vessels thrombi are composed mainly of platelets with little fibrin.
Mechanism of Action
Warfarin is a vitamin K antagonist and will reduce the activity of vitamin-K dependent clotting factors (factors VII, IX, X and II) and of protein C and S.
Both the PT and APTT are usually prolonged but the PT is grossly prolonged and the APTT only mildly.
Indications
Warfarin is licensed for:
- Prophylaxis of systemic embolism in people with rheumatic heart disease and atrial fibrillation
- Prophylaxis after insertion of prosthetic heart valves
- Prophylaxis and treatment of venous thrombosis and pulmonary embolism
- Transient attacks of cerebral ischaemia
Warfarin takes at least 48 to 72 hours for the anticoagulant effect to develop and if an immediate effect is required, heparin must be given concomitantly and continued for at least 5 days and until the INR is greater or equal to 2.0 for more than 24 hours. The duration of treatment is dependent on the indication.
Contraindications
- Haemorrhagic stroke
- Clinically significant bleeding
- Within 72 hours of major surgery with risk of severe bleeding
- Within 48 hours postpartum
- Pregnancy
- Untreated bleeding disorders for example, thrombocytopenia, haemophilia, liver failure and renal failure
- Potential bleeding lesions for example; active peptic ulcer; oesophageal varices; aneurysm; proliferative retinopathy; recent organ biopsy; recent trauma or surgery to head, orbit, or spine; recent stroke; confirmed intracranial or intraspinal bleed
Cautions
Warfarin should be used with caution in any patient at increased risk of haemorrhage with risk factors including:
- People aged over 65 years
- Previous bleeding episode, history of gastrointestinal bleeding or anaemia
- Recent ischaemic stroke, hypertension, heart disease, cerebrovascular disease, renal disease, liver disease, active peptic ulcer
- Recent or imminent surgery or trauma
- Excessive alcohol intake, frequent or significant falls
- Regular use of NSAIDs or other drugs that increase risk of bleeding
Side Effects
- The most common adverse effect of warfarin is bleeding
- Other common adverse effects of warfarin include nausea, vomiting, diarrhoea, jaundice, hepatic dysfunction, pancreatitis, pyrexia, alopecia, purpura, and rash
- Skin necrosis is a rare but serious adverse effect of warfarin; treatment with warfarin should be stopped if warfarin related skin necrosis is suspected
- Calciphylaxis is a rare, but a very serious condition that causes vascular calcification and cutaneous necrosis
Monitoring
The prothrombin time, reported as the INR is used to monitor warfarin therapy; the target INR is dependent on the indication.
Warfarin may need to be omitted for a couple of doses if the INR rises above the target range or even reversed if the INR is > 8.0 or there are signs of bleeding. Phytomenadione (vitamin K) can be given as a specific antidote to warfarin or in cases of major bleeding, dried prothrombin complex (factors II, VII, IX, and X); if dried prothrombin complex is unavailable, fresh frozen plasma can be given but is less effective.
| Scenario | Management |
|---|---|
| INR 5.0 - 8.0, no bleeding | Withhold 1 - 2 doses of warfarin and reduce subsequent maintenance dose |
| INR 5.0 - 8.0, minor bleeding | Stop warfarin, give phytomenadione intravenously, restart warfarin when INR < 5.0 |
| INR > 8.0, no bleeding | Stop warfarin, give phytomenadione orally, restart warfarin when INR < 5.0 |
| INR > 8.0, minor bleeding | Stop warfarin, give phytomenadione intravenously, repeat dose if INR still too high after 24 h, restart warfarin when INR < 5.0 |
| Major bleeding | Stop warfarin, give phytomenadione intravenously, give dried prothrombin complex |
Drug Interactions
| Increased anticoagulant effect | Decreased anticoagulant effect |
|---|---|
| Acute alcohol consumption | Tricyclic antidepressants (can increase or decrease) |
| Amiodarone | St John's wort |
| Antibiotics(co-trimoxazole, metronidazole, quinolones, macrolides) | Vitamin K-containing vitamin complexes, some enteral feeds, mineral supplements, and green vegetables |
| Antidepressants (SSRIs, SNRIs, TCAs) | Rifampicin |
| Azoles | Carbamazepine |
| Cranberry juice | Phenobarbital |
| Corticosteroids | Primidone |
| Fibrates | Azathioprine |
| NSAIDs | Phenytoin |
| Thyroxine | Griseofulvin |
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
