Coumarins systemic

Author: Prof. Dr. med. Peter Altmeyer

Last updated on: 12.11.2021

Synonym(s)

Coumarin derivatives; Phenprocoumon; Vitamin K antagonists

Definition
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Coumarins are vitamin K antagonists (see also Cumnarin general). The basic structure is the 4-hydroxycoumarin, variants derived from it are the dicumarins like:

Dicumarol
Tromexan

and the monocoumaroles such as:

Coumar
Coumarin (warfarin)
Sintron

Coumarins are almost completely resorbed enterally. The plasma protein binding is >90%. The half-life for Marcumar is 6-7 days, for Warfarin 33-45 hours. Vitamin K antagonists (VKA) were the cornerstone of anticoagulation therapy for over 50 years before newer agents, the non-vitamin K-dependent oral anticoagulants (NOAK), became available for clinical use.

Indication
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Recurrence prophylaxis after thromboses and embolisms.

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Limited indication
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Abortus imminens, alcoholism, age > 65 years, epilepsy, angiography, blood formation disorders, severe diabetes, decompensated heart failure, pericardial effusion, vasculitis.

Dosage and method of use
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See Table 1.

Undesirable effects
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Remember!

Bleeding complications (antidote: vitamin K 20 mg/day p.o., in case of life-threatening bleeding: 2.000 IU prothrombin complex as short infusion i.v., repeated every 6-8 hours over 48 hours as well as vitamin K 20 mg/day p.o. until the quick value is stabilized). Also: Allergic reactions, pruritus, hair loss, coumarin necrosis, toxic liver damage, intestinal necrosis.

Interactions
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See Table 1.

Contraindication
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Pregnancy (chondrodysplasia), lactation, aneurysms, bleeding tendency, chronic inflammatory intestinal diseases, florid endocarditis lenta, brain injuries, hypertension (> 180 mm Hg systolic or 105 mm Hg diastolic), visceral carcinomas, leukaemia with bleeding tendency, cavernous pulmonary tuberculosis, ulcers ventriculi or duodeni, manifest renal insufficiency, kidney stones, surgery on CNS, eye, prostate, retinopathy with risk of bleeding, apoplexy, thrombocytopenic purpura, severe thrombocytopenia, open wounds.

Preparations
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Marcumar, Phenpro-ratiopharm, Coumadin

Note(s)
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Remember! For therapy control determination of the Quick- or INR-value every 3-4 weeks!

Patientinformation
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Remember! All patients who receive coumarins should carry an identification card with the daily dose and the quick values (INR values). Patients should be informed in detail about foods that contain a particularly high proportion of vitamin K (antagonizes coumarin effect) and avoid these foods!

Tables
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Major interactions of coumarins

Allopurinol	Bleeding tendency ↑
Anion exchange resins	Coumarin effects ↓
Antirheumatic agents, nonsteroidal	Bleeding tendency ↑, risk of hemorrhagic peptic ulcers
Barbiturates	Coumarin effect ↓
Benzodiarone	Bleeding tendency ↑
Carbamazepine	Coumarin effect ↓
Cephalosporins	Bleeding tendency ↑
Ciclosporin A	Coumarin effect ↓
Cimetidine	Bleeding tendency ↑ with warfarin
Ergotamine	Bleeding tendency ↑
Fibrates	Bleeding tendency ↑
Fibrinolytics	Bleeding tendency ↑
Heparin	Bleeding tendency ↑
Contraceptives, oral	Coumarin effect ↓
Food	Coumarin effect ↓ due to broccoli, beetroot, avocado
Penicillins i.v.	Bleeding tendency ↑
Thyroid hormones	Bleeding tendency ↑
Sulfonylureas	Hypoglycemia
Valproic acid	Bleeding tendency ↑

Major coumarins, dosage, pharmacology.

Substance	HWZ	Dosage	Preparation
Phenprocoumon	160 hrs.	Initial: Day 1: 6-18 mg; Day 2: 6-12 mg. From day 3 dosage based on INR/Quick value: Quick > 30%: Up to 4.5 mg; Quick 20-30%: Max. 1.5 mg.	Marcumar
		Maintenance dose: 1.5-6 mg/day

Warfarin	42 hr.	2.5-10 mg/day for 2-4 days	Coumadin
		Maintenance dose: 2-10 mg/day (based on Quick/INR)
The dosage must be monitored and individually adjusted by determining the thromboplastin time (INR/Quick value); the initial determination must always be made before the start of treatment! The aim is to achieve an effective range of INR 2.0-3.5 or a Quick value of 15-30% of the norm, depending on the type of disease. Daily monitoring of therapy using the INR method. INR values to aim for: Treatment of deep vein thrombosis, pulmonary embolism, thromboembolism with atrial fibrillation: 2.0-3.0. In the case of recurrent deep vein thrombosis, pulmonary embolism, arterial diseases including myocardial infarction: In patients with a high risk of thromboembolism, it may be necessary to aim for a higher INR value. However, an INR value > 4.0 does not provide any additional therapeutic benefit.

Vitamin K content of important foods

	100 g contain	Vitamin K (mg)
Prohibited foods	Broccoli	0,2
	Kale, fresh	0,7
	Cabbage, fresh (savoy, rose, flower, kale)	0,2
	Liver (cod, codfish)	0,1
	Liver (beef, ox, sheep, veal)	0,3
	Muscle (beef, sheep, pork)	0,2
	Salad, fresh	0,1
	Asparagus, fresh	0,4
	Spinach, fresh	0,4

Allowed food	Bananas	0,002
	Peas, beans	0,02
	Strawberries, rose hips	0,01
	Chicken egg, whole	0,05
	Potatoes	0,05
	Cow's milk	0,004
	Liver (pork)	0,03
	Tomatoes	0,008