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CLINICAL PHARMACOKINETICS OF WARFARIN

1. Introduction:

Competitive antagonist to Vitamin K.

Inhibits synthesis of Vitamin K-dependent clotting factors (II, VII, IX and X).

Uses:

- Pulmonary embolism (PE).

- Deep venous thrombosis (DVT).

- Heart valve prosthesis or valvular heart disease.

NB: Warfarin is administered as a racemic mixture.

 

2. Pharmacokinetic Overview:

(a) Absorption:

- Rapid and extensive oral absorption

(F 1.0; peak levels between 2-6hrs).

(b) Distribution:

- Highly bound to albumin in plasma ( 99%).

- Apparent Vd 0.13L/kg (ie 10l).

(c) Elimination:

Warfarin is eliminated almost entirely (> 99%) by metabolism.

The drug has a low hepatic extraction ratio (ie. Cl fu . Cl)

Large inter-individual differences occur in Warfarin elimination rates (eg. t½ ranges from 10 - 45 hours).

The metabolic fates of the Warfarin enantiomers differ markedly:-

	S-Warfarin	R-Warfarin	Racemic Mixture
Metabolic pattern	90% Oxidation	60% Oxidation 40% Reduction	--
Approx Cl (l/hr)	0.30	0.15	0.20
Approx Vd (l)	10	10	10
Approx t½ (hr)	23	46	35
Relative Potency	5 x R-Warfarin

 

3. Anticoagulant Control:

Most frequently measured with the prothrombin time and the result reported as a prothrombin ratio (PR), obtained by dividing the treated patient’s prothrombin time by that of pooled normal plasma.

Therapeutic Anticoagulation:

PR of 2.0 to 4.0 (normal plasma prothrombin time is ~ 12 - 13s).

 

4. Adverse Effects:

- Haemorrhage is the major complication (~ 5 - 30% of patients).

Eg. Haematuria, epistaxis, uterine bleeding, petechial, or simple bruising, but GI, intra-cranial, and retroperitoneal bleeding may also occur.

- Bleeding is most likely and generally more serious when the PR is excessive.

- rx: temporary withdrawal or Warfarin administer Vitamin K.

 

5. Inter-Patient Variability in Response:

An enormous variation in pharmacological response is a characteristic feature of the clinical use of Warfarin.

The average patient requires a daily dose of about 5mg to maintain blood hypocoagulability but dosage requirements can vary from 1 - 25% daily.

Differences in both pharmacokinetics and pharmacodynamics contribute to this variation. Some well documented factors that influence the response to Warfarin are shown in the table:-

 

Table - Factors Influencing the Response to Warfarin
Factor	Effect ¶	Mechanism	Reference
Age	with increasing age	Enhanced receptor site sensitivity	O’Malley et al. (1977) Routledge et al. (1979) Shepherd et al. (1977)
Pregnancy		Increased blood coagulability	Breckenridge (1977)
Liver disease		Defective synthesis of clotting factors	Breckenridge (1977)
Heart failure		Reduced clotting factor synthesis	Breckenridge (1977)
Hyperthyroidism		Increased clotting factor degradation	O’Reilly and Aggeler (1970)
Concomitant drugs Eg. Barbiturates Phenylbutazone		Induced metabolism Inhibited metabolism	Scott and Orme (1983)
¶ Increased (­) or reduced (¯) anticoagulant response.

 

6. Plasma Level Monitoring:

Unfortunately, plasma level monitoring of Warfarin has a very limited role in dosage individualisation of the drug:-

(a) The therapeutic effect can be easily and reliably measured; and

(b) no direct relationship exists between plasma Warfarin concentrations and the anticoagulant response, since the clinical effect is not the drug’s primary pharmacological effect.

The observed clinical response is a function of both the synthesis and degradation rates of the Vitamin K-dependent clotting factors. Warfarin acts only to inhibit the synthesis of these factors.

 

7. Major Drug Interactions With Warfarin:

(i) Pharmacokinetic

(a) Absorption:

Cholestyramine

Binding of Warfarin - absorption

(b) Metabolism:

Amiodarone	metabolism
Co-trimoxazole	metabolism of S-isomer
Barbiturates, Carbamazipine, Rifampicin	metabolism
Cimetidine	metabolism of R-isomer
Metronidazole, Phenylbutazone, Sulphinpyrazone	metabolism of S-isomer

(ii) Pharmacodynamic:

Clofibrate - Potentiates inhibition of synthesis of Vitamin K-dependent clotting factors.

Salicylate - Hypoprothrombinaemic (>3g/day) and anti-platelet effects potentiate Warfarin.

 

8. Clinical Use of Warfarin:

Warfarin, in a daily dose of 10 - 15mg, is commenced on about the fifth day of heparin treatment. Daily dosage is then reduced as the PR approaches the optimum range. This may take 5 - 7 days, while plasma levels of clotting factors II, IX, and X are slowly decreasing.

Heparin infusion therapy is generally continued until the PR has been inside the therapeutic range for 24 hours. Warfarin therapy is then usually continued for 3-6 months, with regular reviews and dosage adjustments as needed.

At present, the measurement of plasma Warfarin levels is only useful to investigate abnormal anticoagulant responses and check compliance.