A Textbook of Clinical Pharmacology and Therapeutics

that the pharmacodynamic response is closely related to
plasma concentration and its pharmacokinetics are more pre-
dictable than those of heparin. Other hirudinanalogues have
also been synthesized. The place of hirudinand its analogues
in therapeutics is currently being established in clinical trials.

ORAL ANTICOAGULANTS

Warfarin, a racemic mixture of R and S stereoisomers, is the
main oral anticoagulant. Phenindioneis an alternative, but
has a number of severe and distinct adverse effects (see
below), so it is seldom used except in rare cases of idiosyn-
cratic sensitivity to warfarin.

Use

The main indications for oral anticoagulation are:

• deep vein thrombosis and pulmonary embolism;


• atrial fibrillation (see Chapter 32);


• mitral stenosis;


• prosthetic valve replacements.

Treatment of deep-vein thrombosis and pulmonary embolus
is started with a heparinto obtain an immediate effect. This is
usually continued for up to seven days to allow stabilization
of the warfarindose. The effect of warfarinis monitored by
measuring the international normalized ratio (INR). (The INR
is the prothrombin time corrected for an international stand-
ard for thromboplastin reagents. Prothrombin time varies
from laboratory to laboratory, but the INR in Oxford should be
the same as that in, say, Boston, facilitating dose adjustment in
these days of international travel.) Before starting treatment, a
baseline value of INR is determined. Provided that the base-
line INR is normal, anticoagulation is started by administer-
ing two consecutive doses 24 hours apart at the same time of
day (most conveniently in the evening). If the baseline INR is
prolonged or the patient has risk factors for bleeding (e.g. old
age or debility, liver disease, heart failure, or recent major
surgery), treatment is started with a lower dose. The INR is
measured daily, and on the morning of day 3 about 50% of
patients will be within the therapeutic range and the heparin
can be discontinued.
Once the situation is stable, the INR is checked weekly for
the first six weeks and then monthly or two-monthly if control
is good. The patient is warned to report immediately if there is
evidence of bleeding, to avoid contact sports or other situ-
ations that put them at increased risk of trauma, to avoid alco-
hol (or at least to restrict intake to a moderate and unvarying
amount), to avoid over-the-counter drugs (other than parac-
etamol) and to check that any prescription drug is not
expected to alter their anticoagulant requirement. Women of
childbearing age should be warned of the risk of teratogenesis
and given advice on contraception. Appropriate target ranges
for different indications reflect the relative risks of thrombo-
sis/haemorrhage in various clinical situations. Table 30.1 lists
the suggested ranges of INR that are acceptable for various
indications.

ANTICOAGULANTS 207

Mechanism of action

Oral anticoagulants interfere with hepatic synthesis of the

vitamin K-dependent coagulation factors II, VII, IX and X.

Preformed factors are present in blood so, unlike heparin, oral

anticoagulants are not effective in vitro and are only active

when given in vivo. Functional forms of factors II, VII, IX and

X contain residues of γ-carboxyglutamic acid. This is formed

by carboxylation of a glutamate residue in the peptide chain of

the precursor. This is accomplished by cycling of vitamin K

between epoxide, quinone and hydroquinone forms. This

cycle is interrupted by warfarin, which is structurally closely

related to vitamin K, and inhibits vitamin K epoxide reductase.

Adverse effects

1. HaemorrhageIf severe, vitamin K is administered
   intravenously, but its effect is delayed and it renders the
   patient resistant to re-warfarinization. Life-threatening
   bleeding requires administration of fresh frozen plasma,
   or specific coagulation factor concentrates, with advice
   from a haematologist.
   2.Other adverse actions of warfarininclude:
   
   
   • teratogenesis;
   
   
   • rashes;
   
   
   • thrombosisis a rare but severe paradoxical effect of
     warfarinand can result in extensive tissue necrosis.
     Vitamin K is involved in the biosynthesis of
     anticoagulant proteins C and S. Protein C has a short
     elimination half-life, and when warfarintreatment is
     started, its plasma concentration declines more rapidly
     than that of the vitamin K-dependent coagulation
     factors, so the resulting imbalance can temporarily
     favour thrombosis.
     3.Adverse effects of phenindione:
   
   
   • interference with iodine uptake by the thyroid;
   
   
   • renal tubular damage;
   
   
   • hepatitis;
   
   
   • agranulocytosis;
   
   
   • dermatitis;
   
   
   • secretion into breast milk.
   
   
   
   

Pharmacokinetics

Following oral administration, absorption is almost complete

and maximum plasma concentrations are reached within

two to eight hours. Approximately 97% is bound to plasma

albumin.Warfarindoes gain access to the fetus, but does not

Table 30.1:Suggested acceptable INR ranges for various indications

Clinical state Target INR range

Prophylaxis of DVT, including surgery on 2.0–2.5

high-risk patients

Treatment of DVT/PE/systemic embolism/ 2.0–3.0

mitral stenosis with embolism

Recurrent DVT/PE while on warfarin; 3.0–4.5

mechanical prosthetic heart valve