Clinical Pharmacology and Therapeutics

ANTICOAGULANTS 207
that the pharmacodynamic response is closely related to
plasma concentration and its pharmacokinetics are more predictable
than those of heparin. Other hirudin analogues have
also been synthesized. The place of hirudin and 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. Phenindione is an alternative, but
has a number of severe and distinct adverse effects (see
below), so it is seldom used except in rare cases of idiosyncratic
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 heparin to obtain an immediate effect. This is
usually continued for up to seven days to allow stabilization
of the warfarin dose. The effect of warfarin is monitored by
measuring the international normalized ratio (INR). (The INR
is the prothrombin time corrected for an international standard
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 baseline
INR is normal, anticoagulation is started by administering
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 situations
that put them at increased risk of trauma, to avoid alcohol
(or at least to restrict intake to a moderate and unvarying
amount), to avoid over-the-counter drugs (other than paracetamol)
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 thrombosis/haemorrhage
in various clinical situations. Table 30.1 lists
the suggested ranges of INR that are acceptable for various
indications.
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
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. Haemorrhage If 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 warfarin include:
• teratogenesis;
• rashes;
• thrombosis is a rare but severe paradoxical effect of
warfarin and 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 warfarin treatment 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. Warfarin does gain access to the fetus, but does not