A Textbook of Clinical Pharmacology and Therapeutics

208 ANTICOAGULANTS AND ANTIPLATELETDRUGS

appear in breast milk in clinically relevant amounts. There is
substantial variation between individuals in warfarint1/2. The R
and S enantiomers are metabolized differently in the liver. The
(active) S enantiomer is metabolized to 7-hydroxywarfarin by a
cytochrome P450-dependent mixed function oxidase, while the
less active R enantiomer is metabolized by soluble enzymes to
warfarin alcohols. Hepatic metabolism is followed by conjuga-
tion and excretion into the gut in the bile. Deconjugation and
reabsorption then occur, completing the enterohepatic cycle.
Knowledge of the plasma concentration of warfarinis not use-
ful in routine clinical practice because the pharmacodynamic
response (INR) can be measured accurately, but it is valuable in
the investigation of patients with unusual resistance to warfarin,
in whom it helps to distinguish poor compliance, abnormal phar-
macokinetics and abnormal sensitivity. Since warfarinacts by
inhibiting synthesis of active vitamin K-dependent clotting fac-
tors, the onset of anticoagulation following dosing depends on the
catabolism of preformed factors. Consequently, the delay between
dosing and effect cannot be shortened by giving a loading dose.

Drug interactions

Potentially important pharmacodynamic interactions with war-
farininclude those with antiplatelet drugs. Aspirinnot only
influences haemostasis by its effect on platelet function, but also
increases the likelihood of peptic ulceration, displaces warfarin
from plasma albumin, and in high doses decreases prothrombin
synthesis. Despite these potential problems, recent clinical exper-
ience suggests that with close monitoring the increased risk of
bleeding when low doses of aspirinare taken regularly with
warfarinmay be more than offset by clinical benefits to patients
at high risk of thromboembolism following cardiac valve
replacement. Broad-spectrum antibiotics potentiate warfarinby
suppressing the synthesis of vitamin K 1 by gut flora.
Several pharmacokinetic interactions with warfarinare of
clinical importance. Several non-steroidal anti-inflammatory
drugs (NSAIDs) and dextropropoxypheneinhibitwarfarin
metabolism. The gastrotoxic and platelet-inhibitory actions of
the NSAIDs further increase the risk of serious haemorrhage.
Cimetidine(but not ranitidine) and amiodaronealso potently
inhibitwarfarinmetabolism and potentiate its effect, as do
other inhibitors of hepatic cytochrome P450, such as erythro-
mycin,ciprofloxacinandomeprazole(Chapter 5). Drugs that
induce hepatic microsomal enzymes, including rifampicin,
carbamazepineandphenobarbital, increase warfarinmetabo-
lism and increase the dose required to produce a therapeutic
effect; furthermore, if the dose is not reduced when such con-
current therapy is discontinued, catastrophic over-anticoagu-
lation and haemorrhage may ensue.

ANTIPLATELET DRUGS

ASPIRIN

Aspirinis the main antiplatelet drug in clinical use. It works by
inhibiting the synthesis of thromboxane A 2 (TXA2), and its use

in the treatment and prevention of ischaemic heart disease is

described in Chapter 29. Numerous clinical trials have demon-

strated its efficacy. Efficacy is not directly related to dose and

low doses cause less adverse effects. TXA 2 is synthesized by

activated platelets and acts on receptors on platelets (causing

further platelet activation) and on vascular smooth muscle

(causing vasoconstriction). Figure 30.3 shows the pathway of its

biosynthesis from arachidonic acid. Aspirininhibits thrombox-

ane synthesis – it acetylates a serine residue in the active site of

constitutive (type I) cyclo-oxygenase (COX-1) in platelets, irre-

versibly blocking this enzyme. The most common side effect is

gastric intolerance and the most common severe adverse reac-

tion is upper gastro-intestinal bleeding. Both effects stem from

inhibition of COX-1 in the stomach, resulting in decreased pro-

duction of the gastroprotective PGE 2.

EPOPROSTENOL (PROSTACYCLIN)

Epoprostenolis the approved drug name for synthetic prosta-

cyclin, the principal endogenous prostaglandin of large artery

endothelium. It acts on specific receptors on the plasma mem-

branes of platelets and vascular smooth muscle. These are

coupled by G-proteins to adenylyl cyclase. Activation of this

enzyme increases the biosynthesis of cyclic adenosine

monophosphate (cAMP), which inhibits platelet aggregation

and relaxes vascular smooth muscle. Epoprostenolrelaxes

pulmonary as well as systemic vasculature, and this underpins

its use in patients with primary pulmonary hypertension. It (or

a related synthetic prostanoid, iloprost) is administered chron-

ically to such patients while awaiting heart–lung transplant-

ation. Epoprostenol inhibits platelet activation during

haemodialysis. It can be used with heparin, but is also effective

as the sole anticoagulant in this setting, and is used for

haemodialysis in patients in whom heparinis contraindicated.

It has also been used in other types of extracorporeal circuit

(e.g. during cardiopulmonary bypass). Epoprostenolhas been

Arachidonic acid

Prostaglandin

endoperoxides

(PGH 2 )

Prostacyclin Thromboxane A 2

Thromboxane A 2 synthase

Vasodilatation

Inhibition of platelet aggregation

Vasoconstriction

Platelet aggregation

Cyclo-oxygenase

Prostacyclin synthase

Figure 30.3:Formation of prostacyclin and thromboxane A 2

in vivo. These two products of arachidonic acid metabolism

exert competing and opposite physiological effects.