A Textbook of Clinical Pharmacology and Therapeutics

ANTICOAGULANTS INPREGNANCY ANDPUERPERIUM 209

used with apparent benefit in acute retinal vessel thrombosis
and in patients with critical limb ischaemia and with platelet
consumption due to multiple organ failure, especially those
with meningococcal sepsis. Rigorous proof of efficacy is diffi-
cult to provide in such settings. Epoprostenolis infused intra-
venously (or, in the case of haemodialysis, into the arterial limb
supplying the dialyzer). It is administered with frequent moni-
toring of blood pressure and heart rate during the period of
dose titration. A modest reduction in diastolic pressure with an
increase in systolic pressure (i.e. increased pulse pressure) and
reflex tachycardia is the expected and desired haemodynamic
effect. If bradycardia and hypotension occur, the infusion should
be temporarily discontinued. The short half-life of epoprostenol
(approximately three minutes) allows for its rapid titration
according to haemodynamic response. Bleeding complications
are unusual.

DIPYRIDAMOLE

Use

Dipyridamolewas introduced as a vasodilator, but provokes
rather than prevents angina (via a steal mechanism). It is used
acutely as in stress tests for ischaemic heart disease (e.g. com-
bined with nuclear medicine myocardial perfusion scanning).
It is also used chronically, combined with aspirin, for its
antiplatelet effect in patients with cerebrovascular disease on
the basis of the European Stroke Prevention Study 2.

Mechanism of action

Dipyridamole inhibits phosphodiesterase which leads to
reduced breakdown of cAMP, and inhibits adenosine uptake
with consequent enhancement of the actions of this mediator
on platelets and vascular smooth muscle.

Drug interactions

Dipyridamoleincreases the potency and duration of action of
adenosine. This may be clinically important in patients receiv-
ingdipyridamolein whom adenosine is considered for treat-
ment of dysrhythmia.

CLOPIDOGREL

Use

Clopidogrel is combined with aspirin to treat patients
with acute coronary syndromes/myocardial infarction and
following percutaneous coronary intervention with stent
placement (Chapter 29). It is also used instead of aspirinin
patients with a contraindication to aspirinand may be mar-
ginally superior to aspirinfor primary prevention (CAPRIE
study).

Mechanism of action

Clopidogrelis an inactive prodrug that is converted in the
liver to an active metabolite that binds to, and irreversibly
inhibits, platelet ADP receptors. Like aspirin, the antiplatelet
effect of clopidogrelis prolonged and lasts for the life of the
platelet.

Adverse effects

Adverse effects include:

• haemorrhage (including intracranial, especially in patients
  with uncontrolled hypertension);


• nausea, vomiting, constipation or diarrhoea;


• headache;


• dizziness, vertigo;


• rash, pruritus.

Contraindications

Contraindications include the following:

• active bleeding;


• breast-feeding;


• use with caution in liver impairment, renal impairment
  and pregnancy.

INHIBITORS OF GLYCOPROTEIN IIb/IIIa

Abciximab, a monoclonal antibody to glycoprotein IIb/IIIa,

when used as an adjunct to heparinandaspirinreduces

occlusion following angioplasty, but can cause bleeding. Its

use is currently restricted to patients undergoing angioplasty

in whom there is a high risk of acute coronary thrombosis.

Hypersensitivity reactions can occur. Alternative small mol-

ecule inhibitors of glycoprotein IIb/IIIa are eptifibatideand

tirofiban; they are used under cardiology supervision in

patients with early myocardial infarction.

ANTICOAGULANTS IN PREGNANCY AND

PUERPERIUM

There is an increased risk of thromboembolism in pregnancy

and women at risk (e.g. those with prosthetic heart valves)

must continue to be anticoagulated. However, warfarin

crosses the placenta and when taken throughout pregnancy

will result in complications in about one-third of cases (16% of

fetuses will be spontaneously aborted or stillborn, 10% will

have post-partum complications (usually due to bleeding)

and 7% will suffer teratogenic effects).

Heparin(both unfractionated and LMWH) does not cross the

placenta and may be self-administered subcutaneously. Long-

termheparinmay cause osteoporosis and there is an increased

risk of retroplacental bleeding. One approach to the management

of pregnancy in women on anticoagulants is to change to sub-

cutaneous low-molecular-weight heparinfrom the time of the

first missed period and remain on this until term, maintaining

a high intake of elemental calcium, as well as adequate but not

excessive intake of vitamin D. Around the time of delivery, it may

be withheld and restarted immediately post-partum, together

withwarfarinand continued until the full effect of warfarinis

re-established. Warfarindoes not enter breast milk to a signifi-

cant extent and mothers may nurse their babies while antico-

agulated on warfarin(in contrast to those on phenindione).