Clinical Pharmacology and Therapeutics

ANTICOAGULANTS IN PREGNANCY AND PUERPERIUM 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 difficult
to provide in such settings. Epoprostenol is infused intravenously
(or, in the case of haemodialysis, into the arterial limb
supplying the dialyzer). It is administered with frequent monitoring
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
Dipyridamole was 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. combined
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
Dipyridamole increases the potency and duration of action of
adenosine. This may be clinically important in patients receiving
dipyridamole in whom adenosine is considered for treatment
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 aspirin in
patients with a contraindication to aspirin and may be marginally
superior to aspirin for primary prevention (CAPRIE
study).
Mechanism of action
Clopidogrel is 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 clopidogrel is 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 heparin and aspirin reduces
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 molecule
inhibitors of glycoprotein IIb/IIIa are eptifibatide and
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. Longterm
heparin may 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 subcutaneous
low-molecular-weight heparin from 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
with warfarin and continued until the full effect of warfarin is
re-established. Warfarin does not enter breast milk to a significant
extent and mothers may nurse their babies while anticoagulated
on warfarin (in contrast to those on phenindione).