A Textbook of Clinical Pharmacology and Therapeutics

206 ANTICOAGULANTS AND ANTIPLATELET DRUGS
heparin should be used rather than low-molecular-weight
preparations in patients with significant renal dysfunction.
UNFRACTIONATED HEPARIN
Unfractionated heparin has been replaced by LMWH for most
indications (see above), but remains important for patients with
impaired or rapidly changing renal function. It is administered
either as an intravenous infusion (to treat established disease)
or by subcutaneous injection (as prophylaxis). Intramuscular
injection must not be used because it causes haematomas.
Intermittent bolus intravenous injections cause a higher frequency
of bleeding complications than does constant intravenous
infusion. For prophylaxis, a low dose is injected
subcutaneously into the fatty layer of the lower abdomen 8- or
12-hourly. Coagulation times are not routinely monitored when
heparin is used prophylactically in this way. Continuous intravenous
infusion is initiated with a bolus followed by a constant
infusion in saline or 5% glucose. Treatment is monitored by
measuring the activated partial thromboplastin time (APTT)
four to six hours after starting treatment and then every six
hours, until two consecutive readings are within the target
range, and thereafter at least daily. Dose adjustments are made
to keep the APTT ratio (i.e. the ratio between the value for the
patient and the value of a control) in the range 1.5–2.5.
Mechanism of action
The main action of heparin is on the coagulation cascade. It
works by binding to antithrombin III, a naturally occurring
inhibitor of thrombin and other serine proteases (factors IXa,
Xa, XIa and XIIa), and enormously potentiating its inhibitory
action. Consequently it is effective in vitro, as well as in vivo,
but is ineffective in (rare) patients with inherited or acquired
deficiency of antithrombin III. A lower concentration is required
to inhibit factor Xa and the other factors early in the cascade
than is needed to antagonize the action of thrombin, providing
the rationale for low-dose heparin in prophylaxis. Heparin also
has complex actions on platelets. As an antithrombin drug, it
inhibits platelet activation by thrombin, but it can also cause
platelet activation and paradoxical thrombosis by an immune
mechanism (see below).
Adverse effects
Adverse effects include:
• bleeding – the chief side effect;
• thrombocytopenia and thrombosis – a modest decrease in
platelet count within the first two days of treatment is
common (approximately one-third of patients), but
clinically unimportant. By contrast, severe thrombocytopenia
(usually occurring between two days and
two weeks) is rare and autoimmune in origin;
• osteoporosis and vertebral collapse – this is a rare
complication described in young adult patients receiving
heparin for longer than ten weeks (usually longer than
three months);
• skin necrosis at the site of subcutaneous injection after
several days treatment;
• alopecia;
• hypersensitivity reactions, including chills, fever, urticaria,
bronchospasm and anaphylactoid reactions, occur rarely;
• hypoaldosteronism – heparin inhibits aldosterone
biosynthesis. This is seldom clinically significant.
Management of heparin-associated bleeding
• Administration should be stopped and the bleeding site
compressed.
• Protamine sulphate is given as a slow intravenous injection
(rapid injection can cause anaphylactoid reactions). It is of
no value if it is more than three hours since heparin was
administered and is only partly effective for LMWH.
Pharmacokinetics
Heparin is not absorbed from the gastro-intestinal tract. The
elimination half-life (t1/2) of unfractionated heparin is in the
range 0.5–2.5 hours and is dose dependent, with a longer t1/2 at higher doses and wide inter-individual variation. The short
t1/2 probably reflects rapid uptake by the reticulo-endothelial
system and there is no reliable evidence of hepatic metabolism.
Heparin also binds non-specifically to endothelial cells,
and to platelet and plasma proteins, and with high affinity to
platelet factor 4, which is released during platelet activation.
The mechanism underlying the dose-dependent clearance is
unknown. The short t1/2 means that a stable plasma concentration
is best achieved by a constant infusion rather than by
intermittent bolus administration. Neither unfractionated
heparin nor LMWH cross the placental barrier and heparin is
used in pregnancy in preference to the coumadins because of
the teratogenic effects of warfarin and other oral anticoagulants.
There is a paucity of evidence on entry of LMWH to
milk and breast-feeding is currently contraindicated.
FONDAPARINUX
Fondaparinux is a synthetic pentasaccharide that selectively
binds and inhibits factor Xa. It is more effective than lowmolecular-weight
heparin in preventing venous thromboembolism
in patients undergoing orthopaedic surgery, and is
as effective as heparin or LMWH in patients with established
deep vein thrombosis or pulmonary embolism. In the setting of
acute coronary syndrome, fondaparinux may be as effective in
reducing ischaemic events, and at the same time safer in terms
of bleeding complications, as compared with LMWH (the
OASIS-5 trial). It is administered by subcutaneous injection
once a day, at a dose that depends on body weight. Its precise
place as compared with LMWH outside of the orthopaedic setting,
is currently debated.
HIRUDIN
Hirudin is the anticoagulant of the leech and can now be synthesized
in bulk by recombinant DNA technology. It is a direct
inhibitor of thrombin and is more specific than heparin.
Unlike heparin, it inhibits clot-associated thrombin and is not
dependent on antithrombin III. Early human studies showed