A Textbook of Clinical Pharmacology and Therapeutics

heparinshould be used rather than low-molecular-weight
preparations in patients with significant renal dysfunction.

UNFRACTIONATED HEPARIN

Unfractionatedheparinhas been replaced by LMWH for most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 fre-
quency of bleeding complications than does constant intra-
venous 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
heparinis used prophylactically in this way. Continuous intra-
venous 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 heparinis 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 heparinin 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 thrombo-
  cytopenia (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
  heparinfor 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 – heparininhibits 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 heparinwas
  administered and is only partly effective for LMWH.

Pharmacokinetics

Heparinis not absorbed from the gastro-intestinal tract. The

elimination half-life (t1/2) of unfractionated heparinis 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

t1/2probably reflects rapid uptake by the reticulo-endothelial

system and there is no reliable evidence of hepatic metab-

olism.Heparinalso 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 t1/2means that a stable plasma concen-

tration is best achieved by a constant infusion rather than by

intermittent bolus administration. Neither unfractionated

heparinnor LMWH cross the placental barrier and heparinis

used in pregnancy in preference to the coumadins because of

the teratogenic effects of warfarinand other oral anticoagu-

lants. There is a paucity of evidence on entry of LMWH to

milk and breast-feeding is currently contraindicated.

FONDAPARINUX

Fondaparinuxis a synthetic pentasaccharide that selectively

binds and inhibits factor Xa. It is more effective than low-

molecular-weight heparinin preventing venous thrombo-

embolism in patients undergoing orthopaedic surgery, and is

as effective as heparinor LMWH in patients with established

deep vein thrombosis or pulmonary embolism. In the setting of

acute coronary syndrome, fondaparinuxmay 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 set-

ting, is currently debated.

HIRUDIN

Hirudinis the anticoagulant of the leech and can now be syn-

thesized in bulk by recombinant DNA technology. It is a direct

inhibitor of thrombin and is more specific than heparin.

Unlikeheparin, it inhibits clot-associated thrombin and is not

dependent on antithrombin III. Early human studies showed

206 ANTICOAGULANTS AND ANTIPLATELETDRUGS