A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
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206 ANTICOAGULANTS AND ANTIPLATELET DRUGS<br />
heparin should be used rather than low-molecular-weight<br />
preparations in patients with significant renal dysfunction.<br />
UNFRACTIONATED HEPARIN<br />
Unfractionated heparin has been replaced by LMWH for most<br />
indications (see above), but remains important for patients with<br />
impaired or rapidly changing renal function. It is administered<br />
either as an intravenous infusion (to treat established disease)<br />
or by subcutaneous injection (as prophylaxis). Intramuscular<br />
injection must not be used because it causes haematomas.<br />
Intermittent bolus intravenous injections cause a higher frequency<br />
<strong>of</strong> bleeding complications than does constant intravenous<br />
infusion. For prophylaxis, a low dose is injected<br />
subcutaneously into the fatty layer <strong>of</strong> the lower abdomen 8- or<br />
12-hourly. Coagulation times are not routinely monitored when<br />
heparin is used prophylactically in this way. Continuous intravenous<br />
infusion is initiated with a bolus followed by a constant<br />
infusion in saline or 5% glucose. Treatment is monitored by<br />
measuring the activated partial thromboplastin time (APTT)<br />
four to six hours after starting treatment <strong>and</strong> then every six<br />
hours, until two consecutive readings are within the target<br />
range, <strong>and</strong> thereafter at least daily. Dose adjustments are made<br />
to keep the APTT ratio (i.e. the ratio between the value for the<br />
patient <strong>and</strong> the value <strong>of</strong> a control) in the range 1.5–2.5.<br />
Mechanism <strong>of</strong> action<br />
The main action <strong>of</strong> heparin is on the coagulation cascade. It<br />
works by binding to antithrombin III, a naturally occurring<br />
inhibitor <strong>of</strong> thrombin <strong>and</strong> other serine proteases (factors IXa,<br />
Xa, XIa <strong>and</strong> XIIa), <strong>and</strong> enormously potentiating its inhibitory<br />
action. Consequently it is effective in vitro, as well as in vivo,<br />
but is ineffective in (rare) patients with inherited or acquired<br />
deficiency <strong>of</strong> antithrombin III. A lower concentration is required<br />
to inhibit factor Xa <strong>and</strong> the other factors early in the cascade<br />
than is needed to antagonize the action <strong>of</strong> thrombin, providing<br />
the rationale for low-dose heparin in prophylaxis. Heparin also<br />
has complex actions on platelets. As an antithrombin drug, it<br />
inhibits platelet activation by thrombin, but it can also cause<br />
platelet activation <strong>and</strong> paradoxical thrombosis by an immune<br />
mechanism (see below).<br />
Adverse effects<br />
Adverse effects include:<br />
• bleeding – the chief side effect;<br />
• thrombocytopenia <strong>and</strong> thrombosis – a modest decrease in<br />
platelet count within the first two days <strong>of</strong> treatment is<br />
common (approximately one-third <strong>of</strong> patients), but<br />
clinically unimportant. By contrast, severe thrombocytopenia<br />
(usually occurring between two days <strong>and</strong><br />
two weeks) is rare <strong>and</strong> autoimmune in origin;<br />
• osteoporosis <strong>and</strong> vertebral collapse – this is a rare<br />
complication described in young adult patients receiving<br />
heparin for longer than ten weeks (usually longer than<br />
three months);<br />
• skin necrosis at the site <strong>of</strong> subcutaneous injection after<br />
several days treatment;<br />
• alopecia;<br />
• hypersensitivity reactions, including chills, fever, urticaria,<br />
bronchospasm <strong>and</strong> anaphylactoid reactions, occur rarely;<br />
• hypoaldosteronism – heparin inhibits aldosterone<br />
biosynthesis. This is seldom clinically significant.<br />
Management <strong>of</strong> heparin-associated bleeding<br />
• Administration should be stopped <strong>and</strong> the bleeding site<br />
compressed.<br />
• Protamine sulphate is given as a slow intravenous injection<br />
(rapid injection can cause anaphylactoid reactions). It is <strong>of</strong><br />
no value if it is more than three hours since heparin was<br />
administered <strong>and</strong> is only partly effective for LMWH.<br />
Pharmacokinetics<br />
Heparin is not absorbed from the gastro-intestinal tract. The<br />
elimination half-life (t 1/2 ) <strong>of</strong> unfractionated heparin is in the<br />
range 0.5–2.5 hours <strong>and</strong> is dose dependent, with a longer t 1/2<br />
at higher doses <strong>and</strong> wide inter-individual variation. The short<br />
t 1/2 probably reflects rapid uptake by the reticulo-endothelial<br />
system <strong>and</strong> there is no reliable evidence <strong>of</strong> hepatic metabolism.<br />
Heparin also binds non-specifically to endothelial cells,<br />
<strong>and</strong> to platelet <strong>and</strong> plasma proteins, <strong>and</strong> with high affinity to<br />
platelet factor 4, which is released during platelet activation.<br />
The mechanism underlying the dose-dependent clearance is<br />
unknown. The short t 1/2 means that a stable plasma concentration<br />
is best achieved by a constant infusion rather than by<br />
intermittent bolus administration. Neither unfractionated<br />
heparin nor LMWH cross the placental barrier <strong>and</strong> heparin is<br />
used in pregnancy in preference to the coumadins because <strong>of</strong><br />
the teratogenic effects <strong>of</strong> warfarin <strong>and</strong> other oral anticoagulants.<br />
There is a paucity <strong>of</strong> evidence on entry <strong>of</strong> LMWH to<br />
milk <strong>and</strong> breast-feeding is currently contraindicated.<br />
FONDAPARINUX<br />
Fondaparinux is a synthetic pentasaccharide that selectively<br />
binds <strong>and</strong> inhibits factor Xa. It is more effective than lowmolecular-weight<br />
heparin in preventing venous thromboembolism<br />
in patients undergoing orthopaedic surgery, <strong>and</strong> is<br />
as effective as heparin or LMWH in patients with established<br />
deep vein thrombosis or pulmonary embolism. In the setting <strong>of</strong><br />
acute coronary syndrome, fondaparinux may be as effective in<br />
reducing ischaemic events, <strong>and</strong> at the same time safer in terms<br />
<strong>of</strong> bleeding complications, as compared with LMWH (the<br />
OASIS-5 trial). It is administered by subcutaneous injection<br />
once a day, at a dose that depends on body weight. Its precise<br />
place as compared with LMWH outside <strong>of</strong> the orthopaedic setting,<br />
is currently debated.<br />
HIRUDIN<br />
Hirudin is the anticoagulant <strong>of</strong> the leech <strong>and</strong> can now be synthesized<br />
in bulk by recombinant DNA technology. It is a direct<br />
inhibitor <strong>of</strong> thrombin <strong>and</strong> is more specific than heparin.<br />
Unlike heparin, it inhibits clot-associated thrombin <strong>and</strong> is not<br />
dependent on antithrombin III. Early human studies showed