Anticoagulant drugs, as their name suggests, prevent the clotting – or coagulation – of blood. There are two types of anticoagulant drug – injectable and oral, both of which have proved their worth on the clinical scene. Anticoagulants are used for a number of purposes, chief among them being venous thromboembolism. They are also used in the treatment of congestive heart failure, stroke, and genetic hypercoagulability. Perhaps unsurprisingly, anticoagulants increase the risk of bleeding, particularly in patients of an advanced age. The following section explores the pharmacology of anticoagulant drugs (injectables) – detailing the various classes, their mechanism of action, pharmacokinetics and – finally – their unwanted effects.
Pharmacology of Anticoagulant Drugs
Here, we’ll assess the pharmacology of the first class in this list:
- Injectable anticoagulants (heparins, hirudins, fondaparinux)
- Oral anticoagulants (vitamin K antagonists)
- Novel oral anticoagulants (dabigatran, rivaroxaban, apixaban)
In later sections we will look at oral anticoagulants and novel oral anticoagulants, but for now we’ll deal solely with the injectable anticoagulants – heparins, hirudins, and fondaparinux. This group of anticoagulants is widely used in clinical practice, not least because of how reliable they’ve proven to be over the years. Our study below of injectable anticoagulant of drugs is not, however, an exhaustive account. Be sure to read around the topic.
Injectable anticoagulants include heparins, hirudins, and fondaparinux.
Heparins are a family of glycosaminoglycans found naturally in cells such as basophils and mast cells. Depending on the type, they have molecular weights in the region of 3,000-30,000 Da. Heparin is available in two main forms: as unfractionated heparin or as low-molecular-weight heparin (LMWH) – with members of the latter group having molecular weights less than 7,000 Da.
Unfractionated heparin works in conjunction with antithrombin III – forming a complex that not only inactivate thrombin, but also several other clotting factors. LMWHs (such as enoxaparin, dalteparin, and tinzaparin) also interact with antithrombin III but in a very different way. The LMWH-antithrombin III complex has greater selectivity in what it inactivates, meaning LMWHs has 4x the ability to inactivate factor Xa compared to unfractionated heparin.
LMWHs inactivate factor Xa - that much we’ve learned. In contrast, unfractionated heparin inactivates factor IXa, Xa, XIa, and XIIa. Heparins in general also promote the release of tissue factor pathway inhibitor (TFPI) from the vascular cell wall; TFPI being an inhibitor of factor Xa. Unfractionated heparin also inhibits platelet aggregation by binding to platelet factor 4.
Heparins also promote the activation of lipoprotein lipase. Though the enzyme breaks down lipoproteins, it simultaneously serves to attenuate platelet adhesiveness. Heparins cannot be administered orally, not least because of their large size and high negative charge – so they must be administered intravenously or subcutaneously; drugs whose onset of action is very rapid.
Expectant mothers aren’t to be concerned, either – as heparins cannot cross the placenta and they cannot enter breastmilk. The two main subclasses of heparins – unfractionated heparin and LMWHs – have very different pharmacokinetic profiles. Unfractionated heparin has variable binding to plasma proteins, meaning dosage varies depending on the target level of anticoagulation. It also has a short half-life, of 30 mins, at low doses.
The half-life increases as dosage increases, however. The vast majority of heparin is metabolized by endothelial cells after it binds to surface receptors. Some, however, it metabolized by the liver, with quite a small amount eliminated unchanged from the kidney. Unfractionated heparin can be administered via repeat IV bolus injections, continuous intravenous infusion, or subcutaneously (low dose for prophylaxis against venous thrombosis).
Unfractionated heparin has around 45 polysaccharide units, in contrast to LMWHs which have around 15 polysaccharides. Complete anticoagulation with LMWHs can be achieved by daily subcutaneous administrations. In addition, LMWHs have little affinity for endothelial cell receptors or plasma protein binding sites – meaning their half-lives oscillate around 3-7 hours. Clinicians can better predict the anticoagulant effect of LMWHs compared to unfractionated heparins.
Unfractionated heparins are monitored using the activated partial thromboplastin time (APTT); a measure of the intrinsic coagulation pathway. In contrast, LMWHs do not require APTT testing. Low-dose subcutaneous unfractionated heparin does not require APTT monitoring, either. Testing is important as the therapeutic window of unfractionated heparins is quite narrow.
Unwanted effects with heparins include haemorrhage – with an increased risk of bleeding in older patients. A peptide, protamine sulphate, can be administered as an antidote should bleeding become too heavy. However, due to poor binding protamine sulphate isn’t effective at reversing the effects of LMWHs. Other unwanted effects include osteoporosis, thrombocytopenia, hyperkalemia, and hypersensitivity reactions.
Other Injectable Anticoagulants
To conclude our summary of pharmacology of anticoagulant drugs (injectables), we now turn to fondaparinux and hirudins.
Fondaparinux is a synthetic pentasaccharide – a sequence of saccharides similar to that of the sequence used by heparin to bind antithrombin III. And similar to LMWHs, fondaparinux enhances the ability of antithrombin III to inactivate factor Xa. Fondaparinux is administered by subcutaneous injection and is eliminated unchanged by the kidney (half-life 18 hours). Unwanted effects include haemorrhage, thrombocytopenia, edema, and gastrointestinal upset.
Hirudins are natural substances produced from the salivary gland of leeches – examples being hirudin, lepirudin, and bivalirudin. They are direct thrombin inhibitors. Lepirudin can replace heparin in patients with heparin-induced thrombocytopenia. Lepirudin is administered intravenously and is mostly eliminated in the urine (half-life 2 hours). Unwanted effects with lepirudin include bleeding, fever, and hypersensitivity reactions.
Hirudins are classified as direct thrombin inhibitors, specifically bivalent DTIs. There are other, univalent DTIs – examples of which include argatroban and dabigatran.
Argatroban is administered intravenously and, like lepirudin, is used in the treatment of heparin-induced thrombocytopenia, though it may also be used to treat PCI (percutaneous coronary intervention). It has a half-life of 50 minutes and is monitored by PTT. It can be used in patients with renal impairment (as it is metabolized via hepatic means, in contrast to lepirudin which is mostly renally cleared). In contrast to argatroban, dabigatran is administered orally (half-life 12-17 hours).
That’s about it for the pharmacology of anticoagulant drugs (injectables). For more information, and to test yourself, why not try our quiz – ten questions covering just about everything in this summary.