Describe the pharmacology of low molecular weight heparin (70% marks). Outline the pharmacology of hirudin (30% marks).
A question that asks for information of the pharmacology should mention pharmaceutical (only briefly), pharmacokinetics and pharmacodynamics of the drug or class of drugs requested. The term “describe” requests of the candidate a greater depth of information than “outline” and both are defined in the “Notes to Candidates” document. Candidates who did well, did so because they had sufficient knowledge of this commonly used class of drugs, and could structure a well organised answer.
| Name | Heparin | Hirudin |
| Class | Parenteral anticoagulant | Direct thrombin inhibitor |
| Chemistry | Glycosaminoglycan | Polypeptide |
| Routes of administration | IV ands subcut | Topical and IV |
| Absorption | Minimal oral bioavailability (~ 1%) | Oral bioavailability 10% |
| Solubility | pKa -2.0 to -4.0, excellent solubility in water | pKa values of about 7.1, 8.4, and 9.2. good water solubility |
| Distribution | Highly protein-bound, mainy to lipoproteins (LDL) | VOD=0.3L/kg; minimally protein bound (only to thrombin) |
| Target receptor | Antithrombin III | Thrombin |
| Metabolism | Sequestered into reticuloendothelial cells and degraded gradually into inactive and renally cleared metabolites. | Minimally metabolised; some hydrolysis in the liver occurs, whcih liberates [eptide fragments and amino acids |
| Elimination | Biphasic (saturable) metabolism: with low doses, a rapid saturable clearance (by reticuloendothelial tissues), which becomes slower with high doses when this system is saturated. Monitored by APTT, which incorporates an assessment of thrombin activity | 90% of the drug is cleared renally. Monitored by APTT or ECT(ecarin time) |
| Time course of action | Half-life of 25 units per Kg = 30 minutes Half-life of 100 units per Kg = 60 minutes Half-life of 400 units per Kg = 150 minutes |
Half life is about 0.8-1.7 hrs |
| Mechanism of action | By binding to antithrombin III and causing the active site to undergo a conformational change, heparin increases its availability to its normal ligands, including factor Xa and thrombin. The result is an increase in the activity of antithrombin, which manifests in the form of the anticoagulant effect | Binds to thrombin, deactivating it and preventing the formation of fibrin (as well as inhibiting other thrombin-driven parts of haemostasis, such as the activation of platelets) |
| Clinical effects | Anticoagulation, bleeding, the possibility of HITS. Also osteopenia, mineralocorticoid deficiency alopecia and LFT derangement |
Anticoagulation is the only clinically apparent effect; no significant side effects apart from bleeding complications |
| Single best reference for further information | TGA PI document | Greinacher et a, 1991 |
Hirsh, Jack, et al. "Mechanism of action and pharmacology of unfractionated heparin." (2001): 1094-1096.
Hirsh, Jack, et al. "Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety." Chest 114.5 (1998): 489S-510S.
Boneu, Bernard, Claudine Caranobe, and Pierre Sie. "3 Pharmacokinetics of heparin and low molecular weight heparin." Bailliere's clinical haematology 3.3 (1990): 531-544.
Rydel, Timothy J., et al. "Refined structure of the hirudin-thrombin complex." Journal of molecular biology 221.2 (1991): 583-601.
Greinacher, Andreas, and Theodore E. Warkentin. "The direct thrombin inhibitor hirudin." Thrombosis and haemostasis 99.11 (2008): 819-829.
Cen, Xiaodong, et al. "Investigation on recombinant hirudin via oral route." Peptides 27.4 (2006): 836-840.