Question 4

Describe the pharmacology of low molecular weight heparin (70% marks). Outline the pharmacology of hirudin (30% marks). 

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College Answer

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.