Compare and contrast the pharmacology of heparin and enoxaparin.
The vast majority of candidates chose to answer this question in tabular format and in doing so were easily able to consolidate a high scoring answer. This also allowed clear identification of important differences, such as molecular weight, mechanism of action, halflife, dose-interval, monitoring, elimination, reversal of effect, the influence of renal impairment and potential side-effects. One exception to this approach would be clinical indications, where these show marked similarity. Candidates should consider writing similarities once whilst incorporating both drugs so as use the time allocated more efficiently.
Syllabus - J2 2a
Reference: Pharmacology and Physiology in Anaesthetic practice, Stoelting 505-511 Basic and Clinical Pharmacology, Katzung 546-548
|Class||Parenteral anticoagulant||Parenteral anticoagulant|
|Routes of administration||IV ands subcut||IV ands subcut|
|Absorption||Minimal oral bioavailability (~ 1%)||Minimal oral bioavailability (~ 1%)|
|Solubility||pKa -2.0 to -4.0, excellent solubility in water||pKa -2.8, excellent solubility in water|
|Distribution||Highly protein-bound, mainy to lipoproteins (LDL)||VOD=0.05L/kg, basically confined to the bloodstream.
Somewhat protein-bound, but less than unfractionated heparin (only the chains which are less than 6000 Da are protein-bound)
|Target receptor||Antithrombin III||Antithrombin III|
|Metabolism||Sequestered into reticuloendothelial cells and degraded gradually into inactive and renally cleared metabolites.||Mainly metabolized by the liver via desulfation and depolymerization to lower molecular weight fragments, which end up beign either less potent or totally inactive|
|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||About 40% of active and inactive fragments combined are excreted renally, which is why low molecular weight heparin is not especially well suited to renal failure patients.
Monitoring is by measurement of anti-Xa activity
|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 4-7 hours.|
|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||By binding to antithrombin III and causing the active site to undergo a conformational change, low molecular weight heparin increases its affinity for factor Xa (but not thrombin). The result is an increase in the activity of antithrombin on Factor Xa, which manifests in the form of the anticoagulant effect.|
|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 the possibility of HITS (which is much smaller than with UFH)|
|Single best reference for further information||TGA PI document||TGA PI document|
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.