Question 5

Compare and contrast unfractionated heparin with low molecular weight heparin. 

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College Answer

This question was generally well answered and lent itself well to a tabular format. Expected information included an approximation of the molecular weights / significance of the differences in size and therefore its mechanism of action.  Other pertinent areas to mention included pharmacokinetic differences and its use in renal failure, side effect profiles, monitoring, predictability of response and reversibility for the two agents.  

Discussion

Name Heparin Enoxaparin
Class Parenteral anticoagulant Parenteral anticoagulant
Chemistry Glycosaminoglycan Glycosaminoglycan
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

References

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.