Outline the differences between heparin and enoxaparin with respect to:
· Phamacokinetics
· Monitoring of effect
· Adverse effects
· Reversal of effect
Candidates were expected to mention the differences between heparin and enoxaparin and to explain why these differences existed and their implications. For example:
heparin Pharmacokinetics -
MW3000-30000. Large variability has significant effects on:
· mechanism of action (IIa, IXa, Xa)
· dosing( 2/3 molecules in dose have no active binding sites)
· bioavailability poor,T1/2 short (rapid uptake by PF4/endo cells/macrophages and
proteins of high MW components) = poor predictability and dose response both IV and
SC, mandates monitoring IV
T1/2 1-2 hours: S/C 2-3 daily doses. Continuous IV – advantage is fast offset.
enoxaparin -
MW3000-5000. Inhibits Xa only.
· bioavailability (100%),longer T1/2 no uptake/protein binding
· predictable activity and dose response = decreased need for monitoring, reliable SC
· No need for IV use
T1/2 4-5 hours, 1-2 daily dosing, but no fast offset.
Better answers were in tabular format under each heading. Higher marks were awarded for mentioning of monitoring pitfalls such as heparin resistance, measuring Xa levels in a timely fashion, and the efficacy and pitfalls of protamine with each agent.
Syallabus J2 2a
Reference: Stoelting 505-511
Katzung 546-548
| 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) |
| Reversal | Protomine 1mg reverses 100 units of heparin | Protamine will reverse up to about 60% to 75% of anti-Xa activity. |
| 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.