Outline the important similarities and differences between unfractionated heparin and enoxaparin using the following headings (20% of marks each):
(i) Mechanism of action
(ii) Pharmacokinetics
(iii) Adverse effects
(iv) Dosing
(v) Monitoring and reversal
These are commonly used and important drugs in intensive care practice and a high level of detail was expected. Unfractionated heparin and enoxaparin have specific differences that influence how we use them in practice and this information was required for full marks. This question was answered well by providing the detail on each domain for both heparin and enoxaparin and then highlighting if this factors into how they are used.
| Unfractionated heparin | Enoxaparin | |
| 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. | Low molecular weight heparin increases the affinity of Antithrombin III for factor Xa (but not thrombin). The result is an increase in the activity of antithrombin on Factor Xa only. |
| Pharmacokinetics |
Both have minimal oral bioavailability (~ 1%) Both have pKa -2.0 to -4.0, excellent solubility in water |
|
| Highly protein-bound (LDL) | Only the chains which are more than 6000 Da are protein-bound | |
| Biphasic (saturable) metabolism by reticuloendothelial cells; 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 | |
|
low doses: rapid clearance by reticuloendothelial tissues, high doses: slower (when this system is saturated). |
About 40% of active and inactive fragments combined are excreted renally | |
| Adverse effects | Bleeding, the possibility of HITS. Also osteopenia, mineralocorticoid deficiency alopecia and LFT derangement |
Bleeding; no significant side effects apart from the possibility of HITS (which is much smaller than with UFH) |
| Dosing | Both have fixed dosing for low-dose prophylaxis | |
| Therapeutic infusion is unadjusted for renal disease, dosed according to a weight-adjusted nomogram and according to the desired APTT range |
Weight-based dosing adjusted to renal function for higher therapeutic doses |
|
| Monitoring |
Monitored by APTT, which incorporates an assessment of thrombin activity. |
Monitoring is by measurement of anti-Xa activity |
| Reversal | Protamine binds heparin to form an inactive stable complex (1mg reverses 100u of heparin) | Protamine only reverses LMWH partially, depending on the degree of sulfonation (eg. for enoxaparin, only about 60% of the effect is reversed). 1mg of protamine will reverse roughly 1mg of enoxaparin. |
Adverse effects
Dosing
Monitoring
Reversal
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.
Sokolowska, Emilia, et al. "The toxicology of heparin reversal with protamine: past, present and future." Expert opinion on drug metabolism & toxicology 12.8 (2016): 897-909.