Anticoagulants
| Property | Warfarin | Heparin | Enoxaparin |
|---|---|---|---|
| Uses | AF, DVT/PE, Prosthetic Valves | AF, DVT/PE, Extra-corporeal Circuit Anticoagulation | DVT Prophylaxis |
| Pharmaceutics | Marevan and coumadin may potentially have different bioavailabilities (it has not been assessed) and so should not be substituted | Mucopolysaccharide organic acid which occurs naturally in the liver and in mast cells, with a highly variable molecular weight (between 5,000 and 25,000 Da) | Smaller fragments of heparin (prepared from UFH), with a mean molecular weight of 5,000 Da |
| Mechanism of Action | Prevents the return of vitamin K to its reduced form, and therefore the gamma-carboxylation of vitamin-K dependent clotting factors (II, VII, IX, X), as well as Protein C and Protein S). | Potentiates the effect of ATIII, rapidly increasing its anti-IIa and anti-Xa effect (1:1 effect). In higher concentrations also inhibits IXa, XIa, XIIa, and platelet aggregation. |
Potentiates the action of ATIII, increasing inhibition of Xa and IIa, but (unlike UFH) in a 4:1 ratio. More predictable effect on Xa standardises dosing and justifies lack of monitoring requirement. |
| Onset | 8-12 hours. Peak at 72 hours due to the half-life of existing clotting factors, and the total body stores of vitamin K | Immediate IV onset | |
| Absorption | 100% bioavailability | IV, SC | SC only |
| Distribution | 99% protein bound | Low lipid solubility, highly protein bound | Does not bind to heparin-binding proteins |
| Metabolism | Complete hepatic metabolism. Significant pharmacokinetic interaction with enzyme inducers and inhibitors. | Hepatic interactions due to enzymatic induction (ETOH, amiodarone, salicylates, NSAIDs) and inhibition (OCP, barbiturates, carbamazepine) | Renal elimination of metabolites |
| Elimination | Faecal and renal elimination of metabolites, t1/2β of 40 hours | Renal of inactive metabolites | Renal of active drug and inactive metabolites |
| CVS | Microthrombi | Hypotension with rapid IV administration | |
| Metabolic | Less osteoporosis due to less protein (and therefore tissue) binding | Osteoporosis | |
| Renal | Inhibits aldosterone secretion | ||
| GIT | N/V | ||
| Haeme | Haemorrhage | Haemorrhage, HITTs | Haemorrhage, lower risk of HITTs than UFH. Less thrombocytopaenia. |
| Immune | Hypersensitivity reactions | ||
| Reversal | - Waiting - Vitamin K - FFP - Prothrombinex |
Reversed with protamine (1mg per 100U). | Incomplete reversal with protamine as only the anti-IIa effect is inhibited. |
| Other | Teratogenic. Complicated pharmacokinetics requiring monitoring using INR. | Requires monitoring with APTT or ATIII levels. Large interpatient variability due to variable amounts of ATIII. 1 unit is the amount of heparin required to prvent 1ml of blood clotting for 24 hours at 0°C |
No monitoring required. |
HITTs
Heparin-Induced Thrombotic Thrombocytopenia comes in two flavours:
- Type I:
- Is non-immune mediated
- Occurs within 4 days of anticoagulant doses
- Is an isolated thrombocytopenia without clinical significance
- Type II:
- Is immune mediated
- Occurs within 4-14 days
- Is associated with serious thrombosis and high mortality (typically from PE) and morbidity (from CVA and limb ischaemia)
Protamine
Protamine is:
- A basic cationic protein derived from salmon sperm which combines with the acidic anionic heparin to form a stable, inactive salt in solution
- Cleared more rapidly than heparin
Rebound anticoagulation may occur.
Adverse effects from protamine include:
- Histamine release
- Bronchospasm
- Hypotension
- Pulmonary hypertension
This can be profound and result in a dramatic increase in RV afterload and EDV, with a corresponding fall in LV preload (interventricular interdependence), leading to dramatic hypotension and arrest.- Mediated by thromboxanes
- Due to protamine-heparin complexes, rather than protamine alone
Administration of protamine in absence of heparin does not lead to pulmonary hypertension.
- Anticoagulation
When given in excess.
References
- Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.
- Smith S, Scarth E, Sasada M. Drugs in Anaesthesia and Intensive Care. 4th Ed. Oxford University Press. 2011.
- ANZCA August/September 2011
- Petkov V. Essential Pharmacology For The ANZCA Primary Examination. Vesselin Petkov. 2012.