Anticoagulants Drugs, Types, action, dosage

 Anticoagulants 

Types

• Heparin. 
• Low molecular weight (LMW) heparin e.g dalteparin, enoxaparin, tinzaparin, fondaparinux. 
• Heparinoids e.g danaparoid.
• Direct thrombin inhibitors, e.g lepirudin, dabigatran, rivaroxaban. 
• Anticoagulant prostanoids, e.g epoprostenol, alprostadil. 
• Sodium citrate. 
• Warfarin. 

Modes of action

• Heparin potentiates naturally occurring antithrombin, reduces platelet adhesion to injured vessels, and promotes in vitro aggregation. 
• LMW heparin appears to influence factor Xa activity specifically, simpler pharmacokinetics allows a smaller dose to be effective.
• Heparanoids are similar to heparin, with 10-20% risk of cross-reactivity. Use is mainly restricted to treating heparin-induced thrombocytopenia syndrome (HITS) and DVT prophylaxis. No antidote is available. 
• Lepirudin is a recombinant form of hirudin that form an irreversible complex with thrombin. It is unrelated to heparin so can be used to treat HITS. Antibody formation occurs 40% of patients treated with lepirudin >6 days. Half-life is long and there is no antidote. 
• Dabigatran and rivaroxaban are being developed for oral thromboprophylaxis or treatment of thromboembolism without monitoring. There is no antidote, but half-lives are short. 
• Prostanoids affect the balance between native TXA2 and PGI2.
• Sodium citrate chelates ionised calcium. 
• Warfarin produces a controlled deficiency of vitamin K dependent coagulation factors ( II, VII, IX and X). Effects develop in 48-72 h. 

Uses

• Maintenance of an extracorporeal circulation. 
• Prevention or treatment of thromboembolism. 

Routes 

• IV (heparin, heparinoids, prostanoids, sodium citrate )
• SC (heparin )
• PO (warfarin)

Side effects 

• Bleeding 
• Hypotension 
• Heparin-induced thrombocytopenia 
• Hypocalcaemia hypernatraemia ( sodium citrate )

Notes

• Alprostadil is less potent than epoprostenol. As it is metabolised in the lungs, systemic vasodilatation effects are usually minimal. 
• For extracorporeal use, citrate have advantages over heparin as it has no antiplatelet activity and is readily haemofiltered.

DRUG DOSAGES

Unfractionated heparin 

Dose is titrated to produce an APTT of 1.5-3 times control. This usually requires 500 - 2000 IU/h with initial loading dose of 3000 - 5000 IU. 

Low molecular weight heparin 

For DVT prophylaxis, give 2500 - 5000 IU dalteparin or 20-40 mg enoxaparin sc daily

For anticoagulation for an extracorporeal circuit, an IV bolus of 35IU/kg dalteparin or 0.25mg/kg enoxaparin is followed by an infusion of 13 IU/kg dalteparin or 0.1 mg/kg enoxaparin. Adjust dose to maintain anti-factor  Xa activity at 0.5-1 IU /mL (or 0.2 - 0.4 IU/mL if high risk of hemorrhage ). 

For DVT pulmonary embolism, give 200 IU /kg dalteparin or 1.5 mg/kg enoxaparin SC daily 

Heparinoids 

Caution in patients with renal insufficiency. 

For DVT, prophylaxis gives 750 anti -Xa units danaparoid SC bd. 

For DVT or pulmonary embolism with history of HITS, give a loading dose of 2500 anti-Xa units danaparoid IVIV, them infusion of 400 U/h for 2h, 300U/h 2h, then maintenance of 200 U/h for five days. Target a therapeutic anti-Xa level during the infusion of 0.5-0.7 anti-Xa units/mL. 

For anticoagulation for an extracorporeal circuit, loading dose of 3,500 anti-Xa units danaparoid IV is followed by continuous infusion of 100 anti-Xa units/h. 

Direct thrombin inhibitors 

Lepirudin 0.1-0.4 mg/kg bolus followed by 0.1 -0.15 mg/kg/h infusion. Caution in patients with renal insufficiency. 

Anticoagulant prostaglandins

Usual dose range is 2.5 -10ng/kg/min. If used for an extracorporeal circulation, infusion should be started 30min prior to commencement. 

Sodium citrate 

Infused at 5mmol/L of extracorporeal blood flow. Monitor Ca2+ (ideally ionised levels and treat as needed ). 

Warfarin

Start at 10/day orally for two days, then 1-6mg/day according to INR. For DVT prophylaxis, pulmonary embolus, mitral stenosis, atrial fibrillation, and tissue value replacement, maintain INR between 2-3, For recurrent DVT or pulmonary embolus, and mechanical valve replacement, the INR should be kept between 3-4.5.