Anti-coagulant drugs

Question 1

Warfarin

Answer 1

• Vitamin K antagonist
• therefore Prevents γ-carboxylation of factors II, VII, IX, X
• Prolongs the extrinsic pathway (tested by measuring prothrombin time)
• Monitored by the international normalised ratio (INR)
• Target INR usually 2.5 for DVT/PE and AF
• Target 3.5 for recurrent VTE or metal heart valves

Question 2

Describe the metabolism of warfarin

Answer 2

Question 3

Describe the Pharmaco-dynamics of warfarin

Answer 3

• reduces the half-life of Factor VII, IX, X and II
• Warfarin can take > 3 days to reach therapeutic levels
• also inhibits the natural anti-coagulants: Protein C and S
• these have a shorter half-life so become prothrombotic before combing anticoagulant because the natural sources (protein C and S) are initially depleted

Question 4

How should warfarin be prescribed?

Answer 4

• usually loaded with low molecular weight heparin (LMWH) cover
• typically: 10mg, 5mg
• a fall in Protein C and S occurs within hours, can result in a temporary procoagulant state
• hence, LMWH is usually continued until the INR is > 2.0 for 2 consecutive days

Question 5

thrombomodulin is a endothelial cell surface receptor

What are Protein C and S? describe their action.

Answer 5

• they are inhibitors of coagulation factor V and VIII
• bothe are vitamin K dependent proteins
• Protein C is activated by a thrombin-Thrombomodulin complex
• activated protein C is able to destroy factor Va and VIIIa
• therefore further thrombin cannot be generated: creating a negative feedback loop
• Protein S promotes the action of protein C
• activated protein C is inactivated by serpins( serum protease inactivators) e.g antithrombin

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Question 6

What other drugs/chemicals does warfarin interact with?

Answer 6

• beware of interactions with other drugs due to cytochrome P450 in the liver
• enzyme inhibitors potentiate warfarin: may want to reduce the dosage
• carbamazepine, azathioprine, allopurinol
• erythromycin, ciprofloxacin, metronidazole, fluconazole
• Enzyme inducers inhibit warfarin: may want to increase the dosage
• rifampicin, amiodarone, citalopram, phenytoin
• Interactions with alcohol: may have a high IRN and are at risk of bleeds

Question 7

What are some side effects of warfarin?

Answer 7

• teratogenic: must use LMW heparin in pregnancy
• significant haemorrhage risk: leads to intracranial bleeds p to 15 a year, increased risk in elderly with a higher INR target
• minor bleeding: 20% per ann.
• skin necrosis
• alopecia: hair loss

Question 8

Explain how warfarin can be reversed

Answer 8

• Give vitamin K 2-10mg iv/po depending on INR level
• 6-12 hours to take into effect so give other treatments first (octaplex)
• The patient can become refractory to re-loading with warfarin
• If life-threatening bleed, give activated prothrombin complex (Octaplex) containing factors II, VII, IX and X (25-50 units per kg), plasma-derived product
• Fresh frozen plasma (FFP) can also be used

Question 9

Heparin

Answer 9

• Mucopolysaccharide that potentiates anti-thrombin
• Irreversibly inactivates factors IIa (thrombin) and Xa
• Administered parenterally

Two formulations of heparin:

• Unfractionated heparin given by i.v. infusion
• Low molecular weight heparin given as s.c. injections

Safe in pregnancy

Question 10

first binds to antithrombin

Describe the action of Heparin

Answer 10

Question 11

How/ when is unfractionated heparin used?

Answer 11

• Not often used due to inconvenience, unless in renal failure
• Given i.v. with 5000U bolus and ~1000U/hour infusion
• Monitored by APTT with a target range of 1.5-2.5 x normal
• Safe in renal failure
• Can be partially reversed with protamine sulphate
• Thrombocytopenia and VTE is a rare complication resulting in heparin-induced thrombocytopenia (HIT)

Question 12

When/ How is Low molecular weight heparin used

Answer 12

• Very convenient due to once daily s.c. injections
• Prescribed according to patient’s weight
• Not usually monitored (but can use the anti-Xa assay)
• Patient must have creatinine clearance of over 30ml/minute

LMW heparin formulations include:

• Tinzaparin (Innohep) 175U/kg
• Enoxaparin (Clexane) 1.5mg/kg
• Dalteparin (Fragmin)

Used for thromboprophylaxis for hospital in-patients:

• 3,500U or 4,500U Tinzaparin
• 20 or 40mg Enoxaparin

Question 13

What are Novel oral anticoagulants?

Answer 13

• alternative to warfarin
• orally available, no monitoring required, has a good safety profile
• Dabigatran: direct thrombin (IIa) inhibitor
• Rivaroxaban: direct factor Xa inhibitor
• trials show that it is as good as warfarin and LMW heparin but the anticoagulation action is irreversible

Question 14

It is a novel anticoagulant drug class

Explain how Dabigatran is used.

Answer 14

• used as a direct inhibitor to factor IIa (thrombin)

Indications (usage)

• used as a VTE (venous thromboembolism) prophylaxis
• treatment for DVTs and PEs
• stroke prevention in atrial fibrillation
• Dosing is 110mg bd or 150mg bd
• must be a creatine clearance of > 30ml/min
• Argatroban: direct thrombin inhibitor given iv: safe in renal failure

Question 15

Explain how Rivaroxaban is used

Answer 15

• is a direct factor Xa inhibitor

Indications:

• VTE prophylaxis
• Used for treatment of DVTs and PEs
• Stroke prevention in atrial fibrillation
• Dosing is 15mg bd for 3 weeks, then 20mg od
• or 15mg od if CrCl is 15-50ml/min
• Apixaban is alternative drug dosed bd (morning and evening), slightly better plasma levels with this drug

Question 16

Describe the action of antiplatelet drugs

Answer 16

Question 17

three glycoprotein inhibitors

List five main types of anti-platelet drugs

Answer 17

• Aspirin: cyclo-oxygenase inhibitor
• Clopidogrel: ADP receptor blocker
• Dipyridamole: inhibits phosphodiesterase
• Prostacyclin: stimulates adenylate cyclase

Glycoprotein IIb/IIIa inhibitors: also used in cardiac clot prevention in patients who have had stents inserted

• Abciximab – monoclonal antibody
• Eptifibatide – snake venom derivative
• Tirofiban – blocks platelet aggregation

Question 18

What are fibrinolytic agents?

Answer 18

• Thrombolytic agents are used to lyse fresh thrombi (arterial) by converting plasminogen to plasmin
• e.g Tissue Plasminogen Activator (tPA, Alteplase) and Streptokinase
• Administered systemically in acute MI, recent thrombotic stroke, major PE or iliofemoral thrombosis
• Standardized dosage regimens have to use within 6 hours
• Beware of contra-indications to thrombolysis