Anticoagulants

Question 1

Unfractioned heparin

Answer 1

Indication: anticoagulation
- moderate renal imapairment and v.fine control

Route:

• i.v bolus and infusion
• s.c for prophylaxis but low bioavailability

Action:

• binds to ATIII causing conformational change and increased activity
• needs to simultaneously bind to ATIII and IIa
• Xa inhibition only needs ATIII binding

Adverse effects:

• bruising/bleeding (intracranial,site of injection,GI,epistaxis)
• heparin induced thrombocytopenia (higher risk)
• hyperkalamia - inhibition of aldosterone secretion
• osteoporosis - rare (higher risk)

Warnings:
- clotting disorders

Interactions:

• other antithrombotic drugs
• ACEi/ARB, amiloride, spironolactone - hyperkalaemia

Other:

• fast onset
• mixed elimination - 1/2 life 30 mins low dose, 2h at high
• unpredictable dose response - binds to endothelial cells, plasma proteins and macrophages

Question 2

Dalteparin/enoxaparin

Answer 2

Indication: anticoagulant

• perioperative prophylaxis of venous thromboembolism
• pregnancy - large size does not cross the placenta
• long term/cancer related VTE (DVT/PE)
• ACS - PCI, reduce recurrence of coronary artery thrombosis post STEMI/NSTEMI

Class: LMWH

Route: almost always s.c

Action: inhibition of Xa specifically by enhancing ATIII activity
(Not long enough to inactivate thrombin IIa)

Adverse effects:

• bruising/bleeding (intracranial,site of injection,GI,epistaxis)
• heparin induced thrombocytopenia (lower risk)
• hyperkalamia - inhibition of aldosterone secretion
• osteoporosis - rare (lower risk)

Warnings:

• clotting disorders
• RENAL IMPAIRMENT

Interactions:

• other antithrombotic drugs
• ACEi/ARB, amiloride, spironolactone - hyperkalaemia

Other:

• more predictable dose response - does not bind to endothelial cells, plasma proteins and macrophages (isnt long enough)
• 90% bioavailibility
• longer half life - 2+ hrs

Question 3

UFH vs LMWH

Answer 3

Dose response: non linear vs predictable

Bioavailibility: s.c variable around 30% vs predictable 90%

Metabolism: dose dependant (protein binding, depolymerisation, desulfation) vs rapid liver or slower renal excretion

Monitoring: unpredictable (aPTT) vs no monitoring

Administration: i.v.i vs s.c

Initiation: i.v bolus then i.v.i vs OD/BD s.c

Half life: 30min low dose, 2hr high dose vs 2+ hrs

Action: i.v infusion fast anticoagulation vs s.c slower onset

Use: moderate renal impairement and v.fine control vs most situations

Question 4

Fondaparinux

Answer 4

Indication: anticoagulation

Class: SYNTHETIC pentasaccharide

Action: selectively inhibits Xa by enhancing ATIII

route: s.c

Adverse effects:

• bruising/bleeding (intracranial,site of injection,GI,epistaxis)
• heparin induced thrombocytopenia (lower risk)
• hyperkalamia - inhibition of aldosterone secretion
• osteoporosis - rare (lower risk)

Warnings:

• clotting disorders
• RENAL IMPAIRMENT

Interactions:

• other antithrombotic drugs
• ACEi/ARB, amiloride, spironolactone - hyperkalaemia

Other: Half life 18hr

Question 5

Protamine sulphate

Answer 5

Indication: heparin reversal

Action:

• forms inactive complex with heparin
• dissociates heparin from ATIII
• irreversible binding

Other:

• greater effect on UFH than LMWH
• no effect on fondaparinux

Question 6

Warfarin

Answer 6

Indication: longer term anticoagulation

• VTE (DVT,PE)
• AF with high risk of stroke
• heart valve replacment

Class: vitamin K antagonist

Action:

• competitive inhibition of VKOR
• inhibits conversion of vitamin k to active reduced form
• stop hepatic synthesis of factors II, VII, IX, X

Pharmacokinetics:

• 95% oral availability - good GI absoprtion
• CYP2C9 polymorphisms cause interindividual variability
• mixture or R and S enantiomers - different potency and metabolism
• response affcted by CYP2C9, vitamin K inatke, alcohol

Adverse effects:
- bleeding (epistaxis and spontaneous retroperitoneal)

Warnings:

• pregnancy - crosses the placenta (1st trimester tetragoneic, 3rd trimester haemorrhage)
• hepatic disease

Interaction:

• amiodarone, clopidogrel - CYP2C9 inhibtion - increase warfarin - increase INR
• barbituates, st jhons wart, rifampicin, phenytoin - CYP2C9 inducers - decrease warfarin - decrease INR
• cephalosprin antibiotics - reduce vitamin K by eliminating gut bacteria
• NSAIDs - displacement of warfarin from plasma albumin (increase INR)
• drugs that decrease GI absoprtion of vitamin K (increase INR)

Other:

• slow onset - circulating active clotting factors present for several days so must be cleared and replaced with non-carbocylated forms (use heparin if anticoagulation needed immediately)
• half life 36-48 hr
• antidote = prothrombin complex concentrate i.v

Question 7

Apixaban/edoxaban/rivaroxaban

Answer 7

Indication: anticoagulant

Class: DOAC

Action: Inhibit both free Xa and that bound with ATIII, do not directly effect thrombin (IIa)

Route: oral

Adverse effects: bleeding

Warnings:

• VERY LOW creatinine clearance (<15ml/min)
• pregnancy and breastfeeding

Interactions: less frequent than warfarin

• affected by CYP inhibitors and inducers
• carbamazepine,phenytoin,barbituates decrease [plasma]
• macrolides increase [plasma]

Other: andexanet and idarucizumab antidotes

Question 8

Dabigatran

Answer 8

Indication: anticoagulant

Class: DOAC

Action: Selective direct competitive thrombin inhibitor, both circulating and thrombus bound IIa

Route: oral

Adverse effects: bleeding

Warnings:

• LOW creatinine clearance (<30ml/min)
• pregnancy and breastfeeding

Interactions: less frequent than warfarin

• affected by CYP inhibitors and inducers
• carbamazepine,phenytoin,barbituates decrease [plasma]
• macrolides increase [plasma]

Other: andexanet and idarucizumab antidotes