Anticoagulants

Question 1

Unfractionated heparin

Answer 1

• 45 polysaccharide mixture (more than LMWH)
• fast onset of action
• 30 min half life at low doses
• 2hr half life at high dose
• unpredictable (so must be titrated)
• given IV bolus and infusion
• binds to AT3 causing conformational change and increased activity of AT3
• if inhibiting IIa then needs to bind to AT3 and IIa
• if inhibiting Xa then only needs to bind to AT3

Question 2

LMWH (dalteparin and enoxaparin)

Answer 2

• 15 polysaccharides which are absorbed more uniformly
• almost always s.c.
• enoxaprin used in ACS and needs to be given IV
• > 90% bioavailability
• longer half-life +2hr
• more predictable dose response because doesnt bind to any cells
• doesnt inhibit IIa
• only inhibits Xa by enhancing AT3 activity

Question 3

Fondaparinux

Answer 3

• synthetic LMWH
• selectively inhibits Xa by binding to AT3
• given s.c.
• half life is 18hrs

Question 4

What are the indications for use of heparins?

Answer 4

• prevention of venous thromboembolism, perioperative prophylaxis with LMWH duration and dose dependant on risk
• used during pregnancy because DOESNT crops placenta but monitor with caution
• used for VTE, DVT and PE
• used for ACS becauses it reduces recurrence and extension of coronary artery
• thrombosis post STEMI in PCI and non PCI patients
• NSTEMI

Question 5

What are the adverse reactions related to heparin?

Answer 5

• bruising and bleeding intracranially, at site of injection, GI, epistaxis, hepatic and renal impairment, elderly or those with carcinoma at higher risk
• heparin-induced thrombocytopenia (1/100 in UFH vs. 1/1000 LMWH)
• allergy/autoimmune response 2-14 days after initiation of heparin
• antibodies to heparin platelet factor 4 complex
• depletion of platelets
• paradoxically can lead to thrombosis as more platelets activated by damaged endothelium
• hyperkalaemia due to inhibition of aldosterone secretion
• osteoporosis is rare but can be due to long-term use, there is higher risk with UFH and more prevalent in pregnancy

Question 6

How is heparin monitored?

Answer 6

UFH

• need APTT when using therapeutic doses
• dose is titrated against APTT

LMWH
-more predictable in its action so little monitoring required

Question 7

Protamine sulphate

Answer 7

• forms inactive complex with heparin
• given i.v. And dissociates heparin from AT3, irreversible binding amount given guided by heparin dose can cause bleeding
• do in vitro test if unsure
• greater effect with UFH then LMWH, no effect on fondaparinux

Question 8

Vitamin K antagonist (warfarin)

Answer 8

• inhibits activation of vitamin K dependant clotting factors (koagulation vitamin)
• inhibits conversion of vitamin K to active reduced form: competitive inhibition of VKOR
• hepatic synthesis of active clotting factors 2, 7, 9, 10 require active vitamin K as cofactor
• delay in onset of action as circulating active clotting factors present for several days
• must be cleared and replaced with noncarboxylated forms (inactive clotting factors)
• half life is 36-48 hours

Question 9

What are the indications for use of warfarin?

Answer 9

• venous thromboembolism
• PE
• DVT and secondary prevention
• superficial vein thrombosis
• AF with high risk of stroke
• heart valve replacement
• generally used in long term anticoagulation c.f. Heparins
• slow onset of action likely to require heparin cover if anticoagulation needed immediately

Question 10

What are the pharmacokinetics of warfarin?

Answer 10

• good GI absorption and taken orally
• +95% bioavailability
• functional CYP2C9 polymorphism contribute to significant inter-individual variability
• [plasma] does not correlate directly with clinical effect
• warfarin is a racemic mixture of 2 enantiomers (R and S which have different potency and metabolised differently)
• crosses placenta so must be avoided n 1st and 3rd trimester
• response affected by CYP2C9 and others such as vitamin K intake
• if fluctuating levels of vitamin K, then must be mindful of warfarin dose

Question 11

What are the adverse drug reactions of warfarin?

Answer 11

• principle ADR is bleeding: a patient taking warfarin is always of clinical interest
• epistaxis and spontaneous retroperitoneal bleeding
• most effective antidote is vitamin K, or prothrombin complex concentrate (given iv)
• perioperative anticoagulation needs to be considered
• BRIDGING therapy with LMWH often required when initiating or temporarily stopping warfarin (surgery, sickness)

Question 12

What are the warfarin drug-drug interactions (DDI)?

Answer 12

• high number
• majority potentiate anticoagulant action but some decrease effects
• inhibition of hepatic metabolism especially CYP2C9 by amiodarone, clopidogrel, intoxicating dose of alcohol, quinolone, metronidazole
• reduce vitamin K by elimating gut bacteria involved in production by using cephalosporin antibiotics
• displacement of warfarin from plasma albumin by using NSAIDS and drugs that decrease GI absorption of vitamin K (will likely increase INR because more warfarin present in blood)
• acceleration of warfarin metabolism will decrease INR, can be done through the use of barbiturates, phenytoin, rifampicin, St. John’s Wort

Question 13

Direct acting oral anticoagulants aka DOAC (apixaban, edoxaban, rivaroxaban)

Answer 13

• directly inhibits Xa whether it is free or bound
• does not have action on IIa
• hepatic metabolism and excreted partly by kidneys
• half life of 10hrs
• given orally once a day

Question 14

Dabigatran

Answer 14

• DOAC
• selectively direct competitive thrombin inhibitor (IIa)
• acts on free and bound IIa
• half life on 9hrs
• given orally 1-2 times a day
• need bridging therapy
• no need for monitoring

Question 15

When would monitoring of DOACS be beneficial?

Answer 15

-to see if the patient is compliant and adhering

Question 16

What are the pros and cons of DOAC?

Answer 16

• bleeding
• must be cautious and adjust dose in GI bleed risk groups
• metabolism an elimatnation by several routes
• dabigatran contraindicated in LOW CREATININE clearance
• other DOACS contraindicated at VERY LOW creatinine clearance
• less frequent interaction than warfarin but affected by CYP inhibitors and inducers
• [plasma] reduced by carbamazepine, phenytoin, and barbiturates
• [plasma] increased by macrolides
• lower intracranial bleed risk c.f. Warfarin
• little info on use in pregnancy and breastfeeding so should avid