Anti-thrombics

Question 1

List the mechanism, pharmacokinentics, adverse reactions and precautions of unfractionated heparin.

Answer 1

inhibits IIa, IXa, Xa and XIa in the presence of antithrombin, relative anti Xa: anti IIa activity 1:1

eliminated by liver and kidney, administered IV, antidote- protamine sulfate; requires routine monitoring

risk of: bleeding, heparin induced thrombocytopenia, osteoporosis

Question 2

List the mechanism, pharmacokinentics, adverse reactions and precautions of low molecular weight heparin.

Answer 2

inhibits Xa and IIa; relative anti Xa: anti IIa ranges 2:1 to 4:1 (shorter chain due to enzymatic depolymerization or UFH)

eliminated by kidney, half-life 4-6hours; predictable dose response (less binding to cells and plasma proteins), SQ admin allows for outpatient treatment

risk of HIT (lower), preferred anticoagulant during pregnancy

Question 3

What are the indications for heparin and LMWH?

Answer 3

treatment of acute venous thrombus embolism, prophylaxis (hospitalized patients)
acute coronary syndromes
peripheral artery occlusive disease (UFH)
high dose in CABG, ECMO and dialysis (UFH)

Question 4

List the mechanism, pharmacokinentics, indications adverse reactions and precautions of Fondaparinux.

Answer 4

synthetic petasaccharide that inhibits Xa only

used in VTE prophylaxis (high risk orthopedics) but mainly used in patients with HIT

binds with high affinity, eliminated by the kidney with a long 17-21 hour half life

risks: there is no HIT risk, there is no antidote

Question 5

Contrast the mechanisms of the pentasacccharide and the long chain of Fondapainux and heparin respectively.

Answer 5

pentasaccharide: conformational activation: binding to the active site causes conformational change second binding site

long chain: template mechanism: drug binds to active site but also wraps around to obstruct the second binding site

Question 6

List the mechanism, pharmacokinentics, indications adverse reactions and precautions of Warfarin.

Answer 6

inhibits vitamin K-depednet carboxylation of the Gla domains (VII, IX, X and prothrombin)

indicated in preventing VTE (3-6mo), prevention of stroke in atrial fibrillation and prevention of stroke in patients with artificial heart

monitored by INR (standardized prothrombin time), Warfarin takes several days to reach therapeutic levels, based on protein half-lives (INR=2.0-3.0)

risks include extensive drug and diet interactions, warfarin-associated skin necrosis (microvascular skin necrosis w/in first week) and is contraindicated in pregnancy (teratogenic)

Question 7

Contrast drugs that inhibit and stimulate warfarin action

Answer 7

(+levels) inhibit warfarin metabolism: phenytoin, metronidazole, choramphenicol, acute alcohol

(-levels) stimulate warfarin metabolism: barbiturates, chronic alcohol

(+levels) displace warfarin from albumin: aspirin, also inhibits platelets

(+levels) decreased vitamin K synthesis: antibiotics

Question 8

Why is warfarin often started with heparin?

Answer 8

because of the differential effect on prothrombic and anti-thrombin proteins (i.e. more rapid decrease in protein C than in prothrombin) there is a transient procoagulant effect when starting warfarin

Question 9

What are treatments for warfarin overdose?

Answer 9

mild cases vitamin K (oral or IV) takes 12-24hrs.
more serious cases: fresh frozen plasma
prothrombin complex concentrate (VII, IX, X and PT)
recombinant factor VIIa (expensive and risk of thrombosis)

Question 10

Give and example of a parenteral direct thrombin inhibitor and its uses.

Answer 10

Argatroban (small molecule active site inhibitor of thrombin)
used in treatment of acute phase HIT (metabolized in liver)

Question 11

Name 2 target specific oral anticoagulants and their targets.

Answer 11

thrombin inhibitor: dabigatran
factor Xa inhibitor: Rivaroxaban

both can be used for tx and prophylaxis of VTE, and stroke prevention in non-valvular atrial fibrillation

Question 12

Give examples of anticoagulants that act via indirect and direct inhibitors.

Answer 12

indirect: unfractioned heparin, LMWH, fondaparinux
direct: argatroban, dabigatran, rivaroxaban

Question 13

Contrast the pharmacology of warfarin and newer direct inhibitors.

Answer 13

warfarin is far more bioavailable, has a much longer half-life, metabolized by p450 and has many drug and food interactions

newer targeted meds have a rapid onset, eliminate bridging therapy, have a predictable dose response and limit drug interactions; lower rate of intracranial hemorrhage

Question 14

What are the limitations of target specific oral anticoagulants?

Answer 14

costly
difficult to monitor
no antidotes
not usable in all warfarin indications (dabigatran is not used with mechanical valves)
because of short half-life, patients who miss a dose are not protected

Question 15

When are anti platelet meds indicated?

Answer 15

coronary artery disease
cerebrovascular disease
PAD
polycythemia vera
vascular procedures including angiopalty and stent placement

Question 16

What is the mechanism and uses of aspirin?

Answer 16

irreversibly inhibits cyclooxygenase (partially blocked by other NSAIDs)
used in unstable angina, prevent CABG graft thrombosis, prevent reocclusion after coronary angioplasty, prevent Afib, prevent MI, and prevent stroke

Question 17

What is the mechanism and uses of clopidogrel? Why might a patient not respond to this drug?

Answer 17

irreversibly block the ADP receptor (antagonist), oral drug is metabolized in the liver to the active form (10%)

patient may be a poor metabolizer and demonstrate resistance

effective in preventing stroke, MI, coronary stent occlusion; note generally the more effective the ADP inhibitor, the higher the bleeding risk

Question 18

Name a IIb-IIIa receptor (of platelet) antagonist and describe how it works.

Answer 18

Abciximab is the Fab portion of monoclonal antibody to IIb IIIa (given IV), blocks platelet aggregation regardless of mechanism of platelet activation (used during PCI)

Question 19

What is the basic mechanism of fibrinolytic agents and what are their associated risks?

Answer 19

activate plasminogen to plasmin, works best in clot bound plasminogen, on the surface of a young clot

major risk includes a systemic lytic state

note urokinase can also work to break up clots although urokinase will work on plasminogen in the lumen as well

Question 20

When are fibrinolytic agents indicated?

Answer 20

MI, peripheral vascular thrombosis for limb salvage, ischemic stroke, massive PE with hemodynamic compromise

(not indicated in routine treatment of VTE)