Blood d/o drugs Flashcards
What do oral anticoagulants generally do?
Inhibit hepatic synthesis of factors 2, 7, 9, 10, C, S
Which factors do C and S deactivate?
Va, VIIIa
What activates the intrinsic clotting cascade?
- damage → exposure of SEC
2. inflammation → kinin activation (prekallikrein, kininogen)
What activates the extrinsic pathway?
Any cellular damage in any tissue will release tissue factor (and activate factor VII)
What two factors can activate factor X?
IXa or VIIa
What factors does heparin act on?
all activated factors of intrinsic and common pathway (XIIa, XIa, IXa, Xa, IIa) - this is why we use PTT to monitor heparin
What factors does warfarin act on?
NOT the activated factors, but the synthesis of vitamin K dependent factors in liver
What factor does argatroban block?
IIa aka thrombin (catalyzes fibrinogen → fibrin)
What drug has the sole activity of blocking thrombin (factor IIa)?
Argatroban
What drugs activate plasminogen → plasmin? What are they called as a class?
Streptokinase and alteplase; called fibrinolytics (because plasmin degrades fibrin clot)
What property of heparin makes it deliverable by IV only?
water soluble
Heparin or warfarin: large polysaccharide? small molecule?
Heparin = large polysaccharide Warfarin = small molecule
As a small, lipid soluble molecule, what properties do you expect warfarin to have?
orally deliverable, metabolized by the liver, crosses placenta, highly plasma protein bound, long half life
Which has a longer half life: heparin or warfarin?
heparin: 2 hr
warfarin: 30+ hr
(remember, warfarin is lipid soluble and heparin is water soluble)
What is the action of heparin?
catalyzes the binding of antithrombin III (a serine protease inhibitor) to inactivate activated factors in intrinsic and common pathway: IIa, IXa, Xa, XIa, XIIa
What is the action of warfarin?
prevents gamma carboxylation of 1972, and CS; no effect on factors already activated
Do heparin or warfarin inhibit clotting in vitro?
heparin only (remember that warfarin only acts in the liver on factor synthesis)
What is INR?
PT of patient / PT of control → standardized measure of PT with no units
What would a target INR be in a patient on warfarin?
1.5 - 2.5 (this means it takes about twice as long for the patients blood to clot in a tube as a control patient)
What are the antidotes for warfarin and heparin?
Warfarin - fresh frozen plasma, (or vitamin K on STEP1 but not done in practice because this would require synthesis of new factors to normalize PT, takes way too long)
Heparin - protamine sulfate
What type of hypersensitivity response is HIT?
II
What property of heparin → HIT?
as a large sugar, very immunogenic when bound to protein (platelet factor IV in this case)
Describe the pathogenesis of HIT
platelet factor IV is on membrane of platelets → opsonization by heparin in 5-10% of patients on heparin → destruction of platelets by splenic Mø → thrombocytopenia
What is the advantage of LMW heparins?
As smaller sugar molecules, they are less likely to cause HIT (remember, the large sugar of heparin + protein (PF4) → immunogenicity)
What drug do you use in place of heparin for patients with HIT? Why?
Argatroban; it is not a sugar like heparin, so low risk of immunogenicity
What drugs would cause decreased absorption of warfarin?
drugs that bind bile, preventing its reuptake (eg. cholestyramine) because warfarin is a lipid that requires emulsification by bile salts to be absorbed
What effect would warfarin have on the fetus if taken during pregnancy?
bone damage
Where do factors V and VIII fit into the coagulation story?
they are not part of the cascade; clotting starts slowly without these factors and are activated by thrombin → acceleration of common pathway; VIIIa activates X and Va activates II (prothrombin); Remember V and VIII as accelerators
How do factors C and S work?
If V and VIII are the accelerator, C and S are the brakes that inactivate both V and VIII
Why does warfarin have an ↑ risk of clotting initially?
removes the brakes before the clotting factors (i.e. protein C which inhibits the accelerators V and VIII) because protein C has a half life of about 14 h and factors have a much longer half life (e.g. IIa T1/2 = 60 h)
What is the order of loss of the following after warfarin administration: intrinsic pathway, protein C, extrinsic pathway?
extrinsic (8 hr) then protein C (14 hr) then intrinsic (24-60 hr)
When is bivalirudin used?
direct thrombin inhibitor (like argatroban) used in patients with unstable angina (in combo with asprin) to perform PCTA (percutatneous transluminal coronary angioplasty)
What effect would warfarin have on the fetus if taken during pregnancy?
bone damage
Where do factors V and VIII fit into the coagulation story?
they are not part of the cascade; clotting starts slowly without these factors and are activated by thrombin → acceleration of common pathway; VIIIa activates X and Va activates II (prothrombin); Remember V and VIII as accelerators
How do factors C and S work?
If V and VIII are the accelerator, C and S are the brakes that inactivate both V and VIII
Why does warfarin have an ↑ risk of clotting initially?
removes the brakes before the clotting factors (i.e. protein C which inhibits the accelerators V and VIII) because protein C has a half life of about 14 h and factors have a much longer half life (e.g. IIa T1/2 = 60 h)
What is the order of loss of the following after warfarin administration: intrinsic pathway, protein C, extrinsic pathway?
extrinsic (8 hr) then protein C (14 hr) then intrinsic (24-60 hr)
When is bivalirudin used?
direct thrombin inhibitor (like argatroban) used in patients with unstable angina (in combo with asprin) to perform PCTA (percutatneous transluminal coronary angioplasty)
What medication is the recombinant synthetic form of tPA (rTPA)?
alteplase
What thrombolytic drug is made from the hemolysins produced by streptococcal bacteria?
streptokinase
4 conditions in which fibrinolytic drugs are used:
- coronary thrombosis in MI
- stroke caused by thrombus (non-hemorrhagic)
- DVT
- PE
What are the differences b/w the fibrinolytics streptokinase and alteplase?
- streptokinase is antigenic (it comes from bacterial product) → can react with strep antibodies and cause anaphylaxis (hypersensitivity); alteplase does not cause allergy b/c recombinant form of human protein;
- streptokinase is very cheap b/c bacterial product and alteplase is very expensive
- streptokinase binds to plasminogen → conformational change → activation to plasmin vs. alteplase binds directly to fibrin (more clot specific instead of causing a general lytic state) → activates plasminogen to plasmin
What is the time window in which thrombolytics can be used?
< 3 hours clinically
What is the antidote for thrombolytic OD (excessive bleeding)?
Antifibrinolysins: aminocaproic acid (EACA = epsilon aminocaproic acid) or tranexamic acid
How does abciximab work?
binds gpIIb/IIIa, blocking binding to fibrinogen
What drug blocks the synthesis of thromboxane A2 thus preventing platelet activation?
asprin - a baby dose is enough to cause irreversible inhibition of platelet aggregation for the life of the platelet
What are the uses for direct antiplatelet drugs (e.g. abciximab)?
acute coronary syndromes (i.e. in process of developing MI) and post-angioplasty; NOT for chronic management (unlike aspirin or clopidogrel)
Path review: which disease has a deficiency in GpIb? GpIIb/IIIa?
GpIb: Bernard Soulier syndrome
GpIIb/IIIa: Glanzmann thrombasthenia
What patients are prescribed asprin for prevention?
Ppl w/ risk for IHD: atherosclerosis, HTN, smokers, diabetics, previous MI, atrial arrhythmias
TIA patients to prevent stroke
How many mg is a baby asprin? What are the side effects?
81-82 mg; very unlikely to have side effects at such a low dosage
When are clopidogrel and ticlopidine used?
as an alternative (effects are equal) to baby asprin for post-MI, TIA, and unstable angina patients
What is the disadvantage of using ADP receptor blockers in place of asprin?
side effects: leukopenia, TTP → risk of hemorrhage
clopidogrel has less risk vs. ticlopidine
What are the uses for direct antiplatelet drugs (e.g. abciximab)?
acute coronary syndromes and post-angioplasty
What are the direct antiplatelet drugs?
abciximab, and the “fib” drugs eptifibatide, tirofiban (fib = fibrinogen receptor antagonist)
