anticoagulants, antiplatelet drugs, fibrinolytics

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how does heparin bind to ATIII?

pentasaccharide sequence (causes an allosteric change in it, accelerates interaction of ATIII with clotting factors)

How does heparin bind to thrombin?

18-saccharide sequence

What anticoagulant should not be given IM?

Unfractionated Heparin (IV=immediate, SC=delayed)

Vit K dep coag factors

2,7,9,10, Protein C&S

Protein C inactivates what factors?

F5 and F8

Indications for Anticoagulant Drugs

1.Pre- and post-surgery management of deep vein and pulmonary thrombosis, and arterial and heart valve emboli
2.Venous stasis: lengthy hospital immobilization
3.Unstable angina and post myocardial infarction: in conjunction with anti-platelet and/or fibrinolytic drugs to prevent re-infarction
4.Disseminated intravascular coagulation

Contraindications/Cautions for Anticoagulant Drugs

1.G.I. ulcerative lesions or occult bleeding; severe hypertension: recent eye, brain or spinal cord surgery; visceral carcinoma; threatened abortion
2.Anti-platelet drugs
3.Presence of thrombocytopenia: may result in serious bleeding
4.Oral anticoagulants (see below) are contraindicated in HIT

What drugs are contraindicated in a pt with HIT?

1) oral anticoagulants Heparin & also Warfarin (would accentuate HIT while trying to cause anticoagulation) 2) Fibrinolytics (inhibits the activity of protein C which inhibits F5 and F8)

What is heparin's metabolism? how is it excreted/eliminated?

initial, rapid zero order mechanism (cellular uptake and depolymerization) followed by slower first-order renal clearance

What anticoagulant has a delayed effect? Why?

Warfarin, takes time to use up VitK dep factors and for appearance of def. factors

MOA of Heparin?

Heparin provides a template for assembly of a ternary complex w/ ATIII and clotting factors, heparin binds ATIII (clotting factor protease inhibitor) through pentasaccharide sequence, binds thrombin via 18 saccharide sequence

MOA of Enoxaparin, & Fondaparinux?

contain pentasaccharide sequence needed for ATIII binding but not 18 sacchardie sequence, Xa selective (LMWH have greater antifactor Xa activity than antithrombin activity w/ goal prevent thrombin formation)

MOA Warfarin?

resembles structure of vitamin K, vitamin K antagonist, inhibits VKOR (vitamin K epoxide reductase), prevents formationof vitK dep clotting factors (turnover of F7 is fastest), lacking gamma carboxylation=coagulation is arrested

What foods are avoided while on Warfarin?

Vit K high rich foods (spinach, green veggies)

What drug(s) has a recombinant form of hirudin, the anticoagulant found in leeches?

Lepirudin, Bivalirudin, Desirudin

MOA of Rivaroxaban?

small molecule active site inhibitor of Factor Xa, alternative to Warfarin, prevention of venous thrombosis

MOA of Dabigotran?

direct thrombin inhibitor that inhibits both free and clot-bound thrombin. Dabigatran prevents thrombin-induced platelet aggregation and the development of a thrombus by preventing the thrombin-mediated conversion of fibrinogen into fibrin during the coagulation cascade

MOA of Argatroban?

Synthetic Antithrombin,N6 substituted analog of arginine

What drugs have no antidotes?

LMWHs (Enoxaparin, Dalteparin, Tinzaparin, Fondaparinux), Direct Thrombin Inhibitors (Lepirudin, Bivalirudin, Desirudin)

low dose aspirin vs high dose aspirin

aspirin is a selective inhibitor of platelets. low dose aspirin acetylates and irreversibly inhibits COX in platelet via prevents Thromboxane A2 (promotes platelet adhesion) formation. high dose aspirin loses COX selectivity and inhibits COX in platelets (TXA2) and on endothelial cells via preventing PGI2,prostacyclin (prevents platelet adhesion) formation.

Who do you not give aspirin to?

asthmatic pts, pts w/ stomach/GI problems, and pts on NSAIDs (competes for binding/catalytic site)

Toxicities of Ticloidine?

GI disturbances, life threatening neutropenia and blood dyscrasias

MOA of Dipyridamole?

inhibits platelet PDE, increases cAMP, inhibits platelet aggregation and release, sometimes combined with aspirin or warfarin

MOA of Ticlopidine?

used as an aspirin alternative, platelet ADP receptor (P2Y12 receptor) inhibitor, irreversibly inhibits platelet ADP receptors and ADP induced exposure of platelet membrane glycoprotein IIb/IIIa and fibrinogen binding to activated platelets

In what way is Clopidogrel(Plavix) better than Ticlopidine?

safer b/c does not have blood dyscrasias and life threatening neutro

If a pt is on Ticlopidine but you realize you need a similar drug that works faster, what drug will you use?

Prasugrel (more potent but faster than Ticloipidine)

Which antiplatelet drugs must be bioactivated?

Clopidogrel (activated by CYP2C19), Prasugrel

What class of drugs do you not want to give with Clopidogrel(Plavix)?

PPIs (Omeprazole), inhibition of CYP2C19 by PPIs prevents Clopidogrel metabolite formation

What antiplatelet drug is a monoclonal ab? How does it work?

Abciximab blocks the binding of fibrinogen and vWF to GPIIb/IIIa complex and inhibits platelet aggregation (noncomp inhibition)

What antiplatelet drugs are small molecules that are competitive inhibitors of GP IIb/IIIa?

Eptifibatide (cyclic heptapeptide) and Tirofiban (nonpeptide)

What drug is used for the treatment of essential thrombocytopenia? How does this drug work?

Anagrelide, decreases platelet count, inhibits platelet aggregation by inhibiting cyclic nucleotide phosphodiesterase

What drug is used for treatment of intermittant claudication? How does this drug work?

Cilostazol, causes vasodilation, inhibits platelet aggregation by inhibiting cyclic nucleotide phosphodiesterase

What fibrinolytic drug is not an enzyme?

Streptokinase

What releases tPA? How does tPA work?

tPA is released by the endothelium. tPA binds fibrin, forming a complex of tPA, fibrin, and plasminogen. Plasminogen is then activated to plasmin, a protease that degrades fibrin (fibrinolysis) but which can also degrade clotting factors (fibrinogenolysis)

Normally, how is plasminogen activity in the plasma inhibited?

PAI-1, alpha-2 antiplasmin

First Generation Fibrinolytics & characteristics

not fibrin specific, cause appreciable systemic fibrinogenolysis and bleeding, Streptokinase, Urokinase

Second Generation Fibrinolytics & characteristics

bind to fibin, this confers specificity of action to cot, specificity is not absolute, less systemic fibrinogenolysis, bleeding is reduced but not eliminated, Alteplase (tPA)

Third Generation Fibrinolytics & characteristics

improved fibrin specificity and kinetics, Reteplase, Tenecteplase

What fibrinolytic drug is antigenic, and thus limits the number of times that you can give it IV? How can you circumvent the antibody reaction?

Streptokinase (obtained from beta hemolytic streptococci), give intracoronary injection that allows delivery to site needed but circumvents antibody reaction

What fibrinolytic drug has a t1/2=20 min , such that it may require several admin to prevent rethrombosis?

Alteplase

MOA of Streptokinase?

forms a 1;1 complex with plasminogen, exposing active site that activates additional plasminogen into plasmin

MOA of Tenecteplase?

AA substitution, more specific and longer half life than alteplase

MOA of Alteplase?

(rTPA) single chain polypeptide that is converted to 2 chain tPA dimer upon exposure to fibrin, more effective that streptokinase

MOA of Urokinase?

endogenous enzyme which activates plasminogen directly, (two chain urokinase type plasminogen activator: tcu-PA)

MOA of Reteplase?

derivative of alteplaste (rt-PA), contains the domain (retains amino acids) necessary for binding fibrin and protease domain of tPA, more rapid onset, more potent than aleteplase

How do you reverse:
a) Unfractionated Heparin?
b) Warfarin?
c) Fibrinolytic drugs, such as Streptokinase or Tenecteplase?

a) Protamine (chemical antagonist, positive charges bind to heparin's negative charges)
b) no exact antidote but give Vit K and plasma or concentrates (ex: FFP) and discontinue warfarin
c) Aminocaproic acid/Amicar, Tranexamic acid (inhibit plasminogen activation and plasmin action, blocks lysine binding interactions)

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