18- Anti-thrombotic & Thrombolytic drugs

d. Aspirin

1. Anticoagulant, except

   a. Heparin

   b., Warfarin

   c. Dalteparin

   d. Aspirin

b. Argatroban

2. A direct thrombin blocker

   a. Dalteraparin

   b. Argatroban

   c. Dipyridamote

   d. Heparin

a. Idarucizumab

3. Antidote for dabigatran toxicity

   a. Idarucizumab

   b. vitamin K

   c. protamine sulfate

   d. fresh plasma

a. cilostazole

4. A drug used to treat intermittent claudication

   a. cilostazole

   b. hydralazine

   c. nitroglycerin

   d. aspirin

c. abciximab

5. GP2b/GP3a blocker

   a. Nestiride

   b. aspirin

   c. abciximab

   d. enoxaparin

von Willebrand factor

When the vascular endothelium is damaged, the exposed collagen binds to what factor?

• TXA2

• ADP

• Serotonin

Activating platelets can can release the aggregation mediators:

• Synthesis of TXA,

• Release of platelet granules,

• Activation of the GPIIB/GPIIIA receptors

Mediators evoke intracellular Ca+2 release. Elevated Ca2+ causes:

Fibrinogen

GPIIB/GPIIIA binds to a receptor to further solidify the platelets together.

Injury to blood vessel → Vasospasm (vasoconstriction) → platelet plug formation → fibrin clot formation → fibrinolysis

NORMAL HEMOSTASIS:

Thrombus

• clot that adheres to a vessel wall

• Thrombosis→ blood clot in the blood vessel

ischemic stroke

Thrombus blockage in the brain

heart attack

Thrombus blockage in the heart

Embolus

• intravascular clot that float in the blood

• Pulmonary embolism

Fibrin

stronger clot

• Aspirin

• Dipyridamole

• Cilostazol

• Adenosine Diphosphate (ADP) inhibitors

• GP-IIb/GP-IIIa Antagonists

• Vorapaxar

Anti-platelets

Aspirin

• MOA: inhibits platelet aggregation by blocking the synthesis of Prostacyclin (PGI2) & Thromboxane (TXA2)

• Prevention of thrombosis, Prevention of second attack of MI

Low dose

At __ dose, Aspirin can selectively inhibit the synthesis of TXA2

Dipyridamole

• vasodilator & Weak antiplatelet drug

• combined with aspirin (+ anti-platelet act)

• MOA: blocks platelet uptake of adenosine = dec platelet aggregation

• Use: vasodilator during myocardial perfusion imaging (Thallium imaging), stroke prevention

Cilostazol

• (antiplatelet + vasodilator)

• MOA: inhibits PDE3 → decrease degradation of cAMP

• Result: inc cAMP = dec platelet agrregation

• Use: treatment of intermittent claudication (pain and weakness in a limb)

Adenosine Diphosphate (ADP) inhibitors

• MOA: block platelet ADP P2Y12 receptors

• Result: decrease GP2B/GP3A receptor activation → no platelet-platelet aggregation

• Clopidogrel

• Prasugrel

Irreversible Adenosine Diphosphate (ADP) inhibitors

• Cangrelor

• Ticagrelor

Reversible Adenosine Diphosphate (ADP) inhibitors

GP-IIb/GP-IIIa Antagonists

• MOA: block GP2B/GP3A receptor (adhesion R)

• Result: decrease cross-linking of platelets by fibrinogen = dec platelet-platelet aggregation

• Abciximab

• Tirofiban

• Eptifibatide

GP-IIb/GP-IIIa Antagonists drugs:

Abciximab

first platelet GP-2b/3a antagonist to be developed

Eptifibatide

a GP-IIb/GP-IIIa that is a cyclic heptapeptide from rattlesnake venom

Vorapaxar

• protease-activated receptor-1 (PAR-1) antagonist

• approved for patients with a history of MI

Intrinsic Pathway

• activation is inside

• slower, but efficient

• starts at activation factor XII → XI → IX → VIII → X → Fibrin

Extrinsic Pathway

• needs tissue factor (for clotting factor)

• needs activator something outside

• faster cascade' less efficient

• starts at activation factor III → VII → X → Fibrin

Factor X

Common factor pathway

Warfarin

• Vitamin K antagonists (inhibits factors IX, X, VII, II)

• Inhibits the synthesis of proteins C and S (endogenous anticoagulants)

factors IX, X, VII, II

Warfarin inhibits the factors:

transient pro-coagulation effect

Initial effect of Warfarin:

Low MW Heparin

If there’s a transient pro-coagulation effect, add __ until anticoagulant effect has developed

pregnant woman

Warfarin is C/I to:

Phytonadione (Vit.K), Fresh Plasma, Factor IX concentration

Warfarin toxicity antidote:

• Warfarin

• Heparin and Related Drugs

• Active Factor X inhibitors (-xaban)

• Direct Thrombin Inhibitors (Heparin Alt)

Anti-Coagulants:

Heparin

• safe to pregnant women

• MOA: potentiates

• immediate onset (parenteral)

bleeding

Heparin’s Toxicity:

Protamine Sulfate

Heparin toxicity antidote:

aPTT

Heparin is measured with:

INR

Warfarin is measured with:

heparin induced thrombocytopenia

A/E Heparin:

direct thrombin inhibitors

Alternative for Heparin

Low MW Heparin

• Dalteparin, Enoxaparinn

• Inactivate Xa

• Less affinity to thrombin

• aPTT does not need to be monitored

Fondaparinux

• more selective inhibitor of Xa

• does not affect thrombin

direct thrombin inhibitors

• MOA: directly inhibits IIa

• Based on protein present in saliva of medicinal leech

• Use: if px has HIT

• Toxicity: Bleeding

Idarucizumab

direct thrombin inhibitors toxicity antidote:

• Argatroban

• Bivalirudin

• Dabigatran

direct thrombin inhibitors:

Argatroban

Tx for prophylaxis and treatment of thrombosis in patients with HIT

Dabigatran

• 1st oral direct thrombin inhibitor

• alternative to warfarin for patients who have been poorly controlled or not well monitored

Apixaban, Edoxaban, Rivaroxaban

Active Factor X inhibitors:

THROMBOLYTIC DRUGS

• Dissolve clot

• Use: Acute MI

• MOA: (+) tPA (an enzyme used to convert plasminogen → plasmin; dissolves clot)

Aminocaproic acid

Thrombolytic drugs toxicity antidote:

• Urokinase

• Streptokinase

1st Generation THROMBOLYTIC DRUGS

• Alteplase

• Reteplase

• Tenecteplase

2nd Generation THROMBOLYTIC DRUGS

• ASA + Clopidogrel

• GPIIb/GIIIa blockers

Tx for Unstable angina & Non-STEMI

Thrombolytic, LMWH, ASA

Tx for STEMI

LMWH, ASA

Tx for Acute Thrombolytics

Clopidogrel, ASA + Dipyridamole

Tx for Prophylaxis

Thrombolytics, LMWH

Tx for Pulmonary Embolism