Flashcards in Anticoagulants Deck (41)
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Anticoagulants
Heparin, Enoxaparin, Lepirudin, Dabigatran, Rivaroxaban, Warfarin
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Fibrinolytics
Streptokinase, Alteplase
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Antithrombotics
Aspirin, Clopidogrel, Vorapaxar, Abciximab
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Thrombogenesis
Immediate hemostatic response of a damaged vessel, Vasospasm
Within seconds, Platelets stick to the exposed collagen of the damaged endothelium, Platelet adhesion
& then to each other, Platelet aggregation
Platelet plug quickly arrests bleeding
Must be reinforced by fibrin for long-term effectiveness
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White thrombus
Forms in high-pressure arteries & decreases arterial flow, Stasis triggers fibrin formation → Stroke, MI
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Red thrombus
Can form around a white thrombus or in low-pressure veins, Platelets form a long tail consisting of a fibrin network in which RBC are enmeshed → DVT → PE
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Blood Coagulation
Blood coagulates by the transformation of soluble fibrinogen → insoluble fibrin
At each step of this cascade, a clotting factor, i.e., zymogen undergoes limited proteolysis & becomes an active protease, VII is activated to VIIa
Protease activates the next clotting factor, Until a solid fibrin clot is formed
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Regulation of Coagulation & Fibrinolysis
Blood coagulation must be confined to the smallest possible area to achieve local hemostasis in response to bleeding, Without causing disseminated coagulation or impaired blood flow
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Blood contains ________ that rapidly inactivate the coagulation proteins as they leave the site of injury, e.g.,
protease inhibitors; antithrombin
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Critical step in fibrinolysis
Conversion of inactive plasminogen into the proteolytic enzyme plasmin
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Heparin
about 50 monosaccharides in a chain
Greatly increases the rate of activity of antithrombin, Heparin (-) binds with antithrombin (+) which inhibits serine protease clotting enzymes
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Heparin inhibits
Inhibits clotting factors IIa (thrombin) & Xa, (IXa, XIa, & XIIa)
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Heparin uses
Thrombosis/Embolism: Prophylaxis (e.g., after major surgery) & active Treatment (e.g., PE, DVT)
Disseminated Intravascular Coagulation (DIC)
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Heparin side effects
Hemorrhage (<10%) anywhere in the body (e.g., GI)
Allergy (chills, fever, urticaria)
Thrombocytopenia (HIT) (Heparin induces antibodies which destroy platelets, also attack the lining of blood vessels which can trigger a coagulation cascade
HIT can cause stroke & other thrombotic complications which can be life threatening)
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Heparin antidote/Hep's activity measured by
protamine; aPTT
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Heparin drug interactions
Cephalosporins, penicillins, NSAIDs (ex aspirin)
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Enoxaparin mech of action
(smaller version of heparin) more sensitive for Xa than IIa
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Enoxaparin therapuetic uses
DVT prophylaxis
DVT Tx (+/- PE)
Unstable angina/Non-Q-wave MI
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Enoxaparin side effects/drug interactions
similar effects to heparin, also hematomas; interacts w/ same drugs as heparin
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Rivaroxaban mech of action; thera uses
Direct Xa inhibitor; Atrial fibrillation: Prevent → Stroke, Systemic embolism
Prophylaxis of DVT: Knee, Hip replacement
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Rivaroxaban side effects and pharmacodynamics
Hemorrhage: Spinal or Epidural anesthesia or puncture; CYP3A4, P-gp
Severe renal & hepatic impairment (↑AUC)
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Lepirudin; thera use
Polypeptide analog of hirudin → Hirudo medicinalis (leech); Heparin-induced thrombocytopenia
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Lepirudin, Argatroban, Dabigatran mech of act
Inhibits thrombin (IIa) by binding to it (1:1 stoichiometry)
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Lepirudin side efect; pharmocokinectics
Allergy- Antibody inhibition b/c of yeast expression; Adjust dose with hepatic function
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Dabigatran; Therapeutic uses
Prodrug; Atrial fibrillation: Prevent systemic embolism, Stroke
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Dabigatran side effects; pharmaco
Hemorrhage (intracranial bleeding), Less bleeding with dabigatran vs. warfarin, GI (dyspepsia, gastritis);
Adjust dose with renal function, Rifampin (P-gp)
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Warfarin
Racemic mixture, S-enantiomer 4 x more potent; Therapeutic efficacy, Measured by international normalized ratio (INR), Therapeutic range, 2.0 to 3.0
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Warfarin mech of action and therap uses
Vitamin K analog & thus blocks the gamma-carboxylation of several glutamate resides in clotting factors II, VII, IX & X; Venous thrombosis: prophylaxis & treatment
Atrial fibrillation: prevent embolization
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Warfarin side effects
Hemorrhage
Necrosis (gangrene of the skin)
Hypercoagulation (transient)
Warfarin blocks the biosynthesis of protein C which inactivate clotting factors Va, VIIIa (via proteolysis), Because of the slow onset of anticoagulation with warfarin therapy, Heparin tx is used for the 1st 5 days
Birth defects (facial, CNS)
Abortion
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treatment of warfarin hemorrhaging
D/C warfarin, Give Vitamin K1 (phytonadione), Give Plasma, Give Factor IX concentrate
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warfarin drug interactions
Bleeding
PK: Amiodarone, Metronidazole, Fluconazole Sulfamethoxazole/Trimethoprim, Clopidogrel
PD: Aspirin, Ceftriaxone, Ginkgo biloba
Clotting
PK: Phenobarbital, Rifampin, Carbamazepine, St. John’s Wort, Cholestyramine
PD: Vitamin K, Hydrochlorothiazide
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mech of action of Streptokinase, Alteplase
Converts plasminogen into plasmin which degrades fibrin & fibrinogen
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thera uses Streptokinase, Alteplase
Acute myocardial infarction (S,A)
Pulmonary embolism (S,A)
Deep vein thrombosis (S)
Arterial thrombosis & embolism (S)
Occluded arteriovenous cannulae (S)
Acute ischemic stroke (A)
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side effects Streptokinase, Alteplase
Hemorrhage
Lysis of fibrin at vascular injury
Systemic plasmin inhibits factors V & VIII
Allergy (anaphylaxis, S)
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aspirin mech of action
Inhibits the synthesis of thromboxane A2, Irreversible acetylation of COX-1/2, Anuclear platelet, Can’t synthesize more COX during its 10-day lifetime
Thromboxane A2 function: platelets c shape, release granules, & aggregation
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aspirin uses, side effects
1o prophylaxis of MI & TIA ;
Bleeding, GI Ulcers
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Clopidogrel mech of action and therapeutic use
P2Y12 receptor antagonist, therefore it interferes with platelet membrane function by inhibiting ADP-induced platelet-fibrinogen binding & subsequent platelet-platelet interaction ; Arterial thromboembolism prophylaxis: Prevent Myocardial infarction, Stroke
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Clopidogrel side effects and pharmacodynamics
Thrombocytopenia, Leukopenia, Thrombotic Thrombocytopenic Purpura; Bioactivated 1o by CYP2C19 & Inhibitor of CYP2C9
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Vorapaxar mech of action and thera use
Mechanism of action:
Protease-activated receptor-1 (PAR-1) antagonist, Inhibits thrombin mediated activation of platelets
Therapeutic use:
Myocardial infarction, Peripheral artery disease, ↓ thrombotic cardiovascular events, With ASA + Clopidogrel
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Vorapaxar side effects and drug interactions
Hemorrhage: contraindicated in patients with 1. active bleeding conditions, 2. history of TIA, 3. stroke & 4. intracranial bleeding, Anemia, Retinopathy (diplopia); CYP3A4 substrate, Anticoagulants (e.g., NSAIDs, SSRIs, warfarin)
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