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Anticoagulants: General
- Drugs that decrease the formation of fibrin clots
- Oral anticoagulants (ie warfarin) inhibit hepatic synthesis of clotting factors 9, 7, 2, 10
- IV anticoagulants (ie heparin) inhibits activity of several activated clot factors (IIa, Xa) via activation of antithrombin III
- Endogenous anticoagulants (Protein C & S) = proteolysis of factors 5a & 8a
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Anticoagulant: Heparin
- Chemical Nature: large polysaccharide, water soluble
- Kinetics: IV, t1/2 = 2 hours, no placental access
- Mechanism: heparin catalyzing binding of antithrombin III (serine protease inhibitor) to factors 2a, 4a, 10a, 11a, 12a = rapid inactivation
- Monitoring: PTT
- Antagonist: protamine sulfate - chemical antagonism (the + charge binds to the negative heparin charge), fast onset
- Clinical use: rapid anticoagulation for thromboses, emboli, unstable angina, DIC, open heart surgery
- Toxicity: bleeding, osteoporosis, HIT, hypersensitivity (II)
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Heparin Induce Thrombocytopenia
Heparin binds to platelets = autoanibody production that destroys platelets & overactivates the remaining ones = thrombocytopenic, hypercoagulable state
Tx: Agatroban: direct thrombin inhibitor, doesn't require ATIII, does not interact w/ heparin-induced antibodies
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Anticoagulant: Warfarin (coumarins)
- Chemical nature: small, lipid soluble derivatives of vit K
- Kinetics: PO, 98% protein bound, liver metabolism, t1/2 = 30 hours, placental access
- Mechanism: decreases hepatic synthesis of 9, 7, 2, 10 (vit K dep factors), Y-carboxylation by inhibiting vit K epoxide reductase; no effect on factors alreayd present, in vivo effects nly
- Monitoring: PT; INR
- Antagonist: vit K = increased cofactor synthesis, slow onset, frest frozen plasma (fast), acts on extrinsic pathway
- Uses: LT anticoagulation (controlled), for thromboses, emboli, post MI, heart valve damage, atrial arrhythmias, etc.
- Toxicity: bleeding, skin necrosis (if low protein C, drug interactions, teratogenic (bone dysmorphogenesis)
- Drug interactions: PO absorption decreased by cholestyramine, any drug that displaces warfarin from the protein (ASA, sulfonamides, phenytoins)
- SLOW hepatic metabolizers via P450:
- inducers: (barbiturates, carbamazepine, rifampin) = decrease PT
- Inhibitors (cimetidine, macrolies, azole antifungals, grapefruit juice) = increase PT
the EX-PresidenT went to WAR(farin)
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Low Molecular weight heparins
- Drugs: enoxaparin, danaparoid
- act more on Xa, better bioavailability, 2-4X longer half-life
- Administration: subQ
- Monitoring: no labs needed
- Not easily reversible
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Protein C Deficiency
- Transient Protein C deficiency when initating tx of warfarin bc factors 8 and C have shortest half life = extrinsic pathway and Protein C are inacrivated, whilst intrinsic pathway remains active for a few days
- Hypercoagulability occurs = hermal vascular thrombosis, skin necrosis
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Anticoagulants: Lepirudin, Bivalirudin
- Hirudin derivatives
- Mechanism: directly inhibit thrombin
- Clinical use: alternative to heparin for anticoagulating in pts with HIT, used with ASA in unstable angina when undergoing percutaneous transluminal coronary angioplasty
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Thrombolytics (Fibronolytics)
- Drugs: streptokinase, urokinase, tPA (alteplase), APSAC (anistreplase)
- Mechanism: directly or indirectly aid in conversion of plasminogen to plasmin = cleaves thrombin and fibrin clots = increased PT, PTT and no change in platelet count
- Clinical use: IV for ST use in early MI, early ischemic stroke, PE, DVT
- Toxicity: bleeding, contraindicated in active bleeding, hx of intracranial bleeding, recent surgery, known bleeding diatheses, severe htn
- Toxicity tx: aminocaproic acid (fibrinolysis inhibitor)
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Thrombolytic: Streptokinase
- Derived from bacteria = antigenic (foreign protein derived from B-hemolytic streptococci); may cause problems if recent/past infection bc strep antibodies can decrease activity
- Acts on both bound and free plasminogen (not clot specific), dpelets circulating plasminogen and factors 5 & 8
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Thrombolytic: Atelplase
- Clot specific, acts mainly on fibrin-bound plasminogin
- natural activator
- no allergy problems
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Clinical features of Thrombolytics
- early administration is key (>60% decrease in post-MI mortality if administered w/in 3 hours)
- ASA, beta blockers, nitrates = decrease mortality (MONA tx)
- adenosine decreases infarct size
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Antiplatelet Drugs:
- ASA
- Ticlopidine & Clopidogrel
- Abciximab, epifibatide, tirofiban
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Thrombous (clot) formation involves 3 things:
- 1. Platelet adhesion to side of vascular injury
- 2. Activation of platelets by factors: TxA2, ADP, collagen, 5HT, thrombin = increased expression of glycoprotein IIb/IIIa receptors
- 3. Aggregation of platelets by cross-linking reaction between fibrinogen & glycoprotein IIb/IIIa receptors
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Antiplatelet Drug: ASA
- Mechanism: acetylates & irreversibly inhibits COX in platelets = prevents conversion of arachidonic acid to TxA2 = increased bleeding time, no effect on PT or PTT
- Clinical use: low doses prevents MI and recurrence; prophylaxis in atrial arrhythmia and TIA
- Toxicity: gastric ulcers, bleeding, hyperventilation, Reye's syndrome, tinnitus (CN 8)
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Antiplatelet Drug: Ticlopidine & Clopidogrel
- Mechanism: blocks ADP receptors on platelets = decreased activation & inhibits fibrinogen binding by preventing glycoprotein IIb/IIIa expression
- Clinical use: alternatives to ASA in TIA, post-MI, unstable angina
- Toxicity: neutropenia
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Antiplatelet Drug: Abciximab, epfibatide, tirofiban
- Mechanism: monoclonal antibody, binds to glycoprotein recepotr IIb/IIIa on activated platelets, prevents aggregation
- Clinical use: acute coronary syndromes, angioplasty
- Toxicity: bleeding, thrombocytopenia
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