Drugs in Blood Disorders

• 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

• 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)

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

• 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)

• Drugs: enoxaparin, danaparoid
• act more on Xa, better bioavailability, 2-4X longer half-life
• Administration: subQ
• Monitoring: no labs needed
• Not easily reversible

• 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

• 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

• 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)

• 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

• Clot specific, acts mainly on fibrin-bound plasminogin
• natural activator
• no allergy problems

• 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

• ASA
• Ticlopidine & Clopidogrel
• Abciximab, epifibatide, tirofiban

• 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

• 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)

• 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

• Mechanism: monoclonal antibody, binds to glycoprotein recepotr IIb/IIIa on activated platelets, prevents aggregation
• Clinical use: acute coronary syndromes, angioplasty
• Toxicity: bleeding, thrombocytopenia