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Pharmacology: HematologyHeme Pharm I: Platelet Drugs & EPO...................................................................................................................................... 2 Heme Pharm II: Heparins, Coumarins, Thrombolytics, Procoagulants ................................................................................... 5

Heme Pharm I: Platelet Drugs & EPONote that platelet inhibitors are used PROPHYLACTICALLY ONLY (they have NO EFFECT on a formed thrombus)

Aspirin (acetyl salicylic acid): the antiplatelet drug supreme! Safe, cheap, effectiveaspirin Mechanism of Action: antiplatelet agent (and anti-inflammatory too). Covalently inhibits cyclooxygenase (which produces thromboxane A2 in platelets) Effects: inhibits thromboxane-A2-mediated platelet aggregation & vasoconstriction (aspirin --> vasodilation). Inhibition is long-lived (platelets don't synthesize new protein; have to wait for new platelets to be made) Administration: Dose to inhibit platelet cyclooxygenase (160mg) is less than dose for anti-inflammatory / antipyretic effects. More than 320mg is counterproductive (can block formation of PGI2 / prostacyclin, a natural inhibitor of platelet aggregation) Other: Safe, effective, and really cost-effective (cheap!)

Dipyridamoledipyridamole Mechanism of Action: antiplatelet agent with dual mechanisms, both leading to increased cAMP: inhibits cyclic nucleotide phosphodiesterase inhibits nucleoside transport/uptake (stimulates adenylate cyclase) Effects: increased intracellular cAMP inhibits platelet aggregation. (also has vasodilator properties) Indications: combination treatment for prophylaxis of thrombosis / embolization Administration: only proven effective in combination (warfarin or aspirin); does not prevent embolization / thrombus by itself Toxicity: headache & hypotension (esp. in high doses More than 320mg is counterproductive (can block formation of PGI2 / prostacyclin, a natural inhibitor of platelet aggregation) Other: Safe, effective, and really cost-effective (cheap!)

Platelet Glycoprotein IIb/IIIa antagonists GP IIb/IIIa: receptor for fibrinogen; plays role in platelet activation ( platelet aggregation, adherence) 3 kinds (antibody, small peptide, small molecule; dont have to memorize names) All cause bleeding but DONT appear to cause increased intercranial bleeding VERY EXPENSIVE ($1500-$2000/course) but may actually save money (prevent re-stenosis post-angioplasty, prevent need for repeat angioplasty / CABG)

mAb: abciximabmAb Mechanism of Action: antiplatelet agent. Blocks GPIIb/IIIa-mediated platelet aggregation IIb/IIIa antagonist Indications: only anti-platelet mAB shown to have anti-thrombotic activity in humans (abciximab) Administration: Always given with heparin & aspirin. Rapidly cleared (10m half life); give as large bolus then slow infusion (18-24h). Half-life of recovery of aggregation is 24h (Fabs remain on platelets & can redistribute to GPIIb/IIIa on new platelets). Toxicity: bleeding (2x vs heparin+aspirin alone) pseudothrombocytopenia (Ab-mediated platelet clumping) Resistance: anti-murine antibodies (6.5% after 1 dose, very important - avoid giving a second time!) Other: chimeric (mouse variable, human constant regions); only Fab portion used. Could use platelet transfusion to reverse side-effects if needed.

small peptide: eptifibatidesmall peptide Mechanism of Action: antiplatelet agent. Blocks GPIIb/IIIa-mediated platelet aggregation by blocking IIb/IIIa antagonist fibrinogen, vWF, vitronectin binding to IIb/IIIa (eptifibatide) Effects: mimics AA sequences important for GPIIb/IIIa binding: (KGD mediates fibrinogen binding; RGD mediates vWF binding) Indications: anti-thrombotic Administration: Given with aspirin + heparin. More slowly cleared than abciximab; still given as rapid large bolus + slow infusion for up to 72 hrs. Rapidly reversible effects (mediated by drug clearance from plasma). Toxicity: bleeding (marginally increased vs heparin+aspirin alone), not immunogenic Other: Elimitated via proteolysis to AA & urinary elimination of unchanged drug

small molecule: tirofibansmall molecule Mechanism of Action: antiplatelet agent. IIb/IIIa antagonist Blocks GPIIb/IIIa-mediated platelet aggregation by inhibiting fibrinogen binding to GPIIb/IIIa (tirofiban) Effects: binds reversibly to IIb/IIIa receptor Indications: anti-thrombotic Administration: Give as large bolus then slow infusion (up to 108h). Toxicity: bleeding (2x vs heparin+aspirin alone) Other: Renal clearance (2h half-life); effects rapidly reversible (mediated by plasma clearance)

ADP Antagonists Looking for better / more expensive aspirin Clopidogrel - Plavix, 2nd to market but maybe less toxic?Mechanism of Action: antiplatelet agents; inhibit ADP-induced platelet aggregation Effects: Bind irreversibly to low-affinity ADP receptors (non-competitive) Block ADP-mediated release of platelet alpha granules / dense granules Inhibit fibrinogen binding to activated platelets indirectly block activation of platelet glycoprotein IIb/IIIa receptor Indications: Slightly better at preventing stroke in pts with TIAs than aspirin; can help prevent coronary thrombosis Administration: long-lived effects (ADP receptor blocked for life span of platelet; need to synthesize new ones: 7-10d) Toxicity: neutropenia (severe but reversible, ticlopidine 1%, clopidogrel 0.1%) bleeding, diarrhea, thrombocytopenia (TTP) Other: CYP450 substrates - activity requires conversion to active metabolite (complicates treatment, as activity varies from pt to pt); inhibit CYP 2C9. Clopidogrel = Plavix; thought to be less toxic than ticlopidine. Much more expensive than aspirin

ticlopidine clopidogrel

Erythropoietin (EPO)erythropoietin (EPO) Mechanism of Action: promotes erythropoiesis (hormone) Effects: 1. binds EPO receptor on erythroid precursor cells 2. causes conformational change & activates Jak-STAT pathway (Jak-2 TK p-lates receptor, recruits STAT-5, which gets p-lated & goes to nucleus as transcription factor) 3. induces red cell maturation gene expression. 4. Actually primarily BLOCKS APOPTOSIS of erythroid precursor cells. Indications: anemia (chronic renal failure, cancer, AIDS) perioperatively (reduce transfusion) illicit (blood doping by athletes) Administration: IV/sub-q, usually start at 80-120 U/kg 3x/wk; sustained effect after its disappearance Toxicity: aggravates hypertension potential increase in thrombosis risk theoretical neoplasm risk (cell growth factor - now a black box warming) Other: 193-AA protein, 1st 23 AA cleaved off, then heavily glycosylated (recombinant form used)

Heme Pharm II: Heparins, Coumarins, Thrombolytics, ProcoagulantsCoagulation System ReviewActivated by Test Intrinsic Phospholipids, particulate matter (kaolin) intrinsic to plasma Activated partial thromboplastin time (APTT) used for heparin monitoring Extrinsic Tissue Factor, phospholipids (thromboplastin) extrinsic to vessel lumen Prothrombin time (PT) used for warfarin monitoring

Endogenous mechanisms to prevent/control thrombosis Prostacyclin(PGI2): inhibits platelet aggregation Heparan sulfate: endothelial cell surface proteoglycan, like heparin boosts antithrombin Antithrombin: specific protease inhibitor (like 1 antitrypsin); interferes with various factors (suicide Protein C: + protein S, VaVi and VIIIa VIIIi substrate for serine proteases) Indications for anticoagulant tx

Prevention: Heparins & coumarins prevent thrombus formation in lots of settings Antiplatelets for long-term prevention (esp. coronary / cerebral artery disease)

Treatment: Heparin (acute) and coumarin (chronic) therapy

Prevent further thrombus formation Dont act on already existing thrombiUsed for: Arterial & venous thrombosis; artificial heart valve thrombi, thrombi assoc. with atrial fibrillation

Dissolution: Thrombolytics (clot busters) Actively dissolve pathologic thrombi Used for: coronary arteries, peripheral arteries, large veins, venous caths Dont prevent thrombus formation: follow with short-term anticoagulation (heparin, sometimes warfarin)

HeparinA Hopkins-discovered drug, disputed discovery, abundant in liver. Heparin = in mast cell secretory granules; heparan is endothelial cell surface molecule

HeparinMechanism of Action: Anticoagulant agent. Several mechanisms of action: Boosts antithrombin activity inhibits intrinsic >>>; extrinsic pathways (APTT primarily prolonged). At high concentrations: o Interfere with platelet aggregation o Activate heparin cofactor II (antithrombin homolog, thrombin-specific) Indications: Prevention & treatment (acute) of thrombosis, but don't dissolve clots (prevent new ones from forming) Administration: 1 unit = amt heparin needed to prevent 1.0 mL plasma from clotting 1 hour after adding calcium chloride (variable MW/size; only 30% of molecules have antithrombin-binding-site, so dose by activity). Continuous / intermittent infusions & sub-q injections

heparin

Toxicity: Bleeding (often inadequte therapeutic monitoring, more common in elderly, worry about intercranial bleeding. Thrombocytopenia (mild is common; severe less frequently & 7-14d post tx initiation, always reversible with discontinuation) Paradoxical thrombosis / white clot syndrome (uncommon), reversible alopecia OSTEOPOROSIS (very important, lots of elderly pts) Reversal of toxicity: STOP THERAPY Can give protamine (positively charged low molecular weight proteins from fish sperm; give equimolar amountto titrate out heparin, only if life-threatening b/c can induce hypotension/anaphylaxis/hypercoagulation. Diabetics who take insulin with protamine are more prone to anaphylaxis: may already have anti-protamine Ab)

Pharmacokinetics: complex & unusual. Vd: c