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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!)
Dipyridamole
dipyridamole 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; don’t have to memorize names)
All cause bleeding but DON’T 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: abciximab
mAb IIb/IIIa antagonist (abciximab)
Mechanism of Action: antiplatelet agent. Blocks GPIIb/IIIa-mediated platelet aggregation Indications: only anti-platelet mAB shown to have anti-thrombotic activity in humans 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: eptifibatide
small peptide IIb/IIIa antagonist (eptifibatide)
Mechanism of Action: antiplatelet agent. Blocks GPIIb/IIIa-mediated platelet aggregation by blocking fibrinogen, vWF, vitronectin binding to IIb/IIIa 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: tirofiban
small molecule IIb/IIIa antagonist (tirofiban)
Mechanism of Action: antiplatelet agent.
Blocks GPIIb/IIIa-mediated platelet aggregation by inhibiting fibrinogen binding to GPIIb/IIIa 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?
ticlopidine clopidogrel
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
Erythropoietin (EPO)
erythropoietin (EPO) Mechanism of Action: promotes erythropoiesis (hormone) Effects:
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)
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).
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 amount to 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: confined to plasma (high MW, neg charge)
not orally bioavailable
clearance is NON-LINEAR (dose-dependent), cleared via RES, longer infusions can diminish clearance
therapeutic monitoring needed to reach target APTT (1.5-2x)
Other: naturally occuring, polymer of D-glucosamine/D-glucoronic acid. Found in mast cell secretory granules but natural function unknown; sulfation/molecular weight variable; prepared from bovine lung/porcine intestinal mucosa
Mechanism of Action: Anticoagulant agent. inhibit Factor Xa but not thrombin.
still bind to antithrombin III
do not prolong APTT but work as well clinically.
Indications: Prevention & treatment (acute) of thrombosis, but don't dissolve clots (prevent new ones forming).
At least as good as preventing DVT as heparin; probably equivalent in treating DVT Administration: Dosed in mg instead of units; give sub-q. Toxicity: Bleeding (same as heparin); thrombocytopenia (maybe less frequently) Pharmacokinetics: less frequent dosing than heparin (reduced binding to plasma proteins / platelets /
cells; increased bioavailability, longer half-life, dose-proportional / more normal PK, not non-linear like heparin) Other: Preparation: depolymerization & size fractionation of HMW heparins; mixed species. Way more expensive but popular (no therapeutic monitoring, given sub-q, a little easier to manage).
Coumarin Anticoagulants Discovered in cattle; produced as rotenticide (still used as rat poison) by Wisconsin Alumni Research Foundation (=WARFarin), suicide attempts
INR = international normalized ratio = PTpatient
PTreference
ISI
Enhanced oral anticoagulant activity ↓ vitamin K absorption Antibiotics, mineral oil, cholestyramine
Displacement from plasma proteins Sailicylates, clofibrate, chloral hydrate
Inhibition of biotransformation Allopurinal, metronidazole, chloramphenicol
Inhibition of platelet aggregation Aspirin, dipyridamole
Mechanism of Action: Anticoagulant agent. Blocks reduction of Vit K by vitamin K reductases Effects: Vitamin K required for factor II, VII, IX, X (and proteins C&S) to have gamma-carboxylated glutamic acid residues, which help bind Ca++ and PLs on platelets to enhance clotting.
1. decreases synthesis of vitamin K-dependent factors (30-50%) 2. factors produced only have 10-40% of normal biologic activity
Indications: Prevention & treatment (chronic) of thrombosis, but don't dissolve clots (prevent new ones from forming) Administration:
therapeutic monitoring with PT (1.2-1.5x normal); INR widely used now.
LONG HALF LIFE + INVOLVEMENT OF CLOTTING FACTORS = LONG TIME TO STEADY STATE. Adjust dose only q48-72h and escalate conservatively
Resistance: occurs but is rare Toxicity & Reversal: less toxicity with lower levels of anticoagulation (and equal efficacy).
Bleeding: reverse with: o FFP to replace coagulation factors (first line for acute bleeding) or o Vitamin K in high doses (some reductases can bypass if enough vit K around; takes longer -
24h, have to wait for synthesis of new factors; effect lasts for days so use only if serious, might have to substitute heparin for 7-10d after high-dose vitamin K)
Skin necrosis: from Protein C inhibition necrotic infarction, watch out for protein C-deficient pts.
Drug interactions: VERY IMPORTANT. See chart above Pharmacokinetics:
Nearly complete absorption,
99% bound to plasma protein (albumin),
metabolism to inactive metabolites by hydroxylation (hepatic) is variable in population, genetically determined; half-life of ~40h.
Time course of antithrombotic effect is different than plasma concentration (circulating half-lives of factors, which have to be re-synthesized: II > IX/X > VII for half-life, so VII recovered first and thrombin last)
Other: Has an asymmetric carbon (racemic mixture, the enantiomers have different potency / metabolism)
Thrombolytics Fibrinolytic system: zymogen cascade; breaks down fibrin (remodel/trim thrombus)
plasmin (activated from plasminogen via plasminogen activator) is key actor o binds fibrin via amino terminus (high lysine affinity) o α2-antiplasmin also binds to plasmin at this site; so plasmin bound to fibrin escapes α2AP inhibition
“lytic state” - Too much plasmin digests physiologic thrombi; consumes plasma coag factors o increases hemorrhage risk o usually prevented by localization of plasminogen activator to endothelial cells & presence of α2AP in circulation
Tissue plasminogen activator (tPA): released in response to hemodynamic indicators of thrombus formation
o Short half-life (3m); inactivated by circulating inhibitor (plasminogen activator inhibitor-1), preventing lytic state o Controls can be overwhelmed by large doses of systemic thrombolytic drugs
Streptokinase: from β-hemolytic strep streptokinase Mechanism of Action: Thrombolytic agent. Not a kinase / protease but binds to plasminogen, induces
conformational change, results in cleavage of arg-val bond & activation of enzyme (plasmin) Indications: clot buster (helps digest pre-existing thrombi) Administration: Need large loading dose to absorb pre-existing Abs; used to give intracoronary but probably not much better. Get it in FAST! Toxicity: Bleeding, allergic reactions, anaphylaxis, fever. VERY ANTIGENIC (don't give more than q6-12m) Pharmacokinetics: Half life of about 80m after Abs absorbed Other: All adults have pre-existing anti-SK antibodies (exposure to strep)
Urokinase
urokinase Mechanism of Action: Thrombolytic agent. Cleaves plasminogen to plasmin directly at arg-val bond (like TPA) Effects: activity not localized at clot (can cause systemic fibrinolysis) Indications: clot buster (helps digest pre-existing thrombi) Toxicity: Bleeding, allergic reactions (less frequent than with streptokinase: skin rash, fever, bronchospasm) Pharmacokinetics: Metabolized by liver, half life 15m Other: Kind of like an early version of TPA
Recombinant Tissue Plasminogen Activator
rtPA Mechanism of Action: Thrombolytic agent. Recombinant serine protease; Effects: Much tighter binding to fibrin-bound plasminogen than circulating free plasminogen (tPA has lysine binding sites at amino terminus) so more active against bound plasminogen (less systemic activity, more localized); can overwhelm control mechanism (serum concentrations 30-300x higher than physiologic [tPA]) Indications: clot buster (helps digest pre-existing thrombi) Administration: IV bolus + short infusion (short half life, bleeding complications) Toxicity: despite localization, can induce lytic state. Bleeding (more in elderly, intercranial is serious).
Pharmacokinetics: Metabolized by liver, identical halflife to tPA (3m) Other: Most common thrombolytic agent in clinical use
Comparison of thrombolytics Efficacy:
All better than heparin for resolving pathologic thrombi
More mature thrombus = less successful thrombolysis
USE WITHIN 6h OF ACUTE MI o rTPA faster onset than SK but outcome equivalent
UK/rTPA have higher success than SK for thrombi in peripheral veins, arteries, indwelling caths Toxicity: all have risk of bleeding, rTPA > SK for intercranial hemorrhage, data mixed on UK vs rtPA/SK Bottom line: very similar, cost is big issue (consider SK 1st for low cost but don’t use repeatedly: antigenic)
t1/2 (m) Antigenic Cost
SK 80 Yes $200-250 UK 15 No $1,000-$1,500 rtPA 3 No $2,000-$2,500
Procoagulant Drugs FFP and clotting factor concentrates are most widely used but not discussed here
ϵ-aminocaproic acid
(ϵ)-Aminocaproic acid Mechanism of Action: Procoagulant agent. Competitive inhibitor of plasmin/plasminogen binding to fibrin Effects: Interferes with fibrinolysis, maintaines hemostasis Indications: Hematuria (excreted rapidly w/o change in urine). Has been hard to demonstrate clear-cut benefit except in some settings (minor surgery in hemophiliacs) Toxicity: