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Aspirin (acetyl salicylic acid): the antiplatelet drug supreme! Safe, cheap, effective
aspirin 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!)
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
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)
Heparin
A Hopkins-discovered drug, disputed discovery, abundant in liver.
Heparin = in mast cell secretory granules; heparan is endothelial cell surface molecule
Heparin
Mechanism 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)
heparin
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
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 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)
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
LMW Heparin
Low molecular Mechanism of Action: Anticoagulant agent. inhibit Factor Xa but not thrombin.
weight heparins still bind to antithrombin III
do not prolong APTT but work as well clinically.
(enoxaparin,
dalteparin, ardeparin) Indications:
Prevention & treatment (acute) of thrombosis, but don't dissolve clots (prevent new ones forming).
& LMW hepanoid At least as good as preventing DVT as heparin; probably equivalent in treating DVT
Administration: Dosed in mg instead of units; give sub-q.
(danaproid)
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
ISI
PTpatient
INR = international normalized ratio =
PTreference
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.
Alopecia
TERATOGENICITY: esp 1st trimester, nasal hypoplasia / stippled epiphyseal calcifications /
abortion / neonatal hemorrhage. STRICTLY CONTRAINDICATED IN PREGNANCY (heparin safer).
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
“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)
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)
Toxicity: despite localization, can induce lytic state. Bleeding (more in elderly, intercranial is serious).
Unique to rtPA:
1. Damages endothelial cell membranes \ increases circulating vWF;
2. mid-moderate thrombocytopenia (10% cases)
Comparison of thrombolytics
Efficacy:
All better than heparin for resolving pathologic thrombi t1/2 (m) Antigenic Cost
More mature thrombus = less successful thrombolysis SK 80 Yes $200-250
UK 15 No $1,000-$1,500
USE WITHIN 6h OF ACUTE MI
rtPA 3 No $2,000-$2,500
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)
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:
Pathogenic thrombi (by inhibiting physiologic thrombolysis)
rare myopathy & muscle necrosis
Pharmacokinetics: Excreted rapidly & unchanged in urine
Desmopressin
Desmopressin Mechanism of Action: Procoagulant agent.
Promotes release of endogenous pools of clotting factors (factor VIII, vWF) into circulation
Indications:
vWD
mild hemophilia (VIII > 5-10% normal)
severe hemophiliacs don't respond (not enough endogenous factor VIII)
Toxicity: electrolyte imbalances; fluid overload (ADH-type activity)
Other: analog of vasopressin (ADH)