You are on page 1of 9

Pharmacology: Hematology

Heme Pharm I: Platelet Drugs & EPO...................................................................................................................................... 2


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

Note 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, 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

mAb 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: eptifibatide


small 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: tirofiban


small 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?

ticlopidine Mechanism of Action: antiplatelet agents; inhibit ADP-induced platelet aggregation


Effects:
clopidogrel  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:
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, Procoagulants
Coagulation System Review
Intrinsic Extrinsic
Activated by Phospholipids, particulate matter (kaolin) Tissue Factor, phospholipids (thromboplastin)
– “intrinsic” to plasma – “extrinsic” to vessel lumen
Test Activated partial thromboplastin time (APTT) Prothrombin time (PT)
– used for heparin monitoring – used for warfarin monitoring

Endogenous mechanisms to prevent/control thrombosis


 Prostacyclin(PGI2): inhibits platelet aggregation  Heparan sulfate: endothelial cell surface
 Antithrombin: specific protease inhibitor (like α1 proteoglycan, like heparin  boosts antithrombin
antitrypsin); interferes with various factors (suicide  Protein C: + protein S, VaVi 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
 Don’t act on already existing thrombi
 Used 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
 Don’t prevent thrombus formation: follow with short-term anticoagulation (heparin, sometimes warfarin)

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)

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

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

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
Decreased clotting factor production Quinidine

Depressed oral anticoagulant activity


Metabolizing enzyme induction Barbituates, glutethimide, griseofulvin
Increased clotting factor production Vitamin K, oral contraceptives
Coumarins 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
(warfarin sodium / glutamic acid residues, which help bind Ca++ and PLs on platelets to enhance clotting.
coumadin, 1. decreases synthesis of vitamin K-dependent factors (30-50%)
dicumarol, etc.) 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.
 Alopecia
 TERATOGENICITY: esp 1st trimester, nasal hypoplasia / stippled epiphyseal calcifications /
abortion / neonatal hemorrhage. STRICTLY CONTRAINDICATED IN PREGNANCY (heparin safer).

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).
 Unique to rtPA:
1. Damages endothelial cell membranes \ increases circulating vWF;
2. mid-moderate thrombocytopenia (10% cases)

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 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)

You might also like