12-Pharmacology of Antithrombotic Therapy 2010 c€¦ · AspirinAspirin zzCovalentlyyyyg; y modifies cyclooxygenase; irreversibly inhibits the enzyme zzSince platelets have no protein

Hemostasis/Thrombosis IVHemostasis/Thrombosis IV

Antithrombotic TherapyAntithrombotic Therapy

Antithrombotic TherapyAntithrombotic TherapyAntithrombotic TherapyAntithrombotic Therapy

Mainstay of battle against thromboembolicMainstay of battle against thromboembolicMainstay of battle against thromboembolic Mainstay of battle against thromboembolic diseasediseaseHot area of new drug researchHot area of new drug researchHot area of new drug researchHot area of new drug researchCannot inhibit clot formation without Cannot inhibit clot formation without increased risk of hemorrhageincreased risk of hemorrhageincreased risk of hemorrhageincreased risk of hemorrhage22ndnd highest cause of iatrogenic highest cause of iatrogenic complicationscomplicationscomplicationscomplications22ndnd most common cause of increased most common cause of increased hospital stayshospital stayshospital stayshospital stays


Hemorrhage is consequence ofHemorrhage is consequence ofHemorrhage is consequence of Hemorrhage is consequence of overaggressive therapyoveraggressive therapyThrombosis is consequence ofThrombosis is consequence ofThrombosis is consequence of Thrombosis is consequence of underaggressive therapyunderaggressive therapyAl b l b t i k fAl b l b t i k fAlways a balance between risk of Always a balance between risk of thrombosis (for which you are giving the thrombosis (for which you are giving the d ) i k f h hd ) i k f h hdrug) vs. risk of hemorrhagedrug) vs. risk of hemorrhage


Antiplatelet agentsAntiplatelet agentsAntiplatelet agentsAntiplatelet agentsPrincipally used for preventing/treating arterial Principally used for preventing/treating arterial thromboembolic diseasethromboembolic diseasethromboembolic diseasethromboembolic disease

AnticoagulantsAnticoagulantsPrincipally used for preventing/treatingPrincipally used for preventing/treatingPrincipally used for preventing/treating Principally used for preventing/treating venous thromboembolic diseasevenous thromboembolic disease

Thrombolytic agentsThrombolytic agentsThrombolytic agentsThrombolytic agentsUsed for dissolution of thrombiUsed for dissolution of thrombi

Antiplatelet TherapyAntiplatelet TherapyAntiplatelet TherapyAntiplatelet TherapyParalyze platelet functionParalyze platelet functiony py pCyclooxygenase inhibitorsCyclooxygenase inhibitors

Irreversible Irreversible –– AspirinAspirinCompetitive inhibitors Competitive inhibitors –– NonNon--steroidal steroidal antiinflammatory drugsantiinflammatory drugs

DipyridamoleDipyridamoleDipyridamoleDipyridamoleGP GP IIbIIb/IIIa inhibitors/IIIa inhibitorsADP receptor inhibitorsADP receptor inhibitorsADP receptor inhibitorsADP receptor inhibitors

TiclopidineTiclopidineClopidogrelClopidogrelPrasugrelPrasugrel

AspirinAspirinAspirinAspirinCovalently modifies cyclooxygenase; irreversibly Covalently modifies cyclooxygenase; irreversibly y y yg ; yy y yg ; yinhibits the enzymeinhibits the enzymeSince platelets have no protein synthetic Since platelets have no protein synthetic

h i d f d bh i d f d bmechanism, cannot correct defect caused by mechanism, cannot correct defect caused by modification of cyclooxygenasemodification of cyclooxygenaseBlocks primary wave of platelet aggregation;Blocks primary wave of platelet aggregation;Blocks primary wave of platelet aggregation; Blocks primary wave of platelet aggregation; NOT secondary waveNOT secondary waveIf enough normal platelets to initiate primary If enough normal platelets to initiate primary e oug o a p ate ets to t ate p a ye oug o a p ate ets to t ate p a yaggregation, ASA poisoned platelets can be aggregation, ASA poisoned platelets can be recruited into platelet plug formationrecruited into platelet plug formation

AspirinAspirinAspirinAspirin

At low dose (81 mg daily) inhibitsAt low dose (81 mg daily) inhibitsAt low dose (81 mg daily), inhibits At low dose (81 mg daily), inhibits thromboxane A2 productionthromboxane A2 production

Blocks both platelet aggregation &Blocks both platelet aggregation &Blocks both platelet aggregation & Blocks both platelet aggregation & vasoconstrictionvasoconstriction

At higher doses (325 mg daily) blocksAt higher doses (325 mg daily) blocksAt higher doses (325 mg daily), blocks At higher doses (325 mg daily), blocks both thromboxane A2 & prostacyclin both thromboxane A2 & prostacyclin (PGI2) production(PGI2) production(PGI2) production(PGI2) production

PGI2 inhibits platelet aggregation & causes PGI2 inhibits platelet aggregation & causes vasodilationvasodilationvasodilationvasodilation

NonNon--steroidal Antiinflammatory steroidal Antiinflammatory DDDrugsDrugs

Competitive inhibitors of cyclooxygenaseCompetitive inhibitors of cyclooxygenaseCompetitive inhibitors of cyclooxygenase Competitive inhibitors of cyclooxygenase (drug must be in system to be effective)(drug must be in system to be effective)Many block both primary & secondaryMany block both primary & secondaryMany block both primary & secondary Many block both primary & secondary waves of platelet aggregationwaves of platelet aggregationA h i hibit l t f ti t tA h i hibit l t f ti t tAs such, inhibit clot formation to a greater As such, inhibit clot formation to a greater extent than does ASAextent than does ASABlocks ASA effects on platelets; ASA Blocks ASA effects on platelets; ASA should be taken firstshould be taken first

DipyridamoleDipyridamoleDipyridamoleDipyridamole

? Mechanism of action? Mechanism of action? Mechanism of action? Mechanism of actionProbably increases cAMP productionProbably increases cAMP productionBlocks calcium release from dense granulesBlocks calcium release from dense granulesBlocks calcium release from dense granules, Blocks calcium release from dense granules, blocking arachidonic acid production & blocking arachidonic acid production & thereby decreasing thromboxane A2thereby decreasing thromboxane A2thereby decreasing thromboxane A2 thereby decreasing thromboxane A2 productionproduction

Decreases platelet aggregationDecreases platelet aggregationDecreases platelet aggregationDecreases platelet aggregationEnhances aspirin’s effect on platelet Enhances aspirin’s effect on platelet aggregationaggregationaggregationaggregation

Glycoprotein IIb/IIIa InhibitorsGlycoprotein IIb/IIIa InhibitorsGlycoprotein IIb/IIIa InhibitorsGlycoprotein IIb/IIIa InhibitorsAll interfere with fibrinogenAll interfere with fibrinogen--induced platelet induced platelet gg ppaggregationaggregation3 classes:3 classes:

Fab fragments (abciximab) Fab fragments (abciximab) PeptidePeptide--based antagonists (eptifibatide)based antagonists (eptifibatide)Small molecule inhibitors (tirofiban)Small molecule inhibitors (tirofiban)Small molecule inhibitors (tirofiban)Small molecule inhibitors (tirofiban)

Extremely potent Extremely potent –– Platelet count functionally Platelet count functionally zerozeroDrug halfDrug half--life:life:

Abciximab Abciximab –– 30 minutes30 minutesEptifibatide/Tirofiban Eptifibatide/Tirofiban –– 22--2.5 hours2.5 hours

GlycoproteinGlycoprotein IIbIIb/IIIa Inhibitors/IIIa InhibitorsGlycoprotein Glycoprotein IIbIIb/IIIa Inhibitors/IIIa Inhibitors

Used to block immediate restenosis Used to block immediate restenosis following cardiac interventionfollowing cardiac interventionggMajor cause of thrombocytopenia (2Major cause of thrombocytopenia (2--10%)10%)Current drugs too potent for longCurrent drugs too potent for long--term useterm useCurrent drugs too potent for longCurrent drugs too potent for long term useterm useOral agents have not proven successful Oral agents have not proven successful thus farthus farthus farthus far

ADP Receptor InhibitorsADP Receptor InhibitorsADP Receptor InhibitorsADP Receptor Inhibitors

Block P2YBlock P2Y12 12 Receptor, inhibiting ADPReceptor, inhibiting ADP--i d d i i f l li d d i i f l linduced activation of plateletsinduced activation of platelets3 drugs currently approved:3 drugs currently approved:

Ticlopidine Ticlopidine –– Rarely usedRarely usedClopidogrelClopidogrelPrasugrelPrasugrel


All longAll long--acting (half life 7acting (half life 7--8 hours, with 8 hours, with ti t b lit ith h lf lif 2ti t b lit ith h lf lif 2 4 d )4 d )active metabolites with half life 2active metabolites with half life 2--4 days); 4 days);

all inhibit transfused platelets as well as all inhibit transfused platelets as well as patient’s plateletspatient’s plateletspatient s plateletspatient s plateletsNo reversing agentNo reversing agent


Uses:Uses:Unstable angina/NonUnstable angina/Non--ST elevation MIST elevation MIST elevation MIST elevation MIPercutaneous coronary intervention (in Percutaneous coronary intervention (in

j ti ith i i )j ti ith i i )conjunction with aspirin)conjunction with aspirin)? Peripheral vascular disease? Peripheral vascular diseaseStrokeStrokeStrokeStroke


Side effects:Side effects:BleedingBleeding

EspEsp with surgerywith surgeryThrombotic thrombocytopenic purpura (Thrombotic thrombocytopenic purpura (espespticlopidine)ticlopidine)Neutropenia (Neutropenia (espesp ticlopidine)ticlopidine)

Anticoagulant TherapyAnticoagulant TherapyAnticoagulant TherapyAnticoagulant Therapy

Inhibitors of coagulation cascadeInhibitors of coagulation cascadeInhibitors of coagulation cascadeInhibitors of coagulation cascadeUseful both for prophylaxis against TE Useful both for prophylaxis against TE disease & treatment of TE diseasedisease & treatment of TE diseasedisease & treatment of TE diseasedisease & treatment of TE diseaseLower doses required for prophylaxisLower doses required for prophylaxisAll agents prevent propagation of clot; All agents prevent propagation of clot; none dissolve clot already formednone dissolve clot already formed

Available AnticoagulantsAvailable AnticoagulantsAvailable AnticoagulantsAvailable Anticoagulants

Older agentsOlder agentsHeparin (Parenteral)Heparin (Parenteral)W f i (O l)W f i (O l)Warfarin (Oral)Warfarin (Oral)

Now, FDA approved (in addition to the Now, FDA approved (in addition to the above):above):above):above):

4 low molecular weight heparins (3 available in 4 low molecular weight heparins (3 available in US)US)1 heparinoid (not available in US)1 heparinoid (not available in US)1 Factor 1 Factor XaXa inhibitorinhibitor4 direct thrombin inhibitors4 direct thrombin inhibitors4 direct thrombin inhibitors4 direct thrombin inhibitors

More to comeMore to come

Heparin/Heparin DerivativesHeparin/Heparin DerivativesHeparin/Heparin DerivativesHeparin/Heparin Derivatives

All act to potentiate antithrombin III’sAll act to potentiate antithrombin III’sAll act to potentiate antithrombin III s All act to potentiate antithrombin III s inactivation of the active enzymes of the inactivation of the active enzymes of the clotting cascadeclotting cascadeclotting cascadeclotting cascadeChemical catalysts Chemical catalysts –– Not consumed in Not consumed in reactions themselvesreactions themselvesreactions themselvesreactions themselvesAll are useful in both preventing All are useful in both preventing th b i & t ti th b b lith b i & t ti th b b lithrombosis & treating thromboembolic thrombosis & treating thromboembolic diseasedisease

ANTITHROMBIN III ANTITHROMBIN III –– Mechanism Mechanism f A if A iof Actionof Action

Unfractionated HeparinUnfractionated HeparinAdAdAdvantagesAdvantages

Long track recordLong track recordLong track recordLong track recordDirt cheapDirt cheapCl l ff ti f t t t & iCl l ff ti f t t t & iClearly effective for treatment & in some Clearly effective for treatment & in some prophylaxis settingsprophylaxis settingsFully reversible with protamineFully reversible with protamineShort halfShort half--lifelife

Unfractionated HeparinUnfractionated HeparinDi dDi dDisadvantagesDisadvantages

Short half lifeShort half life –– Requires continuous infusionRequires continuous infusionShort half life Short half life Requires continuous infusionRequires continuous infusionVariable bioavailabilityVariable bioavailabilityMonitoring required for treatment ofMonitoring required for treatment ofMonitoring required for treatment of Monitoring required for treatment of thromboembolic diseasethromboembolic disease

To ensure attainment of therapeutic anticoagulation, To ensure attainment of therapeutic anticoagulation, p g ,p g ,rather than to prevent bleedingrather than to prevent bleeding

Higher risk of complicationsHigher risk of complicationsEspecially thrombocytopenia with paradoxical Especially thrombocytopenia with paradoxical thromboembolic diseasethromboembolic disease

Low Molecular Weight HeparinsLow Molecular Weight HeparinsAdAdAdvantagesAdvantages

Higher bioavailability; makes dosing without Higher bioavailability; makes dosing without monitoring a reality (except in renal disease, monitoring a reality (except in renal disease, morbid obesity cachexia pregnancy)morbid obesity cachexia pregnancy)morbid obesity, cachexia, pregnancy)morbid obesity, cachexia, pregnancy)Longer halfLonger half--life; therefore can be given life; therefore can be given subcutaneously1subcutaneously1--2x/day2x/daysubcutaneously1subcutaneously1 2x/day2x/dayMuch lower (but not 0) risk of Much lower (but not 0) risk of de novode novothrombocytopeniathrombocytopeniaAt least as effective for treatment; more At least as effective for treatment; more effective for high risk prophylaxis than effective for high risk prophylaxis than heparinheparinheparinheparin

Low Molecular Weight Heparins Low Molecular Weight Heparins DisadvantagesDisadvantages

More expensive than heparinMore expensive than heparinp pp pLonger acting, and only partially reversible with Longer acting, and only partially reversible with protamineprotamineRenally excreted, making dosing problematic in Renally excreted, making dosing problematic in renal diseaserenal diseaseCC ti ith HIT i tib diti ith HIT i tib diCrossCross--reactive with HIT causing antibodiesreactive with HIT causing antibodiesMuch more effective for prophylaxis if given preMuch more effective for prophylaxis if given pre--opopopopAll carry black box warning All carry black box warning vs.vs. use with regional use with regional anesthesiaanesthesia

Low Molecular Weight Low Molecular Weight Heparins (US)Heparins (US)

Enoxaparin (LovenoxEnoxaparin (Lovenox®) ®) –– Approved for VTE Approved for VTE prophylaxis, VTE treatment, acute coronary prophylaxis, VTE treatment, acute coronary syndrome)syndrome)syndrome)syndrome)Dalteparin (Fragmin®) Dalteparin (Fragmin®) –– Same as enoxaparin Same as enoxaparin RE: approvals, except for VTE treatmentRE: approvals, except for VTE treatmentRE: approvals, except for VTE treatmentRE: approvals, except for VTE treatmentTinzaparin (Innohep®) Tinzaparin (Innohep®) –– Approved for Approved for treatment of VTEtreatment of VTEArdeparin (Normiflo®) Ardeparin (Normiflo®) –– Not being marketed Not being marketed in USin USAll b h i il l b d i f h iAll b h i il l b d i f h iAll behave similarly, but dosing of each is All behave similarly, but dosing of each is differentdifferent

FACTOR Xa INHIBITORFACTOR Xa INHIBITORFACTOR Xa INHIBITORFACTOR Xa INHIBITORFondaparinux (Arixtra®) Fondaparinux (Arixtra®) –– Semisynthetic Semisynthetic p ( )p ( ) yysulfated pentasaccharide; active moiety of sulfated pentasaccharide; active moiety of heparinheparinO l i hibi f XO l i hibi f XOnly inhibits factor XaOnly inhibits factor XaBioavailability virtually 100%; can be given QDBioavailability virtually 100%; can be given QDN th b t i i t i l (d tN th b t i i t i l (d tNo thrombocytopenia seen in trials (does not No thrombocytopenia seen in trials (does not bind to platelet factor IV)bind to platelet factor IV)Data clearly shows it to be superior to LMWHData clearly shows it to be superior to LMWHData clearly shows it to be superior to LMWH Data clearly shows it to be superior to LMWH when given postoperatively, & probably superior when given postoperatively, & probably superior to LMWH given preoperativelyto LMWH given preoperatively

FONDAPARINUXFONDAPARINUXFONDAPARINUXFONDAPARINUX

Offers possibilit of postOffers possibilit of post op proph la isop proph la isOffers possibility of postOffers possibility of post--op prophylaxis op prophylaxis against DVT with same or better efficacy as against DVT with same or better efficacy as preop administration of LMWHpreop administration of LMWHpreop administration of LMWHpreop administration of LMWHSmall but real incidence of wound Small but real incidence of wound hematomas (nil if given > 6 hrs posthematomas (nil if given > 6 hrs post--op);op);hematomas (nil if given 6 hrs posthematomas (nil if given 6 hrs post op); op); bleeding risk otherwise similar to LMWHbleeding risk otherwise similar to LMWHAvoids problems with administration of drug Avoids problems with administration of drug p gp gduring regional anesthesia, since can be during regional anesthesia, since can be given after the epidural catheter is pulledgiven after the epidural catheter is pulledApproved for treatment of VTE (7.5 mg QD)Approved for treatment of VTE (7.5 mg QD)

Prophylaxis vs TE DiseaseProphylaxis vs TE DiseaseProphylaxis vs TE DiseaseProphylaxis vs TE Disease

Requires smaller dose than doesRequires smaller dose than doesRequires smaller dose than does Requires smaller dose than does treatmenttreatmentLess risk of bleeding with prophylaxisLess risk of bleeding with prophylaxisLess risk of bleeding with prophylaxis Less risk of bleeding with prophylaxis dosesdosesStratified by risk of developingStratified by risk of developingStratified by risk of developing Stratified by risk of developing thromboembolic diseasethromboembolic diseaseIn surgery patients, preIn surgery patients, pre--op therapyop therapyIn surgery patients, preIn surgery patients, pre op therapy op therapy generally more effective than postgenerally more effective than post--op op therapy (with one exception)therapy (with one exception)py ( p )py ( p )

Primary Risk Factors for VTEPrimary Risk Factors for VTEPrimary Risk Factors for VTEPrimary Risk Factors for VTE

Major SurgeryMajor SurgeryMajor SurgeryMajor SurgeryLeg> Pelvic>Abdominal or ThoracicLeg> Pelvic>Abdominal or Thoracic

Acute MIAcute MIAcute MIAcute MIMajor TraumaMajor TraumaParalytic StrokeParalytic StrokeParalytic StrokeParalytic StrokeCancerCancerS i l C d I jS i l C d I jSpinal Cord InjurySpinal Cord InjuryPelvic FracturePelvic Fracture

Secondary Risk Factors for VTESecondary Risk Factors for VTESecondary Risk Factors for VTESecondary Risk Factors for VTE

Congestive HeartCongestive Heart HematologicalHematologicalCongestive Heart Congestive Heart FailureFailurePrevious VTEPrevious VTE

Hematological Hematological DisordersDisordersCentral Venous Central Venous

ImmobilizationImmobilizationObesityObesity

CatheterCatheterVaricose VeinsVaricose VeinsObesityObesity

Chronic Respiratory Chronic Respiratory FailureFailure

PregnancyPregnancyEstrogen TherapyEstrogen Therapya u ea u e

Increasing AgeIncreasing Agest oge e apyst oge e apy

HospitalizationHospitalization

Prophylaxis vs TE DiseaseProphylaxis vs TE DiseaseProphylaxis vs TE DiseaseProphylaxis vs TE Disease

Low Risk Low Risk –– Minor procedure, otherwise Minor procedure, otherwise healthyhealthyhealthyhealthy

No medications; rapid mobilizationNo medications; rapid mobilization

VTE ProphylaxisVTE ProphylaxisM d Ri kM d Ri kModerate RiskModerate Risk

Moderate Risk Moderate Risk –– Abdominal surgery, Abdominal surgery, g yg ythoracic surgery, Medical patientthoracic surgery, Medical patient

Multiple medical regimens effective, including:Multiple medical regimens effective, including:p g , gp g , gHeparin 5000 units SQ Q 8Heparin 5000 units SQ Q 8--12h12hEnoxaparin 40 mg SQ QDEnoxaparin 40 mg SQ QDDalteparin 5000 units SQDalteparin 5000 units SQ QDQD

VTE ProphylaxisVTE ProphylaxisHi h Ri kHi h Ri kHigh RiskHigh Risk

High Risk High Risk –– Paraplegic, hemiplegic, pelvic Paraplegic, hemiplegic, pelvic gg p g p g pp g p g psurgery, leg surgerysurgery, leg surgery

Moderate risk therapy ineffective; more clearly Moderate risk therapy ineffective; more clearly py ; ypy ; yneeded needed

Enoxaparin 30 mg SQ Q 12hEnoxaparin 30 mg SQ Q 12hFondaparinux 2.5 mg SQ QDFondaparinux 2.5 mg SQ QD

Direct Thrombin InhibitorsDirect Thrombin InhibitorsDirect Thrombin InhibitorsDirect Thrombin Inhibitors

Block active site of thrombinBlock active site of thrombinInhibit both clotInhibit both clot--bound and free thrombinbound and free thrombinInhibit both clotInhibit both clot--bound and free thrombinbound and free thrombinMore potent inhibitors than heparinMore potent inhibitors than heparin


Lepirudin (RefludanLepirudin (Refludan®)®)Lepirudin (RefludanLepirudin (Refludan®) ®) Hirudin derivativeHirudin derivativeHalf life 30Half life 30 40 minutes40 minutesHalf life 30Half life 30--40 minutes40 minutesProblematic in renal diseaseProblematic in renal diseaseNot reversibleNot reversibleNot reversibleNot reversibleApproved for HeparinApproved for Heparin--Induced Induced Thrombocytopenia and ThrombosisThrombocytopenia and ThrombosisThrombocytopenia and ThrombosisThrombocytopenia and Thrombosis


ArgatrobanArgatroban®®ArgatrobanArgatroban®®Small molecule active site blocker of thrombinSmall molecule active site blocker of thrombinHalf life 30Half life 30 40 minutes40 minutesHalf life 30Half life 30--40 minutes40 minutesProblematic in liver diseaseProblematic in liver diseaseNot reversibleNot reversibleNot reversibleNot reversibleApproved for HeparinApproved for Heparin--Induced Induced Thrombocytopenia and Thrombosis & forThrombocytopenia and Thrombosis & forThrombocytopenia and Thrombosis & for Thrombocytopenia and Thrombosis & for Acute Coronary SyndromesAcute Coronary Syndromes


Bivalirudin (AngiomaxBivalirudin (Angiomax®)®)Bivalirudin (AngiomaxBivalirudin (Angiomax®)®)Hirudin derivativeHirudin derivativeShortShort actingactingShortShort--actingactingNot reversibleNot reversibleApproved for unstable angina/angioplastyApproved for unstable angina/angioplastyApproved for unstable angina/angioplastyApproved for unstable angina/angioplasty


DesirudinDesirudinDesirudinDesirudinHirudin derivative (minus 1 sulfate group)Hirudin derivative (minus 1 sulfate group)HalfHalf life 6life 6 7 hours7 hoursHalfHalf--life 6life 6--7 hours7 hoursApproved for DVT prophylaxis in HITApproved for DVT prophylaxis in HITNot yet availableNot yet availableNot yet availableNot yet available

COUMADIN (warfarin)COUMADIN (warfarin)M h i f A tiM h i f A tiMechanism of ActionMechanism of Action

Inhibits Vitamin K dependent carboxylase activityInhibits Vitamin K dependent carboxylase activityInhibits Vitamin K dependent carboxylase activityInhibits Vitamin K dependent carboxylase activityPrevents reduction of Vitamin KPrevents reduction of Vitamin KHumans secrete proteins lackingHumans secrete proteins lacking γγ--Humans secrete proteins lacking Humans secrete proteins lacking γγcarboxyglutamic acid, which are inactive carboxyglutamic acid, which are inactive DOES NOT AFFECT PROTEINS ALREADY DOES NOT AFFECT PROTEINS ALREADY SYNTHESIZEDSYNTHESIZEDMonitor using prothrombin timeMonitor using prothrombin timeM lti l i t ti ith th dM lti l i t ti ith th dMultiple interactions with other drugsMultiple interactions with other drugsAntidoteAntidote--Vitamin KVitamin K

Thrombolytic TherapyThrombolytic TherapyThrombolytic TherapyThrombolytic Therapy

Lyses clot already formedLyses clot already formedLyses clot already formedLyses clot already formedDoes not discriminate between therapeutic Does not discriminate between therapeutic & pathologic thrombosis; therefore& pathologic thrombosis; therefore& pathologic thrombosis; therefore& pathologic thrombosis; thereforeMarkedly increased risk of hemorrhage Markedly increased risk of hemorrhage

d ith th tith b tid ith th tith b ticompared with other antithrombotic compared with other antithrombotic therapiestherapiesOnly therapy documented to prevent Only therapy documented to prevent tissue death in acute arterial thrombosistissue death in acute arterial thrombosis

THROMBOLYTIC THERAPYTHROMBOLYTIC THERAPYStreptokinaseStreptokinase

Purified from bacteria (Streptococcus)Purified from bacteria (Streptococcus)Binds to plasminogen, & complex activates a second Binds to plasminogen, & complex activates a second plasminogen molecule to plasminplasminogen molecule to plasminHigh incidence of allergic reactionsHigh incidence of allergic reactions

UrokinaseUrokinasePurified from urine initiallyPurified from urine initiallyRecombinant form now availableRecombinant form now availableRecombinant form now availableRecombinant form now availableActivates plasminogen directlyActivates plasminogen directly

Tissue plasminogen activatorTissue plasminogen activatorMade by endothelial cellsMade by endothelial cellsIncreased affinity for fibrinIncreased affinity for fibrin--bound plasminogen bound plasminogen relative fibrin specificityrelative fibrin specificityp yp yRecombinant form availableRecombinant form availableActivates plasminogen directlyActivates plasminogen directly

THROMBOLYTIC THERAPYTHROMBOLYTIC THERAPYActionsActions

Used in myocardial infarctionUsed in myocardial infarctionUsed in myocardial infarctionUsed in myocardial infarctionLyses coronary thrombiLyses coronary thrombiImproves/preserves LV functionImproves/preserves LV functionp pp pDecreases mortalityDecreases mortalityHigh rate of reocclusionHigh rate of reocclusion--esp with TPAesp with TPA

Lyses hemostatic plugs everywhereLyses hemostatic plugs everywhereIncreased incidence of bleeding Increased incidence of bleeding -- esp CNSesp CNSLowers plasma fibrinogenLowers plasma fibrinogen

? which drug is superior? which drug is superior

Future Agents (Not yet Future Agents (Not yet approved)approved)approved)approved)

Ri bRi b O l X i hibit i fi lO l X i hibit i fi lRivaroxaban Rivaroxaban –– Oral Xa inhibitor; in final Oral Xa inhibitor; in final stages @ FDA now (approved in Europe & stages @ FDA now (approved in Europe & Canada)Canada)))Dabigatran Dabigatran –– Oral thrombin inhibitor Oral thrombin inhibitor -- @ FDA @ FDA (approved in Europe & Canada)(approved in Europe & Canada)ApixabanApixaban Oral factor Xa inhibitor; in finalOral factor Xa inhibitor; in finalApixaban Apixaban –– Oral factor Xa inhibitor; in final Oral factor Xa inhibitor; in final FDA stages nowFDA stages nowIdraparinux Idraparinux –– Hyperglycosylated Hyperglycosylated pp yp g y yyp g y yfondaparinux; ½ life 1 week; for extended fondaparinux; ½ life 1 week; for extended prophylaxisprophylaxis? Other direct thrombin inhibitors for uses? Other direct thrombin inhibitors for uses? Other direct thrombin inhibitors for uses ? Other direct thrombin inhibitors for uses other than HITother than HIT? Orally active heparin/LMWH derivatives? Orally active heparin/LMWH derivatives

Documents

12-Pharmacology of Antithrombotic Therapy 2010 c€¦ · AspirinAspirin zzCovalentlyyyyg; y modifies cyclooxygenase; irreversibly inhibits the enzyme zzSince platelets have no protein