thrombolytic drugs 2

7/29/2019 Thrombolytic Drugs 2

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THROMBOLYTIC DRUGS

Pathophysiologic Rationale

Re-establ ishing coronary f low dur ing a per iod o f

occlus ion w il l lim it myocardial infarct (MI) size was first

demonstrated in a dog model of MI by Reimer et al. in

1977

These experiments demons trated that after coronaryocc lus ion there wasa wavefron t of ischemic cell death,

wh ich progressed over t ime from the subendocard ium

toward the epicardium

The t ime frame for this pro cess was qui te short , in the

range o f3 to 4 hou rs

Thus these studies pro vided the basis for the rat ionale

thatre-canal izat ion and reperfus ion early in the course

of MI wou ld l imi t m yocardia l necrosis , imp rove lef t

ventr icular funct ion , & improve pat ient outcome


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Wave-front Phenomenon ofIschemic Cell Death


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THROMBOLYTIC DRUGS


Angiographic studies in the early 1980sshowed that early in the course ofMI withST-segment elevation, most patients had

complete coronary occlusion

Pathologic studies established theimportance of plaque rupture in the

pathogenesis of acute coronarysyndromes


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THROMBOLYTIC DRUGS


Acute coronarysyndromes varies withthe degree of thrombus-

induced obstruction,ranging from a persistentcomplete occlusioncorresponding to ST-

segment elevation MI toa subocclusive thrombuscorresponding tounstable angina


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Thrombolytic Therapy Benefit

The ability of streptokinase to lyse clots was first recognizedin the 1930s

Thrombolytic therapy was not applied to acute MI until theearly 1980s after the establishment of the central role ofacute thrombotic coronary occlusion in the pathogenesis ofacute MI

Clinical trials have firmly established the benefit ofthrombolytic therapy for patients with acute MI with ST-segment elevationwithin 12 hours of symptom onset

Patients with unstable angina or MI without ST elevation donot benefit from thrombolytic therapy

Rapid initiation of thrombolytic therapy is essential tooptimize patient outcome because each additional hour ofdelay from symptom onset to treatment corresponds to a0.5% to 1% increase in mortality


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Fibrinolysis


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Mechanism of Thrombolytic

Drugs

They have a common mechanism ofconvertingthe proenzyme plasminogen to the active

enzyme plasmin, which lyses fibrin clot

Plasminogen is converted to plasmin bycleavage of the Arg-Val (560-561) peptide bond

Plasmin, the active two-chain polypeptide, is anonspecific serine protease capable of breakingdown fibrin as well as fibrinogen and factors VandVIII


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Mechanism of Thrombolytic Drugs

The plasmin(ogen) molecule has lysine binding sites, which bind toand degrade fibrin

Fibrin-specific agents are much more active upon binding to fibrin,thereby increasing the affinity for plasminogen at the clot surface


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Thrombolytic DrugsStreptokinase

It is a bacterialprotein produced by group C (beta)-hemolytic streptococci

Mechanism:It binds to plasminogen producing an

"activator complex" that lyses free plasminogen tothe proteolytic enzyme plasmin

Plasmin degrades fibrin clots as well as fibrinogenand other plasma proteins (non-fibrin specific)

Pharmacokinetics:

The t of the activator complex is about 23 minutes

The complex is inactivated by anti-streptococcal

antibodies & by hepatic clearance
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It produces hyperfibrinolytic effect, which decreases plasmafibrinogen levels for 24-36 hrs

A prolonged thrombin time may persist for up to 24 hoursdue to the decrease in plasma levels of fibrinogen

Efficacy: In the GISSI study the reduction in mortality wastime dependent; 47% reduction in mortality in patientstreated within one hour of the onset of chest pain, 23%within three hours, & a 17% reduction between three and

six hours

The reduction was not statistically significant between 6-12hrs

Hospital cost per day is minimal 280 $


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Clinical Uses:

Acute Myocardial Infarction: administered by either theintravenous or the intracoronary route for the reduction ofinfarct size & congestive heart failure associated with AMI

Pulmonary Embolism Deep Vein Thrombosis

Arterial Thrombosis or Embolism: It is not indicated forarterial emboli originating from the left side of the heart due

to the risk of new embolic phenomena such as cerebralembolism.

Occlusion of Arteriovenous Cannulae: for clearing totallyor partially occluded arteriovenous cannulae whenacceptable flow cannot be achieved


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Side-Effects:

Bleeding due to activation of circulatingplasminogen

Hypersensitivity: It is antigenic & can produceallergic reactions like rashes & fever (possibly viaalready present Streptococcal antibodies)


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Anistreplase (APSAC)

AnisoylatedPlasminogen Streptokinase Activator

Complex (APSAC) IS acylated plasminogencombined with streptokinase

It is a prodrug, de-acylated in circulation into theactive plasminogen-SK complex

Similar to SK, it has minimal fibrin specificity & isantigenic

T1/2 is 70-120 min

Hospital cost per day is 1700 $


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Thrombolytic DrugsAlteplase (rt.PA)

It is a tissue plasm inogen activator (t .PA)produced byrecombinant DNA technology of 527 amino acids

Cost per day is around 2200 $

Mechanism:

It is an enzyme which has the property of fibrin-enhancedconversion of plasminogen to plasmin

It produces limited conversion of free plasminogen in theabsence of fibrin

When introduced into the systemic circulation it binds tofibrin in a thrombus and converts the entrappedplasminogen to plasmin followed by activated localfibrinolysis with limited systemic proteolysis


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Thrombolytic DrugsAlteplase

Therapeutic UsesAcute Myocardial Infarction in adults for the improvement

of ventricular function following AMI the reduction of the

incidence of congestive heart failure, and the reduction ofmortality associated with AMI

Acute Ischemic Stroke for improving neurological recoveryand reducing the incidence of disability. Treatment shouldonly be initiated within 3 hours after the onset of strokesymptoms, and after exclusion of intracranial hemorrhage

Pulmonary Embolism: Treatment of acute massivepulmonary embolism


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Thrombolytic Drugs

Alteplase

Pharmacokinetics:

It has very short t1/2 of 5 minutes

Side-Effects:

Bleeding including GIT & cerebral hemorrhage

Allergic reactions, e.g., anaphylactoid reaction,laryngeal edema, rash, and urticaria have been

reported very rarely (


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Reteplase & Tenectaplase

Reteplase is another human t-PA prepared byrecombinant mutation technology

It is fibrin-specific

It has longer duration than alteplaseTenectaplase is another genetically modified

human t-PA prepared by recombinant technology

It is more fibrin-specific & longer duration thanalteplase


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Thrombolytic Drugs

Urokinase

It is an enzyme produced by the kidney, andfound in the urine

It is mainly used in the low molecular weight

form of urokinase obtained from humanneonatal kidney cells grown in tissue culture

Mechanism: It acts on the endogenousfibrinolytic system converting plasminogen tothe enzyme plasmin that degrades fibrin clotsas well as fibrinogen and some other plasmaproteins (Non-fibrin selective)


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Thrombolytic DrugsUrokinase

Urokinase administered by intravenous infusion israpidly cleared by the liver with an elimination half-life for biologic activity of 12-20 minutes

Clinical Uses: For the lyses of acute massive pulmonary emboli


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Contraindications to ThrombolyticTherapy

Absolute contraindications include:

Recent head trauma or caranial tumor

Previous hemorrhagic shock

Stroke or cerebro-vascular events 1 year old

Active internal bleeding

Major surgery within two weeks

Relative contraindications include:

Active peptic ulcer, diabetic retinopathy,pregnancy, uncontrolled HTN


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Fibrinolytic Inhibitors

Aminocaproic Acid & tranexamic cid

They have lysine-like structure

They inhibit fibrinolysis by competitive inhibition

of plasminogen activation

Adjuvant therapy in hemophilia, fibrinolytic

therapy-induced bleeding & postsurgical bleeding

Aprotinin is a serine protease inhibitor It inhibits fibrinolysis by free plasmin

Used to stop bleeding in some surgicalprocedures

thrombolytic drugs 2

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