HIS 29 2Ph cology fbrnlytic drugs-1.ppt...

ROZAIMAH ZAIN-HAMID

Department of Pharmacology and TherapeuticsFaculty of Medicine, Universitas Sumatera Utara

Drugs Used in Disorders of Coagulation

Fibrinolytic drugsFibrinolytic drugs

AntiAnti--thrombotic drugsthrombotic drugs

Anticoagulant drugsAnticoagulant drugs

Drugs used in bleeding Drugs used in bleeding di ddi ddisordersdisorders

Zain-Hamid,R; Faculty of Medicine, Universitas Sumatera Utara.

Fibrinolytic drugs

Lyse thrombi Lyse thrombi (i v administration: generalized lytic state)(i v administration: generalized lytic state)(i.v administration: generalized lytic state)(i.v administration: generalized lytic state)

Catalyzing the formation Catalyzing the formation of the serine protease plasmin of the serine protease plasmin

from its precursor zymogen, plasminogenfrom its precursor zymogen, plasminogenp y g , p gp y g , p g


Fibrinolytic drugs

StreptokinaseStreptokinase

AnistreplaseAnistreplase

UrokinaseUrokinase

Tissue Plasminogen Activator (tTissue Plasminogen Activator (t--PA)PA)


Approaches to reduce nonApproaches to reduce non--selective effects selective effects of fibrinolytic drugsof fibrinolytic drugsof fibrinolytic drugsof fibrinolytic drugs

A new generation of A new generation of prothrombolytic drugsprothrombolytic drugs

IntraIntra--arterial use arterial use (intracoronary inject )(intracoronary inject )

prothrombolytic drugs, prothrombolytic drugs, tissue plasminogen tissue plasminogen activator, may induceactivator, may induce (intracoronary inject.), (intracoronary inject.),

may may t i bl di bt i bl di b

activator, may induce activator, may induce thrombolysis with thrombolysis with <<< systemic fibrinolysis <<< systemic fibrinolysis

systemic bleeding by systemic bleeding by localizing the druglocalizing the drug

or fibrinogen breakdownor fibrinogen breakdown


St t kiStreptokinase


Streptokinase

A protein synthesizes A protein synthesizes by streptococcus combinesby streptococcus combinesby streptococcus combines by streptococcus combines

with the proactivator plasminogen with the proactivator plasminogen

The enzymatic complex The enzymatic complex catalyze conversion catalyze conversion

plasminogen plasminogen active plasminactive plasminZain-Hamid,R; Faculty of Medicine,

Universitas Sumatera Utara.

p gp g pp

Streptokinase

Absence of inhibitors Absence of inhibitors for streptokinase proactivator complexfor streptokinase proactivator complexfor streptokinase proactivator complex, for streptokinase proactivator complex,

permit their use clinicallypermit their use clinically

Administered by i.v infusion Administered by i.v infusion f l di d 250 000 itf l di d 250 000 itof a loading dose : 250,000units, of a loading dose : 250,000units,

followed by 100,000 units/h followed by 100,000 units/h for 24 for 24 -- 72 hours72 hours


U kiUrokinase


Urokinase

A human enzyme synthesized A human enzyme synthesized b th kidb th kidby the kidneyby the kidney

Directly converts Directly converts plasminogenplasminogen active plasminactive plasminplasminogen plasminogen active plasminactive plasmin


Urokinase

Absence of inhibitors for urokinase, Absence of inhibitors for urokinase, permit their use clinicallypermit their use clinicallypermit their use clinicallypermit their use clinically

Plasmin formed inside a thrombus by activatorsPlasmin formed inside a thrombus by activatorsPlasmin formed inside a thrombus by activators,Plasmin formed inside a thrombus by activators,is protected from plasma antiplasmin is protected from plasma antiplasmin

allows it to lyse the thrombus from withinallows it to lyse the thrombus from within


UrokinaseU o ase

Requires a loading dose :Requires a loading dose :Requires a loading dose : Requires a loading dose : 300,000units, given over 10 minutes & 300,000units, given over 10 minutes & maintenance dose of 300 000units/hmaintenance dose of 300 000units/hmaintenance dose of 300,000units/h maintenance dose of 300,000units/h

for 12 hoursfor 12 hours


A i t lAnistreplase


Anistreplase (Anisolated Plasminogen Streptokinase(Anisolated Plasminogen Streptokinase

Activator Complex /APSAC)

Consist a complex Consist a complex of purified human plasminogen &of purified human plasminogen &of purified human plasminogen & of purified human plasminogen &

bacterial streptokinasebacterial streptokinase

Acylated to protect Acylated to protect the enzyme’s active site the enzyme’s active site


Administered anistreplasep

The acyl group spontaneously hydrolizesThe acyl group spontaneously hydrolizes

Freeing the activated Freeing the activated streptokinasestreptokinase--proactivator complexproactivator complex


Anistreplase

Allow for rapid i.v injectionAllow for rapid i.v injection

Greater clot selectivity Greater clot selectivity (more activity on plasminogen (more activity on plasminogen

associated with clot than associated with clot than on free plasminogen in the blood)on free plasminogen in the blood)p g )p g )

More thrombolytic activityMore thrombolytic activity


y yy y

Anistreplase

Is given as a single i v injection:Is given as a single i v injection:Is given as a single i.v injection:Is given as a single i.v injection:30 units over 3 30 units over 3 -- 5 minutes5 minutes


Tissue Plasminogen ActivatorTissue Plasminogen Activator(t-PA)


Tissue Plasminogen Activators (t-PA)

To activate plasminogen To activate plasminogen th t b d t fib ith t b d t fib ithat bound to fibrinthat bound to fibrin

Human tHuman t--PA is manufactured PA is manufactured

Recombinant DNA technologyRecombinant DNA technology


Tissue Plasminogen Activators (t-PA)

Is given by i v injection:Is given by i v injection:Is given by i.v injection: Is given by i.v injection: 60 mg over the 160 mg over the 1stst hour & hour &

40 mg at a rate of 20 mg/h40 mg at a rate of 20 mg/h40 mg at a rate of 20 mg/h40 mg at a rate of 20 mg/h


Clinical application of fibrinolytic therapyfibrinolytic therapy

Early treatment for pulmonary embolusEarly treatment for pulmonary embolusEarly treatment for pulmonary embolus Early treatment for pulmonary embolus may improve survival & may preserve may improve survival & may preserve

ll t l f tit l f tilonglong--term pulmonary functionterm pulmonary function

Should be followed by administrationShould be followed by administrationof heparin & then warfarinof heparin & then warfarin


pp

Warning: fibrinolytic therapyfibrinolytic therapy

Concomitant invasive prosedure Concomitant invasive prosedure must be avoidedmust be avoidedmust be avoidedmust be avoided

Bleeding Bleeding


Contraindication: fibrinolytic therapyfibrinolytic therapy

After recent surgeryAfter recent surgeryAfter recent surgeryAfter recent surgery

Metastatic cancer strokeMetastatic cancer strokeMetastatic cancer, strokeMetastatic cancer, stroke

Underlying hemorrhagic disordersUnderlying hemorrhagic disordersUnderlying hemorrhagic disordersUnderlying hemorrhagic disorders

Zain-Hamid,R; Faculty of Medicine, Universitas Sumatera Utara

Syafiuddin San & Rozaimah San, Kyoto, Nov. ‘06 – Japan.

Arigato Gozaimasu

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HIS 29 2Ph cology fbrnlytic drugs-1.ppt...

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