THROMBOLYTIC DRUGS Pathophysiologic Rationale When an atherosclerotic plaque ruptures thrombosis ...
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Transcript of THROMBOLYTIC DRUGS Pathophysiologic Rationale When an atherosclerotic plaque ruptures thrombosis ...
THROMBOLYTIC DRUGS Pathophysiologic Rationale
When an atherosclerotic plaque ruptures thrombosis occlusion of the artery myocardial infarction necrosis
If we can breakdown the thrombus then we can save the myocardial cells from necrosis.
Clinical trials of thrombolytic drugs showed beneficial in patient with MI with ST segment elevation.
But they weren’t as beneficial when it came to unstable angina or MI with non ST segment elevation
The treatment should be initiated rapidly (less than 6 hours)
Fibrinolysis
TPA: tissue plasminogen activator
Mechanism of Thrombolytic Drugs
They convert plasminogen plasmin which lyses blood clots
Plasmin, is a nonspecific serine protease (capable of breaking down fibrin as well as fibrinogen (main action) and factors V and VIII)
Mechanism of Thrombolytic Drugs
The plasmin(ogen) molecule has lysine binding sites, which bind to fibrin
prodrug
Secreted from kidney
$2200
$280
I- Streptokinase (SK) It is a bacterial protein (not an enzyme)produced by
group C β-hemolytic streptococci.
Plasminogen
SKactivator complex (SK+plasminogen)
PlasminPlasminogen
Activator complex
N.B. Plasmin degrades fibrin clots as well as fibrinogen and other plasma proteins (non-fibrin
specific)
Lysis of fibrin clot
Cont’d
activate
degrade
Cont’d
Pharmacokinetics: The t½ of the activator complex= 23 minutes
The complex is inactivated by anti-streptococcal antibodies & by hepatic clearance
It produces hyperfibrinolytic effect, which decreases plasma fibrinogen levels for 24-36 hrs
A prolonged bleeding time may persist for up to 24 hours due to the decrease in plasma levels of fibrinogen
Cont’d
Efficacy: reduces mortality:o 47 % reduction after one hour of chest pain.o 23% within 3 hourso 17% between 3-6 hours No significant reduction between 6-12 hours Hospital cost per day is minimal 280 $
The advantages are more when take rapidly (at the onset of chest pain)
Cont’d
Cont’d
Clinical Uses: Acute Myocardial Infarction: administered IV or
intracoronary ↓ infarct size and congestive heart failure. Arterial Thrombosis or Embolism: It is not indicated for
arterial emboli originating from the left side of the heart due to the risk of new embolic phenomena such as cerebral embolism.
Occlusion of Arteriovenous Cannulae: for clearing totally or partially occluded arteriovenous cannulae.
Cont’d
Side-Effects: Bleeding due to activation of circulating
plasminogen Hypersensitivity: because it is of bacterial
products so, it is antigenic & can produce allergic reactions like rashes & fever (occurs in 3% of patients)
II- Anistreplase (APSAC)
Anisoylated Plasminogen Streptokinase Activator Complex (APSAC) purified human plasminogen combined with bacterial streptokinase that has been acylated to protect the enzyme’s active site.
It is a prodrug:
APSAC SK-plasminogen complex Similar to SK, it has minimal fibrin specificity & is
antigenic T1/2 is more than SK (70-120 min )
Hospital cost per day is 1700 $
deacylation
III- Alteplase (rt.PA) Formerly known as tissue plasminogen activator (t-PA).
Mechanism of action: It is an enzyme.
rt.PA binds to fibrin conversion of plasminogen to plasmin (inside the clot) fibrinolysis
It acts only on fibrin inside the clot (not free fibrin)
It’s fibrin selective (specific)
It’s fibrin selective (specific)
cont’d
Pharmacokinetics:
t1/2 = 5 minutes
produced by recombinant DNA technology. Cost per day is around 2200 $ (expensive)
Cont’d
Therapeutic Uses Acute Myocardial Infarction:
1. Reduces mortality
2. Improve ventricular function ↓ CHF Acute Ischemic Stroke
1. improves neurological recovery
2. reduces the incidence of disability.
Treatment of acute massive Embolism
•Treatment should only be initiated within 3 hours after the onset of stroke symptoms.
•You have to exclude cerebral hemorrhage to use alteplase (see adverse effect in the next slide)
Cont’d
Side-Effects: Bleeding including GIT & cerebral hemorrhage Allergic reactions: rare (< 0.02% of patients)
(minor effect)
IV- UrokinaseUrokinase It is an enzyme produced by the kidney of
human & also animal ( yet no allergic reaction) and is found in urine.
It is mainly used in the low molecular weight form of urokinase obtained from human neonatal kidney cells grown in tissue culture.
Mechanism: It acts on the endogenous fibrinolytic system converting plasminogen to plasmin that degrades fibrin clots as well as fibrinogen and some other plasma proteins (Non-fibrin selective).
Cont’d
(IV) administration rapidly cleared by the liver t1/2 = 12-20 minutes
Clinical Uses: For the lyses of acute massive pulmonary emboli
Cont’d
Absolute contraindications Relative contraindications
Recent head trauma or cranial tumor
Active peptic ulcer
Previous hemorrhagic shock Diabetic retinopathy
Stroke or cerebrovascular events (1 year old)
Pregnancy
Active internal bleeding Uncontrolled hypertension
Major surgery within the previous two weeks
Contraindications to Thrombolytic Therapy
Fibrinolytic Inhibitors
Aminocaproic Acid & tranexamic acid 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 blocking free plasmin Used to stop bleeding in some surgical
procedures
ZuBDAS, in other words: (butter of the lecture)
1- All thrombolytic drugs cannot be used in case of unstable angina (could mobilize the thrombus embolism) 2- All thrombolytic drugs can be used in case of acute MI (more effective in the first 6 hours).3- SK & Anistriplase have same MOA, ADR & selectivity. The only difference between them is that the anistriplase has relatively longer duration of action. 4- All thrombolytic drugs are non-selective except Alteplase.5- All thrombolytic drugs have short duration of action except anistreplase (relatively)6- All non-selective thrombolytic drugs cause more bleeding tendency than selective. Yet in general all cause bleeding7-Streptokinase may cause hypersensitivity reaction8-Urokinase is used primarily in pulmonary embolism treatment