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