1. 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)

2. TPA: tissue plasminogen activator
Fibrinolysis
TPA: tissue plasminogen activator

3. 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)

4. Mechanism of Thrombolytic Drugs
The plasmin(ogen) molecule has lysine binding sites, which bind to fibrin
$2200
$280
prodrug
Secreted from kidney

5. Classification of thrombolytic drugs
Streptokinase
(SK)
Anistreplase
Alteplase
Urokinase

6. activator complex (SK+plasminogen)
I- Streptokinase (SK)
It is a bacterial protein (not an enzyme)produced by group C β-hemolytic streptococci. SK
activator complex (SK+plasminogen)
Plasminogen
Activator complex
Plasminogen
Plasmin
Lysis of fibrin clot
N.B. Plasmin degrades fibrin clots as well as fibrinogen and other plasma proteins (non-fibrin specific)

7. Cont’d
activate
(-) = break down
degrade

8. 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 hrs
A prolonged bleeding time may persist for up to 24 hours due to the decrease in plasma levels of fibrinogen

9. Cont’d Efficacy: reduces mortality:
47 % reduction after one hour of chest pain.
23% within 3 hours
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)

10. Cont’d Acute MI Occlusion of Arteriovenous Cannulae Uses:
Deep vein thrombosis
Occlusion of Arteriovenous Cannulae
Arterial thrombosis or embolism
Pulmonary embolism

11. 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.

12. 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)

13. 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 ( min )
Hospital cost per day is 1700 $
deacylation

14. It’s fibrin selective (specific)
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)

15. cont’d Cost per day is around 2200 $ (expensive) Pharmacokinetics:
t1/2 = 5 minutes
produced by recombinant DNA technology.
Cost per day is around 2200 $ (expensive)

16. Cont’d Therapeutic Uses Acute Myocardial Infarction: Reduces mortality
Improve ventricular function  ↓ CHF
Acute Ischemic Stroke
improves neurological recovery
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)

17. Cont’d Side-Effects: Bleeding including GIT & cerebral hemorrhage
Allergic reactions: rare (< 0.02% of patients) (minor effect)

18. IV- Urokinase
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).

19. Pharmacokinetics Cont’d (IV) administration
rapidly cleared by the liver
t1/2 = minutes
Clinical Uses:
For the lyses of acute massive pulmonary emboli

20. Contraindications to Thrombolytic Therapy
Cont’d
Contraindications to Thrombolytic Therapy
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

21. 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
The doctor says: (to inhibit bleeding ) is enough

22. 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 bleeding
7-Streptokinase may cause hypersensitivity reaction
8-Urokinase is used primarily in pulmonary embolism treatment