Thrombolytic drugs

These drugs cause the conversion of plasminogen to plasmin causing fibrinolysis leading to dissolution of clots and reperfusion.


Plasmin may also degrade other factors like factor V, VIII and XII.

Note: Clots become more stable as the time passes. So treatment in the beginning is more helpful.

Therapeutic uses:
Previously it was mostly used in serious pulmonary embolism and central deep vein thrombosis but now less commonly used because of increased ability of bleeding.

They are also used to remove clots from catheters and shunts.

Administration:
They are usually administered intravenously.

Adverse effects:
It may cause hemorrhage.

Sometimes dissolution of clots may lead to increased local thrombi leading to increased platelaet aggregation and thrombosis. This incidence can be reduced buy giving aspirin and heparin along with thrombolytic drugs.

Contraindication:
It is contraindicated in pregnancy and in the patients of healing wounds.

Dipyridamole

It is an anticoagulant. It is a phosphodiesterase inhibitor. It is given in combination with aspirin.

Mechanism of action:
It causes inhibition of cyclic nucleotide phosphodiesterase leading to increased intracellular level of cAMP resulting in decreased Thromboxane A2 synthesis.

It may also stop the reuptake and metabolism of adenosine and potentiates prostacyclin effect to decrease platelet binding to thrombogenic surfaces leading to decreased platelet aggregation.


Therapeutic uses:
It is a coronary vasodilator. It is also used prophylactically in angina pectoris.

Adverse effects:
Headache

Eptifibatide and tirofiban

These are Anti-coagulants. Eptifibatide is a cyclic peptide and tirofiban is a non-peptide.

These bind to platelet GP IIb/IIIa receptors at the site that interacts with arginine-glycine-aspartic acid sequence of fibrinogen.


These are almost similar to abciximab in pharmacological aspects.

Abciximab

It is a chimeric (hybrid) monoclonal antibody.

Mechanism of action:
In this hybrid monoclonal antibody i.e. constant regions of human immunoglobulin and Fab fragments of murine monoclonal antibody gets bind to platelet GP IIb/IIIa receptos leading to blockage of the binding of fibrinogen and von Willebrand factor resulting in inhibition of aggregation.

Administration:

It is administered intravenously with aspirin and heparin.

Note: After stoppage of therapy platelet function gradually returns to normal.

Therapeutic uses:
It is used for the prevention of cardiac ischemia.

It is also recommended for patients with unstable angina.

Adverse effects:
It may cause bleeding disorders. Thrombocytopenia may also be caused.

Ticlopidine and clopidogrel

These are thienopyridine derivatives. They cause blockage of platelet aggregation.


Mechanism of action:
ADP gets bind to receptors on platelets resulting in activation of GP IIb/IIIa receptors, which is important for platelet binding to fibrinogen and to each other. Ticlopidine and clopidogrel cause interference in binding of ADP to receptors on platelets.

The inhibitory effect is irreversible and this effect remains as long as the platelet life.

Pharmacokinetics:
The drugs get strongly bind to plasma proteins after ingesting orally. Metabolism takes place extensively in the liver by cytochrome P450 system releasing active metabolites.

Maximum activity reached in 3-6 days. Its elimination takes place through kidney and feces.

Therapeutic uses:
These are effective in the prevention of cerebrovascular disease, cardiovascular disease and peripheral vascular disease.

These are used for insertion of stents in myocardial infarction.

Adverse effects:
It may cause prolonged bleeding. Thrombocytopenic purpura is also another adverse effect. Ticlopidine may also cause neutropenia.

Clopidogrel may also cause abdominal pain, chest pain and flulike symptoms.

Dosage:
Ticlopidine is taken orally in the 250 mg, tablet form BD with food.

The maintenance dose of clopidogrel is 75 mg per day.

Drug interactions:
Food causes interference in the absorption of ticlopidine but not of clopidogrel.

These drugs can stop activity of cytochrome P450 and that is why they may interfere with the metabolism of drugs such as tolbutamide, phenytoin, warfarin, and tamoxifen, if taken together.

Aspirin

Mechanism of action:
Aspirin causes the inhibition of COX-1by irreversible acetylation of serine residue on its active site and by causing a developmental failure of thromboxane A2 synthetase leading to the inhibition of Thromboxane-A2 synthesis.

In the whole process, Thrombin, collagen and ADP results in stimulation of platelets causing activation of platelet membrane phospholipids leading to the liberation of arachidonic acid from membrane phospholipids. COX-1 converts arachidonic acid to prostaglandin H₂ which is then metabolized to thromboxane-A₂ which is then released into plasma to cause a change in the shape of the platelets, release of their granules and promoting the clustering of platelets necessary for rapid formation of hemostatic plug.



Aspirin also causes chemical mediators to influence positively on anti-aggregating properties of prostacyclin (PGI₂) leading to further blockage of platelet aggregation.

The inhibitory effect apparently occurs in portal circulation where it is relatively faster. The effect occurs for 7-10 days.

Therapeutic uses:
It is used prophylactically for short duration of cerebral ischemia so that the incidence of myocardial infarction is reduced.

It is used in combination with other drugs such as heparin or clopidogrel.

Dosage:
For myocardial infarction prophylactically it is used as 325mg/day.

Adverse effects:
It may cause hemorrhage leading to hemorrhagic stroke or GI bleeding.

Anti-thrombotic drugs

These are platelet aggregation inhibitors (through a decreased formation or effect of chemical signals).
Mechanism of action:
In a series of reactions, when a vessel is injured, finally activation of membrane glycoprotein (GP) receptors takes place leading to binding of several adhesive proteins i.e. von Willebrand factor, fibronectin and fibrinogen.

Most important of GP-receptors is GP IIb/IIIa receptors upon which binding of fibrinogen takes place, through platelet activators like TXA2, ADP or thrombin, on two separate platelets resulting in the platelet cross linking and platelet aggregation leading to thrombus formation.

These drugs either cause inhibition of cyclo-oxygenase-1 (COX-1) or block GP IIb/IIIa receptors.