Discuss the mechanism of action of thrombolytic agent and its contraindications?

Thrombolysis is the breakdown (lysis) of blood clots by pharmacological means. It is colloquially referred to as clot busting for this reason. It works by stimulating fibrinolysis by plasmin through infusion of analogs of tissue plasminogen activator, the protein that normally activates plasmin.

Contraindications:-

These are contraindicated in bleeding disorders, active bleeding and when there has been recent surgery. Diabetic retinopathy is a relative contraindication, as is untreated high blood pressure. Warfarin treatment increases risk of bleeding and is a relative contraindication.

Streptokinase is contraindicated in patients who have been previously treated with streptokinase, as there is a risk of anaphylaxis (life-threatening allergic reaction) due to the production of antibodies against the enzyme.

Enzymes are used to cut DNA Since enzymes are also a protein, they have their own code, which can be found on DNA Scientists use it to cut DNA at specific sites when they want to splice genes or mix them together to make a 'hybrid' or a better version, usually with bacteria In DNA, it has its own sequence of nucleotides (a-t-c-g) which each have their own chemical structure. These for nucs are arranged anny order. And if a section of DNA matches the order of the enzyme, the enzyme will attach itself to it and 'cut it', that sequence of genes out. Then the scientist can put his own gene in.

This is straight from the PDR for alteplase:

"Activase is an enzyme (serine protease) which has the property of fibrin-enhanced conversion of plasminogen to plasmin. It produces limited conversion of plasminogen in the absence of fibrin. When introduced into the systemic circulation at pharmacologic concentration, Activase binds to fibrin in a thrombus and converts the entrapped plasminogen to plasmin. This initiates local fibrinolysis with limited systemic proteolysis. Following administration of 100 mg Activase, there is a decrease (16%–36%) in circulating fibrinogen.1,2 In a controlled trial, 8 of 73 patients (11%) receiving Activase (1.25 mg/kg body weight over 3 hours) experienced a decrease in fibrinogen to below 100 mg/dL.2

The clearance of Alteplase in AMI patients has shown that it is rapidly cleared from the plasma with an initial half-life of less than 5 minutes. There is no difference in the dominant initial plasma half-life between the 3-Hour and accelerated regimens for AMI. The plasma clearance of Alteplase is 380–570 mL/min.3,4 The clearance is mediated primarily by the liver. The initial volume of distribution approximates plasma volume."

WARNINGS:

"WARNINGS

Bleeding

The most common complication encountered during Activase therapy is bleeding. The type of bleeding associated with thrombolytic therapy can be divided into two broad categories:

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Internal bleeding, involving intracranial and retroperitoneal sites, or the gastrointestinal, genitourinary, or respiratory tracts.

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Superficial or surface bleeding, observed mainly at invaded or disturbed sites (e.g., venous cutdowns, arterial punctures, sites of recent surgical intervention).

The concomitant use of heparin anticoagulation may contribute to bleeding. Some of the hemorrhage episodes occurred 1 or more days after the effects of Activase had dissipated, but while heparin therapy was continuing.

As fibrin is lysed during Activase therapy, bleeding from recent puncture sites may occur. Therefore, thrombolytic therapy requires careful attention to all potential bleeding sites (including catheter insertion sites, arterial and venous puncture sites, cutdown sites, and needle puncture sites).

Intramuscular injections and nonessential handling of the patient should be avoided during treatment with Activase. Venipunctures should be performed carefully and only as required.

Should an arterial puncture be necessary during an infusion of Activase, it is preferable to use an upper extremity vessel that is accessible to manual compression. Pressure should be applied for at least 30 minutes, a pressure dressing applied, and the puncture site checked frequently for evidence of bleeding.

Should serious bleeding (not controllable by local pressure) occur, the infusion of Activase and any concomitant heparin should be terminated immediately.

Each patient being considered for therapy with Activase should be carefully evaluated and anticipated benefits weighed against potential risks associated with therapy.

In the following conditions, the risks of Activase therapy for all approved indications may be increased and should be weighed against the anticipated benefits:

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Recent major surgery, e.g., coronary artery bypass graft, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels

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Cerebrovascular disease

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Recent gastrointestinal or genitourinary bleeding

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Recent trauma

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Hypertension: systolic BP ≥175 mm Hg and/or diastolic BP ≥110 mm Hg

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High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation

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Acute pericarditis

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Subacute bacterial endocarditis

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Hemostatic defects including those secondary to severe hepatic or renal disease

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Significant hepatic dysfunction

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Pregnancy

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Diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions

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Septic thrombophlebitis or occluded AV cannula at seriously infected site

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Advanced age (e.g., over 75 years old)

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Patients currently receiving oral anticoagulants, e.g., warfarin sodium

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Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location."

CONTRAINDICATIONS:

" Acute Myocardial Infarction or Pulmonary Embolism

Activase therapy in patients with acute myocardial infarction or pulmonary embolism is contraindicated in the following situations because of an increased risk of bleeding:

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Active internal bleeding

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History of cerebrovascular accident

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Recent intracranial or intraspinal surgery or trauma (see WARNINGS )

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Intracranial neoplasm, arteriovenous malformation, or aneurysm

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Known bleeding disorder.