Alteplase (rt-PA) / Tenecteplase

Mechanism

Mechanism of Action

Alteplase and Tenecteplase are recombinant proteins synthesized through biotechnology that act by stimulating the enzymatic dissolution of preformed fibrin clots.

Molecular Physiology of the Recombinant Fibrinolytic System

1. Plasminogen is an inactive zymogen present in plasma that binds to fibrin networks.
2. Alteplase (rt-PA) is a recombinant glycoprotein equivalent to natural human tissue plasminogen activator. It is characterized by being a selective fibrin clot agent: in the absence of fibrin, it has little affinity for circulating free plasminogen.
3. By binding to the fibrin of the thrombus, alteplase catalyzes the proteolytic cleavage of the Arg561-Val562 amino acid bond of plasminogen, converting it into the active proteolytic enzyme: plasmin.
4. Plasmin progressively digests insoluble fibrin through the breaking of internal structural bonds, producing polar fragments known as D-Dimers and soluble degradation fragments, lysing the thrombotic mass.
5. Tenecteplase (TNK-tPA): It is a genetically modified variant of rt-PA through specific substitutions of three key amino acids. It has significantly greater selectivity for fibrin than alteplase, increased resistance to plasma inactivation by the natural inhibitor PAI-1, and a prolonged half-life that makes it possible to administer it comfortably in a single rapid intravenous bolus.

Pharmacokinetics

Pharmacokinetics

• Rout of administration: Exclusively intravenous.
• Bioavailability (F): Does not apply for direct intravascular administration.
• Distribution: Reduced volume of distribution, confined to the intravascular space.
• Metabolism: Rapid hepatic clearance through specific cellular receptors that capture and degrade the protein.
• Half-life (t_1/2): - Alteplase: Extremely rapid initial plasma elimination half-life, less than 5 minutes, with almost total clearance in the first 15 to 20 minutes after completing the infusion.
  - Tenecteplase: Prolonged plasma half-life of about 20 to 24 minutes, allowing prolonged clearance of the single bolus.

Indicators and dose

Indications

• Urgent fibrinolytic treatment of acute myocardial infarction in the acute phase (within a period of less than 12 hours from the onset of symptoms, if primary PCI is not available).
• Thrombolytic treatment of acute ischemic stroke with a course of less than 4.5 hours (after strict exclusion of cerebral bleeding by head CT).
• Thrombolytic treatment of hemodynamically unstable massive acute pulmonary embolism (with cardiogenic shock or persistent hypotension).
• Unclogging of thrombosed central venous access catheters (local ultra-low doses of alteplase).

Dosage and Adjustment

• Alteplase (Acute ischemic stroke): Total recommended dose of 0.9 mg/kg (absolute maximum dose of 90 mg). 10% of the total calculated dose is administered as a rapid intravenous bolus over 1 minute; The remaining 90% is administered as a continuous IV infusion regulated at an interval of 60 minutes.
• Tenecteplase (acute AMI): Rapid single intravenous bolus in 5-10 seconds strictly adjusted by body weight scales, to minimize the risk of overdose and cerebral hemorrhage:
  - Weight < 60 kg: 30 mg.
  - Weight 60 - 70 kg: 35 mg.
  - Weight 70 - 80 kg: 40 mg.
  - Weight 80 - 90 kg: 45 mg.
  - Weight 90 kg: 50 mg.

Pregnancy and Breastfeeding

FDA Category C. Contraindicated unless it is an absolute life-threatening emergency (e.g., massive PE with direct life-threatening involvement). High risk of placental abruption and fatal intrauterine hemorrhage.

Security

Absolute Contraindications

Absolute Fibrinolysis Exclusion Criteria

• History or suspicion of intracranial hemorrhage of any etiology or temporal phase.
• Ischemic stroke with an acute course of less than 3 months.
• Known intracranial neoplasia or cerebral structural vascular malformation.
• Recent severe head injury or recent major CNS surgery of less than 2 months.
• Proven or suspected clinically significant active internal bleeding.
• Suspicion of acute aortic dissection with an evolving course.
• Known bleeding diathesis or severe uncontrolled refractory arterial hypertension (SBP > 185 mmHg / DBP > 110 mmHg).

Adverse Effects (ADR)

• Serious hemorrhage: The risk of fatal intracranial hemorrhage is 0.5% to 1% in rt-PA therapy. Massive hemorrhage from the digestive or retroperitoneal tracts.
• Orolingual angioedema: Transient in nature, incidence of up to 1-2%, predominantly in patients who were under joint therapy with chronic ACE inhibitors (ACE inhibitors).
• Reperfusion arrhythmias: Rapid reestablishment of coronary flow induces acute passage of ions and metabolites, causing ventricular premature beats or self-limited transient bradycardia after lysis.

Interactions

Exponentially increased bleeding risk with concomitant administration of heparins, oral anticoagulants or dual antiplatelet agents. However, in the acute phase of AMI and ischemic stroke, it is prescribed in a combined and strict manner under international clinical practice guidelines.