Usage
Aprotinin is a serine protease inhibitor, specifically a polypeptide derived from bovine lung tissue, used prophylactically to reduce perioperative blood loss and the need for blood transfusions in patients undergoing cardiopulmonary bypass during coronary artery bypass graft (CABG) surgery who are at increased risk for bleeding and transfusions. Its pharmacological classification is antifibrinolytic or haemostatic agent. It acts by inhibiting several serine proteases, including kallikrein, plasmin, and trypsin, which are involved in fibrinolysis (the breakdown of blood clots) and inflammation, as well as contact phase activation of coagulation, which promotes fibrinolysis. As of 2008, its use has been restricted under a limited-use agreement due to potential safety concerns.
Alternate Names
How It Works
Pharmacodynamics: Aprotinin inhibits several serine proteases in the coagulation and inflammatory cascades. By inhibiting plasmin, it prevents the breakdown of fibrin, the key protein in blood clots. Kallikrein inhibition reduces the formation of bradykinin, which contributes to inflammation and vasodilation. Aprotinin’s effect on the contact activation pathway further reinforces its antifibrinolytic properties.
Pharmacokinetics: Administered intravenously, aprotinin is rapidly distributed in the extracellular fluid. The plasma half-life is relatively short (around 2 hours), and the drug undergoes renal elimination, primarily through glomerular filtration. It doesn’t seem to be extensively metabolized in the liver.
Mode of action: Aprotinin binds reversibly to the active site of its target serine proteases, preventing them from interacting with their substrates and thus blocking their enzymatic activity.
Dosage
Note: The following applies to when aprotinin was generally available. As of 2008, access is limited to investigational use under a special treatment protocol, due to safety concerns (increased risk of death).
Standard Dosage
Adults:
Two regimens were recommended:
- Regimen A:
- Test dose: 1 mL (10,000 KIU) administered intravenously at least 10 minutes before the loading dose.
- Loading dose: 280 mg IV over 20-30 minutes after anesthesia induction and before sternotomy.
- Pump prime dose: 280 mg added to the heart-lung machine’s priming solution.
- Continuous infusion dose: 70 mg/hr until the end of surgery.
- Regimen B:
- Test dose: 1 mL (10,000 KIU) at least 10 minutes before the loading dose.
- Loading dose: 140 mg IV over 20-30 minutes after anesthesia induction and before sternotomy.
- Pump prime dose: 140 mg added to the pump prime.
- Continuous infusion dose: 35 mg/hr until the end of surgery.
Maximum total dose: 7 million KIU.
Children:
Safety and efficacy have not been established in patients younger than 18 years old.
Special Cases:
- Elderly patients: Dosage adjustments are not typically necessary.
- Patients with renal impairment: Based on available clinical experience, specific dose adjustment may not be required.
- Patients with hepatic dysfunction: There is no specific dosage recommendation for hepatic dysfunction.
Clinical Use Cases
Aprotinin’s approved indication was limited to reducing blood loss during CABG surgery involving cardiopulmonary bypass in high-risk patients. Off-label uses have been explored but are not currently recommended.
Dosage Adjustments
Dose adjustments are generally not needed based on renal function or age, but may be considered in patients with multiple risk factors for bleeding complications. Currently, the drug is primarily available for investigational use under a special treatment protocol which would outline dosage and eligibility.
Side Effects
Common Side Effects
- Fever
- Nausea
- Vomiting
- Diarrhea
- Constipation
- Atrial fibrillation
Rare but Serious Side Effects
- Anaphylactic/anaphylactoid reactions (hypotension, dyspnea, rash, itching)
- Renal dysfunction/failure
- Myocardial infarction
- Stroke
- Thromboembolic events
Long-Term Effects
Limited data are available on the long-term effects of aprotinin due to the nature of its administration and restricted usage.
Adverse Drug Reactions (ADR)
Severe hypersensitivity reactions, including anaphylaxis, require immediate intervention. Renal failure and thromboembolic events represent serious ADRs.
Contraindications
- Hypersensitivity to aprotinin
- Positive aprotinin-specific IgG antibody test
- Prior aprotinin exposure within the last 12 months
- Concurrent use with certain fibrin sealant products containing aprotinin
Drug Interactions
- Thrombolytic agents (e.g., alteplase, streptokinase): Aprotinin antagonizes their action and should not be used concurrently.
- Aminoglycoside antibiotics: Increased risk of renal dysfunction.
- ACE inhibitors (e.g., captopril): Potential interaction.
- Heparin: Maintain adequate anticoagulation with heparin during aprotinin therapy.
Pregnancy and Breastfeeding
- Pregnancy: Pregnancy Category B. Animal studies haven’t demonstrated fetal harm. Human data are limited. Only use if the potential benefit clearly outweighs the potential risk.
- Breastfeeding: It is unknown whether aprotinin is excreted in human milk. Exercise caution if administering to breastfeeding mothers.
Drug Profile Summary
- Mechanism of Action: Serine protease inhibitor (kallikrein, plasmin, trypsin); inhibits fibrinolysis.
- Side Effects: Common: fever, nausea, vomiting. Serious: anaphylaxis, renal dysfunction, MI, stroke.
- Contraindications: Hypersensitivity, prior aprotinin exposure, positive aprotinin-specific IgG test.
- Drug Interactions: Thrombolytics, aminoglycosides, ACE inhibitors.
- Pregnancy & Breastfeeding: Caution advised; use only if benefit clearly outweighs risk.
- Dosage: (historical; see dosage section) Regimen A/B. Test dose, loading dose, pump prime, continuous infusion. Max: 7 million KIU.
- Monitoring Parameters: Activated clotting time (ACT), heparin levels, renal function, signs of hypersensitivity.
Popular Combinations
Previously, aprotinin was often administered with heparin to maintain anticoagulation during CABG surgery. Now, its use is severely restricted.
Precautions
- Test dose before administration to assess for hypersensitivity.
- Monitor for signs of anaphylaxis/anaphylactoid reactions.
- Closely observe renal function, especially in patients with pre-existing renal disease.
- Ensure adequate anticoagulation with heparin during CABG procedures (when aprotinin was commonly used).
- Avoid rapid intravenous administration due to the risk of hypotension.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Aprotinin?
A: See detailed dosage section above. As of 2008, usage is restricted to investigational use under a special treatment protocol.
Q2: What are the main contraindications for aprotinin?
A: Hypersensitivity to aprotinin, positive aprotinin IgG antibody test, prior exposure to aprotinin within the past 12 months.
Q3: How does aprotinin work to reduce bleeding?
A: It inhibits serine proteases such as plasmin, kallikrein, and trypsin, which are involved in fibrinolysis and inflammation, thus preventing clot breakdown and excessive bleeding.
Q4: What are the most serious side effects associated with aprotinin?
A: Anaphylactic/anaphylactoid reactions, renal dysfunction, myocardial infarction, and stroke.
Q5: Can aprotinin be used in children?
A: Safety and efficacy have not been established in the pediatric population.
Q6: Can aprotinin be used during pregnancy or breastfeeding?
A: Use with caution; only if the potential benefits outweigh the potential risks. Limited human data are available. It is not known if aprotinin is excreted in human breast milk.
Q7: Are there any drug interactions I should be aware of with aprotinin?
A: Avoid concurrent use with thrombolytic agents, and exercise caution with aminoglycosides. Potential interactions with ACE inhibitors also exist.
Q8: Why is aprotinin use currently restricted?
A: Due to concerns over increased risk of death and other adverse events identified in studies, its use is now primarily limited to investigational purposes under a special treatment protocol.
Q9: What monitoring parameters are important when using aprotinin?
A: Activated clotting time (ACT), heparin levels, renal function, signs of hypersensitivity.
Q10: Is aprotinin compatible with all intravenous solutions?
A: No. It is incompatible with corticosteroids, heparin (in concentrated solutions; dilute before mixing), tetracyclines, and nutrient solutions with amino acids or fat emulsions.
