Protamine

[SH4:p509-p511]

• Protamine is a specific antagonist of heparin

Structure

• Strongly alkaline (nearly 2/3 of the amino acid composition if arginine)
• Polycationic
• Low MW
• Found in salmon sperm

Pharmacodynamics

Mechanism of action

[SH4:p510]

• Positively charged alkaline protamine combines with negatively charged acidic heparin
  --> Stable compound without anticoagulation activity
  --> Removed by reticuloendothelial system
• Protamine administered in absence of heparin
  --> Binds to platelet and proteins including fibrinogen
  --> Anticogulant effect

Side-effects

CVS

[SH4:p510]

Hypotension

• Rapid IV injection of protamine may be associated with histamine release
  --> Facial flushing, tachycardia, and hypotension
• Slow injection (over 5 min) is not associated with changes in histamine level or BP changes

Pulmonary hypertension

• Rarely, protamine neutralisation of heparin results in
  --> Secretion of thromboxane and 5HT
• Effects include:
  * Pulmonary vasoconstriction
  * Pulmonary hypertension
  * Bronchoconstriction

NB:

• Pretreatment with COX inhibitors blunt this side effect

Others

Allergic reactions

• Risk factors include:
  * Patients receiving protamine-containing insulin preparations
  * Allergy to fish

NB:

• Despite circulating anti-sperm antibodies in vasectomised or infertile males
  --> No association with allergy to protamine

Pharmacokinetics

Elimination

[SH4:p510]

• Protamine is cleared by reticuloendothelial system
• Clearance is fast (20 min)
  * Faster than heparin clearance
  --> Contribute to heparin rebound

Clinical

Dosage

1 mg of protamine for every 100U of heparin predicted to still be circulating

Alternative heparin antagonists

Alternative heparin antagonist include:

• Hexadimethrine [SH4:p510]
• Platelet factor 4 [SH4:p511]
  * Stored in the alpha granule of platelets
• Heparinase-I [SH4:p511]
  * A specific heparin degrading enzyme