3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.1. Scrap
                  3.1.1.2. Drugs affecting coagulation
                      3.1.1.2.2. Anticoagulants
                          3.1.1.2.2.1. Heparin
 3.1.1.2.2.1.1. Protamine 

Protamine

[SH4:p509-p511]

  • Protamine is a specific antagonist of heparin

Structure

  • Strongly alkaline (nearly 2/3 of the amino acid composition of 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