2011B05 Describe the mechanism of action of protamine when used to reverse
effects of heparin. Outline the side effects of protamine.

 

List:

·      PC

·      PK

·      PD

 

Physicochemical:

Structure

·  Basic cationic polypeptides

·  Derived from salmon sperm

Presentation

·  Aqueous solution

·  50mg in 5mL protamine sulfate

Incompatibilities

·  With some antibiotics: penicillins and cephalosporins

 

Pharmacokinetics:

Administration

·  1mL (10mg) protamine per 1mL (1,000 units) heparin

Time course

·  Onset: within 5 minutes

·  Duration: 2-3 hours

Distribution

·  VD <0.1L/kg

Metabolism

·  Heparin-protamine complex broken down in the reticulo-endothelial system

·  Cl 20mL/kg/min

·  t1/2β 60 mins (cf. heparin 90 mins)

Excretion

·  Urine

 

Pharmacodynamics:

Mechanism

·  Protamine (basic cationic) + heparin (acidic anionic) -> stable salt complex

·  Neutralises high MW but not low MW heparins

o UFH ~100%

o LMWH ~60%

o Fondaparinux 0%

·  Indirectly restores activity of antifactors IIa, Xa (also VIIa/TF, IXa, XIa)

Haemostatic side effects

·  Inconsistent reversal of Xa inhibition

o Doesn’t neutralize low MW heparins present in UFH

·  Anticoagulation if excessive

o Interactions with platelets, fibrinogen

·  Hypercoagability if excessive (examiner says this possible)

·  Re-heparinisation: shorter half life than heparin

Other side effects

·  Systemic hypotension

o If rapid infusion

·  Pulmonary hypertension +/- RV failure

o TXA2 release, complement activation

o Especially if rapid infusion

·  Non-cardiogenic pulmonary oedema

o Cause: ? TXA2 ? complement ? histamine

·  Anaphylaxis:

o IgE mediated

o Sensitisation: Ag on APC -> T cell -> B cell -> IgE -> fix on mast cells

o Repeat exposure: mast cell degranulation -> histamine etc

o Vasodilatation, capillary leak, hypotension

o Bronchospasm

o Risk factors: allergy to protaphane insulin or fish; PHx vasectomy

 

 

 

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