2004A06 Outline the circulatory effects of glyceryl trinitrate.

 

List:

·     PC

·     PK

·     PD

 

Pharmaceutics:

Structure

·  Hydrocarbon backbone

Three nitrate groups

Presentation

·  For IV injection: 50mg in 10mL

·  For sublingual spray: 300mcg actuations

 

Pharmacokinetics:

Administration

·  Infusion 10-200mcg/min

Time course

·  Onset 1-3 mins

·  Peak 5 mins

·  Duration 30 mins

Absorption

·  Well absorbed

·  Metabolised in the gut wall

·  Oral bioav <1%

Distribution

·  Plasma protein binding 10-60%

Metabolism

·  Hydrolysis in liver, RBC, endothelium

·  t1/2β 2-6 mins

Excretion

·  Metabolites -> urine

 

Pharmacodynamics:

Mechanism of action

·  Prodrug

·  Reacts with sulfhydryl groups in endotheliocytes -> nitric oxide (NO)

·  NO diffuses into vascular smooth muscle

·  NO activates guanylyl cyclase -> ↑cGMP -> ↑MLCP, ↑Ca2+ reuptake, ↑K+ efflux -> relaxation

·  Venodilatation > vasodilatation (unclear)

Venous effects

·  ↓Venous return -> ↓preload

Arterial effects

·  ↓SVR -> ↓mAP

·  ↓PVR -> ↓mPAP

·  ↓Coronary VR -> ↑Coronary blood flow

·  ↓CVR -> ↑CBF -> ↑ICP

Other effects

·  Myometrial relaxation

·  Bronchodilatation

·  ↓Platelet aggregation

Specific indications

·  Acute LV failure: ↓preload, ↓afterload

·  Myocardial ischaemia: ↓preload, ↓afterload, ↓O2 consumption, ↑coronary blood flow and O2 supply; but reflex ↑HR

·  Emergency ↓uterine tone at LUSCS

Side effects

·  Reflex ↑HR

·  Flushing, headache

Special

·  Tachyphylaxis – depletion of sulfhydryl groups (fix: withhold 12 hours)

·  Methaemoglobinaemia with prolonged use