2004A06 Outline the circulatory effects of glyceryl trinitrate.

Structure

·   Hydrocarbon backbone

Three nitrate groups

Presentation

·   For IV injection: 50mg in 10mL

·   For sublingual spray: 300mcg actuations

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

·   t_1/2β 2-6 mins

Excretion

·   Metabolites -> urine

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