Describe the pharmacology of glyceryl trinitrate (GTN).

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College Answer

GTN is a commonly used ‘level 1’ drug. The most comprehensive answers included information
on available drug preparations, indications, mechanism of action, pharmacodynamics and
pharmacokinetics and its side-effect profile. It was expected that significant detail be included in
the pharmacodynamic section (e.g. preferential venodilation, reflex tachycardia, effects on
myocardial oxygen demand etc). Common omissions included tachyphylaxis, dosing and its
metabolism. Many answers didn’t mention the first pass effect.

Discussion

Name Glyceryl trinitrate (GTN)
Class Direct vasodilator
Chemistry Organic nitrate
Routes of administration Oral, sublingual, intravenous, transdermal (as patch or cream)
Absorption 40% sublingual biavailability (but only 1% orally - because of extensive first pass metabolism)
Solubility pKa -5.6; very poor water solubility (and excellent fat solubility). 60% protein-bound.
Distribution 3.3L/kg
Target receptor Guanylate cyclase
Mechanism of action "Nitroglycerin forms free radical nitric oxide (NO) which activates guanylate cyclase, resulting in an increase of guanosine 3'5' monophosphate (cyclic GMP) in smooth muscle and other tissues. These events lead to dephosphorylation of myosin light chains, which regulate the contractile state in smooth muscle, and result in vasodilatation."
Metabolism Metabolised in the liver (by reductase enzymes) but also has extrahepatic sites of metabolism, including vascular cell walls and RBC cell walls.
Elimination Elimination half-life is about 30 minutes
Time course of action Onset of the vasodilatory effect occurs approximately 1 to 3 minutes after sublingual nitroglycerin administration and reaches a maximum by 5 minutes postdose. Effects persist for at least 25 minutes
Clinical effects Systemic vasodilation - preferentially venodilation; reduced preload, reduced afterload, and therefore reduced myocardial oxygen demand. Increased intracranial pressure, headache, reflex tachycardia, methaemoglobinaemia (rare). Tolerance develops over sustained use (tachyphylaxis)
Single best reference for further information FDA PI pamphlet for Nitrostat tablets