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

Class Nitrate vasodilator
Chemistry Organic nitrate
Routes of administration Oral, sublingual, intravenous, transdermal (as patch or cream)
Absorption 40% sublingual biavailability (but only 1% orally). Extensive first-pass metabolism.
Solubility pKa -5.6; very poor water solubility (and excellent fat solubility).
Distribution 3.3L/kg VOD; 60% protein-bound.
Target receptor Guanylate cyclase
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
Mechanism of action Acts as a donor of nitric oxide (NO) which activates guanylate cyclase, resulting in an increase of guanosine 3'5' monophosphate (cyclic GMP) in vascular smooth muscle. This hyperpolarises the membrane by increasing potassium channel conductivity and decreases the availability of inracellular calcium, thereby decreasing the resting tone and contractility of vascular smooth muscle.
Clinical effects Systemic vasodilation - preferentially venodilation and cornary arterial dilation; reduced preload, reduced afterload. 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

References

Münzel, Thomas, and Andreas Daiber. "Pharmacology of nitrovasodilators." Nitrite and Nitrate in Human Health and Disease. Humana Press, Cham, 2017. 195-216.

Torfgård, Kristina E., and Johan Ahlner. "Mechanisms of action of nitrates.Cardiovascular drugs and therapy 8.5 (1994): 701-717.

Schulz, V. "Clinical pharmacokinetics of nitroprusside, cyanide, thiosulphate and thiocyanate." Clinical pharmacokinetics 9.3 (1984): 239-251.