Compare and contrast the mechanisms of action and toxicity of sodium nitroprusside and glyceryl trinitrate (GTN).

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College Answer

Some excellent responses to this question showed a clear understanding of the pharmacology 
of these agents – the differing mechanisms of action involving both involving nitric oxide. Better 
answers were able to use this to explain the altered vascular specificity.
Toxicity was similarly well prepared for with a good understanding of the role of cyanide in 
SNP and the low rates of toxicity with GTN. This question was best handled in a tabular format 
which minimised omissions.
Some candidates focused on pharmaceutics, indications and side effects which were not 
allocated any marks.
'Compare & contrast' means the similarities; differences & unique features need to be related 
to each other. Several candidates confused ‘nitrous oxide’ with nitric oxide

Discussion

This was not a straightforward "compare and contrast" question which one might be able to answer with one's brainstem. The examiners wanted to specifically see the differences in the mechanism of action and toxicity, which is slightly more novel and thought provoking. Specifically, one would have to dig deep to find differences in mechanism of action, as ostensibly both drugs exert their effect in basically the same way. You'd have to get creative with definitions of "mechanism" and "action". It does not appear as if pharmacokinetic maters would have attracted any marks, but it was tempting to include them because they attracted marks in previous versions of this question.

GTN vs. Nitroprusside:
Mechanisms of Action and Toxic Effects
Domain Glyceryl Trinitrate (GTN) Glyceryl Trinitrate (GTN)
Delivery of NO  Metabolised by enzymatic breakdown into dinitrate, mononitrate and ulimately glycerol, liberating NO2- Degrades on contact with sulfhydryl groups and haemoglobin, liberating NO
Molecular target Both drugs target soluble guanylate cyclase
Molecular mechanism

Both drugs act as a donor of nitric oxide (NO) which:

  • activates guanylate cyclase, resulting in an increase of  (cyclic GMP) in vascular smooth muscle. This, in urn:
    • hyperpolarises the membrane by increasing potassium channel conductivity
    • decreases the availability of intracellular calcium
    • Phosphorylayes contractile myosin light chains
  • This decreases the resting tone and contractility of vascular smooth muscle.
Distinct pharmacodynamic features

GTN is more selective for:

  • venous capacitance vessels
  • coronary arteries
  • internal mammary arteries

Nitroprusside is relatively nonselective and produces venodilation and arteriodilation equally

Metabolites GTN is metabolised into glycerol, which is incorporated into glycolysis Sodium nitroprusside deghrades into cyanide molecules
Toxicity GTN toxicity is mainly the extension of its desirable effects, and includes hypotension, reflex tachycardia, and headache Nitroprusside toxicity is mainly cyanide toxicity, and includes shock, lactic acidosis, multiorgan system failure, pulmonary oedema and seizures

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.