Compare and contrast the pharmacology of sodium nitroprusside and glyceryl trinitrate.
It was expected candidates would address specific aspects of pharmacology such as action,
mechanism of action, half life and duration of effect, route of administration, potential
toxicity and special precautions. These agents lend themselves to comparison and contrast as
several distinct similarities and differences exist and credit was given for highlighting these.
Specific comments should include that both agents result in blood vessel dilation with extra
credit given for detailing the differences in the balance of arterial versus venous effects
between them. For both agents the effect is mediated through nitric oxide and it was
expected candidates would identify that nitroprusside releases NO spontaneously and GTN
requires enzymatic degradation with the resultant effects on smooth muscle mediated via c
GMP. They are both short acting agents when used intravenously and require careful titration
to measured blood pressure for effect.
Extra credit was given for mentioning that routes other than IV are available for GTN (topical
/ oral) but not for nitroprusside. Comments on special precautions such as Nitroprusside
should be protected from light and GTN given via non PVC giving sets gained additional
marks. In addition to the well described adverse effects of each agent, it was expected candidates would mention the potential for cyanide toxicity with nitroprusside and extra marks were awarded for an indication of usual doses.
Syllabus C2b 2e
References Katzung 10th edition, Goodman and Gillman Chp 31 & 32
This question is essentially the same as Question 3(p.2) from the first paper of 2008, except this time the college omitted "for the treatment of acute hypertension" from the question stem.
|Glyceryl trinitrate (GTN)||Sodium nitroprusside|
|Class||Nitrate vasodilator||Nitrate vasodilator|
|Routes of administration||Oral, sublingual, intravenous, transdermal (as patch or cream)||IV only|
|Absorption||40% sublingual biavailability (but only 1% orally)||0% oral availability, degraded into cyanide almost immediately on contact with mucosal surfaces|
|Solubility||pKa -5.6; very poor water solubility (and excellent fat solubility).||pKa -3.3; minimally fat soluble; highly water soluble|
|Distribution||3.3L/kg VOD; 60% protein-bound.||Virtually no protein binding.|
|Target receptor||Soluble guanylyl cyclase (which is induced by NO)||Soluble guanylyl cyclase (which is induced by NO)|
|Metabolism||Metabolised in the liver (by reductase enzymes) but also has extrahepatic sites of metabolism, including vascular cell walls and RBC cell walls.||Two main mechanisms of metabolism: spontaneous decomposition into ferrous nitrosyl (FeNO) and five cyanide molecules, or reaction with haemoglobin to form cyanmethemoglobin and four cyanide molecules.
It is also degraded by direct light, which requires opaque storage vessels and special handling techniques.
|Elimination||Elimination half-life is about 30 minutes||Immediate onset of effect (seconds); elimination half-life of 2 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||Rapid onset and offset of effect; vasodilation is seen within seconds of beginning the infusion|
|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).||Systemic vasodilation - balanced venodilation and arterial dilation; reduced preload as well as reduced afterload. Increased intracranial pressure, headache, reflex tachycardia, methaemoglobinaemia. Tolerance develops over sustained use (tachyphylaxis). Significant cyanide toxicity can occur with doses in excess of 2mcg/kg/min|
|Single best reference for further information||FDA PI pamphlet for Nitrostat tablets||DBL PI docu|
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.