Outline the pharmacology of sodium nitroprusside (50% of marks). Discuss the mechanisms of toxicity and their management (50% of marks).
Most candidates presented a structured answer and exhibited a good understanding of the
pharmacology of sodium nitroprusside. Few candidates demonstrated an understanding of
the mechanisms of SNP toxicity and details on management of cyanide toxicity were lacking.
Cobalt EDTA is no-longer recommended as initial therapy in the management for cyanide
More specific detail was expected beyond a generic comment on "mechanisims of toxicity"
such as potentially causes of respiratory, renal, hepatic or CNS failure.
Few candidates mentioned adverse effects other than that of cyanide toxicity. Many
candidates also failed to outline the management of sodium nitroprusside toxicity
First, pharmacology of nitroprusside, in a nutshell:
|Chemistry||Cyanide: five cyanide molecules and a ferrous nitrosyl group|
|Routes of administration||IV only|
|Absorption||0% oral availability, degraded into cyanide almost immediately on contact with mucosal surfaces|
|Solubility||pKa -3.3; minimally fat soluble; highly water soluble|
|Distribution||Virtually no protein binding.|
|Target receptor||Soluble guanylyl cyclase (which is induced by NO)|
|Metabolism||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||Immediate onset of effect (seconds); elimination half-life of 2 minutes|
|Time course of action||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 - 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||DBL PI document|
As for the cyanide toxicity, the following points were extracted out of the cyanide poisoning section from the Fellowship Exam, where Question 2 from the first paper of 2006 first mentioned it. It appears this topic straddles both exams. In short:
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.
Hall, Alan H., and Barry H. Rumack. "Clinical toxicology of cyanide." Annals of Emergency Medicine 15.9 (1986): 1067-1074.
Beasley, D. M. G., and W. I. Glass. "Cyanide poisoning: pathophysiology and treatment recommendations." Occupational medicine 48.7 (1998): 427-431.