1999B12 Briefly describe the mechanism and treatment of the toxicity of sodium nitroprusside.

 

List:

·     PC

·     PK

·     PD (mainly this)

 

Physicochemical:

Structure

·  Fe2+ surrounded by 5 x CN- and 1 x NO

Appearance

·  Red powder

Reconstitution

·  With 5% dextrose -> orange solution

Problem

·  Light sensitive -> dark brown

·  Hence bottle and IV line covered with aluminium foil

 

Pharmacokinetics:

Administration

·  0.3-10mcg/kg/min

Time course

·  Onset <1 min

·  Duration 1-10 mins

Absorption

N/A

Distribution

?

Metabolism

·  Reacts with oxyHb -> 1 x nitric oxide (NO) + 5 x cyanide (CN-) + metHb

·  SNP t1/2β 2 mins

Excretion

·  Thiocyanate t1/2β 2 days

 

Pharmacodynamics:

Mechanism

·  NO -> activate guanylyl cyclase -> ↑cGMP -> ↑MLCP activity, ↑Ca2+ reuptake, ↑K+ efflux

Vasodilation

·  Vasodilatation > venodilatation (unclear)

·  ↓SVR (used during aortic cross-clamping), ↓mAP

·  ↓PVR

·  ↓CVR -> ↑CBF, +/-↑ICP

Side effects

·  Reflex ↑HR

Cyanide toxicity

·  Pathophysiology: inhibit cytochrome C oxidase -> histiotoxic hypoxia

·  Toxic concentration: 8mcg/mL

·  Clinical: ↑HR, ↑RR, anxiety, sweating; can be lethal within minutes

·  Lab tests: ↑SvO2, metabolic acidosis

·  Endogenous antidote:

o CN- + metHb -> cyanmetHb

o CN- -> thiocyanate (liver and kidney), 100x less toxic

·  Exogenous antidote:

o Sodium thiosulfate (cyanide -> thiocyanate)

o Dicobalt edetate (chelator)

o Nitrates: metHb binds CN- more avidly

o Hydrocobalamin

Thiocyanate toxicity

·  Vasodilatation, tinnitus

Methaemoglobinaemia

·  Pathophysiology: NO: Fe2+ -> Fe3+; poor O2 carrying capacity

·  SpO2 trend to 84%

·  Significant if total dose SNP >10mg/kg

·  Endogenous antidote: NADH- or NADPH-metHb reductase

·  Exogenous antidote: methylene blue 1-2mg/kg Fe3+ -> Fe2+