G7ii / 20B20 / 15A11: Outline the pharmacology of sodium nitroprusside Discuss the mechanisms of toxicity and their management
20B20: Exam Report
Describe the pharmacology of intravenous sodium nitroprusside
49% of candidates passed this question.
This was a straightforward pharmacology question relating to a relatively common and archetypal intensive care medication. The structure of the question was well handled by most of the candidates; easily falling into the classic pharmaceutics, pharmacokinetic and pharmacodynamics framework. Many candidates had a superficial knowledge of the presentation and formulation of the drug, aside from its light sensitivity. Better answers detailed the drug according to the above-mentioned framework but also accurately highlighted specific
points relevant to the ICU practise such as the metabolic handling of sodium nitroprusside and relating this to the consequences of the various metabolic products.
15A11: Exam Report
Outline the pharmacology of sodium nitroprusside (50% of marks). Discuss the mechanisms of toxicity and their management (50% of marks).
38% of candidates passed this question.
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 toxicity.
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.
G7ii / 15A11: Outline the pharmacology of sodium nitroprusside (50 marks). Discuss the mechanisms of toxicity and their management (50 marks)
Pharmacology
Chemical
An INORGANIC peripheral vasodilator
Use
- Hypertensive crisis
- Aortic dissection prior to surgery
Presentation
IV solution for injection 50mg/2mL
Protect from light
Dose
0.5mcg/kg/min up to 4mcg/kg/min (IV) titrated to response
MoA
A PRODRUG
Diffuses into RBC & reacts with OxyHb to form
- MetHb
- 5CN–
- NO
NO → diffuses into smooth m. cell → binds to & activates GUANYLYL CYCLASE → GTP cGMP → ↑cGMP
- Inhibits Ca2+ entry into smooth m. cell
- Activates K+ channels → hyperpolarises cell (inactive)
- Stimulates ‘cGMP-dependent-protein-kinase’ → activates MLC phosphatases → dephosphorylates MLC
↓
Smooth m. relaxation
PD
CVS: ↓BP, ↓afterL, ↑HR
RESP: blunts HPVC → ↓PaO2
CNS: Cerebral VD → ↑ICP; shifts autoregulation curve LEFT
GI: ↓LES tone, paralytic ileus
Metabolic:
- ↑plasma catecholamines
- ↑RENIN
- Metabolic acidosis
PK
A
Nil oral absorption
D
Confined to plasma
VD = ECF = 15L
M
Pathway 1
In RBC to 5CN– + NO
- 1CN– → reacts with MetHb → forms CyanoMetHb
- 80% 4CN– → enter plasma → in liver metabolised by RHODANESE EN2 → uses thiosulfate ions as ‘sulfur donors’ to detoxify CN–
- Rest 20%: react with hydroxycobalamin → CYANO-COBALAMIN
NB: CyanoMetHb = non toxic
Pathway 2
- Low [ ] SNP
- Reacts with sulphydryl groups of amino-acids present in plasma
E
Thiocyanate & cyanocobalamin excreted in urine
t1/2 2mins
Adverse Effects
CYANIDE TOXICITY
↓BP
Headache
Dizziness
Palpitations
Cyanide Toxicity
Sources
- Smoke inhalaltion
- SNP
- Industrial exposure (metal extraction, electroplating, photography, fumigation)
- Chemical warefare
- Pesticides
- Cyanogenic glycosides such as amygdalin (almonds)
Toxicodynamics
CN– binds ferric (Fe3+) ion of cyt oxidase
Histotoxic hypoxia & lactic acidosis
Stimulates amine release
Causes pulmonary and coronary VC = APO & HF
Stimulates neurotransmitter release (ie NMDA) = seizures and neurotoxicity
Toxicokinetics
A – rapidly absorbed into cells
D – Vd 1.5L/kg, high PPB
M –
CN– metabolised by liver enzyme rhodanese
Rhodanese catalysis the reaction of CN + thiosulfate → thiocyanate + sulphite
Thiocyanate, non toxic at normal levels and excreted in urine
Thiosulfate levels can become depleted
E – 2-3hrs
Ix
History/high index suspicion
Lactate > 10mmol/L
High SvO2 (poor O2 extraction)
Check COHb for coexistant CO poisoning if smoke is inhaled
Cyanide levels take time, but correlate w clinical severity:
>20 microM = symptoms
>40 microM = potentially toxic
>100microM = lethal
Mx
Remove source
ABC
High flow O2
HF = vasopressors, ECMO
Antidote = Hydroxycobalamin (cobalt cyanide binder) then sodium thiosulfate (sulfur donor)
- Author: Krisoula Zahariou