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

  1. Hypertensive crisis
  2. 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

  1. Inhibits Ca2+ entry into smooth m. cell
  2. Activates K+ channels → hyperpolarises cell (inactive)
  3. 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)