G7ii / 16B02: Compare and contrast the mechanisms of action and toxicity of sodium nitroprusside and glyceryl trinitrate (GTN)

16B02: Exam Report

Compare and contrast the mechanisms of action and toxicity of sodium nitroprusside and glyceryl trinitrate (GTN).

55% of candidates passed this question.

Some excellent responses to this question showed a clear understanding of the pharmacology of these agents – the differing mechanisms of action involving both involving nitric oxide. Better answers were able to use this to explain the altered vascular specificity.

Toxicity was similarly well prepared for with a good understanding of the role of cyanide in SNP and the low rates of toxicity with GTN. This question was best handled in a tabular format which minimised omissions.

Some candidates focused on pharmaceutics, indications and side effects which were not allocated any marks.
‘Compare & contrast’ means the similarities; differences & unique features need to be related to each other. Several candidates confused ‘nitrous oxide’ with nitric oxide.

G8iii / 16B02: Compare and contrast the mechanisms of action and toxicity of sodium nitroprusside and glyceryl trinitrate (GTN)

GTN

SNP

Comparison

Definition

GTN

An organic nitrate vasodilator

SNP

An inorganic peripheral vasodilator

MoA

GTN

Prodrug, needs to be denitrated to produce active NO

i.e. reacts with sulfyhydryl groups/ other enzyme reactions to liberate NO

SNP

Also a prodrug;
Diffuses into RBC & reacts with oxyHb to form:

  • MetHb
  • 5CN-
  • NO

Comparison

Both have the same end point to produce NO

Both are prodrugs and require reactions

GTN / SNP

NO

↓

Diffuses into smooth m. cell

↓

Binds to & activates guanyl cyclase

↓

GTP \( \xrightarrow{\text{GC catalyses }} \) cGMP

↓

↑cGMP (2° messenger)

  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

 

Comparison

SNIP = equal relaxation of venous and arterial smooth muscle

GTN = Venous > Aterial diltation

Toxicity

GTN

80% dose absorbed by giving sets

Nitrates cause oxidation of Fe2+ → Fe3+ in Hb

This causes MetHb formation

MetHb cannot bind O2

Oxidation of one heme in the tetratmer causes the others to increase affinity for O2 and thus L ODC shift with Hb less readily releasing O2

Adverse Effects of GTN related to vessel dilatation-

CVS: ↓BP + ↑HR

GI: N & V

CNS: Headache

Haem: MetHb, platelet dysfunction

Tachyphylaxis

SNP

Rebound HTN

SNP toxicity (cyanide toxicity)

Build up of CN- impairs oxidative phosphorelation

Binds Cyt C Oxidase, blocking mitochondrial transport chain

Cellular hypoxia & depletion of ATP

Metabolic acidosis

CYANIDE TOXICITY symptoms:

↓BP

Headache

Dizziness

Palpitations

Comparison

Cyanide blood levels take time.  Requires high index of suspicion

Lactate >8mmol/L is 94% sensitive and 70% specific

CN- toxicity is related to the rate of the infusion rather than the total dose

MetHb levels on ABG