G7ii / 25B09: Compare and contrast the following pharmacology of sodium nitroprusside and glyceryl trinitrate

25B09: Exam Report

Compare and contrast the following pharmacology of sodium nitroprusside and glyceryl trinitrate;

  • Mechanism of action (25% of marks)

  • Pharmacodynamics and toxicity (75% of marks).

  • Treatment of toxicity is NOT required.

21% of candidates passed this question.

The question structure provides a guide to the level of detail required for each section.

High scoring answers discussed the similarities and key differences between the drugs which may influence the use of one over the other.

Both drugs are commonly used level two drugs in the syllabus.

A detailed knowledge of the mechanism of action, pharmacodynamic and adverse effects was expected and well covered in pharmacology textbooks.

In general, given these are both primarily anti-hypertensive agents the cardiovascular pharmacodynamics carried more weight than other system effects.

G7ii / 25B09: Compare and contrast the following pharmacology of sodium nitroprusside and glyceryl trinitrate

Mechanism of Action

  • Both are PRODRUGS delivered IV (GTN can also be SL/topical)
  • One of them undergoes organ metabolism
  • Both work via NO-mediated smooth muscle relaxation

GTN

PRODRUG – denitrated (metabolised) to nitric oxide (NO)

  • Metabolism in liver, RBC and vascular smooth muscle by mitochondrial aldehyde dehydrogenase (ALDH) and/or thiol dependent process (requiring sulfhydryl groups)

Nitric oxide (NO)–mediated smooth muscle relaxation

  • NO → diffuses into smooth m. cell → binds to & activates GUANYLYL CYCLASE → ↑cGMP (conversion of GTP) → Inhibits Ca2+ entry into smooth m. Cell (and ↑ conductivity of K channels)→  smooth muscle relaxation/vasodilation

Venous > Arterial dilation

Benefits in angina are believed to be due to ↓ MVO2 (myocardial oxygen consumption)

SNP

PRODRUG – effects via NO release

  • Diffuses into RBC & reacts with oxyHb to form:
    • MetHb
    • 5CN-
    • NO

Non enzymatic metabolism

Desired effects also via nitric oxide (NO)–mediated smooth muscle relaxation

Final common pathway same as GTN (i.e. ↑cGMP and ↓intracellular Ca2+)

Pharmacodynamics and Toxicity - PD

GTN

Venous > arterial vasodilation

SNP

Equal relaxation of venous and arterial smooth muscle (venous>arterial – slightly)

  • More used in hypertensive crises

CVS

GTN

  • Low dose = veno VD → ↓ preload and stroke volume
    • ↓SBP more than SBP
  • High dose = veno + art VD
    • Vein: ↓HR, ↓LVEDP, ↓PCWP (preL)
    • Art: ↓SVR and MAP, ↓afterL → ↓wall tension → ↓myocardial oxygen demand
    • Dilation of coronary arteries
  • Reflex ↑HR → CO usually unaltered
  • Facilitates subendocardial BF & redistribution to ischaemic areas
  • Relieves coronary vasospasm

SNP

  • ↓ SVR and MAP (much more than GTN)
  • Compensatory ↑HR
  • CO usually maintained
  • ↓Myocardial oxygen consumption (due to ↓afterload)

RESP

GTN

  • Bronchodilatation
  • ↑intrapulmonary shunting
  • hypoxic pulmonary VC unchanged

SNP

  • Reversible ↓ PaO2 – due to attenuation of hypoxic pulm VC

CNS

GTN

  • Cerebral vasodilation = ↑ICP (Minimal compared to SNP)

SNP

  • Cerebral vasodilation → ↑ICP in normocapnic pts
    • “steal” phenomenon can occur

GI

GTN

(Relaxation of GI SM)

  • ↓LES pressure
  • Paralytic ileus

SNP

Metabolic / Other

GTN

SNP

  • Compensatory ↑ in plasma catecholamine concentration and plasma renin activity
  • Metabolic acidosis may also occur

Haem

GTN

↓ Platelet aggregation (clinically insignificant)

SNP

Adverse Effects

GTN

80% dose absorbed by giving sets

CVS: ↓BP & ↑HR

CNS: headache and flushing

GI: nausea & vomiting

Haem: MetHb, platelet dysfunction

Tachyphylaxis

  • Thought to be due to depletion of intracellular sulfhydryl groups or ALDH (needed to breakdown GTN)

“Drug-free” interval of 8 hours between doses may reduce this

SNP

Same CVS and CNS adverse effects as GTN

  • Coronary steal syndrome can occur – more frequent than GTN

 

Initial reaction produces

  • MethHb
  • NO
  • CN-
    • Can react with thiosulfate to form thiocyanate (which itself can be toxic)

 

Toxicities are dose and duration dependent

Cyanide toxicity

  • Pathophysiology:
    • Prolonged therapy leads to depletion of sodium thiosulphate and/or vitamin B12 with resulting saturation of cyanide metabolism/elimination pathways
    • cyanide ion combines with cytochrome oxidase -> impairment of aerobic metabolism (histotoxic hypoxia)→ lactic acidosis
    • Causes pulmonary and coronary VC = APO & HF
    • Stimulates neurotransmitter release (ie NMDA) = seizures and neurotoxicity
  • Toxic concentration: 8mcg/mL (related to rate of infusion)
  • Clinical: ↑HR, ↑RR, anxiety, sweating; can be lethal within minutes

 

Thiocyanate toxicity (renal excretion)

  • Vasodilatation, tinnitus

 

Methaemoglobinaemia

  • Pathophysiology: NO: Fe2+ -> Fe3+; poor O2 carrying capacity  hypoxia
  • SpO2 trend to 84%
  • Significant if total dose SNP >10mg/kg

Severe: Seizures, coma, metabolic acidosis, cardiac arrhythmias, death

Author: Owen Xie