F11iii / 22A04: Describe the mechanisms of action and potential adverse effects of inhaled nitric oxide and prostacyclin

22A04: Exam Report

Describe the mechanisms of action and potential adverse effects of inhaled nitric oxide and prostacyclin

15% of candidates passed this question.

Most candidates were able to describe the mechanism of action of inhaled nitric oxide (iNO), however many demonstrated very little knowledge about prostacyclin and the adverse effects of both commonly used drugs.

General statements about NO, it’s delivery and pharmacological effects did not attract marks candidates are encouraged to read the question and provide information specific to the question.

Methaemoglobin and its effects were reasonably described with many understanding the rational for restricting the concentration of iNO (ppm) because of the risk of N02 formation.

The knowledge related to prostacyclin was very limited. Such limited detail as to its mechanism of action prevented any discussion regarding any differences from iNO.

Many reasonable answers to the iNO component were limited overall due to a paucity of knowledge and incorrect facts in the prostacyclin section.

F11iii / 22A04: Describe the mechanisms of action and potential adverse effects of inhaled nitric oxide and prostacyclin

Nitric Oxide

Prostacyclin

Chemical

Nitric Oxide

Free radical diatomic gas

Prostacyclin

Synthetic PGI2 analogue

Mechanism

Nitric Oxide

Diffuses into vascular smooth muscle

Activates guanylyl cyclase → ↑cGMP

  • ↓ Ca­2+ in cell → smooth muscle relaxation
  • Activates K+ channels → hyperpolarisation
  • ↑ cGMP-dependent protein kinase action. Activates MLC phosphatase → dephosphorylates MLC → inhibits ATPase → no contraction

⇨ Vasodilation

Prostacyclin

Binds to prostacyclin receptor (GPCR)

Activates adenylyl cyclase → ↑cAMP

  • Protein Kinase A phosphorylates MLCK → ↓ MLCK activity → ↓cross-bridging

⇨ Vasodilation

MoA Comparison

  • Both used for management of pulmonary hypertension, ARDS, ↓ RV afterload
  • Both act through second messenger systems to cause smooth muscle relaxation → vasodilation
  • Act on different points of smooth muscle excitation-contraction coupling
  • Both endogenous secreted from endothelial cells

Adverse effects

Nitric Oxide

Pulmonary

  • Tachyphylaxis
  • Rebound pulmonary vasospasm due to diminished nitric oxide production by vascular endothelial cells; Abrupt cessation → profound ↓ PaO2 and ↑ pulmonary BP 2’
  • Formation of Nitrogen Dioxide → pneumonitis & pulmn oedema
  • Toxic doses will form highly reactive oxidant species ie peroxynitrite which induces lipid peroxidation and inhibits mitochondrial respiration
  • Reduced neutrophil recruitment
  • Interferes with surfactant activity
  •  

Extra-Pulmonary

  • Systemic Vasodilation
  • Inhibits platelet adherence & activation, increasing bleeding time
  • MetHb: NO binds to heme
  • DeoxyHb: Hb(Fe2+) + NO → Hb(Fe2+)NO (stable complex)
  • OxyHb: Hb(Fe2+)O2 + NO → Hb(Fe3+) + NO3–
    • Oxidation of iron produces MetHb → cannot bind O2 → functional anaemia & leftward shift in OxyHb dissociation curve

Prostacyclin

  • Bleeding
  • Thrombocytopenia & platelet dysfunction
  • Pain – jaw pain, leg pain, generalised body pain
  • Headache
  • Flushing
  • N + V
  • Hypotension
  • Worsens V/Q mismatch
  • Thyroid disease & anaemia
  • Diarrhoea
  • Cough & throat irritation
  • Inhibition of hypoxic pulmonary vasoconstriction
    • When delivered via inhaled route, only delivered to ventilated alveoli → improved perfusion to match ventilation → ↓dead space → ↑V/Q matching
  • Prostacyclin can be delivered systemically → indiscriminate pulmonary vasodilation → can worsen V/Q mismatch (↑ perfusion to poorly ventilated alveoli → shunt)

Author: Emily Little