Nitric Oxide

Chemical

An inorganic gas & free radical

Use

Tx pulmonary HTN

Presentation

In aluminium cylinders containing 100/800ppm nitric oxide & nitrogen (pure nitric oxide is toxic & corrosive)

Dose

Inhaled at 5 – 20ppm

2 methods for delivery:

  1. limb of circuit during inspiration only
  2. Continuous flow system through entire resp cycle

MoA

  • Diffuses into vascular smooth m.
  • Activates the enzyme GUANALYL CYCLASE
  • GC catalyses formation of 2nd messenger cGMP
  • cGMP activates protein kinases
  • ↓intrac. Ca2+ → smooth m. relaxation → VD

PD

CVS

  • Potent VD
  • Inhibits platelet aggregation

RESP***

  • Inhibits HPVC
  • Vasodilates pulm. vessels selectively because delivered via inhalation

PK

A

Highly lipid soluble, diffuses across PM after inhalation

D

N/A

M

Combines with OxyHb → MetHb + nitrate

E

Nitrate is excreted by kidneys

t ½ 5 secs!

Adverse Effects

Adverse Effect

Tachyphylaxis

Abrupt cessation → profound ↓PaO2 & ↑PAP

 

Must be:

→ Weaned slowly

→ Constant MetHb monitoring

 

MetHb

    • NO binds to heme moiety of Hb
    • Resulting reaction depends on whether/not Hb is oxygenated

 

       DEOXYHb → Hb [Fe2+] + NO → Hb [Fe2+]NO

    •              a stable Hb-NO complex forms which has no VD activity

       OXYHb → Hb [Fe2+]O2 + NO → Hb [Fe3+] (Met Hb) + NO3–(Nitrate ion)

    •               O2 displaced, iron atom oxidised, MetHb + nitrate ion produced

NOTES ON NITRIC OXIDE

 Nitric oxide (NO) is a naturally occurring inorganic gas

Synthesised in Endothelial Cells

  • From arginine by NO synthase
  • Binds GUANULATE CYCLASE
  • ↑CGMP
  • ↓Ca2+ release
  • ↓muscle contraction (smooth muscle) → VD

Properties

  • Volatile gas, easily diffuses across PM
  • Produced by endothelial cells to relax vascular smooth m. & cause VD
  • Produced by enzyme NITRIC OXIDE SYNTHASE
    • NOS produces NO
    • NO diffuses into cell
    • Activates the enzyme GUANYLYL CYCLASE
    • GC catalyses formation of 2nd messenger cGMP
    • cGMP activates protein kinases
    • ↓intracellular Ca2+
    • Smooth m. relaxation → VD

NB: phosphodiesterase inhibitors (e.g. Viagra) cause VD because phosphodiesterase breaks down CGMP