NO interacts with haem containing compounds
- Interacts with haem group in Guanylyl cyclase → increased cGMP
- Phosphorylation of proteins leading to reduced cytosolic Ca2+ → reduced Contraction

When inhaled, pulmonary vasodilation occurs and an increase in the partial pressure of arterial oxygen results.
Dilation of pulmonary vessels in well ventilated lung areas redistributes blood flow away from lung areas where ventilation/perfusion ratios are poor

Agonist at IP receptor
- GsPCR receptor
- → Increased cAMP via adenylyl cyclase
- → Smooth muscle relaxation and inhibits smooth muscle growth

CVS:
potent vasodilator that mediates the hypotension and significant vascular leak characteristic of septic shock.
Inhaled No is a selective pulmonary vasodilator, since it is avidly bound to haemoglobin and thereby inactivated before reaching the systemic circulation.
NO released from the vascular endothelium inhibits platelet aggregation and attenuates platelet and white cell adhesion.
RS:
inhibits hypoxic pulmonary vasoconstriction and preferentially increases blood flow through well-ventilated areas of the lung, thereby improving VQ mismatch
CNS:
increases the cerebral blood flow and appears to have a physiological role as a
neurotransmitter within the autonomic and central nervous systems.
GU:
may play a role in the regulation of renin production and sodium homeostasis in the kidney.
physiological mediator of penile erection.
Metabolic/other:
NO released from macrophages reacts with superoxide ion to form the free radical peroxynitrite which is toxic to bacteria.
Insulin release appears to be modulated by NO.

- Pulmonary vasodilation by agents given via inhalational route → vasodilation of
ventilated blood vessels → increased perfusion → improved V/Q matching
- Improved V/Q matching → increased paO2
- Pulmonary vasodilation → decreased PVR → Decreased RVSP and improves RV
funcion

highly lipid-soluble and diffuses freely across cell membranes

Highly lipid soluble and rapidly absorbed through alveoli

Little Systemic distribution after inhalation

Little Systemic distribution after inhalation

Highly protein bound

- Following inhalation, NO combines with oxyhaemoglobin that is 60–100% saturated, producing methaemoglobin and nitrate.
- During the first 8 hours of NO exposure, methaemoglobin concentrations increase.
- Nitric oxide also reacts with O2 to produce NO2

Rapidly removed from circulation by hydrolysis to 6-oxo-PGF1 alpha in blood

The main metabolite is nitrate (70%) which is excreted by the Kidneys.

Half-life of <5 seconds.

Plasma half life is 30sec-3min

Exposure to 500–2000 ppm of NO results in methaemoglobinaemia and pulmonary
oedema.
Contamination by nitrogen dioxide can similarly lead to pneumonitis and pulmonary oedema.
Thrombocytopoenia
Hypotension

Flushing
Headache
Nausea
Hypotension
Diarrhoea

Manufactured as a byproduct in nitric acid synthesis. In vivo it is synthesized from L-arginine in a process catalyzed by nitric oxide synthase

Epoprostenol:
PGI2 is reconstituted in a highly viscous and basic glycine diluent (causes tracheitis)

PULMONARY VASODILATORS

PULMONARY VASODILATORS

Selective pulmonary vasodilator in pulmonary hypertension
Hypoxic respiratory failure associated with pulmonary hypertension in neonates
RV dysfunction after cardiac surgery, ARDS

1. Pulmonary hypertension
2. Refractory hypoxia
3. Anticoagulation including CRRT and limb ischaemia
4. Pre-eclampsia

Endothelium Derived Relaxing Factor

Produced by NO synthase from arginine in O2
- and NADPH dependent fashion.

Epoprostenol (Inhaled or continuous infusion)
Iloprost (inhaled)

PGI2 is a the main arachidonic acid metabolite in vascular endothelium

Level 3

Level 3

pulmonary vasodilation

pulmonary vasodilation

In aluminium cylinders containing 100/800 ppm of NO and nitrogen
The cylinders may contain either 353 L at standard temperature and pressure (sTP) of NO in nitrogen or 1963 L at sTP.
Pure NO is toxic and corrosive.
No can also be supplied via stainless steel medical gas piping

Can be delivered as a continuous IV infusion or continuous nebulizer

Inh
Dosing is generally between 10 and 40ppm

Inh

Benefits of inhalational route
- Reduced systemic effects
Delivery of drug to ventilated areas → selective vasodilation → improved V/Q

Benefits of inhalational route
- Reduced systemic effects
Delivery of drug to ventilated areas → selective vasodilation → improved V/Q