Core pharmacology

Class Group

Nitro

Legacy Cicm Level

Level 2

Introduction

inorganic complex that acts as a prodrug. 5CN groups and 1NO group attached to Fe molecule covalently bonded to Na.

Indications Uses

used primarily to treat hypertensive emergencies but can also be used in many situations when short-term reduction of cardiac preload and/or afterload is desired

Presentation

only available in injectable form. It is unstable and must be stored out of light and not in alkaline conditions or it rapidly degrades.

Mechanism of action

The nitroso group (−N = O−) in sodium nitroprusside reacts with sulphydryl groups (–SH) in vascular smooth muscle, forming nitric oxide and nitrosothiol derivatives.

Both metab stimulate guanylate cyclase, ↑cGMP levels and produce generalized relaxation of vascular smooth muscle (both arterial and venular dilatation)

Onset Peak Duration

on/dur onset <30 secs; peak effect 2 mins, effect disappears within 3 mins after the infusion is stopped

Physiological effects

Equal Arterial and venous dilation
Attenuates HPV in lungs
Increases ICP due to increase in CBF
Renal blood flow maintained

Adverse Effects Toxicity

Main side effects are from excessive hypotension and include nausea, vomitting, abdominal pain, and postural hypotension.

Abrupt withdrawal may lead to a rebound hypertension.

Longer term there is significant risk of cyanide accumulation and associated toxicity and impaired oxidative phosphorylation.

(See Special points below for further details)

Absorption

IV. BA 100%.

Volume of distribution

15L (ECF)

Metabolism

As per MOA via reaction with OxyHb, then products as:
• Fe recycled by liver
• CN + MetHb → Cyanomethaemoglobin
• CN + Hepatic rhodenase enzymes → Thiocyanate
• CN + B12 → Cyanocobalamin (non-toxic)

Excretion

Urine (as thiocyanate - inactive)

Half-life

Parent drug: <10 minutes; Thiocyanate: 2.7-7 days

Special Points

TOXICITY:
• Cyanide poisoning (↑ lactate, “decoupling” of mitochondrial OxPhos via action on cytochrome oxidase, ↑ mixed venous saturation)
• ↓VR → ↓ CO → Tachycardia + ↑ myocradial contractility → ↑ myocardial oxygen demand
• Coronary steal → worsening myocardial ischaemia
• Rebound hypertension on withdrawal

ANTIDOTE:
1. Disodium edetate – acts via chelation of CN molecules
2. NaNitrate - ↑ methaemoglobin → ↑ cyanmethaemoglobin
3. NaThiosulphate – acts as thiodonor increasing hepatic rhodenase enzyme activity
4. Hydroxycobalamin – Increases conversion of CN to cyanocobalamin
5. Methylene blue – Increases formation of methaemoglobin

Route And Dose

IV. 10-200mcg/min uptitrated to effect