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)

MoA is same for inorganic nitrates although GTN must first combine with Thio containing compound to produce NO. NO activates guanylyl cyclase in smooth muscles which ↑cGMP leading to a ↓intracellular Ca and vasodilation. Venous > arterial dilation and the benefits in angina are believed to be related to decreased MVO2.

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

Venous > arterial dilation
Can cause bronchodilation
↑ICP due to ↑in CBF
Disrupt renal autoregulation in CCF pts.
relaxation of sphincter of Oddi

IV. BA 100%.

Top, SL, IV
BA PO 5%. Rapidly absorbed from the sublingual mucosa and enters the circulation via the SVC. Also absorbed in the gut but high first pass metabolism.

60%

15L (ECF)

~3 L/kg

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)

Hepatic via thiols into NO products

Urine (as thiocyanate - inactive)

Urine (as inactive metabolites)

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

1-4 minutes

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)

Tolerance develops rapidly due to depletion of sulphydryl (thiol) groups reqrd for metabolism of GTN to NO2. Breaks for patches
CNS – headache (intracerebral vasodilatation) and ↑in ICP
CVS – at high doses ↓SVR → ↓afterload, however a compensatory tachycardia (baroreceptor induced) may reduce myocardial blood supply.
GIT – relaxes sphincter of oddi
HAEM – may precipitate methaemoglobinaemia

(See Special points below for further details)

Nitro

Nitro

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

It is used for the treatment of
Stable (and unstable) angina and acute pulmonary oedema.

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

organic nitrate similar to
isosorbide mononitrate and isosorbide dinitrate.

Level 2

Level 2

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

on/dur SL 1-3 mins / 25 mins.
IV immediate/ 5mins

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

PO/SL/TD Patches
Clear liquid with a conc 5mg/ml. IV: glass vial due to GTN being absorbed into some plastics.

IV. 10-200mcg/min uptitrated to effect

400-800mcg SL, 5mg Top, 5-80mcg min uptitrated IV

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

TOXICITY:
Methemoglobinemia can rarely occur at conventional doses.
MetHb is dose-related and it can be even more pronounced in patients with genetic abnormalities of hemoglobin that favor methemoglobin formation.

Methemoglobinemia can be managed with the administration of methylene blue unless the patient has a known G-6-PD deficiency