Core pharmacology

Class Group

Nitro

Legacy Cicm Level

Level 2

Introduction

organic nitrate similar to
isosorbide mononitrate and isosorbide dinitrate.

Indications Uses

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

Presentation

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

Mechanism of action

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.

Onset Peak Duration

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

Physiological effects

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

Adverse Effects Toxicity

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)

Absorption

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.

Protein binding

60%

Volume of distribution

~3 L/kg

Metabolism

Hepatic via thiols into NO products

Excretion

Urine (as inactive metabolites)

Half-life

1-4 minutes

Special Points

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

Route And Dose

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