Pharmacology for Anaesthesia and Intensive Care

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Section IIICardiovascular drugs

GTN Nitrite

NO

Thiols (R-SH)

S-NO-Thiols

Guanylate cyclase ↑cGMP Vasodilation

Figure 15.2.Metabolism of GTN.

in preload, venous return, ventricular end-diastolic pressure and wall tension. This

in turn leads to a reduction in oxygen demand and increased coronary blood flow

to subendocardial regions and is the underlying reason for its use in cardiac failure

and ischaemic heart disease. The reduction in preload may lead to a reduction

in cardiac output although patients with cardiac failure may see a rise in cardiac

output. Postural hypotension may occur. At higher doses systemic vascular resis-

tance falls and augments the fall in blood pressure, which while reducing myocar-

dial work, will reduce coronary artery perfusion pressure and time (secondary to

tachycardia). Coronary artery flow may be increased directly by coronary vasodila-

tion. Tolerance develops within 48 hours and may be due to depletion of sulphydryl

groups within vascular smooth muscle. A daily drug-free period of a few hours pre-

vents tolerance. It has been suggested that infusion of acetylcysteine (providing

sulphydryl groups) may prevent tolerance.


Central nervous system – an increase in intracranial pressure and headache result-

ing from cerebral vasodilation may occur but is often only problematic at the start

of treatment.


Gut–itrelaxes the gastrointestinal sphincters including the sphincter of Oddi.


Haematological – rarely methaemoglobinaemia is precipitated.

Kinetics

GTN is rapidly absorbed from sublingual mucosa and the gastrointestinal tract

although the latter is subject to extensive first-pass hepatic metabolism resulting

in an oral bioavailability of less than 5%. Sublingual effects are seen within 3 min-

utes and last for 30–60 minutes. Hepatic nitrate reductase is responsible for the

metabolism of GTN to glycerol dinitrate and nitrite (NO^2 −)inaprocess that requires

tissue thiols (R-SH). Nitrite is then converted to NO, which confers its mechanism

of action (see above). Under certain conditions nitrite may convert oxyhaemoglobin

to methaemoglobin by oxidation of the ferrous ion (Fe^2 +)tothe ferric ion (Fe^3 +).

Isosorbide dinitrate (ISDN) and isosorbide mononitrate (ISMN)

ISDN is prepared with lactose and mannitol to reduce the risk of explosion. It is well

absorbed from the gut and is subject to extensive first-pass metabolism in the liver