Pharmacology for Anaesthesia and Intensive Care

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16 Antihypertensives

Adrenergic neurone blockade

This group of drugs interferes with the release of noradrenaline from adrenergic

neurones.

Physiology

Noradrenaline is synthesized from tyrosine (see Chapter 12 ) within the adrener-

gic nerve terminal. It is held in storage vesicles and subsequently released into the

neuronal cleft to act on adrenoceptors. Its actions are terminated by:


Uptake1–noradrenaline is taken back into the nerve terminal by a high-affinity

transport system. This provides the main route for terminating its effects. Within

the neurone it is recycled and returned to storage vesicles. However, while in the

cytoplasm some may be de-aminated by MAO.


Uptake 2 – noradrenaline diffuses away from the nerve terminal into the circulation

where it is taken up by extraneuronal tissues including the liver and metabolized

byCOMT.

Guanethidine

Presentation and uses

Guanethidine is available as tablets and as a colourless solution for injection con-

taining 10 mg.ml−^1 .Ithas been used as an antihypertensive agent but is currently

used only for the control of sympathetically mediated chronic pain. The initial anti-

hypertensive dose is 10 mg.day−^1 , which is increased to a maintenance dose of

30–50 mg.day-1.Adose of 20 mg is used when performing an intravenous regional

block for chronic pain. Repeated blocks are usually required.

Mechanism of action

Guanethidine gains access to the adrenergic neurone by utilizing the uptake 1

transport mechanism. Following intravenous administration there is some initial

hypotension by direct vasodilation of arterioles. Subsequently, it displaces nora-

drenaline from its binding sites, which may cause transient hypertension. Finally,

guanethidine reduces the blood pressure by preventing the release of what little

noradrenaline is left in the nerve terminal. Oral administration does not produce

the same triphasic response, as its onset of action is much slower. It does not alter

the secretion of catecholamines by the adrenal medulla.

Effects


Cardiovascular – hypotension is its main action. Postural hypotension is common

as it blocks any compensatory rise in sympathetic tone. Fluid retention leading to

oedema may occur.


Gut–diarrhoea is common.


Miscellaneous – failure to ejaculate.