Guanethidine metabolism

C. McMartin, P. Simpson, The Absorption and Metabolism of Guanethidine in Hypertensive Patients Requiring Different Doses of the Drug , Clin. Pharmacol. Ther. 1971, 12, 73-77. 

An excellent review of the pharmacological actions of adrenergic neurone blocking agents has been given by Boura and Green [10]. The biochemistry of guanethidine itself has been reviewed by Furst [11], with particular emphasis on tissue distribution and metabolism consequently these two topics are not discussed in detail. 

The major routes for the synthesis and metabolism of noradrenaline in adrenergic nerves [375], together with the names of the enzymes concerned, are shown in Figure 3.1. Under normal conditions the rate controlling step in noradrenaline synthesis is the first, and the tissue noradrenaline content can be markedly lowered by inhibition of tyrosine hydroxylase [376]. Tissue noradrenaline levels can also be lowered, but to a lesser extent, by inhibition of dopamine-(3-oxidase [377, 378]. However, the noradrenaline depletion produced by guanethidine is unlikely to result from inhibition of synthesis, since intra-cisternal injection of guanethidine does not prevent the accumulation of noradrenaline which follows brain monoamine oxidase inhibition, even though it does cause depletion of brain noradrenaline [323]. 

Guanethidine monosulfate is metabolized by microsomal iiuymes to 2-(6-carboxyhexylamino)ethylguanidine and iwethidine A/-oxide (Fig. 19-20). Both metabolites have. tty weak antihypertensivc propcrtie.s. Guanethidine mono-... 

Guanethidine (initial dose 10 mg daily) is indicated in the management of moderate to severe hypertension. It is transported to presynaptic terminals by the catecholamine uptake mechanism, and then slowly displaces norepinephrine from its storage sites to be metabolized presynaptically. 

Gill, J.R., Bartter, F.C. Adrenergic nervous system in sodium metabolism. II. Effects of guanethidine on the renal response to sodium deprivation in normal man. New Engl. J. Med. 275, 1466-1471 (1966)... 

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