Moxonidine

Pharmaceuticals

Pharmaceuticals -> Antihypertensives

Pharmaceuticals -> Listed in ZINC15

Danger

H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]

P264, P270, P273, P301+P316, P321, P330, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 47 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

Moxonidine

DILI Positive

DOI:10.1016/j.drudis.2019.09.022

C02AC05

C - Cardiovascular system

QC - Cardiovascular system

Stimulation of central alpha 2-adrenergic receptors is associated with sympathoadrenal suppression and subsequent reduction of blood pressure. As this class was further explored it was discovered that sympathoadrenal activity can also be suppressed by a second pathway with a newly discovered drug target specific to imidazolines. Specifically, moxonidine binds the imidazoline receptor subtype 1 (I1) and to a lesser extent αlpha-2-adrenoreceptors in the RSV causing a reduction of sympathetic activity, reducing systemic vascular resistance and thus arterial blood pressure. Moreover, since alpha-2-adrenergic receptors are considered the primary molecular target that facilitates the most common side effects of sedation and dry mouth that are elicited by most centrally acting antihypertensives, moxonidine differs from these other centrally acting antihypertensives by demonstrating only low affinity for central alpha-2-adrenoceptors compared to the aforementioned I1-imidazoline receptors.

Biotransformation is unimportant with 10-20% of moxonidine undergoing oxidation reactions to the primary 4,5-dehydromoxonidine metabolite and a guanidine derivative by opening of the imidazoline ring. The antihypertensive effects of these 4,5-dehydromoxonidine and guanidine metabolites are only 1/10 and 1/100 the effect of moxonidine. Oxidation on either the methyl group (pyrimidine ring) or on the imidazole ring of moxonidine results in the formation of the hydroxylmethyl moxonidine metabolite or the hydroxy moxonidine metabolite. The hydroxy moxonidine metabolite can be further oxidized to the dihydroxy metabolite or it can lose water to form the dehydrogenated moxonidine metabolite, which itself can be further oxidized to form an N-oxide. Aside from these Phase I metabolites, Phase II metabolism of moxonidine is also evident with the presence of a cysteine conjugate metabolite minus chlorine. Nevertheless, the identification of the hydroxy moxonidine metabolite with a high level of dehydrogenated moxonidine metabolite in human urine samples suggests that dehydrogenation from the hydroxy metabolite to the dehydrogenated moxonidine metabolite represents the primary metabolic pathway in humans. The cytochromes P450 responsible for the metabolism of moxonidine in humans have not yet been determined. Ultimately, the parent moxonidine compound was observed to be the most abundant component in different biological matrices of urinary excretion samples, verifying that metabolism only plays a modest role in the clearance of moxonidine in humans.