Rational treatment of primary hypertension remains elusive, owing to a lack of knowledge about the pathogenesis of blood pressure elevation. Established hypertension is associated with well-described cardiovascular hemodynamic changes. Because the cardiovascular system is self-regulating, the action of an antihypertensive on one of the regulatory mechanisms induces changes in others. A drug-induced decrease of the elevated peripheral resistance leads to compensatory reflex mechanisms. The use of centrally acting drugs avoids compensatory neural reflexes. Furthermore, the participation of the central and autonomic nervous systems in the pathogenesis of hypertension is probable. The development of drugs aimed at controlling the central nervous system (CNS) would, therefore, be reasonable. The use of a,-adrenoceptor agonists, such as clonidine, as antihypertensive agents has declined. The mean reason being a high rate of side effects such as sedation, dry mouth with marked reduction in salivary flow, and other nonspecific effects. The mode of action was explained by stimulation of both pre-and postsynaptic a,-adrenoceptors within the CNS . However, recent investigations have clearly demonstrated that centrally acting drugs like clonidine and moxonidine induce their antihypertensive effects primarily by high affinity binding at the imidazoline receptors. Most of the side effects are induced by an action at aw,-receptors. The difference between clonidine and moxonidine is moxonidine's pronounced selectivity for imidazoline rather than ctzreceptors. Moxonidine and other related compounds may reestablish the use of centrally active drugs in antihypertensive therapy.~ ~~~

In a randomized 2-way cross-over study with eighteen healthy male volunteers, two moxonidine preparations (tablets, treatment A vs. intravenous solution, treatment B) were tested to investigate absolute bioavailability and pharmacokinetics of moxonidine. The preparations were administered as single doses of 0.2 mg; prior to and up to 24 h after administration blood samples were collected and the plasma moxonidine concentrations determined. Urine samples were collected prior to and at scheduled intervals up to 24 h after administration for the determination of unchanged moxonidine. Moxonidine plasma and urine concentrations were determined by a validated gas chromatographic/mass spectrometric method with negative ion chemical ionization. The mean areas under the plasma concentration/time curves were calculated as [mean +/- standard deviation] 3438 +/- 962 pg.h/ml (AUC(0----Tlast)) and 3674 +/- 1009 pg.h/ml (AUC(0----infinity)) for treatment A; 3855 +/- 1157 pg.h/ml (AUC(0----Tlast)) and 4198 +/- 1205 pg.h/ml (AUC(0----infinity)) for treatment B. Mean peak plasma concentrations of 1495 +/- 646 pg/ml were attained at 0.56 +/- 0.28 h after oral treatment, mean peak plasma concentrations after intravenous treatment reached 3965 +/- 1342 pg/ml at 0.17 +/- 0.01 h (= coinciding with end of infusion). The mean terminal half-lives of moxonidine were derived as 1.98 h after administration of the tablet and as 2.18 h after infusion. The amounts of moxonidine excreted in urine during the 24 h following administration (Ae(24h)) in absolute figures and as percentage of the dose administered were 102 +/- 26 micrograms or 51 +/- 13% for the tablet and 122 +/- 33 micrograms or 61 +/- 16% for the infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

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Moxonidine was found to be safe and well tolerated in healthy volunteers. However, the impairments on attentional tasks were greater when moxonidine was co-administered with lorazepam 1 mg. These effects should be considered when moxonidine is codosed with lorazepam, although they were smaller than would have been produced by a single dose of lorazepam 2 mg.

The aim of the study presented here was to determine possible pharmacokinetic interactions of moxonidine and glibenclamide at steady state in 18 healthy male volunteers. Multiple oral doses of 0.2 mg of moxonidine b.i.d. (q. 12 h) and of 2.5 mg of glibenclamide o.i.d. (q. 24 h) were administered alone and in combination in an open, non-randomized, three-treatment design. The preparations were given for 5 days in each of the 3 periods. The results of this multiple dose study did not indicate substantial pharmacokinetic interactions of the drugs. Regarding the influence of glibenclamide on the pharmacokinetics of moxonidine, no significant changes were seen at all. In the presence of moxonidine, a minor decrease of bioavailability of glibenclamide was detectable, as could be derived from the AUC and clearance data. The actual differences were small and not considered to be of clinical significance.