Hypertension Knowledge Centre
Centrally Acting Drugs
Chemistry and mode of action of moxonidine
Chemistry
The chemical structure of moxonidine is shown in figure 24. The imidazoline moiety of moxonidine is believed to be relevant to its principal pharmacological properties.
Figure 24: Chemical structure of moxonidine (the coloured area identifies the imidazoline part of the structure). Adapted from71
Mode of action
The autonomic nervous system is regulated by cardiovascular control centres in the rostral ventrolateral medulla (RVLM) within the medulla oblongata. The degree of sympathetic response appears to be mediated through imidazoline binding sites in the RVLM. The antihypertensive action of moxonidine can be explained in terms of a highly selective agonist effect on imidazoline I1-receptors in the RVLM,16 causing inhibition of sympathetic activity and reduced peripheral resistance.
Microinjection of moxonidine into the RVLM of spontaneously hypertensive rats resulted in rapid, dose-dependent reductions of arterial blood pressure, whereas there was no effect on blood pressure if moxonidine was injected into adjacent (non-RVLM) areas of the medulla.72 In another study, the blood pressure-lowering effect of systemically administered moxonidine was shown to be reversed by injection of efaroxan (an imidazoline I1-receptor antagonist) into the RVLM.73
In vitro, moxonidine has been shown to be a highly selective ligand for I1-receptors, having an approximately 70-fold greater affinity for these receptors compared with α2-adrenergic receptors.16 The selectivity and affinity of moxonidine for I1-receptors has also been confirmed in receptor binding studies in rat renal medulla samples.16
Figure 25: Selectivity of moxonidine for imidazoline (I1) and α2-receptors (Ki = affinity constant). Adapted from16
Older centrally acting agents such as clonidine and alpha-methyldopa are frequently associated with sedation and dry mouth, which are generally thought to be a result of interactions with α2-receptors. The highly selective action of moxonidine on I1-receptors in the RVLM, with lesser effects on α2-receptors, provides antihypertensive efficacy with a relatively low incidence of adverse events (figure 26).
Figure 26: Possible sites of action of moxonidine and the older centrally acting agents clonidine and methyldopa. Adapted from71
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