Moxonidine Mechanism of Action
Moxonidine is a centrally acting antihypertensive agent that works primarily through selective agonism of imidazoline I1 receptors in the rostral ventrolateral medulla (RVLM) of the brainstem, resulting in reduced sympathetic outflow and decreased peripheral vascular resistance. 1, 2
Primary Mechanism
Moxonidine acts on imidazoline I1 receptors located in the RVLM, which is the key cardiovascular control center in the brainstem 1, 3
The drug has 33-fold greater affinity for imidazoline I1 receptors compared to alpha-2 adrenergic receptors, distinguishing it from older centrally acting agents like clonidine (which has only 4-fold selectivity) 1, 3
This selective I1 receptor agonism is responsible for its favorable side effect profile, as it avoids the sedation and dry mouth commonly seen with alpha-2 receptor stimulation 1, 3
Downstream Effects
Sympathetic Nervous System Inhibition
Moxonidine decreases muscle sympathetic nerve activity in both healthy volunteers and hypertensive patients, as demonstrated by direct microneurography measurements 4
Plasma norepinephrine levels decrease significantly (P<0.01), confirming reduced sympathetic tone 4
Plasma epinephrine and renin levels remain unchanged, suggesting selective inhibition of noradrenergic pathways 4
Hemodynamic Consequences
Blood pressure reduction occurs through decreased systemic vascular resistance, not through cardiac effects 1, 3
Heart rate, cardiac output, stroke volume, and pulmonary artery pressures remain unaffected during acute administration 1, 3
Left ventricular end-systolic and end-diastolic volumes decrease, and left ventricular hypertrophy regresses after 6 months of treatment 1, 3
Secondary Molecular Mechanism
Nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS) in the RVLM plays a crucial role in mediating moxonidine's sympathoinhibitory effects 5
Chronic moxonidine administration selectively upregulates iNOS protein expression in the RVLM, suggesting this pathway contributes to sustained antihypertensive effects 5
Blocking iNOS with selective inhibitors dose-dependently attenuates moxonidine's cardiovascular effects, confirming the importance of this NO-mediated mechanism 5
Clinical Pharmacology Considerations
The drug requires much smaller doses when administered intracisternally or directly into the RVLM compared to intravenous administration, confirming its central site of action 1, 3
Despite a plasma half-life of only 2.5 hours, the antihypertensive effect lasts much longer, suggesting retention or prolonged action within the central nervous system 1, 3
Bioavailability approaches 90% after oral administration, with minimal biotransformation and predominantly renal excretion of unchanged drug 1, 3