Moxonidine

Moxonidine

Systematic (IUPAC) name
4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)- 6-methoxy-2-methylpyrimidin-5-amine
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy category	AU: B3
Legal status	UK: POM (Prescription only)
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	88%
Biological half-life	2.2 hours
Excretion	Renal
Identifiers
CAS Number	75438-57-2 N
ATC code	C02AC05 (WHO)
PubChem	CID: 4810
ChemSpider	4645 Y
UNII	CC6X0L40GW Y
KEGG	D05087 Y
ChEMBL	CHEMBL19236 Y
Chemical data
Formula	C9H12ClN5O
Molecular mass	241.677 g/mol
SMILES Clc1nc(nc(OC)c1N/C2=N/CCN2)C
InChI InChI=1S/C9H12ClN5O/c1-5-13-7(10)6(8(14-5)16-2)15-9-11-3-4-12-9/h3-4H2,1-2H3,(H2,11,12,15) Y Key:WPNJAUFVNXKLIM-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

Moxonidine (INN) /mɒkˈsɒnɪdiːn/ is a new-generation centrally acting antihypertensive drug licensed for the treatment of mild to moderate essential hypertension. It may have a role when thiazides, beta-blockers, ACE inhibitors and calcium channel blockers are not appropriate or have failed to control blood pressure. In addition, it demonstrates favourable effects on parameters of the insulin resistance syndrome, apparently independent of blood pressure reduction. It is manufactured by Solvay Pharmaceuticals under the brand name Physiotens.

Mechanism of action

Moxonidine is a selective agonist at the imidazoline receptor subtype 1 (I₁). This receptor subtype is found in both the rostral ventro-lateral pressor and ventromedial depressor areas of the medulla oblongata. Moxonidine therefore causes a decrease in sympathetic nervous system activity and, therefore, a decrease in blood pressure.

Compared to the older central-acting antihypertensives, moxonidine binds with much greater affinity to the imidazoline I₁-receptor than to the α₂-receptor. In contrast, clonidine binds to both receptors with equal affinity.

In addition, moxonidine may also promote sodium excretion, improve insulin resistance and glucose tolerance and protect against hypertensive target organ damage, such as kidney disease and cardiac hypertrophy.

Pharmacodynamic properties

Effects on insulin resistance

In all animal models of insulin resistance, moxonidine had striking effects on the development of insulin resistance, hyperinsulinaemia and impaired glucose homeostasis. Given the importance of insulin resistance as a risk factor for cardiovascular disease, it is of considerable relevance that it has been shown to improve insulin sensitivity.

Based on animal models, it has demonstrated that moxonidine is capable of:

• normalising plasma insulin levels
• improving glucose uptake in peripheral cells
• lowering lipid levels
• decreasing food intake and reducing weight gain in obese animals.

Renal function

Evidence is accumulating to show that sympathetic overactivity is substantially involved in the development and progression of chronic renal failure, contributing to a poor overall cardiovascular prognosis. Moxonidine has been shown to reduce structural renal damage in various models of renal failure.

Cardiac structure

In spontaneously hypertensive rats, moxonidine significantly reduced total heart weight, left ventricular weight and the ratio of ventricular weight to body weight compared with an untreated control group.

Safety pharmacology

Routine toxicology studies have provided no evidence that moxonidine has any teratogenic, mutagenic or carcinogenic potential. No evidence has been found of serious adverse effects on organs or organ systems, and the drug has not been shown to have deleterious effects on perinatal or postnatal growth and development.

Cautions

Moxonidine should be avoided in patients with moderate to severe renal impairment. Abrupt discontinuation of the drug should also be avoided. If concomitant treatment with a beta blocker has to be stopped, the beta blocker should be discontinued first, then moxonidine after a few days. Alcohol may potentiate the hypotensive effects of Moxonidine.

Drug interactions

Concomitant administration of moxonidine and a thiazide diuretic such as hydrochlorothiazide is not indicated, as both drugs' hypotensive effects may be enhanced.

Contra-indications

It is contraindicated if there has been a past history of angioedema; heart conduction disorders (e.g. sick sinus syndrome, second- or third-degree heart block); bradycardia; severe heart failure or coronary artery disease. Also: Raynaud's syndrome, intermittent claudication, epilepsy, depression, Parkinson's disease, glaucoma. Use in pregnancy is discouraged. Moxonidine passes into breast milk.

Excess mortality has been seen in patients with symptomatic heart failure in the MOXCON study. However, the MOXCON trial prescribed very high dose of 3.0 mg daily which is above the normal dose of 0.2-0.6 mg daily.

Side-effects

Noteworthy side effects include dry mouth, headache, fatigue, dizziness, intermittent facial oedema, nausea, sleep disturbances (rarely sedation), asthenia, vasodilatation, and rarely, skin reactions.