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{{Short description|Antihypertensive medication}} |
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{{drugbox | Verifiedfields = changed |
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{{Drugbox |
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| verifiedrevid = 400317371 |
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| Verifiedfields = changed |
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| Watchedfields = changed |
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| IUPAC_name = 4-chloro-''N''-(4,5-dihydro-1''H''-imidazol-2-yl)-<br>6-methoxy-2-methylpyrimidin-5-amine |
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| verifiedrevid = 462255851 |
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| IUPAC_name = 4-Chloro-''N''-(4,5-dihydro-1''H''-imidazol-2-yl)-<br />6-methoxy-2-methylpyrimidin-5-amine |
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| image = Moxonidine.svg |
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| image = Moxonidine.svg |
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| width = 180 |
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| width = 180 |
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<!--Clinical data--> |
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| pronounce = {{IPAc-en|m|ɒ|k|ˈ|s|ɒ|n|ɪ|d|iː|n}} |
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| Drugs.com = {{drugs.com|international|moxonidine}} |
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| pregnancy_AU = B3 |
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| legal_UK = POM |
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| legal_status = Rx-only |
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| routes_of_administration = Oral (]) |
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<!--Pharmacokinetic data--> |
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| bioavailability = 88% (]) |
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| protein_bound = 7.2–10%<ref>{{cite journal| vauthors = Weimann HJ, Rudolph M |title=Clinical Pharmacokinetics of Moxonidine|journal=Journal of Cardiovascular Pharmacology|date=1992|volume=20|issue=Suppl. 4|pages=S37–S41|doi=10.1097/00005344-199220004-00008|doi-access=free}}</ref><ref name="Physiotens PI">{{cite web|title=Physiotens Tablets (moxonidine) Product Information|url=https://gp2u.com.au/static/pdf/P/PHYSIOTENS-PI.pdf|publisher=Abbott Australasia Pty Ltd, 32-34 Lord Street, Botany NSW 2019, Australia|access-date=1 September 2016}}</ref> |
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| metabolism = ] (10–20%)<ref name="Physiotens PI" /> |
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| metabolites = Dehydrogenated moxonidine (major), hydroxymethyl-moxonidine, hydroxy-moxonidine, dihydroxy-moxonidine<ref>{{cite journal | vauthors = He MM, Abraham TL, Lindsay TJ, Schaefer HC, Pouliquen IJ, Payne C, Czeskis B, Shipley LA, Oliver SD, Mitchell MI | display-authors = 6 | title = Metabolism and disposition of the antihypertensive agent moxonidine in humans | journal = Drug Metabolism and Disposition | volume = 31 | issue = 3 | pages = 334–342 | date = March 2003 | pmid = 12584161 | doi = 10.1124/dmd.31.3.334 }}</ref> |
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| elimination_half-life = ~2.2–2.8 hours |
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| excretion = ] (90%),<ref>{{cite journal|last1=Farsang|first1=C|title=Moxonidine: Clinical Profile|journal=Journal of Clinical and Basic Cardiology. An Independent International Scientific Journal|date=2001|volume=4|issue=3|pages=197–299|url=http://www.kup.at/kup/pdf/897.pdf|access-date=1 September 2016}}</ref> feces (~1%)<ref name="Physiotens PI" /> |
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<!--Identifiers--> |
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| CAS_number_Ref = {{cascite|changed|??}} |
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| CAS_number = 75438-57-2 |
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| ATC_prefix = C02 |
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| ATC_suffix = AC05 |
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| PubChem = 4810 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 4645 |
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| ChemSpiderID = 4645 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| InChI = 1/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) |
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| UNII = CC6X0L40GW |
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| InChIKey = WPNJAUFVNXKLIM-UHFFFAOYAJ |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| smiles = Clc1nc(nc(OC)c1N/C2=N/CCN2)C |
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| KEGG = D05087 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 19236 |
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| ChEMBL = 19236 |
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| tradename = Physiotens, Moxon |
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<!--Chemical data--> |
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| C=9 | H=12 | Cl=1 | N=5 | O=1 |
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| smiles = Clc1nc(C)nc(OC)c1NC2=NCCN2 |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 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) |
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| StdInChI = 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) |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = WPNJAUFVNXKLIM-UHFFFAOYSA-N |
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| StdInChIKey = WPNJAUFVNXKLIM-UHFFFAOYSA-N |
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| CAS_number = 75438-57-2 |
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| ATC_prefix = C02 |
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| ATC_suffix = AC05 |
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| PubChem = 4810 |
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| DrugBank = |
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| KEGG_Ref = {{keggcite|changed|kegg}} |
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| KEGG = D05087 |
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| C = 9 | H = 12 | Cl = 1 | N = 5 | O = 1 |
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| molecular_weight = 241.677 g/mol |
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| bioavailability = 88% |
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| protein_bound = |
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| metabolism = |
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| elimination_half-life = 2.2 hours |
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| excretion = ] |
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| pregnancy_AU = B3 |
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| legal_UK = POM |
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| routes_of_administration = Oral |
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}} |
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}} |
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'''Moxonidine''' (]) ({{pronEng|mɒkˈsɒnɪdiːn}}) is a new generation centrally acting ] drug licensed for the treatment of mild to moderate essential ]. It may have a role when ], ]s, ]s and ]s are not appropriate or have failed to control blood pressure. In addition, it demonstrates favourable effects on parameters of the ] syndrome, apparently independent of blood pressure reduction. It is manufactured by ] Pharmaceuticals under the brand name '''Physiotens'''. |
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'''Moxonidine''' (]) is a new-generation alpha-2/imidazoline receptor agonist ] drug licensed for the treatment of mild to moderate ].<ref name=Monox>{{cite journal | vauthors = Fenton C, Keating GM, Lyseng-Williamson KA | title = Moxonidine: a review of its use in essential hypertension | journal = Drugs | volume = 66 | issue = 4 | pages = 477–496 | year = 2006 | pmid = 16597164 | doi = 10.2165/00003495-200666040-00006 | s2cid = 195691757 }}</ref><ref name=pmid10381806>{{cite journal | vauthors = Fairbanks CA, Wilcox GL | title = Moxonidine, a selective alpha2-adrenergic and imidazoline receptor agonist, produces spinal antinociception in mice | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 290 | issue = 1 | pages = 403–412 | date = July 1999 | pmid = 10381806 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10381806 }}</ref> It may have a role when ], ]s, ]s, and ]s are not appropriate or have failed to control blood pressure. In addition, it demonstrates favourable effects on parameters of the ] syndrome, apparently independent of blood pressure reduction. It is also a ] releaser.<ref>{{cite journal | vauthors = Bamberger CM, Mönig H, Mill G, Gödde E, Schulte HM | title = Growth hormone secretion in response to the new centrally acting antihypertensive agent moxonidine in normal human subjects: comparison to clonidine and GHRH | journal = Experimental and Clinical Endocrinology & Diabetes | volume = 103 | issue = 3 | pages = 205–208 | year = 1995 | pmid = 7584524 | doi = 10.1055/s-0029-1211351 }}</ref> It is manufactured by ] Pharmaceuticals (acquired by ] in 2009) under the brand name '''Physiotens''' and Moxon. |
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==Mechanism of actions== |
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Moxonidine is a selective ] at the ] subtype 1 (I<sub>1</sub>). This receptor subtype is found in both the rostral ventro-lateral pressor and ventromedial depressor areas of the ]. Moxonidine therefore causes a decrease in ] activity and, therefore, a decrease in ]. |
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==Mechanism of action== |
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Compared to the older central-acting antihypertensives, moxonidine binds with much greater affinity to the imidazoline I<sub>1</sub>-receptor than to the α<sub>2</sub>-receptor. In contrast, ] binds to both receptors with equal affinity. |
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Moxonidine is a selective ] at the ] subtype 1 (I<sub>1</sub>).<ref name=Monox/> This receptor subtype is found in both the rostral ventro-lateral pressor and ventromedial depressor areas of the ]. Moxonidine therefore causes a decrease in ] activity and, therefore, a decrease in ]. |
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Compared to the older central-acting antihypertensives, moxonidine binds with much greater affinity to the imidazoline I<sub>1</sub>-receptor than to the α<sub>2</sub>-receptor. In contrast, ] binds to both receptors with near equal affinity. Moxonidine has an affinity for I<sub>1</sub> that is 33 times greater than α<sub>2</sub>, compared to clonidine which is only four times greater.<ref>{{cite journal | vauthors = Prichard BN, Owens CW, Graham BR | title = Pharmacology and clinical use of moxonidine, a new centrally acting sympatholytic antihypertensive agent | journal = Journal of Human Hypertension | volume = 11 | issue = Suppl 1 | pages = S29–S45 | date = August 1997 | pmid = 9321737 }}</ref> |
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In addition, moxonidine may also promote ] excretion, improve insulin resistance and ] tolerance and protect against hypertensive target organ damage, such as ] disease and ] ]. |
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In addition, moxonidine may also promote ] excretion, improve insulin resistance and ] tolerance and protect against hypertensive target organ damage, such as ] disease and ] ]. |
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==Pharmacodynamic properties== |
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==Pharmacodynamic properties== |
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{{Unreferenced section|date=April 2016}} |
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'''Effects on insulin resistance''' |
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===Effects on insulin resistance=== |
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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. |
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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. |
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==Contraindications== |
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Based on animal models, it has demonstrated that moxonidine is capable of: |
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It is contraindicated if there has been a past history of ]; heart conduction disorders (e.g. ], second- or third-degree ]); ]; severe ] or ]. Also: ], ], ], depression, ], ]. Use in pregnancy is discouraged. Moxonidine passes into breast milk. |
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* normalising plasma insulin levels |
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* improving glucose uptake in peripheral cells |
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* lowering lipid levels |
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* decreasing food intake and reducing weight gain in obese animals. |
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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.{{medcn|date=November 2023}} |
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'''Renal function''' |
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Excess mortality has been seen in patients with symptomatic ] in the MOXCON study.<ref>{{cite journal | vauthors = Cohn JN, Pfeffer MA, Rouleau J, Sharpe N, Swedberg K, Straub M, Wiltse C, Wright TJ | display-authors = 6 | title = Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON) | journal = European Journal of Heart Failure | volume = 5 | issue = 5 | pages = 659–667 | date = October 2003 | pmid = 14607206 | doi = 10.1016/S1388-9842(03)00163-6 | s2cid = 45883678 | doi-access = free }}</ref> However, the MOXCON trial utilised a very high dose of 3.0 mg daily which is well above the normal dose of 0.2–0.6 mg daily. |
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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. |
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'''Cardiac structure''' |
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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. |
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==Safety pharmacology== |
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==Adverse effects== |
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{{Unreferenced section|date=April 2016}} |
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Noteworthy ]s include dry mouth, headache, fatigue, dizziness, intermittent facial oedema, nausea, sleep disturbances (rarely sedation), ], vasodilatation, and rarely, skin reactions. |
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===Safety=== |
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{{Unreferenced section|date=April 2016}} |
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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. |
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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. |
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==Cautions== |
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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. |
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==Drug interactions== |
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==Drug interactions== |
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Concomitant administration of moxonidine and a thiazide diuretic such as ] is not indicated, as both drugs' hypotensive effects may be enhanced. |
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Concomitant administration of moxonidine and a thiazide diuretic such as ] gave a synergistic antihypertensive effect. |
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<ref>{{cite journal | vauthors = Frei M, Küster L, Gardosch von Krosigk PP, Koch HF, Küppers H | title = Moxonidine and hydrochlorothiazide in combination: a synergistic antihypertensive effect | journal = Journal of Cardiovascular Pharmacology | volume = 24 | issue = Suppl 1 | pages = S25–S28 | year = 1994 | pmid = 7533223 | doi = 10.1097/00005344-199424001-00005 | doi-access = free }}</ref> |
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== See also == |
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==Contra-indications== |
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* ] |
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It is contraindicated if there has been a past history of ]; heart conduction disorders (e.g. ], second- or third-degree ]); ]; severe ] or ], severe liver or renal impairment. Also: ], ], ], depression, ], ]. Use in pregnancy is discouraged. Moxonidine passes into breast milk. |
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== References == |
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Excess mortality has been seen in patients with symptomatic ].<ref>{{cite journal |author=Cohn J ''et al.'' |title=Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON) |journal=Eur J Heart Fail |volume=5 |issue=5 |pages=659–67 |year=2003 |pmid=14607206 |doi=10.1016/S1388-9842(03)00163-6}}</ref> |
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{{Reflist}} |
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== External links == |
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==Side-effects== |
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*{{Commonscatinline}} |
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Noteworthy ]s include dry mouth, headache, fatigue, dizziness, nausea, sleep disturbances (rarely sedation), ], vasodilatation, and rarely, skin reactions. |
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==References== |
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{{Reflist}} |
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{{Antihypertensives and diuretics}} |
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{{Antihypertensives and diuretics}} |
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{{Adrenergic receptor modulators}} |
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{{Imidazoline receptor modulators}} |
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