Moxonidine is a new-generation centrally acting antihypertensive drug approved for the treatment of mild to moderate essential hypertension. It is suggested to be effective in cases where other agents such as thiazides, beta-blockers, ACE inhibitors, and calcium channel blockers are not appropriate or irresponsive. As well, moxonidine has been shown to present blood pressure-independent beneficial effects on insulin resistance syndrome.

Structure

Similar Structures

Synonyms

(2R,4R)-1-[(2S)-5-[(aminoiminomethyl)amino]-1-oxo-2-[[(1,2,3,4-tetrahydro-3-methyl-8- quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2-piperidinecarboxylic acid
Moxonidina
Moxonidine
Moxonidinum

External IDs

BDF-5896 / BDF5896 / BE 5895 / BE5895 / LY-326869 / LY326869

Product Ingredients

Ingredient	UNII	CAS	InChI Key
Moxonidine hydrochloride	5RYW07SK5E	75438-58-3	ZZPAWQYZQVUVHX-UHFFFAOYSA-N

International/Other Brands

Cynt / Physiotens (Solvay Pharmaceuticals)

Categories

UNII

CC6X0L40GW

CAS number

75438-57-2

Weight

Average: 241.677
Monoisotopic: 241.073037738

Chemical Formula

C₉H₁₂ClN₅O

InChI Key

WPNJAUFVNXKLIM-UHFFFAOYSA-N

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)

IUPAC Name

4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-6-methoxy-2-methylpyrimidin-5-amine

SMILES

COC1=NC(C)=NC(Cl)=C1NC1=NCCN1

Pharmacology

Indication

For the treatment of mild to moderate essential or primary hypertension ⁷. Effective as most first-line antihypertensives when used as monotherapy ².

Pharmacodynamics

Antihypertensive agent whose site of action is the Central Nervous System (CNS), specifically involving interactions with I1- imidazoline and alpha-2-adrenergic rececptors within the rostral ventrolateral medulla (RSV). ^Label

Mechanism of action

Stimulation of central alpha 2-adrenergic receptors is associated with sympathoadrenal suppression and subsequent reduction of blood pressure. As this class was further explored it was discovered that sympathoadrenal activity can also be suppressed by a second pathway with a newly discovered drug target specific to imidazolines ⁵. Specifically, moxonidine binds the imidazoline receptor subtype 1 (I1) and to a lesser extent αlpha-2-adrenoreceptors in the RSV causing a reduction of sympathetic activity, reducing systemic vascular resistance and thus arterial blood pressure. ^Label

Moreover, since alpha-2-adrenergic receptors are considered the primary molecular target that facilitates the most common side effects of sedation and dry mouth that are elicited by most centrally acting antihypertensives, moxonidine differs from these other centrally acting antihypertensives by demonstrating only low affinity for central alpha-2-adrenoceptors compared to the aforementioned I1-imidazoline receptors ^Label.

Target	Actions	Organism
AAlpha-2A adrenergic receptor	agonist	Humans
ANischarin	agonist	Humans

Absorption

90% of an oral dose is absorbed with negligible interference from food intake or first pass metabolism, resulting in a high bioavailability of 88%. ^Label

Volume of distribution

1.8±0.4L/kg. ^Label

Protein binding

About 10% of moxonidine is bound to plasma proteins. ^Label

Metabolism

Biotransformation is unimportant ³ with 10-20% of moxonidine undergoing oxidation reactions to the primary 4,5-dehydromoxonidine metabolite and a guanidine derivative by opening of the imidazoline ring. ^Label

The antihypertensive effects of these 4,5-dehydromoxonidine and guanidine metabolites are only 1/10 and 1/100 the effect of moxonidine ^Label.

Oxidation on either the methyl group (pyrimidine ring) or on the imidazole ring of moxonidine results in the formation of the hydroxylmethyl moxonidine metabolite or the hydroxy moxonidine metabolite ⁶. The hydroxy moxonidine metabolite can be further oxidized to the dihydroxy metabolite or it can lose water to form the dehydrogenated moxonidine metabolite, which itself can be further oxidized to form an N-oxide ⁶. Aside from these Phase I metabolites, Phase II metabolism of moxonidine is also evident with the presence of a cysteine conjugate metabolite minus chlorine ⁶. Nevertheless, the identification of the hydroxy moxonidine metabolite with a high level of dehydrogenated moxonidine metabolite in human urine samples suggests that dehydrogenation from the hydroxy metabolite to the dehydrogenated moxonidine metabolite represents the primary metabolic pathway in humans ⁶.

The cytochromes P450 responsible for the metabolism of moxonidine in humans have not yet been determined ⁶.

Ultimately, the parent moxonidine compound was observed to be the most abundant component in different biological matrices of urinary excretion samples, verifying that metabolism only plays a modest role in the clearance of moxonidine in humans ⁶.

Route of elimination

Elimination is nearly entirely via the kidneys with a majority (50 -75%) of overall moxonidine being eliminated unchanged through renal excretion. Ultimately, more than 90% of a dose is eliminated by way of the kidneys within the first 24 hours after administration, with only approximately 1% being eliminiated via faeces. ^Label

Half life

Plasma elimination half life is 2.2 - 2.3 hours while renal elimination half life is 2.6-2.8 hours. ^Label

Clearance

Administered twice daily due to short half life ^Label.

However, lower dosage adjustments and close monitoring is necessary in elderly and renal impairment patients due to reduced clearance. In particular, the exposure AUC can increase by about 50% following a single dose and at steady state in elderly patients and moderately impaired renal function with GFR between 30-60 mL/min can cause AUC increases by 85% and decreases in clearence to 52 %. ^Label

Toxicity

Contraindicated due to known hypersensitivity to an ingredient (Physiotens tablets contain lactose), heart failure, severe renal impairment, < 16 years old, >75 years old, bradycardia, severe bradyarrhythmia, sick sinus syndrome, second or third degree atrioventricular block, malignant arrhythmias. ^Label
Used with caution in patients with history of severe coronary artery disease (CAD), unstable angina, angioneurotic edema. ^Label
Pregnancy Category B3:Avoid use during pregnancy (inadequate data in pregnant woman) and lactation (maternal blood stream transfer to breast milk shown) unless benefit clearly justifies risk. ^Label
Lack of specific therapeutic experience in cases of intermittent claudication, Raynaud's disease, Parkinson's disease, epileptic disorders, gluacoma, and depression suggest moxonidine should not be used in such instances ^Label.
Carcinogenicity and genotoxicity does not appear significant. ^Label
Concurrent administration of other hypotensives or sedative and hypnotics can enhance the hypotensive effect and intensify sedation respectively. ^Label
Avoid concurrent Tricyclic Antidepressant (TCA) use to avoid reduction of monoxidine efficacy. ^Label
Generally well tolerated with dry mouth and headache the most common adverse effects ^Label
Symptoms of overdose correlate with pharmacodynamic properties:hypotension, sedation, orthostatic dysregulation, bradycardia, dry mouth with no specific counter-treatment known. ^Label

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
Unlock Additional Data
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid	1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid may decrease the antihypertensive activities of Moxonidine.
1-benzylimidazole	The risk or severity of hypertension can be increased when 1-benzylimidazole is combined with Moxonidine.
2,5-Dimethoxy-4-ethylamphetamine	The risk or severity of hypertension can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Moxonidine.
2,5-Dimethoxy-4-ethylthioamphetamine	The risk or severity of hypertension can be increased when Moxonidine is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
4-Bromo-2,5-dimethoxyamphetamine	The risk or severity of hypertension can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Moxonidine.
4-Methoxyamphetamine	The risk or severity of hypertension can be increased when 4-Methoxyamphetamine is combined with Moxonidine.
5-methoxy-N,N-dimethyltryptamine	The risk or severity of hypertension can be increased when Moxonidine is combined with 5-methoxy-N,N-dimethyltryptamine.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline	7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypotensive activities of Moxonidine.
Abediterol	The risk or severity of hypertension can be increased when Moxonidine is combined with Abediterol.
Acebutolol	The therapeutic efficacy of Moxonidine can be decreased when used in combination with Acebutolol.

Additional Data Available

Extended Description

Extended description of the mechanism of action and particular properties of each drug interaction.

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Severity

A severity rating for each drug interaction, from minor to major.

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Evidence Level

A rating for the strength of the evidence supporting each drug interaction.

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Action

An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions

Not Available

References

General References

Cohn JN, Pfeffer MA, Rouleau J, Sharpe N, Swedberg K, Straub M, Wiltse C, Wright TJ: Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail. 2003 Oct;5(5):659-67. [PubMed:14607206]
Fenton C, Keating GM, Lyseng-Williamson KA: Moxonidine: a review of its use in essential hypertension. Drugs. 2006;66(4):477-96. [PubMed:16597164]
Prichard BN, Owens CW, Graham BR: Pharmacology and clinical use of moxonidine, a new centrally acting sympatholytic antihypertensive agent. J Hum Hypertens. 1997 Aug;11 Suppl 1:S29-45. [PubMed:9321737]
Prichard BN, Graham BR: I1 imidazoline agonists. General clinical pharmacology of imidazoline receptors: implications for the treatment of the elderly. Drugs Aging. 2000 Aug;17(2):133-59. [PubMed:10984201]
Ernsberger P, Haxhiu MA, Graff LM, Collins LA, Dreshaj I, Grove DL, Graves ME, Schafer SG, Christen MO: A novel mechanism of action for hypertension control: moxonidine as a selective I1-imidazoline agonist. Cardiovasc Drugs Ther. 1994 Mar;8 Suppl 1:27-41. [PubMed:8068578]
He MM, Abraham TL, Lindsay TJ, Schaefer HC, Pouliquen IJ, Payne C, Czeskis B, Shipley LA, Oliver SD, Mitchell MI: Metabolism and disposition of the antihypertensive agent moxonidine in humans. Drug Metab Dispos. 2003 Mar;31(3):334-42. [PubMed:12584161]
Electronic Medicines Compedium Physiotens (Moxonidine) Monograph [Link]

External Links

Human Metabolome Database: HMDB0041938
KEGG Drug: D05087
KEGG Compound: C07451
PubChem Compound: 4810
PubChem Substance: 310265145
ChemSpider: 4645
BindingDB: 50050093
ChEBI: 7009
ChEMBL: CHEMBL19236
Wikipedia: Moxonidine

ATC Codes

C02AC05 — Moxonidine

C02LC05 — Moxonidine and diuretics

FDA label

Download (108 KB)

MSDS

Download (56.5 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
0	Not Yet Recruiting	Other	Postural Tachycardia Syndrome	1
0	Recruiting	Other	Postural Tachycardia Syndrome	1
3	Completed	Treatment	High Blood Pressure (Hypertension)	1
3	Terminated	Prevention	Cardiac Diseases / Vascular Surgery	1
4	Completed	Treatment	Atrial Fibrillation (AF)	1
4	Completed	Treatment	High Blood Pressure (Hypertension) / Metabolic Syndromes / Obesity, Abdominal	1
4	Completed	Treatment	Polycystic Ovaries Syndrome	1
4	Recruiting	Treatment	Arterial Hypertension / Metabolic Syndromes	1
4	Unknown Status	Not Available	BMI >27 kg/m2 / BMI >30 kg/m2	1
4	Unknown Status	Treatment	Diabetic Nephropathies	1
4	Unknown Status	Treatment	High Blood Pressure (Hypertension) / Obesity, Abdominal	1
4	Unknown Status	Treatment	Schizophrenia	1
Not Available	Completed	Basic Science	Arterial Hypertension / Osteopenia	1
Not Available	Completed	Treatment	High Blood Pressure (Hypertension) / Left Ventricular Hypertrophy	1

Pharmacoeconomics

Manufacturers: Not Available
Packagers: Not Available
Dosage forms: Not Available
Prices: Not Available
Patents: Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	197 – 205	MSDS
water solubility	<1 mg/mL	MSDS

Predicted Properties

Property	Value	Source
Water Solubility	0.114 mg/mL	ALOGPS
logP	1.01	ALOGPS
logP	1.54	ChemAxon
logS	-3.3	ALOGPS
pKa (Strongest Basic)	7.26	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	6	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	71.43 Å²	ChemAxon
Rotatable Bond Count	2	ChemAxon
Refractivity	63.41 m³·mol^-1	ChemAxon
Polarizability	23.57 Å³	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	Not Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Taxonomy

Description: This compound belongs to the class of organic compounds known as halopyrimidines. These are aromatic compounds containing a halogen atom linked to a pyrimidine ring. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.
Kingdom: Organic compounds
Super Class: Organoheterocyclic compounds
Class: Diazines
Sub Class: Pyrimidines and pyrimidine derivatives
Direct Parent: Halopyrimidines
Alternative Parents: Aminopyrimidines and derivatives / Alkyl aryl ethers / Aryl chlorides / Imidazolines / Heteroaromatic compounds / Guanidines / Propargyl-type 1,3-dipolar organic compounds / Carboximidamides / Azacyclic compounds / Organopnictogen compounds
show 2 more
Substituents: Alkyl aryl ether / Aminopyrimidine / Halopyrimidine / Aryl chloride / Aryl halide / Heteroaromatic compound / 2-imidazoline / Guanidine / Ether / Azacycle
show 12 more
Molecular Framework: Aromatic heteromonocyclic compounds
External Descriptors: pyrimidines, organohalogen compound (CHEBI:7009)

Targets

Details1. Alpha-2A adrenergic receptor

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Agonist

General Function: Thioesterase binding
Specific Function: Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazo...
Gene Name: ADRA2A
Uniprot ID: P08913
Uniprot Name: Alpha-2A adrenergic receptor
Molecular Weight: 48956.275 Da

References

Zhu QM, Lesnick JD, Jasper JR, MacLennan SJ, Dillon MP, Eglen RM, Blue DR Jr: Cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild-type and D79N alpha2A-adrenoceptor transgenic mice. Br J Pharmacol. 1999 Mar;126(6):1522-30. [PubMed:10217548]
Stone LS, Fairbanks CA, Wilcox GL: Moxonidine, a mixed alpha(2)-adrenergic and imidazoline receptor agonist, identifies a novel adrenergic target for spinal analgesia. Ann N Y Acad Sci. 2003 Dec;1009:378-85. [PubMed:15028616]
Buccafusco JJ, Lapp CA, Westbrooks KL, Ernsberger P: Role of medullary I1-imidazoline and alpha 2-adrenergic receptors in the antihypertensive responses evoked by central administration of clonidine analogs in conscious spontaneously hypertensive rats. J Pharmacol Exp Ther. 1995 Jun;273(3):1162-71. [PubMed:7791087]

Details2. Nischarin

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Agonist

General Function: Phosphatidylinositol binding
Specific Function: Acts either as the functional imidazoline-1 receptor (I1R) candidate or as a membrane-associated mediator of the I1R signaling. Binds numerous imidazoline ligands that induces initiation of cell-si...
Gene Name: NISCH
Uniprot ID: Q9Y2I1
Uniprot Name: Nischarin
Molecular Weight: 166627.105 Da

References

Ernsberger P, Damon TH, Graff LM, Schafer SG, Christen MO: Moxonidine, a centrally acting antihypertensive agent, is a selective ligand for I1-imidazoline sites. J Pharmacol Exp Ther. 1993 Jan;264(1):172-82. [PubMed:8380858]
Buccafusco JJ, Lapp CA, Westbrooks KL, Ernsberger P: Role of medullary I1-imidazoline and alpha 2-adrenergic receptors in the antihypertensive responses evoked by central administration of clonidine analogs in conscious spontaneously hypertensive rats. J Pharmacol Exp Ther. 1995 Jun;273(3):1162-71. [PubMed:7791087]

Drug created on October 23, 2015 14:26 / Updated on December 02, 2019 08:40

Moxonidine

Identification

Structure for Moxonidine (DB09242)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy

Targets

References

References