Moxonidine

This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

Identification

Summary

Moxonidine is an imidazoline/α-2 receptor agonist used to treat hypertension, especially in cases where ACE inhibitors, β-blockers, calcium channel blockers, and thiazides are not appropriate or provide inadequate blood pressure control.

Generic Name

Moxonidine

DrugBank Accession Number

DB09242

Background

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.

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 241.677
Monoisotopic: 241.073037738
Chemical Formula: C₉H₁₂ClN₅O

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

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.

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Associated Conditions

Hypertension

Contraindications & Blackbox Warnings

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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

Adverse Effects

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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

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
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Abaloparatide	The risk or severity of adverse effects can be increased when Abaloparatide is combined with Moxonidine.
Acebutolol	The therapeutic efficacy of Moxonidine can be decreased when used in combination with Acebutolol.
Aceclofenac	The therapeutic efficacy of Moxonidine can be decreased when used in combination with Aceclofenac.
Acemetacin	The therapeutic efficacy of Moxonidine can be decreased when used in combination with Acemetacin.
Acetylsalicylic acid	Acetylsalicylic acid may decrease the antihypertensive activities of Moxonidine.
Aclidinium	The risk or severity of Tachycardia can be increased when Aclidinium is combined with Moxonidine.
Adenosine	The risk or severity of Tachycardia can be increased when Adenosine is combined with Moxonidine.
Alclofenac	The therapeutic efficacy of Moxonidine can be decreased when used in combination with Alclofenac.
Aldesleukin	The risk or severity of adverse effects can be increased when Aldesleukin is combined with Moxonidine.
Alfentanil	Alfentanil may decrease the antihypertensive activities of Moxonidine.

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Food Interactions

Not Available

Products

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Product Ingredients

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

International/Other Brands

Cynt / Physiotens (Solvay Pharmaceuticals)

Unapproved/Other Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
PHYSIOTENS 0,2 MG FILM TABLET, 28 ADET	Moxonidine (0.2 mg)	Tablet, film coated	Oral	ABBOTT LABORATUARLARI İTHALAT İHRACAT VE TİC. LTD. ŞTİ.	2020-08-14	Not applicable
PHYSIOTENS 0,4 MG FILM TABLET, 28 ADET	Moxonidine (0.4 mg)	Tablet, film coated	Oral	ABBOTT LABORATUARLARI İTHALAT İHRACAT VE TİC. LTD. ŞTİ.	2020-08-14	Not applicable

Chemical Identifiers

UNII: CC6X0L40GW
CAS number: 75438-57-2
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

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. [Article]
Fenton C, Keating GM, Lyseng-Williamson KA: Moxonidine: a review of its use in essential hypertension. Drugs. 2006;66(4):477-96. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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
RxNav: 30257
ChEBI: 7009
ChEMBL: CHEMBL19236
ZINC: ZINC000001854466
Wikipedia: Moxonidine

FDA label

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MSDS

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Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Basic Science	Central Sympathetic Nervous System Diseases	1
4	Completed	Treatment	Atrial Fibrillation	1
4	Completed	Treatment	Hypertension / Obesity	1
4	Completed	Treatment	Hypertension / Obesity, Abdominal / Syndrome, Metabolic	1
4	Completed	Treatment	Polycystic Ovarian Syndrome (PCOS)	1
4	Recruiting	Treatment	Hypertension / Obesity	1
4	Unknown Status	Not Available	BMI >27 kg/m2 / Obesity	1
4	Unknown Status	Treatment	Diabetic Nephropathy	1
4	Unknown Status	Treatment	Hypertension Arterial / Syndrome, Metabolic	1
4	Unknown Status	Treatment	Hypertension / Obesity, Abdominal	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, coated	Oral	0.2 mg
Tablet, coated	Oral	0.4 mg
Tablet, film coated	Oral
Tablet, film coated	Oral	0.2 MG
Tablet, film coated	Oral	0.3 MG
Tablet, film coated	Oral	0.4 MG

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

Targets

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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. [Article]
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. [Article]
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. [Article]

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. [Article]
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. [Article]

Drug created at October 23, 2015 20:26 / Updated at May 05, 2021 20:31

Moxonidine

Identification

Structure for Moxonidine (DB09242)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Targets

References

References