Moxonidine

Moxonidine is an antihypertensive agent belonging to the centrally acting alpha-2-adrenergic agonist.

Moxonidine is approved for the treatment of essential or primary Hypertension.

Moxonidine is well absorbed from the GI tract with bioavailability of aprrox 88%. The volume of distribution of moxonidine was about 1.8±0.4L/kg with plasma protein binding of about 10%. It gets metabolised via opening of the imidazoline ring, mainly to 4,5-dehydromoxonidine and to a guanidine derivative, and gets excreted Via urine (approx 50-75% as unchanged drug) with plasma elimination half-life of about 2-3 hr.

The common side effects associated with Moxonidine include headache, sedation, somnolence, hypotension, dizziness, asthenia, bradycardia, dry mouth, vomiting, fatigue and upper abdominal pain, etc.

Moxonidine is available in the form of dosage forms such as tablets

Moxonidine is available in Japan, India, Europe, Ireland, UK.

Moxonidine, belonging to the centrally acting alpha-2-adrenergic agonist, acts as a Antihypertensive agent. Moxonidine works by relaxing blood vessels which makes the heart more efficient at pumping blood around the body.

Moxonidine activates I1-imidazoline receptors (I1-receptors) in the rostroventrolateral medulla (RVLM), thereby reducing the activity of the sympathetic nervous system. Stimulation of central alpha 2-adrenergic receptors is associated with sympathoadrenal suppression and subsequent reduction of blood pressure.

The onset of action of Moxonidine occurs within 30-180 minutes.

The Duration of Action for Moxonidine is 12 hours.

The Tmax was found within 0.5-3 hours and Cmax in blood reached upto 1.29 +/- 0.32 ng/mL

Moxonidine is available in the form of tablets.

Moxonidine tablets should be taken orally by mouth with or without water.

Moxonidine is approved for the treatment of essential or primary Hypertension.

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 could also be suppressed by a second pathway with a newly discovered drug target specific to imidazolines . 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.

Moxonidine is approved for use in the following clinical indications

Hypertension

Moxonidine is used to treat mild to moderate essential Hypertension.

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

Moxonidine is available in various dosage strength : 0.2 mg, 0.3 mg, 0.4 mg

Moxonidine is available in the form of tablets.

Moxonidine should be used for the treatment of essential or primary Hypertension.

Hypertension: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

The dietary restriction should be individualized as per the patient requirements.

Moxonidine may be contraindicated in the following

• Hypersensitivity
• Sick sinus syndrome
• Bradycardia (resting heart rate <50 beats/minute)
• AV-block 2nd and 3rd degree
• Cardiac insufficiency
• Malignant arrhythmias
• Severe renal impairment (GFR < 30 mL/min, serum creatinine concentration >160 mmol/L).

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

Cessation of combination therapy with beta-blockers

• Abrupt cessation of combination therapy with moxonidine and a beta-blocker may result in the rebound hypertension.
• If combination therapy with moxonidine and the beta-blocker is to be ceased, the beta-blocker should be stopped first, and then moxonidine stopped after a few days have elapsed. During cessation of therapy the blood pressure should be regularly monitored.

Atrioventricular block

• Cases of varying degrees of AV block have been reported in the post-marketing setting in patients undergoing moxonidine treatment. Based on these case reports, the causative role of moxonidine in delaying atrioventricular conduction cannot be completely ruled out.
• Therefore, caution is recommended when treating patients with a possible predisposition to developing an AV block. When moxonidine is used in patients with 1st degree AV block, special care should be exercised to avoid bradycardia. Moxonidine must not be used in higher-degree AV blocks.

Other

• Moxonidine should be used with caution in patient with a history of angioneurotic edema. As with other centrally acting antihypertensives, moxonidine should be used with caution in a patient with severe coronary artery disease and unstable angina. There is limited experience in this population.
• Moxonidine should not be used because of the lack of experience in cases of intermittent claudication, Raynaud's Disease, Parkinson's Disease, epileptic disorders, glaucoma, and depression.
• Due to lack of therapeutic experience, the use of moxonidine concomitantly with alcohol or tricyclic antidepressants should be avoided. In limited studies, no rebound effect of the blood pressure after sudden discontinuation of moxonidine treatment has been detected. Nevertheless, it is advised not to interrupt the intake of moxonidine abruptly. moxonidine should be withdrawn gradually over a period of days.
• Due to the presence of lactose in Moxonidine tablets, patients with rare hereditary problems of galactose intolerance, Lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Precautions

• Caution is advised in the administration of moxonidine to patients with renal impairment, as moxonidine is excreted primarily via the kidney. In these patients careful titration of the dose is recommended, especially at the start of therapy.
• Dosing should be initiated with 0.2 mg daily and can be increased to a maximum of 0.4 mg daily for patients with moderate renal impairment (GFR > 30 ml/min but < 60 ml/min) and to a maximum of 0.3 mg daily for patients with severe renal impairment (GFR < 30 ml/min), if clinically indicated and well tolerated.
• If moxonidine is used in combination with a β-blocker and both treatments have to be discontinued, the β-blocker should be discontinued first, and then moxonidine after a few days.
• So far, no rebound effect has been observed on the blood pressure after discontinuing the treatment with moxonidine. However, abrupt discontinuance of the moxonidine treatment is not advisable; instead the dose should be reduced gradually over a period of two weeks.
• The elderly population may be more susceptible to the cardiovascular effects of blood pressure-lowering medicinal products. Therefore therapy should be started with the lowest dose and dose increments should be introduced with caution to prevent the serious consequences.
• Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Consumption of alcohol is not recommended while receiving this medicine as it may increase the risk of adverse effects and lowers the blood pressure.

Moxonidine use in breastfeeding patients is not recommended.

• Pregnancy Category B :

Avoid use during pregnancy (inadequate data in a pregnant woman) and lactation (maternal blood stream transfer to breast milk shown) unless the benefit clearly justifies risk.

• Garlic: Garlic interacts with moxonidine and can further lower the blood pressure.
• Ginger and Goldenseal: The interaction of ginger or goldenseal with moxonidine may alter the effectiveness of moxonidine and produce changes in blood pressure.

The adverse reactions related to molecule Moxonidine can be categorized as

• Common Adverse effects:

Hemodynamic compromise, Dizziness, peripheral ischemia, dry mouth,asthenia, and somnolence.

• Less Common adverse effects:

Asymptomatic and symptomatic hypotension, burning, crawling, itching, numbness.

• Rare adverse effects:

Bradycardia, decompensated heart failure, cardiac arrest, and heart block.

The clinically relevant drug interactions of Moxonidine is briefly summarized here.

• Concomitant administration of moxonidine and other antihypertensive medicinal products result in an additive effect.
• Since tricyclic antidepressants may reduce the effectiveness of centrally acting antihypertensive medicinal products, it is not recommended that tricyclic antidepressants be co-administered with moxonidine.
• Moxonidine can potentiate the sedative effect of tricyclic anti-depressants (avoid co-prescribing), tranquillizers, alcohol, sedatives and hypnotics.
• Moxonidine moderately augmented the impaired performance in cognitive functions in subjects receiving lorazepam. Moxonidine may enhance the sedative effect of benzodiazepines when administered concomitantly.
• Moxonidine is excreted through tubular excretion. Interaction with other medicinal products that are excreted through tubular excretion cannot be excluded.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Symptoms

In the few cases of overdose that have been reported, a dose of 19.6 mg was ingested acutely without a fatality. Signs and symptoms reported included: headache, sedation, somnolence, hypotension, dizziness, asthenia, bradycardia, dry mouth, vomiting, fatigue and upper abdominal pain. In case of a severe overdose, close monitoring of especially consciousness disturbances and respiratory depression is recommended. In addition, based on a few high dose studies in animals, transient Hypertension, tachycardia, and hyperglycemia may also occur.

Treatment

No specific antidote is known. In case of hypotension, circulatory support such as fluids and dopamine administration may be considered. Bradycardia may be treated with atropine. Αlpha-receptor antagonists may diminish or abolish the paradoxical hypertensive effects of a moxonidine overdose.

Pharmacodynamics:

• In various animal models moxonidine has been shown to be a potent antihypertensive. Available experimental data indicate that the site of action of the antihypertensive effect of moxonidine is the central nervous system (CNS).
• Moxonidine has been shown to bind selectively to the I₁-imidazoline receptors in the brain stem. These imidazoline-sensitive receptors are concentrated in the rostral ventrolateral medulla, an area that is of crucial importance for central control of the peripheral sympathetic nervous system. The result of this effect on the I₁-imidazoline receptors has been apparent in reduced activity in the sympathetic nerves. (demonstrated for cardiac, splanchnic and renal sympathetic nerves).
• Moxonidine differs from other available centrally acting antihypertensives by having only a weak affinity for central alpha 2-adrenoceptors compared to I₁-imidazoline receptors alpha-2-adrenoceptors are considered to be the molecular target through which most common adverse reactions of centrally acting antihypertensives such as drowsiness and dry mouth - are mediated. In humans, moxonidine results in a reduction of systemic vascular resistance and, consequently of, arterial blood pressure.
• The effects of moxonidine on mortality and cardiovascular morbidity are currently unknown.

Pharmacokinetics:

• Absorption:

In humans, about 90% of an oral dose of moxonidine is absorbed; it is not subject to first-pass metabolism and its bioavailability is 88%. Food intake does not interfere with moxonidine pharmacokinetics. The maximum plasma level of moxonidine is reached 30 – 180 min after the intake of a film-coated tablet.

• Distribution:

Only about 10% of moxonidine is bound to plasma proteins (Vdss=1.8±0.4 L/kg).

• Metabolism:

Moxonidine is 10 – 20% metabolised, mainly to 4,5-dehydromoxonidine and to a guanidine derivative by opening the imidazoline ring. The hypotensive effect of 4,5-dehydromoxonidine is only 1/10, and that of the guanidine derivative is less than 1/100 of that of moxonidine.

• Excretion:

Moxonidine and its metabolites are eliminated almost entirely via the kidneys. More than 90% of the dose is eliminated via the kidneys in the first 24 hours after administration, while only about 1% is eliminated via feces. The cumulative renal excretion of unchanged moxonidine is about 50 – 75%. The mean plasma elimination half-life of moxonidine is 2.2 – 2.3 hours, and the renal elimination half-life is 2.6 – 2.8 hours. Although moxonidine has a relatively short half-life, it should be administered no more frequently than twice daily.

• https://www.mims.com/india/drug/info/moxonidine?type=full&mtype=generic
• https://www.medindia.net/drugs/drug-food-interactions/moxonidine.htm
• https://www.apollopharmacy.in/salt/MOXONIDINE
• https://go.drugbank.com/drugs/DB09242
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