Isosorbide Mononitrate

Isosorbide Mononitrate is an antianginal agent belonging to Nitrate.

Isosorbide Mononitrate is used in the prevention and treatment of angina in coronary artery disease.

Upon oral administration, Isosorbide mononitrate is rapidly and completely absorbed from the gastrointestinal tract. Isosorbide mononitrate has dose-linear kinetics, and the absolute bioavailability is nearly 100%. The Cmax is reached within 30 to 60 minutes following administration. The volume of distribution is approximately 0.6 L/kg, which is approximately the volume of total body water. Isosorbide mononitrate is about 5% bound to plasma proteins. Isosorbide mononitrate is not subject to first-pass metabolism in the human liver. The elimination half-life of isosorbide mononitrate is about 5 hours. The total body clearance is 115-120 mL/min. In a human radio-labeled drug study, about 93% of the total dose was excreted in the urine within 48 hours. Following oral administration of 20 mg, only 2% of isosorbide mononitrate was excreted unchanged in the urine within 24 hours.

Isosorbide Mononitrate shows common side effects like Bluish discoloration of lips, fingernails, palm, or hands, irregular heartbeat Dizziness, fainting, chest pain, difficulty in breathing, difficulty in swallowing, burning, numbness, tingling in the arms and feet, etc.

Isosorbide Mononitrate is available in the form of Oral Tablets.

Isosorbide Mononitrate is available in India, the US, UK, Canada, Singapore, China, Japan, and Australia.

Isosorbide Mononitrate belonging to the Nitrate acts as an antianginal agent.

Isosorbide mononitrate acts as a prodrug for nitric oxide (NO), which is a potent vasodilator gas that is released when the drug is metabolized. NO activates soluble guanylyl cyclase in vascular endothelial cells, which increases the intracellular concentrations of cyclic GMP (cGMP). cGMP activates cGMP-dependent protein kinases, such as protein kinase G and I, which activate the downstream intracellular cascades. The downstream cascade results in reduced intracellular concentrations of calcium, caused by processes including inhibition of IP₃-mediated pathway, phosphorylation of big calcium-activated potassium channel leading to cell hyperpolarization and reduced calcium influx, and increased calcium efflux via the Ca2+-ATPase-pump. Reduced intracellular calcium concentrations lead to the dephosphorylation of myosin light chains and the relaxation of smooth muscle cells.

The onset of action of Isosorbide Mononitrate is about 30-45 minutes.

The Duration of Action for Isosorbide Mononitrate is about >6 hours (by Immediate release) and 12-24 hours (by Extended).

The Tmax was found within approximately 30-60 minutes.

Isosorbide Mononitrate is available in the form of an Oral Tablet.

Isosorbide Mononitrate tablet is taken by mouth usually once or twice a day.

Isosorbide Mononitrate is an effective medicine to prevent and treat chest pain (angina) caused due to narrowing of blood vessels that carries blood to the heart. It also decreases the load on the heart ensuring effective pumping of blood.

Isosorbide Mononitrate is an antianginal agent belonging to Nitrate. It relaxes the blood vessels and also decreases the pressure on your heart. Thus, it allows the blood to flow easily to your heart.

Isosorbide Mononitrate is approved for use in the following clinical indications

• Angina Pectoris

Isosorbide mononitrate is indicated for the prevention of angina pectoris due to coronary artery disease. The onset of action of oral isosorbide mononitrate is not sufficiently rapid for this product to be useful in aborting an acute anginal episode.

• Angina Pectoris

Immediate release

Oral: 20 mg twice daily; administer the second dose at least 7 hours after the first dose (eg, 8 AM and 3 PM) to decrease tolerance development; patients with small stature may initiate therapy with 5 mg twice daily and titrate to at least 10 mg twice daily in first 2 to 3 days of therapy.

Extended-release

Oral: Initial: 30 to 60 mg once daily in the morning; may titrate after several days to 120 mg once daily; rarely, 240 mg once daily may be required.

Isosorbide Mononitrate is available in various strengths as 10mg, 20mg, 30mg, 60mg and 120mg.

Isosorbide Mononitrate is available in the form of an Oral Tablet.

Isosorbide Mononitrate is contraindicated in patients with

● Patients who are taking certain drugs for erectile dysfunction (phosphodiesterase inhibitors), such as sildenafil, tadalafil, or vardenafil.

● Concomitant use can cause severe hypotension, syncope, or myocardial ischemia.

● Do not use Isosorbide Mononitrate in patients who are taking the soluble guanylate cyclase stimulator riociguat. Concomitant use can cause hypotension

• CNS depression

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving)

• Hypotension/bradycardia

Severe hypotension can occur; paradoxical bradycardia and increased angina pectoris can accompany hypotension. Orthostatic hypotension can also occur; ethanol can accentuate this. Severe hypotension, particularly with upright posture, may occur with even small doses.

• Intracranial pressure increased

Nitrates may precipitate or aggravate increased intracranial pressure and subsequently may worsen clinical outcomes in patients with neurologic injury (eg, intracranial hemorrhage, traumatic brain injury).

• Cardiovascular disease

Not recommended for use in patients with acute myocardial infarction (MI) or heart failure (has not been studied). Use with caution in volume depletion and moderate hypotension, and with extreme caution with inferior wall MI and suspected right ventricular infarctions. The Canadian labeling contraindicates use in acute circulatory failure are associated with marked hypotension, postural hypotension, and myocardial insufficiency due to obstruction (eg, in the presence of aortic or mitral stenosis or constrictive pericarditis).

• Hypertrophic cardiomyopathy with left ventricular outflow tract obstruction

Avoid use in patients with hypertrophic cardiomyopathy with left ventricular outflow tract obstruction; nitrates may reduce preload, exacerbating obstruction and cause hypotension or syncope and/or worsening of heart failure.

• PDE-5 inhibitors

Avoid concurrent use with PDE-5 inhibitors (eg, sildenafil, tadalafil, vardenafil). When nitrate administration becomes medically necessary, may administer nitrates only if 24 hours have elapsed after use of sildenafil or vardenafil.

• Tolerance

Appropriate dosing intervals are needed to minimize tolerance development. Tolerance can only be overcome by short periods of nitrate absence from the body. Dose escalation does not overcome this effect.

Consumption of alcohol during treatment with this medicine may increase the risk of severe side effects. These side effects may include confusion, dizziness, nausea, vomiting, weakness, and fainting.

It is not known whether Isosorbide mononitrate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when isosorbide mononitrate is administered to a nursing woman.

Pregnancy category B & C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant the use of the drug in pregnant women despite potential risks.

No information is available.

Common Adverse effects

• Headache, Dizziness, Nausea/vomiting, Angina pectoris, arrhythmias, atrial fibrillation, hypotension, palpitations, postural hypotension, premature ventricular contractions, supraventricular tachycardia, syncope, pruritus, rash, abdominal pain, diarrhea, dyspepsia, tenesmus, tooth disorder, vomiting, dysuria, impotence, urinary frequency, asthenia, blurred vision, cold sweat, diplopia, edema, malaise, neck stiffness, rigors, agitation, anxiety, confusion, dyscoordination, hypoesthesia, nightmares, bronchitis, pneumonia, upper respiratory tract infection, arthralgia, methemoglobinemia.

Rare Adverse effects

• Acute myocardial infarction, amblyopia, anorexia, asthma, bitter taste, cerebrovascular accident, increased thirst, muscle cramps, neck pain, pallor, prostatic disease, restlessness, syncope, and weight loss.

● Vasodilators

The vasodilating effects of isosorbide mononitrate may be additive with those of other vasodilators.

● Alcohol

Alcohol, in particular, has been found to exhibit additive effects of this variety.

● Calcium channel blockers

Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination.

The common side effects of Isosorbide Mononitrate include the following

• Common
  

Bluish discoloration of lips, fingernails, palm, or hands, irregular heartbeat Dizziness, fainting, chest pain, difficulty in breathing, difficulty in swallowing, burning, numbness, and tingling in the arms and feet.

• Rare

Worsening chest pain, rash, hives, itching, difficulty breathing or swallowing, Low blood pressure, Headache, Nausea or Vomiting, Hives and redness of the skin, agitation and anxiety Sleeplessness.

• Pregnancy

Teratogenic Effects

Pregnancy Category B & C: Reproduction studies performed in rats and rabbits at doses of up to 540 and 810 mg/kg/day, respectively, have revealed no evidence of harm to the fetus due to isosorbide mononitrate. There are, however, no adequate and well-controlled studies on pregnant women. Because animal reproduction studies are not always predictive of human response, Isosorbide mononitrate should be used during pregnancy only if clearly needed.

• Nursing Mothers

It is not known whether Isosorbide mononitrate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when isosorbide mononitrate is administered to a nursing woman.

• Pediatric Use

The safety and effectiveness of isosorbide mononitrate in pediatric patients have not been established.

• Geriatric Use

Clinical studies of Isosorbide mononitrate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

• Hemodynamic Effects

The ill effects of Isosorbide mononitrate overdose are generally the results of isosorbide mononitrate’s capacity to induce vasodilatation, venous pooling, reduced cardiac output, and hypotension. These hemodynamic changes may have protean manifestations, including increased intracranial pressure, with any or all of persistent throbbing headache, confusion, and moderate fever; vertigo; palpitations; visual disturbances; nausea and vomiting (possibly with colic and even bloody diarrhea); syncope (especially in the upright posture); air hunger and dyspnea, later followed by reduced ventilatory effort; diaphoresis, with the skin either flushed or cold and clammy; heart block and bradycardia; paralysis; coma; seizures and death.

• Methemoglobinemia

Methemoglobinemia has been reported in patients receiving other organic nitrates, and it probably could also occur as a side effect of isosorbide mononitrate. Certainly, nitrate ions liberated during the metabolism of isosorbide mononitrate can oxidize hemoglobin into methemoglobin. Even in patients totally without cytochrome b5 reductase activity, however, and even assuming that the nitrate moiety of isosorbide mononitrate is quantitatively applied to oxidation of hemoglobin, about 2 mg/kg of isosorbide mononitrate should be required before any of these patients manifests clinically significant (≥10%) methemoglobinemia. In patients with normal reductase function, significant production of methemoglobin should require even larger doses of isosorbide mononitrate. In one study in which 36 patients received 2-4 weeks of continuous nitroglycerin therapy at 3.1 to 4.4 mg/hr (equivalent, in the total administered dose of nitrate ions, to 7.8-11.1 mg of isosorbide mononitrate per hour), the average methemoglobin level measured was 0.2%; this was comparable to that observed in parallel patients who received placebo.

Pharmacodynamic

Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously greater than a minimally effective concentration. This strategy is inappropriate for organic nitrates. Several well-controlled clinical trials have used exercise testing to assess the antianginal efficacy of continuously delivered nitrates. In the large majority of these trials, active agents were indistinguishable from placebo after 24 hours (or less) of continuous therapy. Attempts to overcome tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates have been absent from the body for several hours has their antianginal efficacy been restored. The drug-free interval sufficient to avoid tolerance to isosorbide mononitrate has not been completely defined. In the only regimen of twice-daily isosorbide mononitrate that has been shown to avoid the development of tolerance, the two doses of Isosorbide mononitrate tablets are given 7 hours apart, so there is a gap of 17 hours between the second dose of each day and the first dose of the next day. Taking account of the relatively long half-life of isosorbide mononitrate this result is consistent with those obtained for other organic nitrates. The asymmetric twice-daily regimen of Isosorbide mononitrate tablets successfully avoided significant rebound/withdrawal effects. The incidence and magnitude of such phenomena have appeared, in studies of other nitrates, to be highly dependent upon the schedule of nitrate administration.

Pharmacokinetics

• Absorption

Upon oral administration, Isosorbide mononitrate is rapidly and completely absorbed from the gastrointestinal tract. Isosorbide mononitrate has dose-linear kinetics, and the absolute bioavailability is nearly 100%. The Cmax is reached within 30 to 60 minutes following administration.

• Distribution

The volume of distribution is approximately 0.6 L/kg, which is approximately the volume of total body water. Isosorbide mononitrate is about 5% bound to plasma proteins.

• Metabolism and Excretion

Isosorbide mononitrate is not subject to first-pass metabolism in the human liver. Detectable metabolites include isosorbide, sorbitol, and 2-glucuronide of mononitrate, which is pharmacologically inactive. The elimination half-life of isosorbide mononitrate is about 5 hours. The elimination half-life of its metabolites, isosorbide and 2-glucuronide of mononitrate, is 8 hours and 6 hours, respectively. The total body clearance is 115-120 mL/min. In a human radio-labeled drug study, about 93% of the total dose was excreted in the urine within 48 hours. Following oral administration of 20 mg, only 2% of isosorbide mononitrate was excreted unchanged in the urine within 24 hours.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020215s024lbl.pdf
• https://reference.medscape.com/drug/imdur-monoket-isosorbide-mononitrate-342275#0
• https://www.syrianclinic.com/med/en/ProfDrugs/IsosorbideMononitratepd.html#mechanism-action
• https://go.drugbank.com/drugs/DB01020
• https://www.uptodate.com/contents/isosorbide-mononitrate-drug-information?search=isosorbide mononitrate&source=panel_search_result&selectedTitle=1~26&usage_type=panel&kp_tab=drug_general&display_rank=1#F185047
• https://www.drugs.com/pregnancy/isosorbide-mononitrate.html