Isosorbide dinitrate

Isosorbide dinitrate is an antianginal agent belonging to Nitrate.

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

Absorption of isosorbide dinitrate after oral dosing is nearly complete, but bioavailability is highly variable (10% to 90%), with extensive first-pass metabolism in the liver. The average bioavailability of isosorbide dinitrate is about 25%. The volume of distribution of isosorbide dinitrate is 2 to 4 L/kg, and this volume is cleared at the rate of 2 to 4 L/min, so ISDN's half-life in serum is about an hour. Extensively hepatic to conjugated active metabolites isosorbide 5-mononitrate and 2-mononitrate with a half-life of about 2 hours. About 80-100% is excreted in urine and feces.

Isosorbide dinitrate shows common side effects like Headache, lightheadedness, dizziness, restlessness, nausea, vomiting, bowel incontinence, xerostomia, weakness, blurred vision, etc.

Isosorbide dinitrate is available in the form of Oral Tablets, Sublingual tablets, and Oral capsules.

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

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

Isosorbide dinitrate and other nitrates form free radical nitric oxide. In smooth muscle, nitric oxide activates guanylate cyclase which increases guanosine 3’5’ monophosphate (cGMP) leading to dephosphorylation of myosin light chains and smooth muscle relaxation. Produces a vasodilator effect on the peripheral veins and arteries with more prominent effects on the veins. Primarily reduces cardiac oxygen demand by decreasing preload (left ventricular end-diastolic pressure); may modestly reduce afterload. Additionally, coronary artery dilation improves collateral flow to ischemic regions.

The onset of action of Isosorbide dinitrate occurs within 2-10 minutes (by Sublingual tablet), 3 minutes (by Chewable table), 45-60 minutes (by the Oral tablet), and 30min (by Extended-release tablet).

The Duration of Action for Isosorbide dinitrate in the body is within 1-2 minutes (by Sublingual tablet), 0.5-2 hours (by Chewable table), 4-6 hours (by the Oral tablet), and 6-12 hours (by Extended-release tablet).

Isosorbide dinitrate is available in the form of an Oral tablet, Sublingual tablets, and Oral capsules.

Isosorbide dinitrate Oral Tablet and Oral Capsule are taken by mouth 2 to 3 times a day.

Isosorbide Dinitrate is used in the prevention and treatment of angina (chest pain that occurs when your heart muscle does not get a sufficient amount of oxygen-rich blood). Angina is caused due to the narrowing of blood vessels that carries blood to your heart.

Isosorbide dinitrate 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. It is available on prescription as tablets, sublingual tablets (placing the tablet under the tongue), and capsules.

• Isosorbide dinitrate is indicated for the prevention of angina pectoris due to coronary-artery disease.

• Angina Pectoris

Sublingual:

2.5 to 5 mg sublingually 15 minutes prior to activity likely to cause an anginal episode

Immediate release:

Initial dose: 5 to 20 mg orally 2 or 3 times a day

Maintenance dose: 10 to 40 mg orally 2 or 3 times a day.

Extended-release:

40 to 160 mg/day orally.

• Angina Pectoris Prophylaxis

Sublingual:

2.5 to 5 mg sublingually 15 minutes prior to activity is likely to cause an anginal episode.

Immediate release:

Initial dose: 5 to 20 mg orally 2 or 3 times a day

Maintenance dose: 10 to 40 mg orally 2 or 3 times a day.

Extended-release:

40 to 160 mg/day orally.

Isosorbide dinitrate is available in various strengths as 2.5mg, 5mg, 10mg, 20mg, 30mg, and 40mg

Isosorbide dinitrate is available in the form of Oral tablets, Sublingual tablets, and Oral capsules.

● Isosorbide dinitrate is contraindicated in patients who are allergic to isosorbide dinitrate or any of its ingredients.

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

• Hypotension/bradycardia:

Severe hypotension can occur; paradoxical bradycardia and increased angina pectoris can accompany hypotension. Orthostatic hypotension can also occur; ethanol can accentuate this. Use with caution in volume depletion and hypotension, and use with extreme caution with inferior wall MI and suspected right ventricular infarctions. 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 in patients with acute MI or HF (cannot easily reverse effects if adverse events develop).

• Hypertrophic cardiomyopathy:

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

• 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. When used for HF in combination with hydralazine, tolerance is less of a concern.

Consumption of alcohol is not recommended during treatment with Isosorbide Dinitrate as it may increase the risk of dizziness, lightheadedness, etc.

It is not known if isosorbide dinitrate is present in breast milk. The manufacturer recommends that caution be exercised when administering isosorbide dinitrate to breastfeeding women.

Pregnancy Category C

At oral doses 35 and 150 times the maximum recommended human daily dose, isosorbide dinitrate has been shown to cause a dose-related increase in embryotoxicity (increase in mummified pups) in rabbits. There are no adequate, well-controlled studies on pregnant women. Isosorbide dinitrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Common Adverse effects

Headache, lightheadedness, dizziness, restlessness, nausea, vomiting, bowel incontinence, xerostomia, weakness, and blurred vision.

• Rare Adverse effects

Methemoglobinemia.

• Alcohol: With Nitrate, it may enhance the vasodilatory effect of Vasodilators.

● Alfuzosin: Nitrate may enhance the hypotensive effect of Blood Pressure Lowering Agents.

● Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine.

● Barbiturates: Concomitant use may enhance the hypotensive effect of Blood Pressure Lowering Agents.

● Brimonidine (Topical): Concomitant use may enhance the hypotensive effect of Blood Pressure Lowering Agents.

● Nitric Oxide: Concomitant use may enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia.

● Obinutuzumab: Concomitant use may enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion.

● Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with the development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents.

● Riociguat: Concomitant use with Vasodilators (Organic Nitrates) may enhance the hypotensive effect of Riociguat.

● Rosiglitazone: Concomitant use with Vasodilators (Organic Nitrates) may enhance the adverse/toxic effect of Rosiglitazone. Specifically, a greater risk of ischemia and other adverse effects has been associated with this combination in some pooled analyses.

● Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia.

The common side effect of Isosorbide dinitrate include the following

• Common
  

Headache, Flushing (warmth, redness, or tingly feeling)

• Rare

lightheadedness, worsening chest pain, fast or slow heart rate, pounding heartbeats, fluttering in your chest, hives, difficulty breathing, and swelling of your face, lips, tongue, or throat.

• Pregnancy

Pregnancy Category C

At oral doses 35 and 150 times the maximum recommended human daily dose, isosorbide dinitrate has been shown to cause a dose-related increase in embryotoxicity (increase in mummified pups) in rabbits. There are no adequate, well-controlled studies on pregnant women. Isosorbide dinitrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Nursing Mothers

It is not known if isosorbide dinitrate is present in breast milk. The manufacturer recommends that caution be exercised when administering isosorbide dinitrate to breastfeeding women.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

Isosorbide dinitrate may be eliminated more slowly in elderly patients. dose selection for an elderly patient should be cautious. Initiate therapy at the low end of the dosing range.

• Symptoms of overdose which are most common include hypotension, throbbing headache, tachycardia, and flushing. Methemoglobinemia may occur with massive doses; hypotension may aggravate symptoms of cardiac ischemia or cerebrovascular disease and may even cause seizures (rare).
• Treatment consists of placing a patient in the recumbent position and administering fluids; alpha-adrenergic vasopressors may be required; treat methemoglobinemia with oxygen and methylene blue at the dose of 1-2mg/kg I.V. slowly.

Pharmacodynamic

Isosorbide Dinitrate is a moderate to long-acting oral organic nitrate used for the relief and prophylactic management of angina pectoris. It relaxes the vascular smooth muscle and consequent dilatation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure.

Pharmacokinetics

• Absorption

Absorption of isosorbide dinitrate after oral dosing is nearly complete, but bioavailability is highly variable (10% to 90%), with extensive first-pass metabolism in the liver. The average bioavailability of isosorbide dinitrate is about 25%.

• Distribution

The volume of distribution of isosorbide dinitrate is 2 to 4 L/kg, and this volume is cleared at the rate of 2 to 4 L/min, so ISDN's half-life in serum is about an hour.

• Metabolism and Excretion

Extensively hepatic to conjugated active metabolites isosorbide 5-mononitrate and 2-mononitrate. Both metabolites have biological activity, especially the 5-mononitrate. With an overall half-life of about 5 hours, the 5-mononitrate is cleared from the serum by denitration to isosorbide, glucuronidation to the 5-mononitrate glucuronide, and denitration/hydration to sorbitol. The 2-mononitrate has been less well studied, but it appears to participate in the same metabolic pathways, with a half-life of about 2 hours. About 80-100% is excreted in urine and feces.

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