Isosorbide dinitrate (3 mg/kg; intratracheal vehicle; 13 days) consistently reduces pulmonary artery pressure and ventricular remodeling in a cardiac neighbor model after myocardial infarction [1]. Isosorbide dinitrate post-treatment has showed effects on myocardial infarction reperfusion

Animal/Disease Models: 5-6 weeks old male juvenile SD (SD (Sprague-Dawley)) rats (200-250 g) [1]
Doses: 3 mg/kg
Route of Administration: intratracheal; The protective effect of the abdomen [2]. Results 13 days after coronary artery ligation: MI size was diminished, and post-MI left ventricular and right ventricular remodeling was alleviated.

Absorption, Distribution and Excretion
Isosorbide nitrate is almost completely absorbed after oral administration, but its bioavailability varies widely (10% to 90%). It undergoes extensive first-pass metabolism in the liver. The average bioavailability of isosorbide nitrate is approximately 25%.
2 to 4 liters/kg
After sublingual administration, the onset of action is 2–3 minutes, and the time to wear off is approximately 2 hours.
After sublingual administration of 5 mg, oral administration of a 5 mg immediate-release tablet, and oral administration of a 20 mg extended-release tablet, the average peak concentrations of isosorbide nitrate were 8.9, 3.1, and 1.4 ng/mL, respectively, reached at 30, 40, and 40 minutes.
After extended-release administration, plasma concentrations remained above half of the average peak concentration for 10 hours.
Prolonged oral administration of isosorbide nitrate (120 to 720 mg daily) leads to persistent presence of the parent compound in plasma and elevated metabolite concentrations.
Because denitration significantly reduces the activity of organic nitrates, their rapid clearance from the blood indicates that, under these conditions, the duration of transient effects is related to the concentration of the parent compound. /Organic Nitrates/
For more complete data on the absorption, distribution, and excretion of isosorbide dinitrates (13 in total), please visit the HSDB record page.

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Metabolism/Metabolites
Hepatic
The major metabolite in plasma after intravenous or oral administration is isosorbide 5-mononitrate.
The main metabolic pathway of isosorbide dinitrates in humans is also enzymatic denitration, followed by the formation of glucuronide.
The biotransformation of organic nitrates is the result of reductive hydrolysis catalyzed by the hepatic enzyme glutathione-organic nitrate reductase. This enzyme converts lipid-soluble organic nitrates into more water-soluble denitration metabolites and inorganic nitrites. /Organic Nitrates/
…The biotransformation of isosorbide dinitrates in dogs and humans results in deesterification. Isosorbide is the main urinary metabolite, along with trace amounts of 2- and 5-mononitrates. Isosorbide dinitrate was not detected in the urine of dogs and humans. For more complete metabolite/metabolite data on isosorbide dinitrate (8 metabolites in total), please visit the HSDB record page.

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Biological half-life
1 hour
Half-life 0.7 hours (0.6-2.0; clearance may decrease and half-life may be prolonged with prolonged administration.) (Data from tables)
The mean plasma elimination half-life of ISMN is approximately 5 hours. (Isosorbide mononitrate)
After sublingual administration…the biological half-life is approximately 8 hours….
The biological half-life is approximately 8 hours; after oral administration, the onset of action is approximately 30 minutes, and the duration of action is 4-6 hours.

Toxicity Summary
Identification: Isosorbide dinitrate is a vasodilator and an antianginal drug. Isosorbide dinitrate is a white to ivory-white, odorless, fine crystalline solid. It is slightly soluble in water and readily soluble in acetone, chloroform, ethanol, and ether. Indications: Isosorbide dinitrate is primarily used to treat patients with ischemic heart disease. It can reduce the frequency, duration, and severity of angina attacks. It improves exercise tolerance and reduces the need for nitroglycerin. It is effective for various types of angina (stable exertional angina, mixed angina, unstable angina, and vasospastic or variant angina). It is also used for acute myocardial infarction to control ischemic pain, lower high blood pressure, and treat pulmonary edema and congestive heart failure. It can also be used to treat severe hypertension. Intravenous infusion can be used for precise blood pressure control. It can be used to control blood pressure during general anesthesia when precise control is required. It can also be used to treat esophageal spasms. Human Exposure: Main Risks and Target Organs: The main risks of isosorbide dinitrate overdose are vasodilation and hypotension (and its complications). The heart and blood vessels are target organs. Methemoglobinemia may occur. Clinical Manifestations Overview: Symptoms of poisoning may appear within minutes to an hour or longer after exposure. Tachycardia, hypotension, followed by bradycardia and collapse, throbbing headache, dizziness, restlessness, syncope, convulsions, and coma may occur. Other symptoms include vomiting, diarrhea, cyanosis, and methemoglobinemia. Respiratory failure may occur in severe cases. Clinical diagnosis is based on the history of exposure and observed signs and symptoms: tachycardia, hypotension, throbbing headache, facial flushing. Contraindications: Hypersensitivity to isosorbide dinitrate. Pre-existing methemoglobinemia. Severe anemia, head trauma, or cerebral hemorrhage. Routes of Exposure: Oral: Oral and absorption via the gastrointestinal tract is the most common route of toxicity. Sublingual absorption is also possible. Skin: Preliminary experience reports exist regarding isosorbide dinitrate cream. Parenteral: Poisoning may occur in patients receiving intravenous isosorbide dinitrate. Absorption via routes of contact: Oral: Isosorbide dinitrate is readily absorbed through the oral mucosa with a short duration of action. After oral administration, it is well absorbed from the gastrointestinal tract. Due to its first-pass effect and short plasma half-life, sustained-release formulations are available. Sublingual administration can achieve peak plasma concentration within 6 minutes. Skin absorption: Isosorbide dinitrate can also be absorbed through the skin from the ointment base. The bioavailability of isosorbide dinitrate after oral or sublingual administration is approximately 29%. Distribution by route of administration: No relevant data available. Biological half-life by route of administration: The terminal elimination half-lives of isosorbide dinitrate after intravenous, sublingual, and oral administration are 54.7 min, 48.8 min, and 47.7 min, respectively. Metabolism: The main metabolic pathway of isosorbide dinitrate in the human body is enzymatic denitration, followed by glucuronide formation. The main initial metabolites, isosorbide mononitrate-2 and isosorbide mononitrate-5, have relatively long half-lives (2-5 hours), which are presumed to at least partially explain the therapeutic effects of isosorbide dinitrate. Due to the "first-pass effect," a significant portion of the drug is metabolized. Elimination pathway: Primarily excreted in the urine as isosorbide glucuronide. Mechanism of action: Toxicokinetics: Isosorbide dinitrate has a vasodilatory effect on the smooth muscle of almost all vascular beds. Nitrates dilate veins and arteries, and at high concentrations, arterioles. The beneficial effects at therapeutic doses and the effects observed in overdose are attributed to the physiological consequences of systemic venous and arteriole dilation. Cardiac preload, systemic blood pressure, and systemic vascular resistance all progressively decrease. Hypotension, circulatory failure, and shock may occur. Methemoglobinemia may occur with overdose of isosorbide dinitrate or during treatment. Pharmacodynamics: Organic nitrates can activate guanylate cyclase, increasing the synthesis of guanylate cyclase (cGMP) in smooth muscle and other tissues. The resulting reactive free radical nitric oxide (NO) can interact with and activate guanylate cyclase. Interactions: Several important interactions may occur with other cardiovascular drugs. Severe orthostatic hypotension has been observed in patients receiving isosorbide dinitrate and hydralazine for chronic heart failure. Sublingual administration of nitrates and β-adrenergic receptor blockers may cause excessive dizziness and syncope. Complete atrioventricular block, and even cardiac arrest, has been reported in patients receiving lidocaine infusions after sublingual administration of nitrates. Disopyramide, tricyclic antidepressants, and other drugs with anticholinergic effects may prevent the dissolution of sublingual isosorbide dinitrate tablets by causing dry mouth. Isosorbide dinitrate can antagonize the effects of acetylcholine, adrenaline, and histamine. Alcohol consumption may enhance its hypotensive effect. Major adverse reactions: The toxicity of nitrates is not affected by their chemical form or route of administration; all nitrates share similar adverse reaction characteristics. Hypotension, reflex tachycardia, and palpitations may occur. Orthostatic hypotension and syncope are particularly common in elderly patients. Severe bradycardia has been reported rarely. Pulsating headache is relatively common; this symptom may subside as tolerance develops. Peripheral edema is also relatively common. Transient hypoxemia and angina pectoris are occasionally seen. Transient ischemic attacks unrelated to blood pressure changes are rare. Therefore, for patients with cerebrovascular disease, it is recommended to start treatment with a low dose. Methemoglobinemia may occur after therapeutic doses. Fatigue, transient dizziness, agitation, and collapse may occur. Skin flushing, sweating, and exfoliative dermatitis have been reported. Nausea and vomiting are uncommon. Although the tolerance of nitrates is well known, its clinical significance remains unclear. Tolerance is best defined as a gradual decrease in efficacy over time, usually requiring increased doses to achieve the desired therapeutic effect. Tolerance can be partial or complete, and may occur only with one nitrate medication; the disappearance of throbbing headache is a useful sign. However, these medications are not suitable for long-term treatment of hypertension due to their diminished antihypertensive effect. The role of arteries and veins in the development of tolerance is unclear. Tolerance can be avoided or reduced by providing a longer (approximately 8 hours) nitrate-free interval. Reducing the daily dose of isosorbide dinitrate also helps achieve this effect. Extended-release formulations are more likely to induce tolerance than short-acting formulations. Protein binding is extremely low. This reaction (orthostatic hypotension) appears to be exacerbated by alcohol (organic nitrates). When taken concurrently with propranolol, a dose reduction of isosorbide dinitrate may be necessary. Sildenafil (Viagra) can enhance the antihypertensive effect of nitrates and is therefore contraindicated when used concurrently with any form of nitrate; there have been reports of death due to concurrent use. Nitrates
Concomitant use of sympathomimetic drugs may reduce the antianginal effect of nitrates. Nitrates may counteract the pressor effect of sympathomimetic drugs, potentially leading to hypotension. Nitrates
Three antianginal drugs, particularly isosorbide dinitrate (5 mg, orally) and propranolol, can reduce the turnover rate of norepinephrine in the rat heart.

[1]. Intratracheal administration of isosorbide dinitrate improves pulmonary artery pressure and ventricular remodeling in a rat model of heart failure following myocardial infarction. Exp Ther Med. 2017 Aug;14(2):1399-1408.

[2]. Cardioprotective Effect of Isosorbide Dinitrate Postconditioning Against Rat Myocardial Ischemia-Reperfusion Injury In Vivo. Med Sci Monit. 2019 Mar 2;25:1629-1636.

Isosorbide dinitrate is a nitrate ester compound and a glucol derivative. It is a vasodilator and a nitric oxide donor. It is a vasodilator used to treat angina pectoris. Its effects are similar to nitroglycerin, but with a slower onset of action. Isosorbide dinitrate is a nitrate vasodilator. The physiological effect of isosorbide dinitrate is achieved through vasodilation. Isosorbide dinitrate is the dinitrate form of isosorbide, an organic nitrate ester with vasodilatory activity. Isosorbide dinitrate relaxes vascular smooth muscle by generating the free radical nitric oxide (NO), which is identical to endothelial relaxing factor (EDRF). Nitric oxide (NO) activates guanylate cyclase, thereby increasing the synthesis of cGMP in smooth muscle, leading to dephosphorylation of light chain myosin, and causing dilation of peripheral arteries and veins. Furthermore, isosorbide dinitrate can dilate coronary arteries, thereby increasing blood circulation in ischemic areas. (NCI05)
A vasodilator used to treat angina pectoris. Its action is similar to nitroglycerin, but with a slower onset of action.
See also: isosorbide dinitrate (contains the active ingredient); hydralazine hydrochloride; isosorbide dinitrate (one of the ingredients).

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Indications
For the prevention of angina pectoris caused by coronary artery disease.

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Mechanism of Action
Isosorbide dinitrate is converted to active nitric oxide, which activates guanylate cyclase. This activation increases the level of cyclic guanosine monophosphate (cGMP). cGMP activates protein kinase, triggering a series of phosphorylation reactions that ultimately lead to dephosphorylation of the myosin light chain in smooth muscle fibers. This ultimately releases calcium ions, causing smooth muscle relaxation and vasodilation.
...nitrate...can activate guanylate cyclase and lead to a significant increase in the concentration of cyclic guanosine monophosphate (cGMP) in most tissues. This effect is clearly due to the action of nitric oxide...nitrate may directly activate the enzyme. /Organic Nitrates/
Isosorbide dinitrate inhibits collagen, adrenaline, arachidonic acid, and ionocarboxylates-induced platelet aggregation and blocks ADP-induced primary and secondary aggregation.

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Therapeutic Uses
Vasodilator
In a small number of patients with diffuse esophageal spasm without gastroesophageal reflux, isosorbide dinitrate has been used to effectively relieve pain, dysphagia, and spasms.
Isosorbide dinitrate (used in combination with cardiac glycosides and diuretics or hydralazine) has been used to effectively treat congestive heart failure or other low cardiac output conditions.
…Isosorbide dinitrate has similar effects to other nitrates and nitrites. This drug is used for acute relief of angina, prevention of conditions that may trigger angina attacks, and long-term prevention of angina.
For more complete data on the therapeutic uses of isosorbide dinitrate (9 in total), please visit the HSDB record page.

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Drug Warnings
…Use with caution in patients with glaucoma.
Long-term use may lead to dependence and tolerance…These potential consequences, along with significant individual variability in clinical response, suggest that long-term use of high-dose isosorbide dinitrate requires extreme caution.
All organic nitrates can occasionally cause drug rashes…/organic nitrates/
The most common user complaints are headaches…and paradoxical exacerbations of angina.Mild gastrointestinal upset, as well as dizziness and other symptoms of orthostatic hypotension may occur.
For more complete data on isosorbide dinitrate (10 total), please visit the HSDB record page.

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Pharmacodynamics
Isosorbide dinitrate is a medium- to long-acting oral organic nitrate used to relieve and prevent angina. It relaxes vascular smooth muscle, thereby dilating peripheral arteries and veins, especially veins. Venous dilation promotes blood pooling in the periphery, reducing venous return, thereby lowering left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic blood pressure, and mean arterial pressure.

C6H8N2O8

236.13

236.028

87-33-2

Isosorbide dinitrate-13C6

6883

White to off-white solid powder

1.7±0.1 g/cm3

365.9±42.0 °C at 760 mmHg

700C

186.6±29.9 °C

0.0±0.8 mmHg at 25°C

1.538

0.9

0

8

2

16

268

4

C1[C@H]([C@@H]2[C@H](O1)[C@H](CO2)O[N+](=O)[O-])O[N+](=O)[O-]

MOYKHGMNXAOIAT-JGWLITMVSA-N

InChI=1S/C6H8N2O8/c9-7(10)15-3-1-13-6-4(16-8(11)12)2-14-5(3)6/h3-6H,1-2H2/t3-,4+,5-,6-/m1/s1

[(3S,3aS,6R,6aS)-3-nitrooxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] nitrate

NSC 80038; Disorlon; Isosorbide dinitrate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 250 mg/mL (~1058.69 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (8.81 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (8.81 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (8.81 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)