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
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%.
2 to 4 L/kg
After sublingual admin, onset of effect is 2-3 min & offset of effect is about 2 hr.
Following sublingual doses of 5 mg, oral conventional tablets of 5 mg, and oral sustained-release tablets of 20 mg, mean peak isosorbide dinitrate levels of 8.9, 3.1, and 1.4 ng/ml, occurred at 30, 40, and 40 min respectively. Plasma levels...after sustained-release dosage...maintained above half of mean peak level for 10 hours.
Chronic oral administration of isosorbide dinitrate (120 to 720 mg daily) has resulted in persistence of parent compound and higher concentration of metabolite in plasma.
Since denitration markedly reduces activity of organic nitrates, their rapid clearance from blood indicates that transient duration of action under these conditions correlates with concentration of parent compounds. /organic nitrates/
For more Absorption, Distribution and Excretion (Complete) data for ISOSORBIDE DINITRATE (13 total), please visit the HSDB record page.

---

Metabolism / Metabolites
Hepatic
After intravenous or oral admin, primary metabolite in plasma is 5-isosorbide mononitrate.
Major route of metabolism of isosorbide dinitrate in man is also by enzymatic denitration followed by formation of glucuronides.
Biotransformation of organic nitrates is result of reductive hydrolysis catalyzed by hepatic enzyme glutathione-organic nitrate reductase. Enzyme converts lipid-soluble organic nitrate esters into more water-soluble denitrated metabolites & inorganic nitrite. /organic nitrates/
...Biotransformation of isosorbide dinitrate in dogs and in man caused de-esterification. Isosorbide is major urinary metabolite, together with very small amount of the 2- and 5-mononitrates. /isosorbide dinitrate/ was absent from urine of dogs & man.
For more Metabolism/Metabolites (Complete) data for ISOSORBIDE DINITRATE (8 total), please visit the HSDB record page.

---

Biological Half-Life
1 hour
Half-life 0.7 hours (0.6-2.0; clearance may be decreased and half-life prolonged after chronic dosing.) /from table/
The mean plasma elimination half-life of ISMN is approx 5 hr. /Isosorbide mononitrate/
After sublingual admin... biological half-life is about 8 hr... .
Biological half-life is about 8 hr; after oral admin, onset is about 30 min & offset 4-6 hr.

Toxicity Summary
IDENTIFICATION: Isosorbide dinitrate is a vasodilator, anti-anginal drug. Isosorbide dinitrate is a fine white to ivory-white odorless crystalline solid. It is sparingly soluble in water; freely soluble in acetone, chloroform, alcohol and ether. Indications: Isosorbide dinitrate is used principally in the management of patients with ischemic heart disease. It reduces the number, duration and severity of episodes of angina pectoris. Exercise tolerance is increased and the requirements for nitroglycerin are reduced. It is effective in all forms of angina, (stable effort angina, mixed angina, unstable angina and vasospastic or variant angina). It is used in acute myocardial infarction in control of ischemic pain, reduction of elevated blood pressure and in the treatment of pulmonary edema and congestive cardiac failure. It is also useful in the treatment of severe hypertension. The iv infusion can be used for precise control of blood pressure. It is used to control blood pressure during general anaesthesia when precise control of blood pressure is important. It may also be used in oesophageal spasm. HUMAN EXPOSURE: Main risks and target organs: Vasodilatation and hypotension (with their accompanying complications) are the main risks with overdose of isosorbide dinitrate. Heart and blood vessels are the target organs. Methemoglobinemia can occur. Summary of clinical effects: Features of poisoning may appear within few minutes to one hour or more after exposure. Tachycardia, hypotension followed by bradycardia and collapse, throbbing headache, dizziness, restlessness, syncope, convulsions and coma could occur. Some of the other features that can be seen include vomiting, diarrhea, cyanosis and methemoglobinemia. Respiratory failure may occur in severe cases. Clinical diagnosis is based on the history of exposure, and signs and symptoms observed: tachycardia, hypotension, throbbing headache, flushing of the face. Contraindications: Hypersensitivity to isosorbide dinitrate. Pre-existing methemoglobinemia. Marked anaemia, head trauma or cerebral hemorrhage. Routes of entry: Oral: Oral entry and absorption through gastro-intestinal tract is the most frequent route of intoxication. Absorption can occur sublingually. Dermal: A preliminary report of experience with isosorbide dinitrate cream is available. Parenteral: Intoxication may occur in patients treated with intravenous isosorbide dinitrate. Absorption by route of exposure: Oral: Isosorbide dinitrate is readily absorbed from the oral mucosa and has a short duration of action. Following oral administration it is well absorbed from the gastrointestinal tract. In view of its first pass effect and short plasma half life, slow release formulations are available. Sublingual administration produces maximal concentration of the drug in plasma within 6 minutes. Dermal: Isosorbide dinitrate is also absorbed through the skin from an ointment base. The bioavailability of isosorbide dinitrate is about 29% following oral or sublingual dosing. Distribution by route of exposure: No data available. Biological half-life by route of exposure: The terminal elimination half-life of isosorbide dinitrate is 54.7 minutes, 48.8 minutes and 47.7 minutes respectively following IV injection, sublingual and oral administration. Metabolism: The major route of metabolism of isosorbide dinitrate in man is by enzymatic denitration followed by formation of glucuronides. The primary initial metabolites, isosorbide-2-mononitrate and isosorbide-5-mononitrate have longer half-lives (2-5 hours) and are presumed to be responsible, at least in part, for the therapeutic efficacy of isosorbide dinitrate. A substantial amount of drug can be metabolized due to the "first pass" effect. Elimination by route of exposure: Largely excreted in urine as isosorbide glucuronide. Mode of action: Toxicodynamics: Isosorbide dinitrate has dilator properties on vascular smooth muscle in virtually all vascular beds. Nitrates dilate veins, arteries, and, in high concentrations, arterioles. The beneficial effects in therapeutic doses and the effects seen with overdose are attributable to the physiologic consequences of systemic venous and arteriolar vasodilation. Cardiac preload, systemic blood pressure and systemic vascular resistance all show a progressive decrease. A state of hypotension, circulatory collapse and shock may result. Methemoglobinemia may occur following overdose of isosorbide dinitrate or during therapy. Pharmacodynamics: Organic nitrates can activate guanylate cyclase and increase the synthesis of guanosine 3', 5' - monophosphate (cyclic GMP) in smooth muscle and other tissues. The reactive free radical nitric oxide (NO) is formed which interacts with and activates guanylate cyclase. Interactions: Several important interactions may occur with other cardiovascular drugs. Severe postural hypotension has been observed in patients given isosorbide dinitrate and hydralazine for chronic cardiac failure.Undue dizziness and faintness may occur with sublingual nitrates and beta-adrenoceptor blocking drugs. Complete AV block has been reported after use of sublingual nitrates in patients receiving lignocaine by infusion. Even cardiac asystole may occur. Disopyramide, tricyclic antidepressants and other drugs with anticholinergic effects may prevent dissolution of sublingual isosorbide dinitrate tablets by causing dry mouth. The effects of acetylcholine, epinephrine and histamine can be antagonized by isosorbide dinitrate. An enhanced hypotensive effect may be seen with alcohol. Main adverse effects: The toxic effects of the nitrates are unaffected by the chemical form or by the route of administration and all the nitrates have a common profile of adverse effects. Hypotension, reflex tachycardia and palpitations may occur. Postural hypotension and syncope are seen, especially in elderly patients. Rarely severe bradycardia has been reported. Throbbing headache is quite common. This symptom is likely to recede as tolerance develops. Peripheral oedema is also frequently seen. Transient hypoxaemia with precipitation of angina is seen occasionally. Transient cerebral ischaemic episodes unrelated to changes in blood pressure are rarely seen. It is therefore advisable to initiate treatment with small doses in patients with cerebrovascular disease. Methaemoglobinaemia may be seen after therapeutic doses. Weakness, transient dizziness, restlessness and collapse may occur. Cutaneous flushing, perspiration and exfoliative dermatitis have all been reported. Nausea and vomiting are not frequent. Although tolerance has long been associated with nitrates, its clinical implications are not clear. Tolerance is best defined as a decreasing pharmacological effect over time, often with a need for an increasing dose to achieve a given action. Tolerance may be partial or complete and may occur with one type of nitrate therapy and not with others; disappearance of the throbbing headache is a useful sign. However, due to an attenuation of the antihypertensive effect, these agents are not useful in the long term management of hypertension. The part played by the arterial and venous sides of the circulation pertaining to the development of tolerance is not clear. By providing a long (approximately 8 hours) nitrate-free interval, the development of tolerance may be avoided or reduced. Decreasing the number of daily doses of isosorbide dinitrate also helps to achieve this effect. Sustained release preparations are more likely to produce tolerance than the short acting preparations.

---

Protein Binding
Very low

---

Interactions
This reaction /postural hypotension/ appears to be accentuated by alcohol. /organic nitrates/
A lower dose of isosorbide dinitrate may be required when given concurrently with propranolol.
Sildenafil /Viagra/ can potentiate the hypotensive effects of nitrates and its use in patients who are concurrently using nitrates in any form is contraindicated; deaths have been reported with concurrent use. /nitrates/
Concurrent use /of sympathomimetics/ may reduce the antianginal effects of nitrates. Nitrates may counteract the pressor effect of sympathomimetics, possibly resulting in hypotension. /nitrates/
Norepinephrine turnover rates in the rat heart were decreased by 3 antianginal agents, particularly isosorbide dinitrate (5 mg, oral) and propranolol.

[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 and a glucitol derivative. It has a role as a vasodilator agent and a nitric oxide donor.
A vasodilator used in the treatment of angina pectoris. Its actions are similar to nitroglycerin but with a slower onset of action.
Isosorbide dinitrate is a Nitrate Vasodilator. The physiologic effect of isosorbide dinitrate is by means of Vasodilation.
Isosorbide Dinitrate is the dinitrate salt form of isosorbide, an organic nitrate with vasodilator activity. Isosorbide dinitrate relaxes vascular smooth muscle by formation of the free radical nitric oxide (NO), which is identical to the endothelium-derived relaxing factor (EDRF). NO activates guanylyl cyclase, thereby increasing the synthesis of cGMP within smooth muscle, resulting in dephosphorylation of light chain myosin and relaxation of peripheral arteries and veins. In addition, isosorbide dinitrate relaxes coronary arteries, thereby increasing the blood circulation through the ischemic area. (NCI05)
A vasodilator used in the treatment of ANGINA PECTORIS. Its actions are similar to NITROGLYCERIN but with a slower onset of action.
See also: Isosorbide (has active moiety); Hydralazine hydrochloride; Isosorbide dinitrate (component of).

---

Drug Indication
For the prevention of angina pectoris due to coronary artery disease.

---

Mechanism of Action
Isosorbide dinitrate is converted to the active nitric oxide to activate guanylate cyclase. This activation increases levels of cyclic guanosine 3',5'-monophosphate (cGMP). cGMP activates protein kinases and causes a series of phosphorylation reactions which leads to dephosphorylation of myosin light chains of smooth muscle fibres. Finally there is a release of calcium ions which causes smooth muscle relaxation and vasodilation.
...Nitrates...are capable of activating guanylate cyclase and causing marked increase in concentration of cyclic guanosine 3',5'-monophosphate (cyclic GMP) in most tissues. This effect is apparently due to action of nitric oxide...nitric acid probably activates the enzyme directly. /organic nitrates/
Isosorbide dinitrate inhibited platelet aggregation with collagen, epinephrine, arachidonate, and ionophore, and blocked both primary and secondary aggregation in response to ADP.

---

Therapeutic Uses
Vasodilator Agents
In a limited number of patients with diffuse esophageal spasm without gastroesophageal reflux, isosorbide dinitrate has been used effectively to relieve pain, dysphagia and spasm.
Isosorbide dinitrate (in combination with cardiac glycosides and diuretics or with hydralazine) has been used effectively for the treatment of congestive heart failure or other low cardiac output states.
...Isosorbide dinitrate shares the actions of the other nitrates and nitrites. The drug is used for the acute relief of angina pectoris, for prophylactic management in situations likely to provoke angina attacks, and for long term prophylactic management of angina pectoris.
For more Therapeutic Uses (Complete) data for ISOSORBIDE DINITRATE (9 total), please visit the HSDB record page.

---

Drug Warnings
...Should be given cautiously in pt with glaucoma.
Dependence and tolerance may occur during chronic use... These possible consequences, as well as large individual variations in clinical response indicates that long-term therapy with high-dose isosorbide dinitrate requires considerable caution.
Drug rash is occasionally produced by all organic nitrates... /organic nitrates/
Most frequent complaint by users...is headache ... also paradoxical increase in anginal pain. Mild gastrointestinal disturbances as well as vertigo and other signs of orthostatic hypotension may occur.
For more Drug Warnings (Complete) data for ISOSORBIDE DINITRATE (10 total), please visit the HSDB record page.

---

Pharmacodynamics
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.

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.

---

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.

---

View More

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.

---

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