Isosorbide dinitrate

236.14

236.14

201-740-9

IA7306519N

757080|80038

DTXSID0045832

C29134

Hard, colorless crystals|DILUTED: IVORY-WHITE, POWDER; UNDILUTED: WHITE, CRYSTALLINE ROSETTES

C01DA08|C - Cardiovascular system

2932999000

129

1.3

Solid

1.7503 (rough estimate)

70 °C

378.59°C (rough estimate)

186.6ºC

1.537

549.7mg/L(25 ºC)

-20°C Freezer

Oral-rat LD50: 747 mg/kg; Oral-Mouse LD50: 1050 mg/kg

In case of heat, the flame is combustible; thermal decomposition emits toxic nitrogen oxide fumes

D20 +135° (alc)

ODORLESS

151.6 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

II

1.1A

UN 2907

5-22

36

Xn

Low temperature, ventilated and dry warehouse; fire prevention; stored separately from oxidant

loss of potentcy is accelerated by exposure to heat and moisture.

P201, P202, P260, P264, P270, P281, P301+P312, P307+P311, P308+P313, P321, P330, P405, P501

H302

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Exptl studies were carried out on pure isosorbide dinitrate and its mixture with lactose to investigate thermal stability, impact and friction sensitivities, and sensitivity to initiation to detonation by std no. 6 and no. 8 strength detonators; compounds had low hazard potential.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl isosorbide dinitrate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.|Drug preparations intended for human use containing certain "coronary vasodilators". The Food and Drug Administraton finds that the following "coronary vasodilators" are extensively regarded by physicians as safe and useful as employed under medical supervision for the management of angina pectoris in some patients. Isosorbide dinitrate is included on this list.

SILVIERI LA, DEANGELIS NJ; ANAL PROFILES DRUG SUBST 4 225 (1975). REVIEW WITH 48 REFERENCES ON ISOSORBIDE DINITRATE, ITS DESCRIPTION, PROPERTIES, SYNTHESIS, STABILITY AND DEGRADATION, METABOLISM, IDENTIFICATION, AND ANALYSIS.

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 44 companies from 5 notifications to the ECHA C&L Inventory.|Danger|H302: Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P264, P270, P281, P301+P312, P307+P311, P308+P313, P321, P330, P405, and P501

moderately toxic

Symptoms of overdose include reduced cardiac output and hypotension.|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.

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.

Very low

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

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.

...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.

...Chronic oral use of isosorbide dinitrate (120 mg/day) led to development of partial tolerance to hemodynamic effects of drug and to cross-tolerance to venodilatation produced by sublingual nitroglycerin.

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.

A diverse group of agents, with unique chemical structures and biochemical requirements, which generate NITRIC OXIDE. These compounds have been used in the treatment of cardiovascular diseases and the management of acute myocardial infarction, acute and chronic congestive heart failure, and surgical control of blood pressure. (Adv Pharmacol 1995;34:361-81) (See all compounds classified as Nitric Oxide Donors.)|Drugs used to cause dilation of the blood vessels. (See all compounds classified as Vasodilator Agents.)

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.

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.

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.

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.

Emergency and supportive measures: Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat hypotension with supine positioning. Intravenous crystalloid fluids, and low-dose pressors if needed. Monitor vital signs and ECG for 4-6 hours. /Nitrates and nitrites/|Specific drugs and antidotes: Symptomatic methemoglobinemia may be treated with methylene blue. /Nitrates and nitrites/|Decontamination: Inhalation: Remove victims from exposure and administer supplemental oxygen if available. Skin and eyes: Remove contaminated clothing and wash with copious soap and water. Irrigate exposed eyes with water or saline. Ingestion: Prehospital: Administer activated charcoal if available. Hospital: Administer activated charcoal. Gastric emptying is not necessary for small ingestions if activated charcoal can be given promptly. /Nitrates and nitrites/|Enhanced elimination: Hemodialysis and hemoperfusion are not effective. Severe methemoglobinemia in infants not responsive to methylene blue therapy may require exchange transfusion. /Nitrates and nitrites/

/HUMAN EXPOSURE STUDIES/ The effect of isosorbide dinitrate (ISDN) on maternal and fetal circulation was assessed in 23 women with pregnancy induced hypertension (PIH). A double-blind randomized design was employed. Each woman was given a sublingual tablet of ISDN (5 mg) or placebo. Maternal blood pressure (BP) and heart rate (HR) were measured before and every 2 min after the medication or placebo, for a total of 20 min. Flow velocity waveforms in the uterine and umbilical arteries were recorded at the same time periods, using pulsed Doppler ultrasound. The ratio of peak systolic to end-diastolic flow velocity (S/D) in those vessels was calculated. After ISDN mean maternal BP fell from 103 +/- 1.8 mm Hg to 90.5 +/- 2.9 mm Hg at 14 min (P<0.0001) and mean maternal HR increased from 97.3 +/- 3.8 beats/min to 115.7 +/- 3.5 beats/min at 12 min (P<0.0001). The mean S/D in the umbilical artery fell from 3.07 +/- 0.33 to 2.58 +/- 0.23 at 8 min (P<0.0007). The mean S/D in the uterine artery fell from 3.27 +/- 0.6 to 2.38 +/- 0.28 at 10 min (P <0.0001). In 7 of 12 women with an early diastolic notch in the uterine artery flow velocity waveform the notch diminished or disappeared within the first 6 min after the medication. No significant change in any of the measured parameters was observed in the placebo group. ...|/HUMAN EXPOSURE STUDIES/ 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/|/HUMAN EXPOSURE STUDIES/ The ill effects of isosorbide dinitrate overdose are generally the results of isosorbide dinitrate'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.

Cardonit 40

SUBLINGUAL TABLETS: 2.5, 5 MG; CHEWABLE ORAL TABLETS: 5, 10 MG; ORAL TABLETS: 5, 10, 20 MG; TIME-RELEASE TABLETS: 40 MG. /FROM TABLE/|Sorbitrate 5, 10, 20, 40 mg tablets|Isordil titradose 5, 10, 20, 30, 40 mg tablets|Dilatrate-SR 40 mg capsules, extended release|Trade Names: Isoket (Pharma-Schwarz, Iso Mack (Mack), Isordril (Wyeth), Sorbitrate (Stuart).

D-Glucitol, 1,4:3,6-dianhydro-, 2,5-dinitrate: ACTIVE

GLC method for determining isosorbide dinitrate in tablets is described.|Method is applicable to single tablet assay for content uniformity determination.

An electron capture GLC method for determining isosorbide dinitrate and two mononitrates in plasma is given.|Title compounds measured in plasma by GLC. Lower limit for detection was 20 ng/mL.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients