硝酸イソソルビド

· CALL 911. Then call emergency response telephone number on shipping paper. If shipping paper not available or no answer, refer to appropriate telephone number listed on the inside back cover.

· ELIMINATE all ignition sources (no smoking, flares, sparks or flames) from immediate area.

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.

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.

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.

/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.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Isosorbide dinitrate

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ No evidence of carcinogenicity was observed in rats exposed to isosorbide mononitrate in their diets at doses of up to 900 mg/kg/day for the first 6 months and 500 mg/kg/day for the remaining duration of a study in which males were dosed for up to 121 wks and females were dosed for up to 137 wks. /Isosorbide mononitrate/

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Studies in rabbits given isosorbide dinitrate in oral doses of 35 and 150 times the maximum daily recommended human dose have shown a dose-related increase in embryotoxicity.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In a modified 2-litter reproduction study, there was no remarkable gross pathology and no altered fertility or gestation among rats fed isosorbide dinitrate at 25 or 100 mg/kg/day.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No effects on fertility were observed in a study in which male and female rats were administered doses of up to 750 mg/kg/day beginning, in males, 9 wks prior to mating, and in females, 2 wks prior to mating. /Isosorbide mononitrate/

For more Non-Human Toxicity Excerpts (Complete) data for ISOSORBIDE DINITRATE (7 total), please visit the HSDB record page.

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/

Isosorbide dinitrate

0.5

2.0

The usual starting dose of isosorbide dinitrate is 5 mg to 20 mg, two or three times daily. For maintenance therapy, 10 mg to 40 mg, two or three times daily is recommended.

Data used to generate the benchmarks include the following: Lowest Daily Dose (LDD): 20 mg/day, Lowest Therapeutic Dose (LTD): 0.3 mg/kg-day, and Screening Dose: 0.00008 mg/kg-day.

20-Aug-21

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.

MEDICATION

Use (kg; approx.) in Germany (2009): >5000

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).