毒理性
isosorbide dinitrate 是一种血管扩张剂，抗心绞痛药物。isosorbide dinitrate 是一种精细的白色至象牙白色无味结晶固体。它在水中微溶；在丙酮、氯仿、酒精和醚中易溶。适应症：isosorbide dinitrate 主要用于治疗缺血性心脏病患者。它减少了心绞痛发作的次数、持续时间和严重程度。运动耐受性提高，硝酸甘油的需求量减少。它对所有形式的心绞痛都有效，（稳定劳累性心绞痛、混合型心绞痛、不稳定型心绞痛和血管痉挛性或变异性心绞痛）。它还用于急性心肌梗死的治疗，以控制缺血性疼痛、降低高血压，治疗肺水肿和充血性心力衰竭。它也用于治疗严重高血压。静脉输液可以用于精确控制血压。它用于全身麻醉时控制血压，此时精确控制血压很重要。它也可用于食管痉挛。人体暴露：主要风险和靶器官：血管扩张和低血压（及其伴随的并发症）是过量使用isosorbide dinitrate 的主要风险。心脏和血管是靶器官。可能出现高铁血红蛋白血症。临床效果概述：接触后几分钟到一小时内可能出现中毒特征。可能出现心动过速、低血压随后出现心动过缓和虚脱、剧烈头痛、头晕、不安、晕厥、抽搐和昏迷。可能出现的其他一些特征包括呕吐、腹泻、发绀和高铁血红蛋白血症。严重病例可能出现呼吸衰竭。临床诊断基于接触史和观察到的体征和症状：心动过速、低血压、剧烈头痛、面部潮红。禁忌症：对isosorbide dinitrate 过敏。预先存在的高铁血红蛋白血症。明显贫血、头部创伤或脑出血。进入途径：口服：口服进入和通过胃肠道的吸收是最常见的毒性途径。可以通过舌下吸收。皮肤：关于isosorbide dinitrate 乳膏的经验的初步报告是可用的。 parenteral：接受静脉isosorbide dinitrate 治疗的患者可能会发生中毒。吸收途径：口服：isosorbide dinitrate 可从口腔黏膜迅速吸收，作用时间短。口服给药后，它从胃肠道中被很好地吸收。由于其首次通过效应和血浆半衰期短，所以有缓释制剂。舌下给药在6分钟内可在血浆中产生最大药物浓度。皮肤：isosorbide dinitrate 也可以从软膏基质的皮肤吸收。isosorbide dinitrate 的生物利用度在口服或舌下给药后约为29%。暴露途径的分布：无数据。暴露途径的生物学半衰期：isosorbide dinitrate 的终末消除半衰期分别为54.7分钟、48.8分钟和47.7分钟，分别静脉注射、舌下和口服给药。代谢：isosorbide dinitrate 在人体的主要代谢途径是通过酶促脱硝化，然后形成葡萄糖苷酸。主要初始代谢物，isosorbide-2-mononitrate 和isosorbide-5-mononitrate 的半衰期较长（2-5小时），至少部分负责isosorbide dinitrate 的治疗效果。大量的药物可由于“首次通过”效应而被代谢。暴露途径的消除：大部分以isosorbide 葡萄糖苷酸的形式从尿液中排出。作用方式：毒代动力学：isosorbide dinitrate 在几乎所有血管床的血管平滑肌上具有扩张性质。硝酸盐扩张静脉、动脉，在较高浓度时扩张小动脉。治疗剂量下的有益效果和过量的效果归因于全身静脉和小动脉血管扩张的生理后果。心脏前负荷、全身血压和全身血管阻力均呈进行性下降。可能导致低血压、循环衰竭和休克的状态。在中毒或治疗期间，可能发生高铁血红蛋白血症。药代动力学：有机硝酸盐可以激活鸟苷酸环化酶，增加平滑肌和其他组织的鸟苷3', 5' -单磷酸（环磷酸鸟苷）的合成。形成反应性自由基一氧化氮（NO），它与鸟苷酸环化酶相互作用并激活它。相互作用：与其他心血管药物可能发生几种重要相互作用。在给予isosorbide dinitrate 和hydralazine 治疗慢性心力衰竭的患者中观察到严重的姿势性低血压。与β-肾上腺素能受体阻断剂合用时，舌下硝酸盐可能会出现过度头晕和晕厥。在接受输注利多卡因的患者中使用舌下硝酸盐后，有完全房室传导阻滞的报道。甚至可能发生心脏停搏。disopyramide、三环类抗抑郁药和具有抗胆碱能作用的其它药物可能会因引起口干而阻止舌下isosorbide dinitrate 片的溶解。isosorbide dinitrate 可拮抗乙酰胆碱、肾上腺素和组胺的作用。与酒精合用可能出现增强的低血压效应。主要不良
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 anesthesia when precise control of blood pressure is important. It may also be used in esophageal 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 anemia, 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 edema is also frequently seen. Transient hypoxaemia with precipitation of angina is seen occasionally. Transient cerebral ischemic 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. Methemoglobinemia 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. /Isosorbide dinitrate/
来源:Hazardous Substances Data Bank (HSDB)
