Diazoxide toxicity

Silvani P, Camporesi A, Mandelli A, Wolfler A, and Salvo I (2004) A case of severe diazoxide toxicity. Paediatric Anaesthesia 14(7) 607-609. 

Since diazoxide is not often used for long-term treatment, toxicities associated with chronic use are rare. The chief concern is the side effects associated with the increased workload on the heart, which may precipitate myocardial ischemia and Na+ and water retention. These undesirable effects can be controlled by concurrent therapy with a (3-blocker and a diuretic. 

The most significant toxicity from diazoxide has been excessive hypotension, resulting from the recommendation to use a fixed dose of 300 mg in all patients. Such hypotension has resulted in stroke and myocardial infarction. The reflex sympathetic response can provoke angina, electrocardiographic evidence of ischemia, and cardiac failure in patients with ischemic heart disease, and diazoxide should be avoided in this situation. 

Diazoxide [dye az OX ide] is a direct-acting arteriolar vasodilator. It has vascular effects like those of hydralazine. For patients with coronary insufficiency, diazoxide is administered intravenously with a p-blocker, which diminishes reflex activation of the heart. Diazoxide is useful in the treatment of hypertensive emergencies, hypertensive encephalopathy, and eclampsia. Excessive hypotension is the most serious toxicity. 

Disulfiram-like reaction with ritonavir, tipranavir, diazoxide Increases levels and toxicity of tacrolimus, cyclosporine, lithium, and phenytoin... 

C. Nitroprusside and Diazoxide These parenteral vasodilators are used in hypertensive emergencies. Nitroprusside is a short-acting agent (duration of action is a few minutes) that must be infused continuously. The drug s mechanism of action involves the release of nitric oxide (from the molecule itself, not from the endothelium), which stimulates guanylyl cyclase and increases cGMP concentration in smooth muscle. The toxicity of nitroprusside includes excessive hypotension, tachycardia, and, if infusion is continued over several days, cumulation of cyanide or thiocyanate ions in the blood. 

Diazoxide is given as intravenous boluses and has a duration of action of several hours. Diazoxide opens potassium channels, thus hyperpolarizing and relaxing smooth muscle cells. This drug also reduces insulin release and can be used to treat hypoglycemia caused by insulin-producing tumors. The toxicity of diazoxide includes hypotension, hyperglycemia, and salt and water retention. 

Three hours after receiving intravenous cisplatin 70 mg/m a patient experienced severe nausea and vomiting and his blood pressure rose from 150/90 to 248/140 mmHg. This was managed with furosemide 40 mg intravenously, hydralazine 10 mg intramuscularly, diazoxide 300 mg intravenously and propranolol 20 mg orally twice daily for 2 days. Nine days later the patient showed evidence of renal impairment (creatinine raised from about 88 micromol/L to 283 micromol/L), which resolved within 3 weeks. The patient was subsequently similarly treated on two occasions with cisplatin and again developed hypertension, but no treatment was given and there was no evidence of renal impairment. The reasons for the renal impairment are not known, but a study in rats indicate that kidney damage may possibly be related to the concentrations of cisplatin, and that furosemide can increase cisplatin levels in the kidney. However, another study in patients found that there was no difference in the toxicity or pharmacokinetics of cisplatin when furosemide was used to induce diuresis, compared with mannitol. Two other studies have also found that furosemide does not alter cisplatin pharmacokinetics. Another study showed that sodium chloride solution with or without furosemide was associated with less cisplatin nephrotoxicity than sodium chloride solution with mannitol. ... 

Smalley, H.E., and R.D. Radeleff. 1971. Enhancement of insecticide toxicity by antidiuretic agent, diazoxide. American Journal of Veterinary Research 32 345. 

Peripheral Vasodilators and Other AntihypertensIves - L-6150 (XXXl), which has hydralazine-like activity with less toxicity, shows no lupus erythema-tosus-llke syndrome in Collie dog studiesA group of 3-amlno-4-halosydnone imines related to PR-G-138 (XXXII) show comparable oral activity to the parent compound in hypertensive rats (ca. 10 mg/kg). - Diazoxide analogs with the benzene ring replaced by thiophene, e.g. 

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