Introduction
Diazoxide is a benzothiadiazine derivative that functions as a potent antihypertensive agent and hyperglycemic medication. Originally developed as an antihypertensive, it gained significant clinical importance for its ability to inhibit insulin release, making it valuable in managing hypoglycemic conditions. Unlike thiazide diuretics, diazoxide promotes sodium retention while producing vasodilation and hyperglycemia.
Mechanism of Action
Diazoxide exerts dual pharmacological effects through distinct mechanisms:
Vasodilatory effect: Directly relaxes arteriolar smooth muscle by activating ATP-sensitive potassium channels, leading to hyperpolarization and reduced calcium influx, resulting in peripheral vasodilation and decreased blood pressure. Hyperglycemic effect: Inhibits insulin secretion from pancreatic beta cells by opening ATP-sensitive potassium channels, which prevents calcium influx and subsequent insulin release. This action increases blood glucose levels by reducing insulin-mediated glucose uptake.Indications
FDA-approved indications:- Management of hypoglycemia due to hyperinsulinism associated with:
- Islet cell adenoma or carcinoma - Extrapancreatic malignancy - Nesidioblastosis - Leucine sensitivity - Post-gastric surgery hypoglycemia
- Emergency treatment of hypertensive crises (parenteral formulation)
- Hypoglycemia management in persistent hyperinsulinemic hypoglycemia of infancy
- Investigation of growth hormone secretion
Dosage and Administration
Oral administration (for hypoglycemia):- Adults: 3-8 mg/kg/day in 2-3 divided doses
- Children: 3-8 mg/kg/day in 2-3 divided doses
- Maximum dose: 15 mg/kg/day
- Adults: 1-3 mg/kg by rapid IV injection (within 30 seconds)
- Repeat dose every 5-15 minutes as needed
- Maximum single dose: 150 mg
- Maximum cumulative dose: 600 mg
- Renal impairment: Use with caution; dose adjustment may be necessary
- Hepatic impairment: Use with caution; monitor closely
- Elderly: Start at lower end of dosing range
Pharmacokinetics
Absorption: Oral bioavailability is approximately 90%; rapidly absorbed with onset of action within 1 hour Distribution: Widely distributed throughout body tissues; 90-95% protein-bound Metabolism: Primarily hepatic via CYP-mediated oxidation and glucuronidation Elimination: Half-life of 20-36 hours; primarily renal excretion (50%) with some fecal elimination Onset/Duration:- Antihypertensive effect: Immediate onset (IV), duration 3-12 hours
- Hyperglycemic effect: Within 1 hour (oral), duration 8 hours
Contraindications
- Hypersensitivity to diazoxide or other sulfonamide-derived drugs
- Compensatory hypertension (e.g., coarctation of the aorta, arteriovenous shunt)
- Dissecting aortic aneurysm
- Pheochromocytoma
- Pregnancy (except when potential benefit justifies potential risk)
- Breastfeeding
Warnings and Precautions
Black Box Warning:- May cause sodium and water retention, potentially leading to congestive heart failure
- May produce severe hypotension, especially in patients receiving other antihypertensive agents
- Use with extreme caution in patients with:
- Coronary artery disease - Congestive heart failure - Impaired renal function - Impaired hepatic function
- May cause hyperglycemia; monitor blood glucose regularly
- Risk of hyperuricemia and gout
- Extravasation may cause tissue irritation and necrosis
- May cause fetal harm; use during pregnancy only if clearly needed
Drug Interactions
Significant interactions:- Antihypertensive agents: Enhanced hypotensive effect
- Diuretics: May counteract sodium-retaining effects
- Oral hypoglycemics/insulin: Antagonizes glucose-lowering effects
- Phenytoin: May displace from protein binding sites
- Warfarin: May be displaced from protein binding sites
- NSAIDs: May reduce antihypertensive effectiveness
Adverse Effects
Common effects (≥10%):- Sodium and fluid retention (30-50%)
- Hyperglycemia (20-40%)
- Nausea, vomiting (15-25%)
- Hypotension (10-20%)
- Congestive heart failure (2-5%)
- Myocardial ischemia/angina (1-3%)
- Cerebral ischemia (1-2%)
- Severe hypersensitivity reactions (<1%)
- Thrombocytopenia (<1%)
- Extravasation injury (IV administration)
- Hyperuricemia (5-10%)
- Headache (5-10%)
- Diaphoresis (5-10%)
- Transient leukopenia (<5%)
Monitoring Parameters
Essential monitoring:- Blood pressure (frequent during IV administration)
- Blood glucose levels (regularly during therapy)
- Body weight and fluid status
- Serum electrolytes (particularly sodium)
- Renal function (BUN, creatinine)
- Liver function tests
- Complete blood count
- Uric acid levels
- For hypoglycemia: Maintain blood glucose >60 mg/dL
- For hypertension: Target appropriate blood pressure reduction
Patient Education
Key points for patients:- Take medication exactly as prescribed; do not stop abruptly
- Regular blood glucose monitoring is essential
- Report any signs of fluid retention (swelling, weight gain)
- Monitor for symptoms of hypotension (dizziness, lightheadedness)
- Maintain regular follow-up appointments
- Inform all healthcare providers about diazoxide use
- Report any new or worsening symptoms promptly
- Maintain consistent meal timing
- Be aware of potential hyperglycemic effects
- Monitor salt intake due to sodium retention risk
- Severe dizziness or fainting
- Chest pain or shortness of breath
- Significant swelling or weight gain
- Severe nausea or vomiting
- Signs of infection (fever, chills)
References
1. American Diabetes Association. (2021). Standards of Medical Care in Diabetes. Diabetes Care, 44(Supplement 1). 2. Brunton, L. L., Hilal-Dandan, R., & Knollmann, B. C. (2018). Goodman & Gilman's: The Pharmacological Basis of Therapeutics (13th ed.). McGraw-Hill. 3. Lexicomp Online. (2023). Diazoxide: Drug Information. Wolters Kluwer. 4. Micromedex Solutions. (2023). Diazoxide Drug Information. IBM Watson Health. 5. National Institute of Diabetes and Digestive and Kidney Diseases. (2021). Hyperinsulinism. NIH Publication. 6. UpToDate. (2023). Diazoxide: Drug Information. Wolters Kluwer. 7. FDA Prescribing Information for Diazoxide (Proglycem). (2022). 8. Thornton, P. S., et al. (2015). Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. Journal of Pediatrics, 167(2), 238-245.
Note: This monograph provides general information and should not replace professional medical advice. Always consult with a qualified healthcare provider for personalized medical guidance.