Diazoxide

Usage

Diazoxide is primarily prescribed for the management of hypoglycemia (low blood sugar) caused by hyperinsulinism (excess insulin). It’s particularly useful in cases involving inoperable islet cell adenoma or carcinoma, nesidioblastosis, or extrapancreatic malignancy. It’s also indicated for the treatment of hypertensive crises (severe high blood pressure), though it’s not a first-line agent in neonates.

Pharmacologically, diazoxide is classified as a potassium channel activator, a non-diuretic thiazide, a hyperglycemic agent, and a vasodilator.

Its mechanism of action involves opening potassium channels in pancreatic beta cells, smooth muscle, and other tissues. In the pancreas, this inhibits insulin release. In blood vessels, it leads to vasodilation and lowers blood pressure.

Alternate Names

Diazoxide is the generic name. Brand names include Proglycem and Eudemine.

How It Works

Pharmacodynamics: Diazoxide primarily acts by opening ATP-sensitive potassium (K_ATP) channels in pancreatic beta cells and vascular smooth muscle. This leads to membrane hyperpolarization, inhibiting insulin release and causing vasodilation, respectively. It also increases hepatic glucose production.

Pharmacokinetics: Diazoxide is well-absorbed orally. Peak plasma concentrations are reached within 1-6 hours. The plasma half-life ranges from 20-60 hours in adults and can be prolonged in patients with renal impairment. Diazoxide crosses the placental barrier and is excreted in breast milk. It is primarily metabolized in the liver and excreted through the kidneys.

Mode of Action: Diazoxide binds to the SUR1 subunit of K_ATP channels, causing them to open. This leads to an influx of potassium ions, hyperpolarizing the cell membrane and reducing excitability. In pancreatic beta cells, this prevents calcium influx and inhibits insulin release. In smooth muscle cells, it causes relaxation and vasodilation.

Elimination Pathways: Diazoxide is primarily metabolized in the liver and then excreted by the kidneys.

Dosage

Standard Dosage

Adults:

Initial: 3 mg/kg/day orally, divided into two or three equal doses every 8-12 hours.

Usual: 3-8 mg/kg/day. Higher doses may be needed in refractory hypoglycemia. Maximum: 15mg/kg/day

Children:

Initial: 3-5 mg/kg/day orally, divided into two or three equal doses every 8-12 hours.

Usual: 3-8 mg/kg/day.

Infants and Newborns: 8-15 mg/kg/day orally, divided into two or three equal doses every 8-12 hours. Initial dose can start at 10mg/kg/day divided every 8 hours.

Special Cases:

• Elderly Patients: Dose adjustments may be needed based on renal function.
• Patients with Renal Impairment: Reduce dose based on creatinine clearance.
• Patients with Hepatic Dysfunction: Caution advised. Monitor closely.
• Patients with Comorbid Conditions: Consider individual patient factors and adjust accordingly.

Clinical Use Cases

Dosage recommendations for these clinical settings are not explicitly defined in the reviewed medical literature. However, diazoxide is not typically used in settings like intubation, surgical procedures, mechanical ventilation, or routine ICU use. Its primary indication remains the management of hypoglycemia secondary to hyperinsulinism. It can be used in emergency situations like hypertensive crises, but its usage in that context has become less frequent due to the availability of alternative agents with better safety profiles.

Dosage Adjustments

Adjustments are based on patient response, blood glucose levels, and renal/hepatic function.

Side Effects

Common Side Effects:

Nausea, vomiting, loss of appetite, abdominal pain, diarrhea, taste changes, headache, dizziness, anxiety, weakness, hirsutism (excessive hair growth), itching, skin rash.

Rare but Serious Side Effects:

Fluid retention (edema), heart failure, hyperglycemia, ketoacidosis, thrombocytopenia, leukopenia, hypotension, allergic reactions.

Long-Term Effects:

Sodium and water retention, hyperglycemia, hyperuricemia, gout, impaired renal function.

Adverse Drug Reactions (ADR):

Fluid retention, congestive heart failure, hyperglycemia, ketoacidosis, severe hypotension.

Contraindications

• Hypersensitivity to diazoxide, thiazides, or sulfonamides.
• Functional hypoglycemia.
• Compensatory hypertension with aortic coarctation or AV shunt.

Drug Interactions

Diazoxide can interact with:

• Antihypertensives: May enhance hypotensive effects.
• Warfarin: Increased risk of bleeding.
• Phenytoin: Altered metabolism of both drugs.
• Thiazide diuretics: Potentiated hyperglycemia and hyperuricemia.
• Other medications: Numerous potential interactions (see DrugBank for a complete list).
• Alcohol: May enhance hypotensive effects.

Pregnancy and Breastfeeding

Diazoxide can cross the placenta and is excreted in breast milk. Use during pregnancy is generally not recommended unless the benefits clearly outweigh the risks. Use during breastfeeding should be approached with caution and requires careful monitoring of the infant.

Drug Profile Summary

• Mechanism of Action: Activates K_ATP channels, inhibiting insulin release and causing vasodilation.
• Side Effects: Nausea, vomiting, hirsutism, fluid retention, hyperglycemia, hypotension.
• Contraindications: Hypersensitivity, functional hypoglycemia.
• Drug Interactions: Antihypertensives, warfarin, phenytoin, thiazides.
• Pregnancy & Breastfeeding: Use with caution; monitor closely.
• Dosage: 3-8 mg/kg/day (adults and children), 8-15 mg/kg/day (infants).
• Monitoring Parameters: Blood glucose, blood pressure, renal function, fluid balance.

Popular Combinations

Diazoxide is sometimes used in combination with thiazide diuretics to mitigate fluid retention.

Precautions

Assess for allergies, cardiac function, renal function, hepatic function, and gout. Exercise caution in patients with diabetes, cardiovascular disease, or compromised renal/hepatic function. Monitor blood glucose and electrolytes.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Diazoxide?

A: Adults and children: 3-8 mg/kg/day divided every 8-12 hours. Infants and newborns: 8-15 mg/kg/day divided every 8-12 hours.

Q2: How does diazoxide work in hypoglycemia?

A: It inhibits insulin release from the pancreas by opening K_ATP channels in pancreatic beta cells.

Q3: What are the common side effects of diazoxide?

A: Nausea, vomiting, hirsutism, fluid retention, and hyperglycemia.

Q4: Is diazoxide safe during pregnancy?

A: Use with caution; only if the benefits clearly outweigh the risks. Consult a specialist.

Q5: Can diazoxide be used in patients with renal impairment?

A: Yes, but with dose reduction based on creatinine clearance.

Q6: What are the major drug interactions with diazoxide?

A: Antihypertensives, warfarin, phenytoin, and thiazide diuretics.

Q7: How should diazoxide be administered?

A: Orally, divided into two or three equal doses.

Q8: What is the role of diazoxide in hypertensive crisis?

A: It acts as a vasodilator, but alternative agents are often preferred due to a more favourable safety profile.

Q9: How is diazoxide metabolized and eliminated?

A: Metabolized in the liver and excreted primarily by the kidneys.

Q10: What monitoring parameters are essential for patients on diazoxide?

A: Blood glucose, blood pressure, renal function tests, fluid balance, and complete blood count (CBC) with differential to monitor for myelosuppression.