DIAZOXIDE, ORAL
Chemistry - Related structurally to the thiazide diuretics, diazoxide occurs as an odorless, white tocreamy-white, crystalline powder with a melting point of about 330°. It is practically insoluble tosparingly soluble in water and slightly soluble in alcohol.
Diazoxide also exhibits hyperglycemic activity by directly inhibiting pancreatic insulin secretion.
This action may be a result of the drug's capability to decrease the intracellular release of ionizedcalcium, thereby preventing the release of insulin from the insulin granules. Diazoxide does notapparently affect the synthesis of insulin, nor does it possess any antineoplastic activity. Diazoxidealso enhances hyperglycemia by stimulating the beta-adrenergic system, thereby stimulatingepinephrine release and inhibiting the uptake of glucose by cells.
Uses, Indications - Oral diazoxide is used in canine medicine for the treatment of hypoglycemiasecondary to hyperinsulin secretion (e.g., insulinoma). Insulinomas are apparently very rare in thecat, and there is little experience with this drug in that species.
Approximately 90% of the drug is bound to plasma proteins and it crosses the placenta and into the
CNS. It is not known if diazoxideis distributed into milk. Diazoxide is partially metabolized in theliver and is excreted as both metabolites and unchanged drug by the kidneys. Serum half-life of thedrug is prolonged in patients with renal impairment.
Contraindications/Precautions - Diazoxide should not be used in patients with functional hypoglycemia or for treating hypoglycemia secondary to insulin overdosage in diabetic patients.
Unless the potential advantages outweigh the risks, do not use in patients hypersensitive to thiazidediuretics.
Because diazoxide can cause sodium and water retention, use cautiously in patients with congestive heart failure or with renal disease.
Administering the drug with meals or temporarily reducing the dose may alleviate the gastrointestinal side effects. Adverse effects may be more readily noted in dogs with concurrent hepaticdisease.
Overdosage - Acute overdosage may result in severe hyperglycemia and ketoacidosis. Treatment should include insulin (see previous monograph) and fluid and electrolytes. Intensive and prolonged monitoring is recommended.
Caution: hypotension may occur.
Diazoxide may displace warfarin or bilirubin from plasma proteins. Phenothiazines (e.g., chlorpromazine) may enhance the hyperglycemic effects of diazoxide. Diazoxide may increase the metabolism, or decrease the protein binding of phenytoin.
Alpha-adrenergic agents (e.g., phenoxybenzamine) may decrease the effectiveness of diazoxide in increasing glucose levels.
Diazoxide may enhance the hypotensive actions of other hypotensive agents (e.g., hydralazine, prazosin, etc.)
Drug/Laboratory Interactions - Diazoxide will cause a false-negative insulin response to glucagon.
Storage, Stability, Compatibility
Diazoxide capsules and oral suspensions should be stored at2-30°C and protected from light. Protect solutions/suspensions from freezing. Do not use darkenedsolutions/suspensions as they may be subpotent.Pharmacology - DIAZOXIDE, ORAL
Although related structurally to the thiazide diuretics, diazoxide does not possessany appreciable diuretic activity. By directly causing a vasodilatory effect on the smooth muscle inperipheral arterioles, diazoxide reduces peripheral resistance and blood pressure. To treat malignanthypertension, intravenous diazoxide is generally required for maximal response.Diazoxide also exhibits hyperglycemic activity by directly inhibiting pancreatic insulin secretion.
This action may be a result of the drug's capability to decrease the intracellular release of ionizedcalcium, thereby preventing the release of insulin from the insulin granules. Diazoxide does notapparently affect the synthesis of insulin, nor does it possess any antineoplastic activity. Diazoxidealso enhances hyperglycemia by stimulating the beta-adrenergic system, thereby stimulatingepinephrine release and inhibiting the uptake of glucose by cells.
Uses, Indications - Oral diazoxide is used in canine medicine for the treatment of hypoglycemiasecondary to hyperinsulin secretion (e.g., insulinoma). Insulinomas are apparently very rare in thecat, and there is little experience with this drug in that species.
Pharmacokinetics - DIAZOXIDE, ORAL
The serum half-life of diazoxide has been reported to be about 5 hours in thedog; other pharmacokinetic parameters in the dog appear to be unavailable. In humans, serumdiazoxide (at 10 mg/kg PO) levels peaked at about 12 hours after dosing with capsules. It is unknown what blood levels are required to obtain hyperglycemic effects. Highest concentrations of diazoxide are found in the kidneys with high levels also found in the liver and adrenal glands.Approximately 90% of the drug is bound to plasma proteins and it crosses the placenta and into the
CNS. It is not known if diazoxideis distributed into milk. Diazoxide is partially metabolized in theliver and is excreted as both metabolites and unchanged drug by the kidneys. Serum half-life of thedrug is prolonged in patients with renal impairment.
Contraindications/Precautions - Diazoxide should not be used in patients with functional hypoglycemia or for treating hypoglycemia secondary to insulin overdosage in diabetic patients.
Unless the potential advantages outweigh the risks, do not use in patients hypersensitive to thiazidediuretics.
Because diazoxide can cause sodium and water retention, use cautiously in patients with congestive heart failure or with renal disease.
Adverse Effects, Warnings
When used to treat insulinomas in dogs, most commonly seen adverse reactions include anorexia, vomiting and/or diarrhea. Other effects that may be seen include tachycardia, hematologic abnormalities (agranulocytosis, aplastic anemia, thrombocytopenia), diabetes mellitus, cataracts (secondary to hyperglycemia?), and sodium and water retention.Administering the drug with meals or temporarily reducing the dose may alleviate the gastrointestinal side effects. Adverse effects may be more readily noted in dogs with concurrent hepaticdisease.
Overdosage - Acute overdosage may result in severe hyperglycemia and ketoacidosis. Treatment should include insulin (see previous monograph) and fluid and electrolytes. Intensive and prolonged monitoring is recommended.
Drug Interactions
Thiazide diuretics may potentiate the hyperglycemic effects of oral diazoxide. Some clinicians have recommended using hydrochlorothiazide (2 - 4 mg/kg/day PO) in combination with diazoxide, if diazoxide is ineffective alone to increase blood glucose levels.Caution: hypotension may occur.
Diazoxide may displace warfarin or bilirubin from plasma proteins. Phenothiazines (e.g., chlorpromazine) may enhance the hyperglycemic effects of diazoxide. Diazoxide may increase the metabolism, or decrease the protein binding of phenytoin.
Alpha-adrenergic agents (e.g., phenoxybenzamine) may decrease the effectiveness of diazoxide in increasing glucose levels.
Diazoxide may enhance the hypotensive actions of other hypotensive agents (e.g., hydralazine, prazosin, etc.)
Drug/Laboratory Interactions - Diazoxide will cause a false-negative insulin response to glucagon.