二氮嗪
二氮嗪（Diazoxide）是一種非利尿性噻嗪類衍生物，在獸醫學中主要用於犬和雪貂的**胰島素瘤**（分泌胰島素的胰島細胞瘤）的內科管理。 雖然它具有強效的直接血管擴張特性（在人類中靜脈注射用於高血壓急症），但其在動物中的口服應用主要是利用其顯著的**升血糖**副作用。透過拮抗胰島素的釋放，它有助於穩定難治性低血糖患者的血糖濃度。 **臨床要點：** - 當單獨使用飲食管理（少量多餐）和糖皮質激素（如潑尼松）無法控制低血糖危機時，通常會結合本藥物使用。 - 由於其結構與噻嗪類利尿劑相似，可能會引起鈉和水瀦留，但它缺乏利尿效果。
作用機制: Diazoxide exerts its hyperglycemic and vasodilatory effects via multiple mechanisms: - **K+ ATP Channel Activation**: It binds to the sulfonylurea receptor 1 (SUR1) subunit of the **ATP-sensitive potassium (K+ ATP) channels** on pancreatic beta cells → channel opening → cellular hyperpolarization → decreased intracellular **calcium (Ca2+)** influx → **inhibition of insulin exocytosis** from secretory granules. - **Beta-Adrenergic Stimulation**: Stimulates the release of **epinephrine**, which promotes hepatic glycogenolysis and inhibits peripheral cellular glucose uptake. - **Vasodilation**: Directly relaxes arteriolar smooth muscle by opening K+ ATP channels in vascular smooth muscle cells → hyperpolarization → vasodilation → decreased peripheral vascular resistance and blood pressure.
各物種劑量
- Hypoglycemia secondary to insulin secreting islet cell tumors · Initially, 5 mg/kg PO twice daily; increase to a maximum of 30 mg/kg PO twice daily to control clinical signs · PO · q12h · Insulinomas are very rare in cats; little experience with this drug in this species.
- Hypoglycemia secondary to insulin secreting islet cell tumors · Begin at 5-10 mg/kg PO q12h. · PO · q12h · Add diazoxide when clinical signs cannot be controlled with prednisone alone. At same time prednisone dosage may be lowered.
- Hypoglycemia secondary to insulin secreting islet cell tumors · Initially, 5 mg/kg PO twice daily; increase to a maximum of 30 mg/kg PO twice daily to control clinical signs · PO · q12h
- Hypoglycemia secondary to insulin secreting islet cell tumors (refractory) · Initially at 10 mg/kg divided twice a day. May gradually increase dosage to 60 mg/kg/day as tolerated and add hydrochlorothiazide (2-4 mg/kg/day). · PO · Divided twice a day · Used if frequent feedings and glucocorticoids fail or cause Cushingoid appearance.
- Adjunctive therapy of hypoglycemia secondary to insulin secreting non-islet cell (extra-pancreatic) tumors · 5-13 mg/kg PO three times daily · PO · q8h · May add hydrochlorothiazide 2-4 mg/kg/day.
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給藥途徑
禁忌症
- Functional hypoglycemia
- Hypoglycemia secondary to insulin overdosage in diabetic patients
- Hypersensitivity to thiazide diuretics (unless benefits outweigh risks)
- Hypersensitivity to thiazides
- Functional hypoglycemia (non-insulinoma)
不良反應
- Anorexia
- Vomiting
- Diarrhea
- Hypersalivation
- Tachycardia
- Agranulocytosis
- Aplastic anemia
- Thrombocytopenia
- Diabetes mellitus
- Cataracts
- Sodium and water retention
- Malaise (ferrets)
- Bone marrow suppression (ferrets)
- Gastrointestinal upset (anorexia, vomiting, diarrhea)
- Hyperglycemia
- Cataracts (rare)
- Bone marrow suppression (rare)
藥物相互作用
- Alpha-adrenergic agents (e.g., phenoxybenzamine) · May decrease the effectiveness of diazoxide in increasing glucose levels
- Hypotensive agents (e.g., hydralazine, prazosin) · Diazoxide may enhance the hypotensive actions of other hypotensive agents
- Phenothiazines (e.g., acepromazine, chlorpromazine) · May enhance the hyperglycemic effects of diazoxide
- Phenytoin · Diazoxide may increase the metabolism, or decrease the protein binding of phenytoin
- Thiazide diuretics (e.g., hydrochlorothiazide) · May potentiate the hyperglycemic effects of oral diazoxide. Can be used synergistically, but caution is advised as hypotension may occur
- Thiazide diuretics · Potentiate hyperglycemic and hyperuricemic effects · moderate
- Phenothiazines · May potentiate hyperglycemia · moderate
- Alpha-adrenergic blockers · May antagonize the effects of diazoxide · moderate
- Highly protein-bound drugs (e.g., NSAIDs, warfarin) · Diazoxide is highly protein-bound and may displace or be displaced by other drugs, altering free drug concentrations · moderate
監測
- Blood (serum) glucose
- CBC (at least every 3-4 months)
- Physical exam (monitor for clinical signs of adverse effects like edema, cataracts, or tachycardia)
- Blood glucose
- Electrolytes (sodium, potassium)
- Complete blood count (CBC) periodically
- Signs of fluid retention/edema
過量
Acute overdosage may result in severe **hyperglycemia** and **ketoacidosis**. - **Treatment**: Administer insulin, intravenous fluids, and correct electrolyte imbalances. - **Monitoring**: Intensive and prolonged monitoring of blood glucose and acid-base status is highly recommended.
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