Mitotane
Mitotane (also known as o,p'-DDD) is an adrenal cytotoxic agent primarily used in veterinary medicine for the medical management of **pituitary-dependent hyperadrenocorticism (PDH)** (Cushing's disease), principally in dogs. It is structurally related to the insecticide DDT (chlorophenothane). Because it causes targeted necrosis of the adrenal cortex, it effectively reduces excessive cortisol production. It is also used for the palliative treatment of adrenal carcinoma in humans and dogs. **Clinical Pearl:** Treatment is typically divided into two distinct phases: an *induction phase* (daily dosing to rapidly destroy hyperplastic adrenal tissue until clinical endpoints are reached) and a *maintenance phase* (weekly or biweekly dosing to prevent regrowth of the adrenal cortex). Close monitoring is mandatory, as overzealous treatment can lead to iatrogenic hypoadrenocorticism (Addison's disease).
Mecanismo: Mitotane acts as a targeted **adrenocortical cytotoxic agent**. * It causes severe, progressive necrosis and atrophy of the **zona fasciculata** and **zona reticularis** of the adrenal gland → drastically reducing the synthesis of glucocorticoids (cortisol). * It relatively spares the **zona glomerulosa**, meaning mineralocorticoid (aldosterone) synthesis is usually unaffected, though clinically significant effects on aldosterone production can occasionally occur. * The exact intracellular mechanism of cytotoxicity is not fully understood, but it is believed to involve metabolic activation within the adrenal mitochondria, leading to irreversible binding to cellular macromolecules and subsequent cell death.
Dosificación por especie
- Hyperadrenocorticism · 30-50 mg/kg · PO · q24h · to effect · Efficacy in cats is very variable, with many showing no response at non-toxic levels. Not recommended.
- Medical treatment of hyperadrenocorticism · 50 mg per ferret PO once daily for one week, then 50 mg PO 2-3 times per week · PO · q24h then 2-3 times/week · Long-term · Have a compounding pharmacy make 50 mg capsules. Can be coated with Nutrical.
- Pituitary-dependent hyperadrenocorticism (Induction - Protocol A) · 25 mg/kg twice a day, PO with food · PO · q12h · Until clinical endpoints occur (usually 4-9 days) · Reduce food by 1/3 the day before. Stop therapy if water consumption approaches 60 mL/kg/day, appetite reduces, vomiting, listlessness, or diarrhea occurs.
- Pituitary-dependent hyperadrenocorticism (Maintenance - Protocol A) · 25-50 mg/kg per week · PO · Divided in as many doses as possible weekly · Long-term · Adjust based on ACTH stimulation test results.
- Pituitary-dependent hyperadrenocorticism (Induction - Protocol B) · 30-50 mg/kg/day PO with a meal once daily or divided q12h · PO · q24h or q12h · 7-10 days · Goal is basal and post-ACTH cortisol between 1-5 micrograms/dL.
- Pituitary-dependent hyperadrenocorticism (Maintenance - Protocol B) · 35-50 mg/kg per week in 2-3 divided doses · PO · Divided weekly · Long-term
- Pituitary-dependent hyperadrenocorticism (Induction - Protocol C) · 50 mg/kg divided q12h · PO · q12h · Until water consumption decreases to <100 mL/kg/day or adverse signs observed (usually 3-7 days) · Max 5-7 days prior to ACTH stim test if water consumption cannot be monitored.
Vías de administración
Contraindicaciones
- Known hypersensitivity to mitotane
- Pregnancy (FDA Category C in humans; Class D in veterinary medicine - embryotoxic/teratogenic)
- Patients that are not eating well (should never be administered to anorexic animals)
- Not recommended in cats (trilostane is more effective and mitotane efficacy is highly variable)
Efectos adversos
- Lethargy
- Ataxia
- Weakness
- Anorexia (loss of appetite)
- Vomiting
- Diarrhea
- Neurologic signs (uncommon)
- Liver changes (congestion, centrolobular atrophy, fatty degeneration)
- Iatrogenic hypoadrenocorticism (requiring long-term glucocorticoid/mineralocorticoid replacement in ~5% of dogs)
- Anorexia
- Diarrhoea
- Acute-onset neurological signs (2-3 weeks post-initiation)
- Iatrogenic hypoadrenocorticism
Interacciones farmacológicas
- CNS Depressants · Additive depressant effects may be seen if used concomitantly. · moderate
- Insulin · Diabetic dogs receiving insulin may have their insulin requirements rapidly decreased when mitotane therapy is instituted. · major
- Phenobarbital · Can induce enzymes and reduce the efficacy of mitotane; conversely, mitotane can induce hepatic microsomal enzymes and increase the metabolism of phenobarbital.
- Spironolactone · Has been demonstrated to block the action of mitotane in dogs; an alternate diuretic is recommended. · major
- Barbiturates · Increases the hepatic metabolism of mitotane · moderate
- Corticosteroids · Increases the hepatic metabolism of mitotane · moderate
Monitorización
- Physical exam and history (especially water consumption, food consumption, and weight)
- ACTH response test (crucial for dose adjustment)
- Serum electrolytes (Na+/K+)
- BUN
- CBC
- Liver enzymes
- Blood glucose
- Appetite (daily during induction)
- ACTH stimulation test (to monitor treatment efficacy)
- Blood glucose (in diabetic patients)
- Clinical signs of weakness, vomiting, or neurological changes
Sobredosis
Because of the drug's toxicity and very long half-life, acute overdosage should be managed aggressively. * **Decontamination:** Emptying the stomach and administering activated charcoal and a cathartic should be considered after a recent ingestion. * **Monitoring & Treatment:** The patient must be closely monitored. Administer systemic glucocorticoids (e.g., dexamethasone or prednisone) and IV fluids if signs of acute hypoadrenocorticism (Addisonian crisis) develop.
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