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Chapter: Modern Medical Toxicology: Miscellaneous Drugs and Poisons: Gastrointestinal and Endocrinal Drugs

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Adrenocorticotropic Hormone and Corticosteroids - Endocrinal Drug

Adrenocorticotropic hormone or ACTH is secreted by the anterior lobe of the pituitary and stimulates the adrenal cortex to produce corticosteroids, i.e. glucocorticoids and mineralocor-ticoids, as well as androgens.

Adrenocorticotropic Hormone and Corticosteroids

Adrenocorticotropic hormone or ACTH is secreted by the anterior lobe of the pituitary and stimulates the adrenal cortex to produce corticosteroids, i.e. glucocorticoids and mineralocor-ticoids, as well as androgens. ACTH release itself is controlled and regulated by corticotropin-releasing hormone or CRH which is secreted by the hypothalamus. It has very limited therapeutic applications and is at present used only for testing the integrity of the hypothalamic-pituitary-adrenal axis (HPA axis) in those patients needing supplemental steroids in stressful situations. For this purpose, a synthetic form of ACTH called cosyntropin is administered intramuscularly or intravenously at a dose of 0.25 mg, and the plasma cortisol level is measured before and (30 minutes) after the test. An increase in cortisol level to greater than 20 mg/100 ml indicates normal response. This is referred to as the cosyntropin stimulation test.

The ACTH can cause hypersensitivity reactions and hyponatraemia.* Cosyntropin is much safer in this regard, and so is generally preferred. Administration of ACTH can induce fatal adrenal haemorrhage.

Corticosteroids

Classically, two types of corticosteroids are described: gluco-corticoids which regulate carbohydrate metabolism, and miner-alocorticoids which regulate electrolyte balance. The mainglucocorticoid in humans is cortisol or hydrocortisone, while the main mineralocorticoid is aldosterone. Over a period of time since the 1950s, several corticosteroids have been identified as well as synthesised: cortisone, desoxycorticosterone, hydro-cortisone, fludrocortisone, prednisone, prednisolone, methyl prednisolone, triamcinolone, beclomethasone, betamethasone, budesonide, paramethasone, rimexolone and dexamethasone.

Topical corticosteroids comprise alclometasone, amci-nonide, betamethasone, budesonide, clobetasol, clocortolone, cortisol, desonide, desoximetasone, dexamethasone, diflora-sone, fluocinolone, fluocinonide, flurandrenolide, halcinonide, hydrocortisone, loteprednol, methyl prednisolone, mometasone, rimexolone and triamcinolone.

Ophthalmic steroids comprise dexamethasone, fluoro-metholone, medrysone and prednisolone.

Inhalational steroids comprise beclomethasone, flunisolide and triamcinolone.

Corticosteroids are used as replacement therapy for acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, and congenital adrenal hyper-plasia. They are also used in the treatment of non-endocrine diseases such as rheumatic disorders, nephrotic syndrome and some forms of glomerulonephritis, allergies, bronchial asthma, ocular diseases, skin diseases and cerebral oedema.

Adverse Effects (chronic therapy)

·              Abrupt withdrawal after prolonged high-dose therapy results in flare up of the underlying disease, acute adrenal insufficiency (Addisonian crisis), and glucocorticoid with- drawal syndrome: fever, myalgia, arthralgia. Pseudotumour cerebri, dysphoria, irritability, emotional lability, depres- sion, fatigue, anxiety, and depersonalisation can also occur. Symptoms may persist for 2 to 8 weeks after discontinu-ation.

·              Fluid and electrolyte abnormalities.

·              Hypertension.

·              Hyperglycaemia.

·              Increased susceptibility to infections and peptic ulceration.

·              Osteoporosis (especially ribs and vertebrae). Chronic inges- tion results in cushingoid appearance, muscle weakness, and osteoporosis.

·              Myopathy (especially weakness of proximal limb muscles). Behavioural disturbances: nervousness, mood changes, insomnia, psychosis. Chronic toxicity may produce psychosis. Higher doses over shorter periods of time, as seen with prednisone and pulse methylprednisolone therapies, has produced psychosis and hallucinations. Mania has been documented during high-dose corticosteroid therapy.

·              Cataract (especially in children). Chronic exposure may cause posterior subcapsulary cataracts and glaucoma; this risk appears to be greater in patients with probable rheu- matoid arthritis.

·              Fat redistribution, acne, hirsutism, striae, ecchymosis.

·              Oral candidiasis has been reported following chronic inha- lations of beclomethasone dipropionate.

·              In one study, conducted to determine the influence of postnatal systemic dexamethasone treatment for neonatal chronic lung disease on subsequent brain growth and development in premature infants, it was determined that systemic dexamethasone administration caused a 22% reduction in total cerebral tissue volume as compared with total cerebral tissue volume in infants not treated with dexamethasone. Cerebral cortical grey matter volume was also reduced by 35% in pre-mature infants treated with dexamethasone as compared with infants not treated with dexamethasone. These findings suggest an impairment in brain growth which may subsequently have a deleterious effect on neurodevelopmental outcome following neonatal administration of dexamethasone. The use of corticoster-oids has been found to increase the incidence of cerebral palsy and neurodevelopmental impairment.

Toxic Effects:

·              Steroid overdose is rarely reported. A single massive doseof corticosteroid is unlikely to cause serious effects, unless there are specific contraindications.

·              One case of suspected acute adrenal insufficiency has been reported after acute overdose. High-dose intravenous “pulse” therapy has a fairly high incidence of adverse effects. Most reactions are neuropsy- chiatric, but cardiac arrhythmias, seizures, and anaphylaxis have been reported.

Treatment

·              Corticosteroid levels are not clinically useful. Emesis and activated charcoal are generally not necessary following corticosteroid overdose. However, they should be consid- ered in the setting of a polypharmacy ingestion. Consider activated charcoal if co-ingestants with the potential for significant toxicity are involved. In chronic toxicity fluids and electrolytes should be monitored closely.

·              Acute adrenal insufficiency: Administration of water, sodium chloride, glucose, and cortisol.

·              Chronic primary adrenal insufficiency: Administration of hydrocortisone, liberal salt intake. Fludrocortisone may have to be added.

·              Secondary adrenal insufficiency: Administration of hydro- cortisone.

·              Psychiatric manifestations: Tapered withdrawal and admin- istration of neuroleptic drugs. Antidepressants may worsen the symptoms.

·              Avoid chronic daily dosage of corticosteroids for dura- tions greater than 3 weeks when possible. When chronic doses for periods greater than 3 weeks are essential, attempts should be made to manage the underlying disease with alternate day dosage. Single daily doses of shorter-acting preparations such as prednisone, predniso- lone, or methylprednisolone on alternate mornings may be used. Adverse effects appear to be more common and more severe with the preparations having longer dura- tion of effect, or when shorter-acting preparations are administered in multiple daily doses. The diet should have adequate protein content but caloric restrictions should be considered because of the apparent appetite stimulation properties of corticosteroids.


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