Drug therapy for Addison’s and Cushing’s disease

Adrenocortical Function

• Secretion into bloodstream controlled by

  • Hypothalamus; anterior pituitary

  • Adrenal cortex

• Various stimuli activate the system; amount of secretion varies according to the need.

  • Governed by a negative feedback system

    • Which does not function during stress responses

Adrenocortical Insufficiency

• Hormones produced by the adrenal cortex, affect almost all body organs

• Extremely important in maintaining homeostasis

  • When secreted in normal amounts

• Disease results from inadequate or excessive secretion

• Primary or secondary

Adrenocortical Insufficiency (Addison’s)Clinical Manifestations

• Reflect loss of sodium, water, and chloride

  • Decreased cardiac output

  • Dehydration

  • Weakness

  • Fatigue

Acute Adrenal Crisis

• AKA Addisonian crisis

• Loss of sodium leads to leads to retention of potassium - hyperkalemia

• Life-threatening condition that occurs when Addison’s disease is the underlying problem and the patient is exposed to minor illness or increased stress

Drugs Used to Treat Addison’s Disease

• Both mineralocorticoids and adrenocorticoids must be replaced – Solu-Cortef.

• Lifetime hormone replacement is necessary.

• Significant adverse effects.

• Assess for therapeutic and adverse effects.

• Patient teaching.

Corticosteroids

• Produced by the adrenal cortex

• Involved in stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels and behavior.

Uses of Corticosteroids

• Use to treat a number of different disorders especially inflammatory or immunologic disorders

• Arthritis

• Dermatitis

• Allergic reactions

• Asthma

• Hepatitis

• Lupus erythematosus

• Inflammatory bowel disease: ulcerative colitis and Crohn’s disease

• Uveitis – inflammation of eye

Glucocorticoids Physiologic Effects

• When glucocorticoids are used to treat nonendocrine disorders, physiologic responses occur as side effects.

• Metabolic effects- influence metabolism of carbohydrates, proteins and fats; elevation of blood glucose; suppression of protein synthesis reduces muscle mass, decrease bone matrix, thinning of skin, Negative nitrogen balance; effect on fat metabolism is stimulation of lipolysis (fat breakdown), fat redistribution, resulting in potbelly, moon face, buffalo hump

• Cardiovascular effects- Glucocorticoids increase number of circulating RBCs (stroke, MI), decrease number of leukocytes, eosinophils, basophils and monocytes

• Effects in water and electrolytes- promote retention of sodium and water, increase excretion of potassium; result is hypernatremia, hypokalemia and edema

Mineralocorticoid and Adrenocorticoid (Hydrocortisone) Pharmacodynamics/Action

• Enters cell and Binds to receptors in cytoplasm to decrease inflammation

• Suppresses migration of polymorphonuclear lymphocytes

• Decreases capillary permeability

Mineralocorticoid and Adrenocorticoid (Hydrocortisone) Uses/Indications

• Addison’s disease

• Primary hypoaldosteronism

• Congenital adrenal hyperplasia

Mineralocorticoid and Adrenocorticoid (Hydrocortisone) Adverse Effects

• Hypertension

• Edema

• Cardiac enlargement

• Hypokalemia

• depression, euphoria, hypertension, PEPTIC ULCER, THROMBOEMBOLISM, cushingoid appearance

Administration of PO Steroids

• Take with meal or snack to decrease intestinal tract upset

• Avoid consuming grapefruit juice

• If once a day dosing – take in am before 9am

• If more than once daily be sure to evenly space time medication is taken

• In long term usage may need to take every other day in the morning so natural production is not totally suppressed

Mineralocorticoids (Fludrocortisone) Pharmacodynamics/Action

Sodium retention and potassium excretion

Mineralocorticoids (Fludrocortisone) Uses/Indications

• Addison’s disease

• Primary hypoaldosteronism

• Congenital adrenal hyperplasia

Mineralocorticoids (Fludrocortisone) Adverse Effects

• HPA axis suppression, growth suppression, hyperglycemia and hypokalemia alkalosis

• Hypertension

• Edema – call if > 5 lbs

• Cardiac enlargement

• Hypokalemia

Adverse effects

• Fluid and electrolyte disturbances- sodium and water retention (weight gain, swelling of lower extremities), potassium loss (muscle weakness or fatigue, irregular pulse, susceptibility to digoxin toxicity)

• Growth retardation- in children

• Psychologic disturbances- hallucinations, mood changes (depression, euphoria, mania)

• Cataracts and Glaucoma

• Peptic Ulcer Disease

• Iatrogenic Cushing’s Syndrome

• Adrenal insufficiency

• Osteoporosis- frequently occurs; observe for compression fractures (back and neck pain); patients should receive calcium and vitamin D supplements and biphosphonate or Calcitonin

• Infection- increase susceptibility, also masks the presence of infection already in progress; avoid exposure to communicable disease; esp. PCP

• Glucose intolerance- hyperglycemia and glycosuria

• Myopathy- high doses; manifests as muscle weakness, proximal arms and legs affected most

Precautions and Contraindications

• Contraindicated in systemic fungal infections and for those receiving live virus vaccines.

• Use cautiously in pediatric patients, pregnant or breast-feeding women; patients with hypertension, heart failure, renal impairment, esophagitis, gastritis, peptic ulcer disease, myasthenia gravis, diabetes, osteoporosis, and infections resistant to treatment

• Glucocorticoids must be WITHDRAWN SLOWLY; withdrawal syndrome symptoms include hypotension, hypoglycemia, myalgia, arthralgia, and fatigue.

• Should be given before 9 am-helps minimize adrenal insufficiency and mimics adrenal release seen in am

Adrenocortical Excess

• Cushing’s disease

• Cause is adrenocortical excess, thus excessive corticotropin

• Cortisol-secreting tumor

• Long-term treatment with pharmacological glucocorticoids

Cushing’s disease clinical manifestations

• Fatty “buffalo hump” at the neck and supraclavicular region

• Moon-faced appearance

• Fragile skin that tears easily

• Broad purple striae

• Bruises may develop

• Impaired wound healing

• Thin hair

• Women have appearance of masculine traits

• Diminished libido

• Depression

• Increased glucose levels

• Osteoporosis and fractures

• Peptic ulcers

addison’s disease vs cushing’s syndrome

Drugs Used to Treat Cushing’s Disease

• Glucocorticoid Antagonists Receptors

• Deoxycortisol Inhibitors prevent conversion to cortisol

  • Ketoconazole

• Antineoplastics for tx of adrenocortical carcinoma

  • Mitotane (Lysodren)

• Goal of drug therapy is to inhibit enzymes contained in cortisol synthesis.

• Adverse effects and contraindications

• Therapeutic and adverse effects

• Patient teaching

• Check tables 45.3 & 45.4

Deoxycortisol Inhibitors (Ketoconazole) Pharmacodynamics/Action

Inhibits enzyme used in production of cortisol

Deoxycortisol Inhibitors (Ketoconazole) Uses/Indications

Control cortisol secretion in Cushing’s Disease

Deoxycortisol Inhibitors (Ketoconazole) Adverse Effects

• Headache, sedation, nausea

• Report clay-colored stools, extreme thirst and yellowing of skin or eyes

• Black Box- hepatotoxicity