Medical Pharmacology Chapter 28:  Physiology and Pharmacology: Adrenocorticosteroids / Adrenocortical Antagonists

• Primary Adrenocortical insufficiency (Addison's Disease)

  • Overview: 

    • Rare; may occur at any age; affects both sexes with equal frequency

  • Etiology/Pathogenesis

    • Addison's disease is caused by progressive destruction of the adrenals (> 90% must be destroyed before symptoms of adrenal insufficiency appear).

    • "Atrophic adrenal, gross, in chronic adrenocortical insufficiency "; KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

• Adrenal gland destruction:

  •  Adrenal: common site for chronic granulomatous diseases, e.g.:

    • Tuberculosis (mainly)

    • Histoplasmosis

    • Coccidiodomycosis

    • Cryptococcosis

  •  Adrenoleukodystrophy: significant demyelination and associated with early death in children.

  •  Adrenomyeloneuropathy: mixed motor/sensory neuropathy with spastic paraplegia  in adults.

  •  AIDS patients have a higher likelihood of adrenal-insufficiency because:

    • Cytomegalovirus frequently involves the adrenal glands:

      • CMV necrotizing adrenalitis

      • Involvement with Mycobacterium avium-intracellulare, Cryptococcus, and Kaposi sarcoma

      • Note: in interpreting results from adrenal function test in AIDS patients that certain medications may potentiates adrenal insufficiency including:

        1. Opiates

        2. Rifampin

        3. Phenytoin (Dilantin)

        4. Ketoconazole (Nizoral)

  • Most frequent cause today is idiopathic atrophy.

    • Autoimmune mechanism is most likely

    • Half of patients have circulating adrenal antibodies

      • Adrenal antigens, e.g.: P450c21

      • Some antibodies may cause adrenal destruction

      • Other antibodies may cause adrenal insufficiency by inhibiting ACTH binding

      • Some individuals also have antibodies to thyroid, parathyroid, and/or gonadal tissue

    • Increased likelihood of:

      1. Chronic lymphocytic thyroiditis

      2. Premature ovarian failure

      3. Type I diabetes mellitus

      4. Hypothyroidism

      5. Hyperthyroidism

    • Presence of two or more autoimmune endocrine disorders in the same patient: polyglandular autoimmune syndrome

• Presenting Clinical Signs and Symptoms

• Asthenia, "Cardinal symptom":

  • Severe fatigue, impairment; bed rest may be necessary

• Hyperpigmentation:

  • Diffuse brown, tan, bronze darkening at elbows, hand creases

  • May include bluish-black mucosal membrane patches

• Arterial hypotension with orthostatic component

• Gastrointestinal disturbances: frequent presenting symptom

• Primary Adrenocortical insufficiency: Laboratory Findings and Diagnostic Testing.

  •  Laboratory findings:

    • Initially:steroid output normal; but adrenal reserve reduced

      • ACTH-adrenal stimulation: produces some normal cortisol increase or no increase

    • More advanced disease: (more adrenal destruction)

      •  Serum sodium, bicarbonate, chloride: reduced

        1. Decreased serum sodium: due to excessive urinary loss (secondary to aldosterone deficiency) and movement into intracellular compartments

        2. extravascular sodium loss -- depleting extracellular fluid; promotes hypotension; elevated plasma angiotensin II and vasopressin promote hyponatremia by reducing free water clearance

      •  Serum potassium: elevated

        • Hyperkalemia due to:

          1. Aldosterone deficiency

          2. Acidosis

          3. Impaired glomerular filtration

  •  Diagnosis

    • Based on ACTH stimulation testing: evaluation of adrenal steroid production reserve capacity

    • Severe adrenal insufficiency: rate of cortisol secretion significantly reduced; low to absent 24 urine cortisol levelto

    • Mild adrenal insufficiency (decreased adrenal reserve)

    • Aldosterone secretion: low-- causing:

      • Salt wasting

      • Increased plasma renin

    • Glucocorticoid Reserve Test

      Shortly after ACTH administration (minutes), cortisol increases in adrenal venous blood. Responsiveness: an indication of functional adrenal gland cortisol production reserve Maximal ACTH stimulation: cortisolsecretion may increase tenfold -- with prolonged ACTH infusion; With 24 hour infusion of cosyntropin, patients with secondary or primary adrenal Insufficiency will have diminished maximal plasma cortisol values Screening Test-- rapid ACTH stimulation test Administer cosyntropin by intravenous or intramuscular injection Measure plasma cortisol levels before and 30 and 60 minutes after: Evaluate for  minimal stimulated normal cortisol increment

1. Goldfien, A.,Adrenocorticosteroids and Adrenocortical Antagonists, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 635-650.

2. Williams, G. H and Dluhy, R. G. , Diseases of the Adrenal Cortex, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2035-2056