Synthetic Adrenocorticosteroids

• Pharmacokinetics
  • Source:
    • Synthesized from cholic acid (from cattle sources) or
    • Synthesized from steroid sapogenins (diosgenin) -- plants
  • Disposition:
    • oral administration; complete absorption
    • metabolized similar to endogenous steroids
    • molecular alterations given rise to differences in:
      • affinity for mineralocorticoid or glucocorticoid receptors
      • extent of protein binding
      • stability
      • spectrum of metabolic products
    • prodrugs may be used (prednisone is converted to prednisolone)

• Pharmacodynamics:
  • Similar to those of cortisol (endogenous agents)

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Clinical Pharmacology

Altered Adrenal Function: Diagnosis and Treatment

• 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)

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  • Adrenal gland destruction:
    •  adrenal: common site for chronic granulomatous diseases, e.g.:
      • tuberculosis (mainly)
      • histoplasmosis
      • coccidiodomycosis
      • cryptococcosis
    •  Adrenoleukodystrophy: significant demyelination -- early death and children
    •  Adrenomyeloneuropathy: mixed motor/sensory neuropathy with spastic paraplegia -- (adults)
    •  AIDS patients-- 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)
    • in early cases, tuberculosis caused 70%-90% of cases
    •  Most frequent cause today is idiopathic atrophy.
      • autoimmune mechanism -- most likely
      • half of patients: 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

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      • 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

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  • Presenting Clinical Signs and Symptoms

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• 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

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