A Textbook of Clinical Pharmacology and Therapeutics

CHAPTER 40
ADRENAL HORMONES
● Adrenal cortex 302 ● Adrenal medulla 305
ADRENAL CORTEX
The adrenal cortex secretes:
1. glucocorticosteroids, principally cortisol (hydrocortisone);
2. mineralocorticoids – principally aldosterone;
3. androgens (relatively small amounts).
GLUCOCORTICOSTEROIDS
The actions of glucocorticosteroids and the effects of their oversecretion
(Cushing’s syndrome) and under-secretion (Addison’s
disease) are summarized in Table 40.1. Glucocorticosteroids
influence carbohydrate and protein metabolism, and play a
vital role in the response to stress. Glucocorticosteroids stimulate
the mobilization of amino acids from skeletal muscle, bone
and skin, promoting their transport to the liver where they are
converted into glucose (gluconeogenesis) and stored as glycogen.
Fat mobilization by catecholamines is potentiated by
glucocorticosteroids. The major therapeutic uses of the glucocorticosteroids
exploit their powerful anti-inflammatory and
immunosuppressive properties. They reduce circulating
eosinophils, basophils and T-lymphocytes, while increasing
neutrophils. Applied topically to skin or mucous membranes,
potent steroids can cause local vasoconstriction and massive
doses administered systemically can cause hypertension due to
generalized vasoconstriction.
Mechanism of action
Glucocorticosteroids combine with a cytoplasmic glucocorticosteroid
receptor causing its dissociation from a phosphorylated
heat shock protein complex. The receptor–glucocorticosteroid
complex translocates to the nucleus, where it binds to glucocorticosteroid
response elements (GREs) in DNA and acts as a
transcription factor. This increases the transcription of various
signal transduction proteins. In addition, the glucocorticosteroid
receptor interacts with both NFκB and AP-1 and inhibits
them from enhancing transcription of many pro-inflammatory
proteins. Thus glucocorticosteroids produce a delayed but profound
anti-inflammatory effect.
Adverse effects
Adverse effects of glucocorticosteroids are common to all
members of the group, and will be discussed before considering
the uses of individual drugs.
Chronic administration causes iatrogenic Cushing’s syndrome
(see Table 40.1). Features include:
• Cushingoid physical appearance;
• impaired resistance to infection;
• salt and water retention; hypokalaemia;
• hypertension;
• hyperglycaemia;
• osteoporosis;
• glucocorticosteroid therapy is weakly linked with peptic
ulceration, and can mask the symptoms and signs of
gastrointestinal perforation;
• mental changes: anxiety, elation, insomnia, depression
and psychosis;
• posterior cataracts;
• proximal myopathy;
• growth retardation in children;
• aseptic necrosis of bone.
Acute adrenal insufficiency can result from rapid withdrawal
after prolonged glucocorticosteroid administration. Gradual
tapered withdrawal is less hazardous. However, even in
patients who have been successfully weaned from chronic treatment
with glucocorticosteroids, for one to two years afterwards
a stressful situation (such as trauma, surgery or infection) may
precipitate an acute adrenal crisis and necessitate the administration
of large amounts of sodium chloride, glucocorticosteroids,
glucose and water. Suppression of the adrenal cortex is
unusual if the daily glucocorticosteroid dose is lower than the
amount usually secreted physiologically. The rate at which
patients can be weaned off glucocorticosteroids depends on
their underlying condition and also on the dose and duration of
therapy. After long-term glucocorticosteroid therapy has been
discontinued the patient should continue to carry a steroid card
for at least one year.