Page 728 - Basic _ Clinical Pharmacology ( PDFDrive )

714 SECTION VII Endocrine Drugs

as overtreatment. To minimize the deposition of immune com- Aldosterone
plexes and the influx of leukocytes and macrophages, 1 mg/kg
per day of prednisone in divided doses is required initially. This Aldosterone is synthesized mainly in the zona glomerulosa of
dosage is maintained until the serious manifestations respond. The the adrenal cortex. Its structure and synthesis are illustrated in
dosage can then be gradually reduced. Figure 39–1. The rate of aldosterone secretion is subject to several
When large doses are required for prolonged periods of time, influences. ACTH produces a moderate stimulation of its release,
alternate-day administration of the compound may be tried. but this effect is not sustained for more than a few days in the
When used in this manner, very large amounts (eg, 100 mg of normal individual. Although aldosterone is no less than one third
prednisone) can sometimes be administered with less marked as effective as cortisol in suppressing ACTH, the quantities of
adverse effects because there is a recovery period between each aldosterone produced by the adrenal cortex and its plasma concen-
dose. The transition to an alternate-day schedule can be made trations are insufficient to participate in any significant feedback
after the disease process is under control. It should be done control of ACTH secretion.
gradually and with additional supportive measures between doses. Without ACTH, aldosterone secretion falls to about half
When selecting a drug for use in large doses, a medium- or the normal rate, indicating that other factors, eg, angiotensin,
intermediate-acting synthetic steroid with little mineralocorti- are able to maintain and perhaps regulate its secretion (see
coid effect is advisable. If possible, it should be given as a single Chapter 17). Independent variations between cortisol and
morning dose. aldosterone secretion can also be demonstrated by means of
lesions in the nervous system such as decerebration, which
C. Special Dosage Forms decreases the secretion of cortisol while increasing the secretion
Local therapy, such as topical preparations for skin disease, oph- of aldosterone.
thalmic forms for eye disease, intra-articular injections for joint
disease, inhaled steroids for asthma, and hydrocortisone enemas A. Physiologic and Pharmacologic Effects
for ulcerative colitis, provides a means of delivering large amounts Aldosterone and other steroids with mineralocorticoid proper-
of steroid to the diseased tissue with reduced systemic effects. ties promote the reabsorption of sodium from the distal part of
Beclomethasone dipropionate, and several other the distal convoluted renal tubule and from the cortical collect-
glucocorticoids—primarily budesonide, flunisolide, and mometa- ing tubules, loosely coupled to the excretion of potassium and
sone furoate, administered as aerosols—have been found to be hydrogen ion. Sodium reabsorption in the sweat and salivary
extremely useful in the treatment of asthma (see Chapter 20). glands, gastrointestinal mucosa, and across cell membranes in
Beclomethasone dipropionate, triamcinolone acetonide, general is also increased. Excessive levels of aldosterone produced
budesonide, flunisolide, fluticasone, and others are available as by tumors or overdosage with synthetic mineralocorticoids lead to
nasal sprays for the topical treatment of allergic rhinitis. They hypokalemia, metabolic alkalosis, increased plasma volume, and
are effective at doses (one or two sprays one, two, or three times hypertension.
daily) that in most patients result in plasma levels that are too low Mineralocorticoids act by binding to the mineralocorticoid
to influence adrenal function or have any other systemic effects. receptor in the cytoplasm of target cells, especially principal cells
Corticosteroids incorporated in ointments, creams, lotions, of the distal convoluted and collecting tubules of the kidney.
and sprays are used extensively in dermatology. These preparations The drug-receptor complex activates a series of events similar to
are discussed in more detail in Chapter 61. those described above for the glucocorticoids and illustrated in
Recently, new timed-release hydrocortisone tablets were devel- Figure 39–4. It is of interest that this receptor has the same affin-
oped for the replacement treatment of Addisonian and congenital ity for cortisol, which is present in much higher concentrations in
adrenal hyperplasia patients. These tablets produce plasma cortisol the extracellular fluid. The specificity for mineralocorticoids in the
levels that are similar to those secreted normally in a circadian kidney appears to be conferred, at least in part, by the presence—
fashion. in the kidney—of the enzyme 11β-hydroxysteroid dehydrogenase
type 2, which converts cortisol to cortisone. The latter has low
affinity for the receptor and is inactive as a mineralocorticoid or
MINERALOCORTICOIDS (ALDOSTERONE, glucocorticoid in the kidney. The major effect of activation of the
DEOXYCORTICOSTERONE, aldosterone receptor is increased expression of Na /K -ATPase and
+
+
FLUDROCORTISONE) the epithelial sodium channel (ENaC).
The most important mineralocorticoid in humans is aldosterone. B. Metabolism
However, small amounts of deoxycorticosterone (DOC) are also Aldosterone is secreted at the rate of 100–200 mcg/d in normal
formed and released. Although the amount is normally insignifi- individuals with a moderate dietary salt intake. The plasma level
cant, DOC was of some importance therapeutically in the past. Its in men (resting supine) is about 0.007 mcg/dL. The half-life of
actions, effects, and metabolism are qualitatively similar to those aldosterone injected in tracer quantities is 15–20 minutes, and it
described below for aldosterone. Fludrocortisone, a synthetic does not appear to be firmly bound to serum proteins.
corticosteroid, is the most commonly prescribed salt-retaining The metabolism of aldosterone is similar to that of cortisol,
hormone. about 50 mcg/24 h appearing in the urine as conjugated