DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1224 (e.g., corticosterone) have appreciable glucocorticoid activity, the
17α-hydroxyl group gives optimal potency.
Introduction of an additional double bond in the 1,2 position
of ring A, as in prednisolone or prednisone, selectively increases glucocorticoid
activity, and results in an enhanced glucocorticoid/
mineralocorticoid potency ratio. This modification also results in
compounds that are metabolized more slowly than hydrocortisone.
Fluorination at the 9α position on ring B enhances both glucocorticoid
and mineralocorticoid activity, possibly related to an
electron-withdrawing effect on the nearby 11β-hydroxyl group.
Fludrocortisone (9α-fluorocortisol) has enhanced activity at the GR
(10 times relative to cortisol) but even greater activity at the MR
(125 times relative to cortisol). It is used in mineralocorticoid
replacement therapy and has no appreciable glucocorticoid effect
at usual daily doses of 0.05-0.2 mg. When combined with the 1,2
double bond in ring A plus other substitutions at C16 on ring D
(Figure 42–7), the 9α-fluoro derivatives formed (e.g., triamcinolone,
dexamethasone, and betamethasone) have marked glucocorticoid
activity—the substitutions at C16 virtually eliminate
mineralocorticoid activity.
Other Substitutions. 6α Substitution on ring B has somewhat unpredictable
effects. 6α-Methylcortisol has increased glucocorticoid and
mineralocorticoid activity, whereas 6α-methylprednisolone has
somewhat greater glucocorticoid activity and somewhat less mineralocorticoid
activity than prednisolone. A number of modifications
convert the glucocorticoids to more lipophilic molecules with
enhanced topical/systemic potency ratios. Examples include the
introduction of an acetonide between hydroxyl groups at C16 and
C17, esterification of the hydroxyl group with valerate at C17, esterification
of hydroxyl groups with propionate at C17 and C21, and
substitution of the hydroxyl group at C21 with chlorine. Other
approaches to achieve local glucocorticoid activity while minimizing
systemic effects involve the formation of analogs that are rapidly
inactivated after absorption (e.g., C21 carboxylate or carbothioate
glucocorticoid esters, which are rapidly metabolized to inactive
21-carboxylic acids) or the formation of inactive analogs that are
selectively activated at their site of action (e.g., glucocorticoid C21
isobutyryl or propionyl esters that are hydrolyzed to active C21 alcohols
by airway-specific esterases).
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Toxicity of Adrenocortical Steroids
Two categories of toxic effects result from the therapeutic
use of corticosteroids: those resulting from withdrawal
of steroid therapy and those resulting from
continued use at supraphysiological doses. The side
effects from both categories are potentially life threatening
and require a careful assessment of the risks and
benefits in each patient.
Withdrawal of Therapy. The most frequent problem in
steroid withdrawal is flare-up of the underlying disease
for which steroids were prescribed. Several other complications
are associated with steroid withdrawal. The
most severe complication of steroid cessation, acute
adrenal insufficiency, results from overly rapid withdrawal
of corticosteroids after prolonged therapy has
suppressed the HPA axis. The therapeutic approach to
acute adrenal insufficiency is detailed later. There is significant
variation among patients with respect to the
degree and duration of adrenal suppression after glucocorticoid
therapy, making it difficult to establish the relative
risk in any given patient. Many patients recover
from glucocorticoid-induced HPA suppression within
several weeks to months; however, in some individuals
the time to recovery can be a year or longer.
In an effort to diminish the risk of iatrogenic acute adrenal
insufficiency, protocols for discontinuing corticosteroid therapy in
patients receiving long-term treatment with corticosteroids have been
proposed, generally without rigorous documentation of their efficacy.
Patients who have received supraphysiological doses of glucocorticoids
for a period of 2-4 weeks within the preceding year
should be considered to have some degree of HPA impairment in
settings of acute stress and should be treated accordingly.
In addition to this most severe form of withdrawal, a characteristic
glucocorticoid withdrawal syndrome consists of fever, myalgia,
arthralgia, and malaise, which may be difficult to differentiate
from some of the underlying diseases for which steroid therapy was
instituted (Hochberg et al., 2003). Finally, pseudotumor cerebri, a
clinical syndrome that includes increased intracranial pressure with
papilledema, is a rare condition that sometimes is associated with
reduction or withdrawal of corticosteroid therapy.
Continued Use of Supraphysiological Glucocorticoid
Doses. Besides the consequences that result from the
suppression of the HPA axis, a number of other complications
result from prolonged therapy with corticosteroids.
These include fluid and electrolyte abnormalities,
hypertension, hyperglycemia, increased susceptibility
to infection, osteoporosis, myopathy, behavioral disturbances,
cataracts, growth arrest, and the characteristic
habitus of steroid overdose, including fat redistribution,
striae, and ecchymoses.
Fluid and Electrolyte Handling. Alterations in fluid and electrolyte
handling can cause hypokalemic alkalosis and hypertension, particularly
in patients with primary hyperaldosteronism secondary to an
adrenal adenoma or in patients treated with potent mineralocorticoids.
Similarly, hypertension is a relatively common manifestation
of glucocorticoid excess, even in patients treated with glucocorticoids
lacking appreciable mineralocorticoid activity.
Metabolic Changes. The effects of glucocorticoids on intermediary
metabolism have already been described. Hyperglycemia with
glycosuria usually can be managed with diet and/or insulin, and its
occurrence should not be a major factor in the decision to continue
corticosteroid therapy or to initiate therapy in diabetic patients.
Immune Responses. Because of their multiple effects to inhibit the
immune system and the inflammatory response, glucocorticoid use
is associated with an increased susceptibility to infection and a risk
for reactivation of latent tuberculosis. In the presence of known
infections of some consequence, glucocorticoids should be
administered only if absolutely necessary and concomitantly with
appropriate and effective antimicrobial or antifungal therapy.