Glucocorticoid Therapy

I. Replacement Therapy

The adrenal cortex (AC) produces the glucocorticoid cortisol (hydrocortisone) in the zona fasciculata and the mineralocorticoid aldosterone in the zona glomerulosa. Both steroid hormones are vitally important in adaptation responses to stress situations, such as disease, trauma, or surgery. Cortisol secretion is stimulated by hypophyseal ACTH; aldosterone secretion by angiotensin II in particular (p.128). In AC failure (primary adrenocortical insuf ciency; Addison disease), both cortisol and aldosterone must be replaced; when ACTH production is deficient (secondary adrenocortical insuf ciency), cortisol alone needs to be replaced. Cortisol is effective when given orally (30 mg/day, 2/3 a.m., 1/3 p.m.). Instresssituations,thedoseis raised 5- to 10-fold. Aldosterone is poorly effective via the oral route; instead, the mineralocorticoid fludrocortisone (0.1 mg/day) is given.

II. Pharmacodynamic Therapy with Glucocorticoids (A)

In unphysiologically high concentrations, cortisol or other glucocorticoids suppress all phases (exudation, proliferation, scar formation) of the inflammatory reaction, i.e., the organism’s defensive measures against foreign or noxious matter. This effect is mediated by multiple components, all of which involve alterations in gene transcription (p.64) Thus, synthesis of the anti-in- flammatory protein lipocortin (macrocortin) is stimulated. Lipocortin inhibits the enzyme phospholipase A2. Consequently, release of arachidonic acid is diminished, along with the formation of inflammatory mediators of the prostaglandin and leukotriene series (pp.196, 200). Conversely, glucocorticoids inhibit synthesis of several proteins that participate in the inflammatory process, including interleukins (p.304) and other cytokines, phospholipase A2 (p.196), and cyclooxyge- nase-2 (p.200). At very high dosage, non-

genomic effects via membrane-bound receptors may also contribute.

Desired effects. As antiallergics, immunosuppressants, or anti-inflammatory drugs, glucocorticoids display excellent ef cacy against “undesired” inflammatory reactions, such as allergy, rheumatoid arthritis, etc.

Unwanted effects. With short-term use, glucocorticoids are practically free of adverse effects, even at the highest dosage. Longterm use islikelytocausechangesmimicking thesignsofCushing syndrome (endogenous overproduction of cortisol). Sequelae of the anti-inflammatory action are lowered resistancetoinfectionanddelayedwoundhealing. Sequelaeofexaggeratedglucocorticoidaction are(a)increasedgluconeogenesisandrelease of glucose, insulin-dependent conversion of glucosetotriglycerides(adipositymainlynoticeableintheface,neck,andtrunk),and“ste- roid-diabetes”ifinsulinreleaseisinsuf cient; (b)increasedproteincatabolismwithatrophy ofskeletalmusculature(thinextremities),osteoporosis,growthretardationininfants,and skin atrophy. Sequelae of the intrinsically weak, but now manifest, mineralocorticoid action of cortisol are salt and fluid retention, hypertension, edema; and KCl loss with danger of hypokalemia. Psychic changes, chiefly intheformofeuphoricormanicmoodswings, also need to be taken into account during chronic intakeofglucocorticoids.

Measures for attenuating or preventing drug-induced Cushing syndrome. (a) Use of cortisol derivatives with less (e.g., prednisolone) or negligible mineralocorticoid activity (e.g., triamcinolone, dexamethasone). Glucocorticoid activity of these congeners is more pronounced. Glucocorticoid, anti-inflammatory, and feedback-inhibitory (p.246) actions on the hypophysis are correlated. An exclusively anti-inflammatory congener does not exist. The “glucocorti- coid”-related Cushinglike symptoms cannot be avoided. The table opposite lists relative

activity (potency) with reference to cortisol, whose mineralocorticoid and glucocorticoid activities are assigned a value of 1.0. All listed glucocorticoids are effective orally.

(b) Local application. This enables therapeutically effective concentrations to be built up at the site of application without a correspondingsystemicexposure. Glucocorticoids that are subject to rapid biotransformation and inactivation following diffusion from the site of action are the preferred choice. Thus, inhalational administration employs glucocorticoids with a high presystemic elimination such as beclomethasone dipropionate, budesonide, flunisolide, or fluticasonepropionate(p.14).Adverseeffects,however,alsooccurlocally:e.g.,withinhalational use, oropharyngeal candidiasis (thrush) and hoarseness; with cutaneous use, skin atrophy, striae, telangiectasias and steroid acne; and with ocular use, cataracts and increased intraocular pressure (glaucoma).

(c) Lowest dosage possible. For long-term medication, a just-suf cient dose should be given. However, in attempting to lower the dose to the minimally effective level, it is necessary to take into account that administration of exogenous glucocorticoids will suppress production of endogenous cortisol owing to activation of an inhibitory feedback mechanism. In this manner, a very low dose could be “buffered,” so that unphysiologically high glucocorticoid activity and the anti-inflammatoryeffect arebothprevented.

Effect of glucocorticoid administration on adrenocortical cortisol production (A). Release of cortisol depends on stimulation by hypophyseal ACTH, which in turn is controlled by hypothalamic corticotropin-re- leasing hormone (CRH). In both in the hypophysis and hypothalamus there are cortisol receptors through which cortisol can exert a feedback inhibition of ACTH or CRH release. By means of these cortisol “sensors,” the regulatory centers can monitor whether the actual blood level of the hormone corresponds to the “set-point.” If the blood level

exceeds the set-point, ACTH output is decreased and thus also the cortisol production. In this way, cortisol level is maintained within the required range. The regulatory centers respond to synthetic glucocorticoids as they do to cortisol. Administration of exogenous cortisol or any other glucocorticoid reduces the amount of endogenous cortisol needed to maintain homeostasis. Release of CRH and ACTH declines (“inhibition of higher centers by exogenous glucocorticoid”) and, hence, cortisol secretion (“adrenocortical suppression”). After weeks of exposure tounphysiologically high glucocorticoid doses, the cortisol-producing portions of the adrenal cortex shrink (“adrenocortical atrophy”). Aldosterone-synthesizing capacity remains unaffected, however. When glucocorticoid medication is suddenly withheld, the atrophic cortex is unable to produce suf cient cortisol and a potentially lifethreatening cortisol deficiency may develop. Therefore, glucocorticoid therapy should always be tapered off by gradual reduction of the dosage.

Regimens for prevention of adrenocortical atrophy. Cortisol secretion is high in the early morning and low in the late evening (circadian rhythm). Accordingly, sensitivity to feedback inhibition must be high in the late evening.

(a)Circadian administration: The daily dose of glucocorticoid is given in the morning. Endogenous cortisol production will already have begun, the regulatory centers being relatively insensitive to inhibition. In theearlymorning hoursof thenextday, CRF/ ACTH release and adrenocortical stimulation will resume.

(b)Alternate day therapy: Twice the daily dose is given on alternate mornings. On the “off” day, endogenous cortisol production is allowed to occur.

The disadvantage with either regimen is a recrudescence of disease symptoms during the glucocorticoid-free interval.

Testosterone (T.) derivatives for clinical use. Because of its good tissue penetrability, testosterone is well suited for percutaneous administration in the form of a patch (transdermal delivery system, p.18). T. esters for i. m. depot injection are T. propionate and T. heptanoate (or enanthate). These are given in oily solution by deep intramuscular injection. Upon diffusion of the ester from the depot, esterases quickly split off the acyl residue to yield free T. With increasing lipophilicity, esters will tend to remain in the depot, and the duration of action therefore lengthens. A T. ester for oral use is the undecanoate. Owing to the fatty acid nature of undecanoic acid, this ester is absorbed into the lymph, enabling itto bypass the liver and enter the general circulation via the thoracic duct. 17-α Methyltestosterone is effective by the oral route owing to its increased metabolic stability, but because of the hepatotoxicityof C17-alkylated androgens(cholestasis, tumors) its use should be avoided.

Androgen receptor antagonists. The antiandrogen cyproterone is a competitive antagonist of testosterone. By virtue of an additional progestin action, it decreases secretion of gonadotropins. Indications: in the male, dampening of sexual drive in hypersexuality, prostatic cancer; in the female, treatment of virilization phenomena, if necessary, with concomitant utilization of the gestagen contraceptive effect.

Flutamide and bicalutamide are structurally different androgen receptor antagonists lacking progestin activity.

Finasteride and dutasteride inhibit 5α- reductase, the enzyme responsible for converting T. to dihydrotestosterone (DHT). Thus, androgenic stimulation is reduced in those tissues where DHT is the active species (e.g., the prostate). T.-dependent tissues and functions are not or hardly affected: e.g., skeletal musculature, feedback inhibition of gonadotropin release, or libido. Both can be used in benign prostatic hyperplasia to shrink the gland and to improve micturition.