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244 Hormones

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

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

 

 

 

 

 

 

 

Glucocorticoid Therapy

245

A. Glucocorticoids: principal and adverse effects

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

e.g., allergy

 

 

Inflammation

 

Unwanted

 

 

 

autoimmune disease,

 

 

 

 

 

 

 

 

 

 

transplant rejection

 

 

redness,

 

 

 

 

 

 

 

 

 

 

 

 

swelling heat,

 

 

 

 

 

 

 

 

 

 

 

pain;

 

 

 

 

 

 

 

Healing of

 

 

scar

 

 

Wanted

 

 

 

tissue injury

 

 

 

 

 

 

 

 

due to bacteria,

 

 

 

 

 

 

 

 

 

 

viruses, fungi, trauma

 

 

 

Mineralocorticoid

 

 

 

 

 

Glucocorticoid

 

 

 

action

 

 

Unphysiologically

 

 

 

action

 

 

 

 

 

 

 

 

high concentration

 

 

 

 

Diabetes

 

 

Hypertension

 

 

 

 

 

 

 

 

mellitus

 

 

 

 

 

 

Cortisol

 

CH2OH

 

 

 

 

 

Na+

 

 

 

HO

 

C

O

 

 

Glucose

 

 

H2O

 

 

 

 

 

OH

 

 

 

 

 

 

 

 

 

 

 

 

Gluconeogenesis

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

 

 

 

 

Amino acids

 

 

 

K+

 

 

 

 

 

 

Protein catabolism

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1

Cortisol

 

1

 

Muscle

Tissue atrophy

 

 

0.8

Prednisolone

 

4

 

weakness

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Potency

0

Triamcinolone

 

7.5

 

Osteo-

 

 

Skin

 

0

Dexamethasone

30

 

porosis

 

 

atrophy

 

 

 

 

 

 

 

 

3000

Aldosterone

 

0.3

 

Growth inhibition

 

 

 

 

 

O CH2OH

 

 

 

 

 

CH2OH

 

 

 

HC C

O

 

 

 

 

 

 

C

O

 

 

 

HO

H

 

 

 

 

HO

 

OH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

Aldosterone

 

O

 

 

 

Prednisolone

 

 

 

 

 

 

 

 

 

 

 

 

CH2OH

 

 

 

CH2OH

 

 

 

 

C

O

 

 

 

C

O

 

 

 

 

 

 

HO

 

 

 

 

 

 

HO

OH

 

 

 

OH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CH3

 

 

 

 

 

 

OH

 

 

 

 

 

 

 

 

F

 

 

 

 

 

F

 

 

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

O

 

Triamcinolone

 

 

 

Dexamethasone

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

246 Hormones

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.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

 

 

 

 

 

Glucocorticoid Therapy

 

247

A. Cortisol release and its modification by glucocorticoids

 

 

 

 

Hypothalamus

 

 

 

 

 

 

 

 

CRH

 

 

 

 

 

 

 

 

 

 

Hypo-

 

 

 

 

 

 

 

 

 

physis

 

 

 

 

 

 

 

 

ACTH

 

 

 

 

Adreno-

 

 

 

 

 

 

 

 

 

cortical

 

 

 

 

 

 

 

 

 

atrophy

 

 

 

 

 

Adrenal

 

 

 

 

 

 

 

 

 

cortex

 

 

 

 

 

 

 

 

Cortisol

 

 

 

Exogenous

 

 

 

 

 

 

 

 

admini-

 

 

 

 

 

30 mg/day

 

 

stration

 

 

 

 

 

Cortisol

 

 

Decrease in

 

Cessation of

 

Cortisol deficiency

production under

 

cortisol production

cortisol production

after abrupt

 

normal

 

 

with cortisol dose

with cortisol dose

cessation of

 

 

conditions

 

 

< daily production

> daily production

administration

 

Cortisol

 

 

Glucocorticoid-induced

 

 

 

 

concentration

 

inhibition of cortisol production

 

 

 

 

 

 

 

normal circadian time-course

 

 

 

 

0

4

8

12

16

20

24

4

8

h

Morning dose

Inhibition of

 

Elimination of

 

Start of early

 

 

 

endogenous

 

exogenous

 

morning

 

 

 

 

cortisol

 

glucocorticoid

 

cortisol

 

 

 

 

production

 

during daytime

 

production

 

 

Glucocorticoid

 

 

 

 

 

 

 

 

concentration

 

 

 

 

 

 

 

 

0

4

8

12

16

20

24

4

8

h

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All rights reserved. Usage subject to terms and conditions of license.

248 Hormones

 

Androgens, Anabolic Steroids,

 

Orally active mesterolone is 1-α-methyldi-

 

Antiandrogens

 

 

 

hydrotestosterone.

 

Androgens are masculinizing substances.

Indication: for hormone replacement in

 

deficiency of endogenous T. production.

 

The endogenous male gonadal hormone is

 

Anabolics are testosterone derivatives

 

the steroid testosterone from the interstitial

 

(e.g.,clostebol,metenolone,nandrolone,sta-

 

Leydig cells of the testis. Testosterone secre-

 

nozolol) that are used in debilitated patients,

 

tion is stimulated by hypophyseal luteinizing

 

and are misused by athletes, because of their

 

hormone (LH), whose release is controlled

 

protein anabolic effect. They act via stimula-

 

by hypothalamic

GnRH

(gonadorelin,

 

tion of androgen receptors and, thus, also

 

p.238). Release of both hormones is subject

 

display androgenic actions (e.g., virilization

 

to feedback inhibition by circulating testo-

 

in females, suppression of spermatogenesis).

 

sterone. Reduction of testosterone to dihy-

 

 

 

drotestosterone occurs in most target organs

Inhibitory Principles

 

(e.g., the prostate gland);

the latter

pos-

 

GnRH superagonists (p.238), such as buser-

 

sesses higher af nity for androgen receptors.

 

elin, leuprolin, goserelin, and triptorelin, are

 

Rapid intrahepatic

degradation (plasma

 

 

t½~ 15 minutes) yields androsterone among

used in patients with metastasizing prostate

cancer to inhibit production of testosterone

other metabolites (17-ketosteroids) that are

which promotes tumor growth. Following a

eliminated as conjugates in the urine. Be-

transient stimulation, gonadotropin release

cause of rapid hepatic metabolism, testoster-

subsides within a few days and testosterone

one is unsuitable for oral use. Although it is

levels fall as low as after surgical removal of

well absorbed, it undergoes virtually com-

the testes.

plete presystemic elimination.

 

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.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Androgens, Anabolic Steroids, Antiandrogens

249

A. Testosterone

 

 

 

 

 

 

 

 

 

Hypothalamus

 

 

Substitution

 

 

O

 

 

 

 

 

 

 

 

 

O

C

 

 

 

 

GnRH

 

 

 

 

 

Testosterone

 

p.o.

 

 

 

 

 

 

 

undecanoate

 

 

 

 

 

 

transdermal

 

 

 

 

 

 

Hypophysis

 

 

 

 

 

 

 

 

 

 

LH

 

 

i.m.

 

 

Intestinal lymph

 

 

 

 

Testosterone ester

 

 

 

 

 

Testosterone

 

 

 

 

 

e.g., skeletal muscle fiber

 

 

 

 

 

 

 

 

 

 

OH

 

 

 

 

Androgen receptor

 

 

 

 

 

 

 

O

 

 

 

 

 

 

Gene expression

 

 

 

 

 

 

 

 

 

 

e.g., Prostatic

 

 

 

 

 

O

 

 

 

gland cell

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Conjugation with

 

 

 

 

 

 

 

 

 

5α -Reductase

 

 

 

 

 

 

 

sulfate, glucuronate

 

 

 

 

HO

 

H

 

 

 

 

 

 

 

 

 

H

 

 

 

 

 

O

 

 

 

Androsterone

 

 

 

 

 

 

 

 

 

 

 

 

 

Dihydro-

H H

 

 

 

 

 

 

 

 

 

testosterone

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

17-Keto-

 

 

 

 

 

 

 

 

 

 

steroid

I n h i b i t o r y P r i n c i p l e s

 

Receptor antagonists

 

 

 

 

 

 

 

GnRH superagonists

 

 

 

 

 

CH3

 

 

 

 

 

 

 

C

O

 

 

 

 

 

 

 

 

 

 

5α -Reductase inhibitor

 

 

H2C

 

 

O C

CH3

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

O

 

CH3

 

 

 

Cyproterone

 

C

NH

C

CH3

 

O

 

 

 

Cl

acetate

 

 

 

CH3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

F3C

Flutamide

CH3

 

 

 

 

 

 

 

 

 

O

N

Finasteride

O2N

NH

C

C

H

 

H

 

 

 

O

CH3

 

 

 

 

 

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

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