Adrenocorticosteroids and Adrenocortical Antagonists

Ma. Victoria M. Villarica, M.D. Fatima College of Medicine

Objectives
Review briefly the adrenal gland Name the different adrenocorticotropic hormones and discuss their effects Identify uses of adrenocorticotropic hormones

Types of steroid hormones

Glucocorticoids; cortisol is the major representative in most mammals Mineralocorticoids; aldosterone being most prominent Androgens such as testosterone Estrogens, including estradiol and estrone Progestogens (also known a progestins) such as progesterone

Adrenal Gland
Adrenal cortex mineralocorticoids, glucocorticoids, adrenal androgens Adrenal medulla - catecholamines

Adrenal Cortex
Outer zone (zona glomerulosa) secretes mineralocorticoids - receptors for angiotensin II and express aldosterone synthase; do not atrophy Inner zone (zona fasciculata and reticularis) secrete glucocorticoids and adrenal androgens - expresses 17-hydroxylase and 11-hydroxylase;
results in atrophy

ACTH
a peptide of 39 amino acids amino acids 15 18: high affinity binding amino acids 6 10: receptor activation synthesized from pro-opiomelanocortin (POMC)

ACTH
Stimulates the synthesis and release of adrenocortical hormones Human ACTH G-protein coupled receptor family activates adenyl cyclase intracellular cyclic AMP (2nd messenger for most steroidogenesis)

Regulation of ACTH secretion

Hypothalamic Pituitary Adrenal axis (HPA axis) - 3 levels of regulation: 1. diurnal rhythm in basal steroidogenesis 2. negative feedback regulation 3. marked increases in steroidogenesis in response to stress

Control of Endocrine Activity

The physiologic effects of hormones depend largely on their concentration in blood and extracellular fluid. Almost inevitably, disease results when hormone concentrations are either too high or too low, and precise control over circulating concentrations of hormones is therefore crucial.

Steroid hormones
All steroid hormones are derived from cholesterol and differ only in the ring structure and side chains attached to it. All steroid hormones are lipid soluble

Extracellular lipoprotein

LH
Cholesterol pool

acetate

ATP cAMP

cholesterol PKA+
Pregnenolone

3bHSD

Progesterone Androstenedione

P450c17
17bHSD

TESTOSTERONE

Steroid hormone production

rate limiting step conversion of cholesterol to pregnenolone sources of cholesterol: circulating cholesterol (LDL), cholesterol esterase, de novo biosynthesis Lack of: - 21--hydroxylase virilization - 11-- hydroxylase hypertension - 17--hydroxylase hypogonadism

Steroidogenic Enzymes
Common name
Side-chain cleavage enzyme; desmolase 3 beta-hydroxysteroid dehydrogenase 17 alpha-hydroxylase/17,20 lyase 21-hydroxylase 11 beta-hydroxylase Aldosterone synthase

"Old" name
P450SCC 3 beta-HSD P450C17 P450C21 P450C11 P450C11AS

Current name
CYP11A1 3 beta-HSD CYP17 CYP21A2 CYP11B1 CYP11B2

Aromatase

P450aro

CYP19

Adrenocorticosteroids
Classification:

A. Mineralocorticoids B. Glucocorticoids C. Adrenal Androgens

A. Mineralocorticoids
Aldosterone electrolyte-balance regulating, saltretaining activity
- promotes reabsorption of Na+ from the distal convoluted tubules and proximal collecting tubules; loosely coupled with K+ and H+ ions excretion - secreted at a rate of 100-200ug/d - t 15-20mins - excreted in the urine as tetrahydroaldosterone and 3-oxo-glucoronide

B. Glucocorticoids
Cortisol carbohydrate metabolism regulating,; intermediary metabolism; immune function
- 10-20 mg daily; circadian rhythm - bound to CBG (90%), albumin (5%) - t =60-90 mins.; - liver (glucoronic acid or sulfates) - 1/3 excreted as 17-hydroxysteroids while 1% is unchanged

CBG (transcortin)
Elevated: pregnancy, hyperthyroidism, estrogen administration Diminished: hypothyroidism, protein deficiency, genetic defects

C. Adrenal Androgens
- Dehydroepiandrosterone (DHEAs) and androstenedione androgenic-estrogenic activity - they do not stimulate or support major androgen dependent pubertal changes in humans) - used in SLE and women with adrenal insufficiency

 Dynamics: MOA - bind to cytosol receptors (steroid receptor complex) - alters gene expression by binding to glucocorticoid-response element (GREs)

Physiologic effects
Carbohydrate metabolism: - protect glucose-dependent tissues from starvation - stimulate gluconeogenesis, glycogen synthesis in the fasting state glucose lipolysis FFA insulin release periphery: glucose utilization and lipogenesis ( fat deposition) Protein metabolism: - protein breakdown (amino acids) - catabolic effects: decrease muscle mass, atrophy of lymphoid tissue, negative nitrogen balance, thinning of the skin

Physiologic effects (cont.):

Lipid metabolism: - redistribution of body fat (buffalo hump, moon facies, supraclavicular area with loss of fat in the extremities) - induce lipolysis in adipocytes ( FFA) - lipogenesis Electrolyte and water balance: - enhances the reabsorption of Na (aldosterone) and renal excretion of free water and interferes with Ca uptake, while there is Ca excretion by the kidneys (glucocorticoids)

Physiologic effects (cont.)

Cardiovascular system: - mineralocorticoid-induced changes hpn - enhance vascular reactivity to other vasoactive substances Skeletal muscle: - normal function (steroid myopathy) CNS: - neurosteroids (regulate neuronal excitability)

Physiologic effects (cont.):

Formed elements of blood:
- minor effects on hgb and erythrocyte production - affect circulating WBC (Addisons: lymphocytosis, mass of lymphoid tissue) Anti-inflammatory and Immunosuppressive action - alter immune response of lymphocytes , monocytes and basophils - release of vasoactive and chemoattractive factors - extravasation of leukocytes to injury - secretion of lipolytic and proteolytic enzymes - effect on cytokine production - fibrosis

Other effects: amounts: - insomnia, euphoria, depression, pseudomotor cerebri, roid rage - peptic ulcer, promote fat redistribution - vit D antagonist on Ca absorption (bone resorption) - # of platelets and RBCs amounts: - psychiatric depression absence: - impaired renal function and fetal lung effects

Synthetic Steroids
source cholic acid (cattle) or steroid sapogenins (diosgenin, hecopenin); absorption: oral, IV, IM, sites of local administration - prolonged effects with occlusive dressing - large areas may cause suppression of HPA axis

Classification of Glucocorticoids
I. Short to medium-acting glucocorticoids: a. Hydrocortisone (cortisol) b. Cortisone c. Prednisone d. Prednisolone e. Methylprednisolone f. Meprednisone

II. Intermediate-acting glucocorticoids

a. Triamcinolone b. Paramethasone c. Fluprednisolone

III. Long-acting glucocorticoids

a. Betamethasone b. Dexamathasone

IV. Mineralocorticoids
1. Deoxycortisone (DOC) serves as precursor of aldosterone

2. Fludrocortisone most widely used;

both mineralocorticoid and glucocorticoid activity; potent salt-retaining activity - treatment of adrenocortical insufficiency

Uses:
A. Diagnosis and treatment of disorders of adrenal function B. Treatment of inflammatory and immunologic disorders

Therapeutic Uses:
A. Replacement Therapy 1. Adrenal Insufficiency a. Acute adrenal insufficiency (acute adrenal crisis)
ssx: GIT symptoms, dhn, hypoNa, hyperK, weakness, lethargy, hypotension cause: - destructive lesions secondary to surgery; TB of the adrenals; bilateral adrenal hgge - abrupt withdrawal of glucocorticoids at high doses or prolonged use mgt: IV : D5 0.3%NaCl solution Monitor for fluid overload Hydrocortisone (cortisol) 100mg bolus, ffed by 100mg every 8 hrs. ; once stable, may give 25mg IM hydrocortisone every 6-8hrs.; thereafter, same mgt with chronic adrenal insufficiency

1. Adrenal Insufficiency (cont.)

b. Chronic Adrenal Insufficiency (Addisons disease) ssx: hyperpigmentation, wt. loss, inability to maintain fasting blood sugar, weakness, fatigue, hypotension cause: APECED (autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy) mgt: Hydrocortisone 20-30mg/day BID + Fludrocortisone acetate 0.05 0.2mg/day (valuable indicator of adequate replacement: disappearance of hyperpigmentation and resolution of electrolyte abnormalities) -monitor plasma ACTH levels or measure urinary free cortisol; dosage adjustments for stress

Addison described : . general languor and debility . remarkable feebleness of the heart's action . irritability of the stomach . peculiar change of the color of the skin

Therapeutic Uses (cont.) 2. Adrenocortical hypofunctioning and hyperfunctioning

a. Congenital Adrenal Hyperplasia
ssx: - after puberty with infertility, hirsutism, amenorrhea and acne; female pseudohermaphroditism; accelerated linear growth but height at maturity is reduced; - salt wasters CV collapse (volume depletion) cause: Genetic disorder; activity of enzymes required for the biosynthesis of corticosteroid is deficient (21 hydroxylase) mgt: 1st seen as acute adrenal crisis oral hydrocortisone 0.6mg/kg/day BID or TID fludrocortisone acetate 0.05-0.2mg/day treatment in-utero: mothers at risk glucocorticoid therapy is initiated before 10 weeks gestation ffed by genotyping and sex determination

Therapeutic Uses 2. Adrenocortical hypofunctioning and hyperfunctioning (cont.)

b. Cushings syndrome cause: pituitary adenoma, tumors of the adrenal gland ssx: round, phletoric face, truncal obesity,
muscle wasting, thinning, purple striae and easy bruising of the skin, poor wound healing, osteoporosis mgt: surgery hydrocortisone 300 mg IV on the day of the surgery, then maintenance oral dose

B. Stimulation of fetal lung maturation

betamethasone 12mg ffed by 12mg 18-24 hrs. later

C. Non-Adrenal Diseases
1. Rheumatic disorders suppress the disease and minimize resultant tissue damage mgt: oral prednisone 10 mg/kg/day (taper thereafter by decreasing 1mg/kg/day every 2-3 wks) - intraarticular injection: triamcinolone acetonide: minimize complications (3-4x/year)

C. Non-Adrenal Diseases (cont.)

2. Renal Disorders nephrotic syndrome mgt: prednisone: 1-2 mg/kg x 6 wks, ffed. by gradual tapering over 6-8 wks or alternate-day therapy (diminished proteinuria in 85% pts in 2-3 wks and 95% pts will have remission in 3 mos. - membranous glomerulonephritis mgt: alternate-day prednisone 8-10 wks ffed by 1-2 month period of tapering

C. Non- Adrenal Diseases (cont.)

3. Allergic Disease: onset of action of glucocorticoid is delayed (6-12hrs.)

anaphylaxis: epinephrine 0.5ml of a 1:1000 solution IM or SQ, repeated every 15 mins up to 3 doses is needed (anaphylaxis)

C. Non-Adrenal Diseases (cont.) 4. Bronchial Asthma role of inflammation in the

immunopathogenesis - onset of action is delayed for 6 12 hrs.

mgt: IV methylprednisolone 60-120mg initially ffed. by

oral prednisone 40-60mg daily as the attack resolves

inhaled steroids reduces bronchial hyperreactivity with

less suppression of adrenal function (SE: dysphonia or oropharyngeal candidiasis) ex: beclomethasone dipropionate, budesonide phosphate, flunisolide, fluticasone, momethasone furoate, triamcinolone acetonide

C. Non-Adrenal Diseases (cont.) 5. Infectious Disease P. carinii pneumonia increases

oxygenation and decreases the incidence of respiratory failure and mortality H. influenzae type b meningitis decrease the long-term neurological impairment

6. Ocular disease 0.1% dexamethasone - C/I: herpes simplex keratitis (clouding of the cornea) , glaucoma

C. Non-Adrenal Diseases (cont.) 7. Skin diseases inflammatory dermatoses 8. GIT diseases inflammatory bowel disease 9. Hepatic diseases prednisolone 80% histologic remission in pts. with chronic, active hepatitis 10. Malignancies ALL, lymphomas

C. Non-Adrenal Diseases (cont.)

11. Cerebral edema neoplasms and parasitic infections but not in CVA or trauma 12. Miscellaneous dis Sarcoidosis (induce remission), thrombocytopenia (decrease bleeding tendency), organ transplantation (reduce Ag expression from grafted tissues, delayed revascularization, interferes with cytotoxic T-lymphocytes and generation of primary Ab formation), spinal cord injury (within 1st 8 hrs: inhibition of freeradical mediated cellular injury ffng ischemia and reperfusion)

D. Diagnostic Application dexamethasone:

suppress production of ACTH

Dexamethasone suppression test differentiates

Cushings syndrome vs. stress and if Cushings syndrome, whether its an adrenal or a pituitary tumor 1. Baseline cortisol levels are determined -urine: 17-hydroxycorticosteroids LIDDLES test 2. Dexamethasone 0.5mg every 6hrs x 48 hrs. measure urinary steroids ( if , (+) Cushings) 3. Dexamethasone 2 mg every 6 hrs. x 48 hrs.measure urinary steroids (if , due to an adrenal tumor; if , due to a pituitary tumor)

Toxicity:
Withdrawal of therapy: ssx: fever, myalgias, arthralgias, malaise, pseudomotor cerebri ( ICP, papilledema) Continued use at supraphysiologic doses ssx: fluid and electrolyte abnormalities, hypertension, hyperglycemia, increased susceptibility to infection, myopathy, behavioral disturbances, cataracts, growth arrest and fat redistribution, acne, hirsutism, striae, ecchymoses, osteonecrosis, peptic ulcer Adrenal suppression - >2 wks.

Contraindications: peptic ulcer, heart disease or Hpn with CHF,

infections, psychoses, diabetes, osteoporosis, glaucoma or herpes simplex infection

Supplemental measures:
Diet rich in potassium and low in sodium Caloric mgt to prevent obesity High protein intake Appropriate antacid therapy Calcium and vit D, physical therapy Alendronate biphosphonate

Antagonists of Adrenocortical Agents

A. Synthetic inhibitors and glucocorticoid antagonists 1. Metyrapone inhibits 11-hydroxylation, interfering with
cortisol and corticosterone synthesis (0.25g BID to 1g QID)

- used in tests of adrenal function (300-500mg q 4hrs. X

6doses, ffed by urine collection) theres a 2-fold in urinary steroids

- treat hypercorticotism: 4 g/day

Synthetic inhibitors and glucocorticoid antagonists (cont.)

2. Aminoglutethimide blocks the conversion of

cholesterol to pregnanenolone and causes a reduction in the synthesis of all hormonally active steroids - breast Ca and Cushings syndrome due to adrenocortical Ca: 250 mg every 6hrs. - enhances metabolism of dexamethasone

Synthetic inhibitors and glucocorticoid antagonists (cont.)

3. Ketoconazole an antifungal imidazole derivative;

potent, non-selective inhibitor of adrenal and gonadal steroid synthesis; hepatotoxic - inhibits cholesterol side chain cleavage - tx of Cushings syndrome inoperable (200-1000mg/d)

4. Mifepristone (RU 486)

11-aminophenyl-substituted 19-norsteroid;
has strong anti-progestin activity; blocks glucocorticoid receptor

Synthetic inhibitors and glucocorticoid antagonists (cont.)

5. Mitotane adrenal Ca; 12 g/daily results in reduction

in tumor mass; caution: adverse effects (80%: LBM, nausea, vomiting, somnolence, skin rashes)

6. Trilostane - 3-17 hydroxysteroid dehydrogenase

inhibitor that interferes with the synthesis of adrenal and gonadal hormones; 30 mg 4x a day - comparable to aminogluthemide

Mineralocorticoid Antagonists
1. Spirinolactone diagnosis of aldosteronism (400500mg/day for 5-8 weeks) - preparing for surgery (300-40mg/day x 2 wks to reduce the incidence of arrhythmias) - hirsutism in women (androgen antagonist at 50-200mg/d x 2-6 mos) - diuretic - treatment of primary hyperaldosteronism (Conns syndrome) 2. Eplerenone in clinical trials 3. Drospirenone progestin in a new oral contraceptive, antagonizes the effect of aldosterone

Hyperldosteronism 1. primary hyperaldosteronism due to an adrenal adenoma (ssx: hypoK, alkalosis, hyperNa HPN, weakness and tetany 2. secondary hyperaldosteronism due to low plasma renin, angiotensin II

Classification of topical corticosteroids based on their potencies

Very potent
Clobetasol propionate 0.05% Betamethasone dipropionate 0.05% Diflucortolone valerate 0.3% Halcinonide 0.1%

Classification of topical corticosteroids based on their potencies (continued)

Potent
Beclomethasone dipropionate 0.025% and 0.05%
Betamethasone valerate 0.1% Budesonide 0.025% Desoxymethasone 0.25% Difluocinolone 0.025% and 0.05% Fluticasone propionate 0.05% Hydrocortisone 17-butyrate 0.1% Momethasone furoate 0.1% Triamcinolone aceonide 0.1%

Classification of topical corticosteroids based on their potencies (continued)

Moderately potent
Betamethasone valerate 0.025% and 0.05% Clobethasone butyrate 0.05% Fluocinolone acetonide 0.01% Fludroxycortide 0.0125%-0.05% Hydrocortisone 1% with urea Triamcinolone acetonide 0.02% and 0.05%

Classification of topical corticosteroids based on their potencies (continued)

Mildly potent
Aclomethasone dipropionate 0.05% Desonide 0.05% Fluocinolone base or acetate 0.1% - 2.5% Methylprednisolone 0.25%

Common side effects of topical corticosteroids

Skin atrophy Striae (groin and axillae) Slowed healing Telangiectasia Purpura Rosacea Acne Perioral dermatitis Hypertrichosis

Summary of adrenocortical agonists and antagonists

Review briefly the adrenal gland Name the different adrenocorticotropic hormones and discuss their effects Identify uses of adrenocorticotropic hormones

Thank You