AdrenocorticosteroidsAdrenocorticosteroidsandand

Adrenocortical AntagonistsAdrenocortical Antagonists

Ma. Victoria M. Villarica, M.D.Ma. Victoria M. Villarica, M.D.

Fatima College of MedicineFatima College of Medicine

Adrenal GlandAdrenal Gland

• Adrenal cortex – mineralocorticoids, glucocorticoids, adrenal androgens (androstenedione and dehydroepiadrosterone)

• Adrenal medulla - catecholamines

Adrenal CortexAdrenal 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 17α-hydroxylase and 11β-hydroxylase; results in atrophy

ACTHACTH

• a peptide of 39 amino acids

• amino acids 15 – 18: high affinity binding

• amino acids 6 – 10: receptor activation

• synthesized from pro-opiomelanocortin (POMC)

ACTHACTH

• 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 secretionRegulation 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

Steroid hormone productionSteroid hormone production

• rate limiting step – conversion of cholesterol to pregnanolone

• sources of cholesterol: circulating cholesterol (LDL), cholesterol esterase, de novo biosynthesis

Adrenal CortexAdrenal Cortex

• Produce and releases natural adrenocortical hormones

• Uses:

a. diagnosis and treatment of disorders of adrenal function

b. treatment of inflammatory and immunologic disorders

AdrenocorticosteroidsAdrenocorticosteroids

Classification: A. Mineralocorticoids

B. Glucocorticoids

C. Gonadal Androgens

A. GlucocorticoidsA. Glucocorticoids

Naturally-occurring: Cortisol

Kinetics: 10-20 mg daily; circadian rhythm;

bound to CBG (90%), albumin (5%);

t ½ =60-90 mins.; liver; 1/3 excreted as

dihydroxyketone metabolites

B. MineralocorticoidsB. Mineralocorticoids

1. Aldosterone – zona glomerulosa

- promotes reabsorption of Na+ from the distal convoluted tubules and proximal collecting tubules; loosely coupled with K+ and H+ ions

- secreted at a rate of 100-200ug/d;

t ½ 15-20mins; excreted in the urine as tetrahydroaldosterone and 3-oxo-glucoronide

2. Deoxycortisone (DOC) – serves as precursor of aldosterone

3. Fludrocortisone – most widely used;

both mineralocorticoid and glucocorticoid activity

C. Adrenal AndrogensC. Adrenal Androgens

- dehydroepiandrosterone (DHEA) and

androstenedione

- 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 effectsPhysiologic effects

Carbohydrate and protein metabolism: protect glucose-dependent tissues from starvation

( gluconeogenesis, glycogen synthesis) periphery: ↓glucose utilization, ↑protein

breakdown (amino acids), activate lipolysis (glycerol)

catabolic effects: decrease muscle mass, atrophy of lymphoid tissue, negative nitrogen balance, thinning of the skin

Physiologic effects (cont.):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)• Electrolyte and water balance: enhances the

reabsorption of Na (aldosterone)

renal excretion of free water and interferes with

Ca uptake, while there is ↑Ca excretion by the kidneys (glucocorticoids)

Physiologic effects (cont.)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:Physiologic effects:

• Formed elements of blood: minor effects on hgb and erythrocyte production; affect circulating WBC (Addison’s: lymphocytosis, ↑ mass of lymphoid tissue)• Anti-inflammatory and Immunosuppressive action • alter immune response of lymphocytes - ↓release of vasoactive and chemoattractive factors, - diminished secretion of lipolytic and proteolytic enzymes - decreased extravasation of leukocytes to injury - decreased fibrosis - effect on cytokine production

Other effects:

↑amounts – insomnia, euphoria, depression, pseudomotor cerebri

↓amounts – psychiatric depression

large doses – peptic ulcer, promote fat distribution; vit D antagonist on Ca absorption; ↑ # of platelets and RBCs

absence – impaired renal function

fetal lung effects

Synthetic SteroidsSynthetic Steroids

Kinetics: source – cholic acid (cattle) or steroid

sapogenins (diosgenin, hecopenin); absorption: oral, IV, IM, sites of local administration

prolonged effects: occlusive dressing, large areas – may cause suppression of HPA axis

Kinetics (cont.)Kinetics (cont.)

• Transport: 90% bound to CBG (transcortin – high affinity but low total binding capacity) and albumin (low affinity but high binding capacity)

10% unbound

• Metabolism – liver

• Excretion - kidneys

Therapeutic Uses:Therapeutic Uses:A. Replacement Therapy 1. Adrenal Insufficiency a. Acute adrenal insufficiency ssx: GIT symptoms, dhn, hypoNa, hyperK, weakness, lethargy,

hypotension cause: disorder of the adrenal 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.)1. Adrenal Insufficiency (cont.) b. Chronic Adrenal Insufficiency (Addison’s disease) ssx:hyperpigmentation, wt. loss, inability to maintain fasting blood sugar, weakness, fatigue, hypotension cause: primary adrenal insufficiency, tuberculosis 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

Therapeutic Uses (cont.)Therapeutic Uses (cont.)2. Adrenocortical hypo- and hyperfunctioning2. Adrenocortical hypo- and hyperfunctioning

a. Congenital Adrenal Hyperplasiassx: 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 β 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

b. Cushing’s 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.B. Stimulation of fetal lung maturation – Stimulation of fetal lung maturation – betamethasone 12mg ffed by 12mg betamethasone 12mg ffed by 12mg 18-24 hrs. later 18-24 hrs. later

C.Nonendocrine Diseases 1. Rheumatic disorders – suppress the disease and minimize resultant tissue damage mgt: prednisone 10 mg/kg/day (taper thereafter by decreasing 1mg/kg/day every 2-3 wks) intraarticular injection: triamcinolone acetonide osteoarthritis : intraarticular injections with interval of 2-3 mos. to minimize complications

C. Non-Endocrine 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-Endocrine Diseases (cont.)

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

- onset of action of glucocorticoid is delayed

C. Non-Endocrine 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 les suppression of adrenal function (dysphonia or oropharyngeal candidiasis)

C. Non-Endocrine 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-Endocrine Diseases (cont.)

7. Skin diseases – inflammatory dermatoses8. GIT diseases – inflammatory bowel disease9. Hepatic diseases – prednisolone – 80% histologic remission in pts. with chronic, active hepatitis10. Malignancies – ALL, lymphomas 11. Cerebral edema12. Miscellaneous dis – Sarcoidosis (induce remission), thrombocytopenia (decrease bleeding tendency), organ transplantation, spinal cod injury

D. Diagnostic Application

• Dexamethasone suppression test – differentiates Cushing’s syndrome vs. stress and if Cushing’s syndrome, whether it’s an adrenal or a pituitary tumor

• Baseline cortisol levels are determined• Dexamethasone 0.5mg every 6hrs x 48

hrs. • Dexamethasone 2 mg every 6 hrs. x 48

hrs.

Toxicity: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 AgentsAntagonists 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

- treat hypercorticotism: 4 g/day

2. Aminoglutethimide – blocks the conversion of cholesterol to pregnanelolone and causes a reduction in the synthesis of all hormonally active steroids; breast Ca and Cushing’s syndrome due to adrenocortical Ca: 250 mg every 6hrs.

- enhances metabolism of dexamethasone

3. Ketoconazole – an antifungal imidazole derivative; potent, non-selective inhibitor of adrenal and gonadal steroid synthesis; tx of Cushing’s syndrome (200-1200mg/d)

4. Mifepristone (RU 486) –

11β-aminophenyl-substituted 19-norsteroid;

has strong anti-progestin activity; blocks

glucocorticoid receptor

5. Mitotane – adrenal Ca; 12 g/daily results in reduction in tumor mass; caution: adverse effects (80%)

6. Trilostane - 3β-17 hydroxysteroid dehydrogenase inhibitor that interferes

with the synthesis of adrenal and gonadal hormones

- comparable to aminogluthemide

B. Mineralocorticoid Antagonists

1. Spirinolactone – diagnosis of aldosteronism (400-500mg/day fro 4-8 days); preparing for surgery (300-40mg/day x 2 wks to reduce the incidence of arrhythmias); hirsutism in women (androgen antagonist 50-200mg/d x 2-6 mos); diuretic

2. Eplerenone – in clinical trials 3. Drospirenone – progestin in a new oral

contraceptive, antagonizes the effect of aldosterone

Classification of Classification of AdrenocorticosteroidsAdrenocorticosteroids

I. Short to medium-acting glucocorticoids:

a. Hydrocortisone (cortisol)

b. Cortisone

c. Prednisone

d. Prednisolone

e. Methylprednisolone

f. Meprednisone

II. Intermediate-acting glucocorticoidsII. Intermediate-acting glucocorticoids

a. Triamcinolone

b. Paramethasone

c. Fluprednisolone

III. Long-acting glucocorticoids a. Betamethasone

b. Dexamathasone

IV. Mineralocorticoids a. Fludrocortisone

b. desoxycorticosterone acetate

        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 

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