Post on 31-Dec-2015
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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