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Adrenocorticosteroids
Adrenocorticosteroids
Adrenocorticosteroids
Adrenocorticosteroids
Adrenocorticosteroids
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Adrenocorticosteroids

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wed may 5, NOT ON THE MIDTERM

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  • 1. Adrenocorticosteroids and Adrenocortical Antagonists Ma. Victoria M. Villarica, M.D. Fatima College of Medicine
  • 2. Objectives
    • Review briefly the adrenal gland
    • Name the different adrenocorticotropic hormones and discuss their effects
    • Identify uses of adrenocorticotropic hormones
  • 3.  
  • 4. 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
  • 5. Adrenal Gland
    • Adrenal cortex – mineralocorticoids, glucocorticoids, adrenal androgens
    • Adrenal medulla - catecholamines
  • 6.  
  • 7. 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 α - hydroxylase and 11 β - hydroxylase; results in atrophy
  • 8. 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)
  • 9. ACTH
    • Stimulates the synthesis and release of adrenocortical hormones
    • Human ACTH – G-protein coupled receptor family -> activates adenyl cyclase -> ↑ intracellular cyclic AMP (2 nd messenger for most steroidogenesis)
  • 10. 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
  • 11. 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.
  • 12.  
  • 13.  
  • 14.
    • 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
    Steroid hormones
  • 15. cholesterol Extracellular lipoprotein Cholesterol pool LH ATP cAMP PKA+ Pregnenolone Progesterone Androstenedione TESTOSTERONE 3  HSD P450c17 17  HSD acetate
  • 16. 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- β -hydroxylase -> virilization
    • 11- β - hydroxylase -> hypertension
    • 17- α -hydroxylase -> hypogonadism
  • 17.  
  • 18. Steroidogenic Enzymes Common name "Old" name Current name Side-chain cleavage enzyme; desmolase P450 SCC CYP11A1 3 beta-hydroxysteroid dehydrogenase 3 beta-HSD 3 beta-HSD 17 alpha-hydroxylase/17,20 lyase P450 C17 CYP17 21-hydroxylase P450 C21 CYP21A2 11 beta-hydroxylase P450 C11 CYP11B1 Aldosterone synthase P450 C11AS CYP11B2 Aromatase P450 aro CYP19
  • 19. Adrenocorticosteroids
    • Classification :
    • A. Mineralocorticoids
    • B. Glucocorticoids
    • C. Adrenal Androgens
  • 20. A. Mineralocorticoids
    • Aldosterone – electrolyte-balance regulating, salt-retaining 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 ½ 15-20mins
    • - excreted in the urine as tetrahydroaldosterone and 3-oxo-glucoronide
  • 21. B. Glucocorticoids
    • Cortisol – carbohydrate metabolism regulating,; intermediary metabolism; immune function
    • - 10-20 mg daily; circadian rhythm
    • - bound to CBG (90%), albumin (5%)
    • - t ½ =60-90 mins.;
    • - liver (glucoronic acid or sulfates)
    • - 1/3 excreted as 17-hydroxysteroids while 1% is unchanged
  • 22. CBG (transcortin)
    • Elevated: pregnancy, hyperthyroidism, estrogen administration
    • Diminished: hypothyroidism, protein deficiency, genetic defects
  • 23. 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
  • 24.
    • Dynamics:
    • MOA - bind to cytosol receptors (steroid receptor complex)
    • - alters gene expression by binding to glucocorticoid-response element (GREs)
  • 25. 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
  • 26. 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)
  • 27. 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)
  • 28. Physiologic effects (cont.):
    • 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 , 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
  • 29.
    • 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
  • 30. 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
  • 31. Classification of Glucocorticoids
    • I. Short to medium-acting glucocorticoids:
    • a. Hydrocortisone (cortisol)
    • b. Cortisone
    • c. Prednisone
    • d. Prednisolone
    • e. Methylprednisolone
    • f. Meprednisone
  • 32. II. Intermediate-acting glucocorticoids
    • a. Triamcinolone
    • b. Paramethasone
    • c. Fluprednisolone
    • III. Long-acting glucocorticoids
    • a. Betamethasone
    • b. Dexamathasone
  • 33.
    • 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
    IV. Mineralocorticoids
  • 34. Uses:
    • A. Diagnosis and treatment of disorders of adrenal function
    • B. Treatment of inflammatory and immunologic disorders
  • 35. 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
  • 36. 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: 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
  • 37.
    •           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 
  • 38.  
  • 39. 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 β hydroxylase)
    • mgt: 1 st 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
  • 40. Therapeutic Uses 2. Adrenocortical hypofunctioning and hyperfunctioning (cont.)
    • 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
  • 41. 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)
  • 42. 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
  • 43. 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)
  • 44. 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
  • 45. 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
  • 46. 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
  • 47. 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 free-radical mediated cellular injury ffng ischemia and reperfusion)
  • 48. D. Diagnostic Application – dexamethasone: suppress production of ACTH
    • 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
    • -urine: 17-hydroxycorticosteroids – LIDDLE’S test
    • Dexamethasone 0.5mg every 6hrs x 48 hrs. – measure urinary steroids ( if ↑, (+) Cushing’s)
    • Dexamethasone 2 mg every 6 hrs. x 48 hrs.- measure urinary steroids (if ↑, due to an adrenal tumor; if ↓, due to a pituitary tumor)
  • 49.  
  • 50. 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
  • 51. 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
  • 52. Antagonists of Adrenocortical Agents
    • 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) -> there’s a 2-fold ↑ in urinary steroids
    • - treat hypercorticotism: 4 g/day
  • 53. 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 Cushing’s syndrome due to adrenocortical Ca: 250 mg every 6hrs.
    • - enhances metabolism of dexamethasone
  • 54.
    • 3. Ketoconazole – an antifungal imidazole derivative; potent, non-selective inhibitor of adrenal and gonadal steroid synthesis; hepatotoxic
    • - inhibits cholesterol side chain cleavage
    • - tx of Cushing’s syndrome –inoperable
    • (200-1000mg/d )
    • 4 . Mifepristone (RU 486) –
    • 11 β -aminophenyl-substituted 19-norsteroid;
    • has strong anti-progestin activity; blocks
    • glucocorticoid receptor
    Synthetic inhibitors and glucocorticoid antagonists (cont.)
  • 55.
    • 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 β -17 hydroxysteroid dehydrogenase inhibitor that interferes with the synthesis of adrenal and gonadal hormones; 30 mg 4x a day
    • - comparable to aminogluthemide
    Synthetic inhibitors and glucocorticoid antagonists (cont.)
  • 56.  
  • 57.
    • Mineralocorticoid Antagonists
    • 1. Spirinolactone – diagnosis of aldosteronism (400-500mg/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 (Conn’s syndrome)
    • 2. Eplerenone – in clinical trials
    • 3. Drospirenone – progestin in a new oral contraceptive, antagonizes the effect of aldosterone
  • 58.
    • 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
  • 59. 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%
  • 60. 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%
  • 61. 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%
  • 62. 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%
  • 63. Common side effects of topical corticosteroids
    • Skin atrophy
    • Striae (groin and axillae)
    • Slowed healing
    • Telangiectasia
    • Purpura
    • Rosacea
    • Acne
    • Perioral dermatitis
    • Hypertrichosis
  • 64. 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
  • 65.
    • Thank You

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