Adrenocorticosteroids

and
Adrenocortical Antagonists

Ma. Victoria M. Villarica RN, MD, DPPS, FPSECP

Fatima College of Medicine
 Objectives
• Review briefly the anatomy and physiology adrenal gland
• Name the different adrenocorticotropic hormones
• Identify adrenocorticotropic hormones and discuss their
pharmacokinetics and pharmacodynamics
• Classify adrenocorticoids according to their action and
potency
• Enumerate the clinical applications of adrenocorticotropic
hormones
• Discuss adrenocortical antagonists and their clinical
applications
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
- ACTH produces moderate stimulation of its
release
- receptors for angiotensin II and express
aldosterone synthase; do not atrophy
• Inner zone (zona fasciculata and reticularis) –
secrete glucocorticoids and adrenal androgens
- absence of ACTH results in atrophy
 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 hormone production
• rate limiting step – conversion of cholesterol
to pregnenolone
• sources of cholesterol: circulating cholesterol
(LDL), cholesterol esterase, de novo
biosynthesis
Lack of:
-21- α-hydroxylase (CYP21A2) → virilization
-11-β- deoxycorticosterone (CYP11β1) →
hypertension with of without hypokalemic
alkalosis
-17-α-hydroxylase (CYP17)→ hypogonadism;
hypertension with or without hypokalemic
alkalosis
 Steroidogenic Enzymes
Common name "Old" name Current name

Side-chain cleavage enzyme; P450SCC CYP11A1

desmolase

3 beta-hydroxysteroid 3 beta-HSD 3 beta-HSD

dehydrogenase
17 alpha-hydroxylase/17,20 lyase P450C17 CYP17

21-hydroxylase P450C21 CYP21A2

11 beta-hydroxylase P450C11 CYP11B1

Aldosterone synthase P450C11AS CYP11B2

Aromatase P450aro CYP19

 Adrenocorticosteroids

Classification:
A. Mineralocorticoids
B. Glucocorticoids
C. Adrenal Androgens
 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
- increase Na reabsorption in sweat, salivary glands. Gastric mucosa
- MOA: binds with mineralocorticoid receptor
- secreted at a rate of 100-200ug/d
- t ½ 15-20mins
- excreted in the urine as tetrahydroaldosterone and 3-oxo-glucoronide in 5-
15mcg/24 hr
Mineralocorticoids (cont.)
Deoxycortisone (DOC)
- 200 mcg/d; t ½ : 70mins.
- ↑ levels with adrenocortical carcinoma; CAH

Fludrocortisone
- both mineralocorticoid and glucocorticoid activity;
potent salt-retaining activity
- most widely used mineralocorticoid
- treatment of adrenocortical insufficiency
- oral dose: 0.1 mg 2 to 7X weekly
 B. Glucocorticoids
Cortisol – carbohydrate metabolism regulating,; intermediary
metabolism; immune function; synthesis and secretion is tightly
regulated by the CNS
- Hydrocortisone; compound F
- 10-20 mg daily; circadian rhythm (24-hour cycles)
- bound to CBG (90%); albumin (5%), free (5%)  exerts effect in target cells; if plasma
cortisol > 20-20mg/dl, CBG is saturated so concentration of free cortisol rises
- t ½ =60-90 mins.; > in hypothyroidism, stress, liver disease or if administered in large
amounts
- liver
- (glucoronic acid or sulfates)
- 1/3 excreted as dihydroxyketone (17-hydroxysteroids ) while 1% is unchanged
- excretion: 1% unchanged (free cortisol)
20% is converted to cortisone by 11-hydroxysteroid dehydrogenase
CBG (transcortin) – α 2 globulin (liver)

• Elevated: pregnancy, hyperthyroidism, estrogen

administration
• Diminished: hypothyroidism, protein deficiency,
genetic defects
• Synthetic Dexamethasone is bound to albumin rather
than CBG
• Dynamics:
MOA - bind to glucocorticoid receptors (cytosol):
(2 genes for glucocorticoid receptor)
(steroid receptor complex)
↓
interact with promoter and regulates
transcription (Hsp 90)
↓ nucleus
- alters gene expression by binding to
glucocorticoid-response element (GREs) and other transcription factors*
*e.g. AP1 and NF-kB – contributes to the regulation of transcription,
affecting growth factors, proinflammatory cytokines
THUS mediating ANTI-GROWTH, ANTI-INFLAMMATORY and
IMMUNOSUPPRESSIVE effects of glucocorticoids
* CLOCK/BMAL-1 – acetyltransferase related to glucocorticoid resistance
 Physiologic effects
- influence the function of most cells
- permissive effect:
diminished catecholamine response in vascular and bronchial
smooth muscle
attenuated lipolytic response to catecholamine ACTH and GH
in the absence of glucocorticoids
 Metabolic 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)
Muscle catabolism:
- ↑protein breakdown (amino acids)
- stimulate phosphoenol pyruvate carboxylase, G6-phosphatase and glycogen
synthase
- catabolic effects: decrease muscle mass, atrophy of lymphoid tissue, negative
nitrogen balance, thinning of the skin
 Metabolic 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 and glycerol)
- lipogenesis

• Electrolyte :
- ↑Ca excretion by the kidneys (antagonize vit.D effect on Ca
absorption)
 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

- suppressive effects on inflammatory cytokines, chemokines and other mediators of
inflammation
- alter immune response of lymphocytes , monocytes
and basophils
- reduces PGs, leukotrienes and PAF
- reduces expression of cyclooxygenase 2 (mast cell)
- ↓ capillary permeability by ↓ amount of histamine released by basophils and
mast cells
- reduced Ab production (large doses > 20g/d prednisone)
- inhibits complement activation
 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
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 (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
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 α hydroxylase)
Dx: ↑ response of 19-hydroxyprogesterone (urine) to ACTH stimulation
-17-hydroxyprogesterone to pregnanetriol in the urine
mgt: 1st seen as acute adrenal crisis

treatment in-utero: mothers at risk – glucocorticoid

therapy is initiated before 10 weeks gestation ffed by
genotyping and sex determination
once stabilized:
hydrocortisone (PO) 12-18mg/m2/d in 2
divided doses (2/3 AM 1/3 PM) or
0.6mg/k/d
+
fludrocortisone 0.05 – 0.2mg/d PO to maintain
normal BP, plasma renin activity and
electrolytes
Therapeutic Uses
2. Adrenocortical hypofunctioning and
hyperfunctioning (cont.)
b. Cushing’s syndrome
cause: pituitary adenoma, tumors of the adrenal gland,
ectopic production of ACTH by other tumors
ssx: round, phletoric face, truncal obesity,
muscle wasting, thinning, purple striae and
easy bruising of the skin, poor wound healing,
osteoporosis
mgt: surgery ; irradiation of pituitary tumor
hydrocortisone 300 mg IV on the day of the
surgery, then maintenance oral dose
 Therapeutic Uses
2. Adrenocortical hypofunctioning and
hyperfunctioning (cont.)
• C. Primary Generalized Glucocorticoid Resistance
(Chrousos syndrome) – rare sporadic or familial
genetic condition due to inactivating
mutations of the glucocorticoid receptor gene
 Therapeutic Uses
2. Adrenocortical hypofunctioning and
hyperfunctioning (cont.)
• D. Aldosteronism
- results from excessive production of aldosterone (adrenal tumor)
- ssx: HPN, weakness, tetany, hypoK, alkalosis, ↑ Na concentration
- secondary aldosteronism: low level of plasma renin activity and
angiotensin 2
Dx: ↑ ratio of plasma aldosterone to renin (>20mcg/24 hrs)
- plasma 18hydroxycortisone is assayed: >85ng/dl = adrenal tumors
<85ng/dl = non-diagnostic
Tx: spirinolactone
Tx: (after surgery) fludrocortisone 0.2 mg BID p.o. X 3days or
DOC acetate 20mg/d IM X 3days
B. Stimulation of fetal lung maturation –
Betamethasone 12mg ffed by 12mg 18-24 hrs. later (34
weeks AOG); less maternal protein binding and placental
metabolism

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 free-radical mediated cellular
injury ffng ischemia and reperfusion)
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

screening test: 1 mg dexamethasone oral at 11 PM then

obtain plasma sample in the morning
result: normal : < 3mcg/dl
Cushing’s : > 5mcg/dl

–
 To r/o depression, anxiety, concurrent illness,
Cushing’s
Liddle’s test:
1. Get urine sample and measure urinary ketosteroids
2. If elevated, proceed to #3
3. Dexamethasone 0.5mg every 6hrs x 48 hrs. – measure
urinary steroids ( if ↑, (+) Cushing’s; then proceed to #4
4. Dexamethasone 2 mg every 6 hrs. x 48 hrs.- measure
urinary steroids (if ↑, due to an adrenal tumor; if ↓, due to
a pituitary tumor)

ACTH level is low – adrenal tumor

ACTH level is elevated – ectopic ACTH –producing 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. ; 2-12 months HPA axis and 6-9
months after (return to normal)
Contraindications: peptic ulcer, heart disease or Hpn with
CHF, infections, psychoses, diabetes, osteoporosis, glaucoma
or herpes simplex infection
 Special precautions
• Hyperglycemia, glucosuria, Na retention with
edema, HPN, hypokalemia, peptic ulcer,
osteoporosis, hidden infections
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
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
 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 or
0.25g BID to 1 g 4x daily) ffed by urine collection) → there’s a 2-
fold ↑ in ACTH (pituitary) secretion and urinary steroids (11-
deoxycortisol)
- treat hypercorticotism: 4 g/day
- used for pregnant women with Cushing’s
- withdrawn in the market
Synthetic inhibitors and glucocorticoid antagonists (cont.)

2. Aminoglutethimide – blocks the conversion of

cholesterol to pregnenolone 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 (reduces
t ½)
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 Cushing’s syndrome –inoperable
(200-1000mg/d)
- se: hepatotoxicity
4. Mifepristone (RU 486) –
11β-aminophenyl-substituted 19-norsteroid; has strong anti-
progestin activity; blocks glucocorticoid receptor
- used for inoperable pts with ectopic ACTH secretion or adrenal
Ca who failed response to other tx
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 - 3β-17 hydroxysteroid dehydrogenase
inhibitor that interferes with the synthesis of adrenal and
gonadal hormones; 30 mg 4x a day
- comparable to aminogluthemide
7. Abiraterone – blocks 17 α hydroxylase and
17,20-lyase
- newest (clinical trials)
 Mineralocorticoid Antagonists

1. Spirinolactone – diagnosis of aldosteronism (400-

500mg/day for 5-8 weeks)
- preparing for surgery (300-400mg/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; 50-100mg/d
3. Drospirenone – progestin in a new oral contraceptive,
antagonizes the effect of aldosterone
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
 Dosage regimen
• Consider seriousness of the disease
• Consider amount of drug required to obtain
desired effect
• Consider duration of therapy
• Use lowest dose possible
• Consider amount required for maintenance of
the desired therapeutic effect
• Use alternate day administration
Summary of adrenocortical agonists
and antagonists……
• Review briefly the anatomy and physiology adrenal gland
• Name the different adrenocorticotropic hormones
• Identify adrenocorticotropic hormones and discuss their
pharmacokinetics and pharmacodynamics
• Classify adrenocorticoids according to their action and
potency
• Enumerate the clinical applications of adrenocortocotropic
hormones
• Discuss adrenocortical antagonists and their clinical
applications
Thank You