Adrenocorticosteroids

and
Adrenocortical Antagonists
Ma. Victoria M. Villarica, M.D.
Fatima College of Medicine
 Adrenal Gland
• Adrenal cortex – mineralocorticoids,
glucocorticoids, adrenal androgens
(androstenedione and
dehydroepiadrosterone)
• 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 17α-hydroxylase and 11β-
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
 Steroid hormone production
• rate limiting step – conversion of
cholesterol to pregnanolone
• sources of cholesterol: circulating
cholesterol (LDL), cholesterol esterase, de
novo biosynthesis
 Adrenal Cortex
• Produce and releases natural
adrenocortical hormones
• Uses:
a. diagnosis and treatment of disorders of
adrenal function
b. treatment of inflammatory and
immunologic disorders
 Adrenocorticosteroids

Classification:
A. Mineralocorticoids
B. Glucocorticoids
C. Gonadal Androgens
 A. 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. 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 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 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.):
• 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.)
• 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:
• 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 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.)
• 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:
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.)
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.)
2. Adrenocortical hypo- 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: 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. Stimulation of fetal lung maturation –
betamethasone 12mg ffed by 12mg
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 dermatoses
8. GIT diseases – inflammatory bowel disease
9. Hepatic diseases – prednisolone – 80%
histologic remission in pts. with chronic, active
hepatitis
10. Malignancies – ALL, lymphomas
11. Cerebral edema
12. 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:
• 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
- 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
Adrenocorticosteroids
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
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 
Thank You