Transcript Adrenocorticosteroids and Adrenocortical Antagonists

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 11βhydroxylase; results in atrophy
ACTH
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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
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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 68hrs.; 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:
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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 (2001200mg/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 (30040mg/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
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