Pharmacologic Therapy of

Hyperfunction &
Hypofunction of The Adrenal
Gland

dr. Shirly Gunawan, Sp.FK
 
Hyperfunction:
 Cushing’s Syndrome
 Hyperaldosteronism

Hypofunction:
 Acute Adrenal Insufficiency
CUSHING’S SYNDROME

Possible Treatment Options Based on Etiology
Etiology

Nondrug
Treatment
Drug Name
Ectopic ACTH Surgery, Metyrapone
syndrome chemotherapy,
irradiation
Pituitary-dependent Surgery, irradiation Mitotane
Metyrapone
Mifepristone
Cyproheptadine
Adrenal adenoma Surgery, Ketokonazole
postoperative
replacement

Adrenal carcinoma Surgery Mitotane

 Pharmacologic Therapy

Four categories based on the anatomic site of action of
the agent:
 Steroidogenesis inhibitors
 Adrenolytics agents
 Neuromodulators of ACTH release
 Glucocorticoid-receptor blocking agents
 Steroidogenesis inhibitors

 Mechanism: block the production of cortisol
 Agents:
 Metyrapone
 Ketoconazole
 Etomidate
 Aminogluthetimid
 Metyrapone

 Inhibits 11 -hydroxylase
 Following administration: sudden  cortisol level
within hours  compensatory  plasma ACTH level
 adrenal steroidogenesis shunted toward androgen
production  significant androgenic side effect:
hirsutism, acne  less ideal for female
 Blocks aldosteron synthesis  weak
mineralocorticoid activity
 Ketokonazole

 The imidazole derivative antifungal
 Multiple mechanism (large doses)  inhibits multiple
CYP enzymes, 11 -hydroxylase, 17 α-hydoxylase
 Therapeutical effect achieved after several weeks
 Exhibit antiandrogenic activity  beneficial for females
but for males: gynecomastia & hypogonadism
 Other benefits:  total & LDL cholesterol level
 Significant side effect: ALT/AST (10%)
 May be used concomitantly with metyrapone 
sinergistic  cortisol level
 Etomidate

 The imidazole derivative
 Inhibits 11 -hydroxylase
 Only parenteral formulation  limited to acute
hypercortisolemia requiring emergecy treatment
 Aminogluthetimide

 Inhibits the conversion of cholesterol to
pregnenolone  inibiting production of cortisol,
aldosterone & androgen
  broad inhibitory actions  broad side effects 
limit the use
 High relapse rates
 Adrenolytics agents


 Agent: mitotane
 A cytotoxic drug, structurally resembles DDT
 Inhibits the 11-hydroxylation of 11-desoxycortisol &
11-desoxycortocosterone  inhibition of cortisol &
corticosterone
 Therapeutical effects after weeks to months
 Exerts cytotoxic effects: atrophy of the adrenal cortex
 Significant neurologic & GI side effects
Neuromodulators of ACTH release


 Pituitary secretion of ACTH mediated by various
neurotransmitters: serotonin, GABA, acetylcholine,
catecholamines 
 Agents: cyproheptadine, ritanserin, ketanserin,
bromocriptine, cabergoline, valproic acid, octreotide,
lanreotide, rosiglitazone, tretinoin
 Cyproheptadine: a non-selective serotonin receptor
antagonist & anticolinergic drug
 Significant side effect: sedation, weight gain  limitid
use
 Glucocorticoid-receptor blocking
agents

 Mifepristone (RU-486): a potent progesterone &
glucocorticoid-receptor antagonist
 Inhibits dexamethasone supression,  endogenous
cortisol & ACTH level
 Highly effective in reversing the manifestation of
hypercortisolism (hyperglicemia, hypertension, weight
gain)
 Induces a compensatory rise in ACTH & cortisol level
 efficacy & toxicity monitoring rely on clinical
sign rather than laboratory assessment
 Drug Monitoring

Drug Adverse Drug Reaction Monitoring Comments


Parameters
Aminogluthetimide Drowsiness, morbiliform Side effects often limit
rash, nausea, vomiting, use
hirsutism, headache,
ataxia
Cyproheptadine Anticholinergic effects Anticholinergic effects
(sedation, weight gain), often limit use
dizziness, blurred vision
Ketokonazole GI upset, dermatologic Liver function tests Approximatelly 10%
reaction, elevated hepatic will experience
transaminase, reversible LFT
hepatotoxicity (rare) elevations
 Drug Monitoring

Drug Adverse Drug Reaction Monitoring Comments

Parameters
Metyrapone Androgenic effects
(hirsutism, acne), blood
pressure & electrolyte

Blood pressure,
electrolytes

abnormalities, mausea,
vomiting, vertigo,
headche, dizziness,
abdominal discomfort,
allergic rash
Mifepristone Hypokalemia, nausea, Serum potassium, Abortifacient; rule out
fatigue, headache, pregnancy testing, pregnancy in woomen
peripheral edema, pelvic ultrasound of childbearing
dizziness, endometrial potentilal
hyperplasia
Mitotane GI upset, nausea, UFC and urinary GI upset up to 80%, GI
diarrhea, lethargy, steroid production, & CNS effects appear
somnolence, CNS serum potassium to be dose dependent
disturbances
 Clinical Controversy

 Traditional strategy for suppressing
hypercortisolism  titrating medications to achieve
normal cortisol level.
 Controversy  some clinicians advocate “a block &
replace” strategy  greater doses of medications
completely suppress endogenous cortisol
production, followed by administration of
physiologic due of glucocorticoid to treat adrenal
insufficiency
HYPERALDOSTERONISM

 Therapeutic Management

 BAH (Bilateral Adrenal Hyperplasia) -Dependent
Management:
 Spironolactone: a nonselective aldosterone receptor
antagonist
 Mechanism: competes with aldosterone for binding at
the receptor
 Activity at androgen & progeterone receptors &
inhibition of tetosterone biosynthesis  side effects:
gynecomastia, menstruation irregularities
 Alternative options: eplerenone, amiloride
 
 Eplerenone: a selective aldosterone receptor
antagonists with high affinity for the aldosterone
receptor & low affinity for androgen and
progesterone receptors

 Amiloride: a potassium-sparring diuretic, less

effective than spironolactone  require additional
therapy to control blood pressure
ADDISONIAN CRISIS
(Acute Adrenal Insufficiency)

 
 A true endocrine emergency  treatment as soon as
the diagnosis is suspected
 Therapy includes:
 Administration of glucocorticoid
 Correction of dehydration, hypovolemia, electrolyte
abnormalities
 General supportive measures
 Treatment of presipitating disorders
 Glucocorticoid Replacement

 Hydrocortisone 100 mg IV every 6 hours for 24 hours 
rapid response (12 hours) OR
Hydrocortisone 100 mg IV (rapid infusion) followed by
continuous infusion (usually 10 mg/h) or intermittent
bolus of 100 to 200 mg every 24 hours

 The patient is stable  ↓ dosage to 50 mg every 6 hour on

the 2nd day
 Taper to maintenance therapy by day 4 or 5 (3 x 10 mg/ day)
 Maintain or ↑ dosage to 200-400mg/day if complication
(sepsis) occur
 General & Supportive Measures

 Fluid replacement with dextrose 5% in normal saline
solution (D5NS)  support blood pressure
 During initial phase  mineralocoticoid replacement
generally unnecessary because of hydrocortisone’s
activity (hydrocotisone 50 mg  fludrocortisone 0,1
mg)
 If hyperkalemia present after the hydrocortisone
mantenance phase  additional mineralocorticoid
supplementation: fludrocortisone acetate 0,1 mg daily
 
 IM cortisone acetate is CONTRAINDICATED
because:
 Absorption is slow
 It requires conversion to cortisol in the liver
 Adequate plasma levels of cortisol are not obtained
 There is inadequate suppression of plasma ACTH
levels  indicating insufficient glucocorticoid activity
 Maintenance Therapy

 life-long glucocorticoid & mineralocorticoid therapy:
 Hydrocortisone 10-15 mg in a.m. (≈basal
production), 5-10 mg in the afternoon (4-5 p.m.) 
prevent side effect: insomnia
 Fludrocortisone 0,05-0,1 mg PO in a.m. (long t ½ 
once a day)
 Increased hydrocortisone dosage during “stress” 
minor stress (double dose), major stress: surgery
(200-300mg/d)
 Response to Therapy

 Adequacy of replacement
 general clinical signs: good appetite & sense of well-
being
 disappearance of weakness, malaise, fatigue,
anorexia. Weight  N, hyperpigmentation improve
 Adequate mineralocorticoid  blood pressure &
electrolytecompotition improve
 Signs of Cushing’s Syndrome  overtreatment
 !!! Excessive dose of glucocorticoids  ↑ risk of
osteoporosis  maintain the lowest amount
 Prevention of Adrenal Crisis

 Patient education  carry card, wear bracelet or
necklace
 Increased glucocorticoid dosage during illness: 60-80
mg/d
Thank You
