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Adrenocortical Fiancee Lee A.

Banzon
Steroids
Adrenal
Cortex

Adrenal
Medulla
Hormones of
adrenal medulla
Catecholamines secreted by
adrenal medulla
1. Adrenaline or epinephrine
2. Noradrenaline or
norepinephrine
3. Dopamine.
Hormones of adrenal cortex
• Adrenocortical hormones are steroids in nature, hence the name
‘corticosteroids’.
• Based on their functions, corticosteroids are classified into three
groups:
1. Mineralocorticoids
2. Glucocorticoids
3. Adrenal Androgens (Sex hormones)
Androgenic Hormones (testosterone and androstenedione.
muscle building)
Anabolic hormones (Synthetic male sex hormone testosterone)
Androgenic Hormones
(testosterone and
androstenedione)
Anabolic
hormones

(Synthetic male
sex hormone
testosterone)
Mineralocorticoids
• Affect the electrolytes “minerals” of the
extracellular fluids
• influence salt and water balances
• Mineralocorticoids are:
1. Aldosterone (very potent, accounts for 90% of all
mineralocorticoid activity)
2. Deoxycorticosterone (1/30 as potent as aldosterone,
but very small quantities secreted)
3. Fludrocortisone (synthetic, slightly more potent than
aldosterone)
Glucocorticoids
• Act mainly on
a. glucose metabolism
b. anti-inflammatory
c. immunosuppressive
• secreted by
a. zona fasciculata
b. zona reticularis

• production
a. diurnal
Glucocorticoids
1. Cortisol syn hydrocortisone (very slight
mineralocorticoid activity, but large
quantity secreted)
2. Methylprednisone (synthetic, five times
as potents as cortisol
3. Prednisone widely used prodrug
4. Prednisolone (active metabloite)
5. Dexamethasone (30 times as potent as cortisol)
6. Corticosterone
7. Cortisone synthetic, slight mineralocorticoid activity)
MOA: Glucocorticoids
MOA: Glucocorticoids
Glucocorticoids reduce inflammation
A. INHIBITION of genes
regulating expression
of:

I. COX-2
II. inducible NOS
III. most inflammatory
cytokines (IL-1 thru
IL-6, IL-8, IL-10, IL-
13, GM-CSF, TNF-α,
Interferon-γ)
B. UPREGULATION of the
expression of Annexin A1,
which in turn:

I. directly inhibits PLA2


(reduces prostaglandin &
leukotriene production)
II. inhibits COX-2 (post-
transcriptional activity)
III. promotes neutrophil
detachment from the
endothelium
IV. reduces neutrophil
penetration through the
endothelium of blood
vessels
Glucocorticoids
Metabolic Effects
1. Increased gluconeogenesis
(glucose formation)
2. Reduce glucose uptake &
utilization by peripheral
tissues
3. Increase protein
breakdown (to provide
amino acids for
gluconeogenesis)
4. Activate lipolysis
Clinical Outcomes

• atrophy of lymphoid
tissue
• decreased muscle mass
• thinning of the skin
(fragile, easy to bruise)
• hyperglycemia,
worsening of diabetes
Glucocorticoids Lipid
Metabolism

• dramatic redistribution of body fat.


• the lipolytic effects of glucocorticoids
themselves
• lipolytic effects of insulin that is released in
response to glucocorticoid-induced
hyperglycemia
Clinical outcomes:
• increased fat in the back of
the neck (buffalo hump)
• increased facial fat (moon
face)
• loss of fat in body
extremities
Glucocorticoids Central Nervous System
• cause diverse
neurological effects &
behavioral changes that
may reflect steroid effects
on neuronal excitability.
• The mechanisms remain
poorly understood.
• Euphoria
• Psychosis
Glucocorticoids Pharmacokinetics

Distributed all over the body


Well absorbed orally
& passes the BBB

In the liver, cortisol is


reversibly converted to Excreted in urine as 17-
cortisone & conjugated with hydroxy corticosteroids
glucuronic & sulfuric acid
Meprednisone

Paramethasone
Fluprednisolone
Therapeutic Effects of Glucocorticoids
Therapeutic Effect Mechanism
Inhibit inflammation by blocking the expression &
synthesis of inflammatory mediators, and by
Anti-inflammatory
inducing the expression of anti-inflammatory
mediators (e.g. Annexin A1)
Directly inhibit T lymphocyte function which
Immunosuppressive
suppresses delayed hypersensitivity reactions
Inhibition of DNA synthesis & epidermal cell
Antiproliferative
turnover
Common Clinical Indications for Systemic Glucocorticoids
Field of Medicine Disorders
Asthma (moderate/severe), allergic rhinitis, anaphylaxis,
Allergy & Pulmonology
urticaria, food/drug allergies
Dermatology Acute severe dermatitis
Endocrinology Adrenal insufficiency
GI Diseases Crohn's Disease (IBD), ulcerative colitis
Hematologic Diseases Leukemia/lymphoma
Ophthalmology Uveitis (eye inflammation)
Rheumatology/Immunolo Rheumatoid arthritis, systemic lupus erythematosus,
gy vasculitis
Multiple sclerosis, organ transplant, nephrotic syndrome,
Other
cerebral edema
Therapeutic uses of the adrenal corticosteroids
Replacement therapy for primary
adrenocortical insufficiency
(Addison's disease)

Replacement therapy for secondary


or tertiary adrenocortical
insufficiency (impaired synthesis of
mineralocorticoids)
• Hydrocortisone-
identical to natural cortisol
Diagnosis of Cushing's
syndrome
Dexamethasone suppression
test (DST) is used to assess
adrenal gland function by
measuring how cortisol
levels change in response to
an injection of
dexamethasone

*depressive psychiatric
states
Replacement
therapy for
congenital adrenal
hyperplasia.
Relief of inflammatory
symptom.

Anti-inflammatory action

The decreased production of


prostaglandins and leukotrienes
and platelet-activating factor
synthesis that results from
activation of phospholipase A2
MOA:
• Allergic Disease

a. bronchial asthma, Reduce the amount


b. chronic obstructive pulmonary disease (COPD
c. allergic rhinitis of histamine that
d. transfusion allergic reactions is released from
basophils and mast
e. Angioneurotic edema,
f. asthma,
g. bee stings, cells, thus
h. contact dermatitis,
i. drug reactions,
diminishing the
j. allergic rhinitis, activation of the
k. serum sickness,
kinin system
l. urticaria
• Beclomethasone dipropionate
• Triamcinolone
Acceleration of lung maturation

• Fetal cortisol is a regulator of


lung maturation.

• Beclomethasone
Dose 1: IM to the mother 48 hours
prior to birth
Dose 2: 24 hours before delivery.
Rheumatic Disorders
• systemic lupus erythematosus

vasculitic disorders
opolyarteritis nodosa
oWegener's granulomatosis
oChurg-Strauss syndrome
ogiant cell arteritis
otendinitis or bursitis
Renal dse. nephrotic syndrome
Infectious Diseases. AIDS patients with Pneumocystis carinii .
Haemophilus influenzae
Ocular Diseases. suppress inflammation (dexamethasone sodium
phosphate solution (ophthalmic drops)
Skin Diseases
Gastrointestinal Diseases
Hepatic Diseases
Malignancies
Cerebral Edema
Miscellaneous Diseases and Conditions.
Sarcoidosis
Thrombocytopenia
Autoimmune Destruction of Erythrocytes
Organ Transplantation
Spinal Cord Injury
Available Preparations of Adrenocortical Steroids and Their Synthetic Analogs
Chinese
Fluocinonide
Side Effects
Side Effect Mechanism

Increased hepatic
Hyperglycemia glucose output &
Diabetes decreased peripheral
glucose utilization
Redistribution of fat from extremities to
Central Obesity, Moon Face, Buffalo Hump the trunk, back of neck & supraclavicular
fossae
Breakdown of protein & diversion of
Muscle Weakness & Wasting
amino acids to glucose production
Increased appetite (CNS effect) and
Weight Gain
increased need for insulin
Inhibit osteoblast formation and promote
Osteoporosis
osteoclastic activity
Increased formation of
microemboli in the arteries
supplying bone, result in increased
Avascular Necrosis
ischemia in bone, affects the
of Femur Head
femoral head, but can occur in any
skeletal site such as the knee,
shoulder, ankle or hand
Thin Skin that
Antiproliferative GC effect on
Bruises Easily &
fibroblasts & keratinocytes,
Poor Wound
resulting in dermal atrophy
Healing
due to ACTH-mediated
Hirsutism & Acne increase of adrenal
androgens

direct effect of ACTH on


Hyperpigmentation
melanocortin 1 receptors
Immunosuppression related to thymic atrophy,
Increased Infections decreased production (number) of neutrophils &
monocytes, decreased production of cytokines

Increased cardiac contractility, increased vascular


Hypertension reactivity to vasoconstrictors
(catecholamines, Ang II)
Hypomania, Normal cortisol levels (eucortisolemia) maintains
Depression, Psychosis emotional balance
Cataract formation & Increased intraocular pressure &
Glaucoma hypoparathyroidism
• The “Cushingoid” mnemonic is a
useful way to remember the
signs & symptoms of
glucocorticoid excess:
• Cataracts
• Ulcers
• Skin: striae, thinning, bruising
• Hypertension/ hirsutism/
hyperglycemia
• Infections
• Necrosis, avascular necrosis of
the femoral head
• Glycosuria
• Osteoporosis, obesity
• Immunosuppression
• Diabetes
• Acute adrenal insufficiency syndrome
(lethal)
Withdrawal • psychologic dependence
• exacerbation of the diseases
• Tapered
• Estrogens - decrease prednisone
clearance

• Phenobarbital, phenytoin, and


rifampicin - increase metabolism of
glucocorticoids
Drug
interactions • May cause digitalis toxicity secondary
to hypokalemia

• Monitor for hypokalemia with co-


administration of diuretics
Inhibitors of adrenocorticoid
biosynthesis
• Metyrapone
Uses:
a. tests of adrenal function
[Note: Dexamethasone suppression is now used more commonly
for diagnosis.]
a. Cushing's syndrome (pregnant)
MOA: interferes with corticosteroid synthesis

adverse effects
• salt and water retention,
• hirsutism,
• transient dizziness,
• gastrointestinal disturbances.
Aminoglutethimide:
• MOA: inhibiting the conversion
of cholesterol to pregnenolone,
thus reduce active steroids.
• Uses:
• breast cancer (androgen and
estrogen)
Note: Tamoxifen replaced
aminoglutethimide
• malignancies of the adrenal
cortex
Ketoconazole:
• antifungal agent
• treatment of Cushing's syndrome.

MOA: strongly inhibits all gonadal


and adrenal steroid hormone
synthesis
Trilostane

• MOA: reversibly inhibits


hydroxysteroid dehydrogenase
thus, affects aldosterone,
cortisol, and gonadal hormone
synthesis.
• treatment of Cushing's
syndrome
• side effects: gastrointestinal
Mifepristone (RU-486)

MOA: forms a complex with the


glucocorticoid receptor It forms a complex
with the glucocorticoid receptor, but the
rapid dissociation of the drug

Uses:
• inoperable patients with ectopic ACTH
syndrome. (Cushing Dse)
Spironolactone
MOA: competes for the
mineralocorticoid receptor
thus, inhibits sodium Uses :
reabsorption in the kidney. hyperaldosteronism
It can also antagonize Hirsutism
aldosterone and
testosterone synthesis. Adverse effects:
Hyperkalemia
Gynecomastia
menstrual irregularities
skin rashes.
Eplerenone

MOA: binds to the mineralocorticoid


receptor, where it acts as an
aldosterone antagonist.

Uses:
a. Antihypertensive
b. Chronic heart failure