Adrenocorticosteroids / Corticosteroids

Adrenocortical Hormones
They are secreted by the Adrenal Cortex.
 BIOSYNTHESIS OF ADRENOCORTICOSTEROIDS

ACTH,NADPH 17,α
17,α Hydroxylase
Hydroxylase 17,20 Lyase
(P450c17)
Cholesterol Pregnenolone 17 Hydroxypregnenolone
3  D. Dehydrdepiandrosterone
3 -Dehydrogenase
3 -D.
17 α H.
Progesteron 17 Hydroxyprogesterone Androstenedione
21 -Hydroxylase 21 -H.
(P450c21)
11- Desoxycorticosterone 11 Desoxycortisol Testosterone
11 -Hydroxylase
11 -H.
(P450c11)
Corticosterone Cortisol Estradiol

Aldosterone

Mineralocorticoid Glucocorticoid Androgen &

pathway pathway Estrogen pathway
Classification of Glucocorticosteroids
A.   Natural
● Cortisol (Hydrocortisone)
● Corticosterone
B.   Synthetic
a) Short to medium acting Glucocorticoids:
• Cortisone
• Prednisone
• Prednisolone
• Methyl Predinsolone
• Meprednisone
b) Intermediate acting Glucocorticoids:
• Triamcinolone
• Paramethasone
• Fluprednisolone
c) Long acting Glucocorticoids:
• Dexamethasone
• Betamethasone Valerate
II. Classification of Mineralocorticoids
Natural:
• Aldosterone
• Desoxy Corticosterone Acetate (Doca)
Synthetic
• Fludrocortisone
GLUCOCORTICOIDS
Source:
Natural: Cortisol (Hydrocortisone)
Synthetic : Cortisol has been synthesized.
Further modifications have delivered a large
number of glucocorticoids with variable DOA &
specificity of actions.
Chemistry & relative activity of corticoids:
Pharmacokinetics
MOA
MOA:
Binds to Glucocorticoids receptor in the
cytoplasm of target cells
D-R complex enters the nucleus.
Initiates series of events like stimulation of
transcription of genes
 Effects of Glucorticosteroids
Physiological Effects:
I. Direct Effects on function of most cells.
2. Permissive Effects: In the absence of glucorticoids many
normal functions become deficient.
e.g. response of vascular & bronchial SM to catecholamine is ↓
in the absence of cortisol & restored by physiological amounts.
Lipolytic response of fat cells to catecholamine., ACTH & GH
are ↓ in the absence of cortisol.
Metabolic Effects: ( Adverse Effects)
On Carbohydrate Metabolism: ↓ uptake & utilization of
glucose by muscle cells , ↑ gluconeogenesis.
Consequences:
Tendency to hyperglycemia & stimulation of insulin release.
Adequate supply of glucose to brain.
Protein Metabolism: Protein & RNA synthesis in liver
↑ catabolism & ↓ anabolism in muscles release of amino
acid from muscle.
Lipid Metabolism: stimulation of lipolysis, ↑ fat deposition
 Catabolic & Anti-anabolic effects. ( Adverse Effects)
These are seen:
1. In lymphoid & connective tissue , muscle, peripheral
fat & skin. Supra physiological amounts produce:
– ↓ muscle mass
– Weakness
– Thinning of skin.
2. On bone --- osteoporosis on long term use, growth
retardation in children
   Anti-Inflammatory & Immunosuppressive Actions
( Beneficial Effects)
On vascular events
On cellular events
On lymphoid areas
On inflammatory & immune mediators
  
 Effects on fetal lung (Beneficial Effects)
Effects on hypothalamic & pituitary hormones:
 Hypothalamic – Pituitary –– Adrenal Axis Inhibition
↓ ACTH ( Adverse Effects)
 ↓ GH ,TSH , LH ( Adverse Effects)
Other Effects: ( Adverse/ Beneficial )
On CNS --depression, ↑ ICP with large doses.
Peptic ulcers
Fat redistribution
On Calcium absorption--- ↓
On RBCs & Platelets---- ↑
Renal effects.
 Therapeutic Uses Of Glucocorticoids

A. Adrenal Uses:
For treatment
1. Replacement therapy for Adrenocortical Insufficiency.
a. Chronic (Addison’s Disease): I/M hydrocortisone 20 -30
mg/day + fludrocortisone.
b. Acute : I/V hydrocortisone 100 mg 8 hrly.
2.Adrenocortical hypo & hyperfunction:
a. Replacement therapy for congenital adrenal
hyperplasia (CAH):
– Injection dexamethasone to pregnant mother at high
risk CAH.
– Infants with CAH in acute adrenal crisis --- I/V
hydrocortisone initially followed by oral therapy.
– Fludrocortisone also given orally.
b. Replacement therapy during & after surgery for
Cushing’s Syndrome due to tumors of Pituitary/ Adrenals
High doses of cortisol during & following the operation
as I/V infusion.
– Dose reduced slowly to maintenance level.
– Then give Fludrocortisone.
For Diagnosis: Dexamethasone suppression test
Diagnosis of Cushing’s Syndrome
Differential Diagnosis of Cushing’s Syndrome
May be due to:
1. Cushing’s disease (Pituitary adenoma): 50% ↓ in
hormone levels.
2. Other causes: Suppression does not occur:
a. Tumors of adrenal cortex— ACTH level low.
b. Ectopic ACTH syndrome--- ACTH level high.
B: To prevent Infant RDS: Stimulation of lung maturation in
fetus in deliveries before 34 wks. ( inj. Betamethasone)
C: Non-adrenal disorders: Mainly due to anti-
inflammatory & immunosuppressant effect:
1. Allergic Reactions: Drug reactions, Anaphylaxis , Angioneurotic
edema , serum sickness, urticaria ,Bees sting , Allergic
rhinitis
2. Rheumatic diseases: Rheumatoid Arthritis, Osteoarthritis,
Bursitis, Tendonitis , SLE, Collagen vascular disorders
3. Renal diseases: Nephrotic syndrome.
4. Pulmonary diseases : Bronchial Asthma, Aspiration
pneumonia, Sarcoidosis. 
5.   Prevention & treatment of : Organ transplant ,
rejection / in bone marrow transplant.
6. GIT diseases. IBD, Non tropical sprue ,
sub acute hepatic necrosis
7. Neurological disorders : Raised ICP , multiple sclerosis.
8. Eye diseases: Ac. Uveitis ,allergic conjunctivitis.
choroiditis , optic neuritis
9. Haematological disorders: Acquired / autoimmune
hemolytic anemia, acute allergic / idiopathic
thrombocytopenic purpura, multiple myeloma,
Leukaemia.
10. Skin diseases: Atopic dermatitis, dermatoses
(localized neurodermatitis) pemphigus, mycosis
fungoides, seborrheic dermatitis, xerosis.
11. Use in Gram negative septicemia. Along with
appropriate anti-biotics.
12. Thyroid disease: Malignant exopthalmos, subacute
thyroiditis.
13.Miscellaneous: Antiemetic in chemotherapy induced
vomiting, Hypercalcemia, Mountain sickness
 Adverse Effects Of Glucocorticoids

ORAL ADMINISTRATION:

A. On Short Term use: less than 2 wks.

• Initially Insomnia & euphoria.
• Subsequently depression.
• Large dose may increase ICP.
• Acute peptic ulcers.
B. On Continued use of supraphysiological
glucocorticoid:
I. Iatrogenic Cushing’s Syndrome:
– Characteristic redistribution of Fat: Moon Face
Buffalo Hump , thin limbs
  Protein Break Down ---- Muscle wasting
– Osteoporosis
– Osteonecrosis of hip
– Thinning of skin ,  Capillary Fragility   
  appetite , Obesity
– Hyperglycemia , Secondary Diabetes
– Hirsutism
 Delayed wound healing
II.
III. susceptibility to infection

IV. Growth retardation in children 

V. Myopathy
VI.  Psychiacric disturbances: Acute Psychosis

VII. Activation/Production of peptic ulcer

VIII. Ocular side effects: Cataract , Glaucoma
IX. Miscellaneous Toxic effects: Hyper coaguability of
blood
X.  Mineralocorticoid Activity: Hypertension ,
oedema.
C. On Withdrawal of therapy:
• Due to suppression of Pituitary Adrenal axis & Patient’s
own capacity to synthesize Glucocorticoids.

POTENTIAL A/E OF INHALED GLUCOCORTICOIDS:

 Oropharyngeal Candidiasis.
 Hoarseness.
 Risk of Osteoprosis & Cataracts.
 Transient growth retardation in children.
Contraindications :
1. Peptic ulcer.
2. Heart disease.
3. Hypertension with heart failure.
4. Certain infectious illnesses --- varicella & T.B.
5. Psychosis
6. Diabetic mellitus
7. Osteoporosis.
8. Glaucoma.
Dosage:
1 .Consider Seriousness of disease , to determine:
The amount of drug --- initially / M.dose
Duration of therapy.
2. For suppressive therapy: Slowly absorbed parenteral
/ small frequent oral doses.
3. As anti-inflammatory / anti- allergic:
Rapidly absorbed parenteral / Large single or less
frequent oral doses.
4. Severe autoimmune conditions --- High doses till
suppression of serious manifestations.
5. Alternate day regimen for long term , after acute
symptoms are controlled.
6. For use in large doses---select intermediate acting
synthetic steroid & give in a single dose.
Mineralocorticoids:
Aldosterone.
Deoxycorticosterone.
Fludrocortisone.
Aldosterone: Mineralocorticoid
Synthesis
Regulation of secretion: ACTH & Angiotensin – II
Pharmacokinetics:
Secreted at rate of 100 -200 μg /day.
Half life 15 – 20 min.
Not firmly bound to serum proteins.
Metabolized in liver .
Conjugates excreted in liver.
MOA:
Binds to Mineralocorticoid receptor in the cytoplasm of
target cells --- Principal cells of distal convoluted &
collecting tubules of the kidney .
D-R complex enters the nucleus.
Initiates series of events like Glucocorticoids
Stimulation of transcription of genes
Increased synthesis of Sodium channels in apical
membrane of principal cells.
Increased influx of Sodium into tubular cells
Physiological & Pharmacological Effects:

Re-absorption of Sodium from DCT & CCT of kidney.

coupled with excretion of Potassium & Hydrogen.
Sodium re-absorption in sweat & Salivary G , GIT
mucosa & across cell membrane is also increased.
Excessive secretion : Hypernatremia , hypokalemia ,
metabolic acidosis , increased plasma volume
Over production :
Primary Hyperaldosteronis --Conn’ syndrome.
Sec. Hyperaldosteronism: CHF , Nephrotic syndrome ,
Hepatic cirrhosis ,
Treatment:
Treat the cause
Aldosterone antagonist-- Spironolactone
Deoxycorticosterone.
Precursor of aldosterone
– Secretion controlled by ACTH.
– Secretion ↑ in adrenocortical carcinoma & congenital
adrenal hyperplasia with ↓ 11β-hydroxylase & 17α-
hydroxylase
Fludrocortisone:
Potent synthetic steroid.
Marked mineralocorticoid & some glucocorticoid activity.
It has longer DOA.
Used for treatment of mineralocorticoid deficiency.
Mineralocorticoid antagonists:
1. Spironolactone: aldosterone androgen antagonists
Useful in:
Primary alsosteronism for diagnosis & treatment.
Treatment of hirsutism in women.
2. Eplerenone: Aldosterone antagonist, used in hypertension.
3. Drospirenone: as progestin in oral contraceptives.
Also antagonizes effects of aldosterone
Adrenal androgens:
Dehydroepiandrosterone (DHEA) --- large amounts
Androstenedione & testosterone --- smaller amounts
Action & uses:
 BIOSYNTHESIS INHIBITORS
&GLUCOCORTICOID ANTAGONISTS

Metyrapone:
Aminoglutethimide:
Ketoconazole
Mefiprestone (RU486)
Mitotane
Trilostane
Metyrapone:
MOA: Selective inhibitor of 11-hydroxylation, interferes
with cortisol & corticosterone synthesis.
Th. Uses:
1. In tests of adrenal & pituitary function.
2. Cushing’s syndrome:
This is the only drug which can be used in pregnancy
with cushing’s syndrome. .
In the management of cortisol excess when its cause is
been determined.
In Cushing’s syndrome with radiation & surgical
treatment.
A/E:
Aminoglutethimide:
Blocks the conversion of cholestrol to pregnenolone &
causes a reduction in the synthesis of all corticosteroids.
Th. Uses:
Carcinoma breast
Cushing’s syndrome
Ketoconazole: Antifungal imidazole .
MOA: In high doses:
Potent & non selective inhibitor of adrenal or gonadal
steroids synthesis.
It inhibits cholestrol side chain cleavage, 17α-hydroxylase,
17, 20-lyase, 3β-dehydrogenase, 11 β-hydroxylase.
Th. Uses:
Cushing’s syndrome.
Mefiprestone (RU 486)
MOA:
1. Glucocorticoid receptor antagonist.
It stabilizes Hsp-glucorticoid receptor complexes.
Alters interaction with poor regulators --- the complex is
transcriptionally inactive.
Inhibition of glucocorticoid receptor activation.
2. Strong anti-progestin activity.
Th. Uses: In resistant cases of Cushing’s syndrome due to:
Ectopic ACTH production.
Adrenal carcinoma.
Mitotane:
Adrenolytic properties useful in carcinoma of adrenal
Trilostane:
3β- hydroxylase inhibitor
Interferes with the synthesis of adrenal or gonadal
hormones.