Adrenal hormones -Glucocorticoids Mechanism of Action, Therapeutic Uses and Adverse Effects

Adrenal hormones are released from the adrenal gland, which is divided into two parts:

1. Adrenal cortex –hormones secreted are known as corticosteroids
2. Adrenal medulla –hormones secreted are known as catecholamines

Anatomically adrenal cortex has three parts or layers:

1. Zona glomerulosa –outermost concerned with secretion of aldosterone (mineralocorticoids)
2. Zona fasciculate –secretion of glucocorticoids
3. Zona reticularis –secretion of androgens

Regulation of Corticosteroids Secretion

Regulation is by two mechanisms:

1. Negative feed back
2. Positive feed back

Glucocorticoids (cortisol) production/secretion is regulated by negative feedback.

Mechanism

Mineralocorticoid (aldosterone) secretion regulation is by positive feedback.

Increased sympathetic activity leads to increased renin which increases aldosterone, resulting in salt and water retention

Chemistry

Steroids are chemically having large cyclopentanoperhydrophenanthrene nucleus.

Classification

Glucocorticoids

Natural

• Cortisol
• Cortisone

Synthetic

• Betamethasone
• Dexamethasone
• Prednisolone
• Triamicinolone
• Prednisone
• Methylprednisolone

Mineralocorticoids

Natural

• Aldosterone
• Desoxycorticosterone acetate (DOCA)
• Corticosterone

Synthetic

• Fludrocortisone

Glucocorticoids (According to Duration of action)

1.      Short Acting (T ½   8-12 Hrs)

• Cortisone –prodrug, converted in liver to cortisol/hydrocortisol
• Cortisol

2.      Intermediate Acting (T ½  12-36 Hrs)

• Prednisolone –very less mineralocorticoid activity as compared to cortisol
• Methylprednisolone –same effects as  prednisolone except given by I/V route of administration
• Triamcinolone –has no mineralocorticoid activity

3.      Long Acting  (T ½   36-72 Hrs)

• Paramethasone
• Betamethasone
• Dexamethasone -very potent anti-inflammatory activity

Glucocorticoids Administered by Inhalation– used in bronchial asthma

• Beclomethasone
• Budesonide
• Fluticasone
• Triamcinolone
• Mometasone

Steroids -Mechanism of Action

All steroids have the same mechanism of action, but differ in production of ultimate proteins.

1. Crossing cell membrane

All steroids enter cell passively.

2. Binding with cytosolic receptor

Mainly present intracellularly. Two types of receptors are involved:

1. GR –alpha
2. GR –beta

(GR = glucocorticoid receptor)

Receptors are distributed throughout the body. Mineralocorticoid receptors are present mainly in excretory organs like kidneys, colon and sweat glands, etc.

Receptors of glucocorticoids are present all over body.

3. Dissociation of receptor from Hsp 90 & 70

Normally receptors are covered by regulatory proteins, which are of two types:

1. HSP-90
2. HSP-70

These are the heat shock proteins, the regulatory and stabilizing proteins. When steroids bind the receptors, they cause displacement of stabilizing proteins from receptor sites.

4. Active transport of steroid-receptor complex into the nucleus
5. Binding of activated receptor with DNA

Receptor separates and steroid binds DNA

6. DNA transcripts the formation of specific mRNA
7. Formation of specific protein  lipocortin (Annexin 1)

mRNA enters cytoplasm and goes to ribosomes to bind them causing formation of specific proteins by the power of translation.

8. Lipocortin (protein) inhibits phospholipase A₂

Phospholipase is responsible for generation of arachidonic acid.

9. Inhibition of formation of arachidonic acid from phospholipid
10. Inhibition of formation of chemical mediators, including prostaglandins and leukotrines.

This is the anti-inflammatory mechanism of glucocorticoids.

Glucocorticoids Pharmacological Actions

Effects are divided into two main categories:

1.      Metabolic Effects

a)      Carbohydrate Metabolism

1. Steroids in carbohydrate metabolism cause and increase in blood levels of glucose.
2. Decrease utilization of glucose
3. Cause increase in gluconeogenesis
4. Cause increased breakdown of glycogen

All effects lead to increased glucose levels, producing diabetogenic effect.

b)      Lipid Metabolism

1. Lipolysis occurs
2. In high doses, redistribution of fat to other parts of the body.

c)      Protein Metabolism

1. Have catabolic effect
2. In high doses, cause loss of protein matrix from bones and cause thinning of skin and wasting of muscles
3. Atrophy of skin, if applied topically
4. Negative nitrogen balance

d)      Water & Electrolyte Balance

Salt and water retention and excretion of potassium.

These effects are minor, in over dosage or prolonged use cause excretion of water

e)      Excretion of urates

On prolonged administration, increase the chances of urine stone formation (urinary canaliculi)

f)       Antivitamin D activity

Some anti-vitamin activity so cause increased excretion of calcium in urine.  

g)      Augment the action of growth hormone on adipocytes

(have specific lipase enzyme).

2.      Non metabolic effects

a)      Anti Inflammatory Action

Most important effect, causing reversal of all signs/symptoms of inflammation without removing cause. Thus have non-specific effect in inflammation.

b)      Lympholytic action

Generalized decrease in lymphoid tissues in body occurs along with lymphocytopenia.

c)      Immunosuppressive action

Cause a decrease in immunity by:

1. Causing decrease in lymphocytes (decreased antibodies formation)
2. Stabilization of mast cell membrane
3. Due to anti-inflammatory effect
4. Some anti-histaminic effect

d)      Effects on Blood

1. Cause increase in RBCs, hemoglobulin, neutrophils and platelets.
2. Most important is that they cause decrease in eosinophils, decrease in basophils and monocytes, leading to anti-allergic effects

e)      CNS

When patient starts taking steroids (in therapeutic doses):

1. Elation occurs
2. Increased appetite
3. Euphoria

If taken in high doses, lead to:

1. Insomnia
2. Even psychotic behaviour

f)       Decrease production of TSH & increased growth hormone production

Pharmacokinetics

1. Natural steroids,
2. After release bind specific proteins known as CBG (corticosteroid binding globulins)
3. Metabolized in liver and excreted in urine
4. Synthetic steroids can be given by various routes of administration:
   • Oral route
   • Topically
   • Inhalation –bronchial asthma
   • Parenteral
   • Intra-articularly –rheumatoid arthritis

Therapeutic uses of Glucocorticoids

1.      Replacement therapy in adrenal disorders

Very important logical use in

a.      Acute adrenal insufficiency

Usually occurs when steroids are given in high doses for long periods and then abruptly stopped, due to negative feedback (availability of hormones), atrophy of adrenal gland occurs.

Treatment is to give hydrocortisone or cortisol 100-200 mg 6 hourly, until condition is controlled.

When giving steroids for long periods, dose is gradually tapered off.

b.      Chronic adrenal insufficiency (Addison’s disease)

Due to tumor of adrenal cortex, infections (tuberculosis of adrenal gland) or removal, chronic insufficiency occurs.

Treatment is to give replacement therapy including glucocorticoids along with mineralocorticoids.

Cortisol in a dose of 20-30 mg, synthetic ones are given in equivalent doses.

Once patient is stabilized, two-thirds of the dose is given in the morning, while one-third in evening.

c.       Congenital adrenal hyperplasia

Very rare congenital defect in synthesis of glucocorticoids, leading to excessive formation of androgens. This may be:

1. Congenital
2. Defect in last step of corticosteroid because of excessive enzyme responsible for synthesis

Androgens are formed one step earlier, especially in pregnant females virulization of female fetus occurs.

Treated by administering glucocorticoids.

2.      Non-adrenal disorders (Empirical Uses)

Ist Line uses

1.  SLE and other Collagen disorder

Autoimmune disorders, very effective and live saving.

2.  Acute leukemias  and lymphomas

In combination with anti-neoplastic drugs

3.  Status asthmaticus/Bronchial asthma

Hydrocortisone is given I/V 100-200 mg 6 hourly, until acute attack is controlled

4.  Gram negative septicemia

Life threatening condition, death may occur, given in combination with anti-microbial drugs.

5.  Cerebral edema

Medical emergency, may occur after head injury.

Dexamethasone is given for cerebral edema.

6.  Glomerulonephritis/Nephrotic syndrome

Affect especially membranous type of glomerulonephritis.

7.  Idiopathic thrombocytopenic purpura –sometimes repond to steroids
8.  Aplastic anemia 
9. Hemolytic anemia (acquired) –respond in emergency
10. Immunosuppression

Used as immunosuppressive in:

1. Rheumatoid arthritis
2. Prevent transplant graft rejection
3. Prevent graft vs. host reaction

11.  Auto immune thyroiditis
12.  Acute mountain sickness      

In combination with acetazolamide and carbonic anhydrase inhibitors

Advantage of combination is that acetazolamide is that these have rapid action, while acetazolamide has delayed effects.

13.  Allergies

Especially seasonal (pollen)

14.  Acceleration of lung maturation in  premature babies

Cortisol causes maturation of lungs and in premature infants, there is decreased release of cortisol so given to mother before delivery esp.

1. Beclomethasone 48 hourly before delivery I/M.
2. Again before 24 hours of delivery

15.            Dermatologic conditions

1. Contact dermatitis
2. Lichen planus
3. Pemphigus
4. Seborrhoeic dermatitis

In most skin conditions steroids are used, esp. non-infective skin conditions.

16.            Ocular conditions

• Acute conjunctivitis
• Choroiditis
• Uveitis

17.            Diagnostic purpose

To access primary and secondary caused of Cushing disease (ACTH excess) give potent steroid, dexamethasone, if after administration decreased levels occur, patient has Cushing disease due to primary dysfunction of adrenal cortex.

If no effect is observed, ACTH excess is due to secondary causes (hyperpituitarism or ectopic production)

2nd/3^rd Line uses

1. Anaphylactic shock -1^st line is adrenaline
2. Ulcerative colitis
3. Crohn’s disease
4. Rheumatoid arthritis
5. Osteoarthritis –non-responding
6. Acute gout –when excessive swelling and pain occurs, along with NSAIDS and Colchicine
7. Myasthenia gravis –along with neostigmine and physostigmine
8. Aspiration syndrome –to avoid aspiration of gastric contents
9. Bronchial asthma –along with other anti-asthmatics oral/inhalational

10.  Acute spinal cord injury –to avoid inflammation and edema

Untoward effects of Glucocorticoids

1. Suppression of adrenal –pituitary axis

Prolonged administration caused negative feedback leading to atrophy of adrenal cortex. Steroids are not withdrawn abruptly, otherwise Addisonians crisis occurs. Dose is gradually tapered, to allow recovery time. Once axis is depressed, it may take months or even years to recover, but when given for short period in low doses (25 mg prednisolone daily for 5-10 days) there is no need to taper off dose.

2. Iatrogenic Cushing’s syndrome –in high doses
3. Hyperglycemia

Due to increased plasma glucose, effect on carbohydrate metabolism

4. Muscle wasting/myopathy

Catabolic effect on proteins

5. CVS

May cause retention of salt and water leading to:

1. Edema
2. Hypertension
3. Even cardiac failure

6. Immunological

Anti-immunity effects, leading to decreased resistance to infections and delayed healing of wounds, making more prone to infections

7. Eye

• When used topically cause glaucoma on prolonged administration
• Posterior subcapsular cataract
• Corneal ulceration

8. GIT

a.      May cause peptic ulcer, due to secretion of HCl and pepsin when taken orally for prolonged periods.
b.      May aggravate ulceration,
c.       In patients of peptic ulcer, may cause painless perforation
d.      May cause increase in candidiasis of GIT
9. Bones

Due to loss of protein matrix may cause osteoporosis, leading to spontaneous fractures.

So patients taking steroids are advised to take calcium and vitamin D supplements to avoid.

10. CNS

In therapeutic doses:

1. Euphoria
2. Elation of mood

In excessive doses:

1. Insomnia
2. Psychotic behavior
3. Aggravate psychosis esp. schizophrenia
4. May cause increase in intracranial pressure on prolonged administration –although rare.

11. Growth suppression

Especially in children due to early closure of epiphysis

12. Hypokalemia

Due to retention of sodium and excretion of potassium. Danger is when patient is taking digoxin or diuretics.

13. Candidiasis

Usually in patients of bronchial asthma, taking steroids by inhalation, due to deposition of steroids in larynx, pharynx, leading to candidiasis.

In larynx ultimately laxity of vocal cords and hoarseness of voice.

1. Nystatin mouth washes
2. Azoles
3. Amphotericin B mouth washes are used
4. Acne & hirsutism

On prolonged administration, especially after topical use.

14. Striae and bruising –esp. when applied to skin

15. Miscellaneous

• Delayed wound healing –decreased immunity, delayed fibrosis
• Skin atrophy –loss of protein matrix
• Tendon rupture
• Menstrual disorders
• Thromboembolism

Contraindications

1. Diabetes
2. Glaucoma
3. CVS disorders
   • Hypertension
   • Cardiac failure

Mineralocorticoids

Drugs causing increased sodium and water retention along with increased elimination of potassium, acting on the late distal part and collecting tubules.

Natural are not used in therapeutics.

Aldosterone hormone cannot be given orally because:

1.      Has short duration of action
2.      In older days, when it was used, it had to be given 5-7 times a day by I/M injection

Synthetic

Fludrocortisone in only used nowadays.

1. Given about 5-7 times a week
2. Can also be given orally

Use

1. Treatment of adrenocortical insufficiency, replacement therapy in combination with glucocorticoids
2. Treatment of hypotension esp. when due to excessive loss of sodium.

Dose

50-300 mcg daily. In children dose of 5 mcg/kg body weight daily by oral route of administration.