Adrenocorticosteroids

Question 1

Steroidal hormones, enter the cell and bind to ________

Hormone-receptor complex translocates into the _____ to modulate _____.

Answer 1

Steroidal hormones, enter the cell and bind to cytosolic receptors.

Hormone-receptor complex translocates into the nucleus to modulate transcription.

Glucocorticoid receptor (GR)  
Mineralocorticoid receptor (MR)

Question 2

Cortisol (Hydrocortisone MOA)

Answer 2

Due to time lag for changes in gene expression and protein synthesis –> most effects of corticosteroids are delayed

Once the appropriate protein synthesized –> effects persist much longer than steroid itself

Question 3

Short acting (t1/2 = 8-12h) : ?

Intermediate acting (t1/2 = 12-36 h) : ?

Long acting: (t1/2 = 36-72 h): ?

Answer 3

Short acting (t1/2 = 8-12h) : Hydrocortisone (cortisol), Cortisone)

Intermediate acting (t1/2 = 12-36 h) : Prednisone, Prednisolone, Methylprednisolone, Triamcinolone, Fluticasone

Long acting: (t1/2 = 36-72 h). Betamethasone, Dexamethasone

Question 4

Action of glucocorticoid

Answer 4

Effects on metabolism, anti inflammatory and immunosuppressant

Permissive actions: facilitates actions of other hormones e.g., response of vascular and bronchial smooth muscles to catecholamines is diminished in the absence of cortisol

Anti-inflammatory & immunosuppressive effects (most imp. property of glucocorticoids) - inhibit all the classic signs of inflammation (erythema, swelling, pain, and heat)

promote synthesis of lipocortins *** which inhibit phospholipase A2 (this inhibits production of arachidonic acid and hence of prostaglandins and leukotrienes)

additionally, inhibit protein-translation of inducible COX -II

Question 5

Action of corticosteroid

Answer 5

salt retaining

Question 6

Prednisone

Answer 6

(pro-drug) lacks glucocorticoid activity until converted to Prednisolone by hepatic enzymes

patients with liver function impairment should be treated with prednisolone rather than prednisone

Question 7

Anti-inflammatory and immunosuppressive effects of glucocorticoids

Answer 7

inhibit the release of IL-1, IL-2, IL-3, IL-6, TNF-alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF)

reduce migration of inflammatory cells to site of injury

Decrease vascular permeability by reducing histamine release and the action of kinins

inhibit the antigenic response of macrophages and leucocytes

decrease lymphocyte production

impair delayed type hypersensitivity reactions

Decrease in the lymphocyte count due to migration of lymphocytes to the lymphoid structures.

Long-term therapy results in involution and atrophy of all lymphoid tissues

also decrease the circulating monocytes, eosionophils and basophils.

Increase neutrophil count in the blood due to decreased migration to the site of injury

Question 8

Metobolic effects of glucocorticoids

Answer 8

Hyperglycemia - increase blood glucose level by stimulation of gluconeogenesis (peripheral amino acids are utilized for gluconeogenesis), decrease peripheral glucose utilization
net effect: hyperglycemia

Protein catabolism - cause protein breakdown and lead to negative nitrogen balance

increase lipolysis (result in increased plasma free fatty acid and ketone body formation).

causes re-distribution of fat (moon face’, ‘buffalo hump’ as seen in Cushing’s syndrome)

Question 9

Glucocorticoids on CVS

Answer 9

Promotes Na+ and water retention ► HTN (mineralocorticoid action)- distal & collecting tubules

Maintains the tones of arterioles and myocardial contractility

due to permissive effect on pressor actions of epinephrine and angiotensin, produce rise in blood pressure

Adrenal insufficiency (Hypoadrenalism) = reduced response to vasoconstrictors (Epi, NE, Angiotensin) = hypotension

Cushing’s syndrome (excess glucocorticoids ) = hypertension

Question 10

Glucocorticoid on stomach

Answer 10

Increased gastric acid and pepsin secretion – may aggravate peptic ulcer
possibly suppress the immune response against H. pylori & also increase the secretion of pepsin & gastric acid

Question 11

Glucocorticoid on skeletal muscle

Answer 11

Optimum concentration is required for the normal functions of skeletal muscles (permissive actions)

Weakness occurs in both hypo- and hypercorticism

Question 12

Hypocorticism

Answer 12

(adrenal insufficiency):

reduced work capacity, weakness and fatigue due to the inadequacy of the circulatory system

Question 13

Hypercorticism

Answer 13

increased mineralocorticoid action -> hypokalemia -> weakness

increased glucocorticoid action -> muscle wasting and myopathy (steroid myopathy in Cushing’s syndrome) -> weakness

increased glucocorticoid action -> muscle wasting and myopathy (steroid myopathy in Cushing’s syndrome ) -> weakness

Question 14

Glucocorticoids on electrolyte and water balance

Answer 14

Aldosterone, natural mineralocorticoid, most potent with respect to fluid and electrolyte balance

Mineralocorticoids act on distal tubules and collecting ducts of the Kidneys

Reabsorption of Na+, water, bicarbonate and increased urinary excretion of K+ and H+ - hypokalemia and alkalosis

Question 15

Glucocorticoid actions on calcium

Answer 15

Inhibits intestinal absorption, and enhances renal excretion of Ca2+

Loss of Ca2+ from bones, negative calcium balance -> Calcium deficiency -> weak & fragile bones (resulting in osteoporosis)

Long term use necessitates calcium supplement**

Question 16

Glucocorticoid on CNS

Answer 16

Mild euphoria, insomnia, anxiety, increased motor activity and restlessness

Adrenal insufficiency (Addison’s disease): apathy, depression and irritability

High doses of glucocorticoids lower seizure threshold: cautiously used in epileptics.

Question 17

What are the effects of glucocorticoids on ACTCH, fibroblast, collagen and surfactant

Answer 17

Inhibition of plasma ACTH and possible adrenal atrophy**

Inhibition of fibroblast growth and collagen synthesis

Induction of surfactant production in the fetal lung **

Question 18

Glucocorticoid use for Addisonian crisis

Answer 18

Replacement therapy
Acute adrenal insufficiency (Addisonian crisis): due to acute lack of corticosteroids
An emergency; characterized by
- GI symptoms (Nausea, vomiting, abdominal pain)
- Dehydration, Hyponatremia
- Hyperkalemia- Weakness and Lethargy
- Hypotension and hypoglycemia, death (if failure to control the disease)

Question 19

Drugs given to treat addisonian crisis

Answer 19

Dexamethasone, Hydrocortisone (cortisol)

Fludrocortisone may also be necessary

Question 20

Glucocorticoid use for addison disease

Answer 20

Similar symptoms as seen in Addisonian crisis, with lesser severity

Hydrocortisone orally in dose of 20-30 mg/day + salt & water

2/3rd dose in morning & 1/3rd dose in afternoon: to mimic diurnal rhythm of cortisol secretion – mostly in the early morning

Some patients may need Fludrocortisone for mineralocorticoid activity

Question 21

Glucocorticoid use in congenital adrenal hyperplasia

Answer 21

(Adrenogenital syndrome)
a group of genetic disorders in which the activity of one of the several enzymes (21α-hydroxylase**, 11β- hydroxylase and 17α-hydroxylase) required for biosynthesis of corticosteroids is deficient

Less production of hydrocortisone and aldosterone -> increased ACTH secretion -> adrenal hyperplasia

Replacement by Hydrocortisone and Fludrocortisone
Decreased ACTH production and decreased stimulation of adrenal cortices.

Question 22

General principles for uses of glucocorticoids in non endocrine disease

harmful dose?
withdrawal?
infection?

Answer 22

Single dose (even excessive) is not harmful

Short courses (even high doses) are not likely to be harmful in the absence of contraindications

Long term use is potentially hazardous: keep the dose minimum, which is found by dose titration

No abrupt withdrawal after a corticosteroid has been given for >2 weeks: may precipitate Addisonian crisis and if not controlled, death can occur

Infection, severe trauma or any stress during corticosteroid therapy -> increase the dose

Question 23

Glucocorticoids in bronchial asthma

Answer 23

Inhalational route/other

Question 24

Glucocorticoids in autoimmune disease

Answer 24

Hemolytic anemia, Thrombocytopenia, etc

Question 25

Glucocorticoids in severe allergic reactions

Answer 25

Allergic rhinitis (Beclomethasone, Triamcinolone) Anaphylaxis, angioneurotic edema, urticaria and serum sickness Even IV injection of corticosteroids takes 1-2 hours to act In case of anaphylactic shock and angioedema of larynx- Epinephrine is DoC

Question 26

Glucocorticoids for inflammation

Answer 26

Rheumatoid arthritis and osteoarthritis

Question 27

Glucocorticoids for infectious diseases

Answer 27

Severe forms of TB, severe lepra reactions, certain forms of bacterial meningitis (H. influenzae) and Pneumocystis jiroveci pneumonia in AIDS patients with hypoxia

Question 28

Glucocorticoids for eye diseases

Answer 28

In allergic and inflammatory diseases of eye, e.g., allergic conjuctivitis, iritis, iridocyclitis, keratitis, etc. Topical application ophthalmic solution/ ointment Prolonged use of corticosteroid eye drops can cause glaucoma Posterior segment afflictions like retinitis, optic neuritis, uveitis require systemic steroid therapy

Question 29

What eye disease are glucocorticoids contraindicated in

Answer 29

Contraindicated in herpes simplex keratitis****

Question 30

Uses of glucocorticoids in skin diseases

Answer 30

Highly effective in many eczematous skin diseases Topical application (e.g., hydrocortisone ointment n eczema) Systemic steroids in severe skin diseases like Pemphigus vulgaris, Exfoliative dermatitis, Stevens-Johnson syndrome, etc.

Question 31

Uses of glucocorticoids in intestinal diseases

Answer 31

In ulcerative colitis, Crohn’s disease Oral or retention enema (Hydrocortisone, prednisone)

Question 32

Uses of glucocorticoids in cerebral edema

Answer 32

Due to cerebral tumor, tubercular meningitis, encephalitis, trauma

Question 33

Which glucocorticoids used to treat cerebral edema

Answer 33

Dexamethasone, Betamethasone

Question 34

Uses of glucocorticoids in malignancies

Answer 34

In acute lymphocytic leukemia and lymphomas because of antilymphocytic affects Also offer symptomatic relief in other advanced malignancies by improving appetite

Question 35

Glucocorticoids in organ transplantation

Answer 35

for immunosuppression

Question 36

Glucocorticoids for septic shock

Answer 36

glucocorticoids help in raising blood pressure by mineralocorticoid action and its permissive action

Question 37

Glucocorticoids for surfactant production

Answer 37

acceleration of lung maturation in a preterm fetus: | Fetal cortisol is an inducer of lung maturation; premature infants can develop respiratory distress syndrome

Question 38

How to prevent respiratory distress in premature infants

Answer 38

Betamethasone/Dexamethasone IM*** to mother *not in second trimester!*

Question 39

Uses of glucocorticoids in renal disease

Answer 39

Nephrotic syndrome – Minimal change disease

Question 40

Uses of glucocorticoids for diagnostic use

Answer 40

Dexamethasone suppression test (DST) for Cushing’s syndrome To see the functioning of hypothalamic-pituitary- adrenal axis (HPA-axis) If low dose suppresses the normal production of hydrocortisone, the HPA- axis is intact If high dose suppresses ACTH production: origin of increased ACTH is pituitary; if not, the origin is ectopic

Question 41

Glucocorticoid ADR

Answer 41

Hypothalamic-pituitary-adrenal axis suppression Cushing’s like syndrome:‘moon face’, ‘fish (narrow ) mouth’, ‘buffalo’ hump, obesity of trunk with thin limbs. Fragile skin, purple striae and easy bruising (typically on lower abdomen and thighs) Hypertension Hyperglycemia (DM) Myopathy: weakness of proximal (shoulder, arm, pelvis, thigh) limb muscles – withdraw steroid Susceptibility to infection: (risk of reactivation of latent TB and appearance of opportunistic infections (Candida, etc) Peptic ulcer Osteoporosis Edema Psychosis Cataract, glaucoma Delayed healing of wounds and surgical incisions Growth retardation in children: by decreasing GH secretion

Question 42

Glucocorticoid contraindications

Answer 42

``` Osteoporosis Psychosis Peptic ulcer Diabetes mellitus Hypertension Viral / fungal infections Pregnancy (esp. 2nd trimester) ```

Question 43

Steroid Withdrawal after prolonged use

Answer 43

Gradual, NOT ABRUPT(weakness, fatigue, decreased appetite nausea/vomiting, abdominal pain, dehydration…) Longer the duration of therapy, slower must be the withdrawal.

Question 44

Steroid withdrawal after use for 2 weeks

Answer 44

If rapid withdrawal is desired, a 50% reduction in dose/day If a patient is treated for longer period, withdrawal should be done very slowly (e.g., 2.5-3 mg of prednisolone or equivalent at intervals of 3-7 days). Alternatively, halve the dose weekly until 25 mg prednisolone or equivalent is reached, after which reduce 1 mg every 3-7 days

Question 45

Aldosterone

Answer 45

Control body water and electrolyte balance especially sodium and potassium Aldosterone acts on the kidney tubules and collecting ducts. Aldosterone: increases reabsorption of Na+, water and bicarbonate from renal tubules decreases reabsorption of K+ and H+ ions from renal tubules Hyperaldosteronism may result in alkalosis and hypokalemia, whereas retention of sodium and water leads to increase in blood volume and blood pressure