Adrenocorticosteroids Flashcards
Steroidal hormones, enter the cell and bind to ________
Hormone-receptor complex translocates into the _____ to modulate _____.
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)
Cortisol (Hydrocortisone MOA)
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
Short acting (t1/2 = 8-12h) : ?
Intermediate acting (t1/2 = 12-36 h) : ?
Long acting: (t1/2 = 36-72 h): ?
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
Action of glucocorticoid
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
Action of corticosteroid
salt retaining
Prednisone
(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
Anti-inflammatory and immunosuppressive effects of glucocorticoids
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
Metobolic effects of glucocorticoids
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)
Glucocorticoids on CVS
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
Glucocorticoid on stomach
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
Glucocorticoid on skeletal muscle
Optimum concentration is required for the normal functions of skeletal muscles (permissive actions)
Weakness occurs in both hypo- and hypercorticism
Hypocorticism
(adrenal insufficiency):
reduced work capacity, weakness and fatigue due to the inadequacy of the circulatory system
Hypercorticism
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
Glucocorticoids on electrolyte and water balance
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
Glucocorticoid actions on calcium
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**
Glucocorticoid on CNS
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.
What are the effects of glucocorticoids on ACTCH, fibroblast, collagen and surfactant
Inhibition of plasma ACTH and possible adrenal atrophy**
Inhibition of fibroblast growth and collagen synthesis
Induction of surfactant production in the fetal lung **
Glucocorticoid use for Addisonian crisis
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)
Drugs given to treat addisonian crisis
Dexamethasone, Hydrocortisone (cortisol)
Fludrocortisone may also be necessary
Glucocorticoid use for addison disease
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
Glucocorticoid use in congenital adrenal hyperplasia
(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.
General principles for uses of glucocorticoids in non endocrine disease
harmful dose?
withdrawal?
infection?
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
Glucocorticoids in bronchial asthma
Inhalational route/other
Glucocorticoids in autoimmune disease
Hemolytic anemia, Thrombocytopenia, etc
Glucocorticoids in severe allergic reactions
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
Glucocorticoids for inflammation
Rheumatoid arthritis and osteoarthritis
Glucocorticoids for infectious diseases
Severe forms of TB, severe lepra reactions, certain forms of bacterial meningitis (H. influenzae) and Pneumocystis jiroveci pneumonia in AIDS patients with hypoxia
Glucocorticoids for eye diseases
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
What eye disease are glucocorticoids contraindicated in
Contraindicated in herpes simplex keratitis**
Uses of glucocorticoids in skin diseases
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.
Uses of glucocorticoids in intestinal diseases
In ulcerative colitis, Crohn’s disease
Oral or retention enema (Hydrocortisone, prednisone)
Uses of glucocorticoids in cerebral edema
Due to cerebral tumor, tubercular meningitis, encephalitis, trauma
Which glucocorticoids used to treat cerebral edema
Dexamethasone, Betamethasone
Uses of glucocorticoids in malignancies
In acute lymphocytic leukemia and lymphomas because of antilymphocytic affects
Also offer symptomatic relief in other advanced malignancies by improving appetite
Glucocorticoids in organ transplantation
for immunosuppression
Glucocorticoids for septic shock
glucocorticoids help in raising blood pressure by mineralocorticoid action and its permissive action
Glucocorticoids for surfactant production
acceleration of lung maturation in a preterm fetus:
Fetal cortisol is an inducer of lung maturation; premature infants can develop respiratory distress syndrome
How to prevent respiratory distress in premature infants
Betamethasone/Dexamethasone IM*** to mother
not in second trimester!
Uses of glucocorticoids in renal disease
Nephrotic syndrome – Minimal change disease
Uses of glucocorticoids for diagnostic use
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
Glucocorticoid ADR
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
Glucocorticoid contraindications
Osteoporosis Psychosis Peptic ulcer Diabetes mellitus Hypertension Viral / fungal infections Pregnancy (esp. 2nd trimester)
Steroid Withdrawal after prolonged use
Gradual, NOT ABRUPT(weakness,fatigue, decreased appetite nausea/vomiting, abdominal pain, dehydration…)
Longer the duration of therapy, slower must be the withdrawal.
Steroid withdrawal after use for 2 weeks
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
Aldosterone
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
