PH 1.38 Describe the mechanism of action, types, doses, side effects, indications and contraindications of corticosteroids
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The document outlines corticosteroids, including their mechanism of action, types, doses, side effects, indications, and contraindications. It describes their physiological roles in metabolism, inflammation, and immune function, alongside therapeutic uses for conditions like adrenal insufficiency and autoimmune diseases. The pharmacokinetics and specific properties of various corticosteroids are also detailed, indicating their clinical applications and potential adverse effects.
PH 1.38 Describe the mechanism of action, types, doses, side effects, indications and contraindications of corticosteroids
- 1. PH1.38 Describe the mechanism of action, types, doses, side effects, indications and contraindications of corticosteroids Dr Pankaj Kumar Gupta, MD Assistant Professor, Department of Pharmacology, ESIC Medical College & Hospital, Faridabad (HARYANA) INDIA
- 2. Specific Learning Objectives • What are the corticosteroids • History and Biosynthesis • Mechanism of action • Physiological and Pharmacological actions • Pharmacokinetics and preparations • Distinctive Features of different corticosteroids • Uses – therapeutic and diagnostic • Adverse reactions • Contraindications
- 3. What are the Corticosteroids
- 4. What are the Corticosteroids • Corticosteroids are a class of chemicals encompassing both laboratory-synthesized and naturally produced hormones. • ‘Corticosteroid’ or ‘corticoid’ includes natural gluco- and mineralo-corticoids and their synthetic analogues. • Steroid hormones help control metabolism, inflammation, immune functions, salt and water balance, development of sexual characteristics, and the ability to withstand illness and injury. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052587/ https://www.mdpi.com/journal/nutrients/special_issues/steroid_hormones
- 5. History • 1855 – Addison`s disease (adrenal insufficiency) • 1856 – Adrenal glands essential for life • 1930 – Cortex > medulla • 1932 – Cushing’s syndrome (a disorder caused by excessive production or administration of glucocorticoid hormones) • 1952 – Aldosterone
- 6. Biosynthesis • The corticoids (both gluco and mineralo) are 21 carbon compounds having a cyclopentanoperhydro- phenanthrene (steroid) nucleus. • They are synthesized in the adrenal cortical cells from cholesterol. • Adrenal steroidogenesis takes place under the influence of ACTH which makes more cholesterol available for conversion to pregnenolone and induces steroidogenic enzymes.
- 9. • Adrenal cortical cells store only minute quantities of the hormones, rate of release is governed by the rate of biosynthesis. • The normal rate of secretion of the two principal corticoids in man is— – Hydrocortisone — 10–20 mg daily (nearly half of this in the few morning hours). – Aldosterone — 0.125 mg daily.
- 10. Feed-back regulation of HPA Axis • The circulating corticosteroids inhibit ACTH release from pituitary as well as CRH production from hypothalamus and thus provide negative feed back regulation of the hypothalamo-pituitary- adrenal (HPA) axis.
- 12. Mechanism of action • Corticosteroids penetrate cells and bind to a high affinity cytoplasmic receptor protein, due to which a structural change occurs in the steroid receptor complex that allows its migration into the nucleus and binding to glucocorticoid response elements (GRE) on the chromatin promoting transcription of specific m-RNA → regulation of protein synthesis. • This process takes at least 30–60 min, effects of corticosteroid are not immediate, and once the appropriate proteins are synthesized—effects persist much longer than the steroid itself.
- 14. Rang et al. Pharmacology – 5st Ed. (2003)
- 16. Mineralo-corticoid Action • The most important physiological mineralocorticoid is aldosterone. • It acts on a specific mineralocorticoid receptor (MR) in DCT. • Producing sodium and fluid retention and potassium excretion. • Aldosterone exerts the 90% of the mineralocorticoid activity. Cortisol also have mineralocorticoid activity, but only 1/400th that of aldosterone. • Excess aldosterone causes hypokalemia & muscle weakness. • Excess aldosterone increases tubular (intercalated cells) hydrogen ion secretion, with resultant mild alkalosis. • Too little aldosterone causes hyperkalemia & cardiac toxicity.
- 18. Action of Glucocorticoids • Metabolic • Anti-inflammatory • Immunosuppressive • Others 1. Carbohydrate 2. Protein 3. Lipid 4. Calcium metabolism 5. Electrolyte and H2O 6. CVS 7. Skeletal Muscle 8. CNS 9. Stomach 10. Growth and Cell Division 11. Blood 12. Anti-inflammatory 13. Immunosuppressant
- 19. Action of Glucocorticoids SN Action Glucocorticoids are Catabolic Hormone Clinical Picture 1 Carbohydrate metabolism •↑ Glycogenesis (↑ Glycogen deposition in liver by activation of hepatic glycogen synthase) •↑ Gluconeogenesis (↓Glucose utilization by peripheral tissues, ↑ Glucose release from liver) •Hyperglycaemia •Resistance to insulin •A diabetes-like state 2 Protein metabolism •↑ Protein breakdown •↑ Amino acid mobilization from peripheral tissues •Production of excess urea •Negative nitrogen balance •↑Uric acid excretion •Muscle wasting •Lympholysis •Loss of osteoid from bone •Thinning of skin 3 Fat metabolism •Permissive action •Promote lipolysis due to glucagon, growth hormone, Adr and thyroxine •↑cAMP induced breakdown of triglycerides •Redistribution of body fat (Subcutaneous tissue over extremities loses fat which is deposited over face, neck and shoulder) •‘Moon face’, ‘fish mouth’ and ‘buffalo hump’ Peripheral adipocytes are less sensitive to insulin and more sensitive to corticosteroid-facilitated lipolytic action of GH and Adr, break down of fat predominates, whereas truncal adipocytes respond mainly to raised insulin levels caused by glucocorticoid induced hyperglycaemia.
- 20. Moon Face
- 22. Buffalo Hump
- 23. Action of Glucocorticoids SN Action Clinical Picture 4 Calcium metabolism •↓ Intestinal absorption •↑ Renal excretion of Ca2+ •Loss of osteoid (decreased formation and increased resorption) indirectly results in loss of Ca2+ from bone •Negative calcium balance •Spongy bones (vertebrae, ribs, pelvis, etc.) are more sensitive (Osteoporosis) 5 Water excretion •The effect on water excretion is independent of action on Na+ transport; •Hydrocortisone, but not aldosterone, maintain normal g.f.r. 6 CVS •Permissive role for the pressor action of Adr and angiotensin, as well as a permissive role in the development of hypertension. •Adrenal insufficiency is attended by low cardiac output, arteriolar dilatation, poor vasoconstrictor response to Adr. These changes along with hypovolemia (due to lack of mineralocorticoid) are responsible for cardiovascular collapse. 7 Stomach •↑Secretion of gastric acid and Pepsin May aggravate peptic ulcer
- 24. Action of Glucocorticoids SN Action Clinical Picture 8 Skeletal muscles •Needed for maintaining the normal function of Skeletal muscle •Weakness occurs in both hypo- and hypercorticism •Hypocorticism: diminished work capacity and weakness- due to hypodynamic circulation. •Hypercorticism: •excess mineralocorticoid action produces hypokalaemia → weakness; •Excess glucocorticoid action causes muscle wasting and myopathy → weakness. •Prolonged use: steroid myopathy 9 CNS •Mild euphoria due to direct effect on brain. •Independent of relief of disease symptoms, and sometimes progresses to cause increased motor activity, insomnia, hypomania or depression. •Maintain the level of sensory perception and normal level of excitability of neurones. High doses lower seizure threshold. Addison’s disease pts suffer from apathy, depression and occasionally psychosis. 10 Foetal lungs •Stimulate production of pulmonary surfactants which are essential for inflation of foetal lungs at birth and air breathing. •Glucocorticoids promote structural and functional maturation of foetal lungs near term
- 25. Action of Glucocorticoids SN Action Clinical Picture 11 Lymphoid tissue and blood cells ↑ the rate of destruction of lymphoid cells (T cells are more sensitive than B cells) ↑ the no. of RBCs, platelets and neutrophils in circulation. Lymphocytes, eosinophils and basophils- count is ↓ due to their sequestration in tissues. Blood counts come back to normal after 24 hours. A marked lytic response is shown by malignant lymphatic cells- basis of their use in lymphomas. 12 Inflammatory responses •Interfere at several steps in the inflammatory response, especially by limitation of recruitment of inflammatory cells at the local site and production of pro- inflammatory mediators like PGs, LTs, PAF through indirect inhibition of phospholipase A2. •Only palliative; do not remove the cause of inflammation 13 Immunological and allergic responses Suppress all types of hypersensitization and allergic phenomena. Factors involved may be inhibition of IL-1 release from macrophages; inhibition of IL-2 formation and action → T cell proliferation is not stimulated; suppression of natural killer cells, etc. Basis is the suppression of CMI in which T cells are primarily involved, e.g. delayed hypersensitivity and graft rejection. Suppression of CMI is the basis of their use in autoimmune diseases and organ transplantation.
- 26. Anti-inflammatory actions of corticosteroids Corticosteroid inhibitory effect
- 27. • Inhibit cell division or synthesis of DNA • Delay the process of healing • Retard the growth of children Growth and Cell division
- 29. Glucocorticoids Kinetics: • Well absorbed orally • Bound to corticosteroid-binding globulin and albumin • Distributed all over the body & passes the BBB • In the liver, cortisol is reversibly converted to cortisone & conjugated with glucuronic & sulfuric acid • Excreted in urine as 17-hydroxy corticosteroids
- 30. Circadian Rhythm • Corticosteroid production follow a circadian rhythm.
- 31. Classification
- 32. Relative activity of systemic corticosteroids
- 34. Distinctive Features of different corticosteroids SN Steroid Distinctive properties Dose & brand 1 Hydrocortisone (cortisol) •Acts rapidly but has short duration of action •Both glucocorticoid & mineralocorticoid activity significantly •Uses: •Replacement therapy •Shock, status asthmaticus, acute adrenal insufficiency •Topically •As suspension for enema in ulcerative colitis •LYCORTIN-S 100 mg/3 ml, 200 mg/5 ml inj; •20 mg morning + 10 mg afternoon orally •100 mg i.v. bolus + 100 mg 8 hourly IV infusion 2 Prednisolone •4 times more potent than hydrocortisone •More selective glucocorticoid •Fluid retention with high doses. •Intermediate duration of action: causes less pituitary-adrenal suppression when a single morning dose or alternate day treatment is given. •Uses •for allergic, inflammatory, autoimmune diseases and in malignancies: •OMNACORTIL 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg tab, 5 mg/ml •Oral susp, 5 mg/ml oral drops •5–60 mg/day oral, •10–40 mg IM., Intraarticular
- 35. Distinctive Features of different corticosteroids SN Steroid Distinctive properties Dose & brand 3 Methylprednisolone •Slightly more potent and more selective than prednisolone: 4–32 mg/day oral. •Methylprednisolone acetate has been used as a retention enema in ulcerative colitis. •Pulse therapy with high dose methylprednisolone (1 g infused IV every 6–8 weeks) in in nonresponsive active rheumatoid arthritis, renal transplant, pemphigus. •Minimal suppression of pituitary- adrenal axis. •SOLU-MEDROL Methylprednisolone (as sod. succinate) 4 mg tab; 40 mg, 125 mg, 0.5 g (8 ml) and 1.0 g (16 ml) inj, for IM or slow IV inj, •DEESOLONE 4, 16 mg tabs, 0.5 g and 1.0 g. inj. •DEPOT MEDROL Methylprednisolone acetate 40 mg/ml and 80 mg/ml susp. for IM or intraarticular injection. 4 Triamcinolone •Slightly more potent than prednisolone but highly selective glucocorticoid •Dose: 4–32 mg/day oral, 5–40 mg IM intraarticular •KENACORT, TRICORT 1, 4, 8 mg tab., 10 mg/ml, 40 mg/ml (as •acetonide) for i.m., intraarticular inj.
- 36. Distinctive Features of different corticosteroids SN Steroid Distinctive properties Dose & brand 5 Dexamethasone •Very potent and highly selective glucocorticoid. •Long-acting •Marked pituitary-adrenal suppression •Fluid retention and hypertension are not a problem. •Uses: •For inflammatory and allergic conditions •For shock, cerebral edema •WYMESONE, DECADRON, DEXONA 0.5 mg tab, 4 mg/ml (as sod. phosphate) for IV/IM. inj., 0.5 mg/ml oral drops; •0.5–5 mg/day oral •4–20 mg/day IV infusion or IM 6 Betamethasone •Similar to dexamethasone, •0.5–5 mg/ day oral, •4–20 mg IM/IV injection •Dexamethasone or betamethasone are preferred in cerebral edema and other states in which fluid retention must be avoided. •BETNESOL, BETACORTRIL, CELESTONE 0.5 mg, 1 mg tab, 4 mg/ml (as sod. phosphate) for IV/IM inj., 0.5 mg/ml oral drops 7 Deflazacort •Glucocorticoid potency is less than of prednisolone, but it lacks mineralocorticoid activity. •Fewer adverse effects due to its lower potency. •Lesser growth retardation, particularly recommended in children •Uses: for inflammatory and immunological disorders. •Dose: 60–120 mg/day initially, 6–18 mg/day for maintenance; •children 0.25–1.5 mg/kg daily or on alternate days. •DEFCORT 1 mg, 6 mg, 12 mg, 18 mg, 24 mg, 30 mg tabs, 6 mg/5 ml syr.
- 37. Distinctive Features of different corticosteroids SN Steroid Distinctive properties Dose & brand 1 Desoxycorticosterone acetate (DOCA) •Mineralocorticoid activity only •Used occasionally for replacement therapy in Addison’s disease •2–5 mg sublingual, •10–20 mg IM once or twice weekly. 2 Fludrocortisone •Potent mineralocorticoid + some glucocorticoid activity •Orally active •Uses •Replacement therapy in Addison’s disease •Congenital adrenal hyperplasia in patients with salt wasting •Idiopathic postural hypotension FLORICORT 100 μg tab. 50–200 μg daily 50–200 μg/day 100–200 μg/day 3 Aldosterone •Most potent mineralocorticoid. •Not used clinically because of low oral bioavailability and difficulties in regulating doses.
- 38. Hydrocortisone Prednisolone Nonfluorinated prednisolones Fluorinated prednisolones Methylprednisolone Betamethasone Dexamethasone Triamcinolone The most used glucocorticoids
- 39. Uses – Therapeutic and Diagnostic
- 40. Uses As a replacement Therapy 1 Acute adrenal insufficiency •An emergency. •Hydrocortisone (100 mg) or dexamethasone (8–16 mg) are given IV, first as a bolus injection and then as infusion, along with isotonic saline in glucose solution. 2 Chronic adrenal insufficiency (Addison’s disease) •Hydrocortisone orally along with adequate salt and water allowance 3 Congenital adrenal hyperplasia (Adrenogenital syndrome) •A familial disorder due to genetic deficiency of steroidogenic enzymes, mostly 21-hydroxylase. •Synthesis of hydrocortisone and aldosterone suffers. •Compensatory increase in ACTH secretion causing adrenocortical hypertrophy. •Enzyme deficiency being only partial in most cases, normal amounts of gluco- and mineralocorticoids are produced along with excessive amounts of weak androgens which produce virilization and/or precocious sexual development. •Salt wasting in severe deficiency. •Hydrocortisone 0.6 mg/ kg daily in divided doses round the clock to maintain feed back suppression of pituitary. •If salt wasting persists—fludrocortisone 50–200 μg/day
- 41. Glucocorticoids Pharmacotherapy for non endocrine diseases
- 42. General principles of Glucocorticoids Pharmacotherapy for non endocrine diseases • Steroids are powerful drugs. They may cause dramatic improvement in many severe diseases as well as produce equally severe adverse effects if not properly used. • The use of steroids in non endocrine disease is empirical and palliative, but may be life-saving. • The following general principles must be observed. – Single dose (even excessive) is not harmful. – Short courses (even high dose) are not likely to be harmful in the absence of contraindications. – Long-term use is potentially hazardous. – No abrupt withdrawal after a corticoid has been given for more than 2 to 3 weeks: may precipitate adrenal insufficiency.
- 43. – Initial dose depends on severity of the disease; start with a high dose in severe illness, while in mild cases start with the lowest dose. – Infection, severe trauma, surgery or any stress during corticoid therapy—increase the dose. – Use local therapy (cutaneous, inhaled, intranasal etc.) wherever possible.
- 44. Uses Pharmacotherapy (for non-endocrine diseases) 1 Arthritides Rheumatoid arthritis: Only in severe cases as adjuvants to NSAIDs Osteoarthritis: Intra-articular injection of steroid is rare, but may be used to control an acute exacerbation. Repeated injections may cause joint destruction. Rheumatic fever: only in severe cases with myocarditis and CHF. Gout: Short course in acute gouty arthritis when NSAIDs have failed to afford relief and colchicine is not tolerated. 2 Collagen diseases Steroids are life saving in systemic lupus erythematosus, polyarteritis nodosa, dermatomyositis, nephrotic syndrome, glomerulonephritis etc. 3 Severe allergic reactions For short periods in anaphylaxis, angioneurotic edema, urticaria and serum sickness. In anaphylactic shock and angioedema of larynx Adr (which acts immediately) is preferred as IV inj of a glucocorticoid takes 1–2 hours to act. Topically in allergic conjunctivitis and rhinitis. 4 Autoimmune diseases Autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura, active chronic hepatitis respond to corticoids. Prednisolone 1–2 mg/kg/day is given till remission. As an adjunctive to neostigmine for remission in severe cases of myasthenia gravis.
- 45. Uses Pharmacotherapy (for non-endocrine diseases) 5 Bronchial asthma •Chronic Asthma- early institution of inhaled glucocorticoid therapy is now recommended in most cases needing inhaled β2 agonists almost daily. •Status asthmaticus- systemic corticosteroids (IV) •Acute asthma exacerbation- short-course of high dose oral corticoid. 6 Other lung diseases •Corticosteroids benefit aspiration pneumonia and pulmonary edema from drowning. •Accelerate lung maturation and surfactant production in the foetal lung and prevent respiratory distress syndrome at birth. •Two doses of betamethasone or dexamethasone 12 mg IM at 24-hour interval may be administered to the mother if premature delivery is contemplated. •Betamethasone or dexamethasone are preferred because of their higher placental transfer. 7 Infective diseases •Indicated only in serious infective diseases to tide over crisis or to prevent complications administered under effective chemotherapeutic cover. •E.g. severe forms of tuberculosis (miliary, meningeal, renal, etc.), severe lepra reaction, certain forms of bacterial meningitis and Pneumocystis carinii pneumonia with hypoxia in AIDS patients. 8 Eye diseases •Used in a large number of inflammatory ocular diseases. •Topical instillation as eye drops or ointment is effective in diseases of the anterior chamber, e.g. allergic conjunctivitis, iritis, iridocyclitis, keratitis, etc. •Should not be used in infective conditions. •Contraindicated in herpes simplex keratitis and in ocular injuries.
- 46. Uses Pharmacotherapy (for non-endocrine diseases) 9 Skin diseases •Topical corticosteroids are highly effective in many eczematous skin diseases. •Systemic therapy is needed (may be life-saving) in pemphigus vulgaris, exfoliative dermatitis, Stevens-Johnson syndrome etc. 10 Intestinal diseases •For Ulcerative colitis, Crohn’s disease & coeliac disease. •Indicated during acute phases—may be used orally or as retention enema (for colonic involvement). Particularly valuable for patients with systemic manifestations, and are given in addition to sulfasalazine/mesalazine + other measures. •Some specialists advocate small maintenance doses to prevent relapses. 11 Neurological conditions •Cerebral edema due to tumours, tubercular meningitis. •Dexa- or betamethasone are preferred •Large doses given i.v. soon after spinal injury may reduce the resulting neurological sequelae. •A short course (2–4 weeks) of oral prednisolone can hasten recovery from Bell’s palsy and acute exacerbation of multiple sclerosis. •Neurocysticercosis: When albendazole/praziquantel is used to kill cysticerci lodged in the brain, prednisolone 40 mg/day or equivalent is given for 2–4 weeks to suppress the reaction to the dying larvae.
- 47. Uses Pharmacotherapy (for non-endocrine diseases) 12 Nausea and vomiting •Dexamethasone 8–20 mg IV is frequently used to augment the antiemetic effect of ondansetron or metoclopramide against highly emetogenic cancer chemotherapy. •High dose glucocorticoids provide modest protection from chemotherapy induced & general anaesthesia associated nausea and vomiting, probably due to their anti-inflammatory action. 13 Malignancies •In combination with chemotherapy of acute lymphatic leukaemia, Hodgkin’s and other lymphomas, because of their marked lympholytic action in these conditions. •In hormone responsive breast carcinoma —causing HPA suppression so as to reduce production of adrenal androgens which are converted to estrogens in the body. •Corticoids also afford symptomatic relief in other advanced malignancies by improving appetite and controlling secondary hypercalcaemia. 14 Organ transplantation and skin allograft •High dose corticoids with other immunosuppressants to prevent the rejection reaction. •Low maintenance doses continued over long term + maintenance doses of companion drugs.
- 48. Uses Pharmacotherapy (for non-endocrine diseases) 15 Septic shock •Low-dose (hydrocortisone 100 mg 8 hourly IV infusion for 5–7 days) therapy in patients who are adrenal deficient and who do not respond adequately to fluid replacement and vasopressors. 16 Thyroid storm •Reduces peripheral T4 to T3 conversion. Hydrocortisone 100 mg i.v. 8 hourly may improve the outcome. 17 To test pituitary- adrenal axis function •Dexamethasone suppresses pituitary-adrenal axis at doses which do not contribute to steroid metabolites in urine. •Responsiveness of the axis can be tested by measuring daily urinary steroid metabolite excretion after dosing with dexamethasone.
- 50. • Cushing’s syndrome • Osteoporosis • Tendency to hyperglycaemia • Negative nitrogen balance • Increased appetite • Increased susceptibility to infections • Obesity, etc. Cushing’s syndrome Adverse effects of Glucocorticoids
- 51. Contraindications SN Contraindications Mechanism 1 Peptic ulcer both gastric mucus production and gastric bicarbonate secretion are impaired by steroid administration, results in a weakening of gastric mucosal defences, also, can irritate the lining of the stomach by inhibiting prostaglandins. 2 Diabetes mellitus Steroids induce insulin resistance by directly interfering with signaling cascades, mainly the GLUT4 transporter, within muscle cells, with the subsequent 30%-50% reduction in insulin-stimulated glucose uptake and a 70% reduction in insulin-stimulated glycogen synthesis. 3 Hypertension Cause the body to retain fluid. Extra fluid in the circulation can cause an increase in blood pressure 4 Pregnancy (risk foetal defects) Prolonged corticosteroid therapy during pregnancy increases the risk of gestational diabetes, pregnancy induced hypertension and preeclampsia. 5 Tuberculosis, mycoses, virosis (including Herpes simplex keratitis), and other infections Immune suppression with corticosteroids predisposes to tuberculosis, mycoses & virosis.
- 52. Contraindications SN Contraindications Mechanism 6 Osteoporosis They act to decrease absorption of calcium from the intestine, and increase urinary calcium loss. 7 Psychosis Abnormalities of the hypothalamo–pituitary–adrenal (HPA) axis can result in mood disorders 8 Epilepsy Can lower the seizure threshold and can potentially provoke seizures 9 Chronic heart failure A high dose of corticosteroids may promote sodium and water retention in patients with HF, potentially leading to worsening of the disease. 10 Renal failure Due to increase risk of hypertension, diabetes, weight gain, short stature, fractures, and infections.
- 53. Dosage withdrawal • Any patient who has received >20–25 mg/day hydrocortisone, or ≥5 mg prednisolone/day or equivalent for longer than 2–3 weeks should be put on a scheme of gradual withdrawal. • Administration of ACTH during withdrawal does not hasten recovery because adrenals recover earlier than pituitary and hypothalamus.
- 54. Topical Glucocorticoids • Glucocorticoids are quite effective when applied topically and are nontoxic to the skin in the short term. • The factors that determine local penetration are the structure of the compound employed, the vehicle, the basic additives, occlusion versus open use, normal skin versus diseased skin, and small areas versus large areas of application. • Fluorinated steroids (dexamethasone, triamcinolone acetonide, betamethasone, and beclomethasone) penetrate the skin better than non-fluorinated steroids, such as hydrocortisone. However, fluorinated steroids also cause more local complications and may be associated with systemic absorption and side effects. Topical corticosteroids in dermatology. Year: 2016, Volume: 82, Issue: 4, July-August.
- 56. References • MLA. Tripathi, K. D. Essentials of Medical Pharmacology. 8th ed., Jaypee Brothers Medical, 2018. • Topical corticosteroids in dermatology. Year: 2016, Volume: 82, Issue: 4, July-August.
- 57. Thanks