INTRODUCTION

corticosteroids are secreted from the adrenal cortex, which play a vital role in maintaining the homeostatic life process. Corticosteroids can be classified on the basis of their major action as glucocorticoids, mineralocorticoids. Glucocorticoids have greater effect on carbohydrate metabolism, cortisol is a naturally secreting variety of glucocorticoid. Mineralocorticoids are most active in enhancing sodium retention and are represented by aldosterone. Other than glucocorticoids and Mineralocorticoids, androgens such as androstenedione, dehydroepiandrosterone are also produced from the adrenal cortex, these corticosteroids except aldosterone are directly regulated by the blood concentration of adrenocorticotrophic hormone(ACTH) Corticosteroids play a complex role in maintaining

The

anti-inflammatory

and

anti-allergic

activities

of

adrenocorticosteriods are of vital importance in medicine and dentistry. These hormones decrease inflammatory response, prevent fibrosis and minimize degeneration. Hence corticosteroids are extensively used in medicine and dentistry either in topical or systemic forms. However, since they suppress the inflammatory response which is essential for healing, grave consequences can result by such suppression. The urgent need then, for thorough understanding of the metabolic effect and undesirable reaction of these drugs is self-evident. Ambulatory patients who are on chronic steroid therapy may require dental treatment. In these patients, acute stress reactions resulting from infection, injury or oral surgical procedures may have serious sequelae.

Further, if steroid therapy is suddenly withdrawn, there is the danger of inducing acute adrenal failure. Accordingly, the dentist should be well versed in the clinical and pharmacological actions of steroids, their side reactions, the disease for which the physician may prescribe steroids and the precautions in managing those patients on steroids.

HISTORY OF CORTICOSTEROIDS
Clinical importance of adrenal glands was first appreciated by ADDISON, who prescribed fatal outcomes in patients with adrenal destruction in 1849.
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BROWN SEQUARD demonstrated bilateral adrenalectomy was

fatal in laboratory animals. It was shown that adrenal cortex rather than the medulla was essential for survival.
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TATE and colleagues isolated and characterized aldosterone, that

had potent effect on fluid and electrolyte balance and termed as mineralocorticoid.

In 1912 Cushing described patients with hypercorticism and later in

1932 recognized that pituitary basophilism represented the cause of adrenal overactivity. ASTWOOD et al 1952 studies ultimately led to purification of HARRIS in 1948 described the role of hypothalamus in pituitary VALE et al 1981-determined the structure of corticotropin releasing ACTH and determination of its chemical structure. control. hormone(crh) a hypothalamic peptide that regulate secretion of ACTH from pituitary.
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HENCH et al 1949 demonstrated dramatic effect of glucocorticoids

and ACTH in treatment of rheumatoid arthritis which set the stage for clinical use of corticosteroid in wide variety of disease states.

PHYSIOLOGY OF CORTICOSTEROID
The adrenal glands are the best thought of as a group of glands juxtaposed for special function. The adrenal medulla, whose major products are the catecholamines, epinephrine (adrenalin), and norepinephrine (noradrenalin) is enveloped by the adrenal cortex, whose major products are steroid hormones such as glucocorticoids, mineralocorticoid and androgen. Adrenal cortex secretes three distinct group of steroid hormonesa. Zona Glomerulosa - Mineralocorticoids consist of aldosterone and deoxycorticosterone.

b. Zona Fasciculata - Glucocorticoids consist of cortisol and hydrocortisone. c. Zona Reticularis - Androgens. The anterior portion of the pitutary gland, the conductor of hormonal orchestra (stimulates the endocrine glands to secrete the hormones which are vital for the functioning of the body) itself secretes adrenocorticotropic hormone (ACTH) which stimulates the adrenal cortex to produce hydrocortisone, cortisol and corticosterone. They are also essential for carbohydrate, fat and protein metabolism, water and electrolyte balance, muscle power bone formation and blood pressure maintenance. In case of deficiency can cause Addisons disease and excess results in Cushings disease.

BIOSYNTHESIS AND CHEMISTRY The corticoids (both glucocorticoids and mineralocorticoids) are 21 carbon compounds having a cyclo perhydro - phenanthrene (steroid) nucleus. They are synthesized in the adrenal cortical cells from cholesterol. Secretory rates of cortical hormones in humans. HORMONE a. b. c. d. Cortisol Aldosterone Corticosterone Dehydroepiandrosterone(DHE) SECRETORYRATE(mg/day) 8-25 0.05-0.2 2-4 15-30

METABOLISM AND EXCRETION OF ADRENAL CORTICOIDS The adrenal corticoids circulate in the plasma partly in free state and mostly bound to protein. The former is the biologically active form. When
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the total plasma cortisol level is 20mg/100ml almost 95% of this is bound to cortisol binding alpha globulin (CBG, Transcortin), while free cortisol is only 1mg/100ml. These steroids are metabolized in the liver and are excreted in the urine only as conjugates of sulfuric and glucoronic acids. The corticoids being water insoluble are excreted in the urine only in traces. The various urinary metabolites can be neutral, 17 ketosteroids and 17 hydroxycorticosteroids are measured to assess adrenal pitutary function.

MECHANISM OF ACTION The mineralo corticoid, aldosterone, and the glucocorticoids,cortisol and corticosterone act by binding to intracellular receptors which then act to modulate gene transcription in target tissues. CIRCULATING CORTICOSTERIODS One half of the circulating aldosterone is bound with low affinity to albumin, while the other half is free. For cortisol, only about 4% is free, the majority of the remainder is bound with high affinity to transcortin corticosteroid binding globulin (CBG). When compared with the physiological glucocorticoids, synthetic glucocorticoids have relatively low affinity for CBG.

THE PHYSIOLOGICAL ROLE OF CBG:

They act as a reservoir of steroid, in that CBG bound glucocorticoid is not metabolized. The binding of steroid by CBG is very temperature dependent, so that higher the temperature the lower the affinity. Free steroid levels in skin capillaries (approximately 28 c) are thus one half to one third of those in viscera (37 c) and high levels are also found at sites of inflammation. At such sites neutrophil elastase can specifically cleave CBG, releasing bound steroid to modulate the inflammatory response.

CORTICOSTEROID RECEPTORS: Steroid receptors are intracellular. Receptors for mineralocorticoids (MR) and glucocorticoids (GR), together with those for androgens (AR) and progestins (PR), form a subfamily within the steroid/thyroid/retinoid / orphan receptor superfamily. MR and GR in the absence of hormone are primarily in the cell cytoplasm, invested by a series of associated proteins. These proteins maintain the receptor in a form with high affinity for steroid, and prevent the receptor from interacting with DNA in the absence of hormone. On binding with the steroid, the receptor shed its associated proteins, translocates to the nucleus, and binds as a dimmer (commonly MR:MR or GR:GR, but with increasing evidence for MR:GR) to particular nucleotide sequences on target genes, known as response (or regulatory) elements. The receptors then

initiate (or on occasion,depress) the transcription of mRNA encoding the proteins, which are corticosteroid - responsive in the particular target tissue. MINERALOCORTICOID ACTIONS: The important natural mineralocorticoids are aldosterone and desoxycorticosteroid. Aldosterone regulates electrolytes, and maintains blood volume and blood pressure. The principal action of mineralocorticoid is enhancement of Na+ reabsorption in the distal convoluted tubule in kidney. There is an associated increase in K+ and H+ excretion. Excess secretion of aldosterone causes sodium retention, there by increase in blood volume and blood pressure. Decreased secretion of aldosterone results in loss of sodium there by decrease in blood volume and blood pressure.

GLUCOCORTICOIDS ACTIONS (CORTISOL & CORTISONE) Secretion of glucocorticoids is regulated completely by ACTH.

1. Carbohydrate and protein metabolism

Glucocorticoids promote glycogen deposition in liver by inducing hepatic glycogen synthetase and promoting gluconeogenesis. They inhibit utilization by peripheral tissues. This along with increased glucose release from liver results in hyperglycemia,resistance to insulin and diabetes like state. They also cause protein breakdown and amnioacid mobilization from peripheral tissues which are responsible for side effects like muscle wasting, lympholysis, loss of osteoid from bone and thinning of skin. The amnioacids so mobilized funnel into liver are used up in gluconeogenesis, excess urea is produced which leads to negative nitrogen balance. Glucocorticoids are thus catabolic. Their functions appear to be oriented in maintaining blood glucose levels during starvation so that brain continues to get its nutrients.
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2. Fat metabolism
The action is primarily permissive in nature : Promote lipolysis due to glucagons, growth hormone, adrenalin and thyroxine. C-amp induced breakdown of triglycerides is enhanced. Fat deposits in different areas responds differently. Redistribution of body fat occurs. Subcutaneous tissue over extremities loses fat,which is deposited over face, neck and shoulder moon face, fish mouth, buffalo hump.

3. Calcium Metabolism
They inhibit intestinal absorption and enhance renal excretion of Ca2+. There is calcium loss from bone directly due to loss of osteoid, which leads to negative calcium balance.

4. Water Excretion
It is independent of action on Na+ transport, hydrocortisone and other glucocorticoids, but not on aldosterone, maintain normal g.f.r. In adrenal insufficiency, the capacity to excrete water load is markedly reduced, such patients are prone to water intoxication from i.v. infusions. Glucocorticoids also enhance secretory activity of renal tubules.

5. CVS
Glucocorticoids restrict capillary permeability, maintain tone of arterioles and myocardial contractility. They have a permissive role in development of Hypertension and should be cautiously used in hypertensives.

6.

SKELETAL MUSCLES Hypocorticism: diminished work capacity and weakness are due to

hypodynamic circulation. Hypercoticism: Increase in Mineralo corticoid action leads to hypokalemia and weakness Increase in glucocorticoid action leads to Muscle wasting and myopathy and weakness. 7. CNS Mild euphoria is common with pharmacological doses of glucocorticoids. This is a direct effect on brain, independent of relief of disease symptoms; sometimes progresses to cause increased motor activity, insomnia;anxiety or depression. 8.

Stomach
Secretion of gastric acid and pepsin is increased and may aggravate

peptic ulcer. 9.

Lymphoid Tissue And Blood Cells

On normal lymphoid tissue the effect is only modest. Malignant

lymphatic cells when used in lymphomas show lytic response. Corticoids increase the number, if RBCs, platelets and neutrophils are in circulation. Decrease in lymphocytes, eosinophils and basophils are not due to destruction of these cells but due to their sequestration in tissues. Blood counts come back to normal after 24 hours.

10. Inflammatory Responses Inflammation is suppressed by glucocorticoids. The action is nonspecific and covers all components and stages of inflammation. The action is direct and hence local-topical use is possible. The cardinal signs of inflamation-redness, heat, swelling and pain are suppressed. Corticoids are only palliative; do not remove the cause of inflammation. They favour spread of infections, as capacity of defensive cells to kill micro organisms is impaired. They also interfere with healing and scar formation: Peptic ulcer may perforate as symptomatically. Indiscriminate use of corticoids is hazardous.

11.

Immunological And Allergic Response

Glucocorticoids impair immunological competence. They suppress all

types of hypersensitization and allergic phenomena. The clinical effect appears to be due to suppression of recruitment of leukocytes at the site of contact with antigen and of inflammatory response to immunological injury. They cause greater suppression of CMI in which T cells are primarily involved. The broad seems to be interruption of communication between cells involved in the immune process by interfering with production or action of lymphokines.

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PHARMACOKINETICS
All natural synthetic corticoids except DOCA, are effectively given by the oral route. Water-soluble esters, e.g. hydrocortisone hemisuccinate, dexamethosone sodium phosphate can be given I.V or I.M., act rapidly and achieve high concentrations in tissue fluids. Insoluble esters, e.g. hydrocortisone acetate triamcinolone acetonide cannot be injected, I.V., but are slowly absorbed from I.M. site and produce more prolonged effects. Hydrocortisone is 90% bound to plasma protein, mostly to a specific corticosteriod binding globulin (Transcortin) as well as to albumin. Transcortin concentration is increased during pregnancy and treatment with oral contraceptives. Corticoid levels in blood are increased but hypercorticism does not occur. Primarily the hepatic microsomal enzymes metabolize the steroids. The metabolites are further conjugated with glucoronic acid or sulfate and are excreted in urine. The plasma t of hydrocortisone is 1.5 hours. However, biological t is longer because of action through intra cellular receptors and regulation of protein synthesis, that effects persist long after the steroid is removed from plasma. The synthetic derivatives are more resistant to metabolism and are longer acting. Phenobarbitone and phenytoin induce metabolism of hydrocortisone prednisolone and dexamethasone etc., to decrease their therapeutic effects.

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PREPARATION AND DOSE

1. HYDROCORTISONE (CORTISOL): Short duration of action and acts rapidly. In addition to primary glucocorticoid, it has significant mineralocorticoid activity also. Used for: Replacement therapy -> 20mg morning + 10mg afternoon daily. Shock, status asthmaticus, acute adrenal insufficiency-> 100mg i.v. Bolus + 8 hourly infusion. AVAILABLE IN VARIOUS FORMS Lycortin S:EFCORLIN soluble 100mg /2ml inj (as hemisuccinate for i.v. inj) Wycort : EFCORLIN 25mg/ml inj (as acetate form / intraarticular inj) 2. CORTISONE: It is inactive as such, hydroxylated in liver to hydrocortisone, slightly less potent than hydrocortisone. Only occasionally used now; 20-100mg /day oral, i.m/corlin 5mg tab.25mg/ml inj. 3. PREDNISOLONE: It is 4 times more potent than hydrocortisone. Has intermediate duration of action. Used for allergic, inflammatory, autoimmune diseases and in malignancies. 5-60mg/day oral, 10-40mg i.m. intraarticular; also topically. DELTACORTRIL:HOSTACORTIN-H, WYSOLONE 5, 10mg tab: 20mg/ml (as acetate) for i.m., intraarticular inj.

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4. METHYLPREDNISOLONE: Slightly more potent and more selective than prednisolone; 432mg/day oral. Methylprednisolone acetate has been used as a retention enema in ulcerative colitis. Pulse therapy with high dose methyl prednisolone (1 g infused i.v. every 6-8 weeks) has been tried in non-responsive active rheumatoid arthritis, renal transplant, pemphigus etc. with good results and minimal suppression of pituitary adrenal axis. SOLO-MEDROL: Methylpredinosolone (as sod.sucinate) 0.5g (8ml) and 1.0g (16ml) inj, for i.m. or slow i.v. inj. 5. TRIAMCINOLONE: Highly i.m. selective glucocorticoid; Also slightly used more potent than prednisolone but highly selectie glucocorticoid: 4-32mg/day, oral 5-40mg intraarticular injection. topically KENACORT, LEDERCORT (as acetonide) for i.m. intraarticular inj, 1,4,8 mg tab; 10mg/ml, 40mg/ml. 6. DEXAMETHASONE: Very potent and highly selective glucocorticoid. Long acting, causes marked pituitary-adrenal suppression. It is used for inflammatory and allergic conditions, 0.5-5mg/day orally. Shock, cerebal edema etc, 4-20mg/day i.v. infusin or i.m. injection. Also used topically. DECADRON, DEXONA 0.5 mg, tab, 4mg/ml (as sod.Phosphate) for i.v., i.m. inj.

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7. BETAMETHASONE Similar to dexamethasone, 0.5 5mg/day oral, 4-20mgi.m., i.v. injection or infusion, also topical. Dexamethasone or betamethosone are preferred in cerebal edema and other states in which fluid retention must be avoided. 8. PARAMETHASONE It has intermediate properties between prednisolone and dexamethasone, 2-20mg/day oral. 9. DESOXYCORTICOSTERONE ACETATE (DOCA): It has only mineralocorticoid activity. Used occasionally for replacement therapy in Addisons disease:2-5mg sublingual, 10-20mg i.m. once or twice weekly. DOCABOLIN 10mg/ml inj. 10.FLUDROCORTISONE A Potent mineralocorticoid having some glucocorticoid activity as well, orally active, used for: Replacement therapy in Addisons disease 50-200mg daily, congenital adrenal hyperplasia 0.2 1mg/day. 11.ALDOSTERONE The most potent mineralocorticoid. Not used clinically because of low oral bioavailability and difficult in regulating doses.

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RELATIVE ACTIVITY AS SYSTEMIC CORTICOSTEROIDS

Compound GLUCOCORTICOIDS Short acting (Biological t<12 hour) Intermediate acting (Biological t 12-36 hours) 1.Hydrocortisone (Cortisol) 2. Cortisone 3. Prednisolone 4. Methyl Prednisolone 5. Triamcinolone Long acting 6. Paramothasone (Biological t > 7. Dexamethasone 36 hours) 8. Betanethasone 9. Desoxycorticosterone acetate 10. Fludrocortisone 11. Aldosterone Gluco 1 0.8 4 5 5 10 25 25 0 10 0.3 Minerals 1 0.8 0.8 0.5 0 0 0 0 100 150 3000 Equivalent Dose(antiinflammatory) 20mg 25mg 5mg 4mg 4mg 2mg 0.75mg 0.75mg Equiv Salt retaining dose 2.5mg sublingual 0.2mg Not used clinically

MINERALO CORTICOID

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TOPICAL

STEROID

PREPARATIONS:POTENCY

AND

AVAILABLE FORMS
LOW MEDIUM FLUOCINOLONE ACETONIDE(SYNLAR)0.01% HYDROCORTISONE 0.25%0.5%1%2.5% BETAMETHASONE BENZOATE(UTICORT)0.025% DESONIDE(DESOWEN)0.05% DEXAMETHASONE(DECADRON)0.1% FLUOCINOLONE(SYNLAR)0.025% TRIAMCINOLONE(KENALOG)0.1% BETAMETHASONE VALERATE(VALISONE)0.1% DEXAMETHASONE ELIXIR(DECADRON)0.5% TRIAMCINOLONE(KENALOG)0.1% HALCINONIDE(HALOG)0.1% FLUCIUNONIDE(LIDEX)0.05% FLUCINOLONE ACETONIDE(SYNLAR)0.2% TRIAMCINOLONE(KENALOG)0.5% BETAMTHASONE C,S C,O C,G C C C,O C,O C S C,O C,O C,O,G,S C C,O SUPER HIGH DIPROPRIATE O

MEDIUM HIGH

HIGH

AUGMENTED(DIPROLENE)0.05% CLOBESTEROL(TEMOVATE)0.05% HALOBETASOL PROPRIATE(ULTRAVATE)0.05% C,O,G C,O

C=CREAM, O=OINTMENT, G=GEL, S=SOLUTION.

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PHARMACOTHERAPY
THERAPEUTIC USES
A. Replacement Therpy 1. Acute Adrenal Insufficiency Hydrocortisone hemisuccinate I.V., 100mg every 4-6 hours. Dextrose in normal saline in adequate amounts Vasopressor drugs to maintain blood pressure Antibiotics 2.Chronic Adrenal Insufficiency (Addisons Disease) Hydrocortisone given orally with adequate salt and water allowance Some patients in addition need a mineralo corticoid; fludrocortisone or DOCA are added. 3.Congential Adrenal Hyperplasia(Adrenogential Syndrome) HYDROCORTISONE 0.6 mg/kg daily in divided doses round the clock to maintain feed back suppression of pituitary. If salt wasting persists fludrocortisone 10-50 3g/kg daily may be added.

General principles in prescribing corticosteroids:

1. Single dose (even excessive) is not harmful; can be used to tide over mortal crisis even when benefit is not certain. 2. short courses(even high dose) are not likely to be harmful in the absence of contra indications. Starting doses can be high in severe illness.

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3. Long - term use is potentially hazardous; Keep the dose to the minimum. 4. No abrupt with drawl after a corticoid has been given for > 2 to 3 weeks; may precipitate adrenal insufficiency. 5. Infection, severe trauma or any stress during corticoid therapy increase the dose. DISEASE FOR WHICH CORTICOIDS ARE PRESCRIBED Allergic Diseases Angioedema Asthma,Bronchial, acute and chronic Dermatitis, contact Dermatitis venenata Insect bites Serum reactions Status asthamaticus Transfusion reactions Urticaria Cardiovascular Diseases Postpericardiotomy syndrome Shock, toxic(septic) Eye Diseases: (together with antimicrobial drugs if infection present) Blepharoconjunctivitis Burns, chemical and thermal (if iritis present) Chorioretinitis,Choroiditis Conjunctivitis,allergic catarrhal, chronic vermal Corneal injuries
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Glaucoma, secondary Herpes zoster Iritis, iridocyclitis Keratitis-non tuberculosis Keratoconjunctivites phyctenular Neurites,optic,acute tetrobulbar,acetie Ophthalmic,sympathetic Retinitis centralis Scleritis Ureitis posterior Gastrointestinal Diseases Ulcerative colitis Crohns disease Celiac disease Infection And Inflammation (In serious situations,together with appropriate antimicrobial drugs) Brucellosis - acute Meningites - meningococal, pneumococcal, tuberculous Radiculitis Thyroiditis, acute non - suppurative Trichiniasis Typhoid fever Mesenchymal Diseases: Arthritis psoriatic, rheumaloid, acute and chronic Dermatomyositis Fibromyositis
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Lupus erythematosus - systemic Polyarteritis Rheumatic fever - acute Scleroderma Synovitis; tenosynovitis Steroids Injected Locally Arthritis traumatic Bursitis Osteoarthritis Tendinitis, Peritendinitis Metabolic Diseases Arthritis, gouty acute Hypoglycemia of childhood; spontaneous Thyroid crisis acute Neoplastic Diseases Carcinoma of breast metastatic (resistant to androgen and estrogens) Pulmonary Diseases: Ragassosis Berylliosis Emphysema, pulmonary Fibrosis, pulmonary Loefflers syndrome Sarcoidois Silicosis
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Skin Diseases Dermatitis - actinic, atopic, contact, enzematoid, exfoliative, seborrheic, stasis. Dermatitis herpertiformis Drug eruptions Eczema - chronic Erythema multiforme Herpes Zoster Lichen Planus Miliaria Neurodematitis Otitis externa (only with intact drum) Pemphigus vulgaris Pityriasis rosea Purpura, allergic Sunburn Steroids Applied Locally Intertigo Lichensimplex chronicus Pruritis, anogential Psoriasis Miscellaneous Conditions Bells palsy Torticollis, acute

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