Corticosteroid

an overall overview in corticosteroids and its application in oral and maxillofacial diagnostic medicine and pathology drawing to the conclusions of the limitations and drawbacks of these medicines. i have also included the precautions to be taken in dental therapeutic procedures fo

1. CORTICOSTEROIDS Presented by : Joe Dsilva

2. CONTENTS Introduction History Functional anatomy and histology of adrenal glands Biosynthesis of steroids Fate of steroids Mineralocorticoids Glucocorticoids

3. Mechanism of action Classification of steroids Uses in medicine Steroids in dentistry Adverse effects Drug interaction Precautions

4. Introduction The adrenal gland is the source of a diverse group of hormones essential for metabolic control, regulation of water and electrolyte balance, and regulation of body’s response to stress. Using cholesterol as a substrate, the adrenal cortex produces a large number of substances collectively known as corticosteroids.

5. History By the middle of 19 th century it was demonstrated that adrenal glands were essential for life Later, it was appreciated that the cortex was more important than the medulla A number of steroidal active principles were isolated and their structures were elucidated by kendall and his coworkers in the 1930s.

6. However, the gate to their great therapeutic potential was opened by Hench (1949) who obtained striking improvement in rheumatoid arthritis by using cortisone. The nobel prize was awarded the very next year to kendall and Hench. Currently, corticosteroids are drugs with one of the broadest spectrum of clinical utility.

7. Functional anatomy and histology of adrenal glands 2 adrenal or suprarenal gland Situated on upper pole of kidney Each gland weighs 4 g Made of cortex and medulla Cortex 80 Medulla 20 develops from neural creast Cortex develops from mesonephros

8. Biosynthesis of steroids Cholesterol Pregnenolone Progesterone 11- Deoxy corticosterone Corticosterone Aldosterone 17 α Hydroxy pregnenolone 17 α Hydroxy progesterone 11 Desoxyhydro cortisone Hydrocortisone Dehydroepiandrosterone Androstenidione Testosterone Formed from cholesterol absorbed directly From circulatimg blood

9. Rate of secretion of the principal steroids

10. REGULATION OF SECRETION

11. FATE OF CORTICOSTEROIDS

12. MECHANISM OF ACTION

13. Mineralocorticoids Source : Zona glomerulosa Functions: 90% of mineralocorticoid activity is provided by aldosterone Aldosterone – life saving hormone

14. Action on EEFECT Sodium metabolism Increases sodium reabsorption from renal tubules On ECF Sodium reabsorption, stimulates water reabsorption thus in term increases ECF volume Blood pressure Increases Potassium ions Increases in excretion of potassium ion s from renal tubules Hydrogen ion Tubular secretion of hydrogen ion , essential to maintain acid base balance. Essentials Of Medical Physiology 3rd Edition, K Sembulingam Ald. Def. Conc of pot ion in xtracellular fluid rises leading to Hyperkalemia leads to cardiac toxicity and arrhythmia .

15. Increase in K + concentration Decrease in Na + Concentration Decrease in ECF volume Decrease in K + concentration Increase in Na+ Concentration Increase in ECF volume Juxtaglomerular apparatus Excretion of K + Retention of Na + Retention of water kidneys Lungs Aldosterone Adrenal cortex angiotensinogen Angiotensin - 1 Angiotensin - 2 Renin Converting Enzyme ACE Stimulation Feedback inhibition Regulation of Aldosterone Secretion Essentials Of Medical Physiology 3rd Edition, K Sembulingam

16. Glucocorticoids Source : zona fasciculata Functions : Cortisol – Life protecting hormone

17. Action ACTION ON EFFECT On carbohydrate metabolism Increases blood glucose level by gluconeogenesis , inhibits glucose uptake and utilization by peripheral cells Protein metabolism Promotes catabolism of protein and increases plasma amino acid and protein content Fat metabolism Metabolism of fatty acid from adipose tissue increases in concentration of fatty acid , increase utilization of fat for energy. Mineral metabolism Enhances sodium retention, potassium excretion. Water metabolism Excretion of water Gluconeogenesis breakdown of protien in extrahepatic cells Particularly muscles release of aminoacid in to circulation. Dec. in glucose uptak is antiinsulin effect. Thus hypersecreation causes edema hypertension, hyperkalemia And muscular weakness. Utilization of fatty acid causes formation of ketone bodies and thus called ketogenic effect

18. Muscles Increases the release of amino acid from muscles by catabolism of protein Blood vessel Decreases the release of eosinophil in RES, decrease the number of lymphocytes, increase in number of neutrophils , RBC and platelets . Vascular response These are essential for constrictor action of adrealine and noradrenaline CNS Essential for normal functioning, insufficiency causes irritability and loss of concentration Hypersecreation causes muscular weakness

19. Permissive action Action of some hormones are executed only in presence of glucocorticoids. This is called permissive action. Examples are : Calorigenic effect of glucagon. Lypolytic effect of catecholamines . Pressor effect of catecholamines . Bronchodilation by catecholamines .

20. Antiinflammatory Action

21. Effects on resistance to stress High resistance to body against stress

22. Anti allergic action Suppresses all type of hypersensitivity reaction and allergic reaction. Suppresion of recruitment of leucocytes at the site of contact with antigen and inflammatory response to immunological injury

23. Immunosuppresive action Suppresses immune system of body by decreasing number of circulating T lymphocytes. Prevent release of interleukin 2 by T cells

24. Emotion, stress, trauma Hypothalamus Corticotropin releasing factor Anterior pituitary ACTH Adrenal cortex Cortisol Feedback inhibition Regulation of Cortisol Secretion

25. Classification of steroids based on their relative activity: GLUCOCORTICOIDS

26. Mineralocorticoids Desoxycorticosterone acetate(DOCA) Fludrocortisone Aldosterone

27. Some Commonly Prescribed Steroids Triamcinolone Kenacort / tricort / kenalog Oral – 1,4,8 mg syrup Topical - Parenteral - 3,10,40 im , iv, intraarticular Dexamethasone Oral – 05 to 9mg /day in 2 to 4 divided dose Topical Parenteral iv 1 to 6mg/kg Betamethasone Oral – 0.5 to 5mg /day Topical – 0.1% cream or .05% gel Parenteral im - 0.25 to 9 mg/day

28. Cortisone Oral Topical Parenteral Prednisolone Hydrocortisone Oral Topical Parenteral

29. Uses In Medicine Replacement therapy

30. Pharmacotherapy : Single dose (even excessive) is not harmful can be used to tide over mortal crisis even when benefit is not certain. Short courses (even high doses) are not likely to be harmful in the absence of contraindications. Starting doses can be high in severe illness

31. Long term use is potentially hazardous: keep the dose to minimum which is found by trial and error, even partial relief may have to be tolerated. No abrupt withdrawal after a corticoid has been given for > 2 to 3 weeks: may precipitate adrenal insufficiency

32. Arthritis Collagen diseases Severe allergic reactions Autoimmune disorders Bronchial asthma Infective diseases Eye diseases Skin diseases Intestinal diseases

33. STEROIDS IN DENTISTRY

34. Steroids in oral surgery Prevention of post operative pain, edema and trismus after 3 rd molar surgery Prevention of post operative edema after orthognathic surgery Prevention of alveolar osteitis

35. Corticosteroids in Orthodontic Tooth Movement Orthodontic tooth movement is characterized by a multiple biological process involving sequential reactions of the periodontal tissue in response to biomechanical forces . In the periodontal ligament, light or heavy mechanical force in traction zone leads to formation new bone or alveolar wall where as the alveolar bone is directly resorbed under light force by osteoblasts . The arachidonic acid metabolites also play an important role in the process of bone remodeling during tooth movement International Journal of Pharmaceutical Sciences Review and Research

36. hydrocortisone at a dose of 10 mg/kg/day for 7 days on rats followed by observed for 20 hours; the teeth showed lower amount of tooth movement it is essential that the patients are reviewed of their prior history of corticosteroids use . longer interval between treatments will help to understand any possible changes in bone International Journal of Pharmaceutical Sciences Review and Research

37. Steroids in endodontics steroid-antibiotic combinations like Ledermix Steroids like hydrocortisone are also mixed with zinc oxide eugenol to be used as root canal sealers. It appears that the action of steroids on root resorption is chemistry dependent. International Journal of Pharmaceutical Sciences Review and Research

38. Steroid in oral medicine

39. Ulcerative Vesiculoerosive diseases Immunologically mediated diseases that affect the oral mucosa present with inflammation and loss of epithelial integrity, through cellular and/or humoral immunity-mediated attack on epithelial connective tissue targets. The main clinical features are ulceration and reddening, with pain that can be severe and debilitating.

40. Corticosteroids play a central role in the treatment of vesiculoerosive lesions. However, the frequency and severity of the adverse effects associated with the use of systemic corticosteroids have led to the increased use of topical corticosteroids (TCs)

41. Topical corticosteroids for ulcerative vesiculoerosive lesions

42. Indications for use Short course of TC – accelerates remission without producing adverse effects Ulcerative disease that have tendency to remit spontaneously Eg RAS, some cases of EM, drug induced ulceration Scully et al., 1999; Chan et al., 2002

43. TC for longer and less predictable periods When disease is chronic Marked tendency for recurrence Eg . RAS, erosive OLP, apecific form of EM, MMP

44. In severe cases of ulceration After a short course of systemic corticosteroids, a maintenance regimen of TC can be used once the disease is controlled. This can prevent recurrence, and also avoids adverse effects assosiated with long course of systemic corticosteroids

45. Protocols for use When a TC is prescribed, especially for prolonged course is predicted The basic rule is that a TC of a potency appropriate to the severity of the clinical symptoms should be used, at the lowest possible concentration and frequency, with maintaining the effectiveness of the treatment. It should always be taken into account that these drugs do not cure the disease but rather control or relieve the symptoms. JDR April 2005 vol. 84 no. 4 294-301

46. The key factors Specific diagnosis Severity of oral disease Presence or absence of extraoral lesion Medical history of patient JDR April 2005 vol. 84 no. 4 294-301

47. Factors that influence the effectiveness of TCs : JDR April 2005 vol. 84 no. 4 294-301 Intrinsic potency of drug : This can be increased by halogenation and esterification of steroid This makes drug more lipophilic and gives it greater penetrability Contact time between the drug and lesion and the Vehicle used to apply it

48. JDR April 2005 vol. 84 no. 4 294-301 Concentration : which can increase its clinical effectiveness, although no additional advantage is obtained beyond certain limits.

49. JDR April 2005 vol. 84 no. 4 294-301 Success of a topical medicine Depend on two main factors Number of application per day High potency – 2 to 3 times Low potency – 5 to 10 times Vehicle used

50. JDR April 2005 vol. 84 no. 4 294-301 Various vehicles Orabase Cyanoacrylate Bioadhesive patch made of cellulose derivatives Gels Orabase contains gelatin, peptin,and sodium carboxymethylcellilose In plasticized hydrocarbon gelthat is free of antibiotic analgesis and antiseptic. Gels have drawback of causing pain in some pt. secondary to irritation byalcohol in there formulation Oitment donot have adhesive proprty and are rarely used

51. Patients prescribed TC in an adherent vehicle should be instructed to Apply a small amount to the target area after meals, and Not to eat or drink for at least 30 min. It is best not to rub the TC in, because this can produce irritation . JDR April 2005 vol. 84 no. 4 294-301

52. Preparations such as orabase will not adhere to wet surface so mucosa and lesion must be dried with guaze before application.

53. For small and accessible erosive lesions, or those located on the gingiva and palate, the lesions can be treated by the Use of an adherent paste in a tray, Which allows for accurate control over the contact time and Ensures that the entire lesional surface is exposed to the drug. JDR April 2005 vol. 84 no. 4 294-301

54. Adhesive denture paste as vehicle for TC can avoid some of above disadvantages this provides stability and bioadhesive properties forperiod of 12 hrs after application, esp. in localized lesions,

55. TC mouthrinses : Contact time can be predicted Drug is in contact with all lesions Are released more readily to oral mucosa when aqueous solution is applied

56. Disadvantage Will be in contact with all mucosa wheather effected or not This also increase the surface area of absorption thus risk of adverse effects This can be exacerbated by presence of ulcerated surfaces and by increased pressure excerted by liquid on mucosa as a result of normal rinsing Can be involumentary ingested

57. Thami and bhalla proposed using saliva as vehicle for TCs which they designated as chew and spit method . Patient is directed to chew or suck betamethasone tab. Mixing it with mouth saliva keeping it without swallowing for as long as possible 10 to 15 min Disadvantage ; Cannot guaranteed that tablet is completely dissolved Cannot be used in dry mouth

58. Systemic steroids for ulcerative vesiculobullous diseases

59. Major aphthae or severe multiple minor aphthae Prednisone therapy should be started at 1.0 mg/kg/day in patients with severe RAU and should be tapered after 1 to 2 weeks . Predisone therapy 1- 2mg /kg/day after breakfast untill the disease is controlled and then maintenance dose of 2.5 to 15mg daily ( Burket 11 th edition ) Natah SS, Konttinen YT. IJOMS 2004;33:221-34.

60. Erythema multiforme Indian J Ophthalmol Jan-Feb 2010;58(1):64-66 Minor EM – 20 to 40 mg/day for 4 to 6 days Severe or rapidly progressing lesions – 60 mg/day slowly tapered by 10mg/day over 6 weeks

61. Pemphigus Vulgaris Mainstay 1-2mg/kg/d. Initial dose of treatment – 0.5 mg/kg/day to 3 mg/kg/d Dose that achieves clinical control is maintained for 2-3 weeks and then gradually tapered. Burket’s Oral Medicine, 11 th edition

62. Pulse therapy Also called short term therapy High dose therapy involves a 48-72 hrs course of intensive steroid administration Single i.v injection of a supra-physiological dose of steroid Dose of 0.5-2g of prednisolone or equivalent

63. Benefits Avoids complications & side effects of long term steroid therapy To achieve immunosuppressive effects similar to those with higher doses of steroids

64. Cicatricial pemphigoid Predisolone – 30 to 60 mg/day 2 to 3 weeks to stop new bullae formation. Tapered by 20% every 2 to 3 weeks until the dose of 10 mg is reached Then maintained on alternate day and reduced by 5 mg every 2 week then stopped

65. Bullous pemphigoid JIAOMR, April-June 2011;23(2):128-131 Clobetasol propionate 20 -40 mg/day is more effective for the treatment.

66. Lichen planus Burkit’s Oral Medicine, 11 th edition JIAOMR, April-June 2011;23(2): 128-131 Prednisolone - 1mg/kg/d for <7 days Tapered to 10-20mg per day for 2 weeks

67. Lupus erythematosus Predisolone – 20 - 30 mg/day for 2- 6 weeks Tapered gradually

68. Steroids in the treatment of benign lesions

69. CGCG J Med Assoc Thai 2008; 91 ( Suppl 3): S90-6 Intralesional injection of triamcinolone can be given in a dose of 1 to 2 mg/kg/d (maximum of 60 mg ). The treatment interval at 4 to 6 weeks.

70. Hemangioma Prednisone at a dose of 20-30 mg/d can be given for 2 weeks to 4 months Intralesional triamcinolone acetonide (4 mg/mL)

71. Steroids in salivary gland disorders

72. Mucocele 0.05% clobetasol propionate 3 times a day for 4 weeks in a mucosal adhesive base. Intralesional injections have also been tried with success. (JOMS 2008;66:1737-9)

73. Steriods in neuralgia

74. Post herpetic neuralgia To reduce incidence of post herpetic neuralgia: Prednisolone 20 to 30 mg/day for 7 – 10 days tapered to 10 mg/day for 1 week

75. Steroids for TMJ disorders

76. Arthritis Oral Surgery Volume 1 Issue 2, Pages 88 - 95 Rheumatoid arthritis - Intraarticular injection – 10 to 40 mg/ml Osteoarthritis - Intraarticular injection – 20 mg/ml(2 injections 14 days apart)

77. Bell’s palsy Significant improvement can be achived when Prednisolone is started within 72 hours of symptom onset 1 mg/kg body weight (maximum 70 mg) in divided doses with meals for six days, and the dose can be reduced gradually over the next four days.

78. OSMF Predisolone – 20 - 30 mg/day for 2 – 4 weeks then gradually taper to discontinue in 1 to 2 months

79. Injections of triamcinolone 10mg/ml diluted in 1 ml of 2% lidocaine with hyaluronidase 1500 IU, biweekly for 4 weeks.

80. Biweekly submucosal injections of a combination of dexamethasone (4mg/ml) and two parts of hyaluronidase , diluted in 1.0 ml of 2% xylocaine by means of a 27 gauge needle, not more than 0.2ml solution per site, for a period of 20 weeks. Significant relief of burning sensation (88%) and improvement of trismus (83%) can be seen in most patients.

81. Adverse effects Due to extention of pharmacological action occuring with prolonged therapy Mineralocorticoids: Sodium and water retention Edema Hypokalemic alkalosis Progressive rise in B.P Weight gain Fluid and electrolyte disturbance

82. Glucocorticoid: GIT: Acute erosive gastritis with hemorrhage Peptic ulcer Intestitial perfortion Pancreatitis Metabolic effects: Hyperglycemia Ketoacidosis Hyperosmolar coma Hypophosphatemia

83. Cushingoidism : Prolonged therapy causes Central obesity with moon face Buffalo hump Pink florid striae are liable to appear on the abdomen, hips and pectoral region and skin may become friable

84. CVS and renal system: Hypertension Salt and water retention Hypokalemic alkalosis CNS: Influence mood, sleep pattern Insomnia Acute psychotic reactions Benign intracranial hypertension Epilepsy

85. Musculoskeletal effects: Proximal myopathy and osteoporosis with compression fractures of vertebrae Acute aseptic necrosis of bone Eyes: Glaucoma

86. Suppression of inflammation and immune response: Latent infection may flare Oppurtunistic infection with low grade pathogens Retardation of linear growth: Occurs in children who receive more than 50 mg of cortisone per m 2 of body surface per day.

87. SUPPRESSION OF HPA axis Depend on both dose and duration of therapy With administration of glucocorticoid, adrenal cortex atrophies With stoppage of exogenous steroid precipitates withdrawal syndromes- Malaise Fever weakness Pain in muscles Joints Reactivation of disease

88. When subjected to stress these patients may undergo acute adrenal insufficiency Any patient who has received >20 to 25 mg /day hydrocortisone or equivalent for more than 2 to 3 weeks should be put on a scheme of gradual withdrawal: 20 mg hydrocortisone/day reduction every week and then still smaller fraction once level is achieved

89. In stressful situation these patients requires protection with exogenous steroids upto 1 year after withdrawal. If patient on steroid therapy develops infection steriod should not be discontinued. Rather dose has to be increased to meet stress of infection.

90. Measures to minimize HPA axis suppression Use of short acting steroids at lowest possible dose Use of steroid at shorest period of time Giving entire daily dose one time in morning Switch to alternate day therapy

91. Alternate day therapy Double dose is taken every other morning Usually preferred for other chronic conditions. Schedule allows rest periods so that adverse effects are decreased while anti-inflammatory effects continue . ADT is used only for maintenance therapy ADT can be started after symptoms have subsided and stabilized.

92. Contraindications: Peptic ulcer Diabetes mellitus Hypertension Pregnancy Herpes simplex keratitis Tuberculosis Osteoporosis Psycosis Epilepsy Renal failure

93. Drug interactions Glucocorticoid dosage decreased: Antibiotics (Erythromycin) Cyclosporine Isoniazid Ketoconazole Estrogen Reduce metabolic clearance

94. Glucocorticoid dosage increased : Cholestyramine Antiepileptic Drugs (Barbiturates, Phenytoin, Carbamazepine) Rifampicin Glucocorticoid dosage needs adjustment: Antianxiety and antipsychotic drugs Antihypertensives Hypoglycemics sympathomimetics

95. Precautions during therapy Before starting therapy: Enquire and check for hypertension, diabetes mellitus, peptic ulcer, any infection

96. During therapy: Prescribe drug with food Diet low in calories and sodium and rich in potassium Check periodically for weight gain, hypertension, hyperglycemia

97. Increase dose in case of stress Instruct patient not to stop abruptly While stopping therapy: Taper therapy

98. Rule of 2 Adrenocortical suppression should be suspected if a patient has received Glucocoticoid therapy through two of the following methods In a dose of 20 mg or more of cortisone or its equivalent Via oral or parenteral route or a continuous period of 2 weeks or longer Within 6 months -2 years of therapy Medical emergencies in dental office, Stanley F.Malamed Complications in Anesthesia - John L. Atlee; Page-132

99. Protocol for Supplementation of Patients on Glucocorticoid Therapy Who Are Undergoing Dental Care ( Burket’s 10th ed )

100. Dental Procedure Previous Systemic Steroid Use Current Systemic Steroid Use Daily alternating Systemic Steroid Use Current topical Systemic Steroid Use Routine procedures If prior usage lasted for > 2 weeks and ceased < 14–30 days ago, give previous maintenance dose If prior usage ceased > 14–30 days ago, no supplementation needed No supplementation needed Treat on steroid dosage day; no further supplementation needed No supplementation needed

101. Dental Procedure Previous Systemic Steroid Use Current Systemic Steroid Use Daily alternating Systemic Steroid Use Current topical Systemic Steroid Use Extractions, surgery, or extensive procedures If prior usage lasted > 2 weeks and ceased < 14–30 days ago, give previous maintenance dose If prior usage ceased > 14–30 days ago, no supplementation needed Double daily dose on day of procedure Double daily dose on first postoperative day when pain is anticipated Treat on steroid dosage day, and give double daily dose on day of procedure Give normal daily dose on first postoperative day when pain is anticipated No supplementation needed

102. Conclusion Corticosteroids play an important role in control of pain & inflammation associated with numerous disease states of oral cavity. Currently corticosteroids are drugs with one of the broadest spectrum of clinical utility. But it should never be used as a substitute to other treatments Lets keep it mind that these drugs do not cure the disease but rather control or relieve the symptoms.

103. References Burket ’ s Oral Medicine 9 th and 11 th edition Corticosteroids in Dentistry, Basavaraj Kallali et al JIAOMR April -June 2011;23(2): 128-131 Steroids in Dentistry - A Review Sambandam V, Int. J. Pharm. Sci. Rev. Res., 22(2), Sep – Oct 2013; nᵒ 44, 240-245 Steroids Application In Oral Diseases, Int J Pharm Bio Sci 2013 Apr; 4(2): (P) 829 - 834

104. Thank You