CORTICOSTEROIDS

Presented by :

Joe Dsilva

CONTENTS

• Introduction

• History

• Functional anatomy and histology of adrenal glands

• Biosynthesis of steroids

• Fate of steroids

• Mineralocorticoids

• Glucocorticoids

• Mechanism of action

• Classification of steroids

• Uses in medicine

• Steroids in dentistry

• Adverse effects

• Drug interaction

• Precautions

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.

History

By the middle of 19th 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.

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.

Functional anatomy and histology of adrenal glands

Biosynthesis of steroidsCholesterol

Pregnenolone

Progesterone

11- Deoxy corticosterone

Corticosterone

Aldosterone

17α Hydroxy pregnenolone

17α Hydroxy progesterone

11 Desoxyhydro cortisone

Hydrocortisone

Dehydroepiandrosterone

Androstenidione

Testosterone

Rate of secretion of the principal steroids

Glucorticoids 10-20 mg daily

Mineralocorticoids – 0.125 mg daily

FATE OF CORTICOSTEROIDS

Degraded mainly in liver

Conjugated to form glucuronides and to a lesser extent form sulphates

25% - excreted in bile and feces

75% - excreted in urine

MECHANISM OF ACTION

Mineralocorticoids Source : Zona glomerulosa

Functions: 90% of mineralocorticoid activity is provided

by aldosterone

Aldosterone – life saving hormone

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

Increase in K+ concentrationDecrease in Na+ ConcentrationDecrease in ECF volume

Decrease in K+ concentrationIncrease in Na+ ConcentrationIncrease in ECF volume

Juxtaglomerular apparatus

Excretion of K+

Retention of Na+

Retention of water

kidneysLungs

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

GlucocorticoidsSource : zona fasciculata

Functions:

Cortisol – Life protecting hormone

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

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

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.

Antiinflammatory Action

Effects on resistance to stress

Physical or mental stress

Increases ACTH

Increase in glucocortic

oid secretion

High resistance

to body against stress

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

Immunosuppresive action

• Suppresses immune system of body by decreasing

number of circulating T lymphocytes.

• Prevent release of interleukin 2 by T cells

Emotion, stress, trauma

Hypothalamus

Corticotropin releasing factor

Anterior pituitary

ACTH

Adrenal cortex

Cortisol

Fee

dbac

k in

hibi

tion

Regulation of Cortisol Secretion

Classification of steroids based on their relative activity:GLUCOCORTICOIDS

Short acting(t1/2 < 12 hr)• Hydrocortison

e • Cortisone

Intermediate acting: (t1/2 12 – 36)• Prednisole• Methyl

prednisole• Triamcinolone

Long acting:(t1/2 > 36 hrs)• Paramethasone• Dexamethason

e• Betamethasone

Mineralocorticoids • Desoxycorticosterone acetate(DOCA)

• Fludrocortisone

• Aldosterone

UsesIn Medicine Replacement therapy

Acute adrenal insufficiency •Hydrocortisone or dexamethasone are given i.v, first as a bolus injection and then as infusion along with istonic saline and glucose solutions.

Chronic adrenal insufficiency

•Hydrocortisone given orally is the most commonly used drug with adequate salt and water allowance

Congenital adrenal hypoplasia

•0.6 mg/kg daily in divided doses round the clock

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

• 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

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

STEROIDS IN DENTISTRY

Steroids in oral surgery

• Prevention of post operative pain, edema and trismus

after 3rd molar surgery

• Prevention of post operative edema after orthognathic

surgery

• Prevention of alveolar osteitis

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

Steroid in oral medicine

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.

• 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)

Topical corticosteroids for ulcerative vesiculoerosive lesions

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

TC for longer and less predictable periods

• When disease is chronic

• Marked tendency for recurrence

• Eg. RAS, erosive OLP, apecific form of EM, MMP

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

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

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

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

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.

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

JDR April 2005 vol. 84 no. 4 294-301

Various vehicles

• Orabase

• Cyanoacrylate

• Bioadhesive patch made of cellulose derivatives

• Gels

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

Preparations such as orabase will not adhere to wet

surface so mucosa and lesion must be dried with guaze

before application.

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

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,

• 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

• 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

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

Systemic steroids for ulcerative

vesiculobullous diseases

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 11th edition )

Natah SS, Konttinen YT. IJOMS 2004;33:221-34.

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

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, 11th edition

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

Benefits

• Avoids complications & side effects of long term steroid

therapy

• To achieve immunosuppressive effects similar to those

with higher doses of steroids

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

Bullous pemphigoid

JIAOMR, April-June 2011;23(2):128-131

Clobetasol propionate

20 -40 mg/day is more effective for the treatment.

Lichen planus

Burkit’s Oral Medicine, 11th editionJIAOMR, April-June 2011;23(2):128-131

Prednisolone - 1mg/kg/d for <7 days

Tapered to 10-20mg per day for 2 weeks

Lupus erythematosus

Predisolone – 20 - 30 mg/day for 2- 6 weeks

Tapered gradually

Steroids in the treatment of benign lesions

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.

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)

Steroids in salivary gland disorders

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)

Steriods in neuralgia

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

Steroids for TMJ disorders

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)

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.

OSMF

Predisolone – 20 - 30 mg/day

for 2 – 4 weeks then gradually

taper to discontinue in 1 to 2

months

Injections of triamcinolone 10mg/ml diluted in 1

ml of 2% lidocaine with hyaluronidase 1500 IU,

biweekly for 4 weeks.

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.

Adverse effectsDue 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

Glucocorticoid:

GIT: Acute erosive gastritis with hemorrhage Peptic ulcer Intestitial perfortion Pancreatitis

Metabolic effects: Hyperglycemia Ketoacidosis Hyperosmolar coma Hypophosphatemia

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

CVS and renal system: Hypertension Salt and water retention Hypokalemic alkalosis

CNS: Influence mood, sleep pattern Insomnia Acute psychotic reactions Benign intracranial hypertension Epilepsy

Musculoskeletal effects: Proximal myopathy and osteoporosis with

compression fractures of vertebrae Acute aseptic necrosis of bone

Eyes: Glaucoma

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 m2 of body surface per day.

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

• 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

• 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.

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

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.

Contraindications:

Peptic ulcer

Diabetes mellitus

Hypertension

Pregnancy

Herpes simplex keratitis

Tuberculosis

Osteoporosis

Psycosis

Epilepsy

Renal failure

Drug interactions

Glucocorticoid dosage decreased: Antibiotics (Erythromycin) Cyclosporine Isoniazid Ketoconazole Estrogen

Reduce metabolic clearance

Glucocorticoid dosage increased: Cholestyramine Antiepileptic Drugs (Barbiturates, Phenytoin,

Carbamazepine) Rifampicin

Glucocorticoid dosage needs adjustment: Antianxiety and antipsychotic drugs Antihypertensives Hypoglycemics sympathomimetics

Precautions during therapy

Before starting therapy: Enquire and check for hypertension, diabetes

mellitus, peptic ulcer, any infection

During therapy: Prescribe drug with food Diet low in calories and sodium and rich in

potassium Check periodically for weight gain, hypertension,

hyperglycemia

Increase dose in case of stress Instruct patient not to stop abruptly

While stopping therapy: Taper therapy

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.MalamedComplications in Anesthesia - John L. Atlee; Page-132

Protocol for Supplementation of Patients on Glucocorticoid Therapy Who Are Undergoing Dental Care

(Burket’s 10th ed)

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 daysago, no supplementation needed

No supplementation needed

Treat on steroid dosage day; no further supplementation needed

No supplementation needed

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

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.

References

• Burket’ s Oral Medicine 9th and 11th edition

• Corticosteroids in Dentistry, Basavaraj Kallali et al

JIAOMRApril-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

Thank You