SOFT STEROIDS

Dr.RENJU.S.RAVI MD

OVERVIEW

Definition Mechanism of action Examples of soft steroids Individual drugs Clinical studies Dissociated Steroids Summary

Definition

Soft steroids are androstene-derived steroids which exhibit anti-inflammatory effects similar to those of conventional corticosteroids without the serious systemic side effects associated therewith.

Steroids with a very good ratio of therapeutic effect and side effects are called soft steroids.

Corticosteroids that are rapidly metabolized to achieve sufficient concentration and duration to cause an anti-inflammatory effect are called soft steroids.(G&G)

MOA OF GLUCOCORTICOIDS GCs cause their effects by binding to the 

glucocorticoid receptor (GR). The activated GR complex, in turn, up-regulates the expression

of anti-inflammatory proteins in the nucleus (transactivation) and represses the expression of proinflammatory proteins in the cytosol by preventing the translocation of other transcription factors from the cytosol into the nucleus (transrepression).

Many adverse effects are predominantly caused by transactivation (diabetes, glaucoma), also partly involved in the mediation of other adverse reactions, such as osteoporosis, skin atrophy, growth retardation, and Cushingoid appearance.

Anti-inflammatory effects are mostly mediated by transrepression (such as the inhibition of the synthesis of proinflammatory cytokines or COX- 2)

Mechanisms of Action

A ‘soft steroid’ is:- Active by itself. Has therapeutic efficacy at the site of application. Is rapidly & predictably inactivated during its systemic

uptake & distribution. Posses the same metabolic stability & high receptor

affinity at the airways & lung as conventional ICS.

Inactivation by further metabolic routes like carboxylestrases, in addition to hepatic CYP450 and occurs at places other than the airways.

Examples of soft steroids Ciclesonide . Loteprednol etabonate. Fluorometholone. Eteprednol dicloacetate. Fluocortin butylester. Butixocort. Tipredane. Hydrocortisone aceponate. Lactone derivative of glucocorticoids. Prednicarbate.

CICLESONIDE (CIC) Prodrug soft steroid. CIC is the pure R epimer of 2’-cyclohexyl-

11beta-hydroxy-21-isobutyryloxy-16-dioxolopregna-1,4-diene-3,20-dione.

Approved by the US Food and Drug Administration in October 2006.

CIC exhibits high pulmonary deposition. It is an inactive parent compound. Active metabolite is desisobutyryl-CIC. Bioactivation occurs in lung by

endogenous esterases.

Des –CIC has anti-inflammatory activity in the lung.

Highly lipophilic and undergoes further esterification in lungs.

Complete first pass metabolism; so undetectable in the serum after oral intake.

Highly protein bound- less CIC in circulation; to cause systemic side effects.

Metabolism in liver.

Uses - bronchial asthma, COPD, allergic rhinitis. Phase 3 trials for hay fever.

DOSE - 80-160µg OD by hydrofluoroalkane metered dose inhaler( preferably in evening)

low potential for local and systemic adverse effects. Very good tolerability.

A/E - headache, nosebleeds, and inflammation of the nose and throat lining

Clinical studies

In two 12-week randomised studies in patients with bronchial asthma, Ciclesonide 80 or 320µg OD was effective as budesonide 400µg at increasing FEV1 & FVC from baseline.

In a randomised double blind studies in patients with asthma controlled with high doses of ICS, FEV1 & FVC decreased significantly from baseline at 12 weeks in patients receiving CIC 320 µg OD.

CIC didn’t suppress biochemical markers of adrenal function 52 week studies.

Taylor DA et al observed significant reduction in the % of eosinophils in induced sputum & airway responsiveness with CIC.

Another study noticed that CIC inhibited both the early as well as late phase asthmatic reaction to allergen.

Loteprednol etabonate

Approved by FDA in march 1998. A promising soft steroid metabolised by

hydrolysis without using the CYP450 Therapeutic ratio is superior to

beclomethasone & budesonide. has little or no effect on 

intraocular pressure.

Useful in treating post operative pain and inflammation following ocular surgery, allergic rhinitis, allergic conjunctivitis, episcleritis and keratitis.

Available as 0.5% drops/gel/ointment A/E – Rare. eye pain, photophobia, foreign body sensation,

conjunctival hemorrhage, blurred vision, lacrimation, posterior capsule opacification – Reported.

FLUOROMETHOLONE

Fluorometholone is a corticosteroid, most often used after laser-based refractive surgery.

Fluorometholone acetate ophthalmic suspension is indicated for use in the treatment of steroid responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the eye.

DISSOCIATED STEROIDS/ SEGRA

A selective glucocorticoid that is able to transrepress without transactivation preserve many of the desirable therapeutic anti-inflammatory effects and minimize undesired side effects.

Dissociated steroids attempt to separate the side-effect mechanisms from the anti-inflammatory mechanisms.

Nonsteroidal selective glucocorticoid receptor activators (SEGRA), such as AL-438 and Maprocorat, are in clinical development.

However, some of the anti-inflammatory effects of corticosteroids may be due to transactivation of anti-inflammatory genes, so SEGRAs may not be as efficacious as existing drugs.

Summary

The soft drug approach has been utilized as a means of delivering potent anti-inflammatory agents close to their site of action while reducing the degree of systemic exposure & thus limiting or eliminating associated systemic & local side effects.

Used in asthma & other allergic & inflammatory disorders. Ciclesonide ,Loteprednol etabonate & Fluorometholone are

the clinically used soft steroids now.

THANK YOU…