SEMINAR ON SOFT STEROIDS

1. SOFT STEROIDS
Dr.RENJU.S.RAVI MD

2. OVERVIEW
 Definition
 Mechanism of action
 Examples of soft steroids
 Individual drugs
 Clinical studies
 Dissociated Steroids
 Summary

3. 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)

4. 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)

5. Mechanisms of Action

6. 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.

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

8. 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.

9.  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.

10.  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

11. 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.

12.  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.

13. 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.

14.  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.

15. 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.

17. 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.

18. 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.

19. THANK YOU…