2. PRESENTATION LAYOUT Introduction to steroids Introduction to
adrenal gland Inflammatory response Pharmacologic principle of
steroids Common ophthalmic steroids Indications, contraindications
and side effects of steroids
3. 3 Steroid" is a chemical name for any substance that has a
characteristic chemical structure consisting of multiple chemical
rings of connected atoms. Contains four cycloalkane rings 3 rings :
cyclohexane 1 ring : cyclopentane INTRODUCTION TO STEROID
4. cortisol dexamethasone Some examples of natural steroids
Vitamin D Cholesterol Estrogen Progesterone Cortisol Some examples
of synthetic steroids Prednisolone Dexamethasone Betamethasone
trimcinolone
5. ADRENAL GLAND Two in number, superior and slight medial to
kidneys Two parts: adrenal cortex (80%) adrenal medulla (20%) Each
weight about 4 grams
6. ADRENAL CORTEX Comprises 3 zones: Zona glomerulosa(15%) Zona
fasciculata(75%) Zona reticularis(10%)
7. ZONA GLOMERULOSA : Produce mineralocorticoids i.e
Aldosterone ZONA FASCICULATA : Produce glucocorticoids e.g Cortisol
, corticosterone , small amount of adrenal androgens and estrogens
ZONA RETICULARIS : Produce androgens e.g Dehydroepiandrosterone
,small amount of estrogen and some glucocorticoids
8. HYPOTHALAMO-PITUITARY- ADRENAL AXIS
9. Secretion of mineralocorticoids depend upon extracellular
fluid concentrations of angiotensin II and potassium Secretion of
glucocorticoids controlled by hypothalmic pituitary axis via
ACTH(adrenocorticotropic hormone) Thus secretion pathway of
mineralocorticoids and glucocorticoids does not depend upon each
other
10. FUNCTION OF MINERALOCORTICOIDS Aldosterone increases renal
tubular reabsorption of sodium and secretion of potassium Excess
Aldosterone increases extracellular fluid volume and arterial
pressure but has only small effect on plasma sodium concentration
Excess aldosterone causes hypokalemia and muscles weakness
11. FUNCTION OF GLUCOCORTICOIDS 1.Effect on carbohydrate
metabolism i.e stimulation of gluconeogenesis Decrease glucose
utilization by the cells Elevate the blood glucose concentration
and cause Adrenal diabetes Cortisol increases the enzyme required
to convert the amino acid into the glucose in liver cells Cortisol
causes mobilization of amino acids from the extrahepatic tissue
mainly from muscles
12. 2.Effect on protein metabolism Reduction of cellular
protein Cortisol increases the liver and plasma protein Excess of
cortisol may cause muscle so weak that person can not rise from the
squatting position Reduction of protein stored in essentially all
body cells except those of liver cells Decreases protein synthesis
and increases catabolism of protein already present
13. 3.Effect on fat metabolism Mobilization of fatty acids
Excess cortisol causes obesity It promotes mobilization of free
fatty acids from adipose tissue Increases the concentration of free
fatty acids in plasma , which increases there utilization for
energy Excess deposition of fat in chest and head regions of body
giving a buffalo like torso and rounded moon face
14. 4.Effect in resisting stress Almost all type of stress (
trauma , infections , intense heat and cold , surgery ) cause
immediate and marked increase adrenocotical secretion of cortisol
Glucocorticoids cause rapid mobilization of amino acids and fat
from there cellular store , making them immediately available both
for energy and synthesis of other compounds
15. 5. Effect on immunity and blood Decreases activation and
migration of leukocytes Lyse and destroy lymphocytes Administration
of large doses of the cortisol causes significant atrophy of all
lymphoid tissue through out the body Cortisol increase the count of
red blood cells , the cause of which is unknown Inhibit migration
of neutrophils to extracellular space and adherence to vascular
endothelium
16. 6.Effect as strong anti-inflammatory agent To know about
anti-inflammatory action , first inflammation should be discussed
Inflammation is the entire complex tissue changes due to noxious
agents Five different stages of the inflammation Inflammation
17. 1.Chemicals such as histamine , bradykinin , proteolytic
enzymes , prostaglandins and leukotrienes from damage tissue cells
activates the inflammation 2. Increases blood flow due to
vasodilation called erythema 3. Leakage of plasma out of
capillaries into damaged area because increase capillary
permiability 4. Infiltration of area by leukocytes 5. After few
days ingrowth of fibrous tissue that often helps in the healing
process
18. Membrane phospholipid Arachidonic acid Chemical and
mechanical stimuli Phospholipase A cyclooxygenase lipooxygenase
endoperoxidases leukotrienes Prostacycli n PGI2 PGE2 , PGD2 , PGF2a
Thromboxane A2 glucocorticoids NSAIDs Basis of inflammation
19. Basic steroidal activities towards inflammation Reduce
histamine release from basophils induced by IgE dependent stimulus
Inhibit phospholipase A2 which prevents biosynthesis of arachidonic
acid and subsequent formation of prostacyclin, prostaglandins and
leukotrienes Decrease capillary permeability and fibroblast
proliferation and the quantity of collagen deposition thus
influencing tissue regeneration and repair The anti-inflammatory
effects are nonspecific, occurring whether the etiology is
allergic, traumatic or infectious
20. Mode of action Every tissue has receptor for steroids Binds
to glucocoticoid receptor in nucleus Because cortisol is lipid
soluble it can easily diffuse through the cell membrane
21. Transactivation : upregulates the expression of
anti-inflammatory proteins in nucleus Transrepression :
downregulates the expression of proinflammatory proteins in
cytosol
22. It is better to understand Increased concentration of drug
better than increased dozes
23. Common Ophthalmic steroids Corticosteroid Derivative
Formulation Concentration Prednisolone Acetate suspension 0.125% or
1% Prednisolone Sodium phosphate solution 0.125% or 1%
Dexamethasone Alcohol Suspension 0.1 Dexamethasone Sodium phosphate
Solution Ointment 0.1 0.05 Flourometholo ne Alcohol Ointment
Suspension 0.1 0.1 Flourometholo ne Acetate Suspension Suspension
0.25 0.1
24. Prednisolone A synthetic analogue of the major
glucocorticoid i.e cortisol or hydrocortisone Effective for
external as well as intraocular inflammation Commercially
formulated as acetate and phosphate ; acetate derivative being more
effective anti-inflammatory agent Not available as an ophthalmic
ointment.
25. Available in concentration of 0.5% and 1% W/V Prednisolone
acetate 1% is considered the standard, by which all other topical
ocular corticosteroids are compared As compared with other topical
ocular steroids , 1% prednisolone acetate is generally considered
the most effective anti-inflammatory agent for anterior segment
ocular inflammation
26. Has the greatest efficacy when compared to all other
available ophthalmic agents So,is more likely to elevate IOP and
have greater side effects than its weaker counterparts Systemic
prednisolone recommendation Tab. Prednisolone acetate 1 mg/kg of
body weight *OD Tab. Ranitidine 150 mg *OD * AC Tab. Calcium * 500
mg * OD
27. Dexamethasone Structurally resemble cortisol Available as
an alcohol or phosphate derivative 0.1% ophthalmic suspension or
solution Alcohol derivative more active than phosphate Resistant to
metabolism after penetration into the aqueous humor.
28. Very effective in reducing ocular inflammation But has the
propensity to increase IOP more than any other topical ophthalmic
corticosteroid Usually limited to shortcourse therapy Dexamethasone
ointment is very useful for nighttime coverage in cases of
uveitis
29. Fluorometholone (FML) Structurally resemble progesterone
Formulated both as an alcohol and acetate derivative Relatively
weaker corticosteroid Decreased risk of unwanted complications,
such as IOP rise
30. Treatment of choice in those patients with a history of
pressure rise due to corticosteroid therapy or previously diagnosed
glaucoma An effective agent in external ocular inflammations , like
conjunctivitis, piguiculitis , scleritis and episleritis Available
as 0.1% drop
31. Medrysone Like fluorometholone , a synthetic derivative of
progesterone Weakest of the available ophthalmic steroids Useful
for superficial ocular inflammations , including allergic and
atopic conjunctivitis Generally do not respond to intraocular
inflammatory conditions Elevates IOP minimally or not at all
32. Betamethasone Available as 0.1% eyedrop or ointment Marked
anti-inflammatory action Low dose is enough So, reduces the risk of
side effects
33. Hydrocortisone 1st corticosteroid used in medicine
Available as 1% eyedrop and 0.5%, 1% or 3% ointment
34. Rimexolone Available as a 1% ophthalmic suspension (Vexol)
Effective in suppressing cells, flare, keratin precipitates and
photophobia Main advantage - more of site-specific action than
other corticosteroids Less tendency to increase the IOP.
35. LOTEPREDNOL Available as 0.2% and 0.5% concentration Less
potent steroid Indicated for temporary relief of the signs and
symptoms of seasonal allergic conjunctivitis
36. Dexamethasone Prednisolone Fluorometholon Medrysone A N T I
N F L A M M A T O R Y A C T I N C R E A S E I N I O P
37. BIOAVAILABILITY OF TOPICAL STEROIDS Fraction of unchanged
drug reaching the systemic circulation Depends upon the ability to
penetrate cornea The ideal steroid should be biphasic i.e
solubility in both the lipid (hydrophobic) layers of the epithelium
and endothelium and the aqueous (hydrophilic) media of the
stroma
38. Acetate and alcohol derivatives more lipophilic i.e fat
soluble Sodium phosphate and hydrochloride more hydrophilic i.e
water soluble So, in intact epithelium , penetration of acetate
greater while in absence of epithelium penetration of phosphate
greater Acetate and alcohol derivatives are more effective then the
phosphate derivatives in suppressing corneal inflammation both in
the presence and absence of corneal epithelium
39. Preparations LOCAL : Eyedrops-suspension or solution
Ointments Injection - subconjuctival , sub-tenons capsule or
retrobulbar SYSTEMIC : Tablets Injections(intra venous) -
40. Routes of administration TOPICAL SYSTEMIC Effective in
anterior segment diseases Effective in posterior segment diseases
Ease of application, relative low cost Difficult application,
relatively high cost Dosage vary with severity of disease Generally
single dose daily Absence of systemic complications Systemic
complications present
41. Ocular indications Topical Systemic Blepharitis Uveitis
Allergic conjunctivitis Allergic keratitis Viral keratitis
Pingueculitis Inflammation of pterygim Cystoid macular edema After
ocular surgery posterior uveitis Systemic ophthalmia Papillitis
Retrobulbar neuritis Scleritis Anterior ischemic optic neuropathy
Malignent exopthalmus Orbital pseudotumor
42. Alternate day therapy Single dose on alternate day systemic
administration of corticosteroids is as effective as divided daily
dose Permits metabolic recovery and prevents toxic side effects
from accumulating Patients receives the entire total dose that
would be given over a 2-day period as a sing dose , every other
morning Alternate-day systemic therapy applies only to shorter
acting systemic steroids like prednisone, in case like chronic
uveitis
43. Double edged sword It only inhibit the inflammatory
response not the cause of inflammation Magical drug
44. Why steroids dozes tapered ?? Synthetic cortisone
medication mimic cortisol,i.e naturally occuring hormone produced
by adrenal gland Excess production of cortisol negative feedback
mechanism (HPA axis) Using large dose for few days or smaller dose
for more than two weeksprolonged decrease in HPA axis function
45. So tapering is required i.e continuing the therapy for
several days in reduced dose Gives time for adrenal glands to
return their normal patterns of secretion Also reduces the chance
of recurrence of the disease
46. Locally (in case of topical) ?? Corticosteroids reduce the
leukocyte cells locally White cells proliferate when therapy stops
Immature cells can produce large quantities of antibodies to
residual antigen in the ocular tissue Massive polymorphonuclear
leukocytic reaction follows the resultant antigen- antibody
reaction
47. This sequence of events , unless interrupted immediately ,
can lead to a recurring , serious necrotizing inflammation Thus
depending upon response and dozes used , topical therapy should
generally be tapered over several days to weeks Removal of corneal
epithelium caused appearance of leukocytes in tear fluid within 2-5
hrs which was greatly reduced by 1% prednisolone and 0.01%
flurbiprofen
55. Generally contraindicated in: Peptic ulcer Osteoporosis (an
increased risk of fracture ) psychoses
56. Should be used with caution in Diabetes mellitus Chronic
renal failure Congestive heart failure worsen the condition
Systemic hypertension Infectious diseases glaucoma
57. Patients with prolonged systemic therapy, lack sufficient
adrenal reserve to respond to stress like trauma and surgery , so
require additional corticosteroids to cover the stress.
58. Adrenal insufficiency Cushings syndrome Peptic ulceration
Osteoporosis Hypertension Muscle weakness or atrophy Inhibition of
growth Diabetes Activation of infection Mood changes Delay in wound
healing SYSTEMIC SIDE EFFECTS
59. OCULAR SIDE EFFECTS Adverse event can occur with all routes
of administration & all preparations currently available. Side
effects more with long term high doses therapy.
60. Posterior subcapsular cataracts Ocular hypertension or
glaucoma Secondary ocular infection Retardation of corneal
epithelial healing Keratitis Corneal thinning or melting Scleral
thinning Uveitis Mydriasis Ptosis Transient ocular discomfort
OCULAR SIDE EFFECT
61. Cataract Occurrence of PSCC with all routes High incidence
found in long term systemic therapy then the topical therapy
Opacity associated with steroid administration resemble with those
produce by ionizing radiation and ocular disease such as uveitis ,
retinitis pigmentosa and retinal detachment
62. Glucocorticoids enter lens fibres reacts with lens
crystallins conformational change within cells release of
sulfhydryl groups Form disulfide bonds protein aggregation CATARACT
Mechanism
63. Mechanism High blood glucose level High level of sorbitol
Indrawing of water Swelling of fibers and disruption of
cytoskeletal structures cataract
64. mechanism Corticosteroid induces the production of the new
lens fibers through equatorial region Which goes and accumulate in
posterior sub capsular region Finally causes cataract
65. Ocular hypertension or glaucoma Reversible elevation of
pressure with repeated use of topical steroids. Steroid induced
glaucoma ; a form of secondary open-angel glaucoma Recently
developments in corticosteroids are aimed at developing agents with
less IOP effect and agents that can be used intraocularly and
periocularly
66. How steroids increase IOP..? GAGs present in the trabecular
meshwork can not depolimerized (stabilizing lysosomal membrane)and
they retain water in extracellular space lead to narrowing of
trabecular meshwork Suppress the phagocytic activity of endothelial
cells of trabecular meshwork leading to collection of deberies in
trabecular meshwork Inhibit the formation of PGE and PGF leading to
decrease in aqueous outflow facility Obstruction of aqueous
outflow
68. Individuals differ in their responsiveness: approximately
4% develop pressures higher than 31 mm Hg after 6 weeks of therapy
with topical dexamethasone Steroid- induce IOP elevation almost
never occurs in less than 5 days and rarely in less than 2 weeks
Steroid-induce IOP rises are usually reversible by discontinuance
of therapy if the drug has not been used for more than 1 year , but
permanent elevations of pressure are common if the therapy has
continued for 18 months or more 1 1 (armaly MF and becker b . Mills
DW ARCH OPHTHALMOL 2003)
69. If IOP rises when we use the steroid ? 1) First stop
steroid therapy and may use other anti- infalmmatory agents like
NSAIDs and cyclosporine 2) If IOP persist at higher level then IOP
lowering agent can be used like beta-blocker , carbonic acid
inhibitor but prostaglandin analogue are contraindicated 3) If IOP
remains at higher level then we can move to other surgical
procedure
70. Retardation of corneal epithelial healing Effect on
collagen synthesis and fibroblastic activity Persistent epithelial
staining can be noted
71. Corticosteroid induce uveitis Pain, photophobia, blurred
vision, and perilimbal (ciliary) hyperemia; anterior chamber cells
and flare
72. Mydriasis Increase in pupillary diameter approximately 1 mm
Belharoptosis Due to inhibition of sympathetic innervation on mular
muscle
73. Other ocular side effects Transient ocular discomfort
Calcium deposits on cornea ; (Dry eye develop a calcific band
keratopathy)
74. SOME IMPORTANT FACTS s Is not s i.e cotricosteroids are not
stored in adrenal gland, they synthesized from cholesterol in the
presence of stimulus They promote growth of skeletal muscle
(anabolic effect) and the development of male sexual
characteristics (androgenic effects) Drugs used by athletes to
boost strength and enhance physical performance Anabolic steroid
??