Corticosteroids the often used but least understood drug
The most coveted drug used but
least understood .
Dr Avijit K Prusty,2nd year PG student
Dept. of Anaesthesiology
SCB medical college,
Guided By-.Assoc Prof Dr Mahendra kumar Nayak
• The term “CORTICOSTEROIDS” derived from 2
• CORTEX=secreted from adrenal cotex
• STEROIDS=have a common steroid nucleus
• These drugs are most commonly used as anti-
inflammatory drugs and hence before going into
topic proper we should have knowledge about
• 1. inflammation 2.stages 3.mediators
• it is a biological response of vascular
tissues to harmful stimuli, such as
pathogens, damaged cells, or irritants.
• Inflammation may ends with either :
Signs of Acute inflammation
• Celsus 4 cardinal signs
Due to vasodilatation by effects mediated by
histamine, bradykinin and prostaglandin.
Due to increased blood flow.
Signs of Acute inflammation
due to increased vascular permeability by the
released mediators and increased exudate in the
due to irritation of nerve ending by inflammation
and the pressure of the swelling on the nerve
ending and also from chemical mediators like
substance P and bradykinin.
Coming to Natural corticosteroids,we will now
discuss under following headings-
• Site of synthesis
• Prototype and physiological effects
• Structure –similarites and dissimilarites in
• Basal secretion and variation
• Reguln of secretion
• The adrenal gland produces
various classes of hormones
each of which aid in dealing
with the stress faced by people
• At least two of these groups –
necessary for life.
• Corticosteriods refer to natural
gluco- and Mineralo-corticoids
and their synthetic analogues.
• The adrenal cortex is a factory of steroid
• 10-30 different steroids are synthesized from
this tissue but two classes are are of
Steroid Class Prototype Physiological effect
Mineralocorticoid Aldosterone(z.glomerulosa) Na,K and H2O homeostasis
Glucose and many other
Adrenal cortex also produces sex steroids-Androgens,Dehydropiandrosterone(DHEA)
A double bond between carbons 4 & 5 in Ring A.
A ketone (=0) on carbon 3 in Ring A.
Carbons 18, 19, 20, and 21 are present.
Carbons 18 and 19 are methyl groups.
Carbon 20 has a ketone group attached (=0) and carbon 21 has a
hydroxyl group attached (-OH).
• Glucocorticoids, in addition, have:
• 1. A functional oxy group at Carbon 11. Either a
ketone or a hydroxyl; actually, those with 11-ketone
(cortisone the naturally occurring one) are converted
to 11-OH before becoming biologically active.
• Mineralocorticoids, on the other hand:
• 1. Do not have a functional oxy group at Carbon 11.
• a. Deoxycorticosterone has no 11-oxy group.
• b. The 11-oxy group on aldosterone is interfered
with by the -CHO group at Carbon position 18
Glucocorticoids Regulate Transcription
GR, glucocorticoid receptor; HSP, heat shock protein; IP, immunophilin;GRE, glucocorticoid receptor
transcription (eg, lipocortin)
¯transcription (IL-1, IL-2,
TNF- a, IF-g)GR
Glucocorticoids - MOA
• Not stored:
– rate of synthesis = rate of release
• Synthesize rhythmically and controlled by irregular
pulses of ACTH, influenced by light and major pulses
occur early in the morning and after meals
• Glucocorticoids act via their receptors located in
• GRs are widely distributed and located almost in all
cells of the body
• They are made up of almost 800 amino acids
Glucocorticoids - MOA
• GR receptors are located in the cytoplasm
• One GR receptor has a DNA binding domain and a ligand
binding domain along with stabilizing proteins (HSP 90 and
• This receptor is incapable of activating transcription
• Binding of free steroid molecule to GR forms an unstable
• Therefore HSP and other proteins get dissociated
• The S+GR complex enters the nucleus and binds to
Glucocorticoids response element (GRE) on gene and regulate
transcription by RNA polymerase II and others
• The resulting mRNA is transported to cytoplasm for
production of protein and bring about final response
Glucocorticoids Are Powerful Immuno-
Corticosteroids affect nearly every facet of immune function,
although less inhibition of humoral arm than cell-mediated arm;
they also induce apoptosis in rapidly-dividing leukocytes
• Multiple mechanisms are involved
- Decrease movement of neutrophils from blood
vessels and decreased activity of neutrophils &
macrophages by altering the gene transcription .
- In macrophages and monocytes
– Arachidonic acid and
metabolites(↓Prostaglandins and ↓interleukins)
are inhibited by inducing Lipocortins that inhibit
•Cytokines are inhibited
– Decreased activity of T-helper cells and
proliferation of T-cells
– Decrease proliferation of fibroblasts.
– Inhibition of chronic inflammation
– Repair is also delayed.
• In endothelial cells-Endothelial leucocyte
adhesion molecule (ELAM) inhibited.
• Release of histamine from basophils is
• In lymphocytes: cytokines-interleukins,
TNF alpha are inhibited.
Glucocorticoids – anti-inflammatory and
• Suppress inflammatory response to all noxious stimuli:
Pathogens, chemical,physical and immune mediated stimuli,
• However,Underlying cause of disease is not corrected
• Reduction in cardinal signs of inflammation
• Anti-inflammatory effects are non—specific and covers all
components of inflammation:
– Effects on concentration, distribution and functions of peripheral
leukocytes – increased neutrophils & their activity
– In macrophages: reduction of arachidonic acid metabolites
(mediators) like PG, LT and PAF synthesis that results from activation of
Basis of exogenous use of most clinical uses
Glucorticoids - Multiple Mechanisms
• Recruitment of WBC & monocyte - macrophage into
affected area & elaboration of chemotactic substances
• Lipocortin: decreased production of PG, LT and PAF
• Negative regulation of COX 2: inducible PG production
• Negative regulation of genes in cytokines of macrophages,
endothelial cells and lymphocytes:
• production of IL (1, 2, 3, 6), TNFα, GM-CSF etc. – fibroblast
proliferation and T-lymphocyte function – interference with
• BP regulation & cardiovascular function
- Sensitizes arterioles to action of
• Decreased capillary permeability
• Maintains normal renal function
Euphoria – in pharmacological doses
Addison's disease – apathy, depression
High doses – induce seizure
-maintain glucose, circulation and
9.Lymphoid and blood cells
• Minor effects on Haemoglobin and RBCs
• Protect against haemolysis of RBC.
• Decrease the number of circulating
lymphocytes,eosinophils, monocytes and basophils.
• Increase circulating polymorphnuclear leukocytes.
• GCs are effective in lymphoid malignancies-- activate
programmed cell death (apoptosis)(T CELLS>B CELLS).
• Absorption: all are rapidly & completely absorbed
• Transcortin 75%(levels increased in pregnancy)
• Albumin 5%
• Free form 20%
• by liver enzymes, conjugation & excretion by urine
• partly excreted as 17-ketosteroids.(test=Zimmerman
• t1/2 of cortisol =1.5 hours
•An ideal GC should have no mineralocorticoid
• Structural changes to the basic cortisol
molecule has resulted in a number of
– minimal mineralocorticoid activity.
– Greater potency
– Longer duration of action
The relative equivalency of different steroids has
generally been defined on the basis of pituitary ACTH
suppressive effect in the morning after single dose of
• For most clinical purposes, synthetic
glucocorticoids are used because they have a
higher affinity for the receptor, are less
activated and have little or no salt-retaining
• Hydrocortisone used for: orally for
replacement therapy, i.v. for shock and
asthma, topically for eczema (ointment) and
enemas (ulcerative colitis).
• Prednisolone the most widely used drug given
orally in inflammation and allergic diseases.
• Betamethasone and dexamethasone: very
potent, w/o salt-retaining properties; thus,
very useful for high-dose therapies (e.g.,
• Beclometasone, diproprionate, budesonide:
pass membranes poorly; more active when
applied topically (severe eczema for local anti-
inflammatory effects) than orally; used in
• Triamcinolone: used for severe asthma and for
local joint inflammation (intra-articular inj.).
• Steroid dose is commonly characterised into:
-Low dose (e.g. <10mg/day of prednisone)
-Medium dose (e.g. 10-20 mg/day of prednisone)
-High dose (e.g. >20mg/day of prednisone. )
• Treatment for less than one month is considered short term
• Treatment continuing for more than 3 months is regarded
as long term, and results in the majority of undesirable side
• Corticosteroids for a few days or weeks are relatively safe.
Dosage & schedule
• Low dosage for replacement therapy
Addison’s disease, anteriorhypopituitarism , post subtotal
cortisone12.5～25 mg/d, or hydrocortisone 10～20 mg/d.
• Universal dosage for long term therapy
inflammations, rheumatoid arthritis, lymphoma, lymphoblastic
Started with prednisone 10～20 mg, 3/d; gradually decreased to
the maintenance dose after obtained the initial effect.
• High dosage for implosive therapy
Serious infections: hydrocortisone i.v.d. 200-300 mg, ≥1 g/d.
Shocks: hydrocortisone v.d. 1 g, 4-6 g/d.
• Do not suddenly stop systemic steroids.
• No tapering is necessary if the course of steroids has
been for less than one week.
• After taking a dose of 30 mg or more per day for 3-4
weeks, reduce the dose by7- 10 mg(25-30%) or less per
day, taking days to weeks to stop altogether.
• A much slower reduction in dose may be required if
the medication has been taken for several months or
• HPA AXIS MAY TAKE MORE THAN 2YRS FOR RECOVERY
• Steroids are a widely used group of drugs in anaesthesia practice,
sometimes with definite indication and sometimes without
• There is an increasing application of steroid therapy during
perioperative period . Some of the current indications are:-
1. Perioperative replacement therapy.
2. Anti-inflammatory uses --hyper-reactive airway
3. Post operative nausea and vomiting (PONV)
4. Analgesia adjunct
5. Day care surgery
7. Septic shock
8. Other indications like – cerebral oedema, spinal cord injury,
various surgical causes.
Steroids in replacement therapy
• Steroid administration is necessary in perioperative
period in patients treated for hypoadrenocorticism
or in a patient with separation of pituitary adrenal
axis owing to present or previous steroid intake.
• The increase in circulating cortisone levels in
response to surgical trauma is one of the important
components of stress response of our body.
• In perioperative setting this response is essential
to avoid haemodynamic instability,
metabolic,electrolyte, and fluid imbalances
• Certainly more suppression may be expected in the
setting of higher and longer duration of steroid
Steroids in hyper-reactive airway
• Their action is mainly anti-inflammatory action
leading to decreased mucosal oedema and prevention
of release of broncho-constricting substances.
• They have a permissive role for bronchodilator
medication (inhaled glucocorticoids-
• The most commonly encountered hyper-reactive
states in anaesthetic practice are--
-patients with history of asthma, recent upper
respiratory tract infection, difficult airway, multiple
intubation attempts,aspiration, foreign body bronchus,
airway surgeries and COPD.
4. Ipratropium Bromide 250 mcg by nebulizer
5. Inj. Hydrocortisone 10mg/kg IV
6. Inj. Aminophylline 5 mg/kg bolus slowly followed by
0.8-1.2 mg/kg/hr slow infusion
7. Inj. Magnesium sulphate 40mg/kg in 50 ml 5% dextrose as
slow infusion over 30 minutes(?)
---- NO RESPONSE?---- ABG—X-ray chest---Serum
Acute Exacerbations BA
Steroids and anaphylactic/ allergic
• Steroids cannot be the mainstay of therapy in
anaphylaxis because of the delayed onset of
action,so they are used as adjunct after initial
treatment with epinephrine
• Glucocorticoids can supplement to primary
therapy to suppress manifestations of allergic
• In very severe diseases intravenous
methylprednisolone 125mg every 6 hours, or
Hydrocortisone 200-300mg iv orequivalent can
Steroids and sepsis/septic shock
• Patients having severe sepsis or in septic shock were found to have
occult or unrecognized adrenal insufficiency.
• sepsis with adrenal insufficiency, steroid supplementation was
associated with significantly higher rate of success in the
withdrawal of vasopressor therapy.
• Some studies have suggested steroid therapy in sepsis is not only
associated with no clinical improvement, but may be harmful.
• Usually steroids are administered in this setting to meet the steroid
requirement of body, for fighting the ongoing stressful condition.
• The commonly used steroid is hydrocortisone
100-125mg.day-1 OR IV Methyl Prednisolone in dose of 30mg/kg
over a period of 30 min followed by 5.4mg/kg /hr for 24 hrs.
• Steroids reduce or prevent of cerebral oedema by-
(1) stabilization of cerebral endothelium, leading to
a decrease in plasma filtration;
(2) increase in lysosomal activity of cerebral
(3) inhibition of release of potentially toxic
substances such as free radicals, fatty acids, and
(4) electrolyte shifts favouring transcapillary efflux
(5) increase in local and global cerebral glucose
use, leading to improved neuronal function.
• The usual but empirical initial dose in brain tumor
patients is an intravenous bolus of 10-50 mg of
dexamethasone, followed by a maintenance dose of
4-6 mg given by the intravenous (IV) route every 6
hours (16 mg/day) (Szabo & Winkler, 1995).
• Corticosteroids can produce an improvement in
neurologic symptoms and reduction in cerebral
edema within the first 8 to 48 hours, with 12 to 24
hours being the usual time frame.
Steroids in PONV
• It is thought to be due to decrease in production of
inflammatory mediators which are known to act on the CTZ
area as well as improve the blood-brain barrier function.
• It is also known to act synergistically with 5HT3receptors
• Optimum dose was found to be 10mgof dexamethasone, and
same dose was found to be highly effective when given
immediately before induction rather than at the end of
• . In meta-analysis of randomized trials ,Hirayama et al found
that dexamethasone was more effective than either droperidol
or metoclopramide in the prevention of PONV induced by
morphine after surgery 72
Steroids and analgesia
• Various routes of administration of steroids
include parenteral, local infiltration at operated
site as an adjuvant in nerve blocks and central-
neuraxial blockade. The mode of analgesic effect
is ill defined, it may be due to their anti-
inflammatory action resulting in decrease of
production of various inflammatory mediators
that play a major role in amplifying and
maintenance of pain perception.
• They have also been seen to increase the
endorphin levels and mood elevation
Steroids and day care surgery
• Steroids decrease the incidence of PONV ,
postoperative pain, establish early oral intake,
produce euphoric effect by decreasing level of
prostaglandins , and elevating those of
• Aasboe et al used betamethasone12 mg
intramuscularly, 30minutes prior to ambulatory
hemorrhoidectomy or hallux valgus correction
and they found significantly less postoperative
pain, less PONV, and better patient satisfaction
Spinal cord injury
• Treatment should begin within 8 hrs of injury.
• A suggested protocol for traumatic cord injury
within 3 hrs of injury includes the use of high
dose methyl prednisolone with an intravenous
bolus of 30mg/kgover 15 min followed by a 45
min pause and then a continuos IV infusion
@5.4mg/kg/hr infusion for 23 hours.
• For Pts within 3-8 hrs of injury,adminster 30
mg/kg IV bolus over 15 min period followed by a
45 min pause and then a continuos IV infusion
@5.4mg/kg/hr infusion for 47hours
Steroids in surgery
• Anti-inflammatory action of steroids have beneficial role to
play in surgery.
• Shimada et al in their retrospective study of patients
undergoing resection of esophagealcarcinoma,reported
that those patients who received methylprednisolone
250mg prior and two days following surgery had low
morbidity rates from anastomotic leakage and liver
• The inflammatory mediators,body temperature and heart
rate were significantly low in steroid group,the author
suggested that improvement may be because of
suppression of local edema leading to improved
microcirculation at operative site and reduction in tissue
injury due to inflammation mediated substances
ROLE OF STERIODS IN THE ICU?
• “Critical Illness Related Corticosteroid Insufficiency”
Inadequate corticosteroid activity for the severity of the
• Thought to be comprised of both a relative lack of cortisol, as
well as tissue resistance to its effects
Possibly due to decreased expression of active form of GC receptor
• Overall incidence of adrenal insufficiency is estimated to be
20% for all-comers, and as high as 60% for pts with septic
shock and burns due to their exaggerated pro-inflammatory
• Diagnosis of adrenal insufficiency has traditionally
relied upon use of total serum cortisol measurement,
usually checking baseline levels and repeating
measurements after stimulation testing with high
dose (250mcg) of cosyntropin (synthetic ACTH).
International Task Force
• Concerning diagnosis and management of
corticosteroid insufficiency in critically ill patient
Recommendations were classified as strong (grade 1)
or weak (grade 2)
Quality of evidence for the recommendation also
A = high quality evidence
B = moderate quality
C = low quality
• 1. Dysfunction of the HPA axis in critical illness is best
described by the term critical illness related
corticosteroid insufficiency (CIRCI)
• 2. The terms absolute or relative adrenal insufficiency
are best avoided in the context of critical illness
• 3. At this time, adrenal insufficiency in critical illness is
best diagnosed by cortisol of <9mcg/dL (after 250
mcg cosyntropin), or a random cortisol of < 10mcg/dL
• 4. The use of free cortisol measurements cannot be
recommended for routine use at this time. Although
the free cortisol assay has advantages…(it) is not
readily available. Furthermore, the normal range of
free cortisol in critically ill pts is currently unclear (2B)
• 5. The ACTH stimulation test should not be used to identify
those patients with septic shock or ARDS who receive
• 6. Hydrocortisone should be considered in the
management strategy of patients with septic shock,
particularly those who have responded poorly to fluid
resuscitation and vasopressor agents (2B)
• 7. Moderate dose glucocortidoids should be considered in
the management strategy of patients with early severe
ARDS (PaO2 / FiO2 <200) and before day 14 in patients with
unresolving ARDS (2B)
• 8. In patients with septic shock, intravenous hydrocortisone
should be given in a dose of 200mg/day in four divided
doses or as a continuous infusion at 10mg/hr (240mg/day).
The optimal initial dosing regimen in patients with early
severe ARDS is 1mg/kg/day of methylprednisolone as a
continuous infusion. (1B)
• 9. The optimal duration of glucocorticoid
treatment…is unclear. However, based on published
studies and pathophysiological data, patients with
septic shock should be treated for 7 or more days
before tapering…patients with early ARDS for 14 or
more days before tapering. (2B)
• 10. Glucocorticoid treatment should be tapered
slowly and not stopped abruptly (2B)
• 11. Treatment with oral fludrocortisone is considered
• 12. Dexamethasone is not recommended for the
treatment of septic shock or ARDS (1B)
• DO NOT Say no to steroids as STEROIDS are life
• But in following conditions where we have to be
- Peptic ulcer, Hypertension,Diabetes mellitus, Viral
and fungal infections, Tuberculosis, Osteoporosis
Epilepsy and psychosis, CHF and renal failure.
• Efforts should be made to reduce steroids induced side
• Choosing a Steroid Benefit/risk ratio is a major
consideration Drugs with primary glucocorticoid activity are
used .Minimal dose to achieve the desired effects is chosen
Stoelting Anesthesia & Co-Existing Disease
K.D Tripathy,Medical pharmacology.
W,F Ganong, Medical physiology
Robbin’s Pathological Basis of Disease