2. INTRODUCTION
• Glucocorticoids play vital role in maintenance & regulation of
immune and circulatory functions
• Extensively used to treat many inflammatory and autoimmune
disorders.
• Anti inflammatory effects of corticosteroids cannot however be
separated from their metabolic effects
8. Adverse effects
• Occur with prolonged use of high doses
• Cushing’s disease
Psychiatric
•Sleep disturbance/activation
•Mood disturbance
•Psychosis
Skin/soft tissue
•Cushingoid appearance
•Abdominal striae
•Acne
•Hirsutism
•Oedema
MSK
•Osteoporosis
•Asceptic necrosis of bone
•Myopathy
Endocrine
•Diabetes mellitus
•Adrenal cortex suppression
Immunologic
•Lymphocytopenia
•Immunosuppression
•False-negative skin test
Neurologic
•Neuropathy
•Pseudomotor cerebri
Opthalmic
•Cataract
•Narrow-angle glaucoma
Cardiovascular
•Hypertension
Developmental
•Growth retardation
9. • The risk of side effects depends on the
Dose
– low dose (< 10 mg/day of prednisone)
– medium dose (10-20 mg/day)
– high dose (> 20 mg/day)
Type of steroid
– long-acting
– short-acting
Length of treatment: (Long-term treatment > 3
months)
Other medical problems
10.
11. FOLLOW UP PROTOCOL
EXAMINATION
• At 1 mth – then after
every 2-3 mth
Blood pressure,wt
Ht & wt plotted on
growth curve(in
children)
Thorough h/o at each
visit for adverse effects
• At least every 6 mth
initially then annually
Opthalmological
examination
LABORATORY
• At 1 mth – then after
every 3-4 mth
K level
FBS
TGL
• Near time of cessation
of long term CS therapy
8-9 am cortisol
level
13. • METABOLIC EFFECTS
• HYPERGLYCAEMIA
• Mechanism:GC-increased hepatic glucose/glycogen
production,gluconeogenesis through protein catabolism,induces IR
decrease glucose entry into cell
• A/D Effects: increased appetite & wt gain
• Therapy Effect:Especially with high CS dose
• Additional risk factor:Family or personal history of DM,obesity,
patients with underlying impaired glucose tolerance or subclinical
diabetes
• Prevention:Dietary measures(low in saturated fat & calories),
Regular monitoring of blood glucose levels & Hb A1C during
therapy is important
• Diagnosis: Fasting glucose level
14.
15. • Management:
Proper diet
Insulin
Oral hypoglycaemics,insulin sensitizers
• Treatment involves reduction in glucocorticoid dose
• If steroid is stopped - hyperglycemia may fully reverse over many
months.
• When hyperglycemia is persistent (mostly during the day with N to
minimally elevated fasting glucose levels) - drugs are prescribed
blood glucose levels < 250 mg/dL - addition of insulin-sensitizing drugs
(thiazolidinediones, metformin) and/or insulin secretagogues
blood glucose levels > 250 mg/dL especially if pt is symptomatic then
insulin therapy should be considered.
16. • HYPERTENSION
Mechanism:MC Effect-Na retention also due to GC induced
vasoconstriction
• A/d Effect:CHF,excessive wt gain,hypokalemia
• Therapy Effect:CS with high MC effect,therapy over 1 yr,pulse CS
• Additional risk factor:Prior hypertension,elderly patient
• Prevention:Na restriction,choose CS with low MC effect
• Diagnosis: Monitor bp
• Management:
1. Na restriction.
2. Treatment is not different from all hypertensive patients, although in
some patients, blocking MC receptors with spironolactone may be more
effective than using other antihypertensives.
3. Thiazides can also be prescribed
•
18. • CUSHINGOID CHANGES
• Mechanism:Altered fat distribution,result of overall fat
catabolism
• A/d Effect:moon facies.truncal obesity,buffalo hump
• Therapy Effect:CS for atleast 2-3 months
• Additional risk factor:Excessive caloric intake due to increased
appetite
• Prevention:Dietary measures,exercise
19. • Diagnosis:
Low ACTH level
Low cortisol level
No response to cosyntropin stimulation test
Higher than normal fasting glucose
Low blood potassium level
Low bone density as measured by dual x-ray
absorptiometry (DEXA)
High cholesterol particularly high TG & low HDL
20.
21. HPA AXIS EFFECTS
• Mechanism:Reduced GC & MC reserves
• A/D Effects:Steroid withdrawl syndrome
Addisonian crisis
• Therapy Effects:Steroid taken>3weeks,evening dose,long
half life followed by abrupt cessation
• Additional risk factors:Major surgery,trauma,illness,severe
gastroenteritis with fluid & electrolyte loss
• Prevention:Appropriate CS tapering
• Diagnosis: By History of patient
• Management: Raise CS dose then taper much more slowly
22. • Pathophysiology: Corticosteroid administration results in a negative
feedback effect via glucocorticoid receptors in anterior
hypothalamus which in turn suppresses production of CRH & ACTH
• Prolonged suppression of ACTH levels leads to atrophy of adrenal
cortex & secondary adrenal insufficiency.
• Therapeutic glucocorticoid administration is M/C cause of
secondary AI
• Chronic administration of exogenous glucocorticoids induces
atrophy of pituitary corticotroph cells.
• Clinically relevant if exogenous steroid therapy is withdrawn too
rapidly.
• C/F: anorexia, nausea, emesis, weight loss, fatigue, myalgias,
arthralgias, headache, abdominal pain, lethargy, postural
hypotension, fever & skin desquamation
24. Strategies to prevent steroid induced HPA axis suppression:
•
•
•
•
•
•
•
•
•
Acute adrenal insufficiency is a feared complication
No good predictive marker to anticipate acute AI
Clinical evaluation remains key element in its diagnosis.
If AI is suspected,HPA suppression can be assessed with dynamic
tests.
During stress situation, steroid administration is then recommended
depending on the severity of the stress.
Long-term steroids should be tapered gradually to allow the adrenal
glands to resume cortisol production.
The first step is reduction from pharmacological to physiological doses.
This depends on the disease activity and the level of control with
steroids.
The next step is to taper from physiological dose to complete
withdrawal and this depends on the degree of HPA suppression.
25. • In short term treatments (< 10 days) irrespective of dosage or
type of steroid cessation of therapy should be abrupt
shortening total length of therapy & diminishing S/Es
• In intermediate term treatments (10-30 days) glucocorticoid
should be withdrawn over a period of 2 weeks with dose
reduction every 4 days
26. • In long term treatments some principles for dose reduction
should be observed prior to medication withdrawal:
(a) switch to short or intermediate-acting glucocortcoids
(b) reduce no. of doses aiming at once-a-day dosing in morning
(c) gradual glucocortcoid dose reduction (e.g. for doses of prednisolone
above 20 mg, the reduction should be no more than 25% every 4
days; for doses between 10-20 mg the reduction should be no more
than 2.5 mg every 7 days and for doses < 10 mg the reduction
should be no more than 2.5 mg every 15 days).
27. Strategies for management of established HPA axis suppression
• In the end of the protocol for dose reduction HPA axis testing can
be performed with morning dosage of serum cortisol.
– Levels greater than 10 mcg/dL indicate adequate recovery
of the axis and allow glucocorticoid withdrawal.
– Levels less than 5 mcg/dL indicate suppressed axis and
need of dose reduction with an additional waiting period
of 2-4 weeks before cessation.
– Cortisol concentration kept between 5 and 10 mcg/dL
requires ACTH stimulation test to ensure adrenal
recovery& adequate endogenous cortisol production in
the face of stressful situations.
28. A suggested algorithm for withdrawal from chronic steroid
therapy. Physiologic doses
of glucocorticoid are equivalent to prednisone 5 to 7.5 mg/d or
hydrocortisone 15 to 20 mg/d.
29. ADRENAL CRISES
• Most crises were due to glucocorticoid dose reduction or lack of
stress-related dose adjustment
• Occurs more often in patients older than > 60 years.
PREVENTION
• Patients should add 5–10 mg hydrocortisone to their normal
regimen shortly before strenuous activities
• More severe physical stress such as fever requires doubling of daily
doses until recovery.
• In vomiting/diarrhoea drug should be administered parenterally.
• For major surgery, trauma and diseases that require monitoring in
intensive care pt should receive iv infusions of 100–150 mg
hydrocortisone in 5% glucose per 24 h.
• Results of some studies advocate lower doses (25–75 mg/ 24 h) for
minor / moderate surgical stress.
30. • MANAGEMENT
• Immediate iv administration of 100 mg hydrocortisone
followed by 100–200 mg in 24 h and continuous infusion
of larger volumes of physiological saline solution (initially
1 L/h) under continuous cardiac monitoring.
• In case of newly diagnosed (or suspected) adrenal crises
treatment must not be delayed by diagnostic work-up.
• Baseline blood samples for ascertainment of cortisol and
ACTH should be drawn immediately before
hydrocortisone administration
31. RENAL SYSTEM - Fluid and electrolyte balance
• Associated with sodium & water retention
• Potassium loss occurs & hypokalaemic alkalosis may develop.
PREVENTION
• The blood pressure should be checked at each outpatient visit &
antihypertensive treatment may be necessary.
• Corticosteroids should be used with extreme caution in patients
with limited cardiac reserve as cardiac failure can develop.
32. MANAGEMENT
• Recommend a low salt diet
• Diet rich in K (most fruits, vegetables, especially broccoli and
carrots, fish & poultry)
• Occasionally K supplements are required.
• If a thiazide diuretic is chosen as the antihypertensive agent the
serum potassium should be carefully monitored.
• Thiazides also have a beneficial effect on osteoporosis by reducing
calcium loss in the urine.
33. STEROIDS AND BONE
• Comparison of normal cycle
of bone remodeling (upper
panel) with an abnormal one
caused by steroid excess
(lower panel)
• Decreased number of
osteoblasts & their premature
apoptosis as well as
incomplete repair of bone in
latter.
• Newly formed bone is in light
tan.
35. RISK FACTORS
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Under 15 years & over 50 years
Gender
Post-menopausal /amenorrhoeic
women
Slim build
Limited mobility
Medications:increase risk of
osteoporosis include thyroxine
&heparin
Dose & duration of steroid use
Underlying medical conditions
which independently could lead
to bone loss such as RA
PREVENTION
•
•
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•
•
•
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Undertake weight bearing exercise
(such as brisk walking)
Stop smoking & alcohol intake
Avoidance of activities such as heavy
lifting, high-impact aerobics &
contact sports
Adequate dietary intake (e.g. 3-4
dairy serves each day) or calcium
tablets up to a daily intake of
1500mg elemental calcium per day
Vitamin D in various forms
including monthly colecalciferol
50,000 units (1.25 mg)
Oestrogen i.e. hormone
replacement tablets in females that
have had early menopause
DOC - Bisphosphonates
(alendronate, etidronate, zolidronic
acid) are prescribed for patients at
higher risk of fracture.
37. PREVENTION
Aim - commence therapies before bone loss occurs.
Studies have demonstrated that bone loss occurs early
Within first 3 to 6 months
Bone loss that has occurred is usually never fully regained
even after steroids are discontinued
• Bisphosphonates(alendronate, cyclical etidronate &
risedronate) our recommended first-line therapy for the
prevention & treatment of GIOP.
• At both lumbar spine & femoral neck
•
•
•
•
41. AVASCULAR NECROSIS(Osteonecrosis)
• AVN : manifested by pain and limitation of motion in one or
more joints.
PATHOPHYSIOLOGY
• intraosseous lipocyte hypertrophy & apoptosis of osteoblastintraosseous hypertension-compression of blood vessels bone ischemia and necrosis.
• increased lipids -cause fat emboli which occlude blood vessels
• fatigue fractures occur which cannot mend.
42. PREVENTION & MANAGEMENT
•
•
•
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•
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Early detection is imp because early intervention may prevent progression
to degenerative joint disease requiring joint replacement.
20 % of pts with AVN have N x-rays & bone scan shows only non-specific
changes
MRI : most sensitive techniques
Patients should be regularly questioned about pain and limitation of
motion of joints
The magnetic resonance T2 weighted image shows a double ring sign
representing a central low intensity area of fat necrosis surrounded by an
increased signal of vascular proliferation; this is pathognomonic for
osteonecrosis
If imaging shows AVN an orthopedic surgeon skilled in early intervention
with core decompression may be able to halt progression of disease
Patients with AVN have an increased risk that other joints will be affected.
The progression of AVN to destructive joint disease may require joint
replacement surgery
43. Growth suppression
• Steroids inhibit linear growth.
• Reduce growth hormone production and direct inhibitory effect on
bone and connective tissue.
• Growth suppression is more likely if steroids are given for > 6 mths.
• Administration of deflazacort (oxazoline derivative of
prednisolone), an alternative form of prednisolone, appears to have
fewer effects on growth & steroid-induced osteoporosis but is not
being commonly used.
44. STEROID INDUCED MYOPATHY
•
•
Direct catabolic effect on skeletal muscle via effects on intermediary
metabolism that provide amino acids as a substrate for gluconeogenesis
May be related to:
decreased protein synthesis
•
•
increased protein degradation
alterations in carbohydrate metabolism
mitochondrial alterations
electrolyte disturbances
decreased sarcolemmal excitability
Interfere with insulin-like growth factor-I (IGF-I) signaling - leading to
increased myocyte apoptosis
Glucocorticoid-induced suppression of Akt1 ultimately results in increased
amounts of ubiquitin-ligase atrogin-1 (MAFbx) that targets muscle
proteins for degradation
45. • Local growth factors production
plays a crucial role in
glucocorticoid-induced muscle
atrophy.
• Glucocorticoids can cause muscle
atrophy by altering the muscle
production of IGF-I and
myostatin, two growth factors
exhibiting opposite effects on
muscle mass development.
• Decrease in IGF-I together with
increase in myostatin both
induced by glucocorticoids inhibit
satellite cells activation as well as
myoblast proliferation and
differentiation.
• In mature muscle fibers, these
growth factor changes cause
downregulation of protein
synthesis and stimulation of
protein degradation.
46. Alterations in protein breakdown signaling induced by glucocorticoids. Stimulatory effects on
protein breakdown results from different mechanisms. First, glucocorticoids (GC) stimulate
several proteolytic systems by activating transcription factor FOXO. Secondly, stimulation of
GSK3β may also be involved in the stimulatory effects of glucocorticoids on protein breakdown.
48. ACUTE
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Associated with high dose iv.
glucocorticoid use
Present as: acute quadriplegia
Muscle stretch reflexes typically are
normal.
Sensory examination should be normal.
Lab: Most pts have high levels of serum
CK as well as associated
myoglobinuria.EMG may be abnormal
Biopsy – distinctive loss of thin
filaments by EM. Shows focal & diffuse
necrosis of all fiber types, without
predilection for type II fibers.
Rx- drug withdrawal, supportive care
rehabilitation
Prognosis - recovery is slow
CHRONIC
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Proximal muscle weakness associated
with cushingoid appearance
Facial & sphincter muscles - spared.
Myalgias become a prominent feature
Pelvic girdle muscles are affected more
severely and earlier than are pectoral
girdle muscles.
Muscle bulk N but muscle atrophy can
occur.
Muscle stretch reflexes typically N
Sensory examination should be N
Lab. - serum levels of CK typically are
within the reference range. Creatinine
excretion in the urine increases
dramatically & can precede clinical
appearance of myopathy by several
days.EMG & NCS are N.Myoglobinuria &
rhabdomyolysis are absent
Biopsy – preferential atrophy of type – II
muscle fibers
Rx – drug withdrawal
49. PREVENTION AND TREATMENT
•
PREVENTION:Exercise, caution with steroid tapering after high dose
•
Rehabilitation Program
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Physical Therapy
Aerobic exercises and resistance training
Range-of-motion exercises (either passive, active-assisted or active depending on degree of
weakness) and stretching exercises should be performed to prevent joint contractures.
Bed mobility, balance activities, transfer training & gait training should be included to
address decreased mobility.
Occupational Therapy
Focus on maximizing patient's ability to independently perform activities of daily living.
Training include use of assistive devices to enhance the patient's performance of self-care
tasks
Balanced forearm orthosis to allow positioning of the upper arm in a manner that permits
more independent feeding
In cases of myopathy caused by long-term corticosteroid use, decreasing dose to < 30 mg/d
threshold may result in resolution of muscle weakness.
In patients in whom myopathy has resulted from a short course of high-dose corticosteroid
use, partial or complete recovery has been reported following the discontinuation of steroid
administration
50. • Other experimental treatment include:
IGF-I
Branched -chain amino acids(leucine)
Glutamine
Creatine
Taurine
Androgens such as testosterone and DHEA
• Various medications like K supplements, phenytoin, vitamin E &
anabolic steroids have been tried as potential treatments
• Treatment recommendations for steroid myopathy are a decrease
in dose of steroid to below a threshold level or the discontinuation
of steroid
• Alternate-day dosing could also be considered.
• Another recommendation is that currently administered steroid be
exchanged for one that is not fluorinated
51. Steroid induced Ocular complications
IT INCLUDES:
•
•
•
•
Conjunctival necrosis
Corneal stromal calcification
Delayed corneal wound healing
Glaucoma:POAG
– Ocular hypertension
– Open angle
– Optic nerve cupping
– VF loss
•
•
•
•
Cataract(Posterior subcapsular cataract)
Retinal/choroidal emboli
Central serous chorioretinopathy
Decreased resistance to infection
52. Pathophysiology: Mechanisms involved in cataract formation
include :
increased glucose levels due to an increased gluconeogenesis
inhibition of Na + /K + -ATPase
inhibition of glucose-6-phosphate-dehydrogenase
inhibition of RNA synthesis
covalent binding of steroids to lens proteins.
• Glucocorticoid-induced morphological & functional changes in
trabecular meshwork (TM) are considered to be main mechanisms
leading to increased intraocular pressure
• Glaucoma is seen mainly with topical- high dose inhaled or oral
steroids and much less commonly with systemic steroids.
• It was found that dexamethasone treatment causes specific
upregulation of the TIGR/MYOC gene(Trabecular Meshwork
Inducible Glucocorticoid Response (TIGR) gene ) in the human TM
cells but not in other cells.
• Mutations in this gene lead to impaired secretion of the protein
resulting in misfolding and accumulation of aggregates inside the
cells.
53. • Children are at greatest risk since they can develop cataracts
with lower doses & shorter treatment durations than adults
• Cataracts may be seen as early as within 6 mths of treatment
& even in children on alternate day therapy.
• Glucocorticoid induced glaucoma is usually observed within a
few weeks after initiation of steroid therapy.
• May also be seen years after cessation of steroid therapy
hence monitoring should continue even after steroids are
stopped.
54. Strategies to prevent development of steroid induced ocular
complications:
• Ophthalmologic examinations are recommended every 6 months
for pts on long-term systemic glucocorticoid therapy.
• Progression of cataract may still occur despite decreasing dose but
discontinuing it may occasionally deter further cataract formation
or reverse lens opacification.
Strategies for treatment of established ocular complications:
• Cataracts often are small but can affect visual acuity significantly
requiring surgical intervention.
• Stopping treatment will halt the progress of cataract but will usually
not reverse the changes already present.
55. GASTROINTESTINAL COMPLICATIONS
Pathophysiology:
increase gastric acid secretion
reduce gastric mucus
gastrin and parietal cell hyperplasia
delay the healing of ulcers
Adverse effects include
Gastritis
Peptic ulcers
Upper gastrointestinal bleeding
Oral candidiasis
Acute pancreatitis - is another major complication especially
in children.
56. Prevention
• minimized by administration of oral steroid with food
• use of antacids - including H2 receptor antagonists or PPI
Treatment of established gastrointestinal complications:
• Any symptoms suggestive of PUD should be promptly investigated
with gastroduodenoscopy & appropriate treatment started in
consultation with gastroenterologist
60. Due to immunosuppression masking of infection symptoms may occur
preventing early clinical recognition.
• Any live virus vaccine should not be given to children
• HIV positive children may be considered for Pneumocystis jeroveci
prophylaxis.
PREVENTIVE MEASURES
•
• Alternate-morning therapy and doses of < 10 mg/d of prednisone
equivalent may significantly reduce the chance of opportunistic
infection.
• History of TB contact should be obtained prior to beginning
therapy
• Baseline chest radiograph & Mantoux test should be done.
• Infection prevention can be improved by general measures like
frequent hand washing, avoiding exposure to infectious cases and
use of appropriate vaccines.
61. Strategies for treatment of established immune suppression:
• There should be no abrupt stoppage of steroid - this will
almost certainly lead to acute AI.
• Safe course is - lower dose of steroid to a level which should
no longer suppress the host’s defences and yet which is
adequate to prevent the development of acute
glucocorticoids withdrawl.
• This level is approx. one and one-half to two times a
physiologic maintenance dose of cortisol
• Appropriate cultures should be obtained but until the results
are known a broad spectrum antibiotic should be given.
62. NEUROLOGICAL MANIFESTATIONS OF
STEROID
•
Steroid-induced psychosis represents spectrum of psychological changes
-can occur at any time during treatment.
•
Mild-to-moderate symptoms include –
•
Agitation
Anxiety
Insomnia
Irritability
Restlessness
Severe symptoms include –
Mania
Depression
Psychosis
•
Often develop after 4 days of corticosteroid therapy although can occur
late in therapy or after treatment ends
63.
64. • Act at steroid specific receptors and suppress filtering by
hippocampus - irrelevant stimuli
• Suppressed hypothalamus pituitary axis & enhanced dopamine
neurotransmission
• Depression via a reduction in serotonin levels.
• First-line treatment- to taper /discontinue steroid
• If this is not possible because of comorbid disease or severe
psychosis consider adding low-dose atypical antipsychotics in pts
with manic / hypomanic symptoms.
• Second-line treatment Consider mood stabilizers such as lithium or
valproic acid in pts with normal RFT
69. Atrophy and striae induced by
topical steroids
Tinea incognito. Signs of dermatophyte
infection are partly suppressed by
treatment with a potent topical steroid
71. HAEMATOLOGICAL EFFECTS
• Polycythaemia a feature of Cushing’s syndrome but does not
appear to be a feature of corticosteroid therapy.
• Promotes blood coagulation and alters the patient’s response to
anticoagulants
• Hence frequent checks on the extent of anticoagulation are
necessary especially if the steroid dose is varying.
72. REPRODUCTIVE SYSTEM
• Men can experience longer
erections / higher frequency of
erections yet a decrease in
sperm production- resulting in
sterility.
• Men might also find that they
are impotent
• According to Concepts of
Chemical Dependency,
prostate cancer has been
found in rare instances.
• In females- interruption of
their menstrual cycle
• Can develop infertility issues
• Both sexes might experience
changes in sex drive, either an
increase in desire or a loss of
desire.
73. STEROIDS AND PREGNANCY
• CATEGORY – C DRUG
• Cataracts , cyclopia, interventricular septal defect, gastroschisis,
cleft lip, hydrocephalus, coarctation of aorta,clubfoot ,LBW,IUGR
stillbirth has been reported
• For maternal disease, derivatives of cortisone and prednisone are
suggested since they are more readily inactivated by placenta as
opposed to dexamethasone & betamethasone which are more
likely to reach the fetus in the active state.
• As with any medication use of steroid must be weighed against
severity of maternal disease.
74. A note on steroid side effects….
Dermatologic and soft
tissue
Skin thinning and purpura, easy bruising, Cushingoid
appearance, alopecia, acne, hirsutism, striae,
hypertrichosis
Ocular
Posterior subcapsular cataract, elevated intraocular
pressure/glaucoma, exophthalmos
Cardiovascular
Hypertension, dyslipidemia, premature atherosclerotic
disease, arrhythmias with pulse infusions
Gastrointestinal
Gastritis, peptic ulcer disease, pancreatitis,
steatohepatitis, visceral perforation
Renal
Hypokalemia, fluid volume shifts
Genitourinary and
reproductive
Amenorrhea/infertility, intrauterine growth retardation
Bone/muscle
Osteoporosis, avascular necrosis, myopathy
Neuropsychiatric
Euphoria, dysphoria/depression, insomnia/akathisia,
psychosis, pseudo tumor cerebri
Endocrine
Diabetes, HPA axis insufficiency
ID
Heightened risk of typical infections, opportunistic
infections, herpes zoster
S. Monrad
75.
76. CONCLUSION
• The appropriate anticipation of these side-effects with timely
implementation of evidence-based guidelines has the potential
significantly to prevent, minimize and treat common and disabling
complications of glucocorticoid therapy.
• When steroids are prescribed measures should be taken to
minimise their side effects.
• Clearly chance of significant side effects increases with dose &
duration of treatment and so minimum dose necessary to control
disease should be given
Cushing's disease
Excess cortisol production
If steroids are given synthetically in excess then patients will develop this condition
Another cause is pituitary adenoma
Oedema – due to the mineralocorticoid activity of some glucocorticoids (cortisone and hydrocortisone in particular) there is fluid retention via anti-diuretic hormone action.