Transcript corticosteroids1.ppt

The principal adrenal
steroids are
mineralocorticoids,
glucocorticoids & sex
hormones.
Main endogenous GC are
hydrocortisone ,
corticosterone.
Glucocorticoids
affect
carbohydrate &
protein
metabolism &
have antiinflammatory &
immunosuppress
ive action.
Main
endogenous
mineralocorticoid
is aldosterone,
affects water and
electrolyte
balance.
A deficiency in corticosteroids [Addison’s
disease] is characterized by muscle
weakness, low BP, depression, loss of
weight, hypoglycaemia.
Excessive production of glucocorticoids is
called Cushing's syndrome.
Excessive production of mineralocorticoids
is called Conn’s syndrome.
1- Metabolic actions:On carbohydrates:
On proteins:On fat:-.
2- Regulatory actions:-
On vascular events:
On cellular events:in areas of acute inflammation:
in areas of chronic inflammation:
in lymphoid areas:
On inflammatory and immune mediators:↓ cytokines including many interleukins,
tumour necrosis factor-α, granulocytemacrophage colony-stimulating factor.
reduced generation of eicosanoids.
decreased generation of IgG
decrease in complement components in
the blood.
Overall effects:-
Corticosteroids bind to one of two types of
intracellular corticosteroid receptor: (MR)
& (GR).
Activated corticosteroid receptors can
affect the expression of target genes by
two independent mechanisms:(1) a direct interaction of the ligandactivated MR or GR with specific DNA
sequences known as glucocorticoid
response elements (GRE),
or (2) the interaction of the activated
receptor with other transcription factors,
such as activator protein -1 (AP-1),
Glucocorticoid receptor domains
Administration can be oral, topical and
parenteral (IV , IM)
The drugs are bound to corticosteroidbinding globulin in the blood and enter
cells by diffusion.
When prolonged use of systemic
glucocorticoids is necessary, therapy on
alternate days or circadian administration
may decrease the unwanted effects.
t ½ofhydrocortisone 90
minutes, biological effects
occur after 2-8 hours.
Inactivated by the
reduction of the double
bond between C4 and C5.
This occurs in liver cells
and elsewhere.
Cortisone and prednisone
are inactive until
converted in vivo to
hydrocortisone and
prednisolone ,
respectively.
Unwanted effects are seen mainly with
prolonged systemic use as antiinflammatory or immunosuppressive agents
(in which case all the metabolic actions are
unwanted), but not usually with
replacement therapy.
The most important are:suppression of response to infection.
suppression of endogenous glucocorticoid
synthesis
Metabolic actions
Osteoporosis
Peptic ulcers
Acute psychosis
Cataracts
Increased intraocular pressure
Iatrogenic Cushing's syndrome
Hydrocortisone
Relative Anti-inflammatory:- 1
Relative sodium retaining:- 1
Duration of action after oral dose:- short
[8-12hours]
Drug of choice for replacement therapy
Cortisone
Relative Anti-inflammatory:- 0.8
Relative sodium retaining:- 0.8
Duration of action after oral dose:-short
[8-12hours]
Cheap;
inactive until converted to hydrocortisone;
not used as anti-inflammatory because of
mineralocorticoid effects.
Prednisolone
Relative Anti-inflammatory:- 4
Relative sodium retaining:- 0.8
Duration of action after oral dose:intermediate [12-36 hours]
Drug of choice for systemic antiinflammatory and immunosuppressive
effects.
Dexamethasone
Relative Anti-inflammatory:- 30
Relative sodium retaining:- minimal
Duration of action after oral dose:- long [3672 hours]
Anti-inflammatory and immunosuppressive,
Used especially where water retention is
undesirable, e.g. cerebral oedema;
Drug of choice for suppression of ACTH
production
Betamethasone
Relative Anti-inflammatory:- 30
Relative sodium retaining:- negligible
Duration of action after oral dose:- long
Anti-inflammatory and
immunosuppressive,
Used especially where water retention is
undesirable
Triamcinolone
Relative Anti-inflammatory:- 5
Relative sodium retaining:- none
Duration of action after oral dose:intermediate [12-36 hours]
Relatively more toxic than others
Beclomethasone dipropionate and
budesonide.
Anti-inflammatory and
immunosuppressive;
effective topically
and as an aerosol
Adrenocortical Insufficiency
Chronic (Addison's Disease)
About 20–30 mg of hydrocortisone must
be given daily, with increased amounts
during periods of stress.
Could be supplemented by an appropriate
amount of fludrocortisone
Acute:Therapy consists of correction of fluid and
electrolyte abnormalities and treatment of
precipitating factors in addition to large
amounts of parenteral hydrocortisone.
Cushing's Syndrome:is treated by surgical removal of the tumor
producing ACTH or cortisol, irradiation of
the pituitary tumor, or resection of one or
both adrenals.
These patients must receive large doses
of cortisol during and following the surgical
procedure.
Replacement therapy for patients with
adrenal failure (Addison's disease).
Anti-inflammatory/immunosuppressive
therapy
in asthma
topically in various inflammatory conditions
of skin, eye, ear or nose (e.g. eczema,
allergic conjunctivitis or rhinitis)
in hypersensitivity states (e.g. severe
allergic reactions)
in miscellaneous diseases with autoimmune
and inflammatory components
e.g. rheumatoid arthritis and other
'connective tissue' diseases,
inflammatory bowel diseases,
to prevent graft-versus-host disease
following organ or bone marrow
transplantation.
In neoplastic disease
– in combination with cytotoxic drugs in treatment
of specific malignancies (e.g. Hodgkin's disease,
acute lymphocytic leukaemia)
– to reduce cerebral oedema in patients with
metastatic or primary brain tumours and in the
postoperative period (dexamethasone is the
drug used)
– as a component of antiemetic treatment in
conjunction with chemotherapy.
Stimulation of Lung Maturation in the
Fetus
Lung maturation in the fetus is regulated
by the fetal secretion of cortisol.
Treatment of the mother with large doses
of glucocorticoid reduces the incidence of
respiratory distress syndrome in infants
delivered prematurely.
Betamethasone is chosen because
maternal protein binding and placental
metabolism of this corticosteroid is less
than that of cortisol
Dexamethasone suppression test measures
the response of the adrenal glands to ACTH.
Dexamethasone is given and levels of
cortisol are measured.
There are two different types of
dexamethasone suppression tests: the lowdose test and the high-dose test.
A normal result is decrease in cortisol levels
upon administration of low- dose
dexamethasone.
If there is not a normal response on the low-dose
test, abnormal secretion of cortisol is likely
(Cushing's Syndrome).
This could be a result of a cortisol-producing
adrenal tumor, a pituitary tumor that produces
ACTH, or a tumor in the body that inappropriately
produces ACTH.
Inhibition of cortisol on high-dose dexamethasone
is indicative of Cushing's disease
If the cortisol levels are unchanged by low and
high-dose dexamethasone then a cortisol
secreting adrenocortical tumor is suspected or an
ectopic ACTH syndrome.
The high-dose test can help distinguish a pituitary
cause (Cushing's Disease) from the others.
•
Low Dexamethasone
• ↓ cortisol
↔ cortisol
• Normal
Cushing's Syndrome
•
• ↓ cortisol
High Dexamethason
↔ cortisol
• Cushing's Disease
Patients receiving glucorticoids must be
monitored carefully for the development of:hyperglycemia,
glycosuria,
sodium retention with edema or hypertension,
hypokalemia,
peptic ulcer,
osteoporosis,
and hidden infections.
peptic ulcer,
heart disease or hypertension with heart
failure,
certain infectious illnesses such as
varicella and tuberculosis,
psychoses,
diabetes,
osteoporosis,
glaucoma.
Mineralocorticoids:- Fludrocortisone is
given orally to produce a mineralocorticoid
effect.
This agent-:
Increases Na+ reabsorption in distal
tubules and increases K+ and H+ efflux
into the tubules.
Acts, like most steroids, on intracellular
receptors that modulate DNA transcription
causing synthesis of protein mediators.
Is used with a glucocorticoid in
replacement therapy.
Fludrocortisone
Relative Anti-inflammatory:- 15
Relative sodium retaining:- 150
Duration of action after oral dose:short [36-72 hours]
Drug of choice for mineralocorticoid effects
Aldosterone
Relative Anti-inflammatory:- none
Relative sodium retaining:- 500
Endogenous mineralocorticoid
The starting substance for synthesis is
cholesterol.
The first step in the synthesis is regulated by
ACTH , is the rate- limiting step.
Metyrapone prevents the β-hydroxylation at C11
, used to test ACTH production , in Cushing’s
syndrome.
Trilostane ,↓ 3β-dehydrogenase, used in
Cushing’s syndrome & primary
hyperaldosteronism.
Others:- aminoglutethimide & ketoconazole.
A relatively selective inhibitor of steroid
synthesis. It inhibits 11-hydroxylation,
interfering with cortisol and corticosterone
synthesis
Metyrapone can reduce cortisol production
to normal levels in some patients with
endogenous Cushing's syndrome.
Useful in the management of severe
manifestations of cortisol excess while the
cause of this condition is being determined
or in conjunction with radiation or surgical
treatment.
It is the only adrenal-inhibiting medication
that can be administered to pregnant
women with Cushing's syndrome.
ADRs:- salt and water retention, hirsutism,
transient dizziness and GIT disturbances.
Ketoconazole, an antifungal imidazole
derivative is a potent and rather
nonselective inhibitor of adrenal and
gonadal steroid synthesis.
Its inhibitory effects on steroid
biosynthesis are seen only at high doses.
Ketoconazole has been used for the
treatment of patients with Cushing's
syndrome due to several causes.
Has some hepatotoxicity
Onset of action is slow, and the effects last for 2–3
days after the drug is discontinued
Used in the treatment of primary aldosteronism
Diagnosis in some patients and in ameliorating the
signs and symptoms
Preparing these patients for surgery
Androgen antagonist and as such is used in
treatment of hirsutism in women
ADRs:-hyperkalemia,cardiac arrhythmia, menstrual
abnormalities, gynecomastia, sedation, headache,
gastrointestinal disturbances, and skin rashes.
A 60-year-old woman was referred
for management of severe
rheumatoid arthritis. She had had
the disease for 15 years and had
been treated until age 55 with
aspirin. She was then switched to
Ibuprofen, which diminished the
gastrointestinal adverse effects
she had developed from aspirin.
One year before referral, she
started to complain of increased
joint pain and stiffness, and
laboratory studies confirmed that
the disease had become more
active.
Several attempts to control her
symptoms with increased dosage
of ibuprofen and with a trial of
another NSAID were not
successful, and the decision was
made to add corticosterolds to the
regimen.
Prednisone was started in a
dosage of 5 mg daily, given in the
morning. After a period of
evaluation, the dose was increased
to 10 mg and then to 15 mg daily.
At this dosage, the patient's
symptoms were tolerable.
Q1
• What are the relative
advantages and
disadvantages of
corticosteroids versus
NSAIDs in the treatment of
inflammatory disease?
Q2
• Why was prednisone given to
this patient in the morning?
Q3
• What is the advantage of
alternate-day therapy with
corticosteroids? Which steroids
are unsuitable for alternate-day
therapy?
Q4
• What are the hazards of longterm glucocorticoid therapy in
chronic disease?
A 28 year old black female was
diagnosed eight months ago with
lupus erythematosus. At that time the
patient was placed on prednisone at a
dose of 0.4 mg/kg (single dose per
day). The patient seeks medical
attention because of a recent weight
loss(12 pounds), down to 120 pounds.
Complaints include: fever, joint pain,
fatigue, and a worsening of facial rash.
Physical exam and laboratory results
confirm that the patient is experiencing
a flare up of her system
lupus erythematosus.
Q1
•
Should this patient's 0.4
mg/kg prednisone dosage
be continued?
– A- yes
– B- no
Q2
•
What is the rationale for using
corticosteroids in managing
systemic lupus erythematosis?
– A- suppression of inflammatory
response
– B- immunosuppressive affects
– C- both
– D- neither
Q3
•
What symptoms are
consistent with an
inflammatory response to
systemic lupus
erythematosus?
–
–
–
–
–
abcde-
fever
joint pain
worsening rash
A&B
A, B & C
Q4
•
What would be a reasonable
corticosteroid(s) for this
patient to manage acute
exacerbation of lupus
erythematosus?
– A- topical preparations for
inflammatory rashes
– B- high-dose bolus (IV)
infusion for acute, severe
presentation
Julie Singer is a 55-year-old white
woman who was admitted to the
emergency department in acute
distress.A previous physical
examination showed hypertension and
diabetes mellitus type 2. The patient’s
present medications include enalapril
40 mg, nifedipine 60 mg, and 100 U
insulin. A physical examination
revealed prominent ankle edema, a
palpable spleen, and hepatomegaly.
Chest radiography
revealed diffuse cardiac enlargement
and left ventricular hypertrophy.
Q1
Based upon the history
and clinical findings,
what is your diagnosis
and what treatment do
you recommend?
Q4
•
What would be a reasonable
corticosteroid(s) for this
patient to manage acute
exacerbation of lupus
erythematosus?
– A- topical preparations for
inflammatory rashes
– B- high-dose bolus (IV)
infusion for acute, severe
presentation
• Glucocorticoides-mediated intiation of transcription.