Corticosteroids Flashcards
How are glucocorticoids synthesized and released?
GCS are synthesized under the influence
of circulating ACTH secreted from the
anterior pituitary gland.
Circadian rhythm in the secretion in healthy humans, with the net blood concentration being highest early in the morning, gradually diminishing throughout the day and reaching a low point in the evening or night.
ACTH secretion itself (also pulsatile in
nature) is regulated by CRF released
from the hypothalamus.
The release of both ACTH and CRF, in
turn, is inhibited by the ensuing rising
concentrations of glucocorticoids in the
blood.
This functional hypothalamic-pituitaryadrenal unit is referred to as the HPA
axis.
What are corticosteroids?
The adrenal secretes a mixture of glucocorticoids; the main hormone in humans is hydrocortisone (also called cortisol).
The mineralocorticoids regulate water and electrolyte balance, and the main endogenous hormone is aldosterone.
In humans, a deficiency in
corticosteroid production is
termed Addison’s disease.
Excessive glucocorticoid
activity results in Cushing’s
syndrome.
What are the general metabolic and systemic effects of glucocorticosteroids?
Metabolic actions
Carbohydrates: decreased uptake and utilisation of glucose
accompanied by increased gluconeogenesis; this causes a
tendency to hyperglycaemia.
Proteins: increased catabolism, reduced anabolism
Lipids: a redistribution of fat, as observed in Cushing’s
syndrome
A negative calcium balance, which may contribute to
osteoporosis:
Decrease of Ca2+ absorption in the gastrointestinal tract
Increase of Ca2+ excretion by the kidney
In higher, non-physiological concentrations, the
glucocorticoids have some mineralocorticoid actions:
Na+
retention and K+
loss-possibly
What are the negative feedback effects of GCS?
Negative feedback effects
Negative feedback effects on the anterior pituitary and
hypothalamus:
Exogenous glucocorticoids depress the secretion of CRF
and ACTH:
Inhibition of the secretion of endogenous glucocorticoids
Atrophy of the adrenal cortex
What are the antiinflammatory and immunosuppressive effects of GCS?
GCS inhibit both the early and the late manifestations
of inflammation:
the initial redness (heat, pain and swelling)
the later stages of wound healing and repair, and the
proliferative reactions seen in chronic inflammation.
GCS suppress the initiation and generation of an
immune response
What are the actions of GCS on inflammatory and other cells?
Neutrophils and other inflammatory cells:
Decreased egress of neutrophils from blood vessels and reduced
activation of neutrophils, macrophages and mast cells secondary to
decreased transcription of the genes for cell adhesion factors and
cytokines
T cells:
Decreased overall activation of T-helper (Th) cells, reduced clonal
proliferation of T cells, and a ‘switch’ from the Th1 to the Th2
immune response
Fibroblasts:
Decreased fibroblast function, less production of collagen and
glycosaminoglycans, and thus reduced healing and repair
Osteoblasts and osteoclasts:
Reduced activity of osteoblasts but increased activation of
osteoclasts and therefore a tendency to develop osteoporosis
What are the actions of GCS on the mediators of inflammatory and immune responses?
Prostanoids
decreased production owing
to decreased expression of
COX-2
Cytokines decreased generation of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL8, TNF-α, etc., secondary to inhibition of gene transcription
Histamine
decreased release from
basophils and mast cells
IgG
decreased production
Annexin-1 (lipocortin)
(inhibitor of PL-A2) and IL-10
increased synthesis
What is the mechanism of action of GCS?
Mechanism of action Glucocorticoids bind to intracellular receptors that then dimerize, migrate to the nucleus and interact with DNA to modify gene transcription, inducing synthesis of some proteins and inhibiting synthesis of others.
Anti-inflammatory and
immunosuppressive actions.
Known actions include: inhibition of transcription of the genes for inducible COX-2, cytokines and interleukins increased synthesis and release of annexin-1
What are the unwanted effects of GCS?
Suppression of the response to infection or injury Osteoporosis Hyperglycaemia Fluid retention, hypertension Peptic ulcer Muscle wasting and proximal muscle weakness In children, inhibition of growth if treatment is continued for more than 6 months Central nervous system effects: euphoria, depression and psychosis Other effects: glaucoma (in genetically predisposed persons), increased incidence of cataracts Acute adrenal insufficiency – in sudden withdrawal of the drugs after prolonged therapy
What are the symptoms of Cushing’s syndrome?
Fat deposits (face, back of shoulders) Hirsutism Purple striae Easy bruising Petechiae
What are the clinical uses of GCS?
Replacement therapy for patients with adrenal failure
(Addison’s disease)
Anti-inflammatory/immunosuppressive therapy:
in bronchial 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:
rheumatoid arthritis and other ‘connective tissue’ diseases
inflammatory bowel diseases
some forms of haemolytic anaemia
idiopathic thrombocytopenic purpura
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:
Hodgkin’s disease,
acute lymphocytic leukaemia
to reduce cerebral oedema in patients with metastatic or
primary brain tumours (dexamethasone)
Urgent, life-threatening conditions Angioneurotic edema Anaphylactic shock Status asthmaticus Toxic pulmonary edema (methylprednisolone) Brain edema (dexamethasone)
What are the principles of adminsitration of GCS?
GCS may be administered orally, systemically or intraarticularly; given by aerosol into the respiratory tract,
administered as drops into the eye or the nose, or applied in
creams or ointments to the skin.
Topical administration diminishes the likelihood of systemic
toxic effects unless large quantities are used.
When prolonged use of systemic glucocorticoids is necessary,
therapy on alternate days may decrease suppression of the
HPA axis and other unwanted effects.
Cessation of therapy: slow and gradual tapering down of the
dose. Recovery of full adrenal function usually takes about 2
months, although it can take 18 months or more.
What are mineralocorticosteroids?
The main endogenous mineralocorticoid is aldosterone.
Its chief action is to increase Na+
reabsorption by the distal
tubules in the kidney, with concomitant increased
excretion of K+ and H+
An excessive secretion of mineralocorticoids:
Conn’s syndrome: marked Na+ and water retention, with
increased extracellular fluid volume, and sometimes
hypokalemia, alkalosis and hypertension.
Decreased secretion of mineralocorticoids:
Addison’s disease: Na+
loss and a marked decrease in
extracellular fluid volume, decreased excretion of K+,
resulting in hyperkalemia.
How are aldosterone synthesis and release regulated?
Electrolyte composition of the plasma
Low plasma Na+ or high plasma K+ concentrations
directly stimulate aldosterone release.
Depletion of body Na+ also activates the reninangiotensin system. Angiotensin II increases the
synthesis and release of aldosterone.
What is the mechanism of action of aldosterone?
Aldosterone acts through: Specific intracellular receptors: transcription and translation of specific proteins: an increase in the number of sodium channels in the apical membrane of the cell subsequently an increase in the number of Na+ -K+ -ATPase molecules in the basolateral membrane causing increased K+ excretion Rapid non-genomic effect: Na+ influx, through an action on the Na+ -H+ exchanger in the apical membrane.
The mineralocorticoid receptor is restricted
to a few tissues:
kidney
transporting epithelia of the colon and
bladder
