STEROID THERAPY AND DRUGS USED IN ADRENAL DYSFUNCTION Flashcards
ADRENOCORTICAL STEROIDS
1)Corticosteroids (glucocorticoids and mineralocorticoids)
2)
androgens
Main glucocorticoid and main mineralocorticoid ?
is cortisol
is aldosterone.
Synthetic glucocorticoids include
bethamethasone, triamcinolone, prednisolone, dexamethasone, paramethasone, methylprednisolone, decorticosterone acetate.
Cortisol (hydrocortisone). pharmacokinetics
Major glucocorticoid
Synthesised in the zona fasciculata.
C-21 steroid.
Secretion follows a diurnal rhythm being maximal around 8am.
Secretion is regulated by ACTH and also influenced by stress.
10-20mg secreted daily.
More than 90% protein bound mainly to CBG and albumin.
T1/2 is 60-90 minutes.
Metabolism is in the liver by glucoronidation or sulfation to form water soluble metabolites which are excreted in the urine.
Cortisol
Mechanism of action
Binding of cortisol to receptor.
Dissociation of receptor from associated proteins.
Interaction with coactivators to induce trasncription of GRE in the regulatory region of the gene.
New protein synthesis.
Glucocorticois can also interact with GRE to inhibit transcription of some genes like POMC, COX-2, NOS2 genes.
Second mechanism of action is by direct interaction to cell membrane receptors to produce quicker responses.
Effects on carbohydrate and protein metabolism.
Increased production of glucose from amino acids and glycerol.
Increased storage of glucose as glycogen.
Diminished glucose utilization in the peripheral tissues.
Increased lipolysis to provide amino acids and glycerol for gluconeogenesis.
Increased protein breakdown.
Net effect is increased blood glucose levels
Effects on lipid metabolism:
Fat redistribution.
Lipolytic effects of agents like growth hormone, beta antagonists are facilitated.
Net effect is increased free fatty acids.
Effects on electrolyte and water balance (mineralocorticoids):
Enhancement of distal tubular reabsorption of Na+.
Increased urinary excretion of K+ and H+.
ECF volume expansion.
Effects on blood
Polycythemia in cushing’s syndrome and anemia in adrenal insufficiency.
Lymphocytopenia and leukocytosis.
Decreased number of eosinophils, monocytes and basophils.
CVS effects
Hypertension can be consequent upon primary hyperaldosteronism.
Enhancement of vascular reactivity to other vasoactive agents.
Antiinflammatory and immunosuppressive effects
Decreased release of vasoactive and chemoattractive factors.
Decreased migration of leucocytes to areas of injury.
Reduced number of circulating lymphocytes, monocytes, eosinophils, basophils and increased neutrophils.
Inhibition of the functions of tissue macrophages and other antigen-presenting cells
Decresaed production of IL-1, IL-6, TNF-alpha, GM-CSF, IFN-γ.
Reduced synthesis of PGs, leukotriene, PAF
Reduced expression of COX2
Reduced antibody production but only by very large doses
CNS effects
High doses cause:
Elevated mood.
Euphoria.
Insomnia.
Restlessness.
Increased motor activity.
Psychosis.
Increased intracranial pressure (pseudotumor cerebri)
Catabolic and antianabolic effects
Decreased muscle mass
Weakness and thinning of the skin
Osteoporosis
Reduced growth in children
Other effects:
Suppression of TSH, LH, ACTH release.
Important effects on fetal lung development.
Normal functioning of skeletal muscles
CBG which has a higher affinity for ? than for ?.
glucorticosteroids than for mineralocorticoids
Principles of therapeutic use of glucocorticoids (5)
The advantage of use must outweigh the risks.
Appropriate dose to achieve a predetermined effect and should be adjusted periodically based on response or development of toxicities.
A single dose even if large is usually safe.
Administration for a short period (up to one week) is usually safe.
The agents are only palliative except in specific replacement settings. (The agents primarily manage symptoms except when used as hormone replacements in specific conditions.)
Uses of glucocorticoids
Replacement therapy in adrenal insufficiency which may be primary or secondary.
Rheumatic disorders.
Diseases of the kidneys.
Allergic disorders.
Skin disorders.
Bronchial asthma.
GIT diseases.
Eye problems.
Malignancies.
Cerebral edema.
Organ transplantation.
Toxicities/ADRs
Iatrogenic Cushing’s syndrome
Peptic ulcer
Masking of bacterial and mycotic infections
Myopathy
Hypomania and acute psychosis
development of posterior subcapsular cataracts
Increased IOP and glaucoma
Benign intracranial hypertension
Growth retardation in children
Sodium and fluid retention leading to elevated bp
Adrenal suppession
Caution
Monitor patients for the development of peptic ulcer, hyperglycemia, glycosuria, osteoporosis, infections, sodium retention, edema, hypertension
Great caution in patients with peptic ulcer, HT, TB, psychosis, DM, osteoporosis, glaucoma.
Preparations
Topical
Opthalmic
Inta-articular injections
Inhaled forms e.g. dipropionate, furoate for asthma and allergic rhinitis
Adrenal insufficiency
can be acute, chronic or a result of congenital adrenal hyperplasia.
Result from inadequate secretion of cortisol and or aldosterone.
Potentially fatal.
Commonly due to abrupt withdrawal of chronic glucocorticoid therapy.
Primary adrenocortical failure is called Addison’s disease.
Causes of Addison’s disease include autoimmune, TB, HIV/AIDS, metastatic carcinomas, bilateral adrenalectomy, lymphoma, intraadrenal hemorrhage, amyloidosis, haemochromatosis, CAH, drugs.
Clinical presentation of adrenal insufficiency
Symptoms due to mineralocorticoid insufficiency include:
Hypotension
Shock
Hyponatremia
Hyperkalemia.
Symptoms due to glucocorticoid insufficiency include:
Weight loss
Malaise
Weakness
Anorexia
Hypoglycemia
Treatment of acute adrenal insufficiency
Administration of normal saline.
Administration of cortisol, 100mg bolus followed by continous infusion at a rate of 50-100mg 8 hrly.
Treatment of precipitating cause.
