Adrenocorticosteroids Flashcards
Hormonal Steroids Overview?
• Glucocorticoids
Effects on intermediary metabolism and immune function
• Mineralocorticoids
Principally salt-retaining activity
• Steroids with androgenic and estrogenic activity
Naturally occurring glucocorticoids? MOA?
• Cortisol (Hydrocortisone)
Synthesis & secretion tightly regulated by CNS
Mechanism of Action
• Effects mediated by widely distributed glucocorticoid
receptors
• Steroid-receptor complex enters the nucleus and interacts
with promoters of (and regulates the transcription of) target genes
• Produce tissue-specific responses
Metabolic Effects of Cortisol?
• 95% of hormonal activity is due to cortisol
Metabolic Effects
• Stimulates and is required for gluconeogenesis &
glycogen synthesis (which maintains hepatic glycogen
availability) in fasting state
→ increase serum glucose levels (thus leading to stimulation of insulin release) & inhibiting uptake by muscle cells
• Stimulates lipolysis (leading to fat deposition and
redistribution & increased release of fatty acids & glycerol)
• Stimulates protein catabolism & release of amino acids
Net Result: Maintenance of an adequate glucose
supply to brain (most apparent in fasting state)
Catabolic Effects of Hydrocortisone?
Catabolic Effects
• In addition to protein catabolism, cortisol also has effects in lymphoid and connective tissue, muscle, peripheral fat and skin (wasting occurs at high concentrations)
• Catabolic effects on bone = osteoporosis
• In children = growth retardation
Both are major limitations in long-term treatment with
glucocorticoids.
Immunosuppressive Effects of Cortisol(Hydrocortisone)?
• Effects on leukocytes
• Increased neutrophils (increased influx into blood & decreased migration from blood vessels)
• Decreased lymphocytes (T and B cells),
monocytes, eosinophils and basophils (movement
from vascular bed to lymphoid tissue)
• Vasoconstriction due possibly to suppression of mast cell degranulation
• Decreased histamine release and capillary
permeability
Anti inflammatory effects of Cortisol(hydrocortisone)?
• Inhibition of phospholipase A2
(through induction &
activation of annexin I) which blocks arachidonic acid release (major precursor of prostaglandins).
• Cyclooxygenase-2 synthesis is reduced (through inhibition of NF-kB).
• Induction of MAPK phosphatase I (inhibits MAPK activated proinflammatory signaling pathways).
Other effects of Cortisol (Hydrocortisone)?
• CNS: behavioral changes (insomnia, euphoria leading to depression)
• Increased intracranial pressure: large doses
• Suppression of release of ACTH, growth hormone,
thyroid-stimulating hormone & luteinizing hormone: chronic use
• Peptic Ulcers: Stimulation of gastric acid. Suppression of immune response to H.pylori?
• Increase platelets & RBCs
• Renal function: is impaired with cortisol deficiency
• Development of fetal lungs
Cortisol PK?
- Relatively short duration of action
- Diffuses poorly across skin (unless inflamed)
- Diffuses well across mucous membranes
- Some salt-retaining effects
Name 2 mineralocorticoids? Describe each
Aldosterone
Fludrocortisone
• Aldosterone
Most important mineralocorticoid in humans
• Fludrocortisone
Synthetic corticosteroid. Most commonly prescribed salt retaining
hormone
Name 6 glucocorticoids?
Prednisone Hydrocortisone Dexamethasone Beclomethasone Triamcinolone Methylprednisolone
Name 5 synthetic glucocorticoids?
- Prednisone
- Methylprednisolone
- Dexamethasone
- Beclomethasone
- Triamcinolone
PK of synthetic glucocorticoids?
- Rapidly and completely absorbed orally
- Selected compounds can also be given IV, IM, topically, intra-articularly & by aerosol
- Long t1/2’s
- Reduced salt-retaining effects
Route of administration for glucocorticoids?
Oral?
IM?
Aerosol?
Oral: All can be given orally
IM: Triamcinolone
Aerosol: Beclomethasone
Triamcinolone
ROA glucocorticoids?
IV, IM?
IV,IM: Dexamethasone Hydrocortisone Methylprednisolone Prednisolone
ROA glucocorticoids?
Topical: Beclomethasone Dexamethasone Hydrocortisone Triamcinolone
MOA of Mineralocorticoids?
Mechanism of Action
• Bind to mineralocorticoid receptor
• Drug-receptor complex acts in similar fashion to
glucocorticoid drug-receptor complex
• Major effect of activation of the aldosterone receptor:
• increased expression of Na+ /K+ ATPase
• increased expression of ENaC
Major effects of Mineralocorticoids?
• Natural mineralocorticoid = Aldosterone
• Major role are as salt-retaining hormones
• Under control and regulation of CRH, ACTH and renin angiotensin
system
• Help to control body’s water volume & electrolyte
concentrations (Na+ & K+)
• promote Na+
reabsorption from renal tubule
• promote K+ and H+ excretion
AE of Mineralocorticoids?
- Hypokalemia
- Metabolic alkalosis
- Increased plasma volume
- Hypertension
Short- to medium acting
glucocorticoids anti-inflammatory to salt retaining ratio?
Hydrocortisone
Prednisone
Methylprednisolone
anti-inflammatory to salt retaining ratio
Hydrocortisone 1:1
Prednisone 4:0.3
Methylprednisolone 5:0.25
Intermediate acting
glucocorticoids and Long-acting glucocorticoids anti-inflammatory to salt retaining ratio?
(intermediate)Triamcinolone
(long acting)Dexamethasone
anti-inflammatory to salt retaining ratio
Triamcinolone 5:0
Dexamethasone 30:0
Mineralocorticoids anti-inflammatory to salt retaining ratio?
Fludrocortisone
Aldosterone
anti-inflammatory to salt retaining ratio?
Fludrocortisone 10:250
Aldosterone 0.3:3000
Undiagnosed acute adrenocortical insufficiency attack treatment?
Undiagnosed Acute attack
Treat with dexamethasone to avoid interference with
testing of cortisol levels.
Fluid and electrolyte replacement are essential
acute adrenocortical insufficiency causes and treatment?
Associated with life-threatening shock, infection or trauma
Treatment should be started immediately
For patients with previous diagnosis:
Large amounts of parenteral corticosteroids +
correction of fluid & electrolyte abnormalities
Can administer salt-retaining hormone once hydrocortisone levels are reduced (~ 5 days)
Chronic adrenocortical insufficiency (addison’s disease) characterization and treatment?
Characterized by weakness, fatigue, weight loss, hypotension, hyperpigmentation, inability to maintain blood glucose levels during fasting
Treatment
Daily oral hydrocortisone (increase dose during stress)
+ mineralocorticoid (fludrocortisone)
DO NOT administer glucocorticoids lacking salt retaining effects
Congenital Adrenal Hyperplasia sequelae
Caused by defects in cortisol synthesis (either in CRH
production by hypothalamus or in corticotropin
production by pituitary)
Decreased steroid levels lead to an increase in ACTH
production and hyperplasia of adrenal gland
→ increased amounts of cortisol precursors that are
diverted to the androgen pathway
Treatment of CAH?
Glucocorticoid admin. leads to suppression of ACTH
Treat initially as an acute adrenal crisis
Once stabilized: oral hydrocortisone or prednisone +
fludrocortisone
Fetus can be protected in high-risk pregnancies
by dexamethasone admin. to mother
Cushing’s Syndrome vs Cushing’s Disease description and treatment?
May occur as a result of bilateral adrenal hyperplasia
secondary to an ACTH-secreting pituitary adenoma
Commonly associated with chronic presence of
excessive glucocorticoids
Treatment
Surgical removal of tumor, irradiation of pituitary tumor,
or resection of one or both adrenals
Patients must receive high doses of cortisol before and
after surgery
Dose has to be slowly decreased to prevent withdrawal
Aldosteronism description, symptoms, and treatment?
Aldosteronism
Primary aldosteronism usually results from excessive
production by adrenal tumor (can be from malignant
tumor)
Symptoms: result from renal loss of K+ (hypokalemia,
alkalosis & elevation of serum Na+)
Diagnosis and Treatment
Spironolactone
Diagnostic Purposes of
Dexamethasone Suppression Test?
• Cushing’s syndrome: dexamethasone suppresses
cortisol release in individuals with pituitary dependent Cushing’s syndrome (not released from adrenal tumors)
• Depressive psychiatric states
Overview of Stimulation of Lung Maturation in Fetus?
Fetal lung maturation is regulated by cortisol secretion
If premature delivery is expected, treatment of the
mother with large doses of glucocorticoids reduces
incidence of respiratory distress syndrome
IM steroids are used (usually dexamethasone)
Non adrenal clinical applications of corticosteroids?
- Numerous immunological inflammatory conditions: asthma, collagen vascular disorders (Rheumatoid arthritis), ocular diseases (uveitis, optic neuritis, exopthalmos),
- Allergic reactions (contact dermatitis, urticaria etc)
- Hodgkin’s lymphoma (prednisone)
- Cerebal Edema (dexamethasone)
- Chemotherapy-induced vomiting
- Hematologic disorders (anemia, leukemia etc)
- Organ transplants (prevention of rejection)
- Renal disorders (nephrotic syndrome)
- Hypercalcemia
- Mountain Sickness
- Inflammatory bowel disease etc.
- Idiopathic orthostatic hypotension (fludrocortisone)
guidelines for corticosteroid treatment?
• Have to balance benefits with adverse effects
• Short-term use = few serious adverse effects
• Try and treat with short-intermediate acting steroids
as much as possible
• Long-term used produces predictable toxicity based
on their physiological effects
AE of corticosteroids first slide?
• Metabolic effects (Cushing’s syndrome manifestations
eg, diabetes, muscle-wasting, osteoporosis)
• Peptic ulcers
• Clinical findings of certain disorders (particularly
bacterial & mycotic infections) may be masked by steroid use
• Myopathy (part. with long-acting steroids)
AE of corticosteroids second slide?
- Nausea, dizziness, weight loss
- CNS (euphoria, psychosis, depression)
- Increased intraocular pressure (glaucoma)
- Posterior subcapsular cataracts
- Sodium & fluid retention, loss of potassium
- Growth retardation (children)
- Adrenal suppression
How to minimize toxicities?
• Local application (eg, as an aerosol in asthma)
• Use as low a dose as possible
• Taper dose soon after achieving treatment goal
• Alternate-day therapy
• Administer patients with adrenal insufficiency
additional ‘stress dose’ during serious illness or prior
to surgery
• Prevent K+ loss with supplementation
• Prevent effects on bone by Ca2+ & vitamin D supplements
Use corticosteroids with caution in these condition?
- Peptic ulcers
- Heart disease or hypertension with heart failure
- TB, varicella zoster infections
- Psychoses
- Diabetes
- Osteoporosis
- Glaucoma
Withdrawal of corticosteroids considerations?
• Abrupt withdrawal can be a serious problem (acute
adrenal insufficiency syndrome can result)
• Dose must be tapered according to individual
• Monitor closely
Corticosteroids antagonist?
Glucocorticoids - Mifepristone
Mineralocorticoids- Spironolactone
Spironolactone moa, clinical applications, and AE?
Spironolactone
Acts by competing with aldosterone for its
receptor (decreasing its effect peripherally)
Clinical Applications:
• Aldosteronism (diagnosis & treatment)
• Hirsutism in women (acts as androgen antag.)
• Diuretic
Adverse Effects:
Hyperkalemia, cardiac arrhythmia, menstrual
abnormalities, gynecomastia, sedation, headache,GI disturbances, skin rashes
Mifepristone moa and clinical applications?
Mifepristone
Antagonist at glucocorticoid & progesterone receptors
Clinical Application:
• Inoperable patients with ectopic ACTH
syndrome or adrenal carcinoma
Name 3 corticosteroid synthesis inhibitors?
Ketoconazole
Aminoglutethimide
Metyrapone
Aminoglutethimide moa and clinical application?
Aminoglutethimide
Blocks conversion of cholesterol to prenenolone
→ reduces synthesis of all hormonally active
steroids
Clinical Application:
• Adrenal cancer (+ hydrocortisone or
dexamethasone)
Ketoconazole moa and clinical application?
Potent & non-selective inhibitor of adrenal &
gonadal steroid synthesis
Clinical Applications:
• Cushings syndrome
• Prostate cancer
Metyrapone moa, clinical application and AE?
Relatively selective inhibitor of steroid 11-
hydroxylation (interferes with cortisol &
corticosterone synthesis)
Clinical Applications:
• Tests of adrenal function
• Treatment of pregnant women with Cushing’s
AE • Salt & water retention • Hirsutism • Transient dizziness • GI disturbances
