Adrenocorticosteroids Flashcards
Hydrocortisone
naturally occuring glucocorticoids
tightly regulated by CNS
inhibited by exogenous cortosil
MOA: gene transcription
effects of hydrocortisone
95% of hormonal activity is d/t cortisol
Gluconeogenesis
increase serum glucose levels leading to stimulation of insulin release and inhibiting uptake by muscle cells
lipolysis
protein catabolism
Net: maintains adequate glucose supply to brain
what is cortisols catabolic effect on bone?
osteoporosis
major limitation for long term use
what is cortisols catabolic effect in children?
growth retardation
major limitation for long term use
cortisol immunosuppressive effects
increased neutrophils
decreased lymphocytes, monocytes, eosinophils, basophils
vasoconstriction d/t suppresion of mast cell degranulation - decreased histamine release and cap permeability
cortisol immunosuppressive effects
vasoconstriction d/t suppresion of mast cell degranulation
decreased histamine release and cap permeability
cortisol anti-inflammatory effects
- inhibition Phospholipase A2 blocking arachidonic acid release
- decreased prostaglandins, prostacyclin, thromboxane
- inhibits NF-KB → inhibits COX-2
- induction of MAPK phosphatase I (inhibits activated proinflammatory signaling pathways)
other effects of cortisol
- behavioural changes: insomnia, euphoria leading to depression
- large doses: increased intracranial pressure
- suppression of ACTH, GH, TSH, LH
- Peptic ulcers: stimulation of H. Pylori, suppression of immune response to H. Pylori
- increase platelets and RBCs
- Impaired renal function
- Development of fetal lungs
cortisol (hydrocortisone) PK
- Relatively short duration of action
- Diffuses poorly across skin (unless inflamed)
- Diffuses well across mucous membranes
- Some salt-retaining effects
Glucocorticoids
- Prednisone
- Hydrocortisone
- Dexamethasone
- Beclomethasone
- Triamcinolone
- Methylprednisolone
Mineralocorticoids
- Aldosterone
- Fludrocortisone
synthetic glucocorticoids
- Rapidly and completely absorbed orally
- Long t1/2’s
- Reduced salt-retaining effects
glucocorticoid administration
all can be taken orally
IM glucocorticoid
triamcinolone
IM, IV glucocorticoid
- Dexamethasone
- Hydrocortisone
- Methylprednisolone
- Prednisolone
Aerosol glucocorticoid
- Beclomethasone
- Triamcinolone
topical glucocorticoid
- Beclomethasone
- Dexamethasone
- Hydrocortisone
- Triamcinolone
Mineralocorticoid MOA
Major effect of activation of the aldosterone receptor:
increased expression of Na+/K+ ATPase
increased expression of ENaC
aldosterone
natural mineralocorticoid
major role: salt-retaining hormones
Na+ reabsorption from renal tubule
K+ H+ excretion
Fludrocortisone
synthetic mineralocorticoid, MCly prescribed
mineralocorticoid AEs
- hypokalemia
- metabolic alkalosis
- increased plasma volume
- HTN
anti-inflammatory vs. salt-retaining effects
treating Chronic adrenocorticol insufficiency
(Addison’s disease)
- weakness, fatigue, weight loss, hypotension, hyperpigmentation, inability to maintain blood glucose levels during fasting
- daily oral Hydrocortisone + Fludrocortisone
- NO dexamethasone (lacks salt-retaining effects)
treating acute adrenocorticol insufficiency
- associated with life-threatening shock, infection or trauma
- start corticosteroids immediately
- for patients with previous dx:
- Large amounts of parenteral corticosteroids + correction of fluid & electrolyte abnormalities
- give salt-retaining hormone once hydrocortisone levels are reduced (~ 5 days)
treating undiagnosed acute attack adrenocorticol insufficiency
dexamethasone to avoid interference with testing of cortisol levels
fluid and electrolyte replacement
treating congenital adrenal hyperplasia
- Glucocorticoid to suppress ACTH
- Treat initially as an acute adrenal crisis
- Once stabilized: oral hydrocortisone or prednisone + fludrocortisone
- fetus protected in high risk pregnancy w/ dexamethasone admin. to mother
Cushing’s Syndrome
- resection of 1 or both adrenals
- must receive high doses of cortisol before and after surgery
- Dose has to be slowly decreased to prevent withdrawal
- cushing disease: irradiation of pituitary tumor
aldosteronism
- Primary aldosteronism: renal loss of K+ (hypokalemia, alkalosis & elevation of serum Na+)
- Treat w/ spironolactone
stimulation of lung maturation of fetus
- Fetal lung maturation regulated by cortisol secretion
- premature delivery is expected?
- give mom large doses of glucocorticoids reduces incidence of respiratory distress syndrome
- IM steroids - dexamethasone
other clinical uses for synthetic 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)
AE of synthetic corticosteroids
- Metabolic effects - Cushing’s syndrome manifestationseg, 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)
- 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)
- low a dose as possible
- Taper dose soon after achieving goal
- Alternate-day therapy
- Administer patients with adrenal insufficiency additional ‘stress dose’ during serious illness or priorto surgery
- Prevent K+ loss with supplementation
- Prevent effects on bone by Ca2+ & vitamin D supplements
corticosteroids should be used in caution in patients with
- Peptic ulcers
- Heart disease or HTN with heart failure
- TB, varicella zoster infections
- Psychoses
- Diabetes
- Osteoporosis
- Glaucoma
___ of glucocortiocoids can be a serious problem (acute adrenal insufficiency syndrome can result)
Dose must be tapered according to individual, Monitor closely
Abrupt withdrawal of glucocortiocoids can be a serious problem (acute adrenal insufficiency syndrome can result)
Dose must be tapered according to individual, Monitor closely
mifepristone
glucocortisol antagonist
Spironolactone /use
- mineralocorticoid antagonist
- competes with aldosterone for its receptor (decreasing its effect peripherally)
- USE:
- Aldosteronism (diagnosis & treatment)
- Hirsutism in women (acts as androgen antagonist)
- Diuretic
Spironolactone AE
- Hyperkalemia
- cardiac arrhythmia
- menstrual abnormalities
- gynecomastia
- sedation
- headache
- GI disturbances
- skin rashes
Mifepristone
Antagonist at glucocorticoid & progesterone receptors
Clinical Application: Inoperable patients with ectopic ACTH syndrome or adrenal carcinoma
synthesis inhibitors
Ketoconazole
Aminoglutethimide
Metyrapone
Aminoglutethimide
- corticosteroid synthesis inhibitor
- Blocks conversion of cholesterol to prenenolone→reduces synthesis of all hormonally active steroids
- use: adrenal cancer (+ hydrocortisone or dexamethasone)
Ketoconazole
Potent & non-selective inhibitor of adrenal & gonadal steroid synthesis
Clinical Applications:
Cushings syndrome, Prostate cancer
Metyrapone
Relatively selective inhibitor of steroid 11- hydroxylation (blocks cortisol synthesis)
Clinical Applications:
Tests of adrenal function
Treatment of pregnant women with Cushing’s
Metyrapone AE
- Salt & water retention
- Hirsutism
- Transient dizziness
- GI disturbances
