Corticosteroids Flashcards
The major glucocorticoid produced by the adrenal cortex is _______. It is synthesized from ________ and its secretion rate follows the circadian rhythm governed by pulses of ______ that peak early morning and after meals
Cortisol; cholesterol; ACTH
Cortisol is primarily bound to _____ in circulation and has a half life of 60-90 mins. It is metabolized by the _____ and excreted in the _____
Corticosteroid-binding globulin (CBG); liver; urine
Describe glucocorticoid receptor binding
Glucocorticoid receptors are intracellular receptors that exist as cytoplasmic complexes with heat shock proteins.
Free hormone enters the cell, binds with glucocorticoids receptor elements (GREs) on cytoplasmic complex which then dissociates from HSPs, dimerizes, and goes to nucleus to alter gene expression
The primary mineralocorticoid produced by the adrenal cortex is ________, which is synthesized mainly in the zona ________. Its release is primarily stimulated by _____
Aldosterone; glomerulosa; ACTH
MOA of aldosterone
Promotes reabsorption of sodium from distal part of DCT and from cortical collecting tubules
Act by binding to mineralocorticoid receptor in the cytoplasm of target cells; major effect of activation of aldosterone receptor is increased expression of Na/K ATPase and ENaC
The specificity for mineralocorticoids in the kidney appears to be conferred by the presence of the enzyme _________, which converts cortisol to cortisone. Cortisone has low affinity for the receptor and is inactive as a mineralocorticoid in the kidney. The role of this enzyme ensures that higher levels of cortisol are avoided in certain tissues like the kidney, colon, and salivary glands
11-beta-HSD type 2
Effects of glucocorticoids on metabolism, including insulin
Glucocorticoids stimulate and are required for gluconeogenesis and glycogen synthesis in fasting state (via stimulation of PEPCK, G6P, and glycogen synthase
They increase serum glucose levels and thus stimulate insulin release, but inhibit uptake of glucose by muscle cells
Stimulate lipolysis via hormone sensitive lipase —> lipogenesis
Actions of glucocorticoids on immune and inflammatory responses
Inhibit functions of tissue macrophages and other APCs — prevents them from phagocytosing and killing microorganisms as well as their production of mediators such as TNF-a, IL-1, IL-12, IFN-y, metalloproteinases, and plasminogen activator
Inhibit phospholipase A2, which reduces synthesis of arachidonic acid (the precursor of prostaglandins, leukotrienes, and PAF)
Reduce expression of COX2 in inflammatory cells, further reducing prostaglandins
Complement activation is unaltered, but its effects are inhibited
Actions of glucocorticoids on muscle, skin, and bones/growth
Decrease muscle mass, cause muscle weakening, and thinning of the skin
Can cause vasoconstriction when applied directly to the skin and decrease capillary permeability by reducing histamine release from basophils and mast cells
Cause osteoporosis in adults; stunts growth in children [Antagonize the effect of vitamin D on calcium absorption]
Glucocorticoid effects on CNS
Produce behavioral disturbances — initially insomnia and euphoria, then depression
Large doses may increase intracranial pressure
Glucocorticoids effects on GI system
Large doses are associated with development of peptic ulcers
Promotion of fat redistribution —> visceral, facial, nuchal, and supraclavicular fat
Most widely used mineralocorticoid with long duration of action; often used in tx of adrenocortical insufficiency (Addisons) because it is potent with both glucocorticoid and mineralocorticoid activity
Fludrocortisone
AEs of fludrocortisone
Salt and fluid retention
CHF
Signs and symptoms of glucocorticoid excess
List 5 short-to-medium acting glucocorticoids
Hydrocortisone (cortisol) Prednisone (prodrug of prednisolone) Prednisolone Methylprednisolone Meprednisone
List 3 intermediate acting glucocorticoids
Triamcinolone
Paramethasone
Fluprednisinolone
2 long-acting glucocorticoids
Betamethasone
Dexamethasone
Common clinical applications for glucocorticoids in endocrine conditions
Primary adrenal insufficiency (Addisons)
Congenital adrenal hyperplasia
[hydrocortisone + fludrocortisone]
Common clinical applications for glucocorticoids in non-endocrine conditions
Immunosuppression: organ or bone marrow transplant, autoimmune disease (MS), hematologic cancers (leukemia)
Inflammatory and allergic conditions: RA, IBD, Asthma/COPD, allergic rhinitis
Skin diseases: inflammatory dermatosis (psoriasis)
Hypersensitivity reactions
General adverse effects of glucocorticoids
Iatrogenic Cushings Insomnia, behavior changes Hyperglycemia, hypokalemia Hidden infections Acute pancreatitis Severe myopathy Nausea, dizziness, weight loss Depression Cataracts Increased IOP and glaucoma Benign intracranial HTN Growth retardation in kids
What co-morbid conditions warrant great caution in the use of glucocorticoids?
Peptic ulcer disease Heart disease Hypertension + CHF Varicella Tuberculosis Psychoses Diabetes Osteoporosis Glaucoma
How should dosing of glucocorticoids be scheduled when it is necessary to maintain continuously elevated plasma levels to suppress ACTH?
Slowly absorbed parenteral preparation OR small oral doses at frequent intervals
How should dosing of glucocorticoids be scheduled when treating inflammatory and allergic disorders?
Fewer, larger doses
[as opposed to small doses at frequent intervals]
How should dosing of glucocorticoids be scheduled when large doses are required for long periods of time?
Alternate-day administration — In this way, very large amounts can sometimes be administered with less marked adverse effects because there is a recovery period between each dose
When prolonged therapy with corticosteroids is anticipated, physician should obtain _____ and ______
CXR; tuberculin test [because dormant TB may be reactivated by therapy]
Signs and symptoms of rapid withdrawal of corticosteroid therapy
Anorexia N/V Weight loss Lethargy Headache Fever Joint or muscle pain Postural hypotension
Which of the following is most potent in terms of anti-inflammatory effects?
A. Hydrocortisone B. Paramethasone C. Betamethasone D. Triamcinolone E. Prednisolone
C. Betamethasone
In order of potency of anti-inflammatory effects from most to least: Betamethasone Dexamethasone Fluprednisolone Paramethasone [Triamcinolone, prednisolone, methylprednisolone, meprednisone] Prednisone Hydrocortisone Cortisone
Which of the following is most potent in terms of salt-retaining effects?
A. Methylprednisolone B. Prednisolone C. Prednisone D. Cortisone E. Hydrocortisone
E. Hydrocortisone
In order of potency of salt-retaining effects from most to least: Hydrocortisone Cortisone Prednisone = prednisolone Methylprednisolone
Which of the following exhibits salt-retaining activity?
A. Methylprednisolone B. Paramethasone C. Fluprednisolone D. Betamethasone E. Dexamethasone F. Triamcinolone
A. Methylprednisolone
Steroid synthesis inhibitor that blocks fungal and mammalian CYP450 enzymes
Ketoconazole
AEs of ketoconazole
Hepatic dysfunction
Many drug-drug CYP450 interactions
Glucocorticoid receptor antagonist that is used in medical abortions, and rarely to tx Cushing’s syndrome
Mifeprestone
AEs of mifeprestone
Vaginal bleeding Abdominal pain GI upset Diarrhea HA
Pharmacologic antagonist of mineralocorticoid receptor that has weak antagonism of androgen receptors; clinically used to tx aldosteronism of any cause, hypokalemia d/t diuretic effect, or post-MI
Spironolactone
[slow onset and offset; duration 24-48 hrs]
AEs of spironolactone
Hyperkalemia
Gynecomastia
Additive interaction with other K+ retaining drugs
