Pharmacology of Corticosteroids and Steroid Antagonists Flashcards
What are the treatment goals when it comes to the pharmacology of corticosteroids?
- Reverse the clinical manifestations by reducing cortisol to normal
- Eradicate any tumor threatening the health
- Avoid permanent dependence on medication
- Avoid permanent hormone deficiency
What is the effect of glucocorticoids on the liver?
Increase glycogen storage
WHat is the effect of corticosteroids on the skeletal msucle?
Play a permissive role for catecholamine-induced glycogenokysis and/or inhibit insulin-stimulated glycogen synthesis
What causes Cushing’s disease?
Excess corticosteroids as a result of the adrenal/pituitary hyperfunction
What are the signs of Cushing’s syndrome?
Moon face
Obesity
Slow wound healing
Hirsutism
Hypokalemia
Fat distribution & deposition at the base of the neck
Weak muscles
What are the different types of Cushing’s disease?
- ACTH-dependent Cushing’s syndrome
- ACTH-independent Cushing’s syndrome
- Pseudo-Cushing syndrome
What are the causes of ACTH-dependent Cushing’s syndrome ?
- Cushing’s disease or ACTH secreting pituitary adenoma
Ectopic ACTH secretion
What are the causes of ACTH-independent Cushing’s syndrome?
- Adrenal adenoma
- Adrenal carcinoma
- Bilateral adrenal hyperplasia
- Iatrogenic Cushing’s syndrome (Exogenous Glucocorticoid exposure)
WHat are the causes of pseudo-Cushing’s syndrome?
Obesity
Alcoholism
Depression
What are the results of an inrease in cortisol levels?
- High BP
- Bone formation inhibition
- Anti-inflammatory
- Decreased immune function
- Increase gluconeogenesis, lipolysis, proteinlysis
What is the difference between Cushing’s disease and Cushing’s syndrome?
Cushing’s disease: Caused by a tumor on the pituitary gland that causes the gland to produce too much ACTH. ACTH is responsible for the production of cortisol –> Too much ACTH then causes the adrenal glands to produce too much cortisol hormone
Cushing’s syndrome: Due to causes outside the bod that increase the levels of cortisol, such as taking medication containing cortisol –> corticosteroids
What is the hypothalamic-pituitary-adrenal axis?
A communication between the three organs
What are the stressors for the HPA axis?
Physical, emotional, or physiological stress stimulates the hypothalamus
What is the function of the hypothalamus?
- Releases Corticotropin-Releasing Hormone (CRH) in response to stress.
- CRH acts on the anterior pituitary gland.
What is the function of the pituitary gland?
- Produces and secretes Adrenocorticotropic Hormone (ACTH) in response to CRH.
- ACTH stimulates the adrenal glands.
What is the function of the adrenal glands?
- Produce cortisol, a glucocorticoid hormone.
- Cortisol is released into the bloodstream and regulates various physiological processes.
How is the HPA axis regulated?
Negative feedback
What is the negative feedback of the HPA axis?
Elevated cortisol levels inhibit CRH and ACTH production through a negative feedback loop. This prevents excessive cortisol release.
What are the manifestations of Cushing’s? (10)
- Decreased growth in children
- Osteoporosis
- Increased appetite
- Glaucoma.
- Increased risk of infections
- Emotional disturbances
- Peripheral edema
- Central distribution of body fat
- Increased risk of diabetes
- Hypokalemia
What are the therapy alternatives for Cushing’s?
Surgical adrenalectomy
Cortisol replacement therapy
What are examples of natural glucocrticoids?
Cortisol
What are examples of synthetic glucocorticoids? (8)
- Cortisone acetate
- Hydroxycortisone
- Prednisone
- Prednisolone
- Methylprednisolone
- Triamcinole
- Dexamethasone
- Betamethasone
What are the different types of glucocorticoid blockers?
- Receptor antagonists
- Synthesis inhibitors
What are the examples of receptor anatgonists?
Glucocorticoid antagonists
Mineralocorticosteroid
What are the examples of glucocorticoid antagonists?
Mifepristone A.
WHat are the examples of mineralocorticosteroids?
Spironolactone
Eplereonone
What are examples of synthesis inhibitors?
Ketoconazole
Aminoglutethimide
Metyrapone
Etomidate
How are cortisone acetate tablets given?
25mg in the morning
12.5mg in the evening
Where are glucocorticoid receptors located? What is the effect of that when it comes to mediaction?
Widely distributed, carefully administered side effects on multiple organs, including the brain!
WHere are mineralocorticoid receptors located?
Receptors are restricted to kidney, colon, salivary glands and sweat glands
And the brain!
What is the effect of short period of cortisol administration?
Cortisol administration, which lasts less than 2 weeks –> no serious effects but insomnia, behavioral changes, and acute peptic ulcers
What are the cellular effects of steroids?
- The steroid present in the blood bound to CBG, binds in free form
- Steroid receptor is associated with heat shock protein HSP90
- Receptor complex H-receptor is formed, HSP0 is released
- H/R enters the nucleus as a dimer binds glucocorticoid-response-elements (GRE) on the gene and regulates transcription factor
- Protein expression
What are the anti-inflammatory effects of glucocorticoids?
They have a suppression effect on inflammatory processes. These drugs increase neutrophils in blood and decrease lymphocytes, eosinophils, basophils, and monocytes
What are the other effects of glucorticoids?
- Glucocrticoids, like cortisol, are required for normal renal excretion of water load.
- They also have effects on the CNS
- Large doses also stimulate gastric acid secretion and decrease resistance to ulcer formation
What is the result of high cortisol levels (renal function)?
Action on the mineralocorticoid receptors (MR)
What are the effects of high doses of glucocorticoids on the CNS?
When given in large doses, these drugs may cause profound behavioural changes
What are the adverse effects of high doses of cortisol? (7)
- Anxiety, depression and headaches
- Weakened immune system
- Heart disease
- Nerve problems
- DIgestive issues
- High blood sugar
- High blood pressure
What are the methods of precaution to minimize these toxicities of high cortisol levels?
- Adopting local applications (like aerosols for asthma) when appropriate
- Keeping the dosage as low as possible and using intermittent administration when satisfactory results can be obtained
- Tapering the dose soon after achieving a therapeutic response
What is done to patients who have had a long-term therapy, in order to avoid adrenal insufficiency?
Additional “stress dose” may need to be given at times of stress, such as before a major surgery, during serious illness, or when an accident occurs
What should happen to the dose when patients are being withdrawn from glucocorticoids?
They should have their doses tapered slowly, over the course of several months, to allow recovery of normal adrenal function
What are the natural glucocorticoids (cortisol)?
Cortisol or hydrocortisone is a steroid hormone, in the glucocorticoid class of hormones
What regulates the secretion of natural glucocorticoids such as cortisol?
regulated by ACTH and varies during the day (circadian cycle): the peak occurs in he morning and the minimum occurs at about midnight
When are natural glucocorticoids like cortisol used as medication?
- It has a small but significant salt-retaining effect –> hypertension in patients with a cortisol-secreting adrenal tumor or pituitary ACTH-secreting tumor
What are the PK of natural glucocorticoids like cortisol? (4)
- In the plasma: mainly bound to corticosteroid-binding globulin (CBG)
- Well absorbed from the GIT after oral administration
- Mianly catabolized by the liver
- Although it diffuses poorly across normal skin, it is readily absorbed across inflamed skin and mucous membranes
What are the examples of synthetic glucocrticoids?
Prednisolone
Dexamethasone
Traimcilone
What is the MOA of synthetic glucocrticoids?
Same MOA as natural glucocorticoids
What are the additional features of synthetic glucocorticoids that are not present in natural glucocorticoids?
Longer half-life
Longer duration of action
Reduced salt-retaining effect
Better penetration of lipid barriers for topical activity
What is the duration of action of different glucocorticoids?
Cortisol –> short
Cortisone –> short
Prednisone –> intermediate
Triamcinolone –> Intermediate
Dexamethasone –> long
What is the salt-retaining effect of mineralocorticoids like?
High, higher than all other steroid hormones, synthetic or normal
What are the different mineralocorticoid examples?
Aldosterone
Fludrocortisone
What is Aldosterone?
The major natural mineralocorticoid in humans
What regulates the secretion of aldosterone?
Its secretion is regulated by ACTH and by the RAAS system
WHat is the importance of aldosterone?
Regulation of blood pressure and blood volume
What is the half-life and activity of alodsterone?
Short half-life and little glucocorticoid activity
What is the MOA of aldosterone?
- Aldosterone and other steroids with mineralocorticoid properties promote the reabsorption of sodium from the DCT and cortical collecting tubules of the kidney
- Mineralocorticoids bind to the mineralocorticoid receptor in the cytoplasm and activate a similar series as glucocorticoids
What is the major effect of activation of the aldosterone receptor?
Increased expression of Na+/K+ ATPase and epithelial sodium channel
What is Fludrocortisone?
The most widely used mineralocorticoid
It is a potent steroid with both glucocorticoid and mineralocorticoid activities
When is Fludrocorticone the favored treatment option? Why?
Favored for replacement therapy after adrenalectomy because of its long duration of action
What is the effect of oral doses of 0.1mg 2 to 7 times weekly?
Potent salt-retaining activity and is used in the treatment of adrenocortical insufficiency associated with mineralocorticoid deficiency
Too small of a dosage to have important anti-inflammatory or antigrowth effects
What is the Mifepristone (RU486)?
It is a competitive inhibitor of glucocorticoid receptors and progesterone receptors and has been used in the treatment of Cushing’s SYNDROME
What other uses does Mifepristone have?
Can be used as an abortive pill (early abortion, with misoprotosol)
What is the activity of Mifepristone?
It is orally active and effective in early pregnancy
What are the side effects of Mifepristone?
Fatigue, nausea, headache, hypokalemia, edema, and endometrial thickening in women
What are other mineralocorticoid receptor antagonists?
Spironolactone and Eplerenone
What are Spironolactone and Eplerenone?
ANtihypertensive, diuretic, potassium-sparing mineralocorticoid receptor anatgonists
What are the therapeutic uses of Spironolocatone and Eplerenone?
Used for hyperaldosteronism, hypokalemia
What is Spironolactone?
A nonspecific steroid hormone receptor antagonist with similar affinity for progesterone and androgen receptors
What are the adverse effects of Spironolactone?
Gynecomastia in men
Dysmenorrhea in women
Hyperkalemia
What is Eplerenone?
Selective for the mineralocorticoid receptor and thus does not cause gynecomastia
What is the averse effect of Eplerenone?
Hyperkalemia
What is the function of inhibitors of steroid synthesis?
Inhibition of adrenal steroid synthesis
What are the examples of inhibitors of steroid synthesis?
Ketoconazole
Aminoglutethimide
Metyrapone
What is Ketoconazole?
An antifungal drug that inhibits the cytochrome P45p enzymes necessary for the synthesis of all steroids and is used in a number of conditions in which reduced steroid levels are desirable
What are the conditions for which Ketoconazole might be used?
Adrenal carcinoma, breast and prostate cancer
What is Aminoglutethimide?
Blocks the conversion of cholesterol to pregnenolone and also inhibits synthesis of all hormonally active steroids
What is Metyrapone?
Inhibits the synthesis of cortisol but not that of cortisol precursors
Which enzymes does Ketoconazole inhibit? (5)
- P450scc
- 17a-hydroxylase
- 11b-hydroxylase
- 18-hydroxylase
- 17,20 desmolase
Which enzymes does Metyrapone inhibit?
11b-hydroxylase
Which enzymes does AMinoglutethimide inhibit?
P450scc
What is the MOA of Ketoconazole?
- Inhibits the first step in cortisol biosynthesis and, to a lesser extent, the conversion of 11-deoxycortisol to cortisol
- It also inhibits ACTH secretion in vitro at therapeutic doses by impairing corticotroph adenylate cyclase activation
What are the adverse effects of Ketoconazole?
Headache
Sedation
Nausea
Vomiting
Men: inhibition of androgen production –> gynecomastia, decreased libido and impotence
Women: decreases estradiol and testosterone production
What are the contraindications for Ketoconazole?
Contraindicated in patients with acute or chronic liver disease since it can cause reversible hepatotoxicity
What are the therapeutic uses of Mitotane?
Cancer of adrenal gland (absence of surgery)
What is Mitotane?
An adrenocorticolytic drug (cytotoxic) that is used primarily for the treatment of adrenal carcinoma
What are the adverse effects of Mitotane?
At a daily dose, the major side effects are nausea, vomiting, and anorexia.
Which layer of the adrenal cortex does Mitotane spare? What is the result of that?
The zona glomerulosa –> mineralocorticoid replacement is usually required only with chronic, high-dose therapy for adrenal carcinoma
