Corticoid steroid 2 lecture 7 Flashcards
distinct zones of the adrenal cortex
zona glomerulosa, zona fasiculata, zona reticularis
What regulates cortisol production
Role of HPA (CRF, ACTH, etc.). POMC and other substances it is a precursor for
Normal rates of secretion and circadian rhythm: morning highest
role of stress/inflammation
rate limiting step
enzymes involved
Why doesn’t cortisol activate the mineralocorticoid receptors as well?
Cortisol-cortisone shuttle (HSD1 and HSD2)
What regulates aldosterone production?
Role of kidney
normal rate of production
role of RAS
Ion changes
Mechanisms of action of corticosteroids
bind to cytoplasmic receptor, which is a ligand activated transcription factor
activate/inhibit the levels of various genes
glucocorticoid effects metabolism:
glucose regulation induce hyperglycemia via a combination of mechanisms
Liver: increased glucose synthesis from amino acids and glycerol, increased glycogen storage
Peripheral tissues: stimulating protein breakdown, increased synthesis of glutamine, promotes lipolysis (all building blocks for glucose), decreased utilization of glucose, decreased uptake of glucose (skin/adipose/fibroblasts/thymocytes/PML)
lead to atrophy of lymphoid tissue decreased muscle mass, negative nitrogen balance and thinning of the skin
fats: redistribution of body fats: round face, and back fat (moon face and buffalo hump) most common. Marked central obesity, reduced peripheral fats
promote lipolytic effects of other agents (GH)
glucocorticoid effect Ca2 balance and cardiovascular and blood
Ca: Induces a negative Ca balance, decreased Ca uptake in the gut, increased Ca secretion by the kidney
Cardiovascular and blood: most glucocorticoids have some mineralocorticoid activity, decreased Na excretion can promote hypertension. Enhances the action of other vasoactive substances (ANG II) (possibly via increased receptor levels). Increase smooth muscle expression of alpha 1 and beta 2 adrenergic receptors. Induceds a mild polycythemia by decreased circulating levels of lymphocytes, eosinophils, monocytes, and basophils, redistribution to tissues not a loss of cells, can be prolonged.
Glucocorticoid effect antiinflammatory
In addition to regulating immune cell number, glucocorticoids have a profound effect on other components of the immune system.
mechanisms partially due to the effect on lymphocyte number
inhibit the production of a number of factors essential for generating inflammatory response: proteolytic enzymes, vasoactive and chemoattractant factors (cytokines). Pro-inflammatory enzymes such as COX-2 and NOS.
Stimulates the synthesis of lipcortin, inhibit phospholipase A2 activity, decreased arachidonic acid release and subsequent production of eicosanoids
Glucocorticoid: endocrine
inhibit thyroid stimulating hormone (TSH) release, can lead to misinterpretation of TSH assays for hyperthyroidism
decreased serum levels of thyroxine binding globulins
inhibits extrathryoidal monodeiodination of T4 leads to decreased T3 levels
pharmacological levels inhibit growth, via inhibition of IGF-1 and its signaling pathways
prolonged glucocorticoid xposure inhbits FSH and LH surge: irregular menses, reduced testosterone in men and women
glucocorticoid effect: Bone/ connective tissue/ skin
inhibits osteoblast function, decreased collagen and osteocalcin synthesis, increased bone reasborption- promotes osteoperosis.
inhibit fibroblast function, dereased synthesis of collage, fibronectin, etc, promotes STRIA and bruising
Mineralcorticoid effects
water and Ion balance. Increased Na/K ATPase expression on the distal tubules and the collecting duct to enhance Na reabsorption and K excretion.
Promotes H excretion and H20 reabsorption
Pseudo cushing’s syndrome
physiological hypercortisolism associated with disorders other than cushing’s syndrome, can be seen in:
significant physical inflammatory stress, such as by a severe bacterial infection.
severe obesity, especially visceral obesity or polycystic ovary syndrome
malnutrition, anorexia nervosa or with intense chronic exercise
psychological stress, severe major depressive disorders and melancholic symptoms
occasionally in chronic alcoholism
Cushing’s syndrome ACTH Dependent
associated with excessive ACTH secretion leading to adrenocortical hyperplasia
Cushing disease (pituitary hypersecretion of ACTH): 65-70%
ectopic secretion of ACTH by nonpituiitary tumor- 10-15%
ectopic seretion of CRH by nonhypotalamic tumors causing pituitary hypersecretion of ACT- less than 1%
iatrogenic or factitious cushing’s syndrome due to administration of exogenous ACTH less than 1%
Cushing’s syndrome ACTH independent
Iatrogenic or factitious cushing’s syndrome, the most common predominantly due to long term glucocorticoid use
adrenocortical adenomas and carcinomas 18-20%
primary pigmented nodular adrenocortical disease (PPNAD), also called bilateral adrenal micronodular yperplasia: <1%
bilateral acronodular adrenal hyperplasia: <1%
Cushing’s syndrome SX
central obesity, round face “moon face”, growth of fat pads around neck “buffalo hump,” excessive sweating, muscle wastage, skin strae neurological complaints including euphoria psycosis and depression
diagnosis of cushing’s syndrome:
- rule out exogenous glucocrticoids or other pharmacological reasons
- 24 hour urine cortisol: accurate 24 hour series of urine samples. False + in physiologic and people who drink lots of water (5L/day stimulates cortisol production) Problems with people who work night shifts
- late night salivary cortisol: late night cortisol should be at nadir, this is preserved in obese and psychiatric patients. Not useful in patients with sleep disorders of shift workers
diagnosis cushing syndrome: dexamethasone test
suppression test are used to assess the status of HPA axis and for the differential diagnosis of adrenal hyperfunction
theory: dexamethasone is a high potency glucocorticoid that will promote the feedback inhibition of the HPA leading to a decrease in ACTH production and then cortisol. If cortisol levels are reduced by dexamethasone then the feedback system is operative. Dexamethasone is used as it does not interffere with the lab test for cortisol
Low dose test: differentiates if cushing’s or not.
baseline cortisol measures over a 48 hr period. In cushing’s no suppression of cortisol. In normal and stressed/obese induced cortisol patients, cortisol levels will be suppressed.
High dose test: differentiates type of cushing
ACTH undectectable but no suppression of cortisol: adrenal tumor
ACTH elevated and no suppression of cortisol: ectopic acth syndrome
ACTH normal to mildly elevated and suppression of cortisol: Cushing’s disease
Metyrapone test cushing syndrome
Inhibit CYP11B1
cushing’s disease indiciated when cortisol reduces and ACTH increases.
if nonpituitary based cushing’s no change in ACTH
TX options cushing syndrome
surgery
block and replace: total ablation of cortisol secretion with addition of replacement glucocorticoid therapy when cortisol levels are extremely low. Most useful in patients with erratic cortisol secretion
normalization: goal is to reduce cortisol levels to normal. Useful in patients with invariant hypercorticolism
aminoglutethimid
Mech: Inhibits CYP11A1 and to a lesser degree CYP11B1. reduces the ysntehsis of all corticosteroids
use: controlling hypercortisolism in patients with cushing’s syndrome caused by adrenal tumors secreting cortisol or acth dependent causes (recently withdrawn, may still be on step 1)
pharmocokinetics: orally
SX: overtime can induce adrenal insufficiency. may need to supplememnt with corticosteroids and fludrocortisones to replace mineralocorticoids. Drowsiness, morbilliform skin rash, nausea/vomiting, anorexia, adrenal insufficiency, hypothyrodism, masculinzation, hirstim, HA, dizziness, hypotension, pruritus, myalgia, fever, actue generalized exanthematous pustulosis
Drug interactions: induce hepatic microsomal enzymes leading to increased metabolism of other drugs such as warfarin, theophyllin and digitoxin
ketoconazole
Mech: antifungal, at higher doses than those employed in antifungal therapy inhibits CYP17 (inhibits glucocorticoid and androgen synthesis). Even higher doses inhibits CYP11A1 thus inhibiting all steroidogenesis. Inhibits corticotroph adenylate cyclase activation (reduces ACTH secretion at therapeutic doses)
use: cushing’s disease
drug interaction: Strong inhibitor of CYP1A2, CYP2C9, and CYP3A4 so considerable potential of drug-drug interactions. inhibits P-glycoprotein so may increases levels of P-gp substrates.
SX and pharmaco: other lecture
contraindicated with ergot derviatives, cisapride, or triazolam due to risk of potentially fatal cardiac arrhythmias
metyrapone
Mech: selective inhibitor of CYP11B1 reducing the biosyntehsis of cortisol
use: hypercorticism resulting from either adrenal neoplasms or tumors producing ACTH ectopically. Diagnostic test for cushing’s syndrome
pharacokinetics: oral and half life of 20-26min
SX: hirsutism: due to increased syntehsis of adrenal androgens upstream from the enzymatic block, nausea, HA, sedation and rash
etomidate
anesthetic drug that blocks 11 beta hydroxylation of dexoycortisol to produce cortisol (will cover in neuro)
given IV at nonhypnotic dose in hospital setting
Mitotane
acts on adrenocortical cell mitochondria to inhibit CYP11B1 and cholesterol side chain cleavage enzymes.
metabolized into an acyl chloride that binds to important macromolecules inthe mitochondria causing mitochondrial destruction and necrosis of adrenocortical cells
distributes to fatty tissue and has a long term effect
not used during pregnancy
need to supplement with exogenous glucocorticoids
Mifepristone (RU-486)
Mech: Inhibit the release of the glucocorticoid receptor from the HSP chaperone proteins: reduces the transcriptional effect of glucocorticoids. Also progesterone antagonist (abortion pill)
Use: controlling hypercortisolism in patients with CUshing’s syndrome caused by: inoperable ectopic ACTH secreting tumors, adrenal carcinomas unresponsive to other therapies (rarely used)
pharmokinetics: rapid oral availability, long half life (20Hr)
SX: vaginal bleeding vey common. ranges from spotty bleeding from 9-16 days up to 30 days and can be quite heavy and prolonged leading to hypovolemic shock. HA, dizziness, abdominal pain, nausea, vomiting, diarrhea, abdominal cramps
drug interactions: induces hepatic microsomal enzymes leading to increased metabolism of other drugs such as warfarin, theophylline, and digitoxin
Adrenal insufficiency
Primary: structural or functional deficiency of the adrenal cortex (addison’s disease): high ACTH levels and low glucocorticoids and mineralcorticoids
secondary: pituitary or hypothalamic deficiency: low ACTH and low normal glucocorticoid/androgens, normal mineralocorticoids
congenital adrenal hyperplasia (CAH)- mutation in enzymes involved in corticosteroid synthesis
Cosyntropin test determine primary and secondary adrenal insufficiency
Cosyntropin is a synthetic ACTH analog: high dose of 250 uG, cosyntropin maximally stimulates adrenocortical steroidogenesis. Cortisol is measured just before administration (baseline) and 30 to 60 minutes after cosyntropin administration (increased levels of circulating cortisol indicates that the adrenal cortex is working)
Primary insufficiency:
combination fo glucocorticoids and mineralocorticoids is required.
hydrocortisone or cortisone are preferred treatment.
supplementation with fludocorrtisone for mineralcorticoid effect
secondary insufficiency
hydrocortisone, cortisone or prednisone, mineralocorticoids are not necessary
replacement therapy with corticosteroids
therapeutic goal is to provide sufficient hormone to maintain normal function
mimic natural levels of glucocorticoids
stimulate the natural circadian rhythm by dividng the dose, 2/3 dose in AM and 1/3 in PM.
mineralocorticoids are given once a day, because their relase does not show circadian effects normally
CAH
deficiency in CYp21 most common (90%): redced levels fo corticosteroids, increased 17 hydroxyprogesterone (clincal test) DHEA and androgens due to lack of feedback inhibition and xs ACTH.
classic severe deficit: females pseduohermaphorditism. . males normal at birth precocious puberty
nonclassic post pubery presentation, (mild androgen excess hirsuitism, amenorrhea)
treat with corticosteroids, females with classic can be treated in utero
aldosternism
excessive production of aldosterone leading to hypertension and hypokalemia
most common form: aldosterone producign adenomas and bilateral idiopathic hyperaldosteronism
less common: unilateral hyperplasia or adrenal hyperplasia, familial hyperaldosteronism, and pure aldosterone producing adrenocorticol carcinomas and ectopic aldosterone secreting tumors
TX: surgery: aldosterone producing adenomas if unilateral. Unilateral hyperplasia.
Aldosterone antagonst
Spironolactone aldactone
Mech: blocks renal aldosterone receptors. Also progesterone agonist and androgen antagonist
Use: diagnostic for aldosteronism and treatment of aldosteronism for non surgical candidates
pharmacokinetics: Oral administration (2-3 days) active metabolite.
SX: brest tenderness and menstrual irregularities in women. impotence, decreased libido, and gynecomastia in men.
Glucortcicoids 1
used to treat a host of disease states, especially those with an inflammatory component. With the exception of replacement therapy, glucocorticoid therapy is empirical. Glucocorticoids have a large number of side effects so the minimal effective does is the gaol of therapy. In long term administration this requires trail and error with frequent re evaluation.
Considerations for starting, maintaining and finishing glucocorticoid therapy: excellent anti-inflammatory activity, underlying cause is still present, corticosteroids are palliative not curative, use for steroid responsive conditions, use only when less toxic substances are ineffective, use the minimum effective dose, (a special large dose will have less side effects), administer locally if possible, topical administration wil lessen systemic effects, avoid rapid withdrawl, glucocorticoids may suppress signs and symptoms of diseases or interfere with diagnostic test, once in remission, use every other day therapy (administer in the morning, duplicate circadian rhtym, reduces suppression of HPA axis, better compliance, less side effects)
Glucocorticoids for rheumatic disorders
Vasculitisis: start with high doses and then taper to minimal effective dose. Used in conjunction with other immunosuppressants.
Arthritis: temporizing agents in progressive disease unresponsive to physiotherapy and NSAIDS. Can be used intraarticular injections for localized control
Gluco: respiratory disorders (asthma)
inhaled, used daily as a prophylactic in moderate to severe asthma. Never the sole medication also still have rescue inhaler
Gluco: allergies
never use to treat severe actue allergy attacks. useful to control short duration allergic disorders. In haled and oral generally but in severe conditions IV.
Gluco: respiratory distress syndrome
given to mothers of babies likely to be premature (24034 weeks). Starting at 48 hr pre birth.
Beclamethasone- 2 doses IM to mother 48 hrs and then 24 hr prior to delivery
dexamethasone: 4 doses IM starting at 48 hr pre then every 12 hours.
gluco: dermatologic problem
useful as a topical application in numerous skin conditions like eczma. Can also be used in skin auto immune diseases.
gluco (crohn’s disease)
used only if other treatment fail. Given orally or via enema (depending on severity). Often high doses given.
gluco: organ transplant
high doses given at time of surgery to prevent rejection, taper to effective dose. Given in conjunction with other immunosupressents. Also used in acute and chronic rejection
rank order of anti-inflammatory potency **
Cortisone
Hydrocortisone and cortisol
Prednisone and prednislone
Methylprednisone
Triaminoclone
Fludocortisone (high mineralcorticoid effect
Bethmeclasone and dexamethasone
glucocorticoids: absorption
many corticosteroids are orally active. water soluble esters can be given rapidly via iv. A more prolonged effect is seen if given im.
Absorption from local sites (skin etc) is also possible. 90% of cortisol bind % to corticosteroid binding globulin and albumin in the plasma.
Binding affinity for other corticosteroids varies with cortisol highest and aldosterone the lowest (low binding of glucoronide conjugates).
CBG levels raised in pregnancy and in estrogen therapy
glucocorticoids: metabolism and activation/deactivation
all hepatic conjugation with glucoronides/sulfate. First pass effect varies by steroid. Renal excretion.
HSD1, 11 beta hydroxysteroid dehydrogenase type 1 isoenzyme activates (cortisone-cortisol) and found in most glucocorticoid target tissues
HSD2, 11 beta hydroxysteroid dehydrogenase type 2 isoenzyme deactivates (cortisol-cortisone): found in mineralcorticoid target tissues, and kidney, colon, salivary glands, and also placenta.
Preparations and route of administration **
Oral: all
Aerosol: becla, flusonide, flutacisone, trimecinolone
Topical: becla, dexame, hydrocortisone, trimic
Iv and im: dexa, hydro, methyl, prednisone
Im: cortisone, deoxycortisone, triaminoclone
gluocorticoids SX
adverse reactions due to long term use/high dose.
probability of adverse reactions are dependent on the dose, period of treatment and type of administration.
example of likelihood of adverse reaction to long term steroids based on dose.
Cushing’s syndrome
Cushing’s syndrome
Cardiovascular: hypertension, edema, Na and Water retention, dependent on mineralocorticoid activity of corticosteroid, hypokalemia
CNS: Euphoria, depression, psychosis, insomnia
immune system: increase susceptibility to infection, especially viral and fungal
GI: peptic ulcer
metabolic: hyperglycemia, muscle catabolism, hyperlipidemia altered fat deposition (moon face), striae
eye: cataracts, glaucoma
osteoporosis: negative ca balance (caused increased parathyroid hormone secretion, cause bone resorption) and inhibition of osteoblasts
adverse reactions of glucocorticoids after withdrawl
HPA suppression lead to adrenal insufficiency
suppression of HPA axis due to feedback loop that inhibits ACTH release.
Decreases acth induced cortisol secretion, promoting secondary adrenocortical insufficiency.
severity depends on individual/ dose/ duration of therapy, can last up to 12 months.
to prevent this should have a “weaning of perod”: gradual reduction of steroid following prolonged therapy, including switching to every over the day therapy
potential flare up of underlying disease processes can occur: corticosteroids are palliative and not a cure
contraindications and precautions of corticosteroids
pediatric use should be approached with care because of the potential for growth and development inhibition. Also the negative calcium balance can cause problems with bone growth and strength.
corticosteroids are highly immunosuppressive and can mask viral and fungal infections so should be used with extreme care in these patients and should be avoided if possible. Can be combined with anti infective agents. Patients on prolonged corticosteroids should avoid exposure to viral infections. Ophthalmic use is contraindicated with the presence of either fungal or viral infections
do not use in conjunction with live virus vaccinations
