L 16 and 17 corticosteriods Flashcards
what hormones does the cortex of the adrenal glands produce
glucocorticoids, mineralocrotoids, androgens
what hormones does the medulla of the adrenal glands produce
epinephrine, norepinephrine
what are glucocorticoids
-stress hormone
-increase circulating glucose concentrations
-potent anti inflammatory effects
what are mineralocorticoids
-Na+ retention
-increase blood volume
-increase blood pressure
what does epinephrine do in the action of stress hormones
-binds to beta-adrenergic receptor (GPCR)
-initiates signal transduction cascade
-induces immediate response
-breaks down glycogen and release glucose
what does cortisol do in terms of action of stress hormones
-binds to glucocorticoid receptor (nuclear hormone receptor)
-regulates gene transduction, and thus translation and protein production
-induces long term, persistent biological response
-induces gluconeogenic enzymes
-inhibit pro inflammatory processes
CRH?
corticotropin releasing hormone
ACTH?
-corticotropin
-adrenocorticotropic hormone
regulation of mineralocorticoids synthesis
-when the pituitary glands is surgically removed in animals, aldosterone synthesis is not affected significantly
-the anterior pituitary does not control the synthesis of mineralocorticoids
-renin-angiotensin-aldosterone system
hormone response elements
-DNA binding of activated dimers bind to specific DNA sequences called GRE, upstream of steroid responsive genes
-binding alters rate of transcription
GRE?
glucocorticoid responsive elements
what kinds of enzymes do glucocorticoids up-regulate for gluconeogensis and anti inflammatory proteins
-PEP carboxykinase: catalyzes the rate limiting step in gluconeogensis
-lipocortin I: suppresses phospholipase A2, which has a critical role in eicosanoid synthesis
mechanisms of immunosuppression by glucocorticoids
-activated glucocorticoid receptor (GR) binds to NFkB and prevents binding of NFkB to its response element
-transcription of cytokine genes are repressed
physiologic effects of glucocorticoids on the liver
-increase gluconeogensis
-increase glycogen storage
-increase blood glucose levels
physiologic effects of glucocorticoids in the muscle
-promotes protein degradation
-decrease protein synthesis
-decrease sensitivity to insulin
-increase blood glucose levels
physiological effects of glucocorticoids in the adipose tissues
-promote lipolysis
-decrease sensitivity to insulin
-increase blood glucose levels
physiologic effects of glucocorticoids in the immune system
-block the synthesis of cytokines (immunosuppression)
-inhibit the production of eicosanoids (anti-inflammation)
adrenal insufficiency
-hypoadrenalism
-decreased secretion of steroid hormones by the adrenal cortex
-cessation of long-term systemic glucocorticoid therapy can lead to addisonian symptoms
causes of adrenal insufficiency
-destruction of the cortex by tuberculorsis or atrophy (primary; addison’s disease)
-deceased secretion of adrenocorticotropin (ACTH) due to disease of anterior pituitary (secondary; no hypoalderosteronism)
symptoms of adrenal insufficiency
-extreme weakness
-anorexia, anemia, nausea, vomiting
-low blood pressure (only in primary)
-hyperpigmentation of the skin (only in primary)
-mental depression
primary adrenal insufficiency
-adrenal defect
-increase in CRH and ACTH
-decrease in cortisol and aldosterone
secondary adrenal insufficiency
-pituitary defect
-increase in CRH
-decrease in ACTH and cortisol
-aldosterone is not affected
tertiary adrenal insufficiency
-hypothalamic defect
-decrease in CRH, ACTH, and cortisol
-aldosterone is not affected
cushing disease
-hyperadrenalism
-long term therapeutic use of systemic glucocorticoids can lead to Cushing symptoms
cushing disease causes
-tumors in the adrenal cortex (adrenal cushing disease)
-increased production of ACTH due to pituitary carcinoma (pituitary cushing disease)
-ectopic production of ACTH due to non-pituitary carcinoma (ectopic cushing disease)
symptoms of cushing disease
-increased protein catabolism (easy bruising, delayed wound healing, muscle wasting) and increased glucose levels
-osteoporosis
-opportunistic infections
adrenal cushing disease
-decrease in CRH and ACTH
-decrease in cortisol
-pituitary cushing disease
-decrease in CRH
-increase in ACTH and cortisol
ectopic cushing disease
-decrease in CRH and ACTH
-increase in cortisol and ectopic ACTH
therapeutic uses of corticosteroids
-primary adrenal insufficiency (addisons diease)
-allergic reactions
-inflammation and autoimmune disease
-asthma
-immunosuppressive
-anti cancer
allergic reactions treated by corticosteroids
insect stings
angioedema
inflammation and autoimmune disease treated by corticosteroids
-Bursitis, synovitis, tendonitis
-Rheumatoid arthritis
-Systemic lupus erythematosus (SLE or lupus)
-Inflammatory bowel disease
-Chronic hepatitis
cortisol vs cortisone
-oxidation of 11 hydroxyl to ketone inactivated glucocorticoids
-cataylzed by 11 beta-hydroxysteroid dehydrogenase in the liver
-the reaction is reversible
*cortisone is as effective as cortisol, when used systemically
*cortisone should not be used to patients with impaired liver functions
short acting systemic corticosteroids
-half life in tissues = 8 – 12 hrs
-Hydrocortisone
-Cortison
intermediate-acting systemic corticosteroids
-half life in tissues= 12-36 hrs
-prednison
-prednisolone
-methylprednisolone
-triamcinolone
long acting systemic corticosteroid
-half life in tissues= 36-54 hrs
-dexamethasone
-betamethasone
synthetic glucocorticoids: fludrocortisone
-9 alpha-F
-greater glucocorticoid activity
-strong mineralocorticoid activity
(intense Na+ retention leading to edema)
-used in mineralocorticoid replacement therapy
synthetic glucocorticoids: prednisone/ prednisolone
-extra double bond between C1 and C2 (altered ring structure)
-more potent glucocorticoid activity (stronger binding to the glucocorticoid receptor)
-reduced mineralocorticoid activity
-interconvertible by 11 beta-hydroxysteroid dehydrogenase
synthetic glucocorticoids: methylprednisolone
-6 alpha-methyl group
-potency similar to that for prednisolone
-reduced mineralocorticoid activity
synthetic glucocorticoids: trimacinolone
-9 alpha-F and 16 alpha-OH
-glucocorticoid activity similar to prednisone
-reduced mineralocorticoid activity
-increased hydrophilicity
-low oral bioavailability
synthetic glucocorticoids: dexamethsone
-16 alpha-methyl group
-increased lipophilicity (increased receptor binding and significantly stronger effect)
-increased stability in human plasma
-reduced mineralocorticoid activity
synthetic glucocorticoids: bethamethasone
-Enantiomer of dexamethasone at 16
-Has similar properties as dexamethasone
21 esters
the hydroxyl group at 21 can be modified to an ester to control the property of glucocorticoid
-prodrugs activated through the hyrolysis by esterases
21 esters acetate and butyrate
-increased lipophilicity
-prolonged action upon IM or intra-articular injections
21 esters succinate
-soluble
-slow hydrolysis (peak in 30-45 min)
21 esters phosphate
-increased solubility
-rapid hydrolysis by phosphatases (10 min)
-IV or IM injection for emergency conditions
mechanisms of glucocorticoid action in asthma
-glucocorticoids do not directly relax airway smooth muscle; little effect on acute bronchoconstriction
-effective in inhibiting airway inflammation
-inhaled glucocorticoids are used prophylactically to control asthma
Glucocorticoids ______ stop an asthma attack while it is happening
will not
how does glucocorticoids inhibit airway inflammation
-Modulation of cytokine and chemokine production
-Inhibition of eicosanoid synthesis
-inhibition of accumulation of immune cells in lung tissue
-Decreased vascular permeability
how does Inhaled glucocorticoids are used prophylactically to control asthma
-Beneficial effects may be seen within 1 week; maximal improvement in lung function may not occur until after several weeks of treatment.
-Compliance is a significant concern
inhaled glucocorticoids: desired properties
-High potency
-Minimal systemic effects
-Prolonged action
inhaled glucocorticoids: solutions
-High lipophilicity
* Tighter binding to the receptor
*Better tissue penetration
*Prolonged action by forming poorly soluble microcrystals
-Low oral bioavailability
*70-90% of inhaled glucocorticoids is swallowed.
-Rapid clearance
*Short half-life
inhaled glucocorticoids: triamcinolone acetonide
-acetonide is resistant to hydrolyisis
-8x more potent than prednisolone
inhaled glucocorticoids: beclomethasone dipropionate
-converted rapidly to 12- monopropionate by hydrolysis
-14x more potent than dexamethsone
inhaled glucocorticoids: flucisolide
-rapid absorption from nasal or lung tissue
-rapid metabolism by the liver
*extensive first pass metabolism
*minimal systemic adverse effect with long term therapy
inhaled glucocorticoids: budesonide
-1:1 mixture of epimers at 16-17 butylactal
-faster topical uptake
-low oral bioavailability
-extensive first pass metabolism
inhaled glucocorticoids: mometasone furoate
-highly potent
-more rapid onset of action
-negligible systemic availability
*rapid metabolism
*low oral bioavailability <1%
inhaled glucocorticoids: fluticasone propionate
-inactivated by hydrolysis of thioester
*rapid first path metabolism
-highly lipophilic and insoluble
*high potent
*poor absorption from GI
* rapid topical uptake
topical glucocorticoids desired properties
-High lipophilicity for fast absorption
-Minimal systemic effect
-Prolonged action
topical glucocorticoids
-Halogenated analogues are usually potent topical glucocorticoids.
-Once absorbed through the skin, topical glucocorticoids are metabolized primarily
in the liver and excreted into the urine or in the bile.
-Glucocorticoids with low potency are safest for chronic application.
*Hydrocortisone cream
-Glucocorticoids with high potency can have a risk of systemic exposure; should be used only for a short duration of treatment.
topical glucocorticoids actonide or ester forms have ____
better potency for topical applications due to high lipophilicity
21 chlorocorticoids
-Substitution of a chlorine atom for the 21 hydroxyl group greatly enhances topical anti-inflammatory activity.
topical glucocorticoids fluticasone propionate and mometasone furoate have only _____ potency
-medium
-High lipophilicity and the highest binding affinity, but poor solubility
-Poor dissolution into inflamed tissue
adverse effects of glucocorticoids
-crossover mineralocorticoid activity
-metabolic effects (increased glucose production)
-cushing like effects (redistribution of fat)
-impaired glucose tolerance
-suppression of immune system
-gastrointestinal
-central nervous systems
-cataracts
-adrenal insufficiency upon withdrawal (addisons crisis)
adverse effects of glucocorticoids: cross over mineralocorticoids activity
-Sodium and water retention
-Development of hypertension
-Correctable with selective synthetic glucocorticoids
adverse effects of glucocorticoids; metabolic effects
-increased glucose production
-Steroid myopathy
*High doses over period of time cause wasting of proximal muscles (e.g. shoulder).
-Reduced long bone growth in children
*May cause premature closing of epiphyseal junction and stop growth.
-Osteoporosis
*Pharmacological doses of glucocorticoids inhibit osteoblasts.
*Can be prevented by bisphosphonate
adverse effects of glucocorticoids: cushing life effects
-redistribution of fate
-moon face
-buffalo bump
adverse effects of glucocorticoids: impaired glucose tolerance
-Hyperglycemia from gluconeogenesis
-Decreased insulin response
*A special problem with diabetes mellitus
*May unmask diabetes mellitus.
adverse effects of glucocorticoids: suppression of immune system
-Increased susceptibility to infections
-Impaired wound healing
adverse effects of glucocorticoids: gastrointestinal
-greater peptic ulcer risk
adverse effects of glucocorticoids: cental nervous system
-linked to glucose metabolism
-euphoria
-depression
adverse effects of glucocorticoids: adrenal insufficiency upon withdrawal
-addison crisis
-Due to negative feedback on hypothalamus and pituitary from prolonged pharmacological doses of glucocorticoids
-Delayed recovery of hypothalamus and pituitary
-Depressed ACTH release and adrenal response to ACTH
-Directly related to dose and duration of therapy
-Symptoms
*Inability to withstand stress
*Hypotension
*Weakness
systemic corticosteroids
-Hydrocortisone
-Cortisone
-Prednisone
-Prednisolone
-Methylprednisolone
-Dexamethasone
-Betamethasone
systemic mineralocorticoid
Fludrocortisone (Florinef®
inhaled glucocorticoids
-Triamcinolone acetonide (Azmacort®)
-Beclomethasone dipropionate (Vanceril ®, Qvar ®)
-Flunisolide (Aerobid ®)
-Budesonide (Pulmicort ®)
-Mometasone furoate (Asmanex®)
-Fluticasone propionate (Flovent ®
topical glucocorticoids
-Triamcinolone acetonide
-Fluocinonide
-Betamethasone valerate
-Clobestasol propionate
-Halobetasol propionate
-Halcinonide
