Adrenal Corticosteroids Drugs DSA Flashcards
adrenal corticoid drugs
- mineralocorticoids
- glucocorticoids
Mineralocorticoids- drug
-Fludrocortisone
Glucocorticoids- short to medium acting (<12 h)
- hydrocortisone
- cortisone
- prednisone
- prednisolone
- methylprednisolone
Glucocorticoids- intermediate acting (12-36 hrs)
-triamcinolone
Glucocorticoids- long acting (>36 hrs)
- betamethasone
- dexamethasone
Inhibitors of adrenal corticosteroid action
- steroid syn inhibitors
- glucocorticoid antagonists
- aldosterone antagonists
steroid syn inhibitors- drugs
-aminoglutethimide
-ketoconazole
-metyrapone
-mitotane
(AKMM)
glucocorticoid antagonists- drugs
-mifepristone
aldosterone antagonists- drugs
- spironolactone
- eplerenone
mineralocorticoids- induced by? regulate?
- Ang II and K
- reg electrolyte, H2O balance and BP
Glucocorticoids- induced by? regulate?
- ACTH
- reg metabolism and immunity
weak androgens- converted into?
- potent androgens in males
- estrogens in females
adrenal corticosteroids- pharmacokinetics- transporters
- hydrophobic- transported by protein carriers
- transcortin (corticosteroid binding globulin- CBG)- high affinity, low capacity transporter- high during pregnancy and hyperthyroidism; low in liver dz
- 90% of blood cortisol, 60% of blood aldosterone
- remainder bound to albumin (low affinity/high capacity)
- albumin- main carrier for synthetic corticosteroid drugs
- plasma cortisol > 20-30- transcortin is saturated
adrenal corticosteroids- pharmacokinetics- liver
- liver produces transcortin
- 80% of cortisol is metabolized by liver
adrenal corticosteroids- t1/2 of cortisol
- 60-90 min
- inc in liver dz, hypothyroidism
adrenal corticosteroids- moa
- ligands at nuclear R’s- TF’s (ligand act) that modulate gene expression
- corticosteroids produce their effects after a lag period
mineralocorticoid effects- target cell types
principal cells of CT and CD of kidney and other epit cells involved in electrolyte transport:
- inc epit Na channel (EnaC)
- inc Na/K pump
- retention of water and Na, loss of K
Direct effects of mineralocorticoids on CV system
-target non-epit tissues of heart and vasculature
Gene expression effects:
-NADPH reductase- ox stress
-collagen, TGFB- fibrosis, cell senescence
-IL-6, cell adhesion molecules- infl
-PAI-1- inhibition of fibrinolysis, blood clotting
Excess aldosterone causes:
-cardiac fibrosis and hypertrophy
-vascular remodeling and infl
glucocorticoid effects- 2 mechanisms
- transactivation- GR-ligand complex binds to GRE in gene promoters to act gene expression- effects on carb, lipid, protein metabolism
- transrepression- GR-ligand complex binds to other TF complexes to suppress their act of gene transcription- NF-KB, AP-1 TF’s; anti infl, immunosuppressive, anti-growth effects
glucocorticoid R isoforms
- GRalpha- prototypical isoform
- GRbeta- doesnt bind ligands, inactiv- induced by TNF-alpha
role of 11B-hydroxysteroid dehydrogenase (11B-HSD) in adrenal corticosteroid action
- aldosterone and cortisol bind the MR with equal affinity
- daily prod rates are predominantly corticosteroids
- 11B-HSD converts cortisol into inactive at MR coritsone- making tissues mineralocorticoid responsive
- dec 11B-HSD activity- results in excessive act of MR mediated by cortisol!!
inhibition of 11B-HSD- causes what?
- inc act of MR by cortisol- causes HTN and edema
- Glycyrrhizin (in licorice) and carbenoxolone inhibits this enzyme
- inact mutations- cause AME (mineralocorticoid excess syndrome)- leads to HTN
Glucocorticoids- metabolic effects- carbohydrates
- inc gluconeogenesis
- inc glucose output into circulation (inc G6P)
- inc glycogen syn (inc glycogen synthase)
- dec glucose uptake by m and adipose tissues (dec GLUT4)
- development of hyperglycemia!!
Glucocorticoids- metabolic effects- lipids
- inc lipolysis- stim of hormone-sensitive lipase in adipose tissue
- inc mobilization of free fa and glycerol into the gluconeogenic pathway
- inc lipogenesis- inc insulin secretion
- net inc in fat deposition!!!
- fat accum in upper body!! thinning arms and legs
Glucocorticoids- metabolic effects- proteins
- dec aa uptake into cells
- dec prot syn
- mobilization of aa’s into gluconeogenic pathway
- skeletal m- suppressed prot syn- myopathy and m wasting
Glucocorticoids- effects on intermediary metabolism antagonize actions of insulin
- favor lipid and prot breakdown to supply substrates for gluconeogenesis
- interference with insulin R signal transduction
Glucocorticoids- effects on immune system and infl
(due to transrepression of NF-kB and AP-1 effects)
- dec PLA2 and COX2- dec prod of prostaglandins and leukotrienes
- dec prod and inc apoptosis of immune cell types
- dec prod of cytokines and their R’s
- dec expression of cell adhesion molecules
- dec transmigration of neutrophils and macrophages from blood into tissues
Glucocorticoids- effects on immune system and infl- consequences
- dec infl
- immune suppression
- dec allergic/hypersensitivity rxns
glucocorticoids effects on other systems- CV
- inc prod of Epi and NE
- inc R sensitivity to Epi and NE
- residual mineralocorticoid activity of glucocorticoids
- dec in capillary permeability
- inc HR and CO
- elevated BP
glucocorticoids effects on other systems- GI
- dec prod of gastro-protective prostaglandins
- dec immune response against H pylori
- inc in gastric acid and pepsin secretion
glucocorticoids effects on other systems- CNS
- insomnia
- irritability
- euphoria, followed by depression
- dec sexual libido in males
glucocorticoids effects on other systems- bone/growth
- dec activity in osteoblasts
- dec intestinal and renal Ca absorption
- inc in osteoclast activity
- growth retardation in children
- osteoporosis, bone fractures
glucocorticoids effects on other systems- skin
- dec collagen syn
- dec fibroblast prolif
- dec wound healing, inc bruising
- fragile and skin thin with stretch marks (called striae)
common clinical indications of adrenal corticosteroid drugs
- replacement therapy
- immunosuppression
- infl and allergic conditions
common clinical indications of adrenal corticosteroid drugs- replacement therapy
- adrenal insuff (Addison’s dz)- glucocorticoid and a mineralocorticoid used!
- congenital adrenal hyperplasia
common clinical indications of adrenal corticosteroid drugs- immunosupression
- after organ or HSC transplantation
- autoimmune dz
- hematological cancers
common clinical indications of adrenal corticosteroid drugs- infl and allergic conditions
- rheumatoid arthritis
- IBD
- asthma and COPD
- allergic rhinitis
- skin dizes- infl dermatoses (psoriasis)
- hypersensitivity rxns
mineralocorticoids- adverse effects
- retention of Na and H2O- edema
- HTN
- inc preload and cardiac enlargement- CHF
- K loss and alkalosis
glucocorticoids- adverse effects
- suppressed ability to fight infections- opportunistic infections!
- hyperglycemia
- skin- striae, easy bruising
- m wasting, steroid myopathy
- HTN
- steroid-induced glaucoma
- cataracts
- peptic ulcers
- psychiatric disorders- euphoria, mania, anxiety
- inc appetite and weight gain
- osteoporosis
- retarded growth in children
adrenal corticosteroid drugs- dosing
- use lowest dose for shortest duration possible!!
- reduce distribution of drugs into systemic circulation (use topical, inhalational routes)
- give single daily doses in morning
- alternate day, short-course, pulse therapy admin
- dose tapering
pt populations in which systemic glucocorticoids admin is problematic
- immunocompromised pts
- diabetics
- infections
- peptic ulcer
- CV conditions- HTN, CHF, angina
- psychiatric conditions
- osteoporosis
- children
Aminoglutethimide- moa, indications, SE’s
- blocks conversion of chol to pregnenolone
- reduces prod of all steroid H’s
- indications- was used for breast cancer tx, adrenocortical cancer
- drowsiness, GI upset
inhibitors of adrenal corticoid action- drugs
- aminoglutethimide
- ketoconazole
- metyrapone
- mitotane
- mifepristone
- spironolactone
- eplerenone
Ketoconazole- moa, indications, SE’s
- P450 inhibition
- reduces syn of adrenal and sex H’s
- antifungal drug, Cushing’s syndrome, suppresses androgenic hair loss, prostate cancer
- SE’s- hepatotoxicity, gynecomastia in males
Metyrapone- moa, indications, SE’s
- inhibition of steroid 11-hydroxylation
- suppresses formation of cortisol and corticosterone
- Cushing’s syndrome! (can be used in pregnant woman!!)
- accum of 11-deoxycortisol- inc aldosterone- Na and H2O retention; inc androgens- hirsutism in women
- GI upset
- dizziness
Mitotane- moa, indications, SE’s
- Na ionofore, Ca ionofore
- PKC and AC inhibitor
- non-selective cytotoxic action of adrenal cortex
- used for adrenal carcinoma!!
- depression, GI upset, rashes
Mifepristone- moa, indications, SE’s
- glucocorticoid R antagonists
- prevents nuclear translocation of GR
- progesterone R antagonist
- Hypercortisolism in pts with cushing’s syndrome
- medical termination of intrauterine pregnancy (anti-progesterone action)
- dizziness, GI upset, fatigue
Spironolactone- moa, indications, SE’s
- aldosterone R antagonist
- also antagonist at androgen R’s
- primary hyperaldosteronism, hirsutism in women, diuretic (tx HF and HTN)
- hyperkalemia, gynecomastia and impotence in men, menstrual abnormalities in women
Eplerenone- moa, indications, SE’s
- antagonist of aldosterone at mineralocorticoid Rs
- lower affinity for androgen Rs vs spironolactone
- used for HTN, HF (reduces cardiac remodeling)
- SEs- hyperkalemia
