Pharm 3 Gluc

Front 1

GLUCOCORTICOIDS

Front 3

how does cortisol increase fight or flight response (2)?

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1) increase epinephrine synthesis; 2) increase sensitivity of tissues to catecholamines

Front 4

what four problems will sustained increase in glucocorticoids cause?

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1) diabetes (from counter-regulation of glucose); 2) CV effects; 3) osteoporosis; 4) (increased bone resorption, decreased Ca++ absorption)

Front 5

what is a synthetic CRH, and what is it used for clinically?

Back 5

cosyntropin, a synthetic CRH, is used to diagnose Cushing's disease

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in what pattern is GC synthesis secreted?

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diurnal

Front 7

what enzymes mediate the direct genomic effects of GC action (3)?

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1) tyrosine aminotransferase (AA degradation); 2) phosphoenolpyruvate carboxykinase; 3) G-6-Phosphatase - last two involved in gluconeogenesis - dysregulation leads to diabetes

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how do indirect genomic effects work?

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GR binds to DNA binding proteins like NFkB and inhibits their ability to upregulate genes

Front 9

what type of genes are downregulated?

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those that stimulate inflammatory response - cytokines like IL-8, 12, and TNF-a

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what are indirect genomic effects initiated by, and what are they important for?

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interactions with membrane bound or cytoplasmic GRs, or interactions with cell membrane - important for eliciting changes in vascular tone

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what actions occur first, genomic or nongenomic?

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nongenomic - they occur very fast

Front 12

what is the treatment for glucocorticoids increasing bone loss through interference with Ca++ uptake and vitamin D actions, in adults?

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administration of oral bisphosphonate, Ca++, vitamin D

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what hormones do GCs inhibit production of, that relate to growth and development?

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sex steroids

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what do excessive amounts of GCs or MCs do to muscle/skeleton?

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can impair muscle, and cause skeletal wasting

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why can large GC doses lead to ulcers?

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suppress immune response against H. pylori

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what is normal treatment for glucocorticoid insufficiency?

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hydrocortisone

Front 17

what is added if it is Addison's (both inner and outer zone destroyed)?

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hydrocortisone + fludrocortisone

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what drugs (3) can pharmacologically reduce cortisol synthesis (3)?

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1) ketoconazole; 2) aminogluthemide; 3) metapyrone

Front 20

GLUCOCORTICOIDS AND INNATE IMMUNE RESPONSE

Front 22

how do glucocorticoids affect cell trafficking and adhesion molecules in innate immune response?

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alter bone marrow release and infiltration and clearance of leukocytes, decrease expression of adhesion molecules, decrease chemokine release at inflammation site

Front 23

in what disease do glucocorticoids prevent inflammatory response from overshooting?

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meningitis

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what cells do they promote survival and proliferation of, and what cells do they induce apoptosis of (innate IR)?

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promote survival of neutrophils, induce apoptosis of eosinophils

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in what case are glucocorticoids used to prevent inflammatory response from overshooting, and how does this work on phagocytes?

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enhance clearance of foreign antigens, toxins, microbes, enhance opsonization, stimulate macrophages to phagocytose

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how does this affect cytokines?

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increase antiinflammatory, decrease proinflammatory

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how do glucocorticoids affect biochemical mediators of inflammation?

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block release of arachadonic acid and thus formation of prostaglandins, thromboxanes, and leukotrienes, decrease NO release, decrease formation of free radicals

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ADAPTIVE/CELLULAR/HUMORAL IMMUNE RESPONSE

Front 31

formation of what particular cell is blocked that may lead to cellular immunodeficiency?

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Th1 helper T cell

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how are dendritic cells affected?

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can't present antigens as well or mature as well

Front 33

formation of what cell is increased by glucocorticoids, and what is the result?

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Th2 helper cell - stimulates humoral immune response and increased antibody formation

Front 34

what may be the underlying mechanism of steroid resistant asthma and ulcerative colitis?

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administration of GCs will increase IgE levels

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what do glucocorticoids do to B cells and why is this useful?

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inhibit proliferation and development, useful for leukemia

Front 36

how else do glucocorticoids relate to IgE secretion?

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prevent the release of IgE-R mediated release of inflammatory mediators, and also deplete tissue mucosal mast cells

Front 37

what AE can glucocorticoids cause in the eye?

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cataracts

Front 38

what is a recently developed drug in glucocorticoid therapy, how does it function, what is it used for, and what are its advantages?

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ZK 216348 - binds GR with high affinity, represses inflammatory response, and does not appear to induce side effects such as thinning of skin and increased glucose

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GLUCOCORTICOID DRUGS AND TREATMENTS

Front 42

how is dose usually determined in glucocorticoid treatment?

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trial and error

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what can happen after abrupt cessation after long term use?

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adrenal insufficiency (may be fatal)

Front 44

what is alternate dose therapy and when is it used?

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GC may suppress allergic phenomena when given every 48 hours, whereas pituitary suppression is shorter lived

Front 45

what iGC is used for asthma and why?

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flucitasone, because it is highly metabolized

Front 46

what is an example of a GC given intravenously?

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hydrocortisone Na++ succinate

Front 47

what is a long acting type of GC?

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intraarticular injection of crystalline, insoluble GC

Front 48

what are the features of pulmonary and dermal administration both (2)?

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high potency, limited systemic effect

Front 49

what drug regimen with GCs is most effective for asthma?

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inhaled GC coadministered with inhaled beta-2 agonists

Front 50

what were said not to be considered significant risks for children (4)?

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decreased growth, decreased bone mineral density, suppressed adrenal glands, cataracts (but height of children should be monitored)

Front 51

what drugs must we know are sued for asthma (2)?

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1) beclomethasone; 2) flucitasone

Front 52

what drugs are used for allergic rhinitis (2), how are they given, and which has higher potency?

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given as nasal spray - 1) beclomethasone (high potency); 2) triamcinolone (medium potency)

Front 53

what are pros and cons of treating allergic rhinitis with GCs?

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broad relief of symptoms, low systemic absorption, but adverse effects

Front 54

what drugs are typically given topically for eczema and psoriasis (2)?

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1) hydrocortisone; 2) betamethasone

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what drug is given as an intralesional injection?

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triamcinolone acetonide

Front 56

what is done for acute eczematous reaction such as poison oak?

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systemic therapy with prednisone, tapered over 21 days

Front 57

what is the goal of GC therapy for MS?

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ameliorate suffering during attacks (6 weeks)

Front 58

what GC drugs are given for MS and how is each administered (2)?

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1) prednisone oral tapering course; 2) methylprednisone IV for 3-5 days

Front 59

what drugs are given for allograft rejection (2)?

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prednisone, methylprednisone

Front 60

what drug is typically given for rheumatic diseases, and what other drugs are used with it (non GC - 2)?

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prednisolone - also NSAID and disease modifying drug

Front 61

what happens to the GC, eventually, and over how long?

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weaning, over as much as two years

Front 62

what type of therapy is often given for RA with methylprednisone?

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pulse therapy IV ofer 3-7 days

Front 63

what GC drug is given as a joint injection for RA?

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triamcinolone acetonide

Front 64

what are GCs able to do for RA?

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decrease pain/disability/inflammation in first year but not sure about long term efficacy, does not alter structural damage

Front 65

what are side effects of treating RA with GCs (2)?

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1) osteoporosis; 2) ulcers

Front 66

in what case are GCs used in Crohn's disease, what drug is used, and why?

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in patients who do not respond to conservative management - oral budesonide is used because it is better tolerated and more effective than prednisolone

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what should be remembered about pharmacokinetics of oral budesonide?

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11% bioavailability because it dissolves in ileum and ascending colon due to pH

Front 68

what malignancy are GCs particularly used for (to induce apoptosis), and what GCs are used (3)?

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lymphoid malignancies, namely ALL - drugs used: 1) prednisone; 2) methylprednisone; 3) dexamethasone

Front 69

how else is it useful in cancer (2)?

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potentiates effeccts of other cytotoxic agents (prednisone/vincristine/doxorubicin/cyclophosphamide for non-Hodgkin's), also treats complications associated with cancer (cerebral edema, pain)

Front 70

what GC drug regimen is used in tuberculous meningitis?

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prednisone for first month

Front 71

what drug is a mineralocorticoid receptor antagonist, and what does it do?

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spironolactone - reduces the expression of gene controlling synthesis of Na/K ATPase

Front 72

what drug is an antagonist of glucocorticoid receptors, and what is it used for (2)?

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RU 486 (Mifepristone) - used in: 1) Cushing's; 2) abortion

Front 73

what drug inhibits the initial and rate-limiting step in the biosynthesis of all physiological steroids?

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aminogluthemide

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what is it used for (in conjunction with other drugs)?

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to treat steroid producing adrenocortical tumor

Front 75

what drug inhibits the terminal step in GC synthesis (11-B hydroxylase) and what is this drug used for?

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metyrapone - used in diagnostic test of adrenal function

Front 76

what drug can block all teroidogenesis and can be used for hirsutism, adrenal carcinomas, and breast cancer?

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ketoconazole

Front 77

in what diseases is glucocorticoid resistance the most problematic (2)?

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asthma, ALL (5% of patients have no response to 7 day therapy with prednisone)

Front 78

what are three new therapeutic develpments with GCs?

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1) develop drugs with transrepression >> transactivation (flucitasone pripionate, RU486, other RU's); 2) develop drugs that specifically inhibit NFkB or TNF (i.e. infliximab for RA); 3) develop retinoic acid derivatives (synergistic actions between RXR and GR)

Front 80

MINERALOCORTICOIDS

Front 82

what genes are directly regulated by aldosterone (2)?

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1) CHIF - challen inducing factor; 2) epithelial sodium channel subunits

Front 83

what were said to directly regulate the Na/K ATPase genes?

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glucocorticoids such as dexamethasone

Front 84

how strongly does aldosterone activate the MR compared to cortisol?

Back 84

equal affinity

Front 85

how do MR and GR compare as far as their ability to activate gene transcription via hormone response element?

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stimulate it equvalently

Front 86

how is specificity gained?

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by location of MR and GR

Front 87

where is the GR located, and where is the MR (5)?

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GR - all cells; MR - kidney, gut, sweat glands, brain, and vascular smooth muscle

Front 88

how else do they differ?

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differential transcriptional activation

Front 89

what key enzyme is expressed only in some mineralocorticoid responsive tissues?

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11B-hydroxysteroid dehydrogenase type 2 (11B-HSD)

Front 90

what are the two main strategies for treating mineralocorticoid excess, and what drug(s) is used for each?

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1) antagonize mineralocorticoid receptor (spironolactone); 2) antagonize Na+ exchange in distal nephrone (amiloride, triamterene)

Front 91

what happens when there is high concentrations of spironolactone?

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inhibits androgen receptor

Front 92

what other problems may spironolactone cuase (2)?

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1) hyperchloremic acidosis; 2) hypokalemia

Front 93

how is mineralocorticoid deficiency treated, and what is the affinity of this drug for MR and GR?

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flucortisone - 10x affinity for MR compared to GR

Front 94

what are side effects of flucortisone, and what should be monitored?

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hypertension, hypokalemia - monitor BP and renin activity

Front 95

what is the treatment for CAH (21-hydroxylase or 17-hydroxyprogesterone deficiency) (2)?

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1) fludrocortisone; 2) hydrocortisone (GC)

Front 96

what is the treatment for primary aldosteronism?

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unilateral adrenalectomy

Front 97

what is the treatment for pseudohypoaldosteronism (a rare form of mineralocorticoid resistance that presents as neonatal renal salt wasting, caused by mutations in mineralocorticoid receptor)?

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sodium supplementation

Front 98

what is the treatment for apparent mineralocorticoid excess (3)?

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1) amiloride and/or spironolactone; 2) antihypertensive; 3) KCl supplements

Front 99

what mutation can cause pregnancy induced hypertension, and why?

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missense mutation (L810) in ligand binding domain of MR allows a number of steroids to act as MR agonists

Front 100

what else can act as an agonist, and what does it cause?

Back 100

spironolactone can act as an agonist, and allow constitutive activity of MR

Front 101

what MR antagonist is more preferred than spironolactone, and why?

Back 101

eplenerone - it is more selective (but has lower affinity for MR)

Front 102

what are the three high potency GC agonists?

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1) beclomethasone; 2) betamethasone; 3) dexamethasone

Front 103

what are the three mid potency GC agonists?

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1) methylprednisone; 2) prednisolone; 3) prednisone

Front 104

what are three inhibitors of cortisol synthesis?

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1) metyrapone; 2) ketoconazole; 3) aminoglutethimide

Front 105

what MR agonist must we know?

Back 105

fludrocortisone

Front 106

what MR antagonists must we know (2)?

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1) spironolactone; 2) eplenerone