Term
| Signs of Cushing's syndrome |
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Definition
- weight gain- face (moon face), and on back of neck (buffalo hump)
-very pronounced stretch marks
-easy bruising
-generalized weakness and fatigue
-wasting of musculature
-menstrual disorders in women (amenorrhea)
-decreased fertility and/or sex drive
-hypertension
-diabetes mellitus |
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Term
| Causes of Cushing's syndrome |
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Definition
-endogenous Cushing's syndrome: pituitary misfunction (tumor) 65%, ectopic ACTH secretion (20%), adrenocorticoid cancer (15%)
-therapeutically-induced Cushing's syndrome: long-term systemic corticoid therapy |
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Term
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Definition
| cortex dystrophy-->hypocorticoidism-->Addison's disease-->Hypotension, hypoglycemia, muscle weakness and fatigue, weight loss/low appetite, muscle/joint pain, abnormal pigmentation, addisonian crisis |
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Term
| challenges to GC drug development- key drug sensitivity issues (desired GC effect: anti-inflammatory) |
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Definition
-excess MC action: Na+ rentention-hypertension
-other cushing's syndrome effects: hyperglycemia, hypocalcemia, fat redistribution, CNS effects
-addisionian crisis upon withdrawal |
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Term
| challenges to GC drug development - how to address therapeutic issues |
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Definition
1. enhance GC/MC selectivity (and GC activity)
2. enhance anti-inflammatory/hyperglycemia selectivity
3. selective delivery (topical/inhaled/intranasal)
4. optimize dosage delivery (key pharmaceutical care issue) |
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Term
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Definition
4,5-double bond required for GC activity
C3 ketone required to GC activity
11-beta hydroxyl required to GC activity
C17 hydroxyl required to GC activity |
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Term
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Definition
4,5-double bond required for MC activity
C3 ketone required to MC activity
11-beta hydroxyl less important MC activity
C17 hydroxyl not required for MC activity |
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Term
| modulation of MR/GR selectivity |
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Definition
-17a hydroxy gives optimal glucocorticoid activity
-1,2-double bond (prenisolone) increases glucocorticoid activity, resulting in enhanced GC to MC potency ratio; compounds are also metabolized more slowly
-9a-F (fludrocortisone) enhances both GC and MC activity
-16-substituent attenuates MC action
-combination of 1,2-dounle bond, substitution at 16, and 9a-fluoro (dexamethasone, betamethasone) marked glucocorticoid activity and virtually no mineralocorticoid action |
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Term
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Definition
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Term
| intermediate acting (GC/MC=5) |
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Definition
-prednisolone
-prednisone
-triamcinolone
-methylprednisolone |
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Term
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Definition
-dexamethasone
-betamethasone |
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Term
| reverse selectivity (GC/MC=0.003) |
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Definition
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Term
| delivery issues- systemic |
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Definition
-steroids can be delivered orally, IM, or IV
-many steroids re administered as ester derivatives
-allows modulation of solubility and release |
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Term
| delivery issues- inhaled and intranasal |
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Definition
-want very potent action with rapid clearance to prevent systemic effects
-compounds can be more lipophilic (tighter binding to receptor) |
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Term
| topical corticosteroids- challenges in topical application |
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Definition
-usually wish long duration of action
-no desire for systemic effects |
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Term
| topical corticosteroids- 3 levels of activity and use |
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Definition
-low level (hydrocortisone acetate) chronic application
-intermediate level (fluticasone proprionate, betamethasone diproprionate) short term treatment of moderate dermatoses
-high potency (clobetasol proprionate) very short term treatment of severe dermatoses |
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Term
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Definition
-would be good as antihypertensive (due to regulation of water balance in kidney). perhaps useful at blocking heart damage after heart attacks
-difficulty: cross reactivity with other nuclear receptors
-spironolactone (Aldactone)- potassium sparing diuretic agent, some use as antihypertensive agent, difficulty with antiprogestin and antiandrogen effects
-eplerenone (Inspra): selective for only mineralocorticoid receptor, newer agent used to treat hypertension, can't be used in connection with any diuretic that causes increases in potassium levels (hyperkalemia) |
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