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81 Cards in this Set
- Front
- Back
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Where are the adrenal glands located?
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kidney
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What is the rate limiting step in cholesterol synthesis?
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HMG-CoA
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What is isoprenoid made of? What is squalene made of?
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mevalonate forms isoprenoid units
6 isoprenoid units form squalene |
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Name an intermediate between squalene and cholesterol
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lanosterol
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Describe the interplay between CRH, ACTH, and Cortisol
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CRH is secreted by the hypothalamus in response to stress
ACTH is released by the pituitary gland in response to CRH Cortisol is released from the adrenal gland in response to ACTH |
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What is released by the hypothalamus along with CRH?
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ADH
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What molecule doe ACTH come from?
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POMC
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What percentage of cortisol is protein bound?
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90%
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What role do the liver and kidney play in glucocorticoid activity?
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kidney inactivates cortisol to cortisone
liver inactivates cortisone to cortisol |
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Provide a basic basic basic MOA of cortisol
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enters the cell, changes the shape of the receptor which then regulates transcription and results in an altered cellular function
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List several metabolic effects of cortisol (glucocorticoids)
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increases blood glucose
increases muscle protein catabolism promotes growth hormone action on adipocytes peripherally lipogenesis in specific areas important permissive effects in the fetus decreases bone formation and osteoporesis peptic ulceration HTN central nervous system effects |
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Briefly list/describe the anti-inflammatory/immunosuppression effects of glucocorticoids on transcription
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decreases the expression of genes that ultimately produce inflammatory cytokines, chemokines, adhesion molecules, enzymes and receptors
increases gene expression of enzymes or receptor inhibitors that decrease the production or effects of inflammatory mediators |
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List the four classes of eicosanoids
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prostaglandins
prostacyclins leukotrienes thromboxanes |
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Which eicosanoids are responsible for vasoconstriction?
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PGF2a
TxA2 LTC4 LTD4 |
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Which eicosanoids are responsible for vasodilation?
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PGI2
PGE1 PGE2 PGD2 LTB4 |
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Which eicosanoids are responsible for chemotaxis?
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LTB4
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Which eicosanoids are responsible for increased vascular permeability?
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LTC4
LTD4 |
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Which eicosanoids are responsible for pain and hyperalgesia?
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PGE2
PGI2 LTB4 |
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Which eicosanoids are responsible for local heat and systemic fever?
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PGE2
PGI2 |
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When are COX-1 and COX-2 present?
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COX-1 is present in normal homeostasis
COX-2 is induced in inflammatoy cells by an inflammatory stimulus |
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What are a few main actions of prostanoids?
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contraction of the uterus
platelet aggregation and vasoconstriction smooth muscle contraction platelet aggreagtion inhibition fever hyperalgesia vasodilation |
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What are a few main actions of leukotrienes?
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bronchoconstriction
vasoconstriction decreased coronary blood flow decreased cardiac contractility plasma exudation |
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What are the main functions of lipoxins?
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modulate the action of leukotrienes and cytokines
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What cells produce PAF? What is required for stimulation?
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neutrophils, eosinophils, mast cells, basophils
PLA2 |
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What effect does cortisol have on immune cell distribution and function?
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decreased neutrophils and macrophages at site of inflammation
decrease in circulating T-lymphocytes, B cells, antibodies decrease in circulating monocytes |
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Describe primary adrenal insufficiency
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Addison's disease
adrenal cortex is selectively destroyed (usually a T cell autoimmune disease) decrease in the production of all classes of adrenocorticoids |
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Describe secondary adrenal insufficiency
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caused by hypothalmic or pituitary disorders or prolonged administration of exogenous glucocorticoids
results in a decrease in ACTH production |
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What is Cushing's syndrome?
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conditions with increased cortisol production
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What are the causes of Cushing's syndrome?
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ACTH secreting pituitary adenoma (Cushing's disease)
ectopic secretion of ACTH (small cell carcinoma of the lung) ectopic CRH secretion cortisol secreting adenoma or carcinoma of the adrenal cortex secondary to exogenous glucocorticoid treatment |
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What are the symptoms of glucocorticoid excess?
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think of moon man diagram
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What effect does a hydroxyl group at C11 have on steroid activity?
Carbonyl at same spot? |
glucocorticoid activity
no glucocorticoid activity |
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What effect does the following change have on steroid activity?
1-2 double bond |
increases glucocorticoid activity
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What effect does the following change have on steroid activity?
methyl group at C6 |
increases glucocorticoid activity
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What effect does the following change have on steroid activity?
methyl group at C16 |
increases glucocorticoid activity
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What effect does the following change have on steroid activity?
F at C9 |
increases glucocorticoid activity and greatly increases mineralocorticoid activity
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How can the mineralocorticoid effect of F at C9 be blunted?
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1-2 double bond
methyl at C16 |
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Describe the antiinflammatory potency, Na-retaining potency, and duration of action for the following agent:
cortisol |
1
1 S |
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Describe the antiinflammatory potency, Na-retaining potency, and duration of action for the following agent:
cortisone |
.8
.8 S |
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Describe the antiinflammatory potency, Na-retaining potency, and duration of action for the following agent:
fludrocortisone |
10
125 I |
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Describe the antiinflammatory potency, Na-retaining potency, and duration of action for the following agent:
prednisone |
4
.8 I |
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Describe the antiinflammatory potency, Na-retaining potency, and duration of action for the following agent:
prednisolone |
4
.8 I |
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Describe the antiinflammatory potency, Na-retaining potency, and duration of action for the following agent:
methylprednisolone |
5
.5 I |
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Describe the antiinflammatory potency, Na-retaining potency, and duration of action for the following agent:
triamcinolone |
5
0 I |
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Describe the antiinflammatory potency, Na-retaining potency, and duration of action for the following agent:
betamethasone |
25
0 L |
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Describe the antiinflammatory potency, Na-retaining potency, and duration of action for the following agent:
Dexamethasone |
25
0 L |
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What four factors alter the duration of action a steroid?
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fraction of drug bound to plasma proteins (higher binding has longer duration)
affinity for 11beta-HSDII (lower affiniity means longer duration) lipophilicity (increased lipophilicity means longer duration) affinity for the glucocorticoid receptor (higher affinity means increased duration) |
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What are the benefits of inhaling glucocorticoids?
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deliver high concentrations of potent glucocorticoids directly to the epithelium of the lung
lower systemic concentrations and fewer side effects |
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What are the benefits of using cutaneous glucocorticoids?
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for dermatologic applications
low systemic concentration high local concentration |
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What are the benefits of using a depot glucocorticoid?
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approach is used primarily for intra-articular (joint administration)
methylprednisolone in PEG is used active drug form is required |
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Describe the use of glucocorticoids in pregnancy
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mother can be given prednisone without fetal side effects b/c the mother's liver converts prednisone to prednisolone and the placental 11beta-HSDII converts prednisolone back to prednisone which the fetal liver cannot convert
dexamethasone or betamethasone can be given to promote fetal lung maturation |
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What is the treatment for primary adrenal insufficiency?
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daily administration of oral hydrocortisone in divided doses
mineralocorticoid is often required also |
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What is the treatment for secondary adrenal insufficiency?
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daily administration of oral hydrocortisone in divided doses
mineralocorticoid is often required also |
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What glucocorticoids are used for rheumatoid disorders?
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prednisone, methylprednisolone
triamcinolone |
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What glucocorticoids are used for allergic diseases?
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methylprednisolone
various others |
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What glucocorticoids are used for asthma?
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methylprednisolone
prednisone various inhaled forms |
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What glucocorticoids are used for fetal lung maturation?
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dexamethasone
betamethasone |
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What glucocorticoids are used for ocular disease?
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dexamethasone
prednisone |
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What glucocorticoids are used for skin diseases?
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hydrocortisone
prednisone |
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What glucocorticoids are used for GI diseases?
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prednisone or budesonide
hydrocortisone ENEMA!!!! |
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What glucocorticoids are used for hepatic disease?
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prednisone
prednisolone |
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What glucocorticoids are used for organ transplantation?
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prednisone
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What glucocorticoids are used for spinal cord injury?
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methylprednisolone
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Mitotane, class
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inhibitor of adrenocortical hormone synthesis
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Aminoglutethimide, class
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inhibitor of adrenocortical hormone synthesis
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ketoconazole, class
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inhibitor of adrenocortical hormone synthesis
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metyrapone, class
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inhibitor of adrenocortical hormone synthesis
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What is the MOA of mitotane?
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unknown but selectively kills adrenocortical cells
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What are the therapeutic uses of mitotane?
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palliation of inoperable adrenocortical carcinoma
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What are the adverse effects of mitotane?
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anorexia, nausea, somnolence, lethargy, dermatitis
must give adrenocorticosteroids because of the cell killing |
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What is the MOA of aminoglutethimide?
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primary inhibits CYP11A1 so all adrenosteroids are reduced
also inhibits CYP11B1 and aromatase |
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What are the therapeutic uses of aminoglutethimide?
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Cushing's syndrome from adrenal tumors/ectopic ACTH secretion
hormonally responsive tumors |
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What are the adverse effects of aminoglutethimide?
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rash, GI effects, neurological effects
glucocorticoid replacement is necessary |
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What is the MOA of ketoconazole?
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inhibits CYP17 and 11A1
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What are the therapeutic uses of ketoconazole?
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most effective drug for Cushing's disease
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What are the adverse effects of ketoconazole?
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hepatic dysfunction, serious drug interactions that need to be studied
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What is the MOA of metyrapone?
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inhibitor of 11B1
cortisol synthesis decreased and ACTH levels are increased cortisol precursor 11-deoxycortisol is increased aldosterone is decreased but 11-deoxycortisol substitutes for its activity |
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What are the adverse effects of metyrapone?
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HA, nausea, sedation, rash, hirsutism
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What do the results of a metyrapone test indicate?
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normal response on HPA axis=pituitary dependent Cushing's syndrome
no change in ACTH or 11-deoxycortisol=ectopic ACTH secretion |
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Mifepristone, class
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glucocorticoid receptor antagoinst
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What is the MOA of mifepristone?
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pregesterone receptor antagonist at low concentrations
glucocorticoid receptor antagoinst at thigher concentrations |
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What are the potential uses of mifepristone?
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treatment of life-threatening glucocorticoid levels in ectopic ACTH syndromem
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