• mineralcorticoids- water, electrolyte balance
• glucocorticoids
  • main effects on carb and protein met.
  • at high levels, antiinflammatory effects
• androgens- androstenedione, dehydroepiandrosterone

• low antiinflammatory potency
• short duration of action
• very very low sodium retaining potency

• high antiinflammatory potency
• long duration of action
• no sodium retaining potency

• intermediate DOA
• moderate antiinflammatory potency
• very very low sodium retaining potency

• VERY HIGH sodium retaining potency (more than all the others)
• high antiinflammaotry potency
• intermediate DOA

mineralocorticoid of choice for replacement therapy (if they cant make aldosterone)

• stimulated by ACTH (except glomerulosa which responds to Ang II and potassium levels)
• zona glomerulosa- has aldosterone synthase enzyme
• zona fasiculata reticularais- 17 alpha hydroxylase and 11 beta hydroxylase to produce cortisol

• hypothalmus release CRH and stimulate corticotropes in ant. pit.
• ant. pit. release ACTH and stimulate adrenal cortex zona fasciculata cells
  • increase synthesis of P450 enzymes
  • increase synthesis of cortisol (negative feedback on hypothalamus and ant. pit.)
• cortisol will negatively feedback on immune system (lymphocytes, macrophages/ monocytes, neutrophils)
• the immune cells release IL-1, IL-2, IL-6, TNF alpha
• the cytokines will cause a positive feedback that stimulate CRH and ACTH release (positive feedback)
  • overrides the negative feedback of cortisol

• stress
• trauma
• surgery
• hypoglycemia
• hemorrhage
• severe infection
• cold
• pain
• fear

1. cortisol comes into the cell via diffusion binds to glucocorticoid R
   • Zn finger binding domains
   • resides in cytosol
2. SR complex dissociates
3. binds to GR protein, causing a confirmational shift in GR protein
4. the cortisol-GR complex moves into nucleus
5. binds to GRE (glucocorticoid response elements) on promoters of various genes
   1. stimulates expression of new proteins
      • lipocortin
      • IkB
   2. transrepression- collect corepressors to alter interactions with other proteins and TF's to inhibit protein expression
6. leads to altered cellular function

• mineralcorticoid receptor binds both glucocorticoid and aldosterone equally well
• however, mineralcorticoid sensitive tissues have 11 beta hydroxysteroid DH converts cortisol to cortisone
  • cortisone cant bind to mineralcorticoid receptor
• this allows aldosterone to be the only hormone influencing tha receptor in mineralcorticoid sensitive tissues

• carb and protein metabolism
  • main goal: maintain blood glucose levels
  • stimulates gluconeogenesis while promoting glycogen depostion
  • promotes protein breakdown, decreased glucose utilization by peripheral tissues (ex: muscle)- AA used as three C backbones by glucose
• lipid metabolism
  • permissive effects to facilitate other hormones such as epi, GH
  • results in increase in fFA's

• long term hypersec. of cortisol
• striae on trunk
• acne
• hirsutism
• leads to:
  • redistribution of body fat to face, back of neck (moon face)
  • loss of fat from extremeties

• CV system- HTN with prolonged high levels (sensitize muscle to effects of RAAS)
• skeletal muscle wasting with prolonged high levels

• excess- mood elevation, euphoria, insomnia, restlessness, increase motor activity
• insufficiency- anxiety, depression, psychosis

• single dose decrease circulating lymphocytes, eosinophils, monocytes, basophils due to redistribution
• prolonged administration leads to decreased lymphoid mass
• some lymphoid malignancies hypersensitive to glucocorticoids- massive apoptosis

• alter immune response to lymphocytes
• alter cytokine release and synthesis from macrophage and monoctyes
• decrease production of PG/LT products

Cant prevent/suppress underlying disease that cause inflammation, but they can suppress inflammation associated with multiple inciting events

• inhibits mobilization of AA
  • induces synthesis of lipocortin
  • lipocortin is an inhibitor of phospholipase A2
• inhibit synthesis of Cox2 such that PG metabolite production is decreased
• decreased cytokines (IL-1, IL-6, TNF alpha)
• decrease acute phase reactants
• decrease ELAM-1 and ICAM-1
• decrease histamine, LT's

PL A2 produces arachodonic acid

1. stimulation of phospholipase A
2. conversion of phospholipids to arachadonic acid via phospholipase A
3. two paths
   1. lipooxygenases created LT's
   2. cyclooxygenases (COX1 and COX2) produce PG's
      • COX 1- stimulated by physiologic stimuli
      • COX 2- stimulated by inflammatory conditions (contribute to pain, heat, swelling)

• produced by macrophages, lymphocytes, NK cells
• activates macrophages, neutrophils
  • increase epithelial permeability
  • increase proteinases, chemokines
  • increase IFN gamma
  • increase NFkB

• glucocorticoid receptor ligand complex increase IkB expression, leading to decrease in NFkB activation
  • decrease cytokine production
  • decrease IL-2 production (needed for cytotoxic T cells)
  • decrease chemotaxis for neutrophils and monocytes
  • decrease TNF alpha

• well absorbed
  • topical preparations
    • skin abraded and broken get good systemic absorption
    • otherwise poor
• liver metabolism
• excreted in urine as active metabolites
• half life of 60-90 minutes, but other analogs have longer half lives

• cessation of therapy (abrupt withdrawl)
  • adrenal has involuted and cannot produce hormone
• use of high doses
  • mimics Cushing's

• acute adrenal insufficiency (cant produce cortisol)
• HPA suppression after prolonged therapy with high doses (1-2 wks)
• rapid withdrawl symptoms
  • fever
  • myalgias
  • arthralgias
  • malaise
• revovery takes wks-months, even yrs
• solution- slowly taper dose

• HPA suppression
• HTN
• hyperglycemia
• increase susceptibility to infection
• osteoporosis, osteonecrosis
• myopathy
• cataracts
• behavioral disturbances
• growth suppression in kids
• Cushing's syndrome

• benefits- antiinflammatory, immunosuppressive
• dx- dexamethasonme for dx various causes of hypercorticism

• rheumatoid arthritis
• asthma
• allergic rhinitis
• ocular diseases
• IBD
• skin and spinal cord injury (protective)

• rheumatic carditis
• transplatnation
• some leukemias
• SLE
• nephrotic syndrome
• polyarteritis nodosa
• pemphigus