Glucocorticoids
- Remember that the11-OH is required for activity
- All glucocorticoids are excreted completely in the urine (no biliary or fecal)
Anti-inflammatory Effects of Glucocorticoids
- effective against ALL FORMS of inflammation
- Requires HIGH DOSES
- Mechanisms
1) induce synthesis of lipocortin which in turn inhibits phospholipase A2
- this inhibits the release of arachidonic acid from the plasma membrane
- inhibition of the production of PGs, PCs, TBX, Leukotrienes, and HETEs
2) also inhibit COX
- Effects of this mechanism
1) inhibition of migration of WBCs to site of tissue damage
2) reduction of “stickiness” of granulocytes to the damaged vascular endothelium
3) inhibition of fibroblast cell activity
General Major Effects of Glucorticoids
Ý gluconeogenesis
Ý glycogen synthesis
ß glucose uptake by cells
Ý lipolysis
ß protein synthesis
Ý proteolysis
ß growth
Ý lympholytic
Ý Anti-inflammatory
Drugs and their 11-hydroxy (OH) Status
Don’t have the 11-OH – need the liver
Cortisone – short acting
Prednisone – intermediate actind
Got the 11-OH – active
Hydrocortisone
Prednisolone – intermediate acting
Dexamethasone – long acting
General Pharmacological Properties of GCs
- metabolism
Ø most excreted unchanged in the urine
- Activation
Ø 11-OH required for activity
Ø if it doesn’t have it, 11 dehydrogenase activity takes place in the liver (opposite of Vitamin D activation with hydroxylation, whose last step occurs in the kidney)
Ø DON’T GIVE those w/o the 11-OH to someone with liver disease
- Plasma protein binding
Ø low or absent
- Side effects
1) Na retention (due to mineralcorticoid activity) – usually occurs with the natural GCs
2) Increased acid secretion in the stomach
3) Antagonism of effects of vitamin D on calcium absorption
- inhibit calcium absorption by the intestine —- increased PTH secretion
- PTH stimulates osteoclast activity
- GCs inhibit osteoblast activity
- GCs increase calcium excretion by the kidney
Diseases and Glucocorticoids for Replacement therapy
- Adrenal insufficiencies
Ø 1o = adrenal deficiency = Addison’s disease
- Symptoms
- fatigue, muscle weakness, hypoTN, hypoglycemia, anorexia, GI disturbances, weight loss, hyponatremia, hyperkalemia, skin pigmentation
Ø 2o = deficiency of pituitary ACTH
- can be iatrogenic (abrupt withdrawal of glucocorticoids)
- Adrenal Excesses
Ø 1o – at level of adrenal
Ø 2o – Cushing’s syndrome
- symptoms
- increased appetite, obesity, lipid redistribution, steroid diabetes, muscle wasting, osteoporosis, skin atrophy, retarded growth, hypogonadism, HTN
- IATROGENIC most common cause – giving too much GCs
- Used in a # of other diseases
- Side effects of high doses
1) mineralocorticoid effects – Na+ retention, K+, H+ excretion = hypokalemic alkalosis
2) Catabolic effects
3) Glucogenic effects – increased blood glucose, increased insulin secretion
4) Suppression of the HPA axis
5) MISC
- Administration for Replacement therapy
Ø give in mornings
Ø alternate day dosing important
- Supplementary Measures to minimize side effects
1) diet – low NA, high K
2) calorie restriction
3) Antacids – 3-4X per day
4) Vitamin D
5) Fluoride tablets
6) Androgen therapy for female patients
7) Physiotherapy for muscle activity.
Tags: acid secretion, antagonism, biliary, dehydrogenase, Glucocorticoids, Glucorticoids, glucose uptake, granulocytes, hydroxy, hydroxylation, inflammation, leukotrienes, liver disease, metabolism, pharmacological properties, plasma, plasma membrane, protein, vitamin d inhibition
