Martin adrenal pharm lecture Flashcards
Glucocorticoid drugs
Cortisol Dexamethasone Hydrocortisone Methylprednisolone Prednisolone Prednisone
Mineralocorticoid drugs
Aldosterone
Fludrocortisone
Regulation of Endogenous Glucocorticoid Levels
Basal levels - diurnal rhythm
Negative Feedback Loop
Stressful stimuli
Secondary Adrenocortical Insufficiency
Due to hypothalamic or pituitary deficiency decreasing ACTH
- Iatrogenic: prolonged glucocorticoid therapy leading to HPA suppression
- Replacement therapy with gradual withdrawal
Pleiotropic effect of glucocorticoids
Regulate carbohydrate, protein, lipid metabolism
increases gluconeogenesis, plasma glucose, lipolysis, protein catabolism
Increase resistance to stress
increased plasma glucose and vasoconstrictor response of Epi/NE
Redistribution of Blood Cells
decreased eosinophils, basophils, monocytes, lymphocytes
increased RBC, platelets, PMNs
Regulation of immune system
cell redistribution
inhibition of inflammatory mediators, prostaglandins, leukotrienes, decreased COX-2 expression, decreased mast cell degranulation
decreased peripheral lymphocyte and macrophage activation and function
Permissive Effects of glucocorticoids
Glucocorticoids induce proteins required for signal transduction by other hormones.
Establish endocrine “set points” or sensitivity for stimulation
Example: epinephrine-stimulated lipolysis
Example: expression of b-adrenergic receptors
Mineralocorticoid Specificity
Tissue specific localization of receptor
– Mineralocorticoid receptor (MR) only in certain tissues, kidney, colon, salivary glands, sweat glands, hippocampus
In these tissues, there is enzymatic protection from cortisol excess (turn cortisol into cortisone, inactive)
Differential binding to GR and MR to transcription factors
Anti-Inflammatory and Immunosuppressive Actions of glucocorticoids
- Glucocorticoids inhibit the production and release of many different cytokines that normally would stimulate the proliferation and function of B and T lymphocytes.
Lipocortin-mediated inhibition of PLA2
Suppression/redistribution of leukocytes
Immune/CNS feedback
Distribution and Metabolism of corticosteroids
CBG (corticosteroid-binding globulin) & albumin
Bound versus free drug or hormone
Only free hormone capable of entering cell and activating receptor
Cortisol, for example, is ≥ 90% bound
Liver metabolism to water-soluble conjugated metabolites
shortest acting corticosteroids
cortisol, cortisone
long-acting corticosteroids
betamethasone, dexamethasone
these are also very potent
intermediate acting corticosteroids
prednisone, prenisolone, methylpredinisolone, tramcinolone
Toxicity of corticosteroids
HPA axis suppression and withdrawal
Continued use of high dose steroid
- HPA suppression
- Consequences of Immunosuppression
- –> Poor wound healing
- –> Opportunistic infections
- Cushing’s Habitus
Hyperglycemia Hypertension Peptic ulcers Myopathy Behavioral changes Cataracts Osteoporosis Osteonecrosis Growth retardation
General Therapeutic Considerations
Individualize therapy always
Reevaluate frequently
Except for replacement therapy, glucocorticoids are neither specific nor curative.
dosing of corticosteroids
A single dose is without harmful side effects!
A short course is without harmful side effects.
Longer than one week, adverse effects are very likely
- their severity being dependent upon length of treatment and dose
- start low, gradually taper up
- taper down slowly
