Please list the general anti-inflammatory and immunological actions of GCS
Effects on eosinophils, lymphocytes, monocytes, mast cells, neutrophils, lipocortin 1, humeral and cellular immunity. There is decreased vascular permeability and several of B adrenergic responsiveness.
How do glucocorticoids affect eosinophils?
decrease formation in bone marrow, increase apoptosis and inhibit prolongation of eosinophil survival and function from IL3/IL5
How do glucocorticoids affect mast cells?
may decrease number of mast cells and synthesis of histamines.
How do glucocorticoids affect lymphocytes and monocytes?
decrease the number of lymphocytes and monocytes that bear low affinity IgE/G receptors, decrease serum Ig levels, decrease cell lymphocyte subpopulations with T cells affected more than B lymphocytes and CD4+ T cells more than CD8+, decrease lymphocyte production
How do glucocorticoids affect neutrophils?
Neutrophilic due to release from bone marrow as well as decreased margination and diapedesis of neutrophils into tissues, decrease chemotaxis, adherence and enzyme secretions.
True or False - Glucocorticoids increase vascular permeability.
FALSE - glucocorticoids decrease vascular permeability - mechanism is unknown.
What effects are seen on lipocortin 1 from glucocorticoids?
increase regulation of lipocortin 1 (phospholipid binding protein), potent anti-inflammatory effects, inhibition of phospholipase A2, decrease production of AA metabolites from LOX/COX pathways, decrease production of PAF.
Glucocorticoids will increase/decrease the number of B adrenergic receptors on cell surfaces.
The number will be increased and this will reverse the decrease B adrenergic responsiveness
How do glucocorticoids affect humeral immunity?
There will decrease Ab synthesis after increased doses and long-term therapy. They will decrease the degree of of suppression of B lymphocyte proliferation
How do glucocorticoids affect cellular immunity?
They decrease the Ag survival, uptake and migration. They decrease the maturation of the dendritic cells. Inhibition of transcriptional activators (NF-kB, AP-1). Decrease IL-1, TNFa, and increase IL-10. They decrease T cell activation and proliferation. They decrease IL-2, IFN-y, decrease NK cell mediated lysis.
Please outline the 2 anatomic locations in the adrenal gland and describe the zones seen within these locations. What type of “steroid” is produced in each zone.
- Cortex - zona glomerulosa - mineralcorticoid
zonal fasiculata - glucocorticoids
zona reticularis - androgens - Medulla - catecholamines
Pleas list all possible side effects that can be seen with steroids
poor dull coat, muscle atrophy, PU/PD/PP, weight gain, behavioural changes, panting, increase risk of infections, UTI, demodicosis and ringworm, atrophic skin, calcinosis cutis, atrophic scars, comedones, milia, teratogenic (first trimester), pancreatitis, GI ulcer, diarrhea, pancreatitis, steroid hepatopathy, DM, adrenal gland suppression, decrease thyroid hormone production.
Cats - rarely iatrogenic bushings, unkempt hair coat, alopecia, skin fragility, HCM, DM, curling of the pinna, decrease seizure threshold
Laminitis
Please describe the mechanism of action of steroids.
GCs passively diffuse into the cell and bind to the GC receptor (GR) then there is a dissociation of heat shock proteins, non-genomic mechanisms of GR that include interference with cytosolic singling molecules, There is translocation of ligand-bound GR into the nuclear, GR molecules transcription by bind to DNA OR GR modulates transcription via interaction with other transcription factors.
What genes are unregulated with GC/GR complex?
Bcl-xL, GILZ, GITR, IkB
How do GCs decrease permeability fo capillary membranes and therefor preventing protein leakage?
They decrease bradykinin production which is a potent vasodilator.
How do GC’s affect FA metabolism?
They minimize the inflammatory response through lipomoudlation which inhibits phospholipase A2 (converts phospholipids to AA). Decrease AA limits precursor molecules for LOX and COX to produce AA derived mediators of inflammation
How do GCS affect neutrophils, lymphocytes and macrophages in the system and how does this look on lab work?
There is a mature neutrophilia (seen with GC and stress). There are increase numbers of mature neutrophils from BM and decrease margination and migration of neutrophils resulting in a prolonged circulating half life.
Lymphopenia - there is redistribution of circulating lymphocytes to non-vascular lymphatic areas.
Macrophages are decreased leading to a decrease in phagocytosis and Ag procession and cell killing. This will affect immediate and delayed hypersensitivity reactions.
What steroids are 6-10 x more potent than prednisone?
Triamcinolone, dexamethasone and betamethasone are 6-10 x more potent and should be given every 72 hours due to the suppression of the HPA axis.
Know the relative GC potencies, mineralocorticoid potencies and equivalent dosing of all steroids.
See chart in
Why is a serum hypoalbuminemia an issue when giving steroids?
When larger doses of GCs are administered the globulin (Glycoprotein that binds GCs, having a low binding capacity) then the albumin becomes the protein used for binding. If low then there is low binding capacity on all fronts and there is an increased risk of toxicity.
Please explain the difference between the formulations of GCs when given IV vs PO
IV solutions are Na phosphate or Na succinate which are water soluble.
Oral GCS contain a free steroid alcohol form
Describe steroid tachyphylaxis
A patient will previously respond well to a steroid but then it apparently loses its effectiveness. Not resistance. Will respond well to a different steroid then after a period of time may be able to return to the previously used steroid and it is effective.
How do steroids affect the H20 balance?
There is a loss of H20 which can be indirect or direct. There is inhibition of ADH production and decrease permeability in the distal rental tubules
How do steroids affect the CNS?
There is a change in mood or behaviour, decrease seizure threshold, decrease response to pyrogens and increased appetite.
