Cellular mechanism of action of steroids. The steroid receptor complex binds to DNA with its zinc fingers; depending on where it binds, proteins are either produced or production blocked.
Glucocorticoids bind to their receptors in the cytoplasm and the receptor - drug complex is then translocated into the nucleus where it interferes with transcriptional regulation to stimulate or inhibit the transcription of mRNA. Variable responses by different cells to steroid therapy may be explained by variable penetration of cells and tissue types, different receptors, variable access to specific DNA sequences in different cells or other variations in intracellular environments.
Energy metabolism
Water and Electrolytes
•decrease calcium absorption (gut)
•increase calcium excretion (kidney)
•polyuria (decreased ADH secretion)
•increase water intake (psychological?)
•increase glomerular filtration rate
Blood and Immune System
•decrease lymphocyte numbers
•decrease eosinophil, monocyte, basophil numbers
•increase neutrophil numbers
•increased release from the bone marrow
•decreased extravascular migration
•lower propensity to marginate on vascular endothelium
•decrease virus induced interferon production
•decrease production of interleukin, prostaglandin, thromboxane, platelet activating factor
•may elevate serum enzymes etc.
serum alkaline phosphatase (common in dogs)
alanine aminotransferase
cholesterol
blood urea nitrogen
•may depress serum thyroxin
Cardiorespiratory system
•chronotropic
•inotropic
•block inflammatory increases in capillary permeability
•permissive to effects of catecholamines
•increase number and affinity of b adrenoreceptors
CNS
•mental dependence
•euphoria
•increased appetite
•depression
•depress chemically mediated pyrexia
•direct inhibition of prostaglandin E2 production in the preoptic hypothalamic vasculature of the thermoregulatory centre
Skin
•calcification of skin
•thinning and weakening of connective tissues
Musculoskeletal system
•inhibition of osteoclast activity
•retardation of growth
•depletion of cartilage matrix
•decreased cartilage compliance
•osteoporosis
•changes to collagen structure
Reproductive system
•normal foetus maturation
•can be teratogenic (cleft palates)
•induce abortion / parturition in some species (alpha substituent group must be present on carbon 16 of the steroid nucleus in order to induce parturition in cattle)
•inhibit spermatogenisis
•inhibit ovulation
Gut and liver
•facilitate absorption of fat
•increase secretion of gastric acid, pepsin, and trypsin
•decreases production and alters the structure of protective mucus
•pancreatitis
•increased fat and glycogen deposits in the liver
•increased serum levels of ALT, GGT and alkaline phosphatase
Glucocorticosteroids exert their anti-inflammatory effects on cells by stimulating or inhibiting the production and effects of:
The anti-inflammatory actions of glucocorticosteroids at a cellular level are due to
•inhibition of recruitment of leukocytes
•inhibition of elaborating of inflammatory mediators by damaged and recruited cells
•interference in the synthesis and activation of catabolic enzymes
•suppression of the generation of granulation tissue.
The use of glucocorticosteroids is generally thought to inhibit primary wound healing. Their controlled use, however, can reduce scar formation and reduce the generation of excessive granulation tissue.
The different types of leukocytes have differing sensitivities to glucocorticosteroid concentrations and their effects are manifested in different ways. The systemic glucocorticosteroid concentrations required to induce a generalized immunosuppression are much larger than anti-inflammatory concentrations. However, a degree of immunosuppression always follows any systemic glucocorticosteroid therapy. In general one can administer a large single dose of a short to medium acting glucocorticosteroid without any serious adverse affect. However, prolonged systemic therapy can be associated with a number of potentially serious affects. (See immunosuppressant notes below)
(diagram)
Endogenous adrenal cortisol production is controlled through the effects of the pituitary produced hormone ACTH. Corticotrophin releasing factor (CRF) and arginine vasopressin (anti-diuretic hormone) (AVP, or ADH), produced in the hypothalamus, are responsible for stimulating the production and release of ACTH from the pituitary. The secretion of CRF from the hypothalamus generally follows a diurnal pattern in man and some animal species, peaking in the morning and being lowest in the evening. This is not the case for our domestic species. A pulsatile increased secretion of CRF is in response to stimuli which signal increased glucocorticoid need such as exercise, trauma, and cold. High plasma cortisol concentrations act as negative feedback, reducing further synthesis and release of AVP and CRF from the hypothalamus, and ACTH from the pituitary and inhibit further production. The presence of significant concentrations of exogenous glucocorticosteroids will also inhibit the synthesis and release of AVP, CRF, and ACTH and as a consequence markedly suppress endogenous plasma cortisol concentrations.
Extended exposure to significant systemic concentrations of exogenous glucocorticosteroids can result in adrenal cortical atrophy. Persistently elevated concentrations may result in a period when the adrenal cortex is non - responsive, or has a diminished response to either stress induced ACTH release, or even exogenous ACTH administration.
