Steroids

Steroids are 21-carbon, 4-ring molecules, with biologically active steroids have a double covalent bond between carbon atoms 4 and 5, and a ketone group at C3. The body endogenously produces steroids which are essential for life; they regulate a variety of functions under normal physiological conditions and have important roles in response to stress. These steroids are produced in the adrenal cortex and are therefore known as "corticosteroids". The corticosteroids can be further divided to mineralocorticoids and glucocorticoids which are synthesised in different areas of the cortex. mineralocorticoids (such as aldosterone) are produced in the zona glomerulosa; glucocorticoids include cortisol (from the zona fasiculata) and corticosterone (from the zona reticularis). Corticosteroids are synthesised from plasma cholesterol which is stored in the adrenal gland and assimilated to corticosteroids as they are required. Endogenous glucocorticoid levels are regulated by the hypothalamus-pituitary adrenal axis, whereas the renin angiotensin aldosterone system controls mineralocorticoid levels.

Mechanism of Action

Steroids cross the cell membrane by diffusion and bind to a steroid-specific cytoplasmic receptor. The receptor-steroid complex then translocates to the nucleus and acts to up- or down-regulate expression of certain genes by increasing or decreasing the transcription of their mRNAs. Sometimes this action is linked to interaction of the complex with transcription activator protein, an enhancer of gene transcription.

Examples of genes which are induced by steroids are angiotensins convertins enzyme and the Beta2-adrenoceptor. Those inhibited include cytokines, cyclo-oxygenase and collagenase.

Actions

Both endogenous and exogenous steroids have a variety of actions. Some of these, such as anti-inflammatory effects, are only seen at pharamacological concentrations.

Metabolic Effects

The metabolic effects of steroids are mainly catabolic and primarily effect carbohydrate and protein metabolism. They include:

• Increasing gluconeogenesis, meaning amino acids and lactate are converted to glucose.
• Inhibition of glucose utilisation, giving hyperglycaemia.
• Increasing glycogen storage. This occurs via insulin release in response to hyperglycaemia.
• Protein breakdown and reduced protein synthesis.
• Redistribution of body fat.
• Decreasing calcium absorption and enhancing calcium excretion.

Systemic Effects

The systemic effects of steroids include:

• Elevation of liver enzymes.
• Induction of abortion and parturition in ruminants. This effect is not noted in the dog or cat.
• Mineralocorticoid activities.
• Alteration of central nervous system function, although this is better described in human medicine.

Anti-Inflammatory Effects

Steroids only have anti-inflammatory actions at pharmacological concentrations. At physiological levels, these do not occur. Both early and late stages of inflammation are acted upon, and steroids affect all types of inflammatory reaction regardless of the inciting cause.

During the inflammatory response, pharmacological levels of steroids have an effect on:

• Blood vessels, to decrease vasodilation and fluid exudation.
• Inflammatory mediators, by:
  • Inhibiting cyclo-oygenase, leading to a decrease in prostanoid levels.
  • Inhibiting phosphlipase-A2, reducing conversion of phospholipid to arachidonate and therfore mediator production.
  • Decreasing generation of inflammatory cytokines.
  • Decreasing histamine release.
• Inflammatory cells. For example,
  • Actions of helper T-cells are reduced.
  • Accumulation of leucocytes in areas of inflammation is decreased.
  • Macrophages are rendered less active in combating micro-organisms.
• Fibroblasts, to decrease their function and cause reduced healing and repair.
• Bone cells
  • Osteoblast activity is reduced.
  • Osteocalst activity is increased.

Immuno-Suppressive Effects

Low doses of steroid inhibit the cellular response, decreasing lymphocytes, eosinophils, monocytes and basophils. However, neutrophil numbers are increased. High steroid doses inhibit the humoral response.

Pharmacokinetic Considerations

Corticosteroids are highly plasma protein bound (around 90%). Binding may be both "generic" (to albumin) and "specific". Specific binding occurs to corticotrophin binding globulin (CBG), which has a high affinity but low capacity and hence binds endogenous corticosteroids only. Albumin binds both endogenous and synthetic steroids.

Corticosteroids have a short half-life, with that of cortisol being only 90 minutes. The drugs are metabolised in the liver, where the C4-5 double bind is reduced and conjugation with sulphate or glucuronic acid occurs. They are then excreted in the urine. Cortisone and prednisone are inactive prodrugs; upon liver metabolism they are converted to hydrocortisone and prednisolone respectively.