Steroids

WIKIDRUGS ANTI-INFLAMMATORY DRUGS

Introduction

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 pharmacological concentrations.

Alterations in steroid dose can influence the action they have. This is particulatly relevant to anti-inflammatory and immuno-suppressive effects.

Metabolic Effects

The metabolic effects of steroids are mainly catabolic and primarily affect 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-oxygenase, leading to a decrease in prostanoid levels.
  • Inhibiting phospholipase-A2, reducing conversion of phospholipid to arachidonate and therefore 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.

As with most drugs, steroids may be administered in a variety of ways. Topical steroids are appropriate for used in the eyes and ears, and on the skin. The structure of the drug can affect how useful it is topically; the C17 aliphatic side chain can influence topical absorption, and acetonide esters (e.g. betamethasone-17-valerate) are well absorbed from the skin but have little systemic access. Steroids are well absorbed orally, and may also be used parenterally, by inhalation and intra-articularly.

Side Effects and Contraindications

Side effects of steroids include:

• Gastric ulceration. This is potentiated by NSAIDs and therefore concurrent use of these drugs is contraindicated.
• Muscle atrophy
• Cutaneous atrophy
• Hyperglycaemia
• Osteoporotic effects. These occur since steroids decrease absorption and increase excretion of calcium. They also increase parathyroid hormone activity, leading to decreases in osteoblastic activity and increases in activity of osteoclasts. Degeneration of epiphyseal cartilage can also occur in young animals.
• Mineralocorticoid activity, resulting in sodium and water retention and loss of potassium.
• Polyuria and polydipsia
• Increased susceptibility to infection, due to immuno-suppressive effects.
• Laminitis in horses
• Corneal ulceration

Suppression of the hypothalamus-pituitary axis can occur. Exogenous steroids extert negative feedback in the same way that endogenous steroids do. This leads to suppression of ACTH formation and storage and may cause atrophy of the pituitary gland. Sudden termination of treatment with exogenous steroids can therefore lead to failure of production of endogenous steroids, causing a crisis. This means that gradual dose reduction is of paramount importance. One method of achieving this is by alternate day thereapy, where a short-acting glucocorticoid in a short-acting formulation us used every other day at times to conincide with peak endogenous steroid levels.

Another serious side effect of steroid administration is iatrogenic Cushing's disease (hyperadrenocorticism). This can result from prolonged glucocorticoid treatement, and signs can include polydipsia, polyuria, polyphagia, elevation of liver enzyme levels and a pot-belly.

Drugs in This Group

The activity and duration of action of some steroid drugs is summarised in the table below.

Compound	Relative glucocorticoid activity	Relative mineralocorticoid activity	Duration of effect (hours)
Hydrocortisone	1	1	8-12
Cortisone	0.8	0.8	8-12
Prednisolone	4	0.8	12-36
Prednisone	4	0.8	12-36
Methylprednisolone	5	Minimal	12-36
Triamcinolone	5	None	24-48
Dexamethasone	30	Minimal	24-28
Betamethasone	30	Minimal	24-48
Fludrocortisone	15	150	8-12

Short acting (less than 24 hours) drugs include:

• Prednisolone
• Prednisone
• Methylprednisolone

Long acting (greater than 24 hours) drugs include:

• Dexamethasone
• Betamethasone
• Triamcinolone

There is a mnemonic to help you remember the actions and potency of the steroid drugs:

• Help (hydrocortisone)
• Pain (prednisolone)
• Management (methylprednisolone);
• Treat (triamcinolone)
• Bad (betamethasone)
• Dermatitis (dexamethasone)

Potency of the drug increases as you go down the list. "Helping pain management" relates to a mainly anti-inflammatory action; "treating bad dermatitis" relates to a mainly immuno-suppressive effect.

Methylprednisolone acetate and triamcinolone acetonide are suitable for intra-articular used. Methylprednisolone acetate is rapidly metabolised to methylprednisolone. Although levels within the joint are maintained for up to 39 days, by 24 hours there is a very low serum concentration of the drug. This steroid has adverse affects on articular cartilage. Triamcinolone acetonide levels in the plasma are higher and maintained for longer, but the drug is undetectable in the joint two weeks post-treatment. It does not have effects on bone remodelling or fragility.

Clinical Uses

Steroids can be used as treatment in a wide variety of clinical scenarios. For example, one major use of steroids is against inflammatory disease. Both acute inflammatory disease (such as allergic reactions) and chronic conditions (such as osteoarthritis) may benefit from the administration of steroids.

Immune-mediated disorders can also be treated with steroids. Initially, high doses are used which are gradually decreased until an effective maintenance dose for that individual is reached. In protocols such as this, steroids may be used in conjunction with other immuno-supressive drugs. Examples of diseases that may be treated this way are immune-mediated haemolytic anaemia, myasthenia gravis and immune-mediated skin disease.

Steroids can be used to treat shock. The timing of treatment is important in this instance, and a high dose of a short-acting glucocorticoid is usually used. Cerebral oedema can also be treated with steroids.

Steroids can be used in the treatment of neoplasia. They are usually used as part of a chemotherapeutic protocol in conjunction with additional chemotherapeutic agents, but also help in the management of secondary complications such as paraneoplastic hypercalcaemia.

As above, some steroids can be used intra-articularly.

Steroids with mineralocorticoid activity are used to treat Addison's Disease. The condition is treated acutely using hydrocortisone, with fludrocortisone being used for long-term management.

Principles of Therapy

• Drugs with minimal mineralocorticoid activity are preferred. This is so that ion and fluid balance is not adversely affected.
• Treatment with steroids is merely palliative. Although it relieves the symptoms, it does not resolve the underlying cause of disease.
• If antimicrobial drugs are used in conjuction with steroids, these should be bactericidal rather than bacteristatic. This is because steroids have an immuno-suppressive effect and so more effective anti-microbials are required.
• Treatment should be withdrawn gradually to reduce the risk of a crisis occuring (see Side Effects and Contraindications).
• Long acting compunds carry a greater risk of toxicity.