Merck Manual

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Scott H. Edwards

, BSc, BVMS, PhD, MANZCVSc, Charles Sturt University

Last full review/revision Apr 2014 | Content last modified May 2014
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Two classes of steroid hormones, mineralocorticoids and glucocorticoids, are naturally synthesized in the adrenal cortex from cholesterol. (Also see The Adrenal Glands.)

Mineralocorticoids (aldosterone) are so named because they are important in maintaining electrolyte homeostasis. However, mineralocorticoids also trigger a broader range of functions in nonclassic target cellular sites, including some effects on wound healing after injury. In addition, a chronic and inappropriate (relative to intravascular volume and dietary sodium intake) increase in aldosterone secretion evokes a wound healing response in the absence of tissue injury. This can lead to antialdosterone (eg, spironolactone) drug treatment being recommended to prevent undesired heart remodeling and fibrosis.

Glucocorticoids suppress virtually every component of the inflammatory process; they inhibit PLA2, decrease synthesis of interleukins and numerous other proinflammatory cytokines, suppress cell-mediated immunity, reduce complement synthesis, and decrease production and activity of leukocytes. Unsurprisingly then, glucocorticoids are by far the most efficacious anti-inflammatory drugs. They are also the most commonly used anti-inflammatory drugs. However, because their pharmacologic and physiologic effects are so broad, the potential for adverse effects is considerable.

Glucocorticoids play significant roles in carbohydrate, protein, and lipid metabolism; the immune response; and the response to stress. Natural glucocorticoids also have some mineralocorticoid activity and therefore affect fluid and electrolyte balance. While corticosteroids can be highly effective in suppressing or preventing inflammation, their physiologic and pharmacologic mechanisms of action are mediated by the same receptor. This explains why their pharmacologic and physiologic effects are inherently linked, and why supraphysiologic exposure to corticoids is potentially detrimental to several metabolic, hormonal, and immunologic functions.

All therapeutic corticosteroids have a 21-carbon steroid skeleton, similar to hydrocortisone (cortisol). Modifications to this skeleton selectively alter the degree of anti-inflammatory activity and the metabolic consequences and vary the duration of activity and protein-binding affinity of the resultant compound. The introduction of an additional double bond between C-1 and C-2 of cortisol in all synthetic corticosteroids selectivity increases glucocorticoid and anti-inflammatory activity. However, this single modification does not affect mineralocorticoid activity, resulting in an enhanced glucocorticoid/mineralocorticoid potency ratio, eg, prednisolone is ~4- to 5-fold more selective than cortisol. Additional fluorination at the C-9 position enhances both glucocorticoid and mineralocorticoid activity, as in 9α-fluorocortisol (fludrocortisone) and isoflupredone. Fludrocortisone (administered as fludrocortisone acetate) is 125-fold more potent than cortisol for mineralocorticoid effect and only 10-fold more for glucocorticoid effect. Thus, it is used in small animal medicine for its mineralocorticoid selectivity in the treatment of adrenocortical insufficiency.

Isoflupredone is used as an anti-inflammatory drug in cattle but lacks selectivity for mineralocortoid effects and increases the risk of severe hypokalemia. When a fluorinated derivative is substituted at the C-16 by an OH radical or a CH3 group, the new C-16 substituted compound (eg, triamcinolone, dexamethasone, betamethasone) has virtually no mineralocorticoid effect but remains a potent anti-inflammatory glucocorticoid. This last substitution on C-16 yields a new property to these fluorocorticosteroids, enabling them to trigger parturition in various species, including cattle. Dexamethasone and flumethasone (short-acting formulations) can induce parturition when administered after 255 days of gestation in cattle, but induced calving is usually associated with a high incidence of adverse effects, including retained placenta.

Many corticoids are administered as esters. Esterification of the alcohol at C-21 determines the extent of water/lipid solubility and controls the in vivo disposition of the compound. Esterification with a monoacid, such as acetic acid, yields water-insoluble drugs (eg, methylprednisolone acetate) that can be used as long-acting formulations when administered by the IM, SC, or intra-articular route. Other water-insoluble esters are diacetate, terbutate, and pivalate. By contrast, esterification of the same corticoid by a diacid such as succinic acid can yield a hydrosoluble ester, due to the second acid function (as for methylprednisolone sodium succinate) allowing a salt to be formed. Phosphate esters are also hydrosoluble. Solutions of free steroids or of hydrosoluble esters can be administered by the IV or IM route and are often used to treat life-threatening conditions such as heaves or hypersensitivity reaction. Esters may also be used PO, but hydrolysis occurs in the lumen of the digestive tract (pancreatic esterase) and the free active moiety is absorbed; thus, a formulation may be long-acting when administered parenterally but short-acting when given orally (eg, prednisolone acetate).

Nearly all esters are inactive prodrugs and require hydrolization to release their active moiety. Hydrolysis by esterases or pseudoesterases may occur either in body fluids such as blood or synovial fluid (acetate) or mainly in liver (succinate). Thus, for a local administration the choice of an appropriate ester is important. Hydrolysis may be only partial; for example, the bioavailability of methylprednisolone (the active moiety) from its hydrosoluble ester, methylprednisolone sodium succinate, is only 50% in dogs after IV administration, which must be considered when determining a dosage regimen.

Substances having a ketone radical in C-11, in lieu of an OH radical required for binding of the corticoid to its cellular receptors, are also prodrugs. Cortisone, prednisone, and methylprednisone are prodrugs of cortisol. These prodrugs are back transformed to their alcohol form in the liver by an 11-β-hydroxylase. There is no reason to administer them locally, because the activity of these prodrugs relies on hepatic metabolic activity. They are not recommended for use in animals with hepatic insufficiency. Prednisone is reported to have poor efficacy for treatment of heaves in horses because it is poorly absorbed, and its active metabolite, prednisolone, is rarely produced. By contrast, prednisolone has good bioavailability and is recommended in horses.

Other structural modifications allow more lipophilic substances to be obtained, such as the introduction of an acetonide between C-16 and C-17 (eg, triamcinolone acetonide). Triamcinolone acetonide, which is not a prodrug of triamcinolone, can be used for intra-articular administration in horses to treat osteoarthritis or as a topical formulation. Esterification at C-17 (valerate) produces a lipophilic compound with an enhanced topical:systemic potency ratio. Other approaches to achieve local glucocorticoid activity while minimizing systemic effects involve the formation of analogues that are rapidly inactivated after their systemic absorption. Fluticasone propionate, which is not a prodrug, is directly used to treat lung conditions. Similarly, beclomethasone dipropionate (a prodrug) locally yields an active metabolite (beclomethasone 17-monopropionate) that in turn yields beclomethasone, which has very weak anti-inflammatory activity.

Therapeutic corticosteroids are typically classified based on their relative glucocorticoid and mineralocorticoid potency (ie, the relative intensity of drug activity related to its concentration, a property that should not be confused with efficacy) as well as duration of effect (see Relative Potencies of Commonly Used Corticosteroids). Compounds with the most potent glucocorticoid activity are also the most potent suppressors of the hypothalamic-pituitary-adrenal axis (HPAA).


Relative Potencies of Commonly Used Corticosteroids


Relative Glucocorticoid Activity

Relative Mineralocorticoid Activity

Duration of Effecta (Alcohol Form)





























Triamcinolone acetonide
















a S = short (~12 hr), I = intermediate (~24 hr), L = long (~48–72 hr)

Mode of Action:

Glucocorticoids are capable of suppressing the inflammatory process through numerous pathways. They interact with specific intracellular receptor proteins in target tissues to alter the expression of corticosteroid-responsive genes. Glucocorticoid-specific receptors in the cell cytoplasm bind with steroid ligands to form hormone-receptor complexes that eventually translocate to the cell nucleus. There, these complexes bind to specific DNA sequences and alter their expression. The complexes may induce the transcription of mRNA, leading to synthesis of new proteins. Such proteins include lipocortin, a protein known to inhibit PLA2a and thereby block the synthesis of prostaglandins, leukotrienes, and PAF. Glucocorticoids also inhibit the production of other mediators, including AA metabolites such as those produced via COX activation (both COX-1 and COX-2), cytokines, the interleukins, adhesion molecules, and enzymes such as collagenase.

Physiologic and Pharmacologic Effects:

Peripherally and in the liver, glucocorticoids have important effects on carbohydrate, protein, and lipid metabolism. In the periphery, glucocorticoids stimulate lipolysis and protein breakdown, releasing glycerol and amino acids that act as substrates for gluconeogenesis. As a result, chronic exposure to excessive glucocorticoids may lead to muscle wasting and redistribution of body fat typical in animals with hyperadrenocorticism. In the liver, glucocorticoids stimulate hepatic gluconeogenesis and increase the hepatic synthesis and storage of glycogen. It is believed that gluconeogenesis is stimulated through the transcription of enzymes such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Glucocorticoids also decrease glucose uptake in peripheral tissues, including adipose tissue and mammary glands, further contributing to an increase in blood glucose. In dairy cattle, the reduction of milk yield is a major mechanism of the glucose-sparing effect of corticoids. In response to increased blood glucose, there is a compensatory increase in insulin. However, glucocorticoids inhibit the suppression of gluconeogenesis by insulin and cause insulin resistance in peripheral tissues, further contributing to hyperglycemia.

Although not as potent as the mineralocorticoid aldosterone, nonfluorinated glucocorticoids (prednisolone and methylprednisolone) do have some effects on water and electrolyte balance, enhancing potassium excretion and sodium retention primarily due to their activity in the kidneys. Fluorinated corticoids, provided that they are substituted at C-16 as in dexamethasone and triamcinolone, have no mineralocorticoid activity but rather exert a polyuric/polydipsic effect due to an inhibition of antidiuretic hormone (ADH) secretion and decreased renal sensitivity to ADH. Glucocorticoids can increase renal excretion and decrease the intestinal absorption of calcium, causing depletion of calcium stores. Glucocorticoids also inhibit osteoblasts, stimulate osteoclasts, and increase parathyroid secretion, which could affect bone healing.

A number of mechanisms are responsible for the anti-inflammatory and immunosuppressive actions of glucocorticoids. In homeostasis, glucocorticoids help maintain normal vascular permeability and microcirculation and stabilize cellular and lysosomal membranes. However, in acute inflammation, glucocorticoids decrease vascular permeability and inhibit the migration and egress of polymorphonuclear lymphocytes into tissues. Glucocorticoids suppress cell-mediated immunity by inducing apoptosis in normal lymphoid cells; inhibiting the clonal expansion of T and B lymphocytes; and reducing the number of circulating eosinophils, basophils, and monocytes. In contrast, glucocorticoids inhibit margination of neutrophils and increase the release of mature neutrophils from the bone marrow. Inflamed tissue, phagocytosis, and toxic oxygen-free radical production are inhibited in macrophages and monocytes. In the later stages of inflammation, glucocorticoids inhibit the activity of fibroblasts, reducing fibrosis and the formation of scar tissue. However, they may also slow wound healing.

Glucocorticoids modulate the synthesis and release of a number of chemical mediators of inflammation, including prostaglandins, leukotrienes, histamine, cytokines, complement, and PAF; they also suppress the production of inducible NO synthase and chondrodestructive enzymes such as collagenase.

Glucocorticoids have effects on other hormone systems. All anti-inflammatory glucocorticoid drugs in use today inhibit the HPAA, which can result in clinically significant adverse effects when stopping a prolonged corticoid treatment.

Administration and Pharmacokinetics:

Steroid formulations are available for oral, parenteral, and topical use. Many, including prednisone, prednisolone, methylprednisolone, and dexamethasone are well absorbed when administered PO and are particularly useful when anti-inflammatory treatment is required for a period of one to several weeks. Other preparations are available for parenteral use. The sodium phosphate and succinate salts are highly water soluble, providing a rapid onset of action when given IV. Other injectable formulations include insoluble esters such as methylprednisolone acetate and triamcinolone acetate, which have limited water solubility. The systemic absorption from these preparations is very slow and may result in anti-inflammatory effects and associated HPAA suppression for several weeks. Corticosteroid preparations available for topical or intralesional administration can be effective in treating inflammation of the skin, eyes, or ears. Although controversial, intra-articular administration of glucocorticoids has been used in people and animals, particularly horses, to manage inflammatory joint disease. In horses, for intra-articular administration, triamcinolone acetonide is preferred over methylprednisolone acetate. Glucocorticoids are absorbed systemically from sites of local administration in amounts that may be sufficient to suppress the HPAA.

Following absorption, ~90% of cortisol is reversibly bound to plasma proteins, primarily corticosteroid-binding globulin (CBG) and albumin. Among synthetic corticoids, only prednisolone binds specifically and with high affinity to CBG. Prednisolone can displace cortisol from its CBG binding site, explaining the immediate decrease of plasma cortisol after prednisolone is administered IV, a decrease not associated with HPAA inhibition. Other synthetic corticoids are mainly bound to albumin. Only the unbound portion is available to exert physiologic and pharmacologic effects and to cross physiologic barriers such as the blood-brain barrier or the udder. Generally, glucocorticoids are metabolized in the liver, where they are reduced and conjugated, forming inactive water-soluble derivatives excreted by the kidney.

Adverse Effects:

Adverse effects of glucocorticoids commonly result from the longterm use of supraphysiologic doses to control inflammatory or immunologic disorders. Longterm administration may lead to iatrogenic Cushing syndrome, characterized by polyuria, polydipsia, bilaterally symmetric alopecia, increased susceptibility to infection, muscle atrophy, and redistribution of body fat. The gluconeogenic and insulin antagonistic effects of glucocorticoids may precipitate the onset of diabetes mellitus or exacerbate diabetes in animals with existing disease. Longterm suppression of the HPAA may cause adrenal gland atrophy and resultant iatrogenic secondary hypoadrenocorticism. In affected animals, abrupt discontinuation of glucocorticoid therapy may lead to an Addisonian-like crisis characterized by lethargy, weakness, vomiting, and diarrhea. In severe cases, circulatory shock and death may result.

Glucocorticoids induce glycogen accumulation in hepatocytes, resulting in hepatopathy and hepatomegaly, and stimulate production of the steroid-specific isoenzyme of alkaline phosphatase. Slow turnover of enterocytes and inhibition of protective prostaglandins in the gut due to glucocorticoids may contribute to development of GI ulceration. Furthermore, glucocorticoids potentiate the ulcerogenic effects of NSAIDs. Glucocorticoids reduce collagen synthesis and may lead to thinning and increased fragility of the skin. Alterations in fluid and electrolyte balance may result in sodium and fluid retention and hypokalemic alkalosis. In horses, high doses of glucocorticoids may induce or exacerbate laminitis. Significant mood and behavioral changes have been described in people receiving corticosteroid therapy and may be seen in animals as well.

Although immunosuppression may be a desired effect of glucocorticoid therapy in autoimmune disease, susceptibility to infection may increase, or latent infections may be reactivated. Urinary tract infections are common in animals receiving glucocorticoids for longterm therapy of inflammatory or immunologic disease. In joints, glucocorticoids may reduce the formation of chondrocyte collagen and synovial fluid and contribute to the development of septic arthritis. Strict aseptic technique must be observed when administering intra-articular injections of steroids.

The adverse effects of longterm (>2 wk) glucocorticoid therapy can be diminished using an alternate-day treatment regimen. Once inflammation has been controlled using daily therapy with a drug that has intermediate duration of activity (eg, oral prednisolone or prednisone), a gradual change to alternate-day therapy can be made.

Therapeutic Uses:

Short-acting soluble steroids such as the succinate esters have been routinely used in the treatment of septic shock, but this indication is controversial. The action of corticoids on hemorrhagic and cardiogenic shock is not established, even though product labeling includes this use as an adjunct to fluid therapy. Glucocorticoids are also routinely used in the treatment of cerebral edema, although controlled clinical trials supporting their effectiveness are lacking.

Glucocorticoids are used commonly to treat allergy and inflammation such as pruritic dermatoses and allergic lung and GI diseases. In acute cases of atopic or flea allergy dermatitis, anti-inflammatory dosages (prednisolone, 0.5–1 mg/kg/day) alleviate pruritus and limit self-trauma from scratching until the underlying cause can be addressed. Similar dosages are used in the management of chronic allergic bronchitis and feline asthma. Short-acting corticosteroids have also been used in treatment of acute respiratory distress syndrome in cattle and chronic obstructive pulmonary disease in horses. Historically, corticosteroids have been used to treat several musculoskeletal disorders, including osteoarthritis, myositis, and immune-mediated arthritis. More recently, the NSAIDs have become first-line therapy for musculoskeletal disorders, particularly in the treatment of osteoarthritis in companion animal species. In most inflammatory conditions, glucocorticoids should be used in conjunction with therapies that target the underlying cause.

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