Corticosteroids--Friend or Foe?
Jill Maddison, BVSc, DipVetClinStud, PhD, FACVSc, MRCVS
The Royal Veterinary College, North Mymms, UK

Glucocorticoids still play a central role in the management of many skin diseases, particularly allergic and immune-mediated dermatoses as well as other immune mediated diseases affecting blood cells, joints, the kidney and other tissues. They are often essential for the successful management of the patient yet have the potential to cause serious and occasionally life-threatening side effects. An understanding of the effects of glucocorticosteroids on tissues and the mechanism by which side effects occur is an important precursor to rational use of these drugs.

Clinical Applications in Small Animal Practice

 Inflammatory disease--particularly allergy

 Immune-mediated disease

 Neoplasia (lymphoma, mast cell tumours)

 Replacement therapy (hypoadrenocorticism--spontaneous, iatrogenic)

 Shock (?)

 Cerebral and spinal cord oedema

Anti-Inflammatory Effects

Corticosteroids:

 Inhibit capillary dilatation, migration of leukocytes, phagocytic activity

 Assist in maintenance of normal circulation and maintenance of cell membrane stability

 Prevent the release of vasoactive amines such as proteases and hydrolases

Corticosteroids thus inhibit both the early and late manifestations of inflammation thus reducing the initial redness, heat and pain, influencing later wound repair and reducing proliferative reactions that may be seen in chronic inflammation.

The anti-inflammatory effects of corticosteroids only occur at pharmacological doses. At the levels normally fund in the body their physiological role is to prevent overshoot of the body's defense reaction which might otherwise be harmful. Evidence for this is that the magnitude and duration of inflammation is greatly increased in adrenalectomised rats.

Stress Leukogram

Animals that are stressed or treated with glucocorticosteroids may have a characteristic white blood cell picture--a stress leukogram. This is manifest as a decreased number of circulating lymphocytes, eosinophils and basophils in association with neutrophilia due to increased release and decreased removal of polymorphs. Such haemograms can be erroneously interpreted as reflecting inflammation and infection, and hence result in unnecessary use of antibiotics.

Steroids and Shock

Steroid may have a role in the treatment of shock provided that treatment is initiated early, intensively and at high doses. There is reasonable evidence that steroids are beneficial for endotoxaemia and in the management of horses with colic but the benefits of their use in the management of haemorrhagic (blood loss) shock is less clear.

The principles of steroid use in shock are that high doses should be used and they should be used early in the course of treatment for a short intensive course. Use of steroids is not a substitute for aggressive fluid and supportive therapy. The steroid should be given intravenously using a soluble ester such as methylprednisolone sodium succinate (fastest uptake) or dexamethasone phosphate (cheaper).

Clinical Pharmacology of Corticosteroids

Synthetic glucocorticoids have been manufactured to increase their anti-inflammatory potency and to reduce mineralocorticoid (sodium and therefore water retention) effects. This has obvious therapeutic advantages but major disadvantages if they are used inappropriately. The glucocorticoid side effects can be serious and the more potent the glucocorticoid, the greater potential for adverse effects.

Potency

Potency is assessed by anti-inflammatory activity on granulomas induced in experimental animals by subcutaneous injection of turpentine or croton oil or by implantation of cotton pledgets.

Hydrocortisone is the standard and is assigned an arbitrary value of one. The relative potency of the various corticosteroids is tabulated in Table 1.

Duration of Action

The duration of action of the synthetic glucocorticoids can be increased by either modification of the steroid molecule (see Table 2) or by complexing the steroid with esters of varying degrees of solubility to prolong release after intramuscular injection (see Table 3).

Synthetic glucocorticoids bind less avidly to plasma proteins, have a longer duration of biologic action because of increased glucocorticoid receptor affinity and are more resistant to hepatic degradation.

Table 1. Relative anti-inflammatory and mineralocorticoid potency of common natural and synthetic corticosteroids administered systemically.

 

Mineralocorticoid
potency(per mg)

Glucocorticoid
potency(per mg)

Anti-inflammatory
equivalent dose(mg)

Cortisone

0.8

0.8

25.0

Hydrocortisone

1.0

1.0

20.0

Prednisolone

0.25

4.0

5.0

Methylprednisolone

Minimal

5.0

4.0

Triamcinolone

0.0

5.0

4.0

Dexamethasone

Minimal

30.0

0.75

Betamethasone

Negligible

35.0

0.6

Fludrocortisone

100

15

 

Table 2. Relative metabolic duration of effects for common glucocorticoids.

Duration

Glucocorticoid

Short acting (less than 12 hours)

Cortisone (8-12 hrs) Hydrocortisone (8-12 hrs)

Intermediate acting > 12-48 hrs

Prednisone (12-36 hrs Prednisolone (12-36 hrs) Methylprednisolone(12-36 hrs)Triamcinolone (24-48 hrs)

Long acting >36 hrs

Dexamethasone (36-54 hrs) Betamethasone (36-54 hrs)

The rate of glucocorticoid absorption is slowed and the duration prolonged if the corticosteroid is bound to a poorly soluble ester e.g., acetate, acetonide for intramuscular injection. The prolongation of effect also means prolongation of suppression of the hypothalamic-pituitary-adrenal axis and there are no clinical advantages that outweigh this problem unless the use of shorter acting agents is impossible e.g., fractious animal, animal with a painful mouth or lack of owner compliance.

It should be noted that the duration of adrenal suppression is greater than the duration of anti-inflammatory effect from depot treatment.

Table 3. Glucocorticosteroid esters, solubility (in water) and duration of steroid release from intramuscular injection.

Very soluble--released for minutes

 

Succinate or
phosphate

Prednisolone sodium succinate (Solu-delta-cortef)
Hydrocortisone sodium succinate (Solu-cortef)
Dexamethasone sodium phosphate (e.g., Dexadreson Colvasone)
Betamethasone (Betsolan soluble)

Moderately insoluble--released for days to weeks

 

Acetate

Prednisolone acetate (e.g., Pred-X)
Methylprednisolone acetate (e.g., DepoMedrol)

Phenylpropionate

Dexamethasone phenylpropionate (e.g., Dexafort)

Isonicotinate

Dexamethasone isonicotinate (e.g., Voren depot)

Poorly soluble--released for weeks

 

Acetonide

Triamcinolone acetonide (e.g., Vetalog, Kenalog)--6-8 week duration of action

Principles of Glucocorticoid Therapy

1.  Use an appropriate dose and the shortest acting effective agent for effect intended, e.g., Appropriate prednisolone doses in dogs:

a.  Anti-inflammatory 0.5-1 mg/kg day

b.  Immunosuppressive > 1.5 mg/kg day (up to 4 mg/kg/day--no clinical advantage in using a higher dose and risk of side effects increased)

c.  Cytotoxic 2 mg/kg/day Cats are relatively steroid resistant and require higher doses than dogs. Doses can usually be safely doubled compared to dogs.

2.  Daily therapy for longer than one-two weeks even with short acting agents such as prednisolone will suppress the adrenal axis and recovery will take longer than one week. Therefore, if corticosteroids are used for longer than a few days, dosage must be tapered off using alternate day therapy. Many glucocorticoid responsive diseases can be managed with chronic alternate day therapy with prednisolone--avoid if possible doses greater than 1 mg/kg every other day. Larger doses saturate the dog's ability to fully metabolise the last dose before the next dose is given, thus negating the primary rationale for alternate day therapy. However, to induce remission of clinical signs or manage their recurrence requires institution of daily therapy at an appropriate dose to control clinical signs, tapered to reach minimum daily dose that will control signs then followed by alternate day therapy to manage the disease.

3.  Abrupt cessation of therapy can result in iatrogenic hypoadrenocorticism (Addisonian crisis) as a result of the failure of normal endogenous cortisol production secondary to ACTH suppression by administered glucocorticoids.

4.  It is important to recognise that individuals vary greatly in their response to the therapeutic and adverse effects of glucocorticoids and there may be qualitative differences between the effects of different glucocorticoids in the same patient.

Precautions

Glucocorticoids should be avoided or used if essential, with care in:

 Infections

 Immature animals

 Patients with bone healing

 Diabetes mellitus

 Protein-losing nephropathies

 Liver disease

 Pregnancy--cleft palates, abortion

 Corneal ulceration--delay healing and may cause corneal perforation

Side Effects

 Polyuria and polydipsia (dogs primarily)

 Polyphagia and weight gain

 GIT ulceration (in the presence of other conditions that increase risk of ulceration or concurrent NSAID use)

 Suppressed immunologic processing of antigens & increased susceptibility to infection

 Recurrence of latent viral infections in cats who are carriers

 Thin skin, alopecia

 Calcinosis cutis

 Bruising

 Hepatomegaly (especially dogs)

 Promotion of gluconeogenesis which can cause hyperglycaemia

 Septic arthritis (from intra-articular injection)

 Steroid arthropathy (suppression of growth of articular cartilage)

 

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Jill Maddison, BVSc, DipVetClinStud, PhD, FACVSc, MRCVS
The Royal Veterinary College
North Mymms, UK


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