Managing Immune-Mediated Diseases: How Can We Avoid Steroid Overdosing Giving Inadequate Amounts of Prednisolone?
World Small Animal Veterinary Association World Congress Proceedings, 2015
David B. Church1
1The Royal Veterinary College, University of London, London, UK

Glucocorticoids play a central role in the management of many disorders encountered in small animal practice and are amongst the most commonly dispensed categories of drug dispensed by veterinarians.

They play an important role in the management of most 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 glucocorticoids on tissues and the mechanisms by which side effects occur is an important precursor to rational use of drugs within this category.

Antiinflammatory Effects

Glucocorticoids have a number of effects which can be best summarized by the following:

 Inhibit capillary dilatation, migration of leukocytes and phagocytic activity of macrophages through a variety of different mechanisms.

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

 Prevent the synthesis and/or release of vasoactive amines such as proteases and hydrolases, various inflammatory mediators.

The antiinflammatory effects of glucocorticoids only occur at pharmacological doses. At the levels normally found in the body their physiological role is to prevent an excessive immune response within the body's defence reactions which might otherwise be harmful.

Immunosuppressive Effects

In addition to the antiinflammatory effects described above, glucocorticoids mediate immunosuppression by influencing several stages of the immune response from the down-regulation of macrophage function to direct suppression of T-lymphocytes and the cell-mediated immune effects that they control. Although B lymphocytes are considered more resistant to the inhibitory effects of glucocorticoids (thus theoretically antibody production should be unaffected by glucocorticoids), interestingly a 14 day course of prednisolone at 2 mg/kg/24 h significantly reduced serum concentrations of the major immunoglobulin classes. Furthermore glucocorticoids reduce antibody affinity for cell-membrane epitopes and inhibit complement pathways.

Clinical Pharmacology of Glucocorticoids

Synthetic glucocorticoids have been manufactured to increase their antiinflammatory 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

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

Table 1. Relative antiinflammatory and mineralocorticoid potency of common natural and synthetic corticosteroids administered systemically

   

Mineralocorticoid potency (per mg)

Glucocorticoid potency (per mg)

Antiinflammatory 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

-

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).

Table 2. Relative metabolic duration of effects for common glucocorticoids

Duration

Glucocorticoid

Short acting (less than 12 hours)

Cortisone (8–12 h)
Hydrocortisone (8–12 h)

Intermediate acting > 12–48 h

Prednisone (12–36 h)
Prednisolone (12–36 h)
Methylprednisolone (12–36 h)
Triamcinolone (24–48 h)

Long acting > 36 h

Dexamethasone (36–54 h)
Betamethasone (36–54 h)

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., Depo-Medrol)

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

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 antiinflammatory effect from depot treatment.

Principles of Glucocorticoid Therapy

Use an appropriate dose and the shortest acting effective agent for effect intended. In the majority of cases receiving oral therapy this will mean prednisolone or prednisone as the soluble ester.

Appropriate prednisolone doses in dogs include:

 Antiinflammatory dose:

 0.5–1 mg/kg day

 "Immunosuppressive" dose:

 In those situations where there is a need for immunosuppression the clinician is almost always looking to induce remission in the first instance and then maintain it for a variable period. The remission inducing dose of prednisolone should be no less than 2 mg/kg day and up to 4 mg/kg/day. There appears to be no clinical advantage in using any higher dose while the risk of side effects is increased. The benefit or otherwise of dividing the dose remains a topic for debate. In the author's opinion there is no advantage in dividing the dose and there may be some disadvantages. Thus for the induction of immunosuppression, the dose of prednisolone should never be less than 2 mg/kg and preferably not divided.

Cats are relatively "steroid resistant" and require higher doses than dogs. Doses can usually be safely increased by 50% compared to the dose in dogs.

Daily therapy for longer than one to 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 glucocorticoids are used for longer than a few days, dosage must be "tapered off." In the author's opinion the ideal way to do this is to start the tapering with 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. Remember the half-life of glucocorticoids is dose dependent; prednisolone has a half-life of greater than 24 hours when administered at doses greater than 1 mg/kg.

However, as mentioned above, the induction of remission of the clinical signs requires institution of daily therapy at an appropriate dose to control these clinical signs. At a reasonable period after the signs have been controlled and thus remission induced, the dose of glucocorticoid can be tapered. The tapering is best achieved by keeping the dose the same but administering the prednisolone on alternate days. If you have chosen a twice daily regime the first part of the tapering should be to reduce from twice daily to once daily and the next part of the tapering is to go from once daily to every second day dosing. The dose can then be reduced in two to three week intervals until a minimum dose required to manage the disorder is established.

When treating immune-mediated disorders, it is also worth remembering there is considerable advantage is using another agent to suppress immune-reactivity which acts via a different mechanism to the glucocorticoid. The aim of this additional agent is to facilitate the maintenance of remission rather than to aid in remission induction. The usual first choice agent is azathioprine in dogs (50 mg/m2/48 h) and chlorambucil (2 mg/cat/48 h) in cats. In the author's opinion both agents should only ever be given as (VIN editor: Text appears to be missing from document.)

Abrupt cessation of therapy can result in iatrogenic hypoadrenocorticism (Addisonian crisis) as a result of the failure of normal endogenous cortisol production secondary to subacute/chronic suppression of the hypothalamic-pituitary adrenal axis by the administered glucocorticoids.

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 é 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 result in hyperglycaemia

 Septic arthritis (from intraarticular 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)

David B. Church
The Royal Veterinary College
University of London
London, UK


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