VetInfo Digest       December 2000

 

This Month:

Rational Use of Glucocorticoids in Veterinary Medicine

Maximum Insulin Dose

Useful URLs from the VetInfo Web Site

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Many of you know that I spent a little more than a week last month being the patient instead of the doctor. This is always an eye-opening experience. I had a gastrointestinal bleeding episode that remains unexplained, despite having gastroscopy, colonoscopy, a barium X-ray series and other lab work. Some of my friends are incredulous that a conclusive diagnosis could not be found with all of the testing that was done. It doesn't surprise me much, at all. In fact, I kind of find it reassuring that human medicine, with all of its advancements and all of the available equipment, still is not a perfect science and that physicians sometimes struggle for answers, too. The other thing that I noticed during my stay was how much the small things that people do for you mean when you are anxious and uncomfortable. A little pain relief, a little reassurance and a few kind words made my stay much more comfortable than it might otherwise have been. Nursing care counts when pets are ill, too!

Thanks to all of you who sent kind notes and who waited a long time for answers to pressing questions without complaint.

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Prednisone and other Glucocorticoids

The glucocorticoids are probably the ultimate "Dr. Jekyll and Mr. Hyde" medications. The ability to help patients live through a number of diseases and to help save function in acute spinal and central nervous system injuries puts this class of medications in the top rank of all medicines for usefulness. On the other hand, even appropriate use of corticosteroids can lead to severe complications and misuse can cause death. It is important to understand when corticosteroids are an appropriate medication and when they are not. It is important to understand the reasoning behind dosing schedules for these medications and to use them properly when they are necessary. Knowing when it is appropriate to use corticosteroids can be the difference between a life of reasonable comfort or constant irritation and even the difference between living or dying from several illnesses.

The term steroid refers to a group of lipids ( things that originate from fat) that have a specific characteristic ring structure. This group of compounds includes the sex hormones, corticosteroids produced by the adrenal glands, bile acids and even the poison produced by poisonous toads. These are naturally occurring compounds. A well recognized subgroup of steroids, anabolic steroids, are synthetic compounds (in most cases) derived from testosterone, which promote growth of body tissues, including muscles. Many people recognize the term "steroid" and associate it solely with these compounds, even though that is an erroneous assumption.

Corticosteroids are a subgroup of steroids which are produced by the adrenal cortex, which is where the name derives from (cortico = pertaining to the cortex). This group of steroids is further subdivided into the glucocorticoids and the mineralocorticoids. Glucocorticoids are mainly produced to influence the metabolism of the body, especially the metabolism of the major nutrients, carbohydrates, protein and fats. They have many other effects in the body, including anti-inflammatory properties and suppression of some portions of the white blood cell system. The naturally occurring glucocorticoid in the body is cortisol, also referred to as hydrocortisone. Mineralocorticoids regulate the electrolyte balance and distribution of water in the body. The primary naturally occurring mineralocorticoid is aldosterone. It is possible for a dog or cat to live with very low levels of glucocorticoids but when mineralocorticoid levels are below normal, there is a great risk of death associated with electrolyte or fluid imbalances. Looked at as a whole, the primary job of corticosteroids in the body is to allow the body to react appropriately to stress, as this encompasses pretty much all of the other effects of both glucocorticoids and mineralocorticoids.

Hormones are substances produced by the body to regulate specific functions of an organ, or organs. Since corticosteroids have effects on several organs, they are considered to be hormones. Many times, the function of one hormone interferes with or enhances the function of another hormone. In the case of corticosteroids, an example of interference with another hormone would be the tendency of corticosteroids to suppress the actions of insulin, making it hard to regulate a diabetic patient who must also receive cortisones as a therapeutic agent.

A natural or induced deficiency of corticosteroids is referred to as hypoadrenocorticism, or Addison's disease. Dr. Addison discovered this condition in 1855 and in 1856 experimental removal of dog's adrenal glands was shown to be fatal. A naturally occurring increase in corticosteroid hormone is referred to as hyperadrenocorticism, or Cushing's disease. This disorder is named after an American surgeon, Dr. Harvey Cushing, who practiced in Boston around the turn of the century (the last one, not the current one!).

From the standpoint of medical therapy, glucocorticoids are used much more frequently than mineralocorticoids. It is important to remember that some of the medications that are classified as glucocorticoids have significant mineralocorticoid effects as well. This is one of the reasons that patients on glucocorticoid medications, such as prednisone, tend to retain fluids and have increased thirst and urinate larger volumes. Early in the use of cortisones, it was noted that patients kept on glucocorticoid medications on a daily basis and then suddenly withdrawn from the medication had a tendency to die in the first few days of the withdrawal period if stressed by events such as surgery. This happened because these medications have a mineralocorticoid effect, even though it is not as strong as the naturally occurring hormones. Suppression of the adrenal gland's natural production of mineralocorticoids occurred with supplementation with hydrocortisone or prednisone. Sudden withdrawal of these medications left patients without the ability to produce their own mineralocorticoids. If these patients were stressed, including surgical procedures or anesthetic procedures while they were deficient in mineralocorticoids, the rise in potassium levels in the blood stream sometimes caused sudden heart failure. This is the origin of the fears over the use of corticosteroids in both human and veterinary medicine. If this were the only side effect of corticosteroids, understanding the problem would have eliminated the reluctance of veterinarians and their clients to use these medications. However, there are a number of other side effects which can occur.

There are many available glucocorticoids. A general comparison of their action shows that some are much more likely to have mineralocorticoid effects than others. Since mineralocorticoid effects are part of the reason that increased drinking and urinating occur with cortisones, it can be helpful to know which preparations have more of these effects. Prednisone and prednisolone, the most commonly used corticosteroids, have sodium retention effects very close to those of hydrocortisone. Most of the newer corticosteroids, whose names end in "asone", such as dexamethasone or betamethasone, have less sodium retentive effect. Some patients still show significant increases in drinking (polydipsia) and urination (polyuria) when these medications are administered but overall these effects are less likely to occur. We have switched from prednisone to dexamethasone in some patients on long term therapy just to get some alleviation from polydipsia or polyuria.

If corticosteroids are used for less than five days they are unlikely to produce harmful side effects in most patients, although in infections or immediate post-surgical situations there could be complications from this use. Dosages necessary to achieve the desired therapeutic effect will vary widely from patient to patient, making it necessary to establish the optimum dosage for corticosteroids on a case by case basis. The longer that corticosteroids must be used in a patient, the more likely it is that complications will occur. This is especially true when it is necessary to use corticosteroids on a daily basis, rather than at longer dosing intervals such as every other day or every third day. The goal in all cases in which long term use of corticosteroids is necessary has to be to use the lowest possible dosage at the longest interval between doses that will control clinical signs. It is better to use a higher dosage in order to reach a state in which alternate day dosing will work, though. For instance, it would be better to use 15 mg of prednisone every other day than to use 5mg per day, if long term use was necessary.

The major medicinal benefit of corticosteroids is their anti-inflammatory effect. It is important to remember that these pharmaceutical agents do not cure the disorder causing the inflammation, nor do they heal body tissues that are damaged, leading to inflammation. They just mask the symptoms of the inflammation, which can allow the patient to heal the underlying problem or which allows the patient to deal with the discomfort of a problem such as allergies, until the time when it will go away on its own, due to a change in season or reduced exposure to the allergen. These are the medications that have led to the oft repeated statement that modern medicines treat the symptoms without providing a cure. In this particular instance, the statement is true, almost all of the time. On the other hand, if an injection of methylprednisolone allows the spinal cord or brain to heal after a traumatic injury when it would not have been able to otherwise, is that really just treating the symptom (the inflammation inhibiting healing)?

These are the known effects of corticosteroids, good and bad:

Glucocorticoids cause in increase in the availability of sugar in the bloodstream and storage of sugar in the liver. Insulin resistance occurs with long term use of corticosteroids, adding to the increased blood sugar. Protein in the muscles is converted to carbohydrate for use as energy, leading to the use of the term "catabolic steroids", or opposite of anabolic steroids, to describe corticosteroids.

• Fats are also affected by corticosteroids. In this case, the problem is mostly redistribution of fats. This is most marked in humans, where fat collects under the skin of the face and neck and disappears from the limbs. In pets, there is often a marked reduction in fat deposition in the limbs, although the facial accumulation of fat doesn't appear to be as common. There is some increase in the utilization of fats for energy associated with corticosteroid use but this probably is not a significant effect.

• Because many of the corticosteroids promote retention of sodium, there is often a bloated feeling or water weight gain associated with the use of cortisones. As noted previously, this effect is noted more with some corticosteroids than with others. A side effect of sodium retention is loss of potassium, which is one of the causes of muscular weakness associated with prolonged corticosteroid use, the other being actual muscle loss as muscle is converted into carbohydrates to be used as energy. In some situations, cortisol and prednisolone can actually increase sodium excretion, rather than causing retention, but these are unusual circumstances, such as excessive intake of dietary sodium. Hypertension (high blood pressure) sometimes occurs with the use of corticosteroids and this effect may also be due to the sodium retention.

• Since muscles are weakened by the use of corticosteroids, the heart is also affected, since it is largely composed of muscle tissue and depends on muscular strength for contractions and its pumping ability. With long term use, corticosteroids will cause cardiovascular weakness.

• There have been many psychological effects of corticosteroids noted. The worst effect is steroid psychosis, which fortunately does seem to be a common effect. Humans sometimes seem to lose touch with reality but dogs and cats usually exhibit an increase in aggressive tendencies if they have this side effect. More commonly there is a sense of well-being associated with short-term use of corticosteroids which sometimes turns into an anxious or depressed state with longer term use. We have noted that many clients say that their pets "never felt better" when we start the administration of corticosteroids and then say it again when we are able to stop chronic use of the medications. I think they are probably right in both instances.

• Glucocorticoids tend to increase the number of red blood cells in the blood stream and also to increase hemoglobin levels. Corticosteroids increase the percentage and actual numbers of neutrophils in the blood stream. This probably occurs due to a number of effects on these cells, including release of neutrophils from the circulating reserves, increased release from the bone marrow and longer duration of time in which neutophils remain in the blood stream rather than going out of it to fight inflammatory situations. Lymphocytes are suppressed by corticosteroids. This can be a very significant effect, to the extent that prednisone is used as chemotherapeutic agent for lymphoma (cancer of the lymphoid tissue). This is probably also one of the reasons that corticosteroids are immunosuppressive, since many of the functions of the immune system are regulated by members of the lymphocyte family, such as T-cells and B-cells.

• Corticosteroids given to juvenile pets may inhibit growth. This is the reason that many veterinarians who are comfortable using corticosteroids in adult animals still try very hard to avoid the use of these compounds in pre-adult dogs and cats.

• The two really beneficial effects of corticosteroids are their anti-inflammatory effect and their immunosuppressive effect. Both of these effects have both good and bad components, though. The anti-inflammatory or immunosuppressive effects of corticosteroids can be so strong that the disease process causing the inflammation may go on unchecked while the patient feels fine, leading to the statement that corticosteroids allow some patients to walk to their graves. However, these effects also make it possible for many patients with severe allergic skin disease, asthma, collapsing trachea, immune-mediated diseases and traumatic injuries to the central nervous system to have some comfort in their lives -- or even may be the difference between staying alive and dying.

• In some patients, the increase in hunger associated with the use of corticosteroids is beneficial. A minor use of these medications is to enhance appetite in patients that need this effect temporarily.
As far as I can tell, no one really knows exactly how corticosteroids produce their anti-inflammatory effect. As a comparison, most non-steroidal anti-inflammatory medications directly inhibit the production of inflammatory agents in damaged tissue, which directly stops the inflammatory process. Corticosteroids do not stop inflammation, they just seem to allow the body to ignore it. I have heard this described as producing an action similar to an asbestos suit. A fireman might be able to walk directly into the flames wearing such a suit but it doesn't put them out. Despite that, it is still better for the fireman to have the suit -- if he can't avoid the flames in the first place.

There are many available corticosteroid products. They vary widely in the strength of their anti-inflammatory effect, their tendency to produce side effects and in their duration of action. A good rule of thumb for determining the duration of action of a corticosteroid is to look at the word that follows the name of the medication.

• succinate or phosphate = duration of action measured in minutes to hours
• dipropionate, acetate, butylacetate, methylacetate or diacetate = duration of action measured in days to weeks
• acetonide or pivulate = duration of action measured in weeks
This is a partial list of the available corticosteroids used in veterinary medicine. Remember that many products, especially eye and ear drops, may contain corticosteroids in addition to other ingredients:

 
Prednisone is probably the most commonly prescribed corticosteroid. It is inexpensive, readily available, has a short duration of action and is a small enough pill that most pets will accept it hidden in something palatable. Prednisone is converted into its active form, prednisolone, in the body. Some vets prefer to give prednisolone rather than prednisone, on the presumption that some pets will not be able to convert the prednisone to the active form. This is a very rare problem, if it occurs. It is best to use prednisone for less than five days if it is to be given on a daily basis. For longer duration of therapy it is much better to give prednisone on an every other day basis. Prednisone is a little more likely to cause excessive drinking and urination than methylprednisolone, dexamethasone and triamcinolone, so some vets prefer these medications as alternatives to prednisone. It is sometimes necessary to use these medications on an every third day basis to avoid problems with adrenal suppression.

There are some commonly used combination products that contain prednisone. One of these is Temeril-P (Rx), used for its anti-inflammatory properties in cases of tracheal collapse or lower airway diseases. It is important to remember that prednisone is being used on a daily basis when Temeril-P is given daily.

Another group of combination products that must be carefully watched for are eye medications containing both an antibiotic and a corticosteroid. The most commonly used product in this category is probably Gentocin Durafilm (Rx), which contains gentamicin and betamethasone but there are combination topicals with hydrocortisone and dexamethasone, as well. If a medication containing cortisone is placed on the surface of the eye when there is an active corneal ulcer or a scratch of the cornea, the inhibition to healing is very strong and lowered resistance to infection also occurs. This can lead to perforation of the eye from a rapidly developing ulcer. It is best never to use an eye medication containing a corticosteroid if there is any question at all that a corneal ulcer may be present.

In dogs, most veterinary practitioners try to avoid the use of longer term corticosteroids such as triamcinolone acetate (Vetalog Rx) and methylprednisolone acetate (DepoMedrol Rx), since these medications will exert an effect for a week or more after administration and dogs are somewhat prone to developing side effects from repeated use of these medications and will sometimes have problems from a single injection. Cats are much more resistant to the effects of corticosteroids, both good and bad. For this reason, the use of longer term injections is more common in cats and also seems to be more effective than alternate day dosing of oral medications such as prednisone. For the most part this seems to work well, although cats with preexisting cardiomyopathy (heart muscle weakness) sometimes have adverse reactions to these injections, which can be scary, and there does seem to be some problem with induction of diabetes in cats prone to this condition, which will sometimes resolve as the effect of the corticosteroid injection wears off.

Veterinary pharmacology professors routinely discourage the use of corticosteroids, with the exception of shock therapy and for spinal cord and CNS injuries. A direct quote from one that I had a discussion with was "Glucocorticoids are overused in general veterinary practice because their effects are so alluring, so I feel that it is my job to present the negative side of the picture strongly enough that students think about those when they are exposed to temptation to use these medications for all sorts of ailments in practice. So I tell them not to use them at all." I know of at least one other professor who feels the need to suppress the desire of his students to use corticosteroids to the point that he makes flat statements that corticosteroids should never be used in veterinary medicine outside of the above exceptions. This is simply overkill. There is a place for rational use of these medications. It can be a frustrating year for new veterinarians who try to practice veterinary medicine "in the real world" without using corticosteroids at all.

The use of corticosteroids can be life saving in endotoxic shock, spinal injuries and central nervous system injuries. It is usually necessary to use very high doses of corticosteroids in these situations but they are usually administered once or twice only. Corticosteroids can be life saving in disorders that require immune suppression, especially immune mediated thrombocytopenia, immune mediated hemolytic anemia, systemic lupus erythematosus and when phemphigus (immune mediated skin disease) occurs. They can be the difference between life and death in asthmatic patients. Corticosteroids provide a great deal of relief for itching in allergies and other inflammatory skin conditions. Unless you have experienced severe allergic disease it is difficult to appreciate just how much comfort these medications can provide. Think of poison ivy and then imagine living with it for months at a time. This is what some of our canine patients with allergic skin disease feel like. Many cases of chronic ear disease will not clear up with antibiotics alone. It is necessary to control the inflammation in the ears in order to allow the immune system and antibiotic or antifungal therapy to work. Failure to do so leads to chronic failure to control the ear disease. These are the types of situations in which corticosteroid use can be very beneficial.

There are significant downsides to the chronic use of corticosteroids. A list of demonstrated side effects includes suppression of the adrenal glands, leading to shock if glucocorticoids are suddenly withdrawn, suppression of the body's defense (immune system) mechanisms leading to worsening of bacterial, viral or fungal illnesses, gastrointestinal system ulceration, prolonged wound healing times, diarrhea (rare), behavioral changes including increased aggression or psychotic behavior, induction of diabetes in patients prone to this condition, cataract induction in dogs, birth defects and weakening of the cartilage substructure in joints, muscle weakness or wasting and increased blood pressure.

There are some good rules for rational use of corticosteroids. Please remember that these are guidelines and that there are going to be exceptions to them.

The first rule is that it is better to use shorter acting corticosteroids whenever possible.

• When using these medications it is better to use them every other day, or at longer intervals, if possible, rather than to use them daily.

• Evaluate the dosage necessary to control chronic conditions on a periodic basis, constantly striving to determine the lowest effective dose.

• The dose of corticosteroids may need to be tapered off prior to discontinuing the medication, if long term use is necessary. Especially if it was necessary to use corticosteroids on a daily basis.

• Antibiotic therapy is necessary when treating with corticosteroids in the face of a bacterial infection, such as skin infection or ear infections.

• Do not use corticosteroid medications for eye disorders if there is a corneal ulcer present.

• Report any deterioration in your pet's condition or any suspicious symptoms to your vet when your pet is taking a corticosteroid.
Corticosteroids will remain controversial medications because they have too many beneficial effects to ignore them and too many side effects to ever feel completely comfortable using them. However, don't get so uptight about their use that you follow the example of one of my clients. I had a client with an older dalmatian who had arthritis so severe that he could not get up. We gave him dexamethasone and he responded very well, having almost a week of good activity before the effect of the injection wore off. The client returned and asked what we did the week before to make her dog better. I said that we gave him dexamethasone but that we could give him prednisone orally since cortisones seemed to help so much. "I can't give him a cortisone, that's an evil medicine," was her response. "I guess you'll have to put him to sleep." I tried to explain that I couldn't see how the use of cortisones, even if turned out to be fatal in six months, was worse than euthanasia now, but to no avail. There are times when it makes sense to use corticosteroids. You just have to pick the times carefully.

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What is the Maximum Dosage for Insulin?

I can't explain why some questions seem to come in bunches, but we have had several requests for information about the maximum acceptable dosage for insulin in a dog or cat over the last couple of months. The answer to this question is that there is no maximum dosage for insulin. A dog or cat with diabetes has to be given the dosage of insulin that will control the blood sugar adequately. If this is 25, 50 or 500 units per day, it does not matter. The only thing that matters is that the blood glucose levels be controlled. There is reason to consider changing the type of insulin when resistance seems to develop to the insulin that is being used. If a dog is well regulated for a long time on 15 units of insulin and then over the course of a month or two the dosage has to be doubled, there is a chance that antibodies have formed to the type of insulin being used. A change from human origin insulin to beef or pork insulin might result in the ability to establish a lower effective dosage again. One standard for considering this type of change has been when the insulin dosage exceeds 1 unit per pound of body weight, which some people seem to have decided was the maximum dosage of insulin allowable. This is simply not the case. Should insulin requirements remain high on the new insulin, it is necessary to give whatever dose will work. In extreme instance in humans, insulin dosages in the thousands of units per day have been used to control extreme resistance to insulin. This is not practical in dogs and cats due to cost, but cost is the limiting factor, not the insulin dosage. If the insulin dosage exceeds 1 unit per pound of body weight, there is reason to be concerned about insulin resistance and to make some attempts to correct that problem but it is still necessary to give whatever dose of insulin it takes to control the blood sugar, until the insulin resistance problem can be resolved, if it is possible to resolve it.

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Finding Information on the VetInfo Web Site

Michal asked me to post the URLs of the five pages that are most useful to subscribers for finding information on the VetInfo web site. For people who like to look for information by using an index, the most useful URLs are:

http://www.vetinfo.com

http://www.vetinfo4dogs.com

http://www.vetinfo4cats.com



For people who prefer to use a search engine, the URL for the two search engines is:

www.vetinfo.com/vetinfo_search_page.html

The URL for the page that probably has the most recent information, although it is unsorted, is:

www.vetinfo.com/Q&A.html

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If you send us e-mail, remember that Michal Justis answers the e-mail at vetinfo@vetinfo.com. E-mail sent to mervet@inna.net is answered by Dr. Michael Richards.

The VetInfo Digest is published by TierCom, Inc., P.O. Box 476, Cobbs Creek, VA 23035. The opinions expressed in this newsletter are those of Michael Richards, DVM., author.

This page was last edited  06/14/05

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