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How to respond to adverse drug reactions
Vet Clin Food Anim 19 (2003) 715–726
How to respond to adverse drug reactions Gordon W. Brumbaugh, DVM, PhD Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4466, USA
Adverse drug reactions (ADRs) are defined as any unintended or undesirable response to a drug [1]. ADRs can be classified by a variety of methods. It is not easy to simplify by classification, an occurrence that is often complex. One of the most simple methods is to separate ADRs into two groups: those that are concentration- or dose-dependent (type A) and those that are not concentration- or dose-dependent (type B). Type A reactions may be manifested clinically as exaggerated pharmacologic responses or toxic responses if circulating concentrations of the drug exceed those that are considered to be therapeutic. If concentrations of the drug are below those considered to be therapeutic and the animal fails to respond, that also constitutes an ADR. Most immune-mediated ADRs are classified as type B reactions, as are the idiosyncratic responses, because they are not concentration- or dose-dependent. The first occurrence of an immunemediated reaction is often not predictable. Subsequent reactions, although they may be manifested differently, should be expected and relatively more predictable in that animal. The subject of ADRs is important to clinical veterinary medicine for several reasons. In this article, four of those reasons are considered. First, ADRs are part of the risk-benefit decision-making process regarding treatment of any patient. Second, many veterinarians eventually have the experience of caring for a patient with an ADR and may desire some guidance about how to respond during that situation. Third, for reasons that vary from curiosity to medicolegal obligations, a cause for the ADR usually is sought, and the attending veterinarian is the most important diagnostic tool. Fourth, reporting ADRs is of medicolegal importance to the profession. It is critical to distinguish between an ADR and an adverse drug experience. An adverse drug experience is defined by the Food and Drug
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Administration, Center for Veterinary Medicine (FDA-CVM) as ‘‘any side effect, injury, toxicity, or sensitivity reaction (or failure to perform as expected) associated with use of an animal drug, whether or not determined to be attributable to the drug’’ [2]. By definition, an ADR must be attributable to the drug. Without attributing the reaction to the drug in question, further discussion is of no clinical relevance. The word reaction implies that there was an inciting action. The inciting action, in the case of an ADR, is the exposure (parenteral, topical, enteral, inspired, or a combination of those routes) to the drug. Without that action, there can be no reaction. The nature of that reaction is paramount to understanding the proper response for care of the patient and for control or prevention of subsequent ADRs. If the reaction is desirable and as intended, all is well and everyone is happy. If the reaction is not intended or desirable, an adversity is declared. All side effects, whether intended or unintended, are not undesirable and are not necessarily ADRs. Lack of response to a medication is an ADR when a response is declared in the product’s labeling and is anticipated and desired. Injection-site reactions and violative residues of medication in edible tissues may be classified legitimately as ADRs.
Incidence of adverse drug reactions No xenobiotic is exempt from the risk of inducing an ADR. A quick review of the package insert of many products for use in people (prescription or over-the-counter) reveals that ADRs occur in response to placebos. Placebos are medically inactive substances, but they cause ADRs. Growing evidence of that fact raises the sarcastic question, ‘‘How can the use of a placebo ever be approved?’’ Assessment of risk usually involves statistical evaluation of the incidence of ADRs caused by the medication in question. The basis for comparison could be any of several measurable variables, such as the number of doses administered, the number of patients that received the medication, the number of courses of treatment with the medication, the number of doses sold, and so forth. Opinions differ regarding which one of those variables is most clinically meaningful. An unabridged review of ADRs in bovine patients is not possible, because published reports [2–4] are of unconfirmed ‘‘events,’’ not of established, factual ADRs. There can be no discussion of incidence of ADRs to particular drugs when it is not known if they actually occurred.
How to respond to an adverse drug reaction Advice from professional liability insurance carriers or attorneys may differ from some points that follow. The reader is advised that contained herein are points that vary in importance from helpful to decisive when
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involved with ADRs in animal patients. These points are intended to be a guide for the reader to incorporate as each deems valuable in his or her practice. Most owners of an animal that is reacting adversely to a medication respond emotionally. The veterinarian may have and experience his or her own emotions but should respond objectively and professionally. At some time during his or her practice, each veterinarian encounters, first-hand or secondary to actions of others, animals that are experiencing an ADR. Apart from being a memorable event, the emotional, mental, and sometimes physical pressures that accompany that case can be demanding. The general types of reactions and basic methods of managing them have been published previously and have not changed markedly for several decades [1,5–7]. Clinical signs of acute ADRs may require seconds to hours before they develop sufficiently to be recognized. Delayed reactions may not become evident for days or weeks. Restraint of the patient that is experiencing an acute ADR may be essential for initial evaluation and care, but a chute or alley may not be appropriate for some animals experiencing an acute ADR. In the judgment of the attending veterinarian, it may be prudent to apply more physical restraint, whereas at other times less restraint may be appropriate for protection of the animal and personnel. If you are the professional in charge and you get injured or incapacitated, who will take over in your absence?
Treat the animal according to the presenting clinical signs After recognition of the existence of an ADR and regardless of cause, administration of the medication in question should be discontinued, and supportive care should be directed at maintaining or supporting life while blocking or decreasing absorption of the offending agent and enhancing elimination of the drug of concern. If the offending agent was administered parenterally, blocking absorption is not possible. For drugs administered orally, treatment with 1 g of activated charcoal per kg body weight administered orally within the first 4 hours is perhaps most likely to reduce or prevent further absorption of the medication and to aid elimination [5–7]. If the offending agent was administered topically, the animal may benefit from a bath to remove the agent before it is absorbed. Soap, shampoo, or detergent may be preferred, but a rinse with only water may dilute the agent sufficiently to be of benefit. Parenteral depot products are designed to prolong absorption; therefore, if an ADR to one of those products occurs, the prolonged absorption may prolong the risk of and duration of that ADR. Care for that patient may need to be prolonged proportionately. Elimination of the drug from the body by natural routes is the most efficient. Obviously, this method requires that the animal be alive to function adequately, and supportive care should be aimed at assisting those
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routes of elimination. Without specific indications, other medications may not be necessary. For some patients with nonlethal reactions, no treatment is necessary. Insufflation with oxygen, correction and maintenance of proper balance of fluids and electrolytes, and temperature control may be sufficient to assist the patient through the initial acute reaction and recuperation.
Anaphylaxic versus anaphylactoid reactions Although the incidence of anaphylactic and anaphylactoid reactions cannot be discussed legitimately, they are arguably two reactions that are frequently lethal. The following discussion of these two histamine-mediated conditions is presented to promote proper pharmacologic management of patients that experience those reactions and to discourage inappropriate use of those diagnoses. Anaphylaxis is one of several types of immune-mediated reactions. In anaphylaxis, the drug or drug-hapten complex is the antigen to which antibodies (primarily immunoglobulin E) have been formed. Those IgE molecules are fixed on mast cells. When the specific antigen is administered, the antigen-antibody interaction results in liberation of histamine that has been manufactured and stored in those mast cells. The free histamine then causes the observed clinical signs [8,9]. Anaphylactoid reactions, as the name implies, are like anaphylaxis. Clinical signs of the two reactions are identical because, in both reactions, they are mediated by histamine. The difference between anaphylaxis and anaphylactoid reactions is the mechanism by which histamine is released from mast cells. In anaphylactoid reactions, histamine is liberated by non–immune-mediated mechanisms that include chemical (opiates), physical (dermatographism), or thermal (usually cold) stimuli that directly cause the mast cells to degranulate. Treatment is the same for patients with either anaphylactic or anaphylactoid reactions. Until and unless an immune-mediated component is proven to induce degranulation of mast cells, the final diagnosis of anaphylaxis cannot be established. Distinction between anaphylactic and anaphylactoid reactions is critical to future management of that patient. Risks of anaphylactic reactions can be reduced by avoiding administration of the specific antigen or cross-reactive antigens. Anaphylactoid reactions can be reduced by prophylactic administration of antihistamines. During an ADR mediated by histamine, the animal is contributing physiologically to its own demise. The most profound contributory effects of histamine are hypotension as a result of peripheral vascular dilation and extravasation of vascular fluid caused by histamine-induced separation of endothelial cells. Vascular congestion and localized edema may occur at multiple sites. If those sites are the skin, urticaria and redness may be observed. Any anatomic location of capillary beds (virtually the entire body) can have the same effects, with associated clinical signs.
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Histamine is metabolized rapidly; it is inactivated in vivo and has an acute action. Effects of that action may be prolonged by several hours after concentrations of histamine have abated. If the effect is extensive and severe, the animal may die within minutes of release of histamine. The treatment of choice for histamine-induced reactions is epinephrine because it is a physiologic antagonist of histamine [10,11], which is to say that whatever histamine causes physiologically, epinephrine causes the opposite effects and therefore reverses effects of histamine by a different mechanism of action. That action and effect of epinephrine, if administered in time, can be sufficiently rapid to save the animal from lethal effects of histamine. Antihistamines are competitive blockers of histamine subtype 1 receptors (H1-blockers) [8,9]. They compete with histamine for the same receptors and as such, produce a clinically beneficial effect only if present in a concentration sufficient to displace histamine from the H1-receptors and then prevent it from re-uniting with those receptors. If clinical signs caused by histamine are present, H1-blockers are seldom of clinical benefit for reversal of those signs. They are of more benefit prophylactically, administered before release of histamine, such as previous to administration of a substance that is known to directly cause release of histamine [8,9]. Glucocorticosteroids are included in this discussion of ADRs for comparative purposes. Glucocorticosteroids do not change production, storage, or response of receptors to histamine [12,13]. They change the inflammatory response to injury which, arguably, plays a role in recovery from some ADRs, but glucocorticoids are of little or no benefit in the treatment of an acute histamine-induced ADR. Any beneficial effect that they may provide at a therapeutic dose occurs hours after they have been administered. The patient may die waiting for any benefit from glucocorticosteroids alone. No controlled studies of treatment of histamine-medicated ADRs in cattle have been found by the author on which referenced recommendations can be made. Personal experience and other nonpublished comments from veterinarians are the basis for the recommendations for the following suggested use of epinephrine. Treatment of choice for a life-threatening, histamine-induced ADR is epinephrine (0.002–0.006 mL of 1:1000 IU epinephrine per kg body weight) administered intravenously, intramuscularly, or divided between those routes. The duration of effect of epinephrine is short, and it may need to be administered repeatedly (every 15–30 minutes) during the first 1 to 2 hours after the ADR begins. The dose usually can be decreased and the interval increased during the first 2 hours, depending on the response of the patient, which can be dramatic. After a beneficial response to epinephrine is observed, antihistamines or glucocorticosteroids may be administered. Their benefits may predominate during the subsequent hours of recovery. There is no evidence of superiority of one antihistamine or glucocorticoid compared with another. Labeled directions for anti-inflammatory doses are indicated, but ‘‘super doses’’ are of no known benefit; however, they are associated with adversities [8–13].
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Although many products that contain antihistamines are labeled for intravenous administration, adverse effects subsequent to intravenous administration of antihistamines do occur, and it is recommend that the intramuscular route be used for parenteral administration of antihistamines to cattle. If an animal is not having a life-threatening, histamine-induced reaction, the use of antihistamines or glucocorticoids is of little benefit. When administered prophylactically, antihistamines should be administered 20 to 30 minutes before an event that may cause liberation of stored histamine. Much of the treatment of ADRs in animals is extrapolated from treatment of human or canine patients. That information may not be applicable to cattle. One reason that human patients with histamine-induced reactions are treated with antihistamines or glucocorticosteroids is that those patients are often pruritic. Pruritus is not a consistent finding with those reactions in large animal species; however, if present, it should be considered an indication for use of antihistamines or glucocorticoids. If pruritus is not present, there is little reason to use them.
Specific reversal agents Many reports of suspected ADRs are not histamine-mediated but rather are direct results of exaggerated pharmacologic action and effect of the medication in question [1–4]. Specific reversal agents are available for some of those compounds, but unless a specific causality relationship with the ADR can be established, administering them may not be beneficial. Interactions of two or more medications also can cause adverse pharmacologic effects. Management of those reactions depends on the specific medications involved. Additional or specific assistance with managing ADRs caused by those products may be available by contacting professional services personnel at the manufacturer of the product. Personnel in those departments are responsible for investigating such requests registered with them. Manufacturers of generically labeled products may not have professional services personnel. When emergency measures are needed, telephone contact may be sufficient initially. That assistance can be provided best in a professional manner if those representatives are treated as professional colleagues. Those individuals cannot divine answers nor can they see through the telephone (unless both ends of the call have compatible technology), so it is important to ask for any assistance available, but answers to specific questions can be answered best. Do not withhold information; be objective, complete, honest, and specific. Remember and apply the ‘‘golden rule.’’ Most of the professional services personnel cannot drop what they are doing at that instant and make an emergency visit to your location; however, a personal visit by one of them or a hired representative (perhaps a colleague in your area) may be possible at a later scheduled time.
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Subsequent to all the initial activity, you should request an investigation by and subsequently submit a written report to the manufacturer of the product. Some professional services personnel investigate without a request. During that investigation, more helpful information may come to light that can be of use in the future. The most important information is the professional assessment or evaluation by the attending veterinarian. That responsibility should be received with the same ethical approach as any other aspect of practice. If the animal does not survive the ADR, the client should be asked to grant permission for a necropsy to be performed. The client or the manufacturer’s representative may request that the necropsy be performed by a certain person or facility in particular, but the most important point is to perform that necropsy in a timely manner. If a necropsy is performed immediately after the gross examination has been completed, and if considered necessary, that veterinarian can contact (by telephone) a pathologist at a diagnostic laboratory, describe the findings, and ask for guidance regarding submission of samples for additional diagnostic evaluation. By doing so, time is not lost, appropriate organs or tissues can be examined, samples can be obtained and submitted properly for more detailed evaluation, and professional service has been rendered. It is advisable to take pictures of the animal and anything that may be of assistance in understanding the particular situation. Proper identification of those elements is important. In addition to the client and professional services personnel, other individuals who may need to be informed of the event include your professional insurance agent or adjuster and attorney. Depending on the reaction (sometimes adverse, sometimes not) of the client, the order and extent of involvement of each may be different, but all should be informed.
Cause The true cause of the reaction is of paramount importance (1) if a specific reversal agent or other specific treatment is available and (2) to control or prevent subsequent reactions of a similar nature. The necessity of a specific causal relationship is supported by a remedial fact about immune-mediated reactions (adverse or beneficial). Those reactions are specific because the antigen-antibody interaction is specific. The attending veterinarian is unequivocally the best diagnostic tool regarding the occurrence of an ADR. Other than a ‘‘challenge’’ study, there is no diagnostic ‘‘test’’; and there is no pathognomonic lesion of an ADR. Interpretation by the attending professional is the most important component, and attention to detail is important. After recognizing the occurrence of an ADR and tending to the needs of the patient, that person’s attention can turn to diagnosing the cause. It is important to remember that a cause may not be determined definitively.
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All products administered to the patient around the time that the ADR occurred should be saved. Do not discard them. Store them in conditions as described on their respective labels and do not use more product from those containers. Those containers and products are invaluable as elements in the chain of evidence for the determination of the cause of the ADR and should be labeled with identifying information and cared for appropriately. Instructions about where to submit those samples and how to handle them will come from parties involved with those aspects. Many times, the only, or most experienced, analytical personnel are at the manufacturer of the product. Although accusations to the contrary may arise, that fact remains. Quality control measures can and should be implemented to maintain confidence in results. Sometimes the cause of the reaction is not sought until after the acute reaction has passed and the emotional and physical activities associated with dealing with the reaction have subsided. As soon as possible, it is important to record details of the events before, during, and after the reaction. Events that may seem inconsequential at first may be important. Included must be such things as the proximate time of administration of the medication; clinical signs and the relative contribution of the initial illness; concurrently administered medication; the principal active ingredient and its metabolites; inactive ingredients; serial or lot number and expiration date; and other clinically relevant information before concluding the probable cause. ‘‘Probable cause,’’ as used scientifically or medically, is considerably different from its use in terms of litigation. Many times, it is not possible to separate the relative contributions of each component in a product or if more than one product was administered concurrently. If more than one product is involved, inherent risks of each compound separately, consecutively, and interactively are present but seldom, if ever, known. For example, if two drugs (A and B) are administered to a healthy animal, the inherent risk of adversity includes the sum or the net of the risk for the respective factors that follow: drug A alone, drug B alone, drug A if drug B caused its effect first, drug B if drug A caused its effect first, and the chemicophysical interaction of drugs A and B creating a different compound. If the animal was diseased, the contribution of the disease alone and interactions with each of the aforementioned factors must be considered. Report The most completely investigated reports of ADRs are those that have been investigated by the professional services personnel of pharmaceutical manufacturers of products in question or associated with ADRs. The attending veterinarian should work with those personnel and should submit to them a written report of all findings and conclusions. In the United States, those pharmaceutical manufacturers are required by federal law to
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report any ADRs to the FDA-CVM [2]. Inadequate information regarding ADRs in animal patients is only a reflection on the quality of reports submitted by owners of the patient or the attending veterinarian. The better the information they receive, the better the reports they can submit to the FDA-CVM. Personnel of the FDA have no obligation to respond to any report of adversity or to determine if a particular product was causative. Products licensed by the United States Department of Agriculture or by the Environmental Protection Agency do not have the same requirements for reporting as do pharmaceutical products. Time allowed for a reply to any request should be appropriate; at the least, it is common courtesy. In this ‘‘microwave’’ age, people seem to think that they are entitled to anything and everything instantaneously. Anyone who actually is involved will attest to the fact that forensic evaluation is seldom as rapid and unambiguous as depicted by the entertainment industry. Reality does not imitate that perception. The emergency that you may be dealing with is one of the activities of any practice. It is no less or more important than are any other clients or patients. Your time is valuable and necessary, as is that of the client and any person involved. A reasonable time is appropriate and can be requested. Allow yourself the same respect to devote your time to solving the problem.
Injection-site reactions The use of ‘‘tissue-friendly’’ animal health products (vitamins, biologics, therapeutic agents) has grown, but it is probably realistic to expect a degree of reaction at the site of injection of any parenteral formulation [14]. The extent of that reaction and the adversity it causes depend on many variables. The endpoint for evaluation is important and can vary from the classic signs of inflammation to necrosis of tissue. No single histologic class of lesion can be associated with any one product. The time of evaluation after injection is also important because replacement of damaged tissue with fibrous tissue, maturation of that fibrous tissue, effect of that fibrous tissue on surrounding tissues (tenderness of meat, scarring of the hide), and the degree to which those changes are considered to be unacceptable affect the classification of that reaction. The economic loss to ‘‘trimmed’’ lesions depends on the amount and the market value of the product removed. Subcutaneous injections in the neck or over the ribs cause minimal reactions to the subcutaneous tissues [14]. Lesions occasionally were noticed in muscle adjacent to the subcutaneous site in the neck, but muscles adjacent to injections over the ribs were not evaluated. Intramuscular injections in the muscles of the neck produced less-noticeable lesions and less economic loss than did injections in the gluteal (top butt) or semimembranosus (inside round) muscles. Generally, it is recommended to administer parenteral products subcutaneously rather than intramuscularly if a choice is
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permitted. The neck seems to be the best anatomic site for either route of administration to minimize tissue reaction. When intramuscular injections are used, it is recommended that no more than 10 mL be administered per site. Low-volume, highly concentrated products are not necessarily the best for minimizing tissue reactions, minimizing risks for residues, or for therapeutic response. (See the article on neonatal adjustments by Brumbaugh elsewhere in this issue.)
Residues In other literature, considerable attention has been afforded the subject of violative residues of drugs in food. The subject is included here because the author considers some instances of residues to be classified legitimately as ADRs by the strictest definition of the term; they are undesired reactions to administration of a product. All instances of residues are not violative, and all violative residues are not the result of negligence. It is important to remember and to educate clients (producers are consumers, too) that live animals are considered to be food, not raw agricultural products. Regulations have been instituted, volunteer or mandatory programs introduced, and a considerable amount of resources have been allocated to reduce risks of violative residues in food products. As those pressures on producers continue to grow and the ‘‘standard’’ is raised, there will continue to be a risk of adverse residues and there will continue to be individuals who are dissatisfied with the results of any or all efforts. No system has been proven to be totally effective at eliminating those risks. There are many ways to evaluate the efficacy of those activities, and improvements always can be made in a dynamic system [15].
Prepare and practice a plan Experience can be a great teacher. . .if you survive the class. The experience of involvement with ADRs in animal patients is no different. It is, however, an experience in which few veterinarians or clients choose to participate. After each incidence of an ADR has passed, it is advisable to reflect on and evaluate the actions taken and what, if anything, could be done to improve the response for subsequent patients. If your personal experience has not included that of an animal with an ADR, it is advisable to plan an approach based on comments and experiences of those who have had that experience. It is one thing to have a formulated plan; it is another to implement it. Practice the plan you have formulated. Include all personnel that might be required to participate. Does each one know what to do or what not to do? With practice, it may be possible to identify potential problems and to take steps to correct them before they interfere with care of a patient. Be open to suggestions from any of the personnel who could improve medical care during the unpleasant situation.
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Points to be considered in that plan may include the following. Stop administration of medication in question. This action is remedial but sometimes is overlooked. Treat the animal according to presenting clinical signs, which requires a prudent examination of the animal followed by treatment as deemed necessary. Are the necessary supplies readily available? Are emergency medications reviewed regularly, and outdated supplies replaced? Is there a chart for doses? In the few seconds to minutes that are needed to respond to an animal with an ADR, there is little time to make those calculations. Contact professional services representatives. A list of manufacturers of products that you use and current contact information should be prepared, readily available, and regularly updated. Investigate causes of the ADR. Regardless of the amount of information available regarding the particular incident, interpretation by the attending veterinarian is the most important diagnostic tool. Properly obtained, submitted, or processed samples of the medication or tissues are helpful in trying to determine the cause of an ADR. When all information has been accumulated and evaluated, submit a written report to the professional services representative of the manufacturer of the product. A copy also may be submitted to the FDA-CVM. Natural or inherent risks of the use of medication in animals include the risk of an ADR. How does that risk compare with the risk of not treating? In addition to the prevalent ‘‘microwave-entitlement’’ attitude, people want to blame something or someone. The occurrence of an ADR is not prima facie evidence of negligence. The cause of the ADR may be found and liability may be placed, but that judgment should be reserved until a thorough investigation is complete. References [1] Brumbaugh GW, Boothe DM. Adverse drug reactions. In: Howard JL, Smith RA, editors. Current veterinary therapy: food animal practice. 4th edition. Philadelphia: W.B. Saunders; 1999. p. 12–7. [2] Bataller N, Keller WC. Monitoring ADRs to veterinary drugs. Vet Clin North Am Food Anim Pract 1999;15(1):13–30. [3] Tja¨lve H. ADRs to veterinary drugs reported in Sweden during 1991–1995. J Vet Pharmacol Ther 1997;20:105–10. [4] Gehring R. Suspected ADRs to veterinary drugs reported in South Africa (January 1998– February 2001). J South African Vet Assoc 2001;72(3):120–6. [5] Szabuniewicz M, Bailey EM, Wiersig DO. Treatment of some common poisonings in animals. Vet Med Small Anim Clin 1971;66(12):1197–205. [6] Szabuniewicz M, Bailey EM, Wiersig DO. Clinical aspects of drug actions and interactions in veterinary practice. Vet Med Small Anim Clin 1973;68(9):1048–58. [7] Brumbaugh GW. Adverse drug reactions and interactions in the horse. Vet Clin North Am Equine Pract 2001;17(3):445–53. [8] Adams HR. Autocoids and antiinflammatory drugs. In: Adams HR, editor. Veterinary pharmacology and therapeutics. Ames (IA): Iowa State University Press; 1995. p. 401–11. [9] Babe KS, Sarafin WE. Histamin, bradykinin, and their antagonists. In: Molinoff PB, Ruddon RW, Gilman AG, editors. Goodman & Gilman’s the pharmacological basis of
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G.W. Brumbaugh / Vet Clin Food Anim 19 (2003) 715–726 therapeutics. 9th edition. New York: McGraw-Hill, Health Professional Division; 1996. p. 581–600. Hoffman BB, Lefkowitz RJ. Catecholamines, sympathetic drugs, and adrenergic receptor antagonists. In: Molinoff PB, Ruddon RW, Gilman AG, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. 9th edition. New York: McGraw-Hill, Health Professional Division; 1996. p. 199–248. Adams HR. Adrenergic agonists and antagonists. In: Adams HR, editor. Veterinary pharmacology and therapeutics. Ames (IA): Iowa State University Press; 1995. p. 87–113. Ferguson DC, Hoenig M. Glucocorticoids, mineralocorticoids, and steroid synthesis inhibitors. In: Adams HR, editor. Veterinary pharmacology and therapeutics. Ames (IA): Iowa State University Press; 1995. p. 622–43. Schimmer BP, Parker KL. Adrenocorticotropic hormone: adrenocortical steroids and their synthetic analogs—inhibitors of the synthesis and actions of adrenocortical hormones. In: Molinoff PB, Ruddon RW, Gilman AG, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. 9th edition. New York: McGraw-Hill, Health Professional Division; 1996. p. 1459–85. Van Donkersgoed J, Dubeski PL, VanderKop M, Aalhus JL, Bygrove S, Starr WN. The effect of animal health products on the formation of injection site lesions in subprimals of experimentally injected beef calves. Can Vet J 2000;41:617–22. Gibbons-Burgener SN, Kaneene JB, Lloyd JW, Erskine RJ. Influence of the Milk and Dairy Beef Quality Assurance Program on dairy farm drug management practices. J Am Vet Med Assoc 2000;216(12):1960–4.
How to respond to adverse drug reactions Gordon W. Brumbaugh, DVM, PhD Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4466, USA
Adverse drug reactions (ADRs) are defined as any unintended or undesirable response to a drug [1]. ADRs can be classified by a variety of methods. It is not easy to simplify by classification, an occurrence that is often complex. One of the most simple methods is to separate ADRs into two groups: those that are concentration- or dose-dependent (type A) and those that are not concentration- or dose-dependent (type B). Type A reactions may be manifested clinically as exaggerated pharmacologic responses or toxic responses if circulating concentrations of the drug exceed those that are considered to be therapeutic. If concentrations of the drug are below those considered to be therapeutic and the animal fails to respond, that also constitutes an ADR. Most immune-mediated ADRs are classified as type B reactions, as are the idiosyncratic responses, because they are not concentration- or dose-dependent. The first occurrence of an immunemediated reaction is often not predictable. Subsequent reactions, although they may be manifested differently, should be expected and relatively more predictable in that animal. The subject of ADRs is important to clinical veterinary medicine for several reasons. In this article, four of those reasons are considered. First, ADRs are part of the risk-benefit decision-making process regarding treatment of any patient. Second, many veterinarians eventually have the experience of caring for a patient with an ADR and may desire some guidance about how to respond during that situation. Third, for reasons that vary from curiosity to medicolegal obligations, a cause for the ADR usually is sought, and the attending veterinarian is the most important diagnostic tool. Fourth, reporting ADRs is of medicolegal importance to the profession. It is critical to distinguish between an ADR and an adverse drug experience. An adverse drug experience is defined by the Food and Drug
E-mail address: [email protected] 0749-0720/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0749-0720(03)00055-0
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Administration, Center for Veterinary Medicine (FDA-CVM) as ‘‘any side effect, injury, toxicity, or sensitivity reaction (or failure to perform as expected) associated with use of an animal drug, whether or not determined to be attributable to the drug’’ [2]. By definition, an ADR must be attributable to the drug. Without attributing the reaction to the drug in question, further discussion is of no clinical relevance. The word reaction implies that there was an inciting action. The inciting action, in the case of an ADR, is the exposure (parenteral, topical, enteral, inspired, or a combination of those routes) to the drug. Without that action, there can be no reaction. The nature of that reaction is paramount to understanding the proper response for care of the patient and for control or prevention of subsequent ADRs. If the reaction is desirable and as intended, all is well and everyone is happy. If the reaction is not intended or desirable, an adversity is declared. All side effects, whether intended or unintended, are not undesirable and are not necessarily ADRs. Lack of response to a medication is an ADR when a response is declared in the product’s labeling and is anticipated and desired. Injection-site reactions and violative residues of medication in edible tissues may be classified legitimately as ADRs.
Incidence of adverse drug reactions No xenobiotic is exempt from the risk of inducing an ADR. A quick review of the package insert of many products for use in people (prescription or over-the-counter) reveals that ADRs occur in response to placebos. Placebos are medically inactive substances, but they cause ADRs. Growing evidence of that fact raises the sarcastic question, ‘‘How can the use of a placebo ever be approved?’’ Assessment of risk usually involves statistical evaluation of the incidence of ADRs caused by the medication in question. The basis for comparison could be any of several measurable variables, such as the number of doses administered, the number of patients that received the medication, the number of courses of treatment with the medication, the number of doses sold, and so forth. Opinions differ regarding which one of those variables is most clinically meaningful. An unabridged review of ADRs in bovine patients is not possible, because published reports [2–4] are of unconfirmed ‘‘events,’’ not of established, factual ADRs. There can be no discussion of incidence of ADRs to particular drugs when it is not known if they actually occurred.
How to respond to an adverse drug reaction Advice from professional liability insurance carriers or attorneys may differ from some points that follow. The reader is advised that contained herein are points that vary in importance from helpful to decisive when
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involved with ADRs in animal patients. These points are intended to be a guide for the reader to incorporate as each deems valuable in his or her practice. Most owners of an animal that is reacting adversely to a medication respond emotionally. The veterinarian may have and experience his or her own emotions but should respond objectively and professionally. At some time during his or her practice, each veterinarian encounters, first-hand or secondary to actions of others, animals that are experiencing an ADR. Apart from being a memorable event, the emotional, mental, and sometimes physical pressures that accompany that case can be demanding. The general types of reactions and basic methods of managing them have been published previously and have not changed markedly for several decades [1,5–7]. Clinical signs of acute ADRs may require seconds to hours before they develop sufficiently to be recognized. Delayed reactions may not become evident for days or weeks. Restraint of the patient that is experiencing an acute ADR may be essential for initial evaluation and care, but a chute or alley may not be appropriate for some animals experiencing an acute ADR. In the judgment of the attending veterinarian, it may be prudent to apply more physical restraint, whereas at other times less restraint may be appropriate for protection of the animal and personnel. If you are the professional in charge and you get injured or incapacitated, who will take over in your absence?
Treat the animal according to the presenting clinical signs After recognition of the existence of an ADR and regardless of cause, administration of the medication in question should be discontinued, and supportive care should be directed at maintaining or supporting life while blocking or decreasing absorption of the offending agent and enhancing elimination of the drug of concern. If the offending agent was administered parenterally, blocking absorption is not possible. For drugs administered orally, treatment with 1 g of activated charcoal per kg body weight administered orally within the first 4 hours is perhaps most likely to reduce or prevent further absorption of the medication and to aid elimination [5–7]. If the offending agent was administered topically, the animal may benefit from a bath to remove the agent before it is absorbed. Soap, shampoo, or detergent may be preferred, but a rinse with only water may dilute the agent sufficiently to be of benefit. Parenteral depot products are designed to prolong absorption; therefore, if an ADR to one of those products occurs, the prolonged absorption may prolong the risk of and duration of that ADR. Care for that patient may need to be prolonged proportionately. Elimination of the drug from the body by natural routes is the most efficient. Obviously, this method requires that the animal be alive to function adequately, and supportive care should be aimed at assisting those
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routes of elimination. Without specific indications, other medications may not be necessary. For some patients with nonlethal reactions, no treatment is necessary. Insufflation with oxygen, correction and maintenance of proper balance of fluids and electrolytes, and temperature control may be sufficient to assist the patient through the initial acute reaction and recuperation.
Anaphylaxic versus anaphylactoid reactions Although the incidence of anaphylactic and anaphylactoid reactions cannot be discussed legitimately, they are arguably two reactions that are frequently lethal. The following discussion of these two histamine-mediated conditions is presented to promote proper pharmacologic management of patients that experience those reactions and to discourage inappropriate use of those diagnoses. Anaphylaxis is one of several types of immune-mediated reactions. In anaphylaxis, the drug or drug-hapten complex is the antigen to which antibodies (primarily immunoglobulin E) have been formed. Those IgE molecules are fixed on mast cells. When the specific antigen is administered, the antigen-antibody interaction results in liberation of histamine that has been manufactured and stored in those mast cells. The free histamine then causes the observed clinical signs [8,9]. Anaphylactoid reactions, as the name implies, are like anaphylaxis. Clinical signs of the two reactions are identical because, in both reactions, they are mediated by histamine. The difference between anaphylaxis and anaphylactoid reactions is the mechanism by which histamine is released from mast cells. In anaphylactoid reactions, histamine is liberated by non–immune-mediated mechanisms that include chemical (opiates), physical (dermatographism), or thermal (usually cold) stimuli that directly cause the mast cells to degranulate. Treatment is the same for patients with either anaphylactic or anaphylactoid reactions. Until and unless an immune-mediated component is proven to induce degranulation of mast cells, the final diagnosis of anaphylaxis cannot be established. Distinction between anaphylactic and anaphylactoid reactions is critical to future management of that patient. Risks of anaphylactic reactions can be reduced by avoiding administration of the specific antigen or cross-reactive antigens. Anaphylactoid reactions can be reduced by prophylactic administration of antihistamines. During an ADR mediated by histamine, the animal is contributing physiologically to its own demise. The most profound contributory effects of histamine are hypotension as a result of peripheral vascular dilation and extravasation of vascular fluid caused by histamine-induced separation of endothelial cells. Vascular congestion and localized edema may occur at multiple sites. If those sites are the skin, urticaria and redness may be observed. Any anatomic location of capillary beds (virtually the entire body) can have the same effects, with associated clinical signs.
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Histamine is metabolized rapidly; it is inactivated in vivo and has an acute action. Effects of that action may be prolonged by several hours after concentrations of histamine have abated. If the effect is extensive and severe, the animal may die within minutes of release of histamine. The treatment of choice for histamine-induced reactions is epinephrine because it is a physiologic antagonist of histamine [10,11], which is to say that whatever histamine causes physiologically, epinephrine causes the opposite effects and therefore reverses effects of histamine by a different mechanism of action. That action and effect of epinephrine, if administered in time, can be sufficiently rapid to save the animal from lethal effects of histamine. Antihistamines are competitive blockers of histamine subtype 1 receptors (H1-blockers) [8,9]. They compete with histamine for the same receptors and as such, produce a clinically beneficial effect only if present in a concentration sufficient to displace histamine from the H1-receptors and then prevent it from re-uniting with those receptors. If clinical signs caused by histamine are present, H1-blockers are seldom of clinical benefit for reversal of those signs. They are of more benefit prophylactically, administered before release of histamine, such as previous to administration of a substance that is known to directly cause release of histamine [8,9]. Glucocorticosteroids are included in this discussion of ADRs for comparative purposes. Glucocorticosteroids do not change production, storage, or response of receptors to histamine [12,13]. They change the inflammatory response to injury which, arguably, plays a role in recovery from some ADRs, but glucocorticoids are of little or no benefit in the treatment of an acute histamine-induced ADR. Any beneficial effect that they may provide at a therapeutic dose occurs hours after they have been administered. The patient may die waiting for any benefit from glucocorticosteroids alone. No controlled studies of treatment of histamine-medicated ADRs in cattle have been found by the author on which referenced recommendations can be made. Personal experience and other nonpublished comments from veterinarians are the basis for the recommendations for the following suggested use of epinephrine. Treatment of choice for a life-threatening, histamine-induced ADR is epinephrine (0.002–0.006 mL of 1:1000 IU epinephrine per kg body weight) administered intravenously, intramuscularly, or divided between those routes. The duration of effect of epinephrine is short, and it may need to be administered repeatedly (every 15–30 minutes) during the first 1 to 2 hours after the ADR begins. The dose usually can be decreased and the interval increased during the first 2 hours, depending on the response of the patient, which can be dramatic. After a beneficial response to epinephrine is observed, antihistamines or glucocorticosteroids may be administered. Their benefits may predominate during the subsequent hours of recovery. There is no evidence of superiority of one antihistamine or glucocorticoid compared with another. Labeled directions for anti-inflammatory doses are indicated, but ‘‘super doses’’ are of no known benefit; however, they are associated with adversities [8–13].
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Although many products that contain antihistamines are labeled for intravenous administration, adverse effects subsequent to intravenous administration of antihistamines do occur, and it is recommend that the intramuscular route be used for parenteral administration of antihistamines to cattle. If an animal is not having a life-threatening, histamine-induced reaction, the use of antihistamines or glucocorticoids is of little benefit. When administered prophylactically, antihistamines should be administered 20 to 30 minutes before an event that may cause liberation of stored histamine. Much of the treatment of ADRs in animals is extrapolated from treatment of human or canine patients. That information may not be applicable to cattle. One reason that human patients with histamine-induced reactions are treated with antihistamines or glucocorticosteroids is that those patients are often pruritic. Pruritus is not a consistent finding with those reactions in large animal species; however, if present, it should be considered an indication for use of antihistamines or glucocorticoids. If pruritus is not present, there is little reason to use them.
Specific reversal agents Many reports of suspected ADRs are not histamine-mediated but rather are direct results of exaggerated pharmacologic action and effect of the medication in question [1–4]. Specific reversal agents are available for some of those compounds, but unless a specific causality relationship with the ADR can be established, administering them may not be beneficial. Interactions of two or more medications also can cause adverse pharmacologic effects. Management of those reactions depends on the specific medications involved. Additional or specific assistance with managing ADRs caused by those products may be available by contacting professional services personnel at the manufacturer of the product. Personnel in those departments are responsible for investigating such requests registered with them. Manufacturers of generically labeled products may not have professional services personnel. When emergency measures are needed, telephone contact may be sufficient initially. That assistance can be provided best in a professional manner if those representatives are treated as professional colleagues. Those individuals cannot divine answers nor can they see through the telephone (unless both ends of the call have compatible technology), so it is important to ask for any assistance available, but answers to specific questions can be answered best. Do not withhold information; be objective, complete, honest, and specific. Remember and apply the ‘‘golden rule.’’ Most of the professional services personnel cannot drop what they are doing at that instant and make an emergency visit to your location; however, a personal visit by one of them or a hired representative (perhaps a colleague in your area) may be possible at a later scheduled time.
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Subsequent to all the initial activity, you should request an investigation by and subsequently submit a written report to the manufacturer of the product. Some professional services personnel investigate without a request. During that investigation, more helpful information may come to light that can be of use in the future. The most important information is the professional assessment or evaluation by the attending veterinarian. That responsibility should be received with the same ethical approach as any other aspect of practice. If the animal does not survive the ADR, the client should be asked to grant permission for a necropsy to be performed. The client or the manufacturer’s representative may request that the necropsy be performed by a certain person or facility in particular, but the most important point is to perform that necropsy in a timely manner. If a necropsy is performed immediately after the gross examination has been completed, and if considered necessary, that veterinarian can contact (by telephone) a pathologist at a diagnostic laboratory, describe the findings, and ask for guidance regarding submission of samples for additional diagnostic evaluation. By doing so, time is not lost, appropriate organs or tissues can be examined, samples can be obtained and submitted properly for more detailed evaluation, and professional service has been rendered. It is advisable to take pictures of the animal and anything that may be of assistance in understanding the particular situation. Proper identification of those elements is important. In addition to the client and professional services personnel, other individuals who may need to be informed of the event include your professional insurance agent or adjuster and attorney. Depending on the reaction (sometimes adverse, sometimes not) of the client, the order and extent of involvement of each may be different, but all should be informed.
Cause The true cause of the reaction is of paramount importance (1) if a specific reversal agent or other specific treatment is available and (2) to control or prevent subsequent reactions of a similar nature. The necessity of a specific causal relationship is supported by a remedial fact about immune-mediated reactions (adverse or beneficial). Those reactions are specific because the antigen-antibody interaction is specific. The attending veterinarian is unequivocally the best diagnostic tool regarding the occurrence of an ADR. Other than a ‘‘challenge’’ study, there is no diagnostic ‘‘test’’; and there is no pathognomonic lesion of an ADR. Interpretation by the attending professional is the most important component, and attention to detail is important. After recognizing the occurrence of an ADR and tending to the needs of the patient, that person’s attention can turn to diagnosing the cause. It is important to remember that a cause may not be determined definitively.
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All products administered to the patient around the time that the ADR occurred should be saved. Do not discard them. Store them in conditions as described on their respective labels and do not use more product from those containers. Those containers and products are invaluable as elements in the chain of evidence for the determination of the cause of the ADR and should be labeled with identifying information and cared for appropriately. Instructions about where to submit those samples and how to handle them will come from parties involved with those aspects. Many times, the only, or most experienced, analytical personnel are at the manufacturer of the product. Although accusations to the contrary may arise, that fact remains. Quality control measures can and should be implemented to maintain confidence in results. Sometimes the cause of the reaction is not sought until after the acute reaction has passed and the emotional and physical activities associated with dealing with the reaction have subsided. As soon as possible, it is important to record details of the events before, during, and after the reaction. Events that may seem inconsequential at first may be important. Included must be such things as the proximate time of administration of the medication; clinical signs and the relative contribution of the initial illness; concurrently administered medication; the principal active ingredient and its metabolites; inactive ingredients; serial or lot number and expiration date; and other clinically relevant information before concluding the probable cause. ‘‘Probable cause,’’ as used scientifically or medically, is considerably different from its use in terms of litigation. Many times, it is not possible to separate the relative contributions of each component in a product or if more than one product was administered concurrently. If more than one product is involved, inherent risks of each compound separately, consecutively, and interactively are present but seldom, if ever, known. For example, if two drugs (A and B) are administered to a healthy animal, the inherent risk of adversity includes the sum or the net of the risk for the respective factors that follow: drug A alone, drug B alone, drug A if drug B caused its effect first, drug B if drug A caused its effect first, and the chemicophysical interaction of drugs A and B creating a different compound. If the animal was diseased, the contribution of the disease alone and interactions with each of the aforementioned factors must be considered. Report The most completely investigated reports of ADRs are those that have been investigated by the professional services personnel of pharmaceutical manufacturers of products in question or associated with ADRs. The attending veterinarian should work with those personnel and should submit to them a written report of all findings and conclusions. In the United States, those pharmaceutical manufacturers are required by federal law to
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report any ADRs to the FDA-CVM [2]. Inadequate information regarding ADRs in animal patients is only a reflection on the quality of reports submitted by owners of the patient or the attending veterinarian. The better the information they receive, the better the reports they can submit to the FDA-CVM. Personnel of the FDA have no obligation to respond to any report of adversity or to determine if a particular product was causative. Products licensed by the United States Department of Agriculture or by the Environmental Protection Agency do not have the same requirements for reporting as do pharmaceutical products. Time allowed for a reply to any request should be appropriate; at the least, it is common courtesy. In this ‘‘microwave’’ age, people seem to think that they are entitled to anything and everything instantaneously. Anyone who actually is involved will attest to the fact that forensic evaluation is seldom as rapid and unambiguous as depicted by the entertainment industry. Reality does not imitate that perception. The emergency that you may be dealing with is one of the activities of any practice. It is no less or more important than are any other clients or patients. Your time is valuable and necessary, as is that of the client and any person involved. A reasonable time is appropriate and can be requested. Allow yourself the same respect to devote your time to solving the problem.
Injection-site reactions The use of ‘‘tissue-friendly’’ animal health products (vitamins, biologics, therapeutic agents) has grown, but it is probably realistic to expect a degree of reaction at the site of injection of any parenteral formulation [14]. The extent of that reaction and the adversity it causes depend on many variables. The endpoint for evaluation is important and can vary from the classic signs of inflammation to necrosis of tissue. No single histologic class of lesion can be associated with any one product. The time of evaluation after injection is also important because replacement of damaged tissue with fibrous tissue, maturation of that fibrous tissue, effect of that fibrous tissue on surrounding tissues (tenderness of meat, scarring of the hide), and the degree to which those changes are considered to be unacceptable affect the classification of that reaction. The economic loss to ‘‘trimmed’’ lesions depends on the amount and the market value of the product removed. Subcutaneous injections in the neck or over the ribs cause minimal reactions to the subcutaneous tissues [14]. Lesions occasionally were noticed in muscle adjacent to the subcutaneous site in the neck, but muscles adjacent to injections over the ribs were not evaluated. Intramuscular injections in the muscles of the neck produced less-noticeable lesions and less economic loss than did injections in the gluteal (top butt) or semimembranosus (inside round) muscles. Generally, it is recommended to administer parenteral products subcutaneously rather than intramuscularly if a choice is
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permitted. The neck seems to be the best anatomic site for either route of administration to minimize tissue reaction. When intramuscular injections are used, it is recommended that no more than 10 mL be administered per site. Low-volume, highly concentrated products are not necessarily the best for minimizing tissue reactions, minimizing risks for residues, or for therapeutic response. (See the article on neonatal adjustments by Brumbaugh elsewhere in this issue.)
Residues In other literature, considerable attention has been afforded the subject of violative residues of drugs in food. The subject is included here because the author considers some instances of residues to be classified legitimately as ADRs by the strictest definition of the term; they are undesired reactions to administration of a product. All instances of residues are not violative, and all violative residues are not the result of negligence. It is important to remember and to educate clients (producers are consumers, too) that live animals are considered to be food, not raw agricultural products. Regulations have been instituted, volunteer or mandatory programs introduced, and a considerable amount of resources have been allocated to reduce risks of violative residues in food products. As those pressures on producers continue to grow and the ‘‘standard’’ is raised, there will continue to be a risk of adverse residues and there will continue to be individuals who are dissatisfied with the results of any or all efforts. No system has been proven to be totally effective at eliminating those risks. There are many ways to evaluate the efficacy of those activities, and improvements always can be made in a dynamic system [15].
Prepare and practice a plan Experience can be a great teacher. . .if you survive the class. The experience of involvement with ADRs in animal patients is no different. It is, however, an experience in which few veterinarians or clients choose to participate. After each incidence of an ADR has passed, it is advisable to reflect on and evaluate the actions taken and what, if anything, could be done to improve the response for subsequent patients. If your personal experience has not included that of an animal with an ADR, it is advisable to plan an approach based on comments and experiences of those who have had that experience. It is one thing to have a formulated plan; it is another to implement it. Practice the plan you have formulated. Include all personnel that might be required to participate. Does each one know what to do or what not to do? With practice, it may be possible to identify potential problems and to take steps to correct them before they interfere with care of a patient. Be open to suggestions from any of the personnel who could improve medical care during the unpleasant situation.
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Points to be considered in that plan may include the following. Stop administration of medication in question. This action is remedial but sometimes is overlooked. Treat the animal according to presenting clinical signs, which requires a prudent examination of the animal followed by treatment as deemed necessary. Are the necessary supplies readily available? Are emergency medications reviewed regularly, and outdated supplies replaced? Is there a chart for doses? In the few seconds to minutes that are needed to respond to an animal with an ADR, there is little time to make those calculations. Contact professional services representatives. A list of manufacturers of products that you use and current contact information should be prepared, readily available, and regularly updated. Investigate causes of the ADR. Regardless of the amount of information available regarding the particular incident, interpretation by the attending veterinarian is the most important diagnostic tool. Properly obtained, submitted, or processed samples of the medication or tissues are helpful in trying to determine the cause of an ADR. When all information has been accumulated and evaluated, submit a written report to the professional services representative of the manufacturer of the product. A copy also may be submitted to the FDA-CVM. Natural or inherent risks of the use of medication in animals include the risk of an ADR. How does that risk compare with the risk of not treating? In addition to the prevalent ‘‘microwave-entitlement’’ attitude, people want to blame something or someone. The occurrence of an ADR is not prima facie evidence of negligence. The cause of the ADR may be found and liability may be placed, but that judgment should be reserved until a thorough investigation is complete. References [1] Brumbaugh GW, Boothe DM. Adverse drug reactions. In: Howard JL, Smith RA, editors. Current veterinary therapy: food animal practice. 4th edition. Philadelphia: W.B. Saunders; 1999. p. 12–7. [2] Bataller N, Keller WC. Monitoring ADRs to veterinary drugs. Vet Clin North Am Food Anim Pract 1999;15(1):13–30. [3] Tja¨lve H. ADRs to veterinary drugs reported in Sweden during 1991–1995. J Vet Pharmacol Ther 1997;20:105–10. [4] Gehring R. Suspected ADRs to veterinary drugs reported in South Africa (January 1998– February 2001). J South African Vet Assoc 2001;72(3):120–6. [5] Szabuniewicz M, Bailey EM, Wiersig DO. Treatment of some common poisonings in animals. Vet Med Small Anim Clin 1971;66(12):1197–205. [6] Szabuniewicz M, Bailey EM, Wiersig DO. Clinical aspects of drug actions and interactions in veterinary practice. Vet Med Small Anim Clin 1973;68(9):1048–58. [7] Brumbaugh GW. Adverse drug reactions and interactions in the horse. Vet Clin North Am Equine Pract 2001;17(3):445–53. [8] Adams HR. Autocoids and antiinflammatory drugs. In: Adams HR, editor. Veterinary pharmacology and therapeutics. Ames (IA): Iowa State University Press; 1995. p. 401–11. [9] Babe KS, Sarafin WE. Histamin, bradykinin, and their antagonists. In: Molinoff PB, Ruddon RW, Gilman AG, editors. Goodman & Gilman’s the pharmacological basis of
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[11] [12]
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G.W. Brumbaugh / Vet Clin Food Anim 19 (2003) 715–726 therapeutics. 9th edition. New York: McGraw-Hill, Health Professional Division; 1996. p. 581–600. Hoffman BB, Lefkowitz RJ. Catecholamines, sympathetic drugs, and adrenergic receptor antagonists. In: Molinoff PB, Ruddon RW, Gilman AG, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. 9th edition. New York: McGraw-Hill, Health Professional Division; 1996. p. 199–248. Adams HR. Adrenergic agonists and antagonists. In: Adams HR, editor. Veterinary pharmacology and therapeutics. Ames (IA): Iowa State University Press; 1995. p. 87–113. Ferguson DC, Hoenig M. Glucocorticoids, mineralocorticoids, and steroid synthesis inhibitors. In: Adams HR, editor. Veterinary pharmacology and therapeutics. Ames (IA): Iowa State University Press; 1995. p. 622–43. Schimmer BP, Parker KL. Adrenocorticotropic hormone: adrenocortical steroids and their synthetic analogs—inhibitors of the synthesis and actions of adrenocortical hormones. In: Molinoff PB, Ruddon RW, Gilman AG, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. 9th edition. New York: McGraw-Hill, Health Professional Division; 1996. p. 1459–85. Van Donkersgoed J, Dubeski PL, VanderKop M, Aalhus JL, Bygrove S, Starr WN. The effect of animal health products on the formation of injection site lesions in subprimals of experimentally injected beef calves. Can Vet J 2000;41:617–22. Gibbons-Burgener SN, Kaneene JB, Lloyd JW, Erskine RJ. Influence of the Milk and Dairy Beef Quality Assurance Program on dairy farm drug management practices. J Am Vet Med Assoc 2000;216(12):1960–4.