Drug-induced diseases: what and when to expect them! (Proceedings)

Drug-induced diseases are commonly encountered and described as adverse drug reactions i.e. an undesirable effect of drug treatment. There are two types of adverse drug reactions: Types A and B. A type A drug reaction is a predictable dose and/or time dependent exaggerated response related to the primary (desired) or secondary (unwanted) pharmacological activity of the drug administered. Lack of response caused by underdosing is also considered a type A drug reaction. A type B drug reaction is an unpredictable dose and/or time-independent unrelated response referred to as a cytotoxic adverse reaction as it generally causes damage to target cells. The parent drug and/or the production of potentially reactive metabolite(s) may be responsible for the cytotoxicity. Contrarily to Type A drug reactions, Type B reactions are largely unavoidable and include some drug allergies and all idiosyncrasies.

Organs most susceptible to Type A reactions are the highly perfused liver and kidneys as they are subjected to the highest concentration of and exposure to systemic drugs. Organs most susceptible to Type B reactions causing drug-induced allergies are organs that contain tissues acting as haptens such as skin and blood-forming units, and tissues that filter and trap immune complexes such as the glomerulus and joints.

The clinical manifestation of an adverse drug reaction will depend on the type of drug reaction (A or B) and the organ(s) involved. Allergic drug reactions, hepatotoxicity, nephrotoxicity, gastrointestinal irritation/toxicity, neurotoxicity, ototoxicity, dermatological manifestations, endocrine system reactions, haematological dyscrasias and pulmonary toxicity have all been identified for different drugs administered to companion animals. Fortunately, not all adverse drug reactions are clinically relevant; however, reporting suspected reactions is important in assuring safe and efficacious drug use in animals.

Objectives

1. Provide the practitioner with an overview of the different types of adverse drug reactions.

2. Provide the practitioner with a general understanding of the different organ-specific drug-induced diseases in the dog and the cat.

3. Provide the practitioner with some specific examples of drug-induced diseases in the dog and cat.

4. Provide the practitioner with some insight as to how to avoid or handle the different drug-induced diseases.

5. Emphasize the importance of adverse drug reaction reporting to the pharmaceutical company and the Food and Drug Administration/Center for Veterinary Medicine (FDA/CVM)

Key pathological and pharmacological features

Allergic drug reactions

There are four types of drug-induced allergic reactions: Types I to IV. A Type I allergic drug reaction is IgE-mediated where drugs act as haptens. This immune-mediated response is immediate and causes anaphylaxis or anaphylactoid-like reactions. Species-specific "shock" organs for dogs are the liver and gastrointestinal tract, and the lungs for cats. Examples of drugs that may cause an anaphylactic reaction are β-lactams by directly causing a physiological response to the immune-mediated histamine release. Examples of drugs that may cause an anaphylactoid reaction are morphine, thiacetarsemide and amphotericin B by causing a non immune-mediated direct mast cell degranulation. The administration of a small test dose may help detect and avoid full-blown reactions. A Type II allergic drug reaction is cytotoxic. It occurs when antibody bound blood cells lyse due to direct binding by IgG and IgM, and are removed from circulation. Targeted cells are stem cells in the bone marrow and mature circulating cells such as RBC, WBC and platelets. This type of allergic reaction may be manifested as haemolytic anemia, agranulocytosis and leucopenia, thrombocytopenia or a combination thereof. A Type III allergic drug reaction is an immune complex disease also called serum sickness. It is induced by the antigen-antibody complexes, mediated by IgG or IgM, and complement activation. Clinical signs will vary according to the affected organ but will usually include fever and lymphadenopathy. This type of reaction has been documented in dogs with the administration of sulphonamide antimicrobial drugs. Potentiated sulphonamide syndrome in dogs includes a variety of intrinsic toxicities such as blood dyscrasias (due to induced folate deficiency), renal tubular acidosis (due to induced crystalluria), nausea, vomiting, hypoglycemia, hypothyroidism, kerotoconjunctivitis sicca (KCS), and idiosyncratic disorders such as drug fever, dermatopathies, liver disease, meningitis, myocarditis, polyarthritis, interstitial nephritis and uveitis. A Type IV allergic drug reaction is cell-mediated and manifested as a delayed hypersensitivity that reflects a cellular response by lymphocytes and macrophages that infiltrate the site and cause mediator release perpetuating the inflammatory response, at the antigen site. Drug-induced allergic reactions may be mild to life-threatening. They are more likely to be life-threatening when they affect major organs such as the liver, kidneys, gastrointestinal tract, lungs and the central nervous system.

Hepatotoxicity

Both Type A and Type B adverse drug reactions can affect the liver. This organ is susceptible to toxic effects of drugs since it receives a large portion of the cardiac output (increased exposure to drugs), is a "portal of entry" for oral drugs, and is a major site of metabolism and excretion of drugs. The potential for hepatotoxicity in companion animals may be enhanced by dietary imbalances (high fat, low protein), by the presence of concomitantly administered drugs that alter the metabolizing enzymes or by altered hepatic blood flow. Documented examples of hepatotoxic drugs include glucocorticoids, anticonvulsant drugs, acetaminophen, carprofen, diazepam (cats), ketoconazole, some benzimidazoles, sulphonamides and thiacetarsamide.

Nephrotoxicity

The kidneys are also vulnerable to the undesirable effects of drugs as they also receive a significant amount of the total cardiac output (25%), are responsible for the reabsorption of salts and water, the passive reabsorption of certain drugs (progressive concentration of the drug in the filtrate), and is also a major site of metabolism and excretion. Furthermore, the kidneys are sensitive to extra-renal factors such as decreased blood flow and dehydration that may predispose them to or exacerbate drug-induced nephrotoxicity. Documented examples of nephrotoxic drugs include aminoglycosides, NSAIDs, ACE inhibitors, Amphotericin B, sulphonamides and thiacetarsamide.

Gastrointestinal irritation/toxicity

Most oral drugs and many intravenously administered drugs (especially if rapid administration) have the potential of causing gastrointestinal adverse drug reactions such as nausea and vomiting. Drugs that inhibit cell division are potentially toxic by impairing the rapid turnover of mucosal epithelial cells of the gastrointestinal tract, independent of the route of administration. This is particularly true for tetracyclines, chloramphenicol (chronic administration) and anticancer drugs. Drugs that affect the chemoreceptor trigger zone (CRTZ) will also cause nausea and vomiting, also independently of the route of administration, namely digoxin, anticancer drugs and most opioids. Gastrointestinal irritation may also be caused by NSAIDs through inhibition of protective prostaglandins, or by alteration of the microflora caused by selected antimicrobial drugs or by drug-induced achlorhydria.

Neurotoxicity

The Central Nervous System (CNS) is particularly vulnerable to direct and indirect drug-induced toxicities due to the high metabolic rate of neurons, their marked need for external nutritional support, and their unique lack of a regenerative capacity leading to accumulated lesions and additive effects of toxic injuries. There is also the possibility of delayed manifestation of an adverse drug reaction when neuronal reserve can no longer compensate, which often makes it difficult to find a drug cause to effect relationship. A compromised blood-brain barrier (BBB) such as in pediatric patients, certain diseases and breed particularities may render the CNS particularly vulnerable to toxic effects of drugs which normally would not cause significant adverse effects when administered at therapeutic doses. Typical clinical signs of neurological drug-induced adverse reactions include emesis, diarrhea, salivation, fever, disorientation, ataxia, trembling, seizures, depression, coma and blindness. Documented examples of drugs associated with neurotoxicities in dogs and cats include ivermectin (Collies and Australian shepherds), phenothiazines, butyrophenones, metoclopramide, tricyclic antidepressants, metronidazole, fluoroquinolones, aminoglycosides (neuromuscular blockade) and amitraz.

Ototoxicity

Drug-induced adverse reactions may affect either the auditory system or the vestibular system or both. Vestibular damage is easier to detect in dogs and cats than auditory damage especially in older cognitively challenged patients. Ototoxic effects may be reversible or irreversible. Anticancer drugs such as vincristine, vinblastine and cisplatin are toxic to the hair cells of the organ of Corti thereby affecting the auditory system of the ear. Furosemide on its own, can cause cochlear damage, or enhance the ototoxicity of aminoglycosides when administerd concomitantly. Other examples of ototoxic drugs include fluoroquinolones, chlorhexidine and propylene glycol.

Dermatological manifestations

Both Type A and B adverse drug reactions are manifested in the skin either as an allergic reaction or an immune-mediated reaction such as lupus erythematosus, pemphigus or pemphigoid skin lesions. Similar to the liver and the kidneys, the skin has metabolizing enzymes which makes it susceptible to drug-induced reactions from the parent drug and/or metabolites. Alopecia or generalized exfoliation has been reported with the administration of anticancer drugs, hormonal therapy, glucocorticoids (cushinoid presentation), hetacillin (cats), and flea collar and lime-sulfur dips, respectively. Eczema or eczematous dermatitis has been associated with coal tar shampoo, diethylcarbamazine, 5-fluorocytosine, griseofulvin, topical neomycin, phenothiazine derivatives and sulphonamides. Pruritus has been associated with human recombinant erythropoietin (with skin or mucocutaneous lesions), KBr, methimazole and diethylcarbamazine; purpura or pemphigus has been reported with chloramphenicol and thiabendazole, whereas urticaria and angioedema were associated with tetracyclines and Vitamin K.

Endocrine system reactions

The endocrine system offers several targets where drugs may interfere with important hormonal axes such as the thyroid and cortisol systems. Drug-induced decrease in hormonal concentration may include the suppression of hormone release, decreased hormone synthesis or altered peripheral metabolism of the hormone. Hypothyroidism may be caused by hepatic metabolizing inducers such as phenobarbital, rifampin and glucocorticoids, or by sulphonamides and antithyroid drugs. A decrease in the hypothalamus-pituitary-adrenal (HPA) axis has been documented in dogs with the use of glucocorticoids. The inhibitory effect of ketoconazole on testosterone and adrenal steroid production has been used to treat prostatic cancer, benign prostatic hypertrophy and hyperadrenocorticism.

Hematological dyscrasias

Drug-induced adverse reactions may affect the bone marrow and/or mature circulating cells. Both the parent drug and/or metabolite(s) may cause toxicity to the stem or mature hematological cells. Anemia, leucopenia or thrombocytopenia, or a combination of all of them (pancytopenia) can reflect drug damage to the bone marrow. Hematological disorders are assessed by cell count, time to onset after drug exposure, course of the reaction and time to resolution after discontinuation of the drug. Reactions may be immunological or non-immunological. Examples of non-immunological reactions include anticancer drugs, estrogen derivatives, phenobarbital (reversible) and chloramphenicol. Manifestation of anemia may be caused by NSAIDs and anticoagulants, due to their predictable pharmacological effect on platelets and coagulation cascade, and in cats by methimazole, propylthiouracil, acetaminophen or benzocaine due to the formation of methemoglobin.

Pulmonary toxicity

Drug toxicity to the lung may be caused by gaseous or particulate toxicants, or systemic exposure. As for the liver, kidneys, skin and hematological cells, lungs are susceptible to the parent drug and metabolite(s) as they possess Clara cells or type II alveolar cells which contain cytochrome P450 enzymes for local metabolism of drugs. Since the "shock" organ for the cat is lungs, Type I allergic drug reactions (Type B adverse drug reactions) are expected in this species, primarily manifested as acute respiratory difficulties.

Additional details

Factors that may predispose a patient to the development of type A adverse drug reactions

     • Pharmacological factors: pharmaceutical, PK and PD drug interactions

     • Pathological factors: renal, hepatic, cardiac and endocrine diseases

     • Physiological factors: age-induced differences, species/breed PK and PD differences and drug disposition (ADME)

Avoiding adverse drug reactions

Type A (predictable) adverse drug reactions

     • Obtain a proper diagnosis and treat according to recommended protocols, using least toxic drug(s) as appropriate.

     • Evaluate patient before and during drug treatment with emphasis on target organ of toxicity (using appropriate diagnostic tests) and remission of clinical signs.

     • Minimize drug interactions.

     • Educate client on the potential toxicities and associated clinical signs, and communicate frequently.

     • Evaluate patient for remission of clinical signs, use the least amount of drug that will have therapeutic effect and discontinue (or wean off slowly) as soon as drug is no longer needed.

     • Use of compounds that help prevent metabolite damage to liver: N-acetylcysteine (intracellular form of glutathione), ascorbic acid (oxygen radical scavenger) and S-adenosylmethionine (SAMe - contributor to a number of methylation reactions in the body).

Type B (unpredictable) adverse drug reactions:

     • Keep abreast on knowledge of potential occurrence of this type of adverse reaction.

     • Frequent patient monitoring is important to avoid potential disastrous situations.

Diagnosing a drug-induced disease

     • Ideally, the offending drug should be discontinued and side effects should be allowed to subside, then a challenge with the same drug should show a similar undesirable pharmacological activity.

     • Limitations include polypharmacy (i.e. difficult to determine which drug is the culprit) and ethical issues (especially when dealing with anaphylactic reactions or severe toxicity).

Conclusion

Although drugs are important tools for treatment of several diseases affecting cats and dogs, they also invariably come with potential predictable and unpredictable undesirable effects. It is not possible to list all possible drug-induced adverse reactions for all drugs in all species. It is thus important to be vigilant and maintain a good veterinarian-client-patient relationship in order to appropriately avoid these reactions or offer appropriate supportive treatment for our patients when needed, and finally, to keep abreast on knowledge of potential occurrence of adverse drug reactions.

References

Boothe, D.M. 2001. Drug-Induced Diseases. Chapter 3 in Small Animal Clinical Pharmacology and Therapeutics. W.B. Saunders Company. pp 41-59.

Cribb et al, 1996. Adverse reactions to sulphonamide and sulphonamide-trimethoprim antimicrobials: clinical syndromes and pathogenesis. Adverse Drug React Toxicol Rev 15: 9-50.

Trepanier, L.A. 1999. Delayed hypersensitivity reactions to sulphonamides: syndromes, pathogenesis and management. Veterinary Dermatology 10(3): 241-248.