Recognizing and treating adverse drug reactions (Proceedings)

The term adverse drug reaction includes any undesired effect of a drug, including a lack of the desired effect. Adverse reactions to veterinary drugs can range from minor to severe and life-threatening.  Veterinary drugs may result in problems in our veterinary patients, as well as in those who treat them.  It is important to recognize these reactions, so they can be prevented whenever possible, or treated quickly and effectively when they do occur.  

Adverse drug reactions in veterinary patients

Types of adverse drug reactions

Adverse drug reactions can be categorized into 6 different classifications: dose-related, non-dose-related (idiosyncratic), dose and time related (chronic), time-related (delayed), withdrawal, and unexpected failure of therapy.

Dose-related reactions are the most commonly seen ADRs.  They are related to the pharmacologic effect of the drug and are predictable and expected.  They typically occur as the drug reaches steady-state concentrations in the plasma (after 5 half-lives of the drug).  Because they are the most frequently diagnosed, they are often preventable, leading to a low mortality rate. Nephrotoxicity with aminoglycosides is a good example.

Non-dose-related (idiosyncratic) reactions are much less common than dose-related ADRs.  They are not related to the pharmacologic action of the drug and are therefore not predictable.  They can occur at any time after drug administration has begun, are often severe and carry a much higher mortality rate.  They may be breed specific, such as occurs with Doberman Pinschers and sulfonamides. 

Hypersensitivity reactions are defined as immune-mediated responses to drug agents.  They are also unpredictable, although once an animal has been sensitized to a drug, it is more likely to react when given the drug again, and reactions with repeated exposure are often more severe. Type I hypersensitivity reactions are true allergic responses to drugs, and they are mediated by IgE.  These are often very severe anaphylactic reaction resulting in severe respiratory compromise due to bronchoconstriction, hypotension and collapse, vomiting and diarrhea, and may be life-threatening if treatment is not promptly administered. .  ProHeart6® was withdrawn from the market due to sometimes fatal hypersensitivity reactions related to allergenic compounds found in the manufacturing process.  The company has changed the process, and the FDA has allowed the drug to be marketed under their Risk Minimization Action Plan (RiskMAP). Type II hypersensitivity reactions are cytotoxic reactions to drug ‘haptens', which are small molecules that bind to plasma proteins and initiate an immune reaction. Type II hypersensitivity reactions are responsible for immune-mediated hemolytic anemia, granulocytopenia, and thrombocytopenia, as seen with sulfonamide use in dogs.  Type III hypersensitivity reaction involve immune complex formation and may occur following the administration of serum biologic products (ie human albumin). Type IV (delayed) hypersensitivity reactions can occur following topical administration of some drugs, resulting in a contact dermatitis.

Dose and time-related (chronic) ADRs occur with chronic administration of a drug.  They are related to the total cumulative dose of the drug administered.  They are relatively rare, but can be predicted in some instances, such as with nephrotoxicity and amphotericin B administration. Temporally, they tend to occur after the drug has been administered for a long period of time (weeks to months). Time-related (delayed) ADRs only become apparent after the drug has been withdrawn for a prolonged period, making them difficult to associate with drug administration. Teratogenesis and carcinogenesis are examples of time-related ADRs.

Withdrawal symptoms occur shortly after the discontinuation of drug use and are often related to a physical dependency on the drug.  Some drugs used in veterinary medicine that may cause withdrawal symptoms include gabapentin, opioids, and corticosteroids. Unexpected failure of therapy occurs commonly, and may be dose-related, or it may be related to drug-drug interactions.  With antibiotic therapies, it could be due to resistant bacteria, or an inadequate dose administered. Compounded drugs may also be a reason for failure of therapy.

Systems affected

The liver is the main organ in the body that detoxifies drugs, making it a prime candidate for adverse drug reactions.  Additionally, the kidney is the main organ in the body for excretion of drugs, and many drugs accumulate in the kidney and urinary tract, making it highly susceptible to drug toxicity, as well.  Other organ systems frequently affected include the gastrointestinal tract, the central nervous system, the bone marrow and the skin. Rarely, the reproductive system, musculoskeletal system, eye and cardiovascular system can also be affected.        

Adverse drug reactions in the liver can involve the biliary system, the hepatocytes, or both. In some instances, an elevation in hepatic enzymes may be noted during treatment, but these return to normal once the drug is withdrawn.  The best example of this is phenobarbital, which causes an increase in ALT and ALP enzymes with prolonged use, without clinical signs of liver disease.  On the other hand, several drugs can also cause hepatopathies, some of which are severe and irreversible.  Many of the drug-induced hepatopathies are idiosyncratic, and therefore unpredictable.  For example, carpofen has been shown to cause hepatocellular toxicity in dogs that have received the drug, based on hyperbilirubinemia, increases in AST, ALT, and ALP, along with clinical signs of icterus, vomiting and anorexia.  This reaction is not repeatable, and several studies examining the effects of long-term administration of carprofen in dogs have not reproduced these results, making it difficult to predict which animals will be affected.    

Many groups of drugs can cause dose-related adverse reactions in the kidney, including aminoglycosides, non-steroidal anti-inflammatory drugs (NSAIDs), and tetracyclines.  These are most commonly diagnosed by increases in creatinine and BUN, however once these enzymes have become elevated in the blood, significant renal damage has already occurred.  More sensitive indicators of renal damage would include measurement of urine output, osmolality, and the urine GGT:creatinine ratio. Nephrotoxicity associated with these drugs can be avoided by using proper dosing regimens, and ensuring that the patient stays well hydrated during therapy.

Adverse drug reactions in the gastrointestinal tract usually involve diarrhea, vomiting, and ulceration.  Oral antibiotics frequently produce diarrhea by disrupting the normal bacterial flora in the colon, resulting in the overgrowth of pathogenic bacteria, such as Clostridium sp or Salmonella sp.  This is most common in horses, and the antibiotics implicated include clindamycin, lincomycin, oxytetracycline, doxycycline, erythromycin and moxifloxacin. Although less frequent in small animals, gastrointestinal side effects can occur with the administration of erythromycin (vomiting and diarrhea), and clindamycin.  NSAIDs are another group of drugs that frequently cause gastrointestinal disturbances, mainly mucosal ulceration in the stomach or large intestines.  Any animal that is on a NSAID should be monitored closely for signs of anorexia, lethargy, and blood in the stools.  Even though the newer, more selective drugs may have a safer gastrointestinal profile than older drugs, they can still initiate gastric ulcers or exacerbate ulceration in patients with pre-existing disease.               

The central nervous system is impenetrable to many drugs, due to the presence of the blood-brain and blood-CSF barriers.  These barriers exclude most water-soluble, high molecular weight or protein bound drugs.  Lipophilic, small molecular weight drugs can penetrate these barriers, and high doses may be associated with CNS side effects.  For example, metronidazole causes a dose dependent neurotoxicity characterized by weakness, nystagmus, ataxia and seizures.  In some patients, the barriers to drug penetration in the CNS are compromised.  This is due to a deficiency in the P-glycoprotein efflux pump that helps to pump drugs out of the CNS.  Herding dogs, including Collies and related breeds such as Shetland Sheepdogs, English Sheepdogs and Australian Shepherds, have a known mutation in the gene that encodes for P-glycoprotein, making them much more susceptible to CNS toxicity caused by drugs such as ivermectin or moxidectin.       

Myelosuppression (decreased cell production in the bone marrow) has been associated with several drugs. These include sulfonamides, chloramphenicol, phenylbutazone and cancer chemotherapeutics. In most instances this is reversible, however aplastic anemia and pancytopenia have been reported secondary to chloramphenicol and phenylbutazone in dogs.  The skin is a common site for allergic reactions, and severe skin diseases, such as toxic epidermal necrolysis (also known as Steven's Johnson syndrome) have been reported after administration of antibiotics (gentamicin, cephalexin, chloramphenicol, sulfonamides) phenobarbital and insecticide dips. Pemphigus foliaceous has recently been associated with topical administration of ProMeris® for Dogs, a combination of metaflumizone and amitraz      used for the treatment and prevention of flea and tick infestations.

Teratogenicity or reproductive problems are rarely reported in veterinary medicine.  Some drugs that have been implicated include the antifungals griseofulvin which is teratogenic in cats, and ketoconazole which can cause early embryonic loss.  Many of the drugs we use in veterinary medicine have not been tested for safety and efficacy of administration during pregnancy however, so the true incidence of reproductive or fetal adverse effects is not known. The fluoroquinolone antibiotics can cause cartilage damage in young foals and puppies. The eye is rarely a target for drug toxicity, however keratoconjunctivitis sicca (KCS or ‘dry eye') can occur after prolonged administration of sulfonamides, and blindness associated with retinal detachment has been associated with cats that receive > 5 mg/kg of enrofloxacin. The heart can be adversely affected by drugs such as the macrolide antibiotic tilmicosin, ionophore antibiotics such as monensin, and newer generation fluoroquinolones, such as moxifloxacin.  

Recognizing adverse drug reactions

Some adverse drug reactions are easy to recognize, as they occur shortly after the drug has begun being administered, and they go away once the drug has been stopped. If the diagnosis is in doubt, and the drug is considered essential for therapy, the animal can be re-challenged with the drug to see if clinical signs recur.  This is risky, particularly with allergic reactions, as the adverse effects may be more pronounced with re-exposure to the drug, therefore the owners should be thoroughly informed of the risks, and the re-exposure should take place in a hospital setting, with frequent monitoring. Dose-related adverse reactions should be expected and monitored for via physical examinations, bloodwork and urinalysis.  Animals with Type II hypersensitivity reactions will often be Coomb's positive, so this test should be performed if this type of hypersensitivity is suspected.

Therapeutic drug monitoring is a useful tool for diagnosing drug toxicity, if available.  For some drugs, the toxic plasma concentrations are known and if the tests come back above a certain level, drug toxicity can be accurately diagnosed.  A good example of this is digoxin. Plasma or serum concentrations greater than 2.5 ng/mL are considered to be toxic.  Unfortunately, for many drugs there are no commercially available tests, or the toxic plasma concentrations are not known.  For these drugs, diagnosis is often made based on clinical impression alone.

Treating adverse drug reactions

In the case of acute oral toxicity, activated charcoal (1-4 gm/kg granules, 6-12 mL/kg suspension) can be administered to help prevent further absorption of the drug or other toxins.  Induction of vomiting with apomorphine at 0.02-0.04 mg/kg IV or IM, 0.2 mg/kg SQ or 6mg tablets (dissolved in 1-2 mL of water) instilled in the eye may be useful in some cases.  In cats, xylazine at 0.4-0.5 mg/kg IV may be a more reliable emetic. 

For anaphylactic shock situations, emergency treatment is necessary.  Fluids should be administered to counteract hypotension.  The fluid rate should be monitored closely, however to prevent the development of pulmonary edema.  Colloids, such as Dextran 70 (10 mL/kg IV over 30 minutes) and hetastarch can also be given to help prevent pulmonary edema.  Epinephrine should be administered at 2.5-5 µg/kg IV or 50 µg/kg endotracheally.  In patients that do not respond to these doses, a constant rate infusion can be started at approximate rates of 0.2-0.4 µg/kg/min. Corticosteroids can also be administered.  Dexamethasone sodium phosphate (0.5-1 mg/kg IV) or prednisolone sodium succinate (15-30 mg/kg IV) are the drugs of choice.  Antihistamines should also be administered.  Diphenhydramine can be given at 3-4 mg/kg IM. 

There are very few specific antidotes for drug toxicity in veterinary medicine.  Acetylcysteine (140 mg/kg loading dose, then 70 mg/kg IV or PO for an additional 5 doses) can be given to cats as a treatment for acetaminophen toxicity.  Protamine sulfate is an antidote for heparin toxicity and can be given IV, slowly, at 1 mg/100 units of heparin administered.  Naloxone hydrochloride (0.01-0.04 mg/kg IV, IM or SQ) can be given to reverse adverse effects of opioids, and atipamezole, given in an equivalent volume, can be used to reverse the effects of α-2 agonist drugs, such as xylazine and medetomidine.

For the vast majority of instances of adverse drug effects, treatment involves removing the animal from the drug and providing supportive care. Drug reactions should all be treated according to the organ system affected.

Prevention of adverse drug reactions

• Whenever possible, use dosages determined from pharmacokinetic studies in the species of interest. 

• Use formulations approved for veterinary species, if possible.

• Compounding of dosage formulations may also be helpful if a veterinary formulation is not available.

• Be aware of changes in drug metabolism and elimination due to age, particularly in neonates and geriatrics.

• Adjust doses in patients with heart failure, liver disease, and renal disease.

• Be aware of drug-drug interactions.

• Perform therapeutic monitoring, especially with aminoglycosides.

Reporting of adverse drug reactions

The Center for Veterinary medicine at the Food and Drug Administration (FDA) defines an adverse drug reaction 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.”  To report adverse drug reactions that occur in your practice, please go to the following website and fill out the appropriate forms to be sent to the FDA:  http://www.fda.gov/cvm/adetoc.htm

Adverse drug reactions in humans to veterinary medicines

Veterinarians, technicians, and clients all have the potential to be exposed to veterinary medicines, some of which can cause adverse reactions if they are inadvertently ingested or injected.  Some of the drugs that pose specific human health hazards are summarized below.      

Flea and tick medications containing imidacloprid have been known to cause skin, respiratory and eye irritation in people applying the drug.  This is thought to be due to the benzyl alcohol vehicle the drug is dissolved in.  Dichlorvos has been associated with skin rashes and mild GI irritation.  Exposure to penicillins during treatment of animals has been known to cause sensitization in those people with allergies to penicillin, resulting in severe anaphylactic responses on repeated exposure.  Contact dermatitis and urticaria has also occurred after exposure to chlorhexidine, penicillins and furazolidone. Chloramphenicol causes a dose-dependent bone marrow suppression in people and animals, however a subset of people will develop idiosyncratic, irreversible aplastic anemia secondary to exposure to very small amounts of the drug.  Accidental injection of the macrolide antibiotic tilmicosin has caused severe cardiac abnormalities (chest pains, ECG abnormalities, and intraventricular conduction delays, death) in people. Ingestion of monensin resulted in severe rhabdomyolysis and death in a 17 year old male.  Injection of xylazine results in depression, bradycardia, and hypotension, and this drug has been used in both homicides and suicides.  Acepromazine and chlorpromazine can cause contact dermatitis and photosensitization/photodermatitis in people.  Halothane has been known to cause hepatotoxicity, neurotoxicity, and abortion in medical workers overexposed to the drug. Isoflurane and the local anesthetics benzocaine and tetrocaine are reported to cause contact dermatitis in some workers. Intentional self-injection of propofol has been fatal to humans, and it has also resulted in drug dependency.  Etorphine is an opiate derivative that is 1000-80,000 times more potent than morphine, depending on the species it is being used in.  The lethal dose following injection of this drug in humans is as low as 30 µg.  Intoxication with etorphine can be successfully treated with opiate reversal agents (naloxone).

Veterinary personnel should be aware of the dangers associated with some of the medications they work with on a daily basis, and precautions should be taken to prevent or minimize exposure.  Similarly, client should be warned of these dangers if they are treating their animals at home.