Case Presentations: Recommendations for Managing Dose-dependent Drug Toxicity
ACVIM 2008
Butch KuKanich, DVM, PhD, DACVCP
Manhattan, KS, USA

Introduction

Dose-dependent drug toxicity can occur under many conditions ranging from accidental exposure to intentional overdose. Toxicity can occur with commonly used medications in veterinary patients, drugs commonly used in humans, but rarely in animals, and can even include over the counter (OTC) veterinary and human medications.

Assessing the Risk

The initial step in managing a dose-dependent drug toxicity is assessing the risk of the suspected drug in the specific animal. An obvious, but important step is recognizing species or breed specific risks of a drug. As an example, signs of acute toxicity of acetaminophen in dogs begin to occur at a single dosage between 100-200 mg/kg whereas signs of toxicity in cats begin occur between doses of 20 and 60 mg/kg.1 Differences within a breed can also be marked. The toxic dose of ivermectin in Collies without an MDR mutation (+/+) is > 2 mg/kg, but a dog with a homozygous mutation exhibits toxicity at 0.12 mg/kg.2 Therefore knowledge of the drug and species specific differences is critical in implementing the best patient management.

Many sources of information are available to help manage dose-dependent drug toxicity (Table 1). The ASPCA Animal Poison Control Center is available for consultations (888-426-4435) 24 hours a day, 365 days a year. A $60 consultation fee is typically charged for their services. Advantages of the ASPCA Animal Poison Control Center are the rapid response and communication, expertise, their extensive database, and case follow-up. The information on the treatment and response for the individual case will be entered into their database and be available for future consultations with recommendations updated based on previous treatment responses and newly available information. The ASPCA Animal Poison Control Center also has numerous articles freely available on their website which typically detail the drug's mechanism of action, pharmacokinetics, pharmacodynamics, manifestations of an overdose, treatment, and references (Table 2). Package inserts are also a useful source of information. Package inserts for veterinary drugs typically include an Animal Safety Studies section which variably describes the effects observed in mandated safety studies at 1, 3, and 5 times the approved dosage. Occasionally, higher doses will also be described. As an example, deracoxib is approved for dogs at a dosage of 1-2 mg/kg/day, but safety studies at 100 mg/kg for 14 days resulted in reduced body weight, vomiting, melena, gastric ulcers, and erosions/ulcerations of the small intestines, but no hepatic or renal lesions (Deracoxib package insert). However it is important to remember safety studies are conducted on young healthy Beagle dogs and may not be applicable to all animals. Another source of information which is freely available are the Freedom of Information (FOI) summaries on the Food and Drug Administration website (http://www.fda.gov/cvm/FOI/foidocs.htm). The FOI summaries contain similar information as the package inserts, but are in much greater detail. Pharmaceutical companies can be very helpful if the drug is their product. The website, http://www.drugs.com/, has information on the pharmacology and toxicology of human drugs, essentially an online Physicians Desk Reference (PDR) under "For Professionals". Sometimes the toxicology information is specific for humans, derived from studies in dogs, or general recommendations for the treatment of intoxication (Table 3). Regardless, the information can be useful for managing an intoxication, or understanding the mechanism of action, pharmacokinetics, and pharmacodynamics of drugs not used routinely in veterinary medicine.

Table 1. Sources of information on dose-dependent drug toxicity.

 ASPCA Poison Control Center

 ASPCA monographs

 Pharmaceutical companies

 Package Inserts

 FOI summaries

 www.drugs.com

 Physicians Desk Reference

Table 2. Freely available ASPCA Monographs (partial list).

 5-Fluorouracil

 Acetaminophen

 Anticoagulant rodenticides

 Antidepressants

 Antihistamines

 Baclofen

 Beta-2 Inhalers

 Calcium channel blockers

 Club drugs

 Cocaine

 Ibuprofen

 Iron supplements

 Local anesthetics

 Marijuana

 Metformin

 Thyroid hormone

Table 3. Excerpt from http://www.drugs.com/ (methylphenidate).

"Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes.

Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage. In the presence of severe intoxication, use a carefully titrated dosage of a short-acting barbiturate before performing gastric lavage.

Other measures to detoxify the gut include administration of activated charcoal and a cathartic.

Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia.

Efficacy of peritoneal dialysis or extracorporeal hemodialysis for Methylphenidate overdosage has not been established."

Initial Management

The most important initial step is to stabilize the animal with appropriate supportive care as true antidotes or antagonists are rarely available. Oxygen, blood, plasma and fluid administration as needed, and control of seizures and arrhythmias are important initial steps. Initial management of a drug overdose in stable animals typically involves decontamination and minimizing drug exposure.

Procedures such as the induction of emesis and administration of activated charcoal are hallmarks for the management of most intoxications. However induction of emesis is not indicated for all intoxicants (Table 4). Apomorphine is commonly used as an emetic agent in dogs due to its rapid effects and high efficacy. Apomorphine stimulates the chemoreceptor trigger zone to induce vomiting primarily through stimulation of dopamine receptors. However apomorphine has antiemetic effects on the emetic center, therefore multiple doses tend to decrease in efficacy. Apomorphine is a CNS and respiratory depressant therefore should be used cautiously in depressed or respiratory depressed / dyspneic animals. The efficacy of apomorphine in the treatment of phenothiazine intoxication will likely be poor as phenothiazines (and metoclopramide) are dopamine antagonists and effective antiemetics. Hydrogen peroxide is often an effective antiemetic and readily available to most clients. Hydrogen peroxide is a peripheral acting emetic which causes gastrointestinal (GI) irritation and distension. Fatal aspiration can occur after hydrogen peroxide administration. Ipecac syrup is rarely recommended for use in dogs and cats. Ipecac stimulates vomiting directly on the GI tract and through stimulation of the chemoreceptor trigger zone by its active component, emetine. Ipecac is more effective than apomorphine to stimulate vomiting in phenothiazine toxicities. Gastric lavage is recommended if emesis does not occur after administration of ipecac as emetine is a cardiac depressant. Xylazine is an effective antiemetic in cats at low doses, 0.05 mg/kg IM. However xylazine should not be used in depressed animals, animals with cardiovascular depression, hyper- or hypotension. It is no longer recommended to use salt solutions or salt as an emetic.

Table 4. Contraindications for emesis induction.

 The intoxicant is corrosive (i.e., acid)

 The patient is comatose or in a state of stupor or delirium

 The intoxicant is a CNS stimulant

 The intoxicant is a petroleum distillate

 The patient is seizuring

Activated charcoal is literally charcoal from wood, lignite, or peat that has been activated to increase the size and numbers of pores available to interact and form stable complexes with intoxicants. Activated charcoal is often administered or combined with a cathartic such as sorbitol to increase rapid movement of the charcoal and charcoal-intoxicant complex. Activated charcoal is minimally effective for heavy metal, alcohol, hydrocarbon, or corrosive toxicities and is not recommended for administration (Table 5). The ideal dosing of activated charcoal has not been determined for dogs and cats. Activated charcoal administered to dogs as a single dose 30 minutes after oral carprofen significantly reduced the absorption of carprofen.3 Activated charcoal can increase the rate of elimination of drugs that are not even in the gastrointestinal tract by binding drug secreted in the bile and preventing reabsorption in the gastrointestinal tract. Administration of multiple doses of activated charcoal to humans administered phenobarbital IV decreased the half-life of phenobarbital from 148 hours to 19 hours.4 An experimental study in pigs examined the effects of oral activated charcoal on the clearance of acetaminophen, digoxin, theophylline, and valproic acid all administered IV.5 The clearances of all of the drugs except valproic acid were significantly increased when multiple doses of activated charcoal was administered. A similar study examined the effects of multiple doses of activated charcoal on the clearance of IV aspirin in pigs, but no significant changes in clearance were observed.6 However, activated charcoal administered to humans significantly decreased the half-life of piroxicam from 53.1 hours in untreated patients to 40 hours.7 Treatment with activated charcoal can be applied to drugs which have not been absorbed from the gastrointestinal tract, but activated charcoal may also increase the elimination of some drugs which have already been absorbed from the gastrointestinal tract.

Table 5. Activated charcoal is not recommended for the following toxicities:

 Heavy metals (lead, mercury, zinc)

 Alcohols (methanol, isopropanol)

 Hydrocarbons

 Corrosives (acids, bases)

Supportive Therapy

Fluid therapy is often recommended for many different types of intoxication. Intravenous fluids accomplish many different goals including maintenance of circulating blood volume, blood pressure, cardiac output, acid-base status, electrolyte concentrations, hydration, and diuresis. Diuresis can serve more purposes than maintaining urine production. Diuresis can increase urine flow through the renal tubules, decreasing renal tubular reabsorption of the intoxicant with a net effect of increasing drug elimination. Studies in humans have demonstrated alkaline diuresis, with IV sodium bicarbonate, decreased the elimination half-life of phenobarbital from 148 hours to 47 hours.4 The exact mechanism of the increased clearance was not determined, but suspected to be due to alkalinization of the urine which ionized phenobarbital, a weak acid. Additionally, the increased urine flow may also decrease renal tubular reabsorption of phenobarbital. Although renal clearance typically only accounts for 15% of phenobarbital elimination, alkaline diuresis can significantly increase the clearance of phenobarbital. It is important to note that excessive fluid therapy can result in electrolyte abnormalities, pulmonary edema, or hypertension. Diuresis with mannitol increases the renal clearance of digoxin by 2-3 fold in experimental models in dogs.8 Furosemide increases the renal clearance of digoxin in humans resulting in a significant reduction in the half-life of digoxin.9

N-acetylcysteine (NAC) is often recommended for the management of acetaminophen (APAP) intoxication as it serves as a replacement for endogenous glutathione. Glutathione (and NAC) directly conjugate with the reactive metabolite of acetaminophen with a resultant effect of decreasing toxicity. However studies in dogs have also shown NAC increases the elimination of acetaminophen.10 The t ½ in APAP only dogs was 1.8 ± 0.2 h whereas dogs treated with APAP and NAC decreased the t ½ of APAP to 1.1 ± 0.1 g. NAC has also been shown to increase survival in human patients with APAP hepatotoxicity despite being administered relatively late in the course of toxicity, 16-36 hours after over dose.11 NAC also appears to decrease the incidence of nephrotoxicity associated with APAP overdose.12 Therefore the actions of NAC may also include a cytoprotective effect due to antioxidant and anti-inflammatory effects. Studies have also indicated NAC increases cardiac output, oxygen delivery, and mean arterial pressure while reducing systemic vascular resistance.12 Administration of activated charcoal and NAC to humans with APAP toxicity has been reported to be more effective than administering either agent alone.13

S-adenosylmethionine (SAMe) has also been advocated as a treatment for APAP toxicity due to binding the reactive metabolites, similar to NAC. Experiments of APAP induced hepatotoxicity in mice indicated SAMe had similar efficacy as NAC.14,15 A case report in the veterinary literature described the treatment of APAP toxicity in a single dog with oral SAMe, along with other supportive measures.16 Although SAMe shows promise as a treatment for APAP induced hepatotoxicity, extensive clinical trials are lacking and NAC is still being recommended as the treatment of choice for APAP toxicity.

Milk thistle extract is a traditional medicine treatment for a variety of diseases including liver disease. Recent interest has also been generated in milk thistle for anti-cancer use. Milk thistle contains silymarin, a flavonoid compound which is thought to exert its effects. However controlled trials have yielded conflicting results of milk thistle / silymarin for its hepatoprotective and antineoplastic effects.17 The effects of silymarin on sawfly induced hepatotoxicosis appeared favorable, but only 2 animals were included per treatment group, therefore the results need to be interpreted cautiously.18 A study examining the effects of silymarin on the nephrotoxicity of supratherapeutic doses of gentamicin in dogs indicated less nephrotoxicity than dogs treated with high dose gentamicin alone.19 The extracts appear to be well tolerated with allergic reactions being the most relevant and severe adverse effect to be concerned with. There has not been any drug-drug interaction reported with milk thistle extracts. Although studies demonstrating the clinical usefulness of milk thistle extracts have been equivocal, the potential for adverse effects appears minimal.

Antidotes

The ideal treatment of a drug intoxication would be an antidote which directly inhibits or antagonizes the intoxicant. Unfortunately few true antidotes are available. Naloxone, naltrexone, and nalbuphine have been used to reverse the effects opioid agonist such as morphine and fentanyl. Nalbuphine reverses the respiratory depressant effects of mu opioid agonists while maintaining some analgesia as it is a mu antagonist and kappa agonist.20 However the large safety profile of opioids and the relative resistance to the respiratory depressant effects of opioids in veterinary species, opioid reversal is rarely indicated. Sympathetic agonist and antagonists and parasympathetic agonist and antagonists can be used as antidotes for some intoxicants. Flumazenil is a benzodiazepine antagonist, but due to the safety profile of benzodiazepines is rarely indicated. Vitamin K (phytonadione) can overcome the anticoagulant effects of warfarin. Folic acid can be used in methotrexate intoxication as methotrexate is a folic acid reductase inhibitor. Glucagon can be used for some anti-hyperglycemic agents. Protamine sulfate can antagonize the effects of heparin intoxication. Digoxin immune Fab can be used to treat digoxin toxicity, but is essentially cost prohibitive.

Conclusion

In conclusion, the appropriate management of dose-dependent drug toxicity will depend on the animal species affected, the suspected intoxicant, the amount of time that has passed since exposure, concurrent medical conditions, presenting condition of the animal, and of course financial considerations.

References

1.  Savides MC, et al. Toxicol Appl Pharmacol. 1984;74(1):26.

2.  Mealey KL, et al. Pharmacogenetics. 2001;11(8):727.

3.  Raekallio MR, et al. Am J Vet Res. 2007;68(4):423.

4.  Frenia ML, et al. J Toxicol Clin Toxicol. 1996;34(2):169.

5.  Chyka PA, et al. Ann Emerg Med. 1995;25(3):356.

6.  Johnson D, et al. Ann Emerg Med. 1995;26(5):569.

7.  Ferry DG, et al. Eur J Clin Pharmacol. 1990;39(6):599.

8.  Koren G, Klein J. Vet Hum Toxicol. 1988;30(1):25.

9.  Rotmensch HH, et al. Arch Intern Med. 1978;138(10):1495.

10. St Omer VE, Mohammad FK. J Vet Pharmacol Ther. 1984;7(4):277.

11. Keays R, et al. BMJ. 1991;303(6809):1026.

12. Proudfoot AT. Toxicol Lett. 1995;82-83:779.

13. Spiller HA, et al. J Emerg Med. 2006;30(1):1.

14. Terneus MV, et al. Toxicology. 2008;244(1):25.

15. Terneus MV, et al. J Pharmacol Exp Ther. 2007;320(1):99.

16. Wallace KP. J Am Anim Hosp Assoc. 2002;38(3):246.

17. Rainone F. Am Fam Physician. 2005;72(7):1285.

18. Thamsborg SM, et al. Vet Hum Toxicol. 1996;38:89.

19. Varzi HN, et al. J Vet Pharmacol Ther. 2007 ;30(5):477.

20. Jaffe RS, et al. Anesthesiology. 1988;68(2):254.

Speaker Information
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Butch KuKanich, DVM, PhD, DACVCP
Kansas State University
Manhattan, KS


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