Accidental Ingestion of Isoniazid Causing Toxicity in a Dog: a Case Report

doi:10.21203/rs.3.rs-2982297/v1

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Case Report

Accidental Ingestion of Isoniazid Causing Toxicity in a Dog: a Case Report

https://doi.org/10.21203/rs.3.rs-2982297/v1

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A seven month old male spitz dog was presented with history of accidental ingestion of Isoniazid tablets. On presentation, signs of seizures, involuntary defecation and urination, vomiting and excess salivation were noticed. Clinical examination revealed tachycardia, ataxia, increased respiratory rate, congested mucus membrane and severe dehydration. Immediately, therapy was aimed at stabilization of the dog with fluid therapy, anticonvulsants (Diazepam) and antidote i.e., Pyridoxine. The clinical signs subsided in four hours of therapy. Complete blood profile revealed hemoconcentration, mild neutrophilia, hypoproteinemia, elevated BUN, creatinine and ALP values. The dog was kept under observation for 48 hours. After 24 hours of therapy, apart from vomiting no other clinical signs were noticed. Fluid therapy along with anti-emetics, proton pump inhibitors and oral pyridoxine was administered for two more days following first day. The dog showed complete recovery on day three of therapy and the biochemical values were back to normal on seventh day. The present case reports a dog with accidental oral ingestion of Isoniazid, its clinical signs and therapeutic management.

Isoniazid toxicity

dog

seizures

antidote

pyridoxine

Isoniazid (Isonicotinic acid hydrazide, INH) is an antimycobacterial agent commonly used for the treatment of tuberculosis in humans. While its use in veterinary medicine is limited to treat Mycobacterium or Actinomyces, but it has a narrow margin of safety in dogs and cats (Justine and Tina, 2015). This drug works by blocking the synthesis of mycolic acid. INH depletes the CNS of pyridoxine and also decreases levels of GABA within the brain. INH induces a state of functional pyridoxine deficiency by at least two mechanisms. First, INH metabolites directly attach to and inactivate pyridoxine species. Second, INH inhibits the enzyme pyridoxine phosphokinase; this enzyme is necessary to activate pyridoxine to pyridoxal 5' phosphate, the cofactor in many "pyridoxine-dependent" reactions. Functional pyridoxine deficiency is the likely mechanism of INH-induced peripheral neuropathy (Rama, 2023).

Isoniazid toxicosis occasionally occurs in dogs when they accidentally ingest the tablets of the owner medications. In our case the dog accidently ingested the Isoniazid tablets which were placed on the table by the owner, who is a nursing supervisor. Clinical signs associated with isoniazid toxicosis in dogs include central nervous system signs with or without seizure, gastrointestinal signs, hyperthermia, cardiovascular abnormalities, and urogenital abnormalities (Schmid et al., 2017). Pyridoxine (vitamin B6), the direct antagonist of isoniazid, can alleviate the clinical signs if administered rapidly. Furthermore, anticonvulsant therapy, fluid therapy, and supportive care are required depending on the clinical signs of isoniazid toxicity. Overall, the prognosis for isoniazid toxicosis ranges from poor to grave because the immediate initiation of treatments, such as pyridoxine administration, is rarely possible (Jimin et al., 2021).

This case report presents the details of a dog with isoniazid ingestion, severe seizures, ataxia, vomiting and salivation. The therapeutic plan for Isoniazid toxicity is also discussed. To our knowledge, this is the first report of isoniazid toxicosis in a dog in India. Thus, the objective of the present report is to provide awareness of isoniazid intoxication to veterinary clinicians in India.

A seven-month-old male spitz dog weighing 10 kgs was presented to the Department of Veterinary Clinical Complex, College of Veterinary Science, Garividi with generalized seizures following ingestion of isoniazid. The owner reported an observed ingestion of Isoniazid tablets (100 mg), six tablets at once by the dog. The owner is a nursing supervisor and she placed the bottle containing isoniazid tablets on the table, which is meant for dispensing to the neighboring client. During this period, the dog playfully opened the bottle and accidentally ingested six number of tablets i.e., 600 mg of Isoniazid. On physical examination, the dog showed tachycardia (heart rate of 144 beats per minute), tachypnea (respiratory rate of 73 breaths per minute), congested mucus membrane, temperature of 101°F, STT < 6–8 sec. Clinical signs of seizures (4–5 episodes), salivation, involuntary urination and defecation, vomiting (q²) and ataxia were evident. The case was treated under emergency with diazepam at the dose of 0.5 mg/kg bwt, intravenously to reduce the seizures. Intravenous infusion of Ringers lactate and Normal Saline was administered at 50 ml/kg bwt (maintenance and replacement therapy) as the dog is severely dehydrated. Antidote Pyridoxine HCL is given at the dose of 6 ml (600 mg) intravenously, as the dose rate of pyridoxine is dependent on amount (mg) of isoniazid ingested. Whole blood and serum was collected to rule out any organ damage by the ingested drug. CBC revealed mild neutrophilia, hemoconcentration, hypoproteinemia, elevated BUN, creatinine and ALP values. ALT and AST were in the normal range on Day 1 (Table 1). The dog was kept under observation for 48 hours. After 24 hours of therapy, apart from vomiting no other clinical signs were noticed. Fluid therapy (RL and NS) along with anti-emetics (Inj. Vomikind® @ 0.5 mg/kg bwt IV), proton pump inhibitor (Inj. Pantop® @ 1mg/kg bwt IV) and oral pyridoxine (Pyricontin® -100 mg @ two BID) was administered for two more days following first day. However, oral Diazepam was suggested if seizures reoccur, but the owner reported there was no episodes of seizures thereafter. The dog showed complete recovery on day three of therapy and the biochemical values were back to normal on seventh day.

Table 1

Complete blood profile of a dog with Isoniazid toxicity pre and post therapy
S. No.	Parameters	Reference range	0 day	7th day
1.	Hemoglobin (g/dl)	12–15	11.6	10.9
2.	PCV (%)	37–55	47	39
3.	RBC (million/µl)	5.5–8.5	7.3	6.8
4.	WBC (thousands/µl)	6–17	11.05	11.20
5.	Neutrophils (%)	60–77	79	74
6.	Lymphocytes (%)	12–30	18	24
7.	Monocytes (%)	3–10	01	01
8.	Eosinophils (%)	0–9	02	01
9.	Basophils (%)	0–2	-	-
10.	Glucose (mg/dl)	65–118	102. 53	96.21
11.	Total protein (g/dl)	5.4–7.1	5.84	6.78
12.	Albumin (g/dl)	2.3–3.8	3.28	2.90
13.	BUN (mg/dl)	10–28	37.47	24.42
14.	Creatinine (mg/dl)	0.5–1.5	3.21	1.13
15.	ALT (U/L)	21–102	68.09	53.02
16.	AST (U/L)	23–66	40.66	42.0
17.	ALP (U/L)	20–156	215.59	113.65

Isoniazid is one of the anti-tuberculosis drugs commonly used for treatment of tuberculosis in humans. Isoniazid is of very limited use in veterinary practice and toxicity is seen when dogs accidentally ingest these medications. Jimin et al., 2021 and Schmid et al., 2017 reported isoniazid toxicity in dogs either by accidental ingestion or by experimental studies, respectively. Isoniazid plasma levels peak about 1 to 2 hours postingestion. The drug diffuses into all body fluids and cells and has low lipid solubility (Truven Health Anlaytics, Microdex Solutions®). Isoniazid is metabolized in the liver (acetylation and dehydrazination) and excreted through the urine. The half-life is 4 hours but can be prolonged in an overdose situation. The median lethal dose of isoniazid in dogs is estimated to be 50 mg/kg (Villar et al., 1995). The drug is mostly marketed as 100 and 300 mg of isoniazid per tablet. In the present case, the dog ingested 600 mg of Isoniazid; which means LD₅₀ of 60 mg/kg. However, Schmid et al., 2017 in their study reported at least 29.4 mg/kg of isoniazid can be lethal to dogs. Justine and Tina (2015) stated that in dogs, seizures can be seen at 50 mg/kg. The clinical signs of Isoniazid toxicosis can result in CNS signs (refractory seizures, coma), GI signs (hypersalivation, vomiting, diarrhea), acid-base disturbances (metabolic acidosis), hyperthermia (secondary to seizures) and organ injury (myocardial injury, secondary acute kidney injury or hepatopathy) (Justine and Tina, 2015). In the present study nervous signs i.e., seizures and ataxia, GI signs (salivation and vomitings) and elevated BUN and creatinine owing to renal injury was evident. Jimin et al., 2021 reported hypoproteinemia, elevated ALT, AST, ALP and elevated BUN and creatinine resulting in secondary hepatic and renal damage but Chin et al., 1979 didn’t report secondary hepatic or renal damage. In the present study, hypoproteinemia, elevated ALP and elevated BUN and creatinine were seen. The changes in the biochemical values attributing to isoniazid toxicity could not be explained due to lack of literature clinically in dogs. However, elevated ALP may be due to seizures (muscle distress), elevated BUN and creatinine may be due to drug causing injury to the kidney as the drug is excreted through urine. Hypoproteinemia was previously identified in a dog with acute renal failure after isoniazid ingestion but the exact cause of hypoalbuminemia in the dog has not been clarified.

The ideal treatment combines Pyridoxine (vitamin B₆) given as a single intravenous bolus at an equivalent dose to the amount of isoniazid ingested and anticonvulsants like diazepam @ 0.5 to 1 mg per kg bw. If the amount of isoniazid ingested is unknown, the suggested dose is 71 mg/kg. This combination acts synergistically to improve GABAergic transmission in the CNS and has proved effective, even after several seizure episodes, as often encountered in clinical situations (Villar et al., 1995 and Chin et al., 1978). However, anti convulsant therapy is often ineffective until pyridoxine is administered. The antidote pyridoxine should be administered promptly, because it is a direct antagonist of isoniazid and will quickly reverse the clinical signs.

Justine and Tina, 2015 stated that decontamination is rarely possible in these cases because of the rapid onset of signs (30 minutes to 2 hours). If the animal is clinically normal, emesis can be attempted in the practice. Emesis should not be induced in patients with clinical abnormalities because of risk for aspiration pneumonia. If an animal is clinically affected and has ingested a large number of pills, gastric lavage may be necessary under anesthesia (with a protected airway).

Supportive treatment with fluid therapy and liver protectants may be helpful. Immediate IV access should be established. In the present case, vomiting was persistent on second day. So, proton pump inhibitor (Pantaprazole) and anti- emetic (Ondansetron) was administered to minimize the GI signs. Fluid therapy with crystalloid solutions (RL and NS) was administered for three days to enhance urinary excretion of isoniazid, to help perfuse the patient, and to minimize acute kidney injury and also treat metabolic acidosis, if any. CBC should be rechecked after 3–5 days of therapy to rule out the status of hepatic and kidney injury. In the present case, the dog recovered completely on third day of therapy and thankfully there was no biochemical abnormalities on day 7. The prognosis for isoniazid toxicosis is fair if pyridoxine is administered quickly. If CNS signs are present and dog fail to respond to therapy, the prognosis is guarded to grave.

Veterinarians should be aware of clinical signs and its therapeutic management in accidental ingestion of isoniazid causing toxicosis in dogs. Always caution the pet owners about the dangers of human prescription medications. As the literature available about the isoniazid toxicosis in dog is limited and this is the first case report in India, this paper provides information about clinical signs, use of the antidote pyridoxine, and supportive care to ensure good outcome in the isoniazid toxicosis cases in dogs.

Chin L, Sievers ML, Laird HE, Herrier RN, Picchioni AL. Evaluation of diazepam and pyridoxine as antidotes to isoniazid intoxication in rats and dogs. Toxicol Appl Pharmacol. 1978;45:713–22.
Chin L, Sievers ML, Herrier RN, Picchioni AL. Convulsions as the etiology of lactic acidosis in acute isoniazid toxicity in dogs. Toxicol Appl Pharmacol. 1979;49:377–84.
Isoniazid. Truven Health Analytics, Micromedex Solutions. website. www.micromedex.com.
Oh J, Kim H-S, Kang J-H, Kang B-T. Mhan-Pyo Yang and Hakhyun Kim. 2021. A Case of Isoniazid Intoxication in a Dog. J Vet Clin, 38:204–9.
Justine and Tina Lee and Tina Wismer. 2015. Isoniazid toxicosis in dogs. Peer reviewed. Clinician’s Brief. cliniciansbrief.com.
Rama DR. 2023. Isoniazid (INH) poisoning. Upto Date. https://www.uptodate.com/contents/isoniazid-inh-poisoning.
Schmid DR, Lee JA, Wismer TA, Diniz PPVP, Murtaugh RJ. Isoniazid toxicosis in dogs: 137 cases (2004–2014). J Am Vet Med Assoc. 2017;251:689–95.
Villar D, Knight MK, Holdin J, Barret GH, Buck WB. Treatment of acute isoniazid overdose in dogs. Vet Hum Toxicol. 1995;37(5):473–7.

No competing interests reported.

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Accidental Ingestion of Isoniazid Causing Toxicity in a Dog: a Case Report

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