ACUTE IZONIAZID POISONING WITH PRESENTATION OF A CLINICAL CASE

slower. A clinical case of poisoning with 30 tablets of Rimicid by a 16-year-old girl suicidal attempt was presented. The results of the TC analysis confirm intoxication with the drug, and the retrospective assessment of the concentration over a past period of time using the elimination half-life has revealed an extremely high dose of ingested isoniazid.


INTRODUCTION
Acute exogenous intoxications in childhood are becoming more frequent both around the world and in our country. This is directly dependent on the characteristics of the child's body, the dynamics of their physical and mental development. [1,2,3] Suicidal acts through acute exogenous intoxications in children are a serious challenge for toxicologists, as they include conscious and intentional selfharm associated with many social and medical problems. The most common toxic noxa are drugs that are very affordable and are found in abundance in every home. [1,2,4,5] We will present a case of attempted suicide with isoniazid in a 16-year-old girl.
Rimicide, isoniazid or isonide are medicinal products that belong to the group of anti-tuberculosis drugs. The active substance is isoniazid and is used for the treatment of pulmonary and extrapulmonary forms of tuberculosis, as well as for the prevention of close contact with infected individuals. [2,6,7,8] Pharmacokinetics. Isoniazid is a drug that is rapidly absorbed, reaching a maximum serum concentration in 2 hours and penetrating all body fluids. The volume of distribution is approximately 0.6 l/kg. [2,9,10] Isoniazid is insignificantly bound to plasma proteins. The main route of its metabolism is acetylation by the enzyme N-acetyltransferase. Depending on the activity of the enzyme N-acetyltransferase, there are so-called "fast" and "slow" acetylators (genetically determined). [11,12] In 50-60% of white and black Americans, the activity of acetylating enzymes is low, and they belong to the group of slow acetylators in which the T½ of isoniazid is 180 minutes. In 90% of Asians and Eskimos, this activity is high, and the T½ of isoniazid is equal to 70 minutes -they are defined as fast acetylators. For Bulgaria, the ratio of fast to slow acetylators is approximately 1:1. The end products of degradation are: acetylhydrazine and isonicotinic acid or hydrazine. [2,9,13,14,15] Mechanism of toxic effect. Isoniazid causes pyridoxine deficiency in at least two ways: 1. Hydrazones, metabolites of isoniazid, inhibit the pyridoxal kinase, which converts pyridoxine to the active form, pyridoxal-5-phosphate. In addition, the interaction of isoniazid with pyridoxal phosphate forms an inactive hydrazone complex, which is excreted by the kidneys. [16] 2. Pyridoxine deficiency disrupts the synthesis and metabolism of GABA, the main inhibitory mediator of the central nervous system. Depletion of GABA stores is the most likely cause of epileptic seizures in isoniazid poisoning. [1,2,9,17,18] There are also individual features of isonicotinic acid poisoning, and in some people, its metabolism is significantly slower. [6,9,19,20] Clinical manifestation of acute poisoning. In the case of isonicotinic drug poisoning, the clinical manifestation is dominated by cerebrotoxic syndrome with manifestations of tremor, attacks of tonic-clonic seizures, resistance to conventional treatment, and, respectively, gradual changes in consciousness to coma. These symptoms may occur 30 minutes after taking the drug. [1,17,19,21] The paraclinic is characterized by severe metabolic acidosis. Early toxic effects include: vomiting, slurred speech, dizziness and tachycardia, but acute overdose may lead to the development of epileptic seizure without any previous symptoms. [2,9,17] In severe poisoning, a coma develops rapidly and lasts 24-36 hours, persisting after cessation of seizures and correction of acidosis. [2,9,17] Acute toxic effects of isoniazid also include hypotension, hyperthermia, acute renal failure, toxic hepatitis, hyperglycemia, glycosuria and ketonuria. [1,6,19,22] Diagnosis. Acute isoniazid poisoning may be suggested by anamnestic data, clinical manifestations, and chemotoxicological analysis (measurement of isoniazid plasma concentrations and urine screening).
The diagnosis can be made at plasma concentrations of isoniazid: [2,9] -over 10 mg/L, established 1 hour after taking the preparation; -more than 3.2 mg/L, two hours after taking the preparation, -and more than 0.2 mg/L after the sixth hour. Plasma testing of isoniazid is not always possible in the first hours because toxicological testing requires the use of a specialized laboratory, which is not always available and/or requires the transport of samples. On the other hand, in the beginning, the priority is to start treatment due to the urgency of the condition and, in the background -confirmation of the diagnosis. [2,6,9] Seizures may occur with more than 20 mg/kg of isoniazid and always occur with a dose greater than 35-40 mg/kg. A dose of 80 mg/kg is highly toxic and dose above 120 mg/kg is lethal. [6,9] Daily dose regimen: -in children 10 mg/kg/day (10 to 15 mg/kg/day); -in adults 5 mg/kg/day (4 to 6 mg/kg/day). [3,6]

CLINICAL CASE
The patient is a girl, T.E.M., 16 years old, who was admitted to the Toxicology Clinic of the University Hospital "Dr G. Stranski" EAD -Pleven with suicidal attempt, realized at home after a family scandal. She is thought to have ingested more than 30 isoniazid (rimicide) tablets, which the mother was taking as maintenance therapy. About 20 minutes after taking the pills, she felt bad and admitted to the relatives what she had done. Within minutes, she fell unconscious and had a tonic-clonic seizure with foaming from the mouth and biting her tongue.
She was brought by private transport to the Emergency Department of the University Hospital "Dr G. Stranski" EAD -Pleven, in a comatose state with tonicclonic seizures, miotic pupils, with a slow reaction to light. After consultation with a clinical toxicologist, she was treated with diazepam, gastric lavage (after intubation) and, at the same time, started antidote treatment with vit. B6 intravenously. Due to evidence of severe metabolic acidosis, the correction was made with sodium bicarbonate, and she was hospitalized in the Clinic of Toxicology.
A total of 1800 mg of vitamin B6 (36 ampoules of 50 mg/1 mL) was administered until clearing the consciousness. Over the next four days, a further 900 mg (18 ampoules) of pyridoxine was given in decreasing doses as maintenance treatment. Antidote treatment was accompanied by nootropic drugs with non-specific antidote effect, detoxification-depuration, symptomatic and organ protective therapy. Diazepam also continued to be used, as benzodiazepines have been shown to potentiate the action of pyridoxine. [9,23,24] Symptoms of toxic encephalopathy were observed until the third day.
The patient was consulted by a psychiatrist, who stated that it was a "mixed disorder of behavior and emotions "and proposed outpatient monitoring.
The blood count was characterized by extreme leukocytosis up to 31 600, which began to normalize the next day, the rest of the blood indicators were normal.
Chemical-toxicological analysis: Blood and urine from the patient were taken and sent for examination to the specialized Chemical Toxicology Laboratory at the Military Medical Academy in Sofia after the sixth hour of taking the drug.