Introduction
Background
Isoniazid (isonicotinic acid hydrazide [INH]) is an antimicrobial that has been used as a first-line agent for prophylaxis and treatment of tuberculosis since 1952. Patients with a recently positive purified protein derivative (PPD) skin test and normal chest radiograph findings routinely are given a 6- to 9-month course of INH. Patients with active disease are put on a regimen of INH combined with other antituberculous medications. Because of errors in dosage or intentional overdose, life-threatening toxicity may result.
Pathophysiology
Isoniazid binds to pyridoxal-5-phosphate, the active form of pyridoxine (vitamin B-6), to form INH-pyridoxal hydrazones. Pyridoxal-5-phosphate is a cofactor for glutamic acid decarboxylase and GABA transaminase in the GABA synthetic pathway. INH overdose results in decreased pyridoxal-5-phosphate, decreased GABA synthesis, increased cerebral excitability, and seizures. Co-ingestion of ethanol potentiates toxicity by enhancing degradation of phosphorylated pyridoxine.
Toxic effects of INH also result from inhibition of lactate dehydrogenase, an enzyme that converts lactate to pyruvate, and from inhibition of cytochrome P450. Pharmacogenetic studies suggest that patients with certain cytochrome P450 genotypes may be more predisposed to hepatotoxicity during INH therapy for latent tuberculosis.1
INH undergoes N -acetylation in the liver to a variety of products that include acetylhydrazine, a potent hepatotoxin. These metabolites are excreted in the urine. With long-term administration at therapeutic doses, INH can cause clinically significant liver injury in 1% of patients and elevated liver enzyme levels in 10-20% of patients.
In vitro studies of a variety of animal cell lines demonstrated that INH toxicity results from the induction of apoptosis with associated disruption of mitochondrial membrane potential and DNA strand breaks.2
Frequency
United States
A surveillance of cases of INH poisoning by the American Association of Poison Control Centers from 1985-1993 revealed a low number of 138 cases in 1985, with no fatalities, and a high number of 2656 cases in 1991, with 6 fatalities. A more recent review of all cases of drug-induced seizures reported to the California Poison Control System revealed that of 386 cases, 23 (5.9%) were due to INH.3
In a study of 83 healthcare workers who received a 6-month course of INH, 34 (41%) developed an adverse effect. In 26 of these 34 patients, toxicity resulted in discontinuation of therapy.4
Hepatotoxicity occurs on average in 9.2 of 1000 patients taking INH for antituberculosis therapy.5
Mortality/Morbidity
Acute ingestion by adults with as little as 1.5 g of INH can lead to mild toxicity.6 Ingestion of 6-10 g may be fatal, while ingestion of 15 g is usually fatal if not appropriately treated.
- The overall mortality rate for acute INH toxicity has been estimated to be 19%. With current methods of supportive care, however, this figure may be high.
- From 1972-1988, an estimated 152 fatalities were caused by INH-related hepatitis. A more recent literature review estimates hepatotoxicity to occur in 9.2 of 1000 patients taking INH for antituberculosis therapy, with a case-fatality rate of 4.7%.5
Race
The rate of acetylation of INH in the liver is race-dependent, with 60% of African Americans and whites being slow acetylators, compared with 10-20% of Asians.
- While slow acetylators appear more prone to INH-induced hepatitis and neuropathy with long-term use, whether the rate of acetylation affects acute toxicity is unclear.
- Because of the influx of immigrants from Southeast Asia over the past 2 decades, mini-epidemics of acute INH toxicity have been reported in this population because many of them undergo INH therapy.
- In a review of possible INH-associated hepatitis fatalities identified from 1969-1989, a total of 38% occurred in African Americans, 40% in non-Hispanic whites, 15% in Hispanics, 1% in Asians, and 4% in Native Americans.
Sex
In a review of all possible INH-associated hepatitis fatalities from 1969-1989 in which the sex of the patient was identified, 111 (69%) occurred in females. Postpartum women may be at increased risk.
In a study of 41 patients in New York City who were hospitalized at least overnight for INH toxicity, 27 (82%) were female.7
Age
Patients of all ages may experience either chronic or acute INH toxicity. Susceptibility to INH-induced hepatitis and subsequent death appears to increase with advancing age. For example, a report of a 7-year experience with INH hepatotoxicity in a public health tuberculosis clinic revealed 4.40 events per 1000 for patients aged 25-34 years, 8.54 for patients aged 35-49 years, and 20.83 for those 50 years old or older.8
Clinical
History
Symptoms are usually observed within 45 minutes of acute overdose but may be delayed up to 2 hours, when peak absorption occurs.
- Nausea
- Vomiting
- Dizziness
- Light sensitivity
Physical
- Seizures
- Seizures may be observed after ingestion of less than 40 mg/kg and are typical following doses of 80-150 mg/kg.
- Seizures may occur abruptly and are often generalized and tonic-clonic, but focal seizures have been described.
- The clinical triad of acute neurotoxicity consists of seizures (refractory to standard anticonvulsants), metabolic acidosis, and coma; it is usually observed in ingestions of more than 200 mg/kg.
- Hyperpyrexia
- Hypotension
- Tachycardia
- Urinary retention
- Hemorrhage (in the setting of disseminated intravascular coagulation [DIC])
- Ataxia
- Slurred speech
- Stupor
- Hyperreflexia
- Areflexia
- Cyanosis
- Adverse effects from long-term ingestion include the following:
- Peripheral neuritis - Uncommon in healthy individuals but more common in persons with diabetes, those with alcoholism, and malnourished elderly individuals
- Hepatitis - Increased risk with concomitant use of carbamazepine, phenobarbital, rifampin, and alcohol abuse
- INH is known to cause a positive antinuclear antibody (ANA) in 25% of patients and clinically apparent drug-induced lupus, characterized by fever, rash, arthralgias, arthritis, and constitutional symptoms, in approximately 1% of patients.
- In rare cases, isoniazid causes mania, depression, obsessive-compulsive disorder, and psychosis, believed to result from its ability to act as a monoamine oxidase inhibitor (MAOI) or through depletion of pyridoxine. Rarely, an MAOI tyramine syndrome may occur following the ingestion of tyramine-containing foods (eg, red wines, cheese).
- A hypersensitivity reaction is observed in 2% of patients using INH. Signs and symptoms include fever, lymphadenopathy, and skin rashes. Other adverse effects from long-term use include the following:
- Fever, gastrointestinal upset, oliguria, arthralgias, malaise
- Ataxia
- Optic neuritis
- Paresthesias
- Encephalopathy
More on Toxicity, Isoniazid |
 Overview: Toxicity, Isoniazid |
| Differential Diagnoses & Workup: Toxicity, Isoniazid |
| Treatment & Medication: Toxicity, Isoniazid |
| Follow-up: Toxicity, Isoniazid |
| References |
| Next Page » |
References
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Further Reading
Keywords
isoniazid toxicity, isoniazid poisoning, isoniazid exposure, treatment, symptoms, causes, isonicotinic acid hydrazide, INH, antituberculous medications, treatment of tuberculosis, prophylaxis of tuberculosis, isoniazid overdose, INH overdose, INH toxicity, INH poisoning, isoniazid ingestion, INH ingestion, tuberculosis treatment
