By Cyrus Rangan, MD, FAAP
Isoniazid (INH, isonicotinic hydrazide) is a synthetic derivative of nicotinamide (vitamin B3). It has been used for over 50 years in the prophylaxis and treatment of tuberculosis. Patients are generally prescribed daily doses for 6-9 month periods. So-called “slow acetylators” may develop chronic side effects more readily with daily dosing, such as peripheral neuropathy, agitation, insomnia, and abdominal complaints; these patients sometimes benefit from every-other-day dosing schedules. Acute overdose of INH has the unique toxicological profile of causing the sudden onset of seizures. High level of clinical suspicion and prompt treatment with a specific antidote can prevent serious adverse outcomes.
A 14-year-old female in status epilepticus was brought to the Emergency Department (ED) by paramedics at 6:00pm. Her mother found her in her bedroom, where she was having a generalized, tonic-clonic seizure. The seizure lasted for 2 minutes, followed by another seizure 5 minutes later. Upon arrival, paramedics found her in a post-ictal state, with lethargy and minimal response to stimulation. Her vital signs showed a temperature of 36.9°C; pulse 95/min; respirations 21/min; and blood pressure 116/68 mm/Hg, and her fingerstick glucose was normal. After another seizure, medics administered diazepam, 5 mg IV. Five minutes later, she had another generalized seizure and was subsequently administered two more doses of 5 mg of diazepam IV en route to the ED, each dose of which was followed by another generalized seizure.
In the ED, the patient’s vital signs were temperature 36.5°C; pulse 85/min; respirations 18/min; and blood pressure 110/61. She promptly manifested another generalized seizure. She was administered lorazepam, 10 mg, IV, followed by fosphenytoin, 1000 mg, IV. Ten minutes later, she had another generalized seizure. She was then administered pyridoxine, 5 gm, resulting in a complete resolution of seizures.
Laboratory studies revealed sodium 139, potassium 4.0, chloride 109, bicarbonate 11, glucose 129, AST 39, ALT 33, WBC 14,000/mm3 without left shift, hemoglobin 12.9 g/dL, and platelets 420,000. An arterial blood gas returned with serum pH 7.21, PCO2 34, and PO2 296 on 5L oxygen by facemask.
Patient history from mother revealed a positive PPD skin test 4 months ago, after which the patient was prescribed INH, 300 mg/day for a 9-month period. The patient awoke with a normal mental status 4 hours after admission, and revealed that she had overlooked her last 2 weeks of INH dosages because of final exams, and subsequently took 14 pills that night to “catch up.” She was admitted to an inpatient ward, where she was observed and discharged home in stable condition in the morning.
- Why did convulsions continue despite the administrations of benzodiazepines, barbiturates, and fosphenytoin?
- Why didn’t the patient require intervention (i.e. sodium bicarbonate) for her severe acidemia?
- Why were transaminases not significantly elevated?
The resurgence of tuberculosis has been met with a corresponding increase in reported cases of INH poisoning. Of the antitubercular medications, INH is most commonly ingested in cases of overdose. From 1999-2003, 2053 cases of INH poisoning were reported to the American Association of Poison Control Centers (AAPCC). Over 50% of those exposures were intentional, with 5 reported deaths.
INH is rapidly absorbed from the gastrointestinal tract within one hour. In the liver, INH enters 4 metabolic pathways: (1) methylation and (2) acetylation, both of which yield inactive metabolites; (3) cytochrome P-450 hydrolysis, which yields toxic hydrazines and hydrazides (these intermediates may cause mild hepatic toxicity over time); and (4) dehydrazination, which yields a group of toxic compounds known as hydrazones. Dehydrazination and production of hydrazones are significantly enhanced with acute overdose of INH.
The presence of hydrazine and hydrazide metabolites adversely impacts the metabolism of pyridoxine (vitamin B6). It is important to note that pyridoxine is an inactive pro-drug, and must be metabolized by pyridoxine phosphokinase to its activated form, pyridoxal-5’-phosphate. These metabolites alter pyridoxine metabolism by three mechanisms (see Figure below): (a) free inactive pyridoxine forms complexes with the INH metabolites of methylation, acetylation, and cytochrome P-450 hydrolysis (all are rapidly excreted); (b) hydrazones directly inhibit the enzyme pyridoxine phosphokinase; and (c) pyridoxal-5’-phosphate is partially inactivated by metabolites of acetylation and cytochrome P-450 hydrolysis. Therefore, after acute overdose of INH, the availability of pyridoxal-5’-phosphate is severely diminished.
Pyridoxal-5’-phosphate is a cofactor for the enzyme L-glutamic acid decarboxylase (L-GAD). This enzyme catalyzes (d) the conversion of glutamic acid (the brain’s most abundant excitatory neurotransmitter) to gamma aminobutyric acid (GABA, the brain’s most abundant inhibitory neurotransmitter). Depletion of pyridoxal-5’-phosphate inhibits the activity of L-GAD, thereby severely limiting normal GABA production. Depletion of GABA, along with an acutely elevated glutamic acid:GABA ratio, forces the brain into a state of hyper-excitation. Generalized tonic-clonic seizures are the end result. Replenishment of pyridoxine promptly restores production of GABA.
Anion gap metabolic acidosis is a known consequence of INH overdose. By substituting for NAD in the Krebs cycle, chronic INH ingestion does lead to very mild elevations in lactic, beta-hydroxybutyric, and acetoacetic acids. However, the contribution of this mechanism to metabolic acidosis is minimal. It should be noted that severe acidemia arising after acute INH overdose is actually a direct result of significant lactic acid production from seizures. In the absence of seizures, acidemia in the setting of acute INH overdose generally does not occur.
Seizures can occur 30 minutes to 3 hours after acute INH overdose. Typically, INH-induced seizures are brief in duration but multiple, generalized, unremitting episodes may occur. Onset of seizures is abrupt, and often without warning. Patients may exhibit initial symptoms of nausea, vomiting, confusion, hallucinations, anticholinergic findings, hyperreflexia, blurry vision, and slurred speech. Co-ingestion of ethanol may exacerbate toxicity, as ethanol degrades pyridoxal-5’-phosphate.
Although there is no established threshold dose, seizures have been observed with single ingestions of as little as 3 grams of INH in an adult and 1 gram in a child. Patients with prolonged seizures may exhibit rhabdomyolysis-induced renal failure. Pulmonary aspiration may also occur. Death, though rare, results from seizure-induced severe acidosis with cardiovascular collapse, and tends to occur in patients with delayed presentation or delay in diagnosis.
INH is a weak monoamine oxidase (MAO) inhibitor. Acute toxicity may include MAOI reactions, especially in the presence of other psychotropic substances.
History of recent INH overdose is the diagnostic key to most cases of INH-induced seizures. If information regarding overdose is unavailable, family history of a recent positive PPD skin test in any member of the household, including the patient, should be obtained. History of psychiatric illness may be a diagnostic clue; however, unsuspecting patients receiving treatment for tuberculosis may take an intentional overdose to catch up on missed daily dosages of INH. The presence or absence of other neurological signs and symptoms does not predict whether seizures will occur.
Laboratory abnormalities in acute overdose of INH may include anion-gap metabolic acidosis, low arterial pH, elevated creatinine phosphokinase, and leukocytosis. Unexplained anion gap metabolic acidosis in patients with new-onset seizures should raise suspicion for INH-induced seizures. In patients with known ingestion of INH in the absence of other ingestions or medical problems, routine laboratory studies generally do not alter clinical outcome, and abnormalities tend to resolve spontaneously. Serum assays of INH are available, but are not clinically useful in settings of acute poisoning; INH levels do not correlate with severity of toxicity, and symptoms resolve long before levels are returned.
A suspected diagnosis of acute INH poisoning can be confirmed by challenging the patient with an appropriate dose of pyridoxine, especially in a patient with seizures that are refractory to conventional anti-epileptic medications. Seizures in this setting should promptly resolve, unless brain injury has already occurred. A successful diagnostic challenge with pyridoxine may also suggest Congenital Pyridoxine Deficiency (especially in neonates and young infants); or exposure to Gyromitra mushrooms or rocket fuel, both of which contain monomethylhydrazines that are converted to toxic metabolites like those of INH. Chronic exposure to INH may lead to peripheral neuropathy, persistent elevation of hepatic transaminases, and pellagra in malnourished patients. However, these toxicities are generally not observed after cases of acute poisoning.
Patients presenting to the ED shortly after acute ingestion and prior to the onset of seizures should receive activated charcoal to prevent further absorption of INH. Asymptomatic patients should be observed in the ED for 4-6 hours after overdose. Symptomatic patients should be placed on a cardiorespiratory monitor, and observed until physical findings have resolved completely. Seizures are best treated with intravenous pyridoxine at a dose of 1 gram per 1 gram of ingested INH. Prompt resolution of seizure activity and resolution of mental status to baseline is typically observed. If the amount of INH ingested is not known, a standard 5 grams IV dose of pyridoxine is given empirically. Repeated doses of pyridoxine, 5 grams IV should be administered every 30 minutes until seizures have resolved. Seizures that do not resolve after a total of 15 gm of pyridoxine should prompt the clinician to explore other etiologies for seizure activity. If an adequate supply of intravenous pyridoxine is not immediately accessible, patients may benefit from a subtherapeutic dose of pyridoxine with adjunctive administration of a benzodiazepine or barbiturate.
Although INH exhibits minimal plasma protein binding and low volume of distribution, both the short half-life of INH and prompt response to intravenous pyridoxine preclude the need for advanced methods of drug removal such as dialysis or exchange transfusion.
Typical hospital pharmacy stocking levels of intravenous pyridoxine often do not meet the demands of the acutely poisoned INH patient. The California Poison Control System can aid health care providers and hospital pharmacies in acquiring intravenous pyridoxine from nearby facilities.
Discussion of case questions
- Benzodiazepines and barbiturates treat seizures by enhancing the activity of GABA in excitable tissues of the CNS. Because INH metabolites inhibit the production of GABA, the actions of these medications are severely limited. Fosphenytoin is often not clinically useful in the treatment of generalized seizures induced by INH or other poisons.
- Acidemia from INH-induced seizures may be profound. The lowest-ever recorded serum pH was 6.49, followed by a full recovery. Although acidemia may be severe, it is transient, and tends to resolve spontaneously after seizures have ceased.
- Transaminases are elevated in select patients with chronic ingestion of INH, even with prophylactic dosing of pyridoxine. After acute overdose, INH saturates the metabolic pathways that produce the toxic intermediates that cause hepatic damage. Saturation of these pathways, along with the short half-life of INH, prevents excessive amounts of toxic intermediates from being produced in the acute overdose setting. For this reason, it is rarely necessary to check serum transaminases after acute INH poisoning.