Isoniazid

Pharmacokinetics

After oral administration, isoniazid reaches a peak plasma concentration of 3–5 mg/l within 1–2 hours. It equilibrates into all body fluids and tissues and 75–95% is excreted in the urine within 24 hours. The most important urinary metabolites are products of acetylation (acetylisoniazid) and hydrolysis (isonicotinic acid). Isonicotinyl glycine, isonicotinyl hydrazones, and N-methylisoniazid appear in only small amounts. The rate of acetylation of isoniazid significantly alters its plasma concentrations and half-life. The mean half-life of isoniazid in rapid acetylators is about 70 minutes and in slow acetylators 3 hours.

General adverse effects and adverse reactions

In a survey of more than 2000 patients treated with isoniazid, the most frequent adverse reactions were rash (2%), fever (1.2%), jaundice (0.6%), and peripheral neuropathy (0.2%). Seizures can also occur. Morbilliform, maculopapular, purpuric, and urticarial rashes, with or without fever, are considered to be of allergic origin. Hematological adverse effects consist of agranulocytosis, thrombocytopenia, pure red cell aplasia, and eosinophilia [ ]. Dyspnea, with thoracic pain, cough, fever, and eosinophilia, as well as micronodular densities in the chest X-ray, may also be due to an immunological process [ ]. Vasculitis associated with antinuclear antibodies has been observed, as well as arthritic symptoms [ ]. Liver damage (mainly hepatocellular) has been considered another form of hypersensitivity reaction, but usually occurs during combined antituberculosis treatment with rifampicin in combination with anticonvulsants or halothane, or in association with alcoholism. Some are of the opinion that the main factor that induces liver damage is the fast acetylator phenotype [ ], while others have found no correlation [ ]. No increase in cancer deaths was observed in a series of 338 women treated with isoniazid for pulmonary tuberculosis [ ]. Isoniazid is a potent inhibitor of hepatic enzymes and interferes with the metabolism of many drugs, such as rifampicin [ , ].

Respiratory

Symptoms suggestive of bronchial obstruction occur only very rarely during isoniazid treatment [ ].

Nervous system

Untoward neurological effects (peripheral neuropathy and focal seizures) occur in 2% of patients if pyridoxine is not given and in 12–20% taking higher doses of isoniazid (10–15 mg/kg) [ ]. Peripheral neuropathy due to isoniazid results from inhibition of the formation of the co-enzyme form of vitamin B ₆ , pyridoxine.

Peripheral neuropathy was noted by several authors in up to 20% of malnourished patients and fast acetylators taking isoniazid in doses over 5–6 mg/kg. Only 2% of patients taking 5 mg/kg of isoniazid plus pyridoxine developed neuropathy. Numbness or tingling of the extremities in the glove-and-stocking distribution can occur early during treatment with isoniazid when pyridoxine is not given; there is hyperesthesia, reduced vibration and position sense, and exaggerated or reduced tendon reflexes, but ataxia, muscle weakness, and even paralysis can develop. Shoulder–arm syndrome has also been described.

Neurohistology shows disappearance of synaptic vesicles, mitochondrial swelling or condensation, and fragmentation of axon endings. Alterations in the lumbar and sacral spinal ganglia and the spinal cord have also been reported [ ].

The addition of pyridoxine to usual doses of isoniazid of 5 mg/kg/day in adults and 8–10 mg/kg/day in children markedly reduces neurotoxicity [ ]. Adherence to therapy is improved by prescribing combined tablets containing 20 mg of pyridoxine per 100 mg of isoniazid. In otherwise healthy people, prescription of pyridoxine is not mandatory. However, it should be routinely given to malnourished patients and those predisposed to neuropathy (for example pregnant women, elderly people, and people with diabetes, alcoholism, or uremia) [ ].

Pellagra-associated encephalopathy has been suspected as an adverse effect of isoniazid administration in several patients with tuberculosis. Deficiency of niacin (nicotinic acid) is characterized by dermatitis, diarrhea, and dementia. Other symptoms can occur, such as seizures, hallucinations, spasticity, and glossitis. Pellagra induced by isoniazid is promoted by malnutrition or a vegetarian diet with low intake of the nicotinamide precursors tryptophan and nicotinic acid. Specific supplementation is essential [ ].

Seizures have been reported in a patient with isoniazid toxicity [ ].

• A 5-year-old girl with pulmonary tuberculosis was given rifampicin, pyrazinamide, ethambutol, and isoniazid + pyridoxine. After 1 week she became somnolent, with a reduced appetite and vomiting, followed by two seizures lasting about 5 minutes and fluctuating consciousness. A CT scan showed swollen thalami and brainstem. An MRI scan showed symmetrically increased signals in the thalami and more subtle symmetrical involvement of the medulla, the dentate nuclei, and hippocampi. MR angiography, venography, and MR spectroscopy were normal. The serum isoniazid concentration 12 hours after the seizures was 147 μmol/l (20 mg/l). Owing to a dispensing error, she had received 750 mg/day (43 mg/kg/day) instead of 250 mg/day. Her medications were withheld and pyridoxine 25 mg/day was continued. She had no further seizures and regained consciousness within 48 hours. A repeat MRI scan 3 days later showed partial resolution of the lesions in the thalami, hippocampi, cerebellum, and brainstem; by 7 weeks there was complete resolution and full recovery.

Acute isoniazid intoxication is rare and is classically identified by a triad of signs and symptoms—seizures refractory to standard anticonvulsants, metabolic acidosis, and coma. The initial picture often mimic encephalitis. Laboratory findings often include metabolic acidosis, hyperglycemia, hypokalemia, glycosuria, and ketonuria, mimicking diabetic ketoacidosis. The nervous system effects, particularly seizures, result from the ability of isoniazid to react with pyridoxine, a co-factor for the production of gamma-aminobutyric acid (GABA). Isoniazid and pyridoxine form a compound that is rapidly excreted in the urine, resulting in acute GABA deficiency. Status epilepticus after overdose of isoniazid has been reported [ ].

• A previously healthy 10-year girl developed noisy irregular breathing during sleep. She vomited repeatedly and was agitated and not fully responsive to commands. Her only regular medication was isoniazid 400 mg/day because of recent contact with active tuberculosis. On the assumption that she had taken an overdose of isoniazid, she was given activated charcoal via nasogastric tube and pyridoxine 5 mg/kg and sodium bicarbonate intravenously. There was rapid improvement and she recovered full consciousness within a few hours.

Sensory systems

Optic neuritis and atrophy have occurred in patients taking isoniazid [ ].

Psychological, psychiatric

Isoniazid can cause neuropsychiatric syndromes, including euphoria, transient impairment of memory, separation of ideas and reality, loss of self-control, psychoses [ ], and obsessive-compulsive neurosis [ ]. Isoniazid should be used with caution in patients with pre-existing psychoses, as it can cause relapse of paranoid schizophrenia [ ]. Patients on chronic dialysis appear to be vulnerable to neurological adverse drug reactions, because of abnormal metabolism of uremic toxins. It is therefore recommended that a higher than usual dose of pyridoxine be given to patients on dialysis taking isoniazid [ , ].

Endocrine

Gynecomastia is a rare adverse reaction to isoniazid [ ], as is Cushing’s syndrome [ ]. These effects have been attributed to inhibition of glucocorticoid metabolism. Precocious puberty has been attributed to contamination with diethylstilbestrol [ ].

Metabolism

Isoniazid can cause transient hyperglycemia in overdose [ , ].

In five volunteers taking isoniazid 15 mg/kg/day over a period of 6 weeks, serum cholesterol concentrations were reduced [ ].

Hematologic

Agranulocytosis, thrombocytopenia, hemolytic anemia, sideroblastic anemia [ ], pure red cell aplasia [ ], methemoglobinemia, and eosinophilia can occur exceptionally during isoniazid treatment [ ]. An acquired coagulation factor XIII inhibitor developed in a patient taking isoniazid and resulted in a bleeding disorder [ ].

Gastrointestinal

No severe gastrointestinal adverse reactions to isoniazid have been observed; symptoms are limited to such as epigastric distress, gastric burning, and dry mouth. Of 814 patients with pulmonary tuberculosis treated for 9 months with isoniazid and rifampicin, 18 had minor symptoms of gastrointestinal intolerance [ ]. Nausea can occur, particularly if the drug is taken before breakfast or in combination with other antituberculosis drugs; 5.5% of 912 patients taking a fixed tablet combination of isoniazid, protionamide, and diaphenyl sulfone plus rifampicin had sensations of fullness, nausea, or vomiting [ ].

Liver

Abnormal liver function is the most commonly described adverse effect of isoniazid. It may be related to acetylator phenotype.

Hepatotoxicity caused considerable alarm after an episode in Washington DC, when 19 of 2231 government employees given isoniazid prophylaxis developed clinical signs of liver disease within 6 months; 13 were severely jaundiced and 2 died [ ].

Of 13 838 individuals treated prophylactically, 114 developed overt hepatic disease [ ]. There were 13 deaths, submassive necrosis in nine cases, and massive necrosis in four. The 20 other patients from whom hepatic tissue was available included 16 with moderately severe acute hepatocellular injury (four with a mixed hepatocellular–cholestatic pattern), and four with chronic hepatic damage (one with cirrhosis). The effects of liver disease before the onset of jaundice included vague digestive and “viral” disease-like complaints, some with and some without gastrointestinal symptoms. Jaundice was the presenting complaint in 10%, fever and rash were reported in under 4%, and there was a modest eosinophilia in about 10%. Liver damage was recognized during the first month of administration in 15% and during the second month in a further 31%. The other 54% had taken isoniazid for 2–11 months. Although liver damage in these patients may have been related to isoniazid, some probably had viral hepatitis.

In a study of isoniazid prophylactic therapy in Seattle, USA, only 11 patients of 11 141 had hepatotoxic reactions [ ]. The rate was 0.1% of those starting and 0.15% of those completing the course of therapy. The duration of therapy was not stated, but 10 of the 11 episodes occurred within 3 months of starting.

The mechanism responsible for hepatotoxicity is not known. A metabolite of isoniazid, acetylhydrazine, causes hepatic damage and may play a role. Alcoholic hepatitis is an aggravating factor. The sensitivity of chronic carriers of hepatitis B virus is controversial [ ]. In an investigation in which the urinary metabolic profile of isoniazid was assayed in patients who developed isoniazid-related liver damage, it was impossible to predict which patients would be susceptible. It was also impossible to show that rifampicin plays a significant role in inducing liver damage when added to isoniazid [ , ]. Nevertheless, it is conceivable that enzyme induction by rifampicin alters the metabolism of isoniazid. Further risk factors are alcoholism, malnutrition, diabetes, previous liver damage, renal insufficiency, and drug abuse.

Age is another susceptibility factor: hepatic damage seems to be rare in patients under the age of 20; the incidence of liver toxicity is 0.3% between the ages of 20 and 34, and increases with age to 1.2% between 34 and 49 and 2.3% over the age of 50 [ ].

Liver damage usually appears 1–2 months after the start of therapy. In children, raised liver enzymes are common during the first few months of treatment, but withdrawal is seldom necessary. A careful watch should be kept for early symptoms of isoniazid-induced hepatitis, such as malaise, fatigue, nausea, and epigastric distress. The dangers of continuing isoniazid after the onset of symptoms of toxicity have been highlighted [ ]. The earliest symptoms of isoniazid toxicity should be clearly described to the patient, particularly to hepatitis B carriers, who may be more susceptible to hepatotoxicity [ ].

It is advisable to measure the liver enzymes aspartate aminotransferase and alanine aminotransferase before treatment and monthly thereafter, for as long as isoniazid administration lasts. Isoniazid should be withdrawn if the aminotransferases increase to over five times normal [ ].

Drug users have multiple risk factors for hepatotoxicity, including chronic infection with hepatitis C. In a prospective study among drug users the only two factors that were independently associated with isoniazid hepatotoxicity were excessive alcohol consumption (OR = 4.2, 95% CI = 1.6, 10.8) and a high baseline alanine aminotransferase activity (OR = 4.3, 95% CI = 1.6, 11.4) [ ]. The presence of hepatitis C antibodies by itself did not confer an additional risk of toxicity, which was observed in 20 of 415 patients (4.8%). In another study, among 3788 patients taking isoniazid in a US county tuberculosis clinic, 673 (18%) had one or more adverse effects, including 10 (0.3%) with isoniazid-associated liver damage [ ]. There were higher rates with increasing age, but the overall rates were not alarming, even in individuals with risk factors. However, the greatest obstacle to the successful use of isoniazid preventive therapy is not toxicity but low completion rates.

There have been no clinical trials of the benefits and harms of routinely monitoring liver function tests for all patients taking isoniazid for latent tuberculosis infection. Data from two case series have suggested that routine liver function test monitoring leads to withdrawal of isoniazid prophylaxis from about 6% of patients because of abnormal results [ , ]. This is 10–60 times the hepatitis rate found in case series using a symptom-based monitoring strategy [ ]. In a pooled analysis of more than 200 000 patients taking isoniazid prophylaxis there was a hepatitis rate of 1.2% and only two deaths. There is an increased risk of hepatitis in advancing age; in one series the rates were 3/1000 in those aged 20–34 years, 12/1000 in those aged 35–49 years, and 23/1000 in those aged 50–64 years. The CDC and ATS joint guidelines for treatment of latent tuberculosis infection state that baseline laboratory testing is not routinely indicated, even for those over 35 years but may be considered for patients who are taking other hepatotoxic drugs or have chronic medical conditions. Baseline measurements of bilirubin and aspartate aminotransferase or alanine aminotransferase along with monthly monitoring of liver function tests are recommended for patients with pre-existing liver disease, patients with HIV infection, pregnant or postpartum women, and alcoholics. Isoniazid should be withdrawn if liver function tests exceed five times the upper limit of the reference range or three times the upper limit if the patient is symptomatic.

Hepatotoxicity, defined as aspartate aminotransferase activity more than five times the upper limit of the reference range, associated with the treatment of latent tuberculosis has been evaluated over 7 years in a retrospective study in adults [ ]. Of 3377 patients taking isoniazid, 19 had high aspartate aminotransferase activities (5.6 per 1000 patients). Only one of the 19 had prodromal symptoms associated with hepatotoxicity. After 1, 3, and 6 months of therapy the numbers of hepatotoxic events per 1000 patients were 2.75, 7.20, and 4.10 respectively. Age over 49 years and a baseline aspartate aminotransferase activity above the upper limit of normal were susceptibility factors. Moderate to severe hepatotoxicity often occurs without symptoms, which emphasizes the value of aminotransferase monitoring.

Pancreas

Acute pancreatitis has been attributed to isoniazid [ , ].

• A 42-year-old Asian man developed clinical, biochemical, and imaging features of acute pancreatitis 11 days after starting to take rifampicin, isoniazid, and pyrazinamide for spinal tuberculosis [ ]. He had no history of excessive alcohol or other drug therapy. He improved after withdrawal of all drugs, but the pancreatitis recurred on reintroduction of isoniazid and resolved after withdrawal.

Causality here was difficult to establish. Pancreatitis has rarely been seen in patients who have taken an overdose of isoniazid. Rifampicin, also used in this case, is more likely to cause pancreatitis in usual doses.

Urinary tract

Isoniazid can rarely cause renal damage [ ].

Urinary retention is a rare complication of isoniazid overdose [ ].

Skin

Morbilliform, maculopapular, or urticarial rashes have been observed in up to 2% of patients [ ]. In one study, acneiform eruptions developed in only 11 cases (1.4%), including 0.5% of patients taking isoniazid, 1.5% of patients taking rifampicin, and 0.6% of patients taking ethambutol [ ].

Acquired cutis laxa has been mentioned in a single child taking isoniazid, but it was probably coincidental [ ].

Erythema nodosum and purpura have been described in patients taking isoniazid [ ].

Pellagra has been reported in a patient taking isoniazid, despite concomitant pyridoxine prophylaxis [ ].

• A 52-year-old man developed pellagra with a classical photosensitive distribution after taking isoniazid for 14 months; the first 6 months being treatment for possible tuberculous meningitis, the rest to provide antituberculosis protection while glucocorticoids were given for possible neurosarcoidosis. He was said to take alcohol only occasionally and took pyridoxine throughout the entire period of treatment. He improved rapidly on withdrawal of isoniazid and supplementation with nicotinamide.

The authors noted that isoniazid-induced pellagra was first described in 1956, shortly after the introduction of isoniazid for the treatment of tuberculosis, but that subsequent reports have been very uncommon.

Isoniazid has also been reported to cause subepidermal blistering [ ].

• A 63-year-old man developed bullous lesions on the trunk and limbs and a six-fold rise in liver enzymes 15 days after treatment for tuberculosis. His skin recovered and his liver enzymes returned to normal within 2 weeks of withdrawal of all treatment, but the abnormalities recurred when treatment was resumed. At this point a skin biopsy showed subepidermal blistering. Once again withdrawal of treatment led to improvement, and when treatment was resumed without isoniazid the improvement continued.

Desensitization to isoniazid has been attempted in some patients with drug fever or rashes. A procedure of rush desensitization over a few days or a week can be used, starting with 1 mg orally and increasing the dosage every second day [ ] or even every few hours.

Musculoskeletal

Arthritic symptoms, with back pain, bilateral proximal interphalangeal joint involvement, arthralgia of the knees, elbows, and wrists, and the so-called “shoulder–arm” syndrome with cervicobrachial neuralgia can occur [ ].

Rhabdomyolysis occurred in subjects with isoniazid poisoning in a retrospective analysis of 270 patients seen over a 5-year period at the Phillipine General Hospital in Manilla [ ]. Skeletal muscle creatine kinase activity was raised in 31 of the 52 evaluable subjects who had taken more than 2.4 g/day of isoniazid. Creatine kinase activity peaked on days 5–6 and fell thereafter. Two patients developed acute renal insufficiency and required dialysis. Seizures occurred in all patients, and their duration, but not their frequency, correlated with raised creatine kinase activity. However, it is likely that factors other than seizures contribute to rhabdomyolysis in patients with isoniazid poisoning.