Isoniazid

Brand Names: INH, Laniazid, Isonicotinic Acid Hydrazide

Clinical Names: Isoniazid

Summary

generic name: Isoniazid

trade names: INH®, Laniazid®, Isonicotinic Acid Hydrazide.

type of drug: Tuberculostatic bactericidal agent.

used to treat: Prevention or treatment of tuberculosis, often in conjunction with other drugs such as Rifampicin.

overview of interactions:

• nutrient affected by drug: Vitamin B6 (Pyridoxine)

• nutrient affecting drug toxicity: Vitamin C

• nutrient affected by drug: Vitamin D




Interactions

nutrient affected by drug: Vitamin B6 (Pyridoxine)

• mechanism: This hydrazine derivative is a vitamin B6 antagonist, inactivating PLP and sometimes leading to peripheral neuropathies. Intravenous pyridoxine is considered the specific antidote for seizures due to acute isoniazid neurotoxicity.

• nutritional support: Individuals taking Isoniazid will typically benefit from taking supplemental B6. Optimal dose unknown. One study of children with tuberculosis found no significant benefit from supplementation with vitamin B6. However, a review concluded that: "Given in gram-per-gram amounts of the isoniazid ingested, pyridoxine (vitamin B6) usually eliminates seizure activity and helps to correct the patient's metabolic acidosis."
(Mbala L, et al. Trop Doct 1998 Apr;28(2):103-104; Romero JA, et al. Am Fam Physician 1998 Feb 15;57(4):749-752; Glenn GM, et al. Vet Hum Toxicol 1995 Aug;37(4):342-245; Snider DE Jr. Tubercle 1980 Dec;61(4):191-196.)

nutrient affecting drug toxicity: Vitamin C

• research: In vitro research indicates beneficial effects from vitamin C supplementation (as acsorbic acid) against the formation of the free radical intermediates due to isoniazid (INAH) and its metabolites.
(Matsuki Y, et al. Yakugaku Zasshi 1991 Oct;111(10):600-605.)

• nutritional support: A substantial dosage of vitamin C is usually required to achieve the desired antioxidant activity. Physicians experienced in nutritional therapy might give vitamin C at levels ranging from one gram twice daily to as high as two grams 3-4 times daily. Excessive vitamin C will result in diarrhea, at that point dropping the dose will result in a safe and effective dose. If high doses of vitamin C are used for an extended period, e.g., over 1,000 mg for more than three weeks, supplemental copper will ensure that the vitamin C does not deplete copper. A multivitamin/mineral formulation would usually provide an adequate source for copper.

nutrient affected by drug: Vitamin D

• mechanism: Research indicates that antituberculous drugs, including isoniazid, induce vitamin D deficiency. Vitamin D levels have been found to be lowered in children with tuberculosis, untreated and using isoniazid.

• nutritional support: Vitamin D supplementation may be of great value in addition to antituberculous drugs in the treatment of tuberculous children, and its use is highly recommended. Exposure to sunlight is the simplest and most natural way to provide activated vitamin D; it might be noted that sunshine and mountain air were characteristic of the great sanitoriums. However, when vitamin D is to be supplemented orally, the typical dosage would be in the range of 200-400 IU per day, depending on size and body weight. It is important to remember that excessive vitamin D can be harmful; though toxicity due to accumulation would be unlikely in this patient population, especially at doses less than 1,000 IU per day.
(Morcos MM, et al. Boll Chim Farm 1998 May;137(5):157-164.)

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References

Adler M, Girsh-Solomonovich Z, Raikhlin-Eisenkraft B. [Pyridoxine for severe metabolic acidosis and seizures due to isoniazid overdose]. Harefuah 1993 May 16;124(10):616-618. [Article in Hebrew]
Abstract: A 15-year-old girl took 3 g of isoniazid (15 tablets) in a suicide attempt and was brought unconscious to the emergency room. She was in respiratory failure, with seizures that could not be stopped with diazepam. Severe metabolic acidosis with normal serum lactate developed (pH 6.85), but did not improve after infusion of bicarbonate. Intravenous administration of pyridoxine led to prompt cessation of the seizures and to gradual improvement of acid-base status. She recovered consciousness after several hours and was discharged a week later.

Bengoa JM, Bolt MJ, Rosenberg IH. Hepatic vitamin D 25-hydroxylase inhibition by cimetidine and isoniazid. J Lab Clin Med 1984 Oct;104(4):546-552.

Brodie MJ, Boobis AR, Hillyard CJ, Abeyasekera G, Stevenson JC, MacIntyre I, Park BK. Effect of rifampicin and isoniazid on vitamin D metabolism. Clin Pharmacol Ther 1982 Oct;32(4):525-530.
Abstract: Rifampicin, 600 mg, and isoniazid, 300 mg daily for 14 days, reduced circulating levels of 25-hydroxy vitamin D (25-OHD) and 1 alpha, 25-dihydroxy vitamin D (1,25(OH)2D) by 34% (P less than 0.01) and 23% (P less than 0.05) in eight healthy subjects. This was accompanied by a rise in parathyroid hormone (PTH) of 57% (P less than 0.01), but not by a fall in serum calcium or phosphate levels. There was induction of endogenous cortisol oxidation in all subjects, but only in four fast acetylators was there a concomitant increase in antipyrine elimination. In the four slow acetylators antipyrine metabolism was inhibited after the first dose of the drugs. In nine tuberculous patients followed serially there was a fall in 25-OHD and 1,25 (OD)2D and a rise in PTH at the end of 1 mo (P less than 0.05). After 6 mo therapy 25-OHD concentration was further reduced (P less than 0.01), but there was no significant change in 1,25 (OH)2D or PTH levels. Combination treatment with rifampicin and isoniazid perturbs vitamin D metabolism, but less than might have been predicted from reports on each drug given alone. Nevertheless, tuberculous patients with already compromised calcium homeostasis receiving this combination of drugs should be carefully monitored.

Glenn GM, Krober MS, Kelly P, McCarty J, Weir M. Pyridoxine as therapy in theophylline-induced seizures. Vet Hum Toxicol 1995 Aug;37(4):342-245.
Abstract: Theophylline-induced seizures have significant morbidity and mortality and are difficult to treat. Theophylline therapy for asthma has been observed to depress plasma pyridoxal 5'-phosphate (PLP) levels which may decrease gamma-aminobutyric acid (GABA) synthesis and thereby contribute to seizures. We hypothesized that treatment with pyridoxine might prove beneficial in theophylline-induced seizures. One hundred thirty-nine mice were injected with 250 mg theophylline/kg ip and 89 mice were injected with 250-750 mg pyridoxine/kg ip as treatment. Decreased rates of seizure (42 vs 70%, p < 0.002) and death (29 vs 56%, p < 0.002) were observed. Six New Zealand White rabbits were given 115 mg theophylline/kg iv over 50 min followed by treatment with an iv bolus of 115 mg pyridoxine/kg, with subsequent continuous drip infusion of 230 mg/kg over 50 min. Serum theophylline levels and plasma PLP levels showed significant negative correlation prior to pyridoxine infusion with a mean peak theophylline level of 182 micrograms/ml and a mean low PLP level of 64 nM/L. Electroencephalogram (EEG) tracings were obtained before infusions, during theophylline infusion and during pyridoxine infusion. All 6 rabbits developed abnormal EEGs during theophylline infusion and all 6 rabbit EEG patterns returned to baseline during treatment with pyridoxine. These findings suggest that pyridoxine may partially reverse theophylline-induced central nervous system toxicity.

Gnam W, Flint A, Goldbloom D. Isoniazid-induced hallucinosis: response to pyridoxine. Psychosomatics 1993 Nov;34(6):537-539. (Letter)

Hoffer A. Isoniazid and pyridoxine. CMAJ 1993 Nov 1;149(9):1232. (Letter)

Kovacs CS, Jones G, Yendt ER. Primary hyperparathyroidism masked by antituberculous therapy-induced vitamin D deficiency. Clin Endocrinol (Oxf) 1994 Dec;41(6):831-836. Abstract: Antituberculous chemotherapy agents, particularly rifampicin and isoniazid, affect vitamin D metabolism and can create biochemical evidence of vitamin D deficiency. Vitamin D deficiency induces a state of resistance to parathyroid hormone. This study sought to explain the temporary resolution of hypercalcaemia and hypercalciuria, during antituberculous chemotherapy with rifampicin and isoniazid, in a subject with a surgically proven parathyroid adenoma and coincidental spinal tuberculosis. Serum ionized calcium, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, plasma parathyroid hormone, and 24-hour urine excretions of calcium, inorganic phosphorus and hydroxyproline were sequentially measured over a 3-year interval that included 18 months of antituberculous chemotherapy. Initial serum ionized calcium was 1.52 mmol/l (normal 1.20-1.35 mmol/l), 24-hour urine calcium excretion was 9.40 mmol/day (normal 1.25 to 7.50 mmol/day) and plasma intact PTH was 9.2 pmol/l (normal 0.0-4.5 pmol/l). During antituberculous chemotherapy the serum ionized calcium and 24-hour urine calcium excretion were normal but the plasma PTH rose to higher levels. Following completion of the chemotherapy, hypercalcaemia and hypercalciuria returned with levels similar to those observed pretreatment. Serum 25-hydroxyvitamin D was low at 6.25 nmol/l (normal 20 to 90 nmol/l) during antituberculous chemotherapy, but was normal before and after. Serum 1,25-dihydroxyvitamin D was normal throughout the 3-year interval. We conclude that the antituberculous chemotherapy induced relative vitamin D deficiency and resistance to parathyroid hormone action, thereby masking the hyperparathyroidism and hypercalcaemia until the chemotherapy was completed.

Langdana A, Agarwal M, Kelgeri C, Kamat P. Pyridoxine in acute isoniazid overdose. Indian Pediatr 1996 Feb;33(2):132-134.

Mahashur AA. Isoniazid induced peripheral neuropathy. J Assoc Physicians India 1992 Oct;40(10):651-652.

Matsuki Y, Akazawa M, Tsuchiya K, Sakurai H, Kiwada H, Goromaru T. [Effects of ascorbic acid on the free radical formations of isoniazid and its metabolites]. Yakugaku Zasshi 1991 Oct;111(10):600-605. [Article in Japanese]
Abstract: By the use of electron spin resonance (ESR) spectroscopy and of spin-trapping technique, the effects of ascorbic acid on the formation of the free radical intermediates due to isoniazid (INAH) and its metabolites were investigated with a microsomal system. When alpha-(4-pyridyl 1-oxide)-N-tert butylnitrone (4-POBN) was used as a spin trapping agent, the ESR signal due to hydrazine (Hy) was formed to be most intensive among others. Therefore, it was presumed that Hy is a potent intermediate to cause an INAH-induced hepatic injury. In the presence of ascorbic acid (AA), the free radical formation of Hy, INAH and acetyl hydrazine was significantly inhibited, suggesting that AA may affect the INAH-hepatitis. By the addition of inhibitors of cytochrome P-450 like metyrapone and CO, the generation of the radical from Hy decreased, confirming that the radical is formed by the cytochrome P-450 dependent microsome systems. The 4-POBN-trapped radical species generated from Hy was presumed to be the hydrazyl radical by the results of mass spectrometry.

Mbala L, Matendo R, Nkailu R. Is vitamin B6 supplementation of isoniazid therapy useful in childhood tuberculosis.  Trop Doct 1998 Apr;28(2):103-104.
Abstract: We present the results of a prospective single blind placebo controlled study performed to establish whether vitamin B6 supplementation of isoniazid therapy is useful in childhood tuberculosis. Eighty-five children suffering from tuberculosis (TB) and admitted between 1 October 1993 and 31 March 1995 to the Hospital of IME-Kimpese (Lower Zaire) were included. All were treated with isoniazid and other antitubercular drugs and were randomized to receive either vitamin B6 supplementation or placebo. No case of neurological or neuropsychiatric disorder was observed in the two groups during the 6 months of the treatment and 3 months after the treatment. These results suggest that the vitamin B6 supplementation of isoniazid therapy is unnecessary in childhood TB.

Morcos MM, Gabr AA, Samuel S, Kamel M, el Baz M, el Beshry M, Michail RR. Vitamin D administration to tuberculous children and its value. Boll Chim Farm 1998 May;137(5):157-164.
Abstract: Our study was done to assess the value of administration of vitamin D to tuberculous children. The study included twenty four newly diagnosed tuberculous children; eleven males and thirteen females. Their age ranged from one and half to thirteen years. Thirteen patients were extra thoracic type of T.B., while only seven were intrathoracic and the rest were mixed. They were randomly divided into two Groups according to the treatment administered: Group A patients were given Rifampicin, Isoniazid and Streptomycin. Group B received in addition vitamin D. After eight weeks therapy, the patients of each group were evaluated regarding clinical, laboratory, and radiological improvement. Vitamin D level is raised after treatment in both Groups A and B, but this rise is not significant. It also showed insignificant difference between the two groups. Vitamin D level showed very high significant decrease in tuberculous children than matched healthy controls (non tuberculous children). Calcium was significantly elevated after treatment in Group A whereas no significant change was detected in Group B. Phosphorous was highly significantly elevated after treatment in Group A, whereas in Group B it is just significantly elevated. Alkaline phosphatase level in both groups A and B were slightly decreased after treatment. However, this decrease was not significant. Clinical improvement was more evident in Group B patients (those taking vitamin D) as compared to Group A patients. The same was noted with X-ray and Sonographic findings. We concluded that vitamin D therapy may be of great value in addition to antituberculous drugs in the treatment of tuberculous children, and its use is highly recommended.

Pellock JM, Howell J, Kendig EL Jr, Baker H. Pyridoxine deficiency in children treated with isoniazid. Chest 1985 May;87(5):658-661.
Abstract: Isoniazid-induced deficiency of pyridoxine (vitamin B6) is reportedly not uncommon in adults but rare in children. In the present study, 38 children had serum levels of pyridoxine tested while receiving therapy with isoniazid. A biologic assay using the protozoan Tetrahymena thermophila determined pyridoxine status after 2 to 18 months of therapy with isoniazid. Five children (13 percent) were deficient. None had definitive clinical symptoms or signs consistent with pyridoxine deficiency. Three had normal nerve conduction velocity. Children receiving isoniazid in dosages greater than 10 mg/kg/day had a higher incidence of deficiency. Present recommendations for withholding pyridoxine prophylaxis from children receiving isoniazid therapy must be reconsidered in light of these findings, particularly in those children who are debilitated or have a poor nutritional history with a known pyridoxine deficit prior to therapy with isoniazid.

Romero JA, Kuczler FJ Jr. Isoniazid overdose: recognition and management. Am Fam Physician 1998 Feb 15;57(4):749-752. (Review)
Abstract: Since isoniazid is increasingly being used to control the spread of tuberculosis, physicians must be aware of its potentially fatal effects. The ingestion of toxic amounts of isoniazid causes recurrent seizures, profound metabolic acidosis, coma and even death. In adults, toxicity can occur with the acute ingestion of as little as 1.5 g of isoniazid. Doses larger than 30 mg per kg often produce seizures. When ingested in amounts of 80 to 150 mg per kg or more, isoniazid can be rapidly fatal. The first signs and symptoms of isoniazid toxicity usually appear 30 minutes to two hours after ingestion and include nausea, vomiting, slurred speech, dizziness, tachycardia and urinary retention, followed by stupor, coma and recurrent grand mal seizures. The seizures produced by isoniazid toxicity are often refractory to anticonvulsant therapy. Given in gram-per-gram amounts of the isoniazid ingested, pyridoxine (vitamin B6) usually eliminates seizure activity and helps to correct the patient's metabolic acidosis. Isoniazid toxicity should be suspected in any patient who presents with refractory seizures and metabolic acidosis.

Shah BR, Santucci K, Sinert R, Steiner P. Acute isoniazid neurotoxicity in an urban hospital. Pediatrics 1995 May;95(5):700-704.
Abstract: OBJECTIVES. To describe the presentation and treatment of acute isoniazid (INH) neurotoxicity appearing at an inner-city municipal hospital. DESIGN. Case series. PARTICIPANTS. Seven patients (eight patient visits) with an age range of 5 days to 14.9 years. RESULTS. At our institution, no children appeared with acute INH neurotoxicity in the period 1985 through 1990, whereas seven patients were treated from 1991 through 1993. This paralleled the rise in the number of children with tuberculous infection and disease seen at our institution, from an average 96 per year to 213 per year during these two time periods. All seven patients were receiving INH daily for tuberculosis (TB) prophylaxis. Accidental ingestion (five episodes) and suicidal attempts (three episodes) accounted for these visits. The total amount ingested range from 14.3 to 99.3 mg/kg (mean, 54 mg/kg). All but one patient presented with afebrile seizures. One patient presented twice with seizures. Acute INH neurotoxicity was not suspected on the first admission; however, when readmitted 4 weeks later with another seizure, the diagnosis of acute INH neurotoxicity was made. INTERVENTION. Intravenous pyridoxine was used in five episodes. Because it was not a stocked item in our pediatric emergency cart (as well as at another hospital, necessitating a transfer of a patient with refractory seizures to our hospital), the average delay was 5.8 hours (range, 1.3 to 13 hours) before it was given. Two patients with refractory seizures failed to respond to anticonvulsants, and their seizures were controlled only after parenteral pyridoxine. CONCLUSIONS. We have seen an increased incidence of acute INH neurotoxicity because of the resurgence of TB in New York City. Others as well may see a similar rise based on local trends in TB infection and disease. Acute INH toxicity should be suspected in children presenting with seizures with or without fever. In patients with a known access to INH, seizures should be considered to be caused by INH toxicity unless proved otherwise. Parenteral pyridoxine, the specific antidote for INH-induced refractory seizures, should be readily available in every emergency department in the areas similarly experiencing increasing trends of TB.

Snider DE Jr. Pyridoxine supplementation during isoniazid therapy. Tubercle 1980 Dec;61(4):191-196. (Review)
Abstract: Vitamin B6 (pyridoxine) supplementation during isoniazid (INH) therapy is necessary in some patients to prevent the development of peripheral neuropathy. In vivo pyridoxine is converted into coenzymes which play an essential role in the metabolism of protein, carbohydrates, fatty acids, and several other substances, including brain amines, INH apparently competitively inhibits the action of pyridoxine in these metabolic functions. The reported frequency of INH-induced neuropathy in various studies is reviewed and population groups at relatively high risk of developing this complication are identified. The routine use of pyridoxine supplementation to prevent peripheral neuropathy in high risk populations is recommended.

Toppet M, Vainsel M, Vertongen F, Fuss M, Cantraine F. [Sequential development of vitamin D metabolites under isoniazid and rifampicin therapy]. Arch Fr Pediatr 1988 Feb;45(2):145-148. [Article in French]
Abstract: A sequential study of 25-hydroxy vitamin D (25-OH-D), 1.25 dihydroxy vitamin D [1.25 (OH)2-D], PTH, alkaline phosphatase and gammaglutamyl transpeptidase (gamma GT) was undertaken in a series of 46 children with asymptomatic tuberculosis treated by isoniazid (INH) alone or associated with rifampin (RMP). These parameters were measured before treatment, 1 month, 3 months after the onset and at the end of treatment (6 months). In order to reduce the influence of the time of the year on the 25-OH-D levels, 22 patients were selected for whom the whole treatment took place between October and May of the following year. In this group, 13 children were treated by INH and RMP, 9 by INH alone. A statistically significant decrease in 25-OH-D levels could be demonstrated after 3 months of treatment in 13 patients under INH and RMP as well as a significant increase in alkaline phosphatase and gamma GT levels. In 9 patients given INH alone, 1.25 (OH)2-D levels decreased after 3 months without significant changes in 25-OH-D, alkaline phosphatase or gamma GT levels. These results emphasize the need for regular biochemical supervision, even if no sign of rickets is observed in these patients.