Pyridin-4-carbonsäurehydrazid

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

log Kow = -0.70

-0.8

-0.5

COLORLESS OR WHITE CRYSTALS, OR A WHITE, CRYSTALLINE POWDER

Crystals from alcohol

greater than or equal to 100 mg/mL at 77 °F (NTP, 1992)

Solubility in alcohol at 25 °C: about 2, in boiling alcohol: about 10%; in chloroform: about 0.1%. Practically insoluble in ether, benzene.

Sol in methyl ethyl ketone, acetone

In water, 1.4X10+5 mg/L at 25 °C

3.49e+01 g/L

374 °F (NTP, 1992)

> 250 °C

Breast Feeding; Lactation; Milk, Human; Anti-Infective Agents; Antitubercular Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Antituberculosis medicines

Warning

H302 (98.5%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P280, P301+P317, P302+P352, P321, P330, P332+P317, P362+P364, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 400 reports by companies from 13 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

H302: Harmful if swallowed [Warning Acute toxicity, oral]

This chemical is combustible. (NTP, 1992)

Combustible. Gives off irritating or toxic fumes (or gases) in a fire.

SYMPTOMS: Symptoms of exposure to this compound include irritation of the skin, peripheral nerve sensory changes, somnolence, anorexia, sweating, respiratory depression, urine changes and toxic psychosis. Other symptoms include dizziness, paresthesias, fatal hepatitis, metabolic acidosis, convulsions and coma. It can cause headache, muscle twitching, deafness, polyneuritis, paralysis and pyridoxine deficiency. It can also cause nausea, vomiting, atropinic signs such as mydriasis, brightly colored lights and other visual hallucinations, tachycardia, peripheral neuropathy, other central nervous system reactions, stupor, exhaustion, urinary retention, liver damage, bone marrow damage and death. Exposure may cause fatigue, weakness, malaise, toxic encephalopathy, optic neuritis, optic atrophy, memory impairment, epigastric distress, elevated serum transaminases (SGOT, SGPT), bilirubinemia, bilirubinuria, jaundice, agranulocytosis hemolytic anemia, sideroblastic anemia, aplastic anemia, thrombocytopenia, eosinophilia, fever, skin eruptions (morbilliform, maculopapular, purpuric or exfoliative), lymphadenopathy, vasculitis, pellagra, hyperglycemia, gynecomastia, rheumatic syndrome, systemic lupus erythematosus-like syndrome, blurred vision, respiratory distress, central nervous system depression, severe and intractable seizures and acetonuria. Exposure may also cause gastrointestinal effects, liver necrosis, slight euphoria, irritability, nervousness, insomnia, excessive dreaming and giddiness. Other symptoms include peripheral neuritis, burning of the feet, reduction of central vision and papilledema. Hyperreflexia, vertigo, ataxia, tinnitus, hepatic reactions, hypersensitivity reactions and lethargy may occur. Constipation, difficulty in starting urination, dryness of the mouth, mood-elevating effect and mental disturbances, ranging from minor personality changes to major mental derangements. This compound may also cause skin rash, urticaria, arthritic symptoms such as back pain, bilateral proximal interphalangeal joint involvement, arthralgia of the knees, elbows and wrists and "shoulder-hand" syndrome; separation of ideas and reality, florid psychosis, loss of self-control, excessive sedation, incoordination and methemoglobinemia.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl isoniazid, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Currie B et al; Acetylator Phenotype and Short-course Chemotherapy for Tuberculosis in Papua New Guinea. P N G Med J 32 (4): 259-62 (1989). Acetylator status and other factors influencing isoniazid-induced peripheral neuropathy are discussed, and statistics from Papua New Guinea are presented.

Holdiness MR; Teratology of the Antituberculosis Drugs. Early Hum Dev 15 (2): 61-74 (1987). The teratogenic effects of twelve antituberculosis drugs in animal models and man are reviewed. Isoniazid is considered one of the safest for maternal use.

Holdiness MR; Transplacental Pharmacokinetics of the Antituberculosis Drugs. Clin Pharmacokinet 13 (Aug): 125-9 (1987). A review of reports of antituberculosis drugs given during pregnancy shows information indicating placental transfer of isoniazid.

ISONIAZID is incompatible with chloral, aldehydes, iodine, hypochlorites and ferric salts. It is also incompatible with oxidizers. It may react with sugars and ketones. It can react as a weak acid or a weak base. It can be decomposed by oxidative and reductive reactions. (NTP, 1992)

Acute Tox. 4 (98.5%)

Acute toxicity (Oral) - Category 4

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. A water spray may also be used. (NTP, 1992)

Use water spray, powder, foam, carbon dioxide.

Fresh air, rest. Refer immediately for medical attention.

Remove contaminated clothes. Rinse and then wash skin with water and soap.

First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then refer for medical attention.

Rinse mouth. Give a slurry of activated charcoal in water to drink. Refer immediately for medical attention.

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

Store below 40 °C (104 °C), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. Protect from freezing. NOTE: Crystallization may occur at low temperatures. Upon warming to room temperature, the crystals will redissolve.

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

Sweep spilled substance into covered sealable containers. If appropriate, moisten first to prevent dusting. Carefully collect remainder. Then store and dispose of according to local regulations. Personal protection: P2 filter respirator for harmful particles.

Concurrent use of prednisolone, and probably other related adrenocorticoids, with isoniazid may increase hepatic metabolism and/or excretion of isoniazid, leading to decreased plasma concentration and effectiveness of isoniazid, especially in patients who are rapid acetylators; isoniazid dosage adjustments may be required.

Concurrent daily use of alcohol may result in increased incidence of isoniazid-induced hepatotoxicity and increased metabolism of isoniazid; dosage adjustments of isoniazid may be necessary; patients should be monitored closely for signs of hepatotoxicity and should be advised to restrict intake of alcoholic beverages.

Chronic preoperative or perioperative use of isoniazid, a hepatic enzyme inhibitor, may decrease the plasma clearance and prolong the duration of action of alfentanil.

Antacids may delay and decrease absorption and serum concentrations of orally administered isoniazid; concurrent use should be avoided, or patients should be advised to take oral isoniazid at least 1 hour before aluminum-containing antacids.

For more Interactions (Complete) data for ISONIAZID (23 total), please visit the HSDB record page.

Adverse reactions include rash, abnormal liver function tests, hepatitis, peripheral neuropathy, mild central nervous system (CNS) effects. In vivo, Isoniazid reacts with pyridoxal to form a hydrazone, and thus inhibits generation of pyridoxal phosphate. Isoniazid also combines with pyridoxal phosphate; high doses interfere with the coenzyme function of the latter.

Despite its limited use, isoniazid remains one of the most common causes of serious, idiosyncratic liver injury and is the single major cause of death from drug-induced liver injury in the United States and most countries of the world. Therapy with isoniazid is associated with transient serum aminotransferase elevations in 10% to 20% of patients, and levels rising above 5 times the upper limit of the normal range (ULN) in 3% to 5%. These rates vary by age and by whether isoniazid is given alone or combined with other antituberculosis agents. The enzyme elevations are usually asymptomatic and often resolve even with continuation of therapy without dose adjustment (Case 1 and 2).

Occupational hepatotoxin - Secondary hepatotoxins: the potential for toxic effect in the occupational setting is based on cases of poisoning by human ingestion or animal experimentation.

Various adverse effects have been reported with INH use; most are transient and low-grade. Patients commonly experience gastrointestinal effects; some also report rash and pruritus. Peripheral neuropathy is also a commonly associated adverse event of INH therapy, although its incidence is less than 0.2%. The risk may increase in patients with diabetes, HIV, nutritional deficiency, renal failure, alcoholism, and in women who are pregnant or breastfeeding. The mechanism of INH-induced peripheral neuropathy appears to involve interference of INH metabolites with vitamin B6 (pyridoxine) metabolism, resulting in decreased amounts of biologically active B6. Thus, the treatment and prevention of peripheral neuropathy caused by INH is pyridoxine supplementation during treatment.

The substance can be absorbed into the body by ingestion.

Readily absorbed following oral administration; however, may undergo significant first pass metabolism. Absorption and bioavailability are reduced when isoniazid is administered with food.

IDENTIFICATION: Isoniazid is used for the treatment of tuberculosis. Isoniazid is a colorless, odorless, white crystalline powder slowly affected by exposure to air and to light. It is soluble in water, alcohol, slightly soluble in chloroform and very slightly soluble in ether. Isoniazid is an antimycobacterial agent which is bactericidal for both extracellular and intracellular organisms. It is the primary drug for the treatment of tuberculosis when the disease is caused by isoniazid-sensitive strains of the Mycobacterium tuberculosis. In combination with rifampicin, ethambutol or pyrazinamide, isoniazid INH line agent in the treatment of pulmonary and extrapulmonary tuberculosis. It is a component of all combined antituberculosis chemotherapy regimens. Isoniazid may be used for tuberculosis prophylaxis. HUMAN EXPOSURE: Main risks and target organs: CNS is the target organ of isoniazid acute toxicity. Isoniazid induces generalized convulsions, coma and metabolic acidosis. Death may occur from acute respiratory failure or hypotension. Liver and peripheral nervous and hematologic systems are the main target organs of isoniazid chronic toxicity. Isoniazid INH may induce acute hepatitis, peripheral neuropathy, haemolytic anemia. Summary of clinical effects: Toxicity appears after a short delay of 0.5 to 4 hours following ingestion. Symptoms may include: slurred speech, hallucinations, coma; generalized convulsions, status epilepticus; respiratory failure, hypotension; severe metabolic acidosis, fever; rhabdomyolysis; gastrointestinal symptoms (nausea, vomiting) are frequent prior to the onset of convulsions. Hepatitis, peripheral neuropathy and hemolytic anemia are manifestations of chronic toxicity. Severe isoniazid poisoning is characterized by the clinical triad of: repetitive convulsions not responsive to usual treatment; metabolic acidosis and coma. Chronic isoniazid toxicity produces nausea, vomiting, restlessness, fever and many other signs and symptoms. Toxic hepatitis and hemolytic anemia may be observed, as well as other hematological effects and psychosis. Contraindications: Known severe adverse reactions or hypersensitivity due to the drug. Previous hepatitis associated with isoniazid. Isoniazid should not be used in patients with acute liver disease. Isoniazid may precipitate porphyria. Convulsions may be precipitated in patients with epilepsy. Liver function should be monitored regularly in patients with previous hepatic disease. Routes of entry: Oral: This is the most frequent route of intoxication because the drug is usually administered orally. Parenteral: No case has been reported, but isoniazid intoxication may occur after parenteral administration. Absorption by route of exposure: Oral: isoniazid is rapidly and almost completely (90-95%) absorbed from the gastrointestinal tract. Peak plasma concentrations are reached within 1 to 2 hours after ingestion. When INH is administered with food, the extent of absorption and the peak plasma concentration may be reduced. Distribution by route of exposure: Protein binding is less than 10 to 15 %. Isoniazid is distributed into all body tissues and fluids (pleural, ascitic fluids, saliva, CSF) with tissue or fluid levels similar to serum levels. Skin contains large amounts and acts as a storage depot. Isoniazid penetrates well into caseous lesions. Isoniazid readily crosses the placenta. The concentrations in milk are approximately equal to plasma maternal concentrations. Biological half-life by route of exposure: The plasma half-life in patients with normal renal and hepatic function is 1 to 4 hours, depending on the rate of metabolism: it is 0.5 to 1.6 hours in fast acetylators and 2 to 5 hours in slow acetylators. The plasma halflife may be prolonged to 4.3 hours in patients with impaired hepatic function or severe renal impairment. Plasma half life may also be prolonged in acute overdose. Metabolism: The major route of isoniazid metabolism is hepatic acetylation by N-acetyl transferase which produces acetylisoniazid. The rate of acetylation is genetically determined. Acetyisoniazid is further hydrolysed to isonicotinic acid and acetylhydrazine, both of which are excreted in the urine. Isonicotinic acid is conjugated with glycine. Acetylhydrazine is further metabolized to diacetylhydrazine and may be converted by the hepatic microsomal enzymes to the reactive metabolite (presumed to be hydrazine) which are thought responsible for isoniazid-induced hepatotoxicity. Elimination and excretion: Kidney: In adults with normal renal function, approximately 50 to 70% of a 5 mg/kg oral dose is excreted in urine within 24 hours as unchanged drug and as metabolites. The percentage of the different compounds excreted varies with the acetylator phenotype. Breast milk: 0.75 to 2.3% of the dose is excreted into breast milk in 24 hours. This corresponds to 6-20% of a usual therapeutic pediatric dose. Other routes: Small amounts of the drug are excreted in saliva, sputum and feces. Mode of action: Toxicodynamics: Tonic-clonic seizures and severe metabolic acidosis are the most common features in isoniazid overdose. Seizures: The precipitating mechanism of the seizures is not exactly known but it may be related to the isoniazid induced deficiency of pyridoxine. INH produces pharmacologic changes in pyridoxine metabolism. Increased renal excretion of pyridoxine by formation of isoniazid pyridoxine hydrazones. The hydrazones competitively inhibit pyridoxine kinase, the activating enzyme that converts pyridoxine to the physiologically active pyridoxal phosphate. Inactivation of the pyridoxal containing enzymes. The subsequent reduction in pyridoxine and pyridoxal phosphate inhibits the formation of the inhibitory neurotransmitter, gamma aminobutyric acid or GABA. This reduction in GABA levels may explain the seizures in patients with isoniazid poisoning. Metabolic acidosis: The metabolic acidosis may be related to: a lactic acidosis due to the seizures, a blockage in the conversion of lactate to pyruvate, an increased metabolism of fatty acids resulting from an impaired glucose metabolism with hyperglycemia and ketonuria. Neuropathy: Peripheral neuropathy secondary to chronic exposure is due to the deficiency of pyridoxine and pyridoxal phosphate. Hepatitis: Hepatitis is due to a toxic metabolite of monoacetyl hydrazine, which binds covalently to liver proteins. In some patients an allergic mechanism has also been proposed: acylation of hepatic macromolecules by acetyl hydrazine may lead to the release of antigenic macromolecules which induce the formation of antibodies directed against the liver. Pharmacodynamics: The exact mechanism of action of isoniazid is not known. Isoniazid may act by inhibition of mycolic acid synthesis and disruption of the cell wall in susceptible organisms. Since mycolic acids are unique to mycobacteria, this action explains the high degree of selectivity of the antimicrobial activity. Mutation conferring resistance may occur in susceptible microorganisms. There is a cross resistance between isoniazid, rifampicin and ethambutol. However the simultaneous use of two of these drugs markedly delays the emergence of resistant mutants either agent. Carcinogenicity: There is no evidence to support carcinogenic effects in humans. A recent study did not detect an increase in cancer deaths in a series of 338 women treated with INH for pulmonary tuberculosis. Several other studies fail to show a carcinogenic effect, including a study in which 25,000 patients followed up for 9 to 14 years and a study of 3,842 patients in the UK. Interactions: Several drugs may interact with INH: Drugs which interfere with INH pharmacokinetics: Aminosalicylic acid, procainamide, propranolol increase INH serum levels by reduction of the acetylation. Aluminium-containing antacids decrease the gastrointestinal absorption of the drug. Pyrazinamide decreases the serum levels of INH. Drugs which decrease serum levels when used with INH: Cyclosporine, enflurane, folic acid, ketoconazole, verapamil. Drugs which increase serum levels when used with INH: Carbamazepine, diazepam, dicoumarol, ethosuximide, phenytoin, primidone, theophylline. Other interactions: The concomitant administration of INH and the following drugs may produce: psychiatric responses: tricyclic antidepressants; hyperglycaemia: chlorpropamide; agitation or parkinsonian tremor: levodopa; hypotension: pethidine (meperidine); increased incidence of hepatotoxicity: rifampicin; hypertension, tachycardia, hyperthermia: monoamine oxidase inhibitors. Main adverse effects: Peripheral neuropathy and hepatotoxicity are the most frequently observed adverse effects of INH. Hepatotoxicity: Asymptomatic elevation of serum aspartate transferase (SGOT) is noted in 10-20 % of the patients. This increase is usually transient and the level returns to normal with continuing therapy. INH should be discontinued in patients with a transaminase level three times greater than normal. Hepatitis with jaundice may occur (0.5 %). In most cases, hepatitis occurs within the 3 months following the onset of the treatment. Some factors predisposing to INH hepatotoxicity include: age, alcohol, rapid acetylator status, concomitant administration of isoniazid and rifampicin. Peripheral neuropathies: Peripheral neuropathy is the most common side effect of INH. It is secondary to a pyridoxine deficiency. The predisposing factors are: alcohol, slow acetylator status, diabetes, malnutrition, pregnancy. Peripheral neuropathy is dose-related: it is uncommon at low doses and very frequent with high doses. Treatment and prophylaxis are based on administration of pyridoxine. Other adverse reactions: Hematologic: disseminated intravascular coagulation; granulocytosis, eosinophilia, anemia (hemolytic, aplastic, sideroblastic, megaloblastic), thrombocytopenia. Neurologic: peripheral neuropathy, hypersensitivity meningitis, dystonias, encephalopathy, seizures, cerebellar syndromes. Psychiatric: confusional states, transient memory impairment, delirium. Endocrine/metabolic: hyperglycemia, hypocalcemia, porphyria, gynecomastia. Gastrointestinal: abdominal pain, acute pancreatitis. Kidney: nephrotoxicity is a very rare complication, (1 case of acute renal insufficiency has been described). Ocular: optic neuropathy (especially when combined therapy with INH and ethambutol); optic atrophy Dermatologic: pellagra (due to a nicotinic acid deficiency), exfoliative dermatitis, Steven-Johnson syndrome; cutaneous reactions (2%), urticaria, angioneurotic oedema, morbilliform eruptions, purpura, acneiform eruptions, photosensitivity. Musculoskeletal: arthritis, arthralgias, systemic lupus erythematosis; antinuclear antibodies in the serum may appear, especially in slow acetylators, approximately five months after the onset of therapy.

The liver metabolizes INH primarily by acetylation with N-acetyl transferase 2 (NAT2). Three metabolites have implications that correlate with the liver injury associated with the drug: acetyl hydrazine (AcHz), hydrazine (Hz), and a metabolite from the bioactivation of INH itself. Considerable variation is apparent in the acetylation rate and elimination half-life from individual to individual, which is not accounted for by dose and concentration. This appears to contribute to the risk of hepatotoxicity and the other adverse effects associated with the drug.

Isoniazid is a prodrug and must be activated by bacterial catalase. Specficially, activation is associated with reduction of the mycobacterial ferric KatG catalase-peroxidase by hydrazine and reaction with oxygen to form an oxyferrous enzyme complex. Once activated, isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and extracellular <i>Mycobacterium tuberculosis</i> organisms. Specifically isoniazid inhibits InhA, the enoyl reductase from <i>Mycobacterium tuberculosis</i>, by forming a covalent adduct with the NAD cofactor. It is the INH-NAD adduct that acts as a slow, tight-binding competitive inhibitor of InhA.

Sore throat. Cough. Nausea. Vomiting. Hallucinations. Tremor.

Redness. Pain.

Dizziness. Confusion. Nausea. Vomiting. Weakness. Convulsions. Unconsciousness.

/SIGNS AND SYMPTOMS/ Patients may be asymptomatic for 30 minutes to 2 hours after an acute overdose. Early symptoms include nausea and vomiting, dizziness, slurred speech, lethargy, disorientation, and hyperreflexia. Seizures usually occur within 1 to 3 hours after ingestion, and are often repetitive and refractory to usual anticonvulsants. Lactic acid accumulation produces an anion gap metabolic acidosis within a few hours, which is often severe and refractory to sodium bicarbonate. Hyperglycemia, glycosuria, and ketonuria have also been reported.

/SIGNS AND SYMPTOMS/ Overdosage of isoniazid has produced nausea, vomiting, dizziness. slurred speech, blurred vision, and visual hallucinations (including bright colors and strange designs). Symptoms of overdosage usually occur within 30 minutes to 3 hours following ingestion of the drug. After marked overdosage, respiratory distress and CNS depression, progressing rapidly from stupor to coma, severe intractable seizures, metabolic acidosis, acetonuria, and hyperglycemia have occurred. If untreated or treated inadequately, isoniazid overdosage may be fatal. Isoniazid-induced seizures are thought to be associated with decreased gamma-aminobutyric acid (GABA) concentrations in the CNS, possibly resulting from inhibition by isoniazid of brain pyridoxal-5-phosphate activity.

/CASE REPORTS/ Accidental or intentional isoniazid overdose is not uncommon. Two patients suffering from pulmonary tuberculosis ingested isoniazid (9 g and 12 g respectively) intentionally following acute personal stress. One patient presented with oliguria and coma whereas seizures were the dominant feature in the second case. Serum levels of isoniazid were high in both cases. Satisfactory clinical recovery followed after the administration of iv pyridoxine.

/CASE REPORTS/ Two cases of acute isoniazid poisoning in patients who ingested 7.5 g and 5.0 g of isoniazid respectively, with the intention of committing suicide are presented. Both were admitted unconscious, with ventilatory insufficiency and convulsions. Hepatic dysfunction and peripheral neuropathy were notable complications.

Isonicotinic acid hydrazide (Isoniazid)

Group 3: Not classifiable as to its carcinogenicity to humans

Volume 4: (1974) Some Aromatic Amines, Hydrazine and Related Substances, N-Nitroso Compounds and Miscellaneous Alkylating Agents

1987

1987

3, not classifiable as to its carcinogenicity to humans. (L135)

Drug Induced Liver Injury Rank (DILIrank 2.0)

Isoniazid

vMost-DILI-concern

8

Box warning

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Acute Exposure/ In rabbits isoniazid penetrates readily into the eye either following topical orsystemic administration but without notable toxic effect. Massive doses injected SC in rabbits have been shown to cause hemorrhage in the meninges at the base of the brain and in the region of the optic nerves, but no inflammatory or degenerative changes in the nerves themselves. Intrathecal injection of isoniazid in rabbits was more seriously damaging, and it is felt that the route of administration was a critical factor in causing optic neuritis in a series of patients who were treated by intrathecal administration of isoniazid for tuberculous meningitis.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The subacute effect of a low dose of isoniazid (10 mg/kg/day for 11 days) in phenobarbitone sodium pretreated rabbits (60 mg/kg/day for 4 days) on various lipid parameters in plasma, liver and adipose tissue was investigated. While treatment with phenobarbitone sodium or isoniazid alone did not alter the lipid levels in plasma and tissues, isoniazid treatment in phenobarbitone sodium pretreated rabbits elevated the levels of plasma total lipid and cholesterol. In adipose tissue there was a decrease in total lipid, triglyceride and cholesterol and an elevation in free fatty acid. In contrast, all these parameters were found to be elevated in the liver. It is proposed that the enhanced release of primary amine functional groups from isoniazid during microsomal induction by phenobarbitone sodium treatment caused increased deposition of lipids in the liver, which is presumably an outcome of enhanced breakdown and mobilization of lipids from the adipose tissue.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ ... CB/SE RATS /WERE GIVEN/ DAILY DOSES OF ABOUT 35 MG INH IN DRINKING WATER FOR 48 WEEKS. OF MALES, 1/49 DEVELOPED LIVER TUMOR AND 2/49 ... LUNG TUMORS. OF FEMALES, 11/40 HAD FIBROADENOMAS OF MAMMARY GLAND. NO ... TUMORS WERE FOUND IN ... CONTROLS ... KILLED AT 104 WEEKS.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ ... DD MICE /WERE INJECTED/ SC WITH 2 MG INH EVERY 2 DAYS FOR 18 WEEKS. INCIDENCE OF PULMONARY TUMORS (ADENOMAS) IN 15 ANIMALS SURVIVING 7 MON WAS 53% IN EXPTL GROUP AND 11% IN 9 CONTROL ANIMALS.

For more Non-Human Toxicity Excerpts (Complete) data for ISONIAZID (13 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl isoniazid, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

J04AC01

J - Antiinfectives for systemic use

QJ - Antiinfectives for systemic use

J04AC01

Isoniazid is a bactericidal agent active against organisms of the genus Mycobacterium, specifically <i>M. tuberculosis</i>, <i>M. bovis</i> and <i>M. kansasii</i>. It is a highly specific agent, ineffective against other microorganisms. Isoniazid is bactericidal when mycobacteria grow rapidly and bacteriostatic when they grow slowly.

Isoniazid is a prodrug and must be activated by bacterial catalase. Specficially, activation is associated with reduction of the mycobacterial ferric KatG catalase-peroxidase by hydrazine and reaction with oxygen to form an oxyferrous enzyme complex. Once activated, isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and extracellular <i>Mycobacterium tuberculosis</i> organisms. Specifically isoniazid inhibits InhA, the enoyl reductase from <i>Mycobacterium tuberculosis</i>, by forming a covalent adduct with the NAD cofactor. It is the INH-NAD adduct that acts as a slow, tight-binding competitive inhibitor of InhA.

Although the mechanism of action of isoniazid is unknown, several hypotheses have been proposed. These include effects on lipids, nucleic acid biosynthesis, and glycolysis. ... /It has been suggested that/ a primary action of isoniazid /is/ to inhibit the biosynthesis of mycolic acids, important constituents of the mycobacterial cell wall. Because mycolic acids are unique to mycobacteria, this action would explain the high degree of selectivity of the antimicrobial activity of isoniazid. Exposure to isoniazid leads to a loss of acid fastness and a decrease in the quantity of methanol-extractable lipid of the microorganisms.

Isoniazid is bacteriostatic for "resting" bacilli but is bactericidal for rapidly dividing microorganisms. The minimal tuberculostatic concentration is 0.025 to 0.05 ug/ml.

Fast acetylators: 0.5 to 1.6 hours. Slow acetylators: 2 to 5 hours.

Adults (including elderly patients)- Fast acetylators: 0.5 to 1.6 hr. Slow acetylators: 2 to 5 hr. Acute and chronic liver disease: May be prolonged (6.7 hr vs 3.2 hr in controls),

Children (age 1.5 to 15 years)-2.3 to 4.9 hours.

Neonates-7.8 and 19.8 hours in newborns who received isoniazid transplacentally. The long half-life may be due to the limited acetylation capacity of neonates.

Primarily hepatic. Isoniazid is acetylated by N -acetyl transferase to N -acetylisoniazid; it is then biotransformed to isonicotinic acid and monoacetylhydrazine. Monoacetylhydrazine is associated with hepatotoxicity via formation of a reactive intermediate metabolite when N-hydroxylated by the cytochrome P450 mixed oxidase system. The rate of acetylation is genetically determined. Slow acetylators are characterized by a relative lack of hepatic N -acetyltransferase.

Isoniazid is inactivated in the liver, mainly by acetylation and dehydrazination. Metabolites of the drug include acetylisoniazid, isonicotinic acid, monoacetylhydrazine, diacetylhydrazine, and isonicotinyl glycine.

/IN MAN/ ... MOST IMPORTANT METABOLITES OF INH IN URINE /WERE FOUND/ TO BE 1-ACETYL-2-ISONICOTINOYLHYDRAZINE (ACETYL INH), N-ACETYL-N'-ISONICOTINIC ACID, ISONICOTINYLGLYCINE, PYRUVIC ACID ISONICOTINYLHYDRAZONE AND ALPHA-OXOGLUTARIC ACID ISONICOTINYLHYDRAZONE ... .

IN VIVO METABOLISM OF INH IN RABBIT ... YIELDS ISONICOTINIC ACID AND AMMONIA, LATTER BEING DERIVED FROM RAPID BREAKDOWN OF HYDRAZINE GROUP ... .

Acetylation of acetylisoniazid results in the formation of monoacetylhydrazine which has been shown to be a potent hepatotoxin in animals. Microsomal metabolism of monoacetylhydrazine in animals results in production of a reactive acylating species capable of covalently binding with tissue macromolecules (i.e., liver protein) and subsequently causing hepatic necrosis.

For more Metabolism/Metabolites (Complete) data for ISONIAZID (6 total), please visit the HSDB record page.

V83O1VOZ8L

ISONIAZID

Established Pharmacologic Class [EPC] - Antimycobacterial

Isoniazid is an Antimycobacterial.

ISONIAZID

Antimycobacterial [EPC]

Drugs used in the treatment of tuberculosis. They are divided into two main classes: first-line agents, those with the greatest efficacy and acceptable degrees of toxicity used successfully in the great majority of cases; and second-line drugs used in drug-resistant cases or those in which some other patient-related condition has compromised the effectiveness of primary therapy.

Compounds that interfere with FATTY ACID SYNTHASE resulting in a reduction of FATTY ACIDS. This is a target mechanism in humans of some ANTINEOPLASTIC AGENTS and ANTI-OBESITY AGENTS and of some ANTI-INFECTIVE AGENTS which interfere with CELL WALL and CELL MEMBRANE formation.

Readily absorbed following oral administration; however, may undergo significant first pass metabolism. Absorption and bioavailability are reduced when isoniazid is administered with food.

From 50 to 70 percent of a dose of isoniazid is excreted in the urine within 24 hours.

ISONIAZID DIFFUSES READILY INTO ALL BODY FLUIDS AND CELLS. THE DRUG IS DETECTABLE IN SIGNIFICANT QUANTITIES IN PLEURAL AND ASCITIC FLUIDS; CONCENTRATIONS IN CEREBROSPINAL FLUID ARE SIMILAR TO THOSE IN THE PLASMA. ISONIAZID PENETRATES WELL INTO CASEOUS MATERIAL. THE CONCENTRATION OF THE AGENT IS INITIALLY HIGHER IN THE PLASMA AND MUSCLE THAN IN THE INFECTED TISSUE, BUT THE LATTER RETAINS THE DRUG FOR A LONG TIME IN QUANTITIES WELL ABOVE THOSE REQUIRED FOR BACTERIOSTASIS.

FROM 75 TO 95% OF A DOSE OF ISONIAZID IS EXCRETED IN THE URINE WITHIN 24 HR, MOSTLY AS METABOLITES.

Readily absorbed following oral administration; however, may undergo significant first pass metabolism. Absorption and bioavailability were reduced when isoniazid was administered with food.

Widely distributed to all fluids and tissues, including cerebrospinal fluid, pleural and ascitic fluids, skin, sputum, saliva, lungs, muscle, and caseous tissue. Crosses the placenta and is excreted in breast milk.

Used as a chemical intermediate for the synthesis of furonazide; glyconiazide; iproniazid.

MEDICATION: Antitubercular Agents

MEDICATION (VET)

Use (kg; approx.) in Germany (2009): >500

For the treatment of all forms of tuberculosis in which organisms are susceptible.

(1972) 5.35X10+7 GRAMS

(1975) 6.01X10+6 GRAMS (PRINCPL CUSTMS DISTS)

(1972) PROBABLY GREATER THAN 4.54X10+5 GRAMS

(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS

OXIDATION OF 4-METHYLPYRIDINE OR 4-ETHYLPYRIDINE TO ISONICOTINIC ACID, WHICH IS REACTED AS THE METHYL OR ETHYL ESTER WITH HYDRAZINE OR HYDRAZINE HYDRATE

/IT IS/ PREPARED BY CONDENSING ISONICOTINIC ACID ETHYL ESTER WITH HYDRAZINE; FROM 4-CYANOPYRIDINE AND HYDRAZINE.

Prepared by condensing pyridine-4-carboxyethylate and hydrazine.

... Obtained by reaction of isonicotinic esters such as ethyl isonicotinate, or the 4-nitrile, with hydrazine.

... INH IS AVAILABLE IN A USP GRADE CONTAINING A MIN OF 98% OF ACTIVE INGREDIENT. SMALL AMT OF ISOMERIC COMPD AND HYDRAZINE MAY BE PRESENT.

Rifampicin is also supplied in combination with isoniazid...this combination is known as Rifamate (Merrell Dow), Rifinah (Merrell Dow), and Rimactazid (CIBA).

Powder: Oral: Solution: 50 mg/5 mL, Isoniazid Syrup (with sorbitol 70%), (Allscripts, Carolina Medical, Versa); Tablets: 100 mg, 300 mg. Parenteral: Injection: 100 mg/mL, Nydrazid (with chlorobutanol 0.25%), (Sandoz).

4-Pyridinecarboxylic acid, hydrazide: ACTIVE

Prepn: Meyer, Mally, Monatsh. 33, 400 (1912); Lock, Pharm. Ind. 14, 366 (1952); Urbanski et al., Rocz. Chem. 27, 161 (1953); Gasson, U.S. Pat. 2,830,994 (1958 to Distillers).