Isoniazid

Isoniazid is an Antitubercular agent belonging to mycobacterial infection.

Isoniazid is used in the treatment of Tuberculosis, active and Tuberculosis, latent infection.

Isoniazid is completely and rapidly absorbed from the GI tract, and after IM injection, the food reduces the rate and extent of absorption. It gets distributed to all body tissues and fluids, including CSFand gets metabolized in Hepatic to acetylisoniazid with a decay rate determined genetically by acetylation phenotype; it undergoes further hydrolysis to isonicotinic acid and phenylhydrazine and get excreted through Urine (75% to 95% as unchanged drug and metabolites); small amounts excreted in feces and saliva.

The onset of Action of Isoniazid for Fast acetylators: 0.5 to 1.6 hours. Slow acetylators: 2 to 5 hours

The Duration of Action of Isoniazid was within 1-2 days.

The Tmax of Isoniazid was achieved within 1 to 2 hours .Cmax was about 1,200 ng/ml

Isoniazid shows common side effects like Constipation, nausea, vomiting, dry mouth, epigastric distress, acute pancreatitis.etc

Isoniazid is available in the form of tablets , injection, and Syrup.

Isoniazid is available in India, Germany, Canada, Italy, USA

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 Mycobacterium tuberculosis organisms.

Isoniazid is available in the form of tablets , injection, and Syrup.

• Tablet and Syrup: Do not administer with food.
• Intramuscular: IM injection may be used for patients who are unable to either take or absorb oral therapy. Inject deep IM into a large muscle mass.

Isoniazid is used in the treatment of Tuberculosis, active and Tuberculosis, latent infection.

Isoniazid is a isonicotinic acid hydrazide derivative that inhibits the synthesis of mycolic acids, an essential components of the bacterial cell wall. It is bactericidal at therapeutic levels against the actively growing extracellular and intracellular Mycobacterium tuberculosis organisms.

Isoniazid is approved for use in the following clinical indications

Tuberculosis, active: Treatment of susceptible active Tuberculosis (eg, Mycobacterium tuberculosis) infections.

Tuberculosis, latent infection: Treatment of latent tuberculosis infection (LTBI) caused by M. tuberculosis (also referred to as prophylaxis or preventive therapy).

Isoniazid is available in various strengths as 100 mg/mL (10 mL), 50 mg/5 mL (473 mL), 100 mg.

Isoniazid is available in the form of tablets, injection and Syrup.

• Dosage Adjustment in Kidney Patient

Oral, IM:

● Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction.

● Hemodialysis, intermittent (thrice weekly): Slightly dialyzable (9.2%): No dosage adjustment necessary when scheduled dose falls on a dialysis day, administer after hemodialysis.

● Peritoneal dialysis: Slightly dialyzable (CAPD accounts for 1.3% of total clearance): No dosage adjustment necessary .

● CRRT: No dosage adjustment necessary .

● PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (expert opinion).

• Dosage Adjustment in Hepatic impairment Patient

There are no dosage adjustments provided in the manufacturer’s labeling; however, use with caution, may accumulate and additional liver damage may occur in patients with preexisting liver disease. Contraindicated in patients with acute liver disease or previous isoniazid-associated hepatic injury.

For ALT or AST >3 times the ULN: discontinue or temporarily withhold treatment. Treatment with isoniazid for latent tuberculosis infection should be deferred in patients with acute hepatic diseases.

● Dosage Adjustment for Pediatric Patients:-

● Tuberculosis, active; treatment for drug-susceptible:

● Note: Always use in combination with other antitubercular drugs. Any regimens using less than once-daily dosing should administer dosing as directly observed therapy (DOT). Some experts recommend DOT for all pediatric patients. Isoniazid dosing differs depending on the frequency of dosing/treatment regimen selected; consult current guidelines for detailed information.

● Once daily or 5 times weekly (DOT):

● Infants, Children, and Adolescents <15 years, weighing ≤40 kg: Oral, IM: 10 to 15 mg/kg/dose once daily (or 5 days/week by DOT); maximum dose: 300 mg/dose.

● Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years: Oral, IM: 5 mg/kg/dose once daily (or 5 days/week by DOT); typical dose: 300 mg/dose.

● Three-times-weekly DOT: Note: Three-times-weekly DOT may be used as an alternative to daily therapy in patients without HIV with noncavitary and/or smear-negative disease. Though three-times-weekly regimen is preferred to twice-weekly, data to guide dosing are limited; suggested dosing based on twice-weekly regimen.

● Infants, Children, and Adolescents <15 years, weighing ≤40 kg: Oral, IM: 20 to 30 mg/kg/dose three times weekly by DOT; maximum dose: 900 mg/dose.

● Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years: Oral, IM: 15 mg/kg/dose three times weekly by DOT (typical dose: 900 mg).

● Twice-weekly DOT: Note: Regimen not generally recommended; do not use in HIV patients or those with smear-positive and/or cavitary disease, and only use after completion of a 2-week once-daily (or 5-times-weekly) regimen in the intensive phase. Missed doses result in the equivalent of once-weekly dosing which has been shown to be inferior and is associated with treatment failure, relapse, and development of drug resistance.

● Infants, Children, and Adolescents <15 years, weighing ≤40 kg: Oral, IM: 20 to 30 mg/kg/dose twice weekly by DOT; maximum dose: 900 mg/dose.

● Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years: Oral, IM: 15 mg/kg/dose twice weekly by DOT; typical dose: 900 mg/dose.

● Duration of therapy: Treatment regimens consist of an initial 2-month intensive phase of a 4-drug regimen, followed by a continuation phase of isoniazid and Isoniazid . Duration of continuation phase is ≥4 months; should be longer for cavitary disease with positive cultures at completion of intensive phase (7 months), bone and joint disease (≥4 to 7 months), and CNS disease (7 to 10 months).

● Tuberculosis, active; treatment for drug-resistant:

● Note: Use should only be considered in patients with low-level isoniazid resistance; do not use in patients with high-level isoniazid resistance. Always use in combination with other antitubercular drugs; expert consultation for optimal regimen and duration of treatment is advised .

● Infants, Children, and Adolescents: Oral, IM: 15 to 20 mg/kg/day as part of an appropriate combination regimen. Administer in combination with pyridoxine.

● Tuberculosis, latent infection; treatment:

● Preferred regimen varies between guidelines and based on patient characteristics; regimens should not be used in patients known or presumed to be infected with resistant strains of Tuberculosis (TB) .

● Isoniazid combination therapy: Note: Preferred regimens

● Rifapentine combination: Independent of HIV status: Note: May be administered by DOT or self-administered therapy (SAT) at the clinician’s discretion based on local practice, patient attributes/preferences, and other factors including risk for TB disease progression . Only use in HIV-infected patients if antiretroviral therapy has acceptable drug-drug interactions with rifapentine.

● Children 2 to 11 years: Oral: Isoniazid 25 mg/kg/dose once weekly for 12 weeks (12 doses); maximum dose: 900 mg/dose.

● Children ≥12 years and Adolescents: Oral: Isoniazid 15 mg/kg/dose once weekly for 12 weeks (12 doses), round dose up to nearest 50 or 100 mg; maximum dose: 900 mg/dose .

● Isoniazid combination: Independent of HIV status: Note: Only use in HIV-infected patients if antiretroviral therapy has acceptable drug-drug interactions with Isoniazid .

● Infants, Children, and Adolescents: Oral: Isoniazid 10 to 20 mg/kg/dose once daily (maximum dose: 300 mg/dose) for 3 months.

● Infants, Children, and Adolescents; independent of HIV status:

● Daily regimen: Oral: 10 to 20 mg/kg/dose once daily for 6 to 9 months; maximum dose: 300 mg/dose; while the CDC recommends a 6-month duration, 9 months may be considered; direct comparative efficacy data for 6 months versus 9 months are lacking and risk of hepatotoxicity is greater with longer durations . Note: Some organizations recommend an upper limit of 15 mg/kg/dose (maximum dose: 300 mg/dose).

● Twice-weekly regimen: Oral: 20 to 40 mg/kg/dose twice weekly for 6 to 9 months; maximum dose: 900 mg/dose; must be administered by DOT; while the CDC recommends a 6-month duration, 9 months may be considered; direct comparative efficacy data are lacking for 6 months versus 9 months and risk of hepatotoxicity is greater with longer durations.

● Pulmonary nontuberculous mycobacterial infection; treatment:

Children and Adolescents: Oral: 10 mg/kg/dose once daily as part of an appropriate combination regimen; maximum dose: 300 mg/dose

Do not take with food; avoid tyramine- and/or histamine-containing foods. Increase dietary intake of folate, niacin, magnesium

Hypersensitivity to isoniazid or any component of the formulation, including drug-induced hepatitis; acute liver disease; previous history of hepatic injury during isoniazid therapy; previous severe adverse reaction (drug fever, chills, arthritis) to isoniazid

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Renal impairment: Use with caution in patients with severe renal impairment.

Other warnings/precautions

• Appropriate use: Multidrug regimens should be utilized for the treatment of active Tuberculosis to prevent the emergence of drug resistance.

Isoniazid may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Isoniazid is present in breast milk.

Due to the potential for serious adverse reactions in the breastfeeding infant, the manufacturer recommends a decision be made whether to discontinue breastfeeding or to discontinue the drug, considering the importance of treatment to the mother. Breastfeeding is not a contraindication during therapy for drug-susceptible Tuberculosis in patients deemed noninfectious who are treated with first-line agents (ie, Isoniazid ). Exposure to Isoniazid via breast milk should not be considered effective treatment for the breastfeeding infant

Pregnancy Category C

Isoniazid has been shown to be teratogenic in rodents. Congenital malformations, primarily spina bifida, were increased in the offspring of pregnant rats given Isoniazid during organogenesis at oral doses of 150 to 250 mg/kg/day (about 1 to 2 times the maximum recommended human dose based on body surface area comparisons). Cleft palate was increased in a dose-dependent fashion in fetuses of pregnant mice treated at oral doses of 50 to 200 mg/kg (about 0.2 to 0.8 times the maximum recommended human dose based on body surface area comparisons). Imperfect osteogenesis and embryotoxicity were also reported in pregnant rabbits given Isoniazid at oral doses up to 200 mg/kg/day (about 3 times the maximum recommended human dose based on body surface area comparisons).

• Administration with food significantly reduces bioavailability. Management: Avoid administration with food.
• Isoniazid may decrease folic acid absorption and alters pyridoxine metabolism.

Management: Increase dietary intake of folate, niacin, and magnesium.

• Tyramine-containing food: Isoniazid has weak monoamine oxidase inhibiting activity and may potentially inhibit tyramine metabolism. Several case reports of mild reactions (flushing, palpitations, headache, mild increase in blood pressure, diaphoresis) after ingestion of certain types of cheese or red wine, have been reported.

Management: Manufacturer’s labeling recommends avoiding tyramine-containing foods (eg, aged or matured cheese, air-dried or cured meats including sausages and salamis; fava or broad bean pods, tap/draft beers, Marmite concentrate, sauerkraut, soy sauce, and other soybean condiments). However, the clinical relevance of the tyramine reaction for the vast majority of patients receiving isoniazid has been questioned due to isoniazid’s weak MAO inhibition and the relatively few published case reports of the interaction. Although not fully investigated, it has been proposed that the reaction has a genetic component and may only be significant in poor or intermediate acetylates since isoniazid is primarily inactivated by acetylation.

• Histamine-containing food: Isoniazid may also inhibit diamine oxidase resulting in headache, sweating, palpitations, flushing, diarrhea, itching, wheezing, dyspnea or hypotension to histamine-containing foods (eg, skipjack, tuna, saury, other tropical fish).

Management: Manufacturer’s labeling recommends avoiding histamine-containing foods; corticosteroids and antihistamines may be administered if histamine intoxication occurs

• Common Adverse effects

Aplastic, sideroblastic, or haemolytic anaemia, agranulocytosis, eosinophilia, thrombocytopenia.

• Less Common Adverse effects:

Hyperglycaemia, metabolic acidosis, nicotinic acid deficiency.

• Rare Adverse effects

Toxic epidermal necrolysis.

• May increase the risk of hepatotoxicity when given with halothane or isoniazid. May decrease the serum concentrations, thus reducing the efficacy of praziquantel. May enhance the adverse effect, particularly bleeding, when given concomitantly with cefazolin and other cephalosporins containing N-methylthiotetrazole side chain. May increase metabolism and decrease serum concentrations and effects of antiarrhythmics (e.g. disopyramide, quinidine), antiepileptics (e.g. phenytoin,), barbiturates, hormone antagonist (e.g. tamoxifen, toremifene), antipsychotics (e.g. haloperidol, aripiprazole), anticoagulants (e.g. warfarin), antifungals (e.g. fluconazole, ketoconazole), other antiretrovirals (e.g. zidovudine, indinavir, efavirenz), hepatitis C antiviral drugs (e.g. daclatasvir), beta-blockers (e.g. bisoprolol), Ca channel blocker (e.g. diltiazem), anxiolytics and hypnotics (e.g. diazepam), certain antibacterials (e.g. chloramphenicol, clarithromycin), corticosteroids, cardiac glycosides, hormonal contraceptives (e.g. oestrogens, progestogens), antidiabetic agents (e.g. glipizide, rosiglitazone), immunosuppressants (e.g. ciclosporin, tacrolimus), thyroid hormone (e.g. levothyroxine), analgesics (e.g. methadone, morphine), selective 5-HT3 receptor antagonists (e.g. ondansetron), statins that are metabolised by CYP3A4 (e.g. simvastatin), TCAs (e.g. amitriptyline, nortriptyline), cytotoxics (e.g. imatinib), enalapril, losartan, irinotecan, theophylline, quinine, riluzole. Absorption may be reduced by antacids. Concomitant use with atovaquone increased plasma concentrations of rifampicin and decreased plasma concentrations of atovaquone. Increased plasma concentrations with probenecid and trimethoprim-sulfamethoxazole.
• Potentially Fatal: Increased risk of severe hepatotoxicity with saquinavir/ritonavir combination. It may substantially decrease the plasma concentrations and efficacy of atazanavir, darunavir, fosamprenavir, saquinavir, tipranavir which may result in the development of viral resistance.

The common side effects of Isoniazid include the following

Constipation, Diarrhea, Heartburn, pain in the back, arm, or legs, Headache, joint pain.

Symptoms:

Nausea, vomiting, vertigo, dizziness, slurred speech, blurred vision, visual hallucinations (including bright colours and strange designs), metabolic acidosis, acetonuria, and hyperglycaemia. CNS depression, seizures and respiratory distress that may progress rapidly from stupor to coma may occur after marked overdosage.

Management:

Symptomatic and supportive treatment. Give activated charcoal and perform gastric lavage. Secure the airway and ensure adequate ventilation. Administer IV anticonvulsants for seizures and IV pyridoxine as clinically indicated based on the ingested dose. Correct acidosis with Na bicarbonate. May perform forced diuresis, haemodialysis and peritoneal dialysis if necessary.

Pharmacodynamic

Isoniazid is thought to inhibit bacterial DNA-dependent RNA polymerase, which appears to occur as a result of drug binding in the polymerase subunit deep within the DNA/RNA channel, facilitating direct blocking of the elongating RNA. This effect is thought to be concentration related .

Pharmacokinetics

● Absorption: Readily and completely absorbed from the gastrointestinal tract and after IM inj. Reduced rate and extent of absorption with food. Time to peak plasma concentration: 1-2 hours (oral).

● Distribution: Distributed in all body tissues and fluids, including CSF. Crosses the placenta and enters breast milk. Plasma protein binding: Approx 10-15%.

● Metabolism: Metabolised in the liver and small intestine via acetylation to acetylisoniazid by N-acetyltransferase; undergoes further hydrolysis to isonicotinic acid and monoacetylhydrazine. Isonicotinic acid is then conjugated with glycine into isonicotinyl glycine while monoacetylhydrazine is further acetylated to diacetylhydrazine. Unmetabolised isoniazid is conjugated to hydrazones.

● Excretion: Via Urine (75-95% as unchanged drug and metabolites); faeces and saliva (small amounts). Elimination half-life: 0.5-1.6 hours (fast acetylators); 2-5 hours (slow acetylators).

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
• https://reference.medscape.com/drug/colestid-Isoniazid -342452
• https://go.drugbank.com/drugs/DB00375
• https://www.sciencedirect.com/topics/medicine-and-dentistry/Isoniazid
• https://europepmc.org/article/med/6988203