Isoniazid: A Comprehensive Pharmacological and Clinical Review of Its Spectrum, Efficacy, Safety Profile, Resistance and Adverse Drug Reactions

Tuberculosis is a chronic granulomatous disease that has more than 1 million cases per year in India. It is caused by bacteria Mycobacterium tuberculosis. Generally, it affects the pulmonary portion of the human body, but it can also affect other parts if it remains . As per WHO statistics for 2014, there were 9.6 million new TB cases globally, to which India was the highest contributor with 2.2 million cases. India has the dubious distinction of being the highest TB burden country for the past many years; where about 600 people die from TB every day. Thus, TB kills more adults in India than any other infectious disease. In 2012 the Government of India has declared TB to be a notifiable disease, so that any doctor who treats a TB patient has to notify it to the Govt. Control and treatment of TB in India is covered under a National programme which provides free treatment to all TB cases. The Revised National Tuberculosis Control Programme (RNTCP) was launched in 1997, and its treatment guidelines have been successively revised, the last time in 2016.*

Isoniazid is an excellent antitubercular agent and an essential component of all antitubercular drugs. It acts on extracellular as well as on intracellular TB (bacilli present within macrophages), and is equally active in acidic or alkaline medium. It is one of the cheapest antitubercular drugs. .Its full therapeutic potential could be utilized only after 1952 when isoniazid was produced to accompany it. Among the available antitubercular drugs Isoniazid has gained prominence due to its proven efficacy, safety, affordability, and additional metabolic benefits. It is recommended by most international guidelines as the initial drug of a choice in patient with tuberculosis. 

2. HISTORICAL BACKGROUND:

Early Development (1910s–1940s):

Isoniazid is a derivative of isonicotinic acid. Compounds related to it were first synthesized in the early 20th century, but their medical importance was not recognized at that time.

Discovery of Antitubercular Activity (1951–1952):

The antitubercular properties of isoniazid were independently discovered around 1951– 1952 by researchers at pharmaceutical companies such as Bayer, Hoffmann-La Roche, and Squibb.

Introduction into Clinical Use (1952):

Isoniazid was introduced into clinical practice in 1952, marking a major breakthrough in the treatment of Tuberculosis. It quickly became one of the most effective and widely used anti-TB drugs.

Impact on Tuberculosis Treatment:

Before isoniazid, treatment relied on drugs like Streptomycin and Para-aminosalicylic acid, which had limitations such as toxicity and resistance.Isoniazid significantly improved cure rates and reduced mortality.

Role in Combination Therapy:

Due to rapid resistance when used alone, isoniazid became a key component of multidrug therapy, often combined with Rifampicin and other agents.

 3. CHEMICAL STRUCTURE AND PHYSIOCHEMICAL PROPERTIES:

Isoniazid is chemically known as Isonicotinic acid hydrazide (also called isonicotinyl hydrazine). It has a molecular formula of C?H?N?O and molecular weight 137.14 g/mol and it Contains a pyridine ring (heterocyclic aromatic ring with one nitrogen)Has a hydrazide functional group (-CONHNH?)Substitution at para (4-position). It is oddourless and occurs as nearly colorless crystalline solid that is very soluble in water. Taste is slightly sweet at first and then bitter. pH (1% aqueous solution) 5.5-6.5. pH (5% aqueous solution) 6-8.It is prepared by reacting the methyl ester of Isonicotinic acid with hydrazine.

Fig.1 Structure of isoniazid

 4. CLASSIFICATION:

Isoniazid is pharmacologically classified as a hydrazine derivative antitubercular agent.

Isoniazid is categorized under the Biopharmaceutics Classification System (BCS) as a Class III drug, characterized by high aqueous solubility but low intestinal permeability. This classification presents specific challenges in drug delivery, often necessitating high doses and specialized formulation strategies to overcome limited absorption windows in the upper gastrointestinal tract.

Key classification: 

• Chemical Class: Hydrazine drivative 
• Therapeutic Class: Antitubercular agents
• BCS Class: Class III (High Solubility, Low Permeability)
• Therapeutic Indication: First line drug for tuberculosis 

5. MECHANISM OF ACTION:

The primary mechanism of action of INH is inhibition of synthesis of mycolic acids which are unique fatty acid components of mycobacterial cell wall. This may explain the high selectivity of INH for mycobacteria (it is not active against any other microorganism). The lipid content of mycobacteria exposed to INH is reduced. Two gene products labelled ‘InhA’ and ‘KasA’, which function in mycolic acid synthesis are the targets of INH action. INH enters sensitive mycobacteria which convert it by a catalase-peroxidase enzyme into a reactive metabolite. This then forms adduct with NAD that inhibits InhA and KasA. The reactive INH metabolite forms adduct with NADP as well which inhibits mycobacterial DHFRase resulting in interruption of DNA synthesis.

Fig.2 Mechanism of action of Isoniazid

 6. PHARMACOKINETICS:

Isoniazid is completely absorbed orally and penetrates all body tissues, tubercular cavities, placenta and meninges. It is extensively metabolized in liver; most important pathway being N-acetylation by NAT2. The acetylated metabolite is excreted in urine. The rate of INH acetylation shows genetic variation. There are either:

Fast acetylators (30–40% of Indians) — t½ of INH is 1 hr.

Slow acetylators (60–70% of Indians) — t½ of INH is 3 hr.

The proportion of fast and slow acetylators differs in different parts of the world. However, acetylator status does not matter if INH is taken daily, but biweekly regimens are less effective in fast acetylators. Isoniazid induced peripheral neuritis is more common in slow acetylators. A hepatotoxic minor metabolite is produced by CYP2E1 from acetylhydrazine.

7. PHARMACODYNAMICS:

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

8. RESISTANCE MECHANISM:

Isoniazid is about 1 in 10? tubercle bacilli is inherently resistant to clinically attained INH concentrations. If INH is given alone, such bacilli proliferate selectively and after 2–3 months (sometimes even earlier) an apparently resistant infection emerges. The most common mechanism which confers high level INH resistance is by mutation of the catalase-peroxidase (KatG) gene so that the bacilli do not generate the reactive metabolite of INH. This type of resistance cannot be overcome; INH should be stopped. INH resistance may also involve mutation in the inhA gene. Low level INH resistance or that by inhA mutation resulting in overproduction of the carrier ‘InhA’, can be overcome by using ‘high dose INH’. Resistance based on efflux of INH from the bacterial cell is also possible. 

The incidence of primary INH resistance varies widely among different populations, depending on the extent of use and misuse of INH in that area. According to WHO, the global weighted mean of any INH resistance (excluding MDR) among new TB patients is 7.4%. In India resistance to INH alone or in combination with other anti-TB drugs is estimated to be 18%. No cross resistance with other antitubercular drugs occurs, and INH has good resistance preventing action when combined with other anti-TB drugs.

9. DOSE AND ADMINISTRATION: 

Forms and strengths

• 300 mg and 100 mg tablets
• 100 mg and 50 mg dispersible tablets, to be dispersed in 10 ml water.

Dosage

• 
  Child under 30 kg: 10 mg/kg (7 to 15 mg/kg) once daily
• Child 30 kg and over and adult: 5 mg/kg (4 to 6 mg/kg) once daily
• Maximum dose: 300 mg daily

 10.DRUG INTERACTION:

Aluminium hydroxide inhibits INH absorption. INH retards phenytoin, carbamazepine, diazepam, theophylline and warfarin metabolism by inhibiting CYP2C19 and CYP3A4, and may raise their blood levels. Since rifampin is an enzyme inducer, its concurrent use counteracts the inhibitory effect of INH. However, the net effect on metabolism of many drugs is unpredictable. PAS inhibits INH metabolism and prolongs its t½.

 11. DRUG FOOD INTERACTION:

• Administer vitamin supplements. Vitamin B6 (pyridoxine) should be given with isoniazid to prevent deficiency.
• Avoid alcohol. Avoid drinking alcoholic beverages such as unpasteurized beer; unless approved by your physician, as they may contain tyramine. Consuming alcohol may also increase the risk of isoniazid induced hepatitis and neuropathy.
• Avoid tyramine-containing foods and supplements. Tyramine-containing foods include cheese, red wine, fava beans, pickled food, cured food, and alcoholic beverages.

12. ADVERSE EFFECTS

Isoniazid is well tolerated by most patients. Peripheral neuritis and a variety of neurological manifestations (paresthesias, numbness, mental disturbances, rarely convulsions) are the most important dose-dependent toxic effects. These are due to interference with production of the active coenzyme pyridoxal phosphate from pyridoxine, and its increased excretion in urine.

Pyridoxine given prophylactically (10 mg/day) prevents the neurotoxicity even with higher doses. Prophylactic pyridoxine must be given to diabetics, chronic alcoholics, malnourished, pregnant, lactating and HIV infected patients, and when high dose INH is used. INH neurotoxicity is treated by pyridoxine 100 mg/day.

Hepatitis, a major adverse effect of INH, is rare in children, but more common in older people and in alcoholics (chronic alcoholism induces CYP2E1 which generates the hepatotoxic metabolite). INH must be stopped at the first sign of hepatotoxicity, which is due to dose-related damage to liver cells, and is reversible on stopping the drug.

Other side effects are lethargy, rashes, mild anaemia and arthralgia. 

13. CONTRAINDICATION AND PRECAUTIONS:

Do not administer to patients with severe hepatic impairment. 

May cause:

• peripheral neuropathy; o hepatotoxicity;
• hypersensitivity reactions, arthragias, optic neuritis, psychotic reactions, seizures and depression.

   Monitor closely: