1. INTRODUCTION:

Tuberculosis (TB) persists to be one of the major public health issues of the twenty-first century in worldwide. TB remains a serious public health difficulty, particularly in underdeveloped countries and among vulnerable populations such as those with weakened immune systems or limited access to healthcare. TB is primarily caused by Mycobacterium tuberculosis, a bacterium that first and foremostly affects the lungs but can also affect other organs. The disease spreads through airborne transmission when individuals with active TB cough or sneeze, releasing infectious droplets. Clinical manifestations of TB vary but commonly include persistent cough, fever, night sweats, and weight loss. Diagnosis often involves a combination of microbiological tests (such as sputum smear microscopy, culture, and molecular tests) and imaging studies (like chest X-rays or CT scans). Early detection and prompt initiation of treatment are crucial to prevent complications and reduce transmission. The emergence of extensively drug-resistant tuberculosis (XDR-TB) and the development of multidrug-resistant tuberculosis (MDR-TB) present additional obstacles to the prevention, treatment, and management of this fatal illness. Approximately one-third population (globaly) has inactive(latent) TB, which is also caused by Mycobacterium tuberculosis, but causes no symptoms. 10% of people who are latently infected go on to have active illness at some point in their lives^1-3. Controlling M. tuberculosis is a huge difficulty because, despite their lack of symptoms, the majority of infected persons act as a reservoir for the infection.The risk of both M. tuberculosis infection and latent infection activation is significantly increased by HIV infection. The reason behind the challenges associated with co-administering anti-TB and anti-HIV medications due to drug interactions, treating coinfections of HIV and M. tuberculosis is another serious issue. Regretfully, the majority of medications used to treat tuberculosis were created forty years or more ago^4-6. TB treatment is time-consuming and difficult. There is an immediate need for new regimens that are effective against MDR and XDR-TB, may be used in conjunction with antiretroviral medications, and can shorten and simplify the period of treatment for active disease. In an effort to address the substantial unmet medical requirements, the Global Alliance for TB Drug Development (TB Alliance) was established in 2000⁷. Treatment of tuberculosis (TB) indicates a critical aspect of global healthcare efforts, aiming to combat the spread of this infectious disease and alleviate its impact on affected individuals and communities. The cornerstone of TB treatment revolves around a combination of antibiotics, typically administered over an expanded period to ensure complete eradication of the bacterial infection. Public health strategies for TB control include vaccination with Bacillus Calmette-Guérin (BCG), contact tracing of TB cases, infection control measures, and promoting health education and awareness. Successful TB treatment not only focuses on eliminating the active infection but also involves managing drug interactions, monitoring for side effects, and addressing any underlying conditions that may complicate recovery. The primary drugs used in TB treatment are isoniazid, rifampicin, ethambutol, and pyrazinamide, often given together in what is known as directly observed therapy (DOTS). These drugs play a crucial role in various stages of TB treatment, from initial infection control to long-term management, particularly in drug-sensitive and drug-resistant cases^5-7.

It is very much necessary to find out information about the pharmaceuticals that are now on the market and those that are still under development in order to carry out our drug development and discovery initiatives⁸. The findings reveal that data pertinent to tuberculosis medication research is incredibly dispersed and often contained in decades-old primary literature. Comprehensive information on multiple aspects of the various medications is hard to get by. Numerous evaluations go into great detail on a specific issue, focusing on things like contrasting treatment alternatives, animal models, or physical traits. When there is not a single, comprehensive source for vital information, researchers frequently have to invest a lot of effort in finding it^4-5.

2.Overview of Tuberculosis: TB is a particular one ancient disease to affect humans, with evidence suggesting its presence as far back as ancient Egypt and China around 3000 BCE. Historically, TB has been a major cause of illness and death worldwide, with evidence of its presence dating back thousands of years. Despite advancements in medical science and the availability of treatment, TB continues to affect millions annually, posing challenges due to drug resistance and socio-economic factors⁹. It is a disease that has shaped human history and continues to impact global health significant. The history of TB dates back millennia, with evidence of its presence found in ancient human remains. A turning point in the understanding and recognition of TB as a contagious disease was marked by the 19th century. In 1882, German scientist Robert Koch identified and isolated Mycobacterium tuberculosis, the bacterium responsible for causing TB, using his newly developed staining technique. Koch's discovery provided a crucial foundation for understanding the microbiological basis of TB and tiled the approach for future advancements in diagnosis and treatment. Throughout history, TB has been known by various names—consumption, phthisis, or the White Plague—and has been a leading reason of death around the world. These diseases leading to a wide range of symptoms and complications. Additionally, TB can spread easily from one person to another one throughout the air, making it a major concern for global health authorities. Two billion people approximately one-fourth of the world’s population may be infected with tuberculosis (TB), and each year, 10.6 million of them become ill¹⁰. Despite being avoidable and treatable, TB remains a deadly disease. around the world, over 3,500 population losing their livings to TB on a daily basis totalling 1.3 million demise every year. Additionally, around 30 percent of people who become ill with TB are missed by healthcare screenings and diagnostics and do not get the care they need, leading to poor health outcomes and an increased spread of TB in communities Each untreated person can spread tuberculosis (TB) to 10 to 15 additional individuals annually, and 10% of those infected will eventually develop active TB, affecting a total of two billion people^11-13.

3. Symptoms of Tuberculosis: Tuberculosis (TB) is a bacterial infection generate by Mycobacterium tuberculosis. Tuberculosis (TB) can manifest with a variety of symptoms, depending on whether the infection is latent (inactive) or active. It primarily affects the lungs but also spread to other parts of the human body, leading to diverse clinical presentations. TB are generally two types such as Pulmonary Tuberculosis (affecting the lungs) and Extrapulmonary Tuberculosis (affecting other portions of the human body)¹⁴. The symptoms of TB can vary depending on which portion of the body is affected, but the most common symptoms include:

1.1. Pulmonary Tuberculosis (affecting the lungs)^15:

I. Persistent Cough: A cough that lasts for three weeks or further.

II. Coughing up Blood: Haemoptysis, or spit out blood or sputum.

III. Chest Pain: Pain that is often worse with breathing or coughing.

IV. Weight Loss: Unexplained weight loss.

V. Fever: Low-grade fevers that may become more pronounced in the evenings.

VI. Night Sweats: Profuse sweating at night.

VII. Fatigue: Persistent tiredness and lack of energy.

VIII. Loss of Appetite: Decreased interest in eating.

1.2. Extrapulmonary Tuberculosis ((affecting other portions of the human body):

I. Lymph Nodes: Swelling and tenderness in the lymph nodes, particularly in the neck (scrofula).

II. Bones and Joints: Pain and swelling in bones and joints, leading to conditions such as Pott’s disease (spinal TB).

III. Genitourinary System: Painful urination, blood in urine, pelvic pain (genitourinary TB).

IV. Central Nervous System: Headaches, nausea, vomiting, and neurological deficits (tuberculous meningitis).

V. Abdomen: Abdominal pain, swelling, and possible ascites (abdominal TB).

a. General Symptoms:

b. Malaise: A general feeling of discomfort or illness.

c. Chills: Feeling cold or shivering.

Table 1: Represented the comparison of the symptom between the active and latent tuberculosis

Sputum Production	Often produces sputum, may be blood-stained	No sputum production
Chest Pain	Common, especially with coughing	Uncommon
Fever	Common, low-grade fever, especially in evenings	No fever (except in some cases of reactivation)
Fatigue	Common	May be present, but usually mild
Night Sweats	Common, profuse sweating at night	Rare
Shortness of Breath	Common, especially with exertion	Uncommon
Weight Loss	Common, unintentional weight loss	Rare
Lymph Node Swelling	Uncommon	Uncommon
Risk of Transmission	Highly infectious	Not infectious (cannot transmit TB to others)
Other Systemic Symptoms	May include loss of appetite, malaise, chills	Typically, absent

4.Transmission of TB:

Tuberculosis is an infectious diseases spread by air and contact with the person suffering from active TB. The infection and duration of diseases determined by host and bacterial variables. People with smear-positive pulmonary tuberculosis are extremely infectious, and the level of infectiousness is reflection to rise with the level of smear positivity. In an immense study of domicile contact in Peru, smear-positive index cases had a greater risk of infection than smear-negative index cases, independent of age. Individuals with smear-negative tuberculosis cases may, nonetheless, spread tuberculosis. Person with contagious tuberculosis can be treated well, resulting in a quick reduction in infectiousness. It is hypothesized that HIV-infected individuals with index tuberculosis cases, especially those with advanced immunosuppression, may be less likely to transmit the disease to household contacts compared to HIV-uninfected individuals. This could be due to a higher probability of having smear-negative tuberculosis and a shorter period of infectiousness because of a more rapid succession to death^16-18.

I. Airborne Transmission: TB is mainly propagated through the air from an individual suffering from active TB by their lung’s coughs, sneezes, spits, laughs, or talks. This releases tiny droplets containing the bacteria into the air. Another person can then inhale these droplets and become infected⁵.

II. Close Contact: Prolonged close contact with someone suffering from active TB increases the chance of transmission. This is more likely in crowded or enclosed environments with poor ventilation⁶.

III. Risk Factors for Transmission: Factors that increase the chance of TB transmission include: Spending prolonged time with a person has untreated active TB patient or living or working in crowded or enclosed environments or weakened immune system (e.g., due to HIV infection, certain medications, or conditions like diabetes)⁷.

5. Susceptible person for Tuberculosis: Individuals who are in close connection with person has infectious tuberculosis at a higher risk of suitable infected themselves and, if they do contract the disease, are more likely in order to develop tuberculosis, particularly through the first year of exposure¹⁹. In countries with high rates of tuberculosis and HIV, such as South Africa and Zambia, household contacts who are HIV-positive are nearly five times more likely to contract tuberculosis compared to those who are HIV-negative²⁰.

Table 3: Classification of 1^st and 2^nd line drug used in tuberculosis

First line drugs	Second line drugs
Pyrazinamide (Z)	Fluoro-quinolones	Oral drugs	Injectables
Ethambutol (E)	Ofloxacin	Rifabutin	Kanamycin
Rifampicin (R)	Levofloxacin	Cycloserine	Amikacin
Isoniazid (H)	Moxifloxacin	Rifapentine	Capreomycin
Streptomycin (S)	Ciprofloxacin

2.2. First-line drugs used in Tuberculosis: Tuberculosis (TB) continues to be a major global health issue, with millions of new cases reported annually. The cornerstone of TB treatment lies in a specific group of medications known as first-line drugs. These drugs form the backbone of tuberculosis therapy due to their efficacy, safety profile, and ability to combat Mycobacterium tuberculosis, the bacterium responsible for the disease. Understanding the mechanisms of action and the character of these first-line drugs is crucial in managing TB effectively and preventing the spread of drug-resistant strains³⁰.

Isoniazid (INH, H): Isoniazid (INH) is a cornerstone of tuberculosis (TB) treatment, often used as a first-line drug due to its potent bactericidal effects against Mycobacterium tuberculosis. Isoniazid is a bactericidal drug that works by inhibiting the synthesis of mycolic acids, essential components of the mycobacterial cell wall. This disruption leads to cell death and effectively reduces the bacterial load in the body. Higher doses of isoniazid have been demonstrated to increase toxicity, despite the drug being generally safe and tolerated. Although MDR-TB is by definition resistant to isoniazid, some research suggests that high doses of the drug may be effective against certain strains of MDR-TB. For this reason, isoniazid is included in both the WHO-recommended standard DR-TB regimen and the shortened regimen^2-8.

· Clinically Use: Beyond active TB treatment, Isoniazid is also used prophylactically to prevent TB in individuals who have been susceptible to the bacteria or who are at significant risk of expanding active disease, such as those with HIV/AIDS.

· Duration: In standard TB treatment regimens, Isoniazid is typically administered daily or several times a week, depending on the protocol used in different regions. Treatment duration with Isoniazid can range from six to nine months for active TB, and up to 12 months for latent TB contagion.

· Adverse Effects: While generally well-tolerated, Isoniazid can cause side effects such as hepatotoxicity (liver damage), peripheral neuropathy (damage to nerves), and gastrointestinal disturbances. Monitoring liver function is crucial during treatment. Loss or blurriness of vision, convulsions (seizures), fever along with sore throat, pain in the joints are the common Adverse effect ^9-11.

· Resistance: Resistance to Isoniazid can develop, especially when the drug is used alone or improperly. Therefore, it is essential to use Isoniazid in combination with other TB drugs as a section of a comprehensive treatment regimen to prevent resistance and ensure effective therapy¹².

· Drug interaction: Isoniazid CYP3A4 enzyme inhibitor metabolism of Phenytoin is excreted in urine.

· Pharmacokinetic: The pharmacokinetics of Isoniazid (INH) describe how the drug is absorbed, distributed, metabolized, and eliminated in the body. Isoniazid is commonly administered orally, either as a tablet or syrup. It is rapidly and completely absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within first to second hours subsequently of the oral administration. The absorption can be delayed but not significantly reduced when taken with food. Isoniazid distributes widely throughout body tissues and fluids, including the liver, lungs, kidneys, and cerebrospinal fluid (CSF). Approximately 10-15% of Isoniazid binds to plasma proteins, primarily albumin. Isoniazid undergoes extensive hepatic metabolism primarily by acetylation. It is metabolized by the liver enzyme N-acetyltransferase (NAT) to form acetylisoniazid (active metabolite) and further metabolites, including isonicotinic acid and monoacetylhydrazine. NAT enzyme activity shows genetic polymorphism, leading to slow or fast acetylators. Slow acetylators have a significant risk of toxicity due to slower metabolism. The elimination half-life of Isoniazid is approximately 1-4 hours in fast acetylators and can be prolonged up to 7-15 hours in slow acetylators. Isoniazid and its biological compounds are primarily eliminated in the urine, with about 75% of the dose excreted unchanged within 24 hours^30-35.

Figure 1: structure of isoniazid

Bottom of Form

INH enters to the Mtb cell

↓

INH inhibits enzyme enoyl-ACP reductase

↓

Inhibition of mycolic acid synthesis

↓

Disruption of cell wall synthesis

↓

Cell wall integrity compromised

Flow chart 1: Represented the MOA for isoniazid

Mechanism of action: The unique structure of Isoniazid allows it to selectively inhibit the synthesis of mycolic acids, which are crucial elements of the mycobacterial cell wall. This disruption leads to cell wall damage and ultimately bacterial cell death, making Isoniazid an essential component of tuberculosis treatment regimen.

· Rifampicin: Rifampicin, also known as rifampin, is a key antibiotic used in the treatment of tuberculosis (TB) One of the main agents responsible for inducing TB-killing activity in the usual four-drug, six-month regimen for treating DS-TB is rifampin. For patients on HIV treatment, rifabutin is a better option because rifampin interacts with a lot of other drugs, most notably protease inhibitors. Currently, a number of studies are looking into the safety and effectiveness of higher dosages of rifampin as well as whether or not they can reduce the course of TB treatment. Rifampicin is a first-line antibiotic recommended by the WHO for the therapy of drug-sensitive TB^32-34.

· Clinical Use: Rifampicin is a first-line antibiotic recommended by the WHO for the treatment of TB. It is typically used in combine with other first-line drugs such as Isoniazid, Pyrazinamide, and Ethambutol to prevent the emergence of drug resistance and achieve optimal treatment outcomes³⁵.

· Duration: Rifampicin significantly shortens the duration of TB treatment compared to regimens without it, reducing the therapy duration from years to several months. Rifampicin prophylaxis is typically given daily for a specified duration, often ranging from 3 to 6 months, depending on local guidelines and the specific risk factors of the individual³⁶.

· Treatment Regimens: Rifampicin is typically administered daily or intermittently (e.g., three times per week) in combination with other drugs for six to nine months for drug-sensitive TB. Rifampicin is also utelized in regimens for multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), often with additional second-line drugs³⁷.

· Adverse Effects:

Hepatotoxicity: Rifampicin can cause liver enzyme elevation and hepatitis, necessitating monitoring during treatment.

Orange Discoloration: It can lead to harmless orange discoloration of bodily fluids, including urine, sweat, and tears.

Drug Interactions: Rifampicin induces the metabolism of many drugs, potentially affecting their efficacy. Close monitoring and dose adjustments are necessary when co-administered with other medications.

Pharmacokinetic: Rifampicin is an essential antibiotic in the treatment of tuberculosis (TB), involves its absorption, distribution, metabolism, and elimination in the body. Rifampicin is well-absorbed orally and can also be administered intravenously. Absorption is reduced when taken with food, so it is generally recommended to take rifampicin on an empty stomach for optimal absorption. After oral administration, peak plasma concentrations are reached within 2 to 4 hours. Rifampicin penetrates well into various body tissues along with fluids, like liver, spleen, kidneys, and cerebrospinal fluid (CSF). Rifampicin binds extensively to plasma proteins, primarily albumin, which may influence its distribution and elimination. Rifampicin undergoes extensive hepatic metabolism primarily by the enzyme CYP3A4 in the liver. The elimination half-life of rifampicin is relatively short, typically around 2 to 5 hours in adults. However, in patients with damaged liver function or in neonates, it can be prolonged. Rifampicin and its biological compounds are primarily excreted in bile, with a small amount excreted in urine^36-40.

Figure 2: Structure of rifampicin

Mechanism of action: Rifampicin, also known as rifampin, is a complex molecule with a distinct chemical structure. Rifampicin resistance in Mycobacterium tuberculosis (Mtb) primarily occurs due to mutations in the rpoB gene, which encodes the beta subunit of RNA polymerase. Rifampicin binds to this enzyme to inhibit RNA synthesis, and mutations in the rpoB gene can alter the binding site, reducing or eliminating the drug’s effectiveness. Rifampicin enters the bacterial cell through passive diffusion and specifically binds to the beta subunit of bacterial RNA polymerase, which is essential for RNA synthesis. By binding to RNA polymerase, rifampicin inhibits the initiation of RNA synthesis, thereby preventing transcription of bacterial RNA. The inhibition of RNA synthesis leads to a blockade in the synthesis of bacterial proteins, including essential enzymes and structural components. With the interruption of protein synthesis, bacterial growth is halted, leading to bacteriostatic or bactericidal effects depending on the concentration and duration of exposure^36-38.

INH enters to the Mtb cell

Binds to RNA polymerase beta subunit

Blocks protein synthesis

Inhibits RNA synthesis

Pyrazinamide (PZA): Pyrazinamide (PZA) is an essential component of the first-line treatment pattern for tuberculosis (TB). It plays a crucial role in the effective management of both drug-sensitive and some drug-resistant forms of TB. Pyrazinamide is part of the standard regimen for DR-TB including the reduced regimen suggested by WHO for DS-TB. Activists should demand the quick development of a rapid test to identify pyrazinamide resistance together with the extra research necessary to discover the ideal dose and duration of treatment for pyrazinamide in regimens that do not include rifampin³⁹.

· Clinical Use: It is primarily used during the preliminary intensive phase of TB treatment, typically for the initial two months of therapy. Pyrazinamide helps to rapidly reduce the bacterial load in the body.

· Efficacy: Pyrazinamide is highly effective against Mycobacterium tuberculosis when used in addition with other drugs. Its inclusion in treatment regimens has significantly improved cure rates and reduced the duration of therapy.

· Duration: Pyrazinamide is typically administered for the first 2 months of treatment. This initial phase aims to rapidly reduce the bacterial load in the body and consists of an association of four drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol).

· Adverse Effects: General side effects include hepatotoxicity (liver toxicity), hyperuricemia (elevated uric acid levels), and gastrointestinal disturbances. Monitoring liver function and serum uric acid levels is recommended during treatment.

· Drug Resistance: Resistance to pyrazinamide can develop, particularly in cases of multidrug-resistant TB (MDR-TB). Resistance is often associated with mutations in the pncA gene, which codes for the enzyme pyrazinamidase, essential for the activation of pyrazinamide⁴⁰.

· Pharmacokinetics: It refers to the absorption, distribution, metabolism, and excretion (ADME) of a drug within the body. Pyrazinamide is well absorbed from the gastrointestinal tract after oral administration. Food does not significantly affect its absorption, so it can be taken with or without food. It is distributing widely throughout the body, including penetrating well into various tissues and fluids, comprising cerebrospinal fluid (CSF). It has good penetration into caseous lesions, which are characteristic of tuberculosis infection. Pyrazinamide undergoes partial hepatic metabolism. The primary site of metabolism is in the liver, where it is converted by pyrazinamidase to its active form, pyrazinoic acid (POA). Pyrazinamide and its metabolites are primarily excreted via the kidneys. Approximately 70-80% of an administered dose is excreted unchanging in the urine within 24 hours. Renal function affects the excretion rate, and dosage adjustments may be necessary in patients with impaired kidney function. The elimination half-life of pyrazinamide is relatively short, typically around 9-10 hours in adults with normal renal function. This relatively short half-life contributes to its daily dosing schedule during the intensive phase of tuberculosis treatment^35-39.

Figure 3: Structure of Pyrazinamide

· Mechanism of action: Pyrazinamide exerts its antimycobacterial effect by disrupting the synthesis of myolic acids, essentials components present in the cell wall of mycobacterium. Actively replicating bacteria, particularly those are an in acidic environment such as within macro phages and in necrotic tissue⁴⁰.

Activation of pyranizamide inside the bacteria cell

Pyrazinamide is converted into pyrazinoic acid by the enzyme pyrazinamidase (PncA).

Pyrazinoic acid accumulates in acidic environments (e.g., macrophage phagosomes).

Disruption of Mycobacterial Metabolism by Inhibits fatty acid synthase I (FAS-I),

kills mycobacteria

Ethambutol: Ethambutol is an essential component in the therapy of tuberculosis (TB), particularly in multidrug therapy regimens. It plays a crucial role in combating the bacteria that cause TB, primarily Mycobacterium tuberculosis. Ethambutol is included in the WHO-shortened regimen for DR-TB including the usual six-month, four-drug regimen for the first treatment of DS-TB. While there are many reliable, worldwide suppliers of generic ethambutol^5-9.

· Clinical Use: Ethambutol is typically used in addition with other first-line drugs such as isoniazid, rifampicin, and pyrazinamide for the treatment of TB. This combination therapy is essential to prevent the formation of drug resistance which is effectively eradicate the bacteria from the body ^15-17.

· Duration: Ethambutol is usually given daily for the first 2 months. if the patient's TB is susceptible to the medications and the early phase is successful, the continuation phase begins. Ethambutol may continue to be used in the continuance phase, which typically lasts for 4 to 7 months relying on the overall regimen and the patient's response to treatment⁴⁰.

· Adverse effect: several adverse effects is seen in the use of ethambutol for the therapy of TB. This are ocular Toxicity, peripheral Neuropathy, gastrointestinal disturbances, hypersensitivity reactions, elevated liver enzymes, renal toxicity etc ⁴¹.

· Side Effects: Apart from optic neuritis, other common side effects of ethambutol include gastrointestinal disturbances (such as nausea, vomiting, and gastric distress), skin rash, and joint pain. These side effects are generally reversible upon discontinuation of the drug ⁴².

· Pharmacokinetic: Ethambutol is well-absorbed from the GIT after oral administration. Ethambutol is rapidly and well-absorbed from the GIT. Peak plasma concentrations are usually reached within 2 to 4 hours after oral administration. This drug distributes widely throughout the body, including into various tissues and fluids. It penetrates well into the cerebrospinal fluid (CSF), which is important for treating TB that affects the central nervous system. Ethambutol undergoes minimal metabolism in the liver. The majority (about 70-80%) of the drug is excreted unchanged in the urine. The elimination half-life of ethambutol is approximately 3 to 4 hours in patients with normal kidney function^43-45.

· Mechanism of Action: Ethambutol prevent the synthesis of mycobacterial cell wall components by specifically targeting an enzyme involved in cell wall biosynthesis. This disrupts the formation of the cell wall, weakening the bacteria and forming them more impressionable to the immune system and other antibiotics used in combination therapy⁴⁶.

Figure 4: Structure of Ethambutol

Ethambutol is ingested orally

Distribution throughout the body, including into Mycobacterium tuberculosis cells

Ethambutol targets an enzyme involved in the synthesis of arabinogalactan, an essential component of mycobacterial cell walls

Inhibition of arabinosyl transferase enzyme

Disruption of cell wall synthesis in Mycobacterium tuberculosis

Streptomycin:

Streptomycin belongs to the class of aminoglycoside antibiotics. When no other medication from group B is available, streptomycin—which was the first drug approved for the treatment of tuberculosis (TB)—is still occasionally used to treat double-negative tuberculosis (DR-TB). Nevertheless, resistance to streptomycin does not deem an isolate to be XDR-TB, in contrast to resistance to the other injectable drugs (amikacin, capreomycin, and kanamycin)⁴⁷.

Clinical Use: Streptomycin was historically one of the first effective drugs used against TB. However, due to the emergence of drug-resistant strains and the development of safer and more effective alternatives, its use as a first-line agent has diminished in many parts of the world. Streptomycin may be considered in the treatment of multidrug-resistant tuberculosis (MDR-TB) or extensively drug-resistant tuberculosis (XDR-TB) when other options are limited. In some settings, streptomycin is still used as part of combination therapy, especially in resource-limited settings where access to newer drugs may be restricted^15-19.

· Duration: Streptomycin is usually given for the first 2 months (8 weeks) of TB treatment, if the patient's TB is drug-sensitive and the initial phase is successful, streptomycin is typically discontinued^20-22.

· Adverse Effects: Streptomycin can cause several side effects, including: Ototoxicity means damage to the inner ear structures leading to hearing loss or imbalance. Monitoring of auditory function is essential during treatment. Kidney damage also known as Nephrotoxicity and allergic reactions means leads to rash to anaphylaxis^25-28.

· Pharmacokinetics: Understanding the pharmacokinetics of streptomycin is crucial for optimizing its use in the treatment of tuberculosis (TB). Streptomycin is administered via intramuscular injection because it has poor oral bioavailability. After injection, it is rapidly absorbed into the bloodstream and distributed throughout the body. This drug distributes widely into various body tissues and fluids, including lung tissue where Mycobacterium tuberculosis resides. It can cross the blood-brain barrier and enter the cerebrospinal fluid, which is important in treating TB that affects the central nervous system. Streptomycin is primarily eliminated unchanged by the kidneys. It undergoes minimal metabolism in the body. The elimination half-life of streptomycin is relatively short, typically around 2 to 3 hours in patients with normal kidney function^32-36.

Figure 5: Structure of Streptomycin

Mechanism of action: Streptomycin belongs to the class of aminoglycoside antibiotics. Its primary mechanism of action against Mycobacterium tuberculosis involves Inhibition of protein synthesis where streptomycin binds to the 30S ribosomal subunit of the bacterial ribosome. This binding disrupts the initiation complex and causes misreading of mRNA ultimately leading to inhibition of protein synthesis^35-38.

Impact on 1^st line drug in the treatment of tuberculosis: First-line drugs are crucial in the treatment of tuberculosis (TB) as they form the backbone of the standard therapy regimen. First-line drugs play a pivotal role in the treatment of tuberculosis (TB) due to their efficacy, safety profile, and widespread availability. These drugs, including isoniazid, rifampicin, pyrazinamide, and ethambutol, are the cornerstone of TB therapy recommended by global health organizations like the World Health Organization (WHO). They are chosen based on their ability to target different stages of Mycobacterium tuberculosis growth and their synergistic effects when used in combination. Isoniazid and rifampicin, for instance, are bactericidal agents that target actively dividing bacteria by inhibiting key metabolic pathways essential for cell wall synthesis and protein production. Pyrazinamide acts on dormant bacteria and those residing in acidic environments, while ethambutol disrupts cell wall synthesis. The effectiveness of these drugs lies not only in their individual actions but also in their combined ability to prevent the emergence of drug-resistant strains when used in a multi-drug regimen. This approach ensures high cure rates and reduces the risk of treatment failure and disease relapse, making first-line drugs indispensable in global efforts to control and eliminate tuberculosis^39-42.

CONCLUSIONS:

Tuberculosis remains a formidable challenge to public health worldwide, particularly affecting vulnerable populations and low-resource regions. Despite significant progress in diagnosis, treatment, and prevention efforts, TB continues to exact a heavy toll in terms of illness, mortality, and socioeconomic burden. The emergence of drug-resistant strains further complicates treatment regimens and underscores the urgency for innovative therapeutic approaches. In conclusion, first-line drugs represent the cornerstone of effective tuberculosis (TB) treatment, playing a pivotal role in achieving high cure rates and reducing the burden of drug-resistant TB strains worldwide. Isoniazid, rifampicin, pyrazinamide, and ethambutol are essential components of standardized treatment regimens recommended by global health authorities. Their synergistic actions target different aspects of Mycobacterium tuberculosis growth and metabolism, ensuring comprehensive eradication of the bacteria and minimizing the likelihood of therapy failure and relapse. The continued use and proper administration of these drugs are paramount in achieving successful TB treatment outcomes, underscoring their indispensable role in global TB control endeavors.

This review highlighting on the impact of 1^st line drug therapy for the remedy of tuberculosis as well as described the first-line drug treatment protocols, emphasizing their effectiveness, mechanisms of action, and challenges in administration.

In conclusion, addressing the global strain of TB requires a multifaceted approach encompassing prevention, diagnosis, treatment, and research. By leveraging advancements in molecular epidemiology, drug development, and public health strategies, we can strive towards the ultimate goal of eliminating TB as a community health threat. Collaborative efforts including governments, healthcare service providers, researchers, and communities are essential to achieve this ambitious objective and ensure a TB-free future for all.

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Received on 22.05.2025 Revised on 19.08.2025

Accepted on 31.10.2025 Published on 22.01.2026

Available online from January 29, 2026

Asian J. Pharm. Res. 2026; 16(1):33-43.

DOI: 10.52711/2231-5691.2026.00005

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

TYPE	NAME	Characteristics
First-line Agents: Group A,	Isoniazid (INH) Rifampicin (RIF) Pyrazinamide (PZA) Ethambutol (EMB)	These medications are used to treat DS-TB initially. These medications, which are broad-spectrum antibiotics, are being studied as a part of alternative regimens for streamlining and expediting TB therapy. They are thought to be the most crucial part of the conventional and abbreviated regimens for DR-TB that the WHO recommends.
Group B, second line injectable agents:	Amikacin, Kanamycin, Capreomycin,	These injectable medications support the standard and abbreviated regimens for DR-TB recommended by the World Health Organization, although they may be avoided if efficient all-oral regimens were created and made accessible.
Group C, other core Anti-tuberculosis drug	Fluoroquinolones (e.g., Levofloxacin, Moxifloxacin) Ethionamide Para-aminosalicylic acid (PAS) Cycloserine Linezolid Clofazimine	This category includes medications that are part of the WHO-recommended reduced regimen, and at least two medications from this group are required to construct the conventional five-drug core regimen for DR-TB.
Group D, Repurposed and New Anti-Tuberculosis Drugs:	Bedaquiline Delamanid Pretomanid	These medications can be added to the normal WHO-recommended five-drug core regimen for DR-TB, used as a stand-in in cases of drug toxicity or intolerance, or utilized when a five-drug regimen cannot be created using medications from the other groups due to resistance or access problems.