AN OVERVIEW ON TUBERCULOSIS

About Authors:
Anamika singh*¹, Neha Singh²
¹M.Pharm (Department of Pharmacology)
²M.Pharm (Department of Pharmaceutics)
Noida Institute of Engineering and Technology.
*anamika1303@gmail.com

Abstract
Tuberculosis is a leading killer of young adults worldwide and the global scourge of multi-drug resistant tuberculosis is reaching epidemic proportions. It is endemic in most developing countries and resurgent in developed and developing countries with high rates of human immunodeficiency virus infection. This article reviews the current situation in terms of drug delivery approaches for tuberculosis chemotherapy. A number of novel implant-, microparticulate-, and various other carrier-based drug delivery systems incorporating the principal anti-tuberculosis agents have been fabricated that either target the site of tuberculosis infection or reduce the dosing frequency with the aim of improving patient outcomes. These developments in drug delivery represent attractive options with significant merit, however, there is a requisite to manufacture an oral system, which directly addresses issues of unacceptable rifampicin bioavailability in fixed-dose combinations. This is fostered by the need to deliver medications to patients more efficiently and with fewer side effects, especially in developing countries. The fabrication of a polymeric once-daily oral multiparticulate fixed-dose combination of the principal anti-tuberculosis drugs, which attains segregated delivery of rifampicin and isoniazid for improved rifampicin bioavailability, could be a step in the right direction in addressing issues of treatment failure due to patient non-compliance.

REFERENCE ID: PHARMATUTOR-ART-1837

Introduction
Tuberculosis (TB) is an infectious disease caused by bacteria whose scientific name is Mycobacterium tuberculosis. It was first isolated in 1882 by a German physician named Robert Koch who received the Nobel Prize for this discovery. TB most commonly affects the lungs but also can involve almost any organ of the body. Many years ago, this disease was referred to as "consumption" because without effective treatment, these patients often would waste away. Today, of course, tuberculosis usually can be treated successfully with antibiotics.

There is also a group of organisms referred to as atypical tuberculosis. These involve other types of bacteria that are in the Mycobacterium family. Often, these organisms do not cause disease and are referred to as "colonizers" because they simply live alongside other bacteria in our bodies without causing damage. At times, these bacteria can cause an infection that is sometimes clinically like typical tuberculosis. When these atypical mycobacteria cause infection, they are often very difficult to cure. Often, drug therapy for these organisms must be administered for one and a half to two years and requires multiple medications.One third of the world's population is thought to have been infected with M.tuberculosis, and new infections occur at a rate of about one per second. In 2007 there were an estimated 13.7 million chronic active cases, and in 2010 there were 8.8 million new cases, and 1.5 million deaths, mostly in developing countries. The absolute number of tuberculosis cases has been decreasing since 2006 and new cases since 2002. In addition, more people in the developing world contract tuberculosis because their immune systems are more likely to be compromised due to higher rates of AIDS. The distribution of tuberculosis is not uniform across the globe; about 80% of the population in many Asian and African countries test positive in tuberculin tests, while only 5–10% of the U.S. population test positive.

Signs and Symptoms
Main symptoms of variants and stages of tuberculosis with many symptoms overlapping with other variants, while others are more (but not entirely) specific for certain variants. Multiple variants may be present simultaneously.Only about 5-10% of those without HIV, infected with tuberculosis develop active disease during their lifetime. In contrast 30% of those co-infected with HIV develop active disease. Tuberculosis may infect any part of the body but most commonly occurs in the lungs (known as pulmonary tuberculosis). Extra pulmonary TB is when tuberculosis occurs outside of the lungs and may co-exist with pulmonary TB. General symptoms such as: fever, chills, night sweats, appetite loss, weight loss, fatigue, and finger clubbing may also occur.

Figure 1- sign and symptoms of tuberculosis

Diagnosis
Mycobacterium tuberculosis(stained red) in sputum
Diagnosing tuberculosis based on signs and symptoms is difficult. A definitive diagnosis is made by identifying the causative organism (Mycobacterium tuberculosis) in a clinical sample (for example, sputum or pus). When this is not possible, a probable—although sometimes inconclusive—diagnosis may be made using imaging (X-rays or scans), a tuberculin skin test (Mantoux test), or a, Interferon Gamma Release Assay (IGRA).

Figure 2- Mycobacterium tuberculosis (stained red) in sputum

Mantoux tuberculin skin test
Mantoux tuberculin skin tests are often used for routine screening of high risk individuals. Currently, latent infection is diagnosed in a non-immunized person by a tuberculin skin test, which yields a delayed hypersensitivity type response to an extract made from M. tuberculosis Those immunized for TB or with past-cleared infection will respond with delayed hypersensitivity parallel to those currently in a state of infection, so the test must be used with caution, particularly with regard to persons from countries where TB immunization is common.

Figure 3- Mantoux tuberculin skin test

Prevention
Tuberculosis prevention and control efforts primarily rely on the vaccination of infants and the detection and appropriate treatment of active cases. The World Health Organization has achieved some success with improved treatment success and a small decrease in case numbers.

Vaccines
The only currently available vaccine as of 2011 is Bacillus Calmette-Guérin (BCG) which while effective against disseminated disease in childhood, confers inconsistent protection against pulmonary disease. It is the most widely used vaccine worldwide with more than 90% of children vaccinated However the immunity that it induces, decreases after about ten years.

Public Health

The World Health Organization (WHO) declared TB a global health emergency in 1993 and in 2006 the Stop TB Partnership developed a Global Plan to Stop Tuberculosis that aims to save 14 million lives between its launch and 2015. A number of targets that they have set are not likely to be achieved by 2015 due to the increase in HIV associated tuberculosis and multi-drug resistant tuberculosis.

Classification of Antitubercular Drugs
CLASSIFICATION:
First line drug: These drug have high anti tubercular efficacy as well as low toxicity; are used routinely.

Isoniazid(H)
Rifampin
pyrazinamide(Z)
Ethambutol(E)
Streptomycin(S)

Second line drug: These drugs have either low anti tubercular efficacy or high toxicity or both are used in special circumstances only.

Thiacetazone(Tzn)
Paraaminosalicylic acid(PAS)
Ethionamide(Etm)
Cycloserine(Cys)
Kanamycin(Kmc)
Amikacin(Am)
Capreomycin(Cpr)

Newer Drugs:

Ciprofloxacin
Ofloxacin
Clarithromycin
Azithromycin
Rifabutin

DETAILS OF ANTI-TUBERCULAR DRUGS:

First line drugs:

1.Isoniazid

Isoniazid is the anti tubercular drug parexcellence,and an essential component of all anti tubercular regimens, unless the patient is not able to tolerate it or bacilli are resistant. It is primarily tuberculocidal. Fast multiplying organisms are rapidly killed, but quiescent once only inhibited. It act on extraceller as well as on intracellular TB; is equally active in acidic and alkaline medium. It is one of the cheapest anti tubercular drugs.

Pharmacokinetics
INH is completely absorbed orally and penetrates all body tissues,Tubercular Cavities, placenta and meninges. It is extensively metabolized in liver; most important pathway being acetylation- metabolites are excreted in urine.

2.Rifampin (Rifampicin,R)

It is a semi synthetic derivative of rifamycin B obtained from Streptomyces mediterranei . Rifampin is bactericidal toM. tuberculosis and many other gram –positive and gram- negative bacteria like- staph. aureus, N.meningitidis, H. influenzae, E.coli, klebsiella , pseudomonas, proteus and legionella. Against TB bacilli, it is as efficacious as isonicotinylhydrazine(INH) and better than all other drugs.

Pharmacokinetics
It is well absorbed orally , widely distributed in the body ,penetrates cavities, caseous masses, placenta and meninges . It is metabolite in liver to an active deacetylated metabolite which is excreted mainly in bile, some in urine also. Rifampin and its desacetyl derivative undergo enterohepatic circulation, the t1/2 of rifampin is variable (2-5hrs).

3. Pyrazinamide (Z)

Pyrazinamide, discovered in 1952, is one of four drugs taken as part of a standard treatment regimen to treat TB. Pyrazinamide can also be used as part of a treatment regimen to treat Multidrug-resistant tuberculosis (MDR-TB), usually involving five drugs.

Side effects:
Pyrazinamide can cause nausea, vomiting, joint pain and jaundice. Pyrazinamide is contraindicated in patients with severe liver disease.

Given the lack of safety data, pyrazinamide is not recommended by the Center for Disease Control and Prevention (CDC) during pregnancy. However, it is nevertheless routinely used during pregnancy and no significant adverse events have been reported.

4. Ethambutol

Ethambutol (commonly abbreviated EMB or simply E) is a bacteriostaticanti mycobacterialdrugprescribed to treat tuberculosis. It is usually given in combination with other tuberculosis drugs, such as isoniazid, rifampicinand pyrazinamide.It is sold under the trade names Myambutol and Servambutol.

Pharmacokinetics
It is well absorbed from the gastrointestinal tract and well distributed in body tissues and fluids. 50% is excreted unchanged in urine.

5.Streptomycin

Streptomycinis an antibiotic drug, the first of a class of drugs called amino glycosides to be discovered, and was the first antibiotic remedy for tuberculosis.It is derived from the actinobacterium Streptomyces griseus. Streptomycin is a bactericidal antibiotic. Streptomycin cannot be given orally, but must be administered by regular intramuscular injections. An adverse effect of this medicine is ototoxicity. It is not to be confused with the anti-thrombotic agent streptokinase.

Second line drug:
1. Thiacetazone (Tzn)

Thiacetazone(Tzn) is a tuberculostatic, low efficacy drug; does not add to the therapeutic effect of H, S or E, but delays resistance to these drugs. It is orally active, and primarily excreted unchanged in urine with a t1/2 of 12 hr.

The major adverse effects of Tzn are hepatitis, exfoliated dermatitis, stevens-johnson syndrome and rarely bone marrow dispersion.

2. Para amino salicylic acid (PAS)

4-aminosalicylic acid, commonly known as PAS, is an antibiotic used to treat tuberculosis. This organic compound has been use since the 1940s for the treatment of inflammatory bowel diseases (IBDs), where it has shown greater potency in ulcerative colitis and Crohn's disease.

3. Ethionamide(Etm)
It is tuberculostic drug of moderate efficacy introduced in 1956. It acts on both extra and intracellular organism. Atypical mycobacteria are sensitive. Resistance to Etm developed rapidly and some cross resistance with Tzn is seen. It is absorbed orally, distributed all over, including CSF, completely metabolized and has short duration of action (t1/2 2-3hr).

Anorexia, nausea, vomiting, and abdominal upset are common, especially in Indian Patients.

4. Cycloserine(Cys)
It is an antibiotic obtained from S.orchidaceus, and is a chemical analogue of D-alanine: inhibits bacterial cell wall synthesis by inactivating the enzymes. Cycloserine is absorbed orally, diffuses all over, CSF concentration is equal to that in plasma. About 1/3^rd of a dose is metabolized, the rest is excreted unchanged by kidney.

5. Kanamycin(Kmc), Amikacin(Am) and Capreomycin(Cpr)
Are more toxic antibiotics used as reserve drugs in rare cases not responding to the usual therapy, or infection by atypical mycobacteria. Anyone these used at a time in combination with the commonly employed drug to which resistance has not developed.

Newer Drugs:

1. Ciprofloxacin

Ciprofloxacin (International Nonproprietary Name-INN) is a synthetic antibioticof the fluoroquinolonedrug class.

It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of protein. Ciprofloxacin was first patented in 1983 by Bayer A.G. and subsequently approved by the U.S. Food and Drug Administration (FDA) in 1987.

2. Ofloxacin

Ofloxacinis a synthetic chemotherapeuticantibiotic of the fluoroquinolone drug class considered to be a second-generation fluoroquinolone. The original brand, Floxin, has been discontinued by the manufacturer in the United States on 18 June 2009, though generic equivalents continue to be available.

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3. Clarithromycin

Clarithromycinis a macrolide antibioticused to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia(especially atypical pneumonias associated with Chlamydia pneumoniae or Taiwan Acute Respiratory (TWAR) ), skin and skin structure infections. In addition, it is sometimes used to treat Legionellosis, Helicobacter pylori, and lyme disease.

4. Azithromycin

Azithromycin (Zithromax, and others) is an azalide, a subclass of macrolide antibiotics. Azithromycin is one of the world's best-selling antibiotics. It is derived from erythromycin, with a methyl-substituted nitrogen atom incorporated into the lactone ring, thus making the lactone ring 15-membered.Azithromycin is used to treat or prevent certain bacterial infections, most often those causing middle ear infections, strep throat, pneumonia, typhoid, and sinusitis. In recent years, it has been used primarily to prevent bacterial infections in infants and those with weaker immune systems.

5. Rifabutin

Rifabutin(Rfb) is a bactericidal antibiotic drug primarily used in the treatment of tuberculosis. The drug is a semi-synthetic derivative of rifamycin S. Its effect is based on blocking the DNA-dependent RNA-polymerase of the bacteria. It is effective against Gram-positive and some Gram-negative bacteria, but also against the highly resistant Mycobacteria, e.g. Mycobacterium tuberculosis, M. leprae and M. avium intracellulare.

Conclusion
Tuberculosis can be controlled if appropriate policies are followed, effective clinical and public health management is ensured, and there are committed and co-ordinated efforts from within and outside the health sector. However, in the context of a large epidemic of AIDS, TB incidence will inevitably increase. By 2001, less than 30% of global TB cases were reported to have received effective diagnosis, treatment and monitoring. Rapid expansion of effective TB control services is urgently required, both to avert the continued high burden of morbidity and mortality from TB and because of the HIV pandemic.

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