Antituberculosis

Antimycobacterial drugs

Anti Tubercular Drugs

Mycobacterium tuberculosis is a causative bacterium for infectious disease tuberculosis. It can affect lungs, genitourinary tract skeleton system, and meninges. Mycobacterium tuberculosis grows slowly, can survive in unfavorable condition, and develop resistant to several antimicrobial agents. Thus tuberculosis requires multidrug therapy.

Classification: Antitubercular drugs are classified into following two groups

·         First Line Drug

·         Second Line Drug

First Line Drugs: Isoniazid, Rifampicin, Ethambutol, Pyrazinamide, and Streptomycin

Second Line Drug: Kanamycin, Amikacin, Cycloserin, Capreomycin, Viomycin, Thiacitazone, Ethionamide, Para-Amino Salicylic Acid (PAS), Quinolones.

Following factors decreases tuberculosis treatment effectiveness and develop drug resistance.

·         Patient non-compliance,

·         Development of intracellular persistors.

·         Chronic Infection,

·         Drug Resistance.

Tuberculosis chemotherapy requires a longer duration of treatment. M. tuberculosis may develop resistance to antitubercular drugs during therapy. Thus single drug therapy will not be effective. Multidrug therapy is recommended for a complete cure for tuberculosis and to prevent drug resistance. Minimum two bactericidal drugs should be used. Treatment should be continued even after disappearance of tuberculosis clinical symptoms. It is must to eradicate all living M. Bacterium in the body.

·         First Line Drug: It is also called essential drug to treat tuberculosis. Isoniazid, Rifampicin, Ethambutol, Streptomycin, and pyrazinamide are considered as first-line drug and essential drug to treat tuberculosis. They have good efficacy and acceptable toxicity. This combination therapy is recommended to treat tuberculosis in an ambulatory patient.

Chemotherapy duration is divided into two phases

o   Intensive Phase (Initial phase)

o   Continuous phase

Four antitubercular drugs are administered in intensive phase. After the disappearance of clinical symptoms, fewer drugs are administered in continuous phase to eradicate M. tuberculosis from the body.

            This chemotherapy duration will depend upon categories of tuberculosis. There are four categories of tuberculosis. These are

·         Category I:    Newly diagnosed tuberculosis or tuberculosis in seriously ill  

·                                 patients

·         Category II:  Treatment failure and relapse

·         Category III: Tuberculosis with pulmonary smear negative and    

                        extrapulmonary tuberculosis.

·         Category IV: Chronic tuberculosis

Category I: Newly diagnosed tuberculosis or tuberculosis in seriously ill patients

WHO Recommendations:

Initial phase: Isoniazid, Rifampicin, Pyrazinamide, and Streptomycin or Ethambutol are administered daily for two months (Eight Weeks).

At end of the initial phase, sputum should have smear negative. If sputum remains smear positive then initial phase is extended by four weeks. After four weeks continuous phase is started without sputum test.

Continuous phase: Continuous phase is started after completion of the initial phase. Isoniazid and rifampicin are administered daily for four months three times in a day. In complicated case of tuberculosis isoniazid and rifampicin are administered six to seven months.

Alternative continuous phase:

·         Isoniazid and Thiavitazone or

·         Isoniazid and ethambutol Combinations are administered daily for six months.

·         Tuberculosis with proven or suspected HIV is treated by using thiacetazone in place of ethambutol.

Category II: Treatment failure and relapse: Category II tuberculosis indicates the development of multidrug resistance in M. tuberculosis. It requires treatment under direct supervision of medical practitioners. It is called DOT (Direct observation therapy) by WHO.

Initial phase: Isoniazid, rifampicin, pyrazinamide, streptomycin, and ethambutol are administered daily for eight weeks. Thus this combination is continued for next four weeks without streptomycin.

Continuous phase: Isoniazid, rifampicin, and ethambutol are administered three times in a week under direct supervision of medical practitioner i.e. DOT. If DOT is not possible, then continuous phase is continued for five months.

Category III: Tuberculosis with pulmonary smear-negative and extrapulmonary tuberculosis.

Initial phase: Isoniazid, Rifampicin, and pyrazinamide are administered daily or three times in a week for two weeks.  

  Continuous Phase: Isoniazid and rifampicin daily for four months. Or

Isoniazid and rifampicin two or three times in a week for four months.

Category IV: Chronic tuberculosis: Tuberculosis persists even after completion of the initial phase and continuous phase is considered as chronic tuberculosis. It is very difficult to treat. It requires second-line drugs. Second line drugs are very expensive, more toxic and even less effective than first-line drugs. In spite of all efforts only half of cases are curable. Thus in India, the only isoniazid is recommended to treat such cases. Isoniazid is administered throughout life.  It reduces M. tuberculosis activity and also reduces drug-resistant M. tuberculosis transmission.

National Tuberculosis Control Program (NTCP) in India recommended following drug dose schedule to treat tuberculosis in category I patients.

Drug                            Intensive Phase                       Continuous Phase

                                    2-Months                                 4- Months

Isoniazid                    300 mg                                    300 mg

Rifampicin                  600 mg                                    600mg

Pyrazinamide              2000 mg

Ethambutol                 1200 mg

Intermittent treatment of tuberculosis for category I patients

Isoniazid Tablet         400 mg

Rifampicin Tablet       600mg

FIRST LINE DRUG

ISONIAZID: It is bactericidal, relatively nontoxic and inexpensive drug. Thus it is ideal and primary drug to treat tuberculosis. It acts as bactericidal against active M. tuberculosis and bacteriostatic against inactive (resting) M. tuberculosis. It is always used in combination with other antimicrobial drugs. It is metabolized by acetylation and hydrolysis.

Mechanism of Action: Micolic acid is an important constituent of the Mycobacterium tuberculosis cells' outer cell wall. M.tuberculosis is acid-fast bacteria due to micolic acid. Isoniazid inhibits biosynthesis of micolic acid that makes outer cell wall week leads t death of cells.

Pharmacokinetics: It can be administered by oral or parenteral route. It is well absorbed orally. Foods especially carbohydrate foods and antacids interfere in the absorption of isoniazid upon oral administration. It is well distributed throughout the body including CSF. Infected tissues retain it for a longer duration. It is metabolized by acetylation and hydrolysis. Thus fast acetylator will require high dose and slow acetylator will require low dose. The dose should also be reduced in a patient suffering from the chronic liver disease.
It is excreted in saliva, sputum, milk and by glomerular filtration into urine,    

Adverse Effects: Adverse effects are very low except hypersensitivity. Common side effects are hepatitis, peripheral neuritis, fever, and rashes. Side effects precipitate in less than 5% of patients. Vitamin B 6 (Pyridoxine) should be administered to prevent neuritis. 
Drug Interaction: Isoniazid inhibits the metabolism of phenytoin. This potentiates phenytoin adverse effects. Rifampicin stimulates secretion of hepatic microsomal enzymes secretion. Isoniazid is metabolized in the liver to form isonicotinic acid and hydrazine. Hydrazine is hepatic toxic. Rifampicin increases isoniazid metabolism by two times. Thus isoniazid becomes more hepatotoxic in presence of rifampicin. 

Cautions: Isoniazid is administered with rifampicin. Rifampicin has a tendency to enhance hepatic microsomal enzyme biosynthesis. Thus rifampicin increases the rate of metabolism of isoniazid.

Rifampicin: It is broad-spectrum antibiotics. Bacteria develop drug resistance to rifampicin very rapidly. Thus it is used always with other antimicrobial agents in the treatment of tuberculosis.

Mechanism of action: It forms complex with the beta subunit of DNA dependent RNA polymerase enzyme of bacteria. Thus it inhibits initiations of chain formation in RNA synthesis. 

Pharmacokinetics: It is well absorbed upon oral administration. It is also well distributed throughout all tissues. Its penetration into CNS is low but it attains therapeutic level easily even in absence of inflammation. It is metabolized in the liver. Metabolites also have antibacterial activity. Metabolites enter into enterohepatic circulation and excreted in feces. Both metabolized and the unmetabolized drug is also excreted in urine. It changes the color of urine, feces, saliva, sweat, sputum, and tears to orange-red.

Adverse Effects: It shows minor adverse effects like nausea, vomiting, rash, and fever.
Drug interactions:  It includes hepatic microsomal enzyme secretion. Thus it decreases the half-life of other drugs. 

Pyrazinamide: It is a synthetic derivative of nicotinic acid. It acts as a prodrug and does not produce any activity against bacteria. It is metabolized by enzyme pyrizinamidase enzyme of bacteria to active pyrizinoic acid that acts as bactericidal agent. Thus it produces an antibacterial effect only against pyrizinamidase producing bacteria. It is active against Mycobacterium tuberculosis in acidic medium phagosomes and lysosomes. 
It is well absorbed from GIT, well distributed in body tissues including CSF. It is rapidly metabolized in the liver. Pyrazinamide with rifampicin and isoniazid may cause hepatic dysfunction uric acid retention and precipitate gout. 

Ethambutol: It is bacteriostatic to several Mycobacterium species. It is used in combination with other antitubercular drugs like rifampicin, isoniazid, and pyrazinamide. It is well absorbed from GIT, well distributed throughout the body including CSF. Both active drug and its metabolites are excreted in urine.
Adverse Effect: Neuritis, Problem to distinguish red and green, Uric acid retention to cause gout.

Streptomycin: It is bactericidal that acts in alkaline media. It is not absorbed from GIT thus it is administered by intramuscular route. It has good tissue penetration including CSF. (Detail in streptomycin chapter) 

Second Line Drug

It is reserved for tuberculosis resistant to First Line Drug.

Aminosalicylic Acid: It is a bacteriostatic agent. It produces severe side effect like anorexia, nausea, epigastric pain, diarrhea. It is rarely used.

Ethionamide: It is a bacteriostatic derivative of thio iso nicotinamide. It is a sructural analog of isoniazid. It is well absorbed from GIT, well distributed throughout the body including CSF. It inhibits acetylation of isoniazid. 

  Cycloserin: IT IS analog of amino acid analin. Thus it interferes with bacterial cell wall synthesis. and acts as bacteriostatic. It is well absorbed from GIT, well distributed throughout the body including CSF. Both active drug and its metabolites are excreted in urine. Renal dysfunction may cause its accumulation 
Adverse Effects: CNS disturbance, headache, vertigo, visual disturbance, convulsion and other psychotic disturbance.

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