Antitubercular Drugs Question And Answers

Antitubercular Drugs

Question 5. Classify/name the antituberculosis drugs. Describe the mechanism of action, adverse effects, and antitubercular actions of any 3 of them.
Or
Short notes: INH, rifampicin, pyrazinamide, ethambutol, first-line antitubercular drugs
Answer:

Based on antitubercular activity, drugs may be grouped as:

Read And Learn More: Pharmacology Question And Answers

First-Line Drugs:

First-line drugs are superior in efficacy to second-line drugs.

Isoniazid (INH):

• Most effective and cheapest primary antitubercular drug—effective both in acidic and alkaline mediums. INH is tuberculocidal for rapidly multiplying bacilli but static for resting bacilli.
• INH destroys:
  • Intracellular bacilli as it freely penetrates macrophages
  • Bacilli multiply in the walls of the cavities.
• Thus it is effective against both intra- and extracellular organisms.
• If used alone, mycobacteria develop resistance → should be used in combination.

Isoniazid  Mechanism of Action:

• INH inhibits the synthesis of mycolic acids which are important components of the mycobacterial cell wall.
• The cell wall of mycobacteria has large amounts of mycolic acids which form important components of it.
• INH, a prodrug, freely enters the mycobacteria and is converted to an active form by an enzyme [catalase-peroxidases (KatG)] present in the mycobacteria.
• This active form covalently binds certain enzymes and thereby inhibits mycolic acid synthesis.
• Resistance to INH is seen when there is overproduction of the enzymes that are inhibited by INH.

Isoniazid  Pharmacokinetics:

• INH is completely absorbed orally and penetrates all tissues, tubercular cavities, ascitic fluid, necrotic tissues, caseous material, and CSF.
• Metabolized by acetylation which is genetically determined.
• People can be fast or slow acetylators depending on their genetic inheritance—slow acetylators respond better.½

Isoniazid  Adverse Effects:

• Peripheral neuritis: Peripheral neuritis due to interference with utilization and increased excretion of pyridoxine can be avoided by giving prophylactic pyridoxine (10–50 mg) with INH.  Seen in patients with comorbid conditions like AIDS, diabetes, and malnutrition.

• Hepatitis: Hepatitis is more common in alcoholics and in the elderly. Rarely INH can cause hepatic necrosis with anorexia, nausea, vomiting and jaundice—can be fatal.  With the first sign of hepatic necrosis stop INH.
• CNS toxicity: CNS toxicity psychosis and seizures—rare epileptics are more prone and pyridoxine helps.
• Other minor effects: minor effects are anorexia, gastrointestinal discomfort, fever, and allergic reactions can occur. Hemolysis can occur in patients with G6PD deficiency.

Rifampicin:

• Rifampicin (rifampin) is an antibiotic obtained from Streptomyces mediterranei. The other rifamycins are rifabutin and rifapentine.
• Rifampicin is bactericidal to M. tuberculosis, M. leprae, and atypical mycobacteria. It also inhibits most gram-positive and gram-negative bacteria like Staph. aureus, N. meningitidis, E. coli, Proteus, Pseudomonas and Legionella.

Rifampicin Antitubercular action:

• Rifampicin is a highly effective, tuberculocidal and is the only drug that acts on persisters; acts on both intra- and extracellular organisms and is effective against tubercle bacilli resistant to other drugs—it is called a ‘sterilizing agent’.
• If used alone resistance develops.

Rifampicin Mechanism of action:

• Rifampicin binds to the β subunit of DNA-dependent RNA polymerase and inhibits RNA synthesis in the bacteria.
• It is bactericidal. Moreover, it reaches the cavities, and caseous material, and penetrates macrophages.

Resistance → genetic mutation → ↓ binding of rifampicin to RNA polymerase.

Rifampicin Pharmacokinetics:

• Rifampicin is well-absorbed and has good tissue penetrability—good CSF concentrations are reached in the presence of meningitis.
• It also appears in saliva, tears, and sweat. It is metabolized in the liver. It is a microsomal enzyme inducer—hence can result in many drug interactions.
• Rifampicin is excreted through the bile and undergoes enterohepatic circulation.

Rifampicin Adverse Effects:

• Hepatotoxicity: Rifampicin can cause hepatitis. Patients receiving other hepatotoxic drugs or with any liver dysfunction and chronic alcoholics should be carefully monitored—deaths have been reported. However, with normal liver function, hepatitis is rare.

• Gastrointestinal disturbances: Epigastric distress, nausea, vomiting, abdominal cramps, and diarrhea can occur.
• Flu-like syndrome: With fever, body ache, chills and hemolytic anemia is more common in intermittent dosing regimens.
• CNS symptoms: Include headache, drowsiness, dizziness, ataxia, confusion, and peripheral neuropathy with pain and numbness in the extremities and muscle weakness.
• Hypersensitivity reactions: With fever, skin rashes, and urticaria, rarely renal manifestations with nephritis, hemolysis, hematuria, and renal insufficiency can occur
• Staining of secretions: Tears, saliva, and sweat—get an orange-red color and the patient should be informed about this. Soft contact lens may be stained.

Rifampicin Drug Interactions:

• Salicylates may delay the absorption and reduce the bioavailability of rifampicin. When both are needed in a patient, there should be a gap of 8–12 hours between them.
• Salicylate → ↓ Absorption of rifampicin → ↓ Bioavailability → Gap of 8–12 hours needed
• Rifampicin is a microsomal enzyme inducer → faster metabolism of many drugs like anticoagulants, hormonal contraceptives, corticosteroids, ketoconazole, cyclosporine, some anticonvulsants, antiretroviral protease inhibitors, and NNRTIs.
• Oral contraceptive failures can occur—higher doses of estrogen should be used or alternative methods of contraception followed.

Rifampicin Uses:

• Tuberculosis and atypical mycobacterial infections: Used with other antitubercular drugs. It can also be used for prophylaxis as an alternative to INH.
• Leprosy: Leprosy 600 mg once monthly supervised.
• Prophylaxis: H. influenzae and meningococcal meningitis in close contact.

Antitubercular actions and important adverse effects of some antitubercular drugs:

• Resistant staphylococcal infections: Rifampicin with a beta-lactam antibiotic or
  vancomycin.
• Brucellosis: Rifampicin 600–900 mg + doxycycline 200 mg daily for 6 weeks—drug of choice.
• Pneumococcal meningitis: Rifampicin + ceftriaxone alternative to penicillin.
• To eradicate carrier state: Rifampicin eradicates the nasal carrier state of N. meningitidis, H. influenzae, and S. aureus—600 mg BD for 2 days.

Rifabutin:

Similar to rifampicin but causes milder enzyme induction → Rifabutin is preferred when drug interactions are likely in tuberculosis patients with AIDS who are receiving antiretroviral drugs, viz. protease inhibitors (PIs) and NNRTIs. It is also useful for chemoprophylaxis of atypical mycobacterial infections.

Rifapentine:

It is similar to rifampicin and can be used in tuberculosis in place of rifampicin. It should be avoided in AIDS patients because of the risk of development of resistance.

Pyrazinamide

Pyrazinamide is an analog of nicotinamide.

Pyrazinamide Mechanism of action:

• It is tuberculocidal and requires acidic pH (5.5) for its tuberculocidal activity.
• This is advantageous because tubercle bacilli live in the macrophages (phagosomes) where the pH is acidic. The mechanism of action is not exactly known.
• Pyrazinamide is converted to its active metabolite pyrazinoic acid by an enzyme pyrazinamidase present in the mycobacteria.
• This metabolite may inhibit the synthesis of mycolic acids by the mycobacteria. If used alone, resistance develops.
• Pyrazinamide is well absorbed and widely distributed in the tissues including to CSF.

1. Hepatotoxicity:

• Hepatotoxicity is dose-dependent—and can result initially in raised serum transaminases, jaundice, and rarely hepatic necrosis. Deaths due to hepatic necrosis have been reported.
• Liver function tests should be done before starting pyrazinamide and it should be avoided in patients with hepatic impairment. Patients should be monitored.

2. Hyperuricemia:

• Hyperuricemia due to decreased excretion of uric acid may result in gouty arthritis.
• Pyrazinamide → ↓ Uric acid excretion → Hyperuricemia → Gouty arthritis

3. Other effects like arthralgia, anorexia, vomiting, fever, and rashes may be seen.

Streptomycin:

• It is tuberculocidal
• Acts only against extracellular organisms due to the poor penetrating power
• To be given IM
• When used alone resistance develops
• Because of the disadvantages and its toxicity → Oto- and nephrotoxicity → streptomycin is not preferred used in a combination regimen.

Ethambutol

• Ethambutol is tuberculostatic and acts on fast-multiplying bacilli in the cavities. It is also effective against atypical mycobacteria. It inhibits the incorporation of mycolic acids into the mycobacterial cell wall by inhibiting certain enzymes (arabinosyltransferases) involved in it.
• Ethambutol is well absorbed and crosses the BBB in the presence of meningeal inflammation.
• Half the dose is excreted through the kidneys and the dose should be reduced in renal failure.
• Dose: 15–25 mg/OD.

Ethambutol Adverse effects:

• Optic neuritis resulting in decreased visual acuity and inability to differentiate red from green is an important adverse effect that needs withdrawal of the drug. Color vision should be monitored during treatment.
• Ethambutol is to be avoided in children because their ability to differentiate red from green cannot be reliably tested. Other adverse effects include nausea, anorexia, headache, fever, and allergic reactions.
• Ethambutol → ↓ renal excretion of uric acid → hyperuricemia.

Newer Drugs:

Bedaquiline: Bedaquiline is a newly introduced drug with a unique mechanism of action. It binds to and inhibits mycobacterial ATP synthase and thereby interferes with the generation of energy. It is tuberculocidal.

• Fatty food increases its bioavailability, is extensively bound to plasma proteins, and is metabolized by microsomal enzymes (cytochrome P450).
• Coadministration of other microsomal enzyme inducers like rifampicin and also enzyme inhibitors should be avoided.

Bedaquiline Adverse effects:

• Since bedaquiline can cause QTc prolongation, other drugs that prolong QTc should be avoided along with it.
• Hepatotoxicity, nausea, arthralgia, and headache are reported.

Bedaquiline Uses: MDR tuberculosis along with other antitubercular drugs.

Delamanid:

• Delamanid is a nitroimidazole activated by a nitroreductase that blocks the synthesis of mycolic acids in mycobacterial cell walls.
• Nausea, dizziness, and QT prolongation are common.

Second-line Drugs:

Second-line drugs are generally less effective and more toxic when compared to first-line drugs. They are used only if the organism is resistant to first-line drugs.

Thiacetazone:

• Thiacetazone is tuberculostatic with low efficacy; it delays the development of resistance to other drugs and its low cost makes it a suitable drug in combination regimens.
• Hepatotoxicity, dermatitis, allergic reactions, and GI side effects may occur.

Ethionamide:

• This tuberculostatic drug is effective against both intra- and extracellular organisms. It is also effective in atypical mycobacteria.
• Anorexia, nausea, vomiting, and metallic taste in the mouth are common. It can also cause hepatitis, skin rashes, and peripheral neuritis (needs prophylactic pyridoxine).

Para-aminosalicylic acid (PAS):

• Para-aminosalicylic acid (PAS) related to sulfonamides is tuberculostatic. Gastrointestinal effects like nausea, anorexia, epigastric pain, and diarrhea make it a poorly tolerated drug.
• Allergic reactions and hepatitis are also seen. It is rarely used.

Amikacin, kanamycin and capreomycin:

• These are second-line drugs that need parenteral administration. They are oto- and nephrotoxic and are used only in resistant cases.
• Amikacin is also effective against atypical mycobacteria. They are used in combination regimens in the treatment of multidrug-resistant tuberculosis (MDR-TB).

Cycloserine:

• Cycloserine inhibits cell wall synthesis, is tuberculostatic, and is also effective against some gram-positive organisms.
• It causes CNS toxicity including headache, tremors, psychosis, and sometimes seizures. It is used only in resistant tuberculosis.

Fluoroquinolones:

• Many FQs inhibit tubercle bacilli as well as atypical mycobacteria in addition to gram-positive and gram-negative bacteria.
• They enter into the cells and destroy intracellular mycobacteria. They may be used in combination regimens for resistant tuberculosis.
• Ciprofloxacin, levofloxacin, moxifloxacin, sparfloxacin, and ofloxacin have been used along with second-line drugs in MDR-TB.

Linezolid:

• Linezolid is effective in tuberculosis → Penetrability into cells is good and is lethal to intracellular bacilli.
• It can be used in a single daily dose of 600 mg along with second-line drugs only in the treatment of MDR tuberculosis.

A combination of drugs is used in tuberculosis for:

• Rapid response
• Lower failure rates
• Delay the development of resistance
• Reduce toxicity
• Shorten the course of treatment.

Directly observed treatment short course (DOTS) chemotherapy:

• The success of chemotherapy depends on the regular intake of drugs by the patients.
• DOTS chemotherapy is a strategy that involves providing the most effective medicine and confirming that it is taken—a health worker ensures that the drug is taken by the patient.

RNTCP:

• RNTCP The Government of India along with WHO and World Bank revised the national TB program as Revised National Tuberculosis Control Programme (RNTCP) which was introduced in 1993.
• After launching the RNTCP program, the death rate has been reduced.

The RNTCP has revised the treatment schedule in 2016 with 2 major changes:

• Introduction of daily dose regimen and
• Supply of fixed dose combinations (FDC).

The program uses technology to monitor the regular intake of tablets, i.e. to ensure better patient compliance.

Under the RNTCP program, antitubercular drugs are available as 4-drug FDC and 3-drug FDC. A single tablet of 4-FDC contains isoniazid 75 mg, rifampicin 150 mg, pyrazinamide 400 mg and ethambutol 275 mg. The number of tablets to be taken daily depends on the patient’s body weight

FDC for tuberculosis:

Resistant tuberculosis:

• If sputum remains positive even after 6 months of treatment, organisms are likely to be resistant. Resistance may be to one or multiple drugs.
• The patient should be hospitalized or isolated to prevent the spread of resistant strains.

Chemoprophylaxis is given only in:

• Contacts of open cases especially children.
• Patients with the old inactive disease who have not been adequately treated. INH is used daily (5 mg/kg) for 6–12 months. Rifampicin can be used as an alternative to INH.
• HIV-infected patients exposed to multidrug-resistant tuberculosis—rifampicin and pyrazinamide are given daily for 2 months.

Tuberculosis in AIDS patients:

AIDS patients are likely to have more severe and rapidly progressing tuberculosis. Moreover, adverse effects of antitubercular drugs are more common in them. They should be given more vigorous and supervised chemotherapy as per the guidelines of Dots.

Drugs For Mycobacterium Avium Complex (Mac):

Infection with MAC is more common in HIV patients and is more severe in them. With the use of prophylactic regimens, the incidence of MAC infections has greatly decreased. In non-HIV patients, MAC infection causes milder disease with chronic productive cough.

The drugs effective are:

• Rifabutin
• Clarithromycin
• Azithromycin
• Ethambutol
• Clofazimine
• Amikacin

The macrolides, clarithromycin (500 mg BD) or azithromycin (500 mg OD), or ethambutol is the preferred regimen (rifabutin may be added) for MAC infection and needs lifelong treatment. Fluoroquinolones like ciprofloxacin, ofloxacin, and sparfloxacin have useful activity against MAC bacteria. (4 drug regimen with ciprofloxacin + clarithromycin + rifabutin + amikacin) is effective. Rifabutin, clarithromycin or azithromycin may be used for prophylaxis.

Drugs Used In The Treatment Of Leprosy

Leprosy caused by Mycobacterium leprae is a chronic infectious disease affecting the skin, mucous membranes, and nerves. Hansen discovered Lepra bacillus in 1873. As Lepra bacillus does not grow on artificial media and cannot be transmitted to all animals, it is difficult to culture this organism and study the effect of drugs.

Drugs Used In Leprosy:

• Sulfones: Dapsone
• Rifampicin
• Clofazimine
• Ethionamide and protionamide.

Dapsone: Dapsone is diamino diphenyl sulfone (DDS) and is related to sulfonamides.

Dapsone Mechanism of action: 

• Like sulfonamides, dapsone inhibits the incorporation of para-aminobenzoic acid (PABA) into folic acid. The lepra bacillus develops resistance to dapsone on prolonged use. Hence it should be used with other drugs in leprosy.
• Dapsone is leprostatic. Though it inhibits the growth of many other bacteria, the dose needed is high and is, therefore, not used.
• Dapsone is completely absorbed on oral administration and reaches high concentrations in the skin infected with lepra bacillus than the normal skin.
• It is metabolized in the liver and excreted in the bile.

Dapsone Adverse effects:

• Dapsone is well-tolerated—anorexia, nausea, and vomiting are common. Fever, pruritus, rashes and dermatitis can occur.
• Hemolytic anemia is the most important dose-related toxicity (more common in patients with G6PD deficiency). Iron preparations should be given to prevent anemia.
• Hepatitis and agranulocytosis are seen. Patients with lepromatous leprosy may develop lepra reactions.

Dapsone Uses:

• Leprosy: Dapsone is used for both treatment and chemoprophylaxis.
• P. jiroveci: Dapsone with trimethoprim → in P. jiroveci infections in AIDS—both for the prevention and treatment.
• Dermatitis herpetiformis, a chronic blistering skin disease seen in patients with celiac disease, can be treated with dapsone 50–300 mg/day.

Rifampicin

• Rapidly lepricidal and highly effective—a single dose of 1,500 mg can kill 99% of the lepra bacilli
• Given once monthly
• Used with dapsone, it shortens the duration of treatment
• A component of multidrug regimen for leprosy.

Clofazimine:

• A dye has weak septicidal action
• Also has weak anti-inflammatory property useful in suppressing lepra reactions
• Used orally in multidrug regimens
• Imparts a reddish-black discoloration to the skin especially exposed parts which remain for several months
• Can cause dryness of the skin, itching, phototoxicity, and gastrointestinal disturbances.

Ethionamide:

• Ethionamide is lepricidal but more toxic than dapsone
• Can cause gastric irritation, peripheral neuritis and hepatotoxicity
• Used in multidrug regimen as an alternative to clofazimine.

Other Drugs:

• Fluoroquinolones: Ofloxacin is lepricidal and is suitable for use in multidrug regimens in leprosy along with rifampicin. (Ofloxacin 400 mg + rifampicin 600 mg daily for 28 days).
• Minocycline: Has useful activity against M. leprae and is being tried in combination regimens to shorten the duration of treatment. Given 100 mg daily but should not be used in children and pregnant women.
• Clarithromycin: Clarithromycin, a macrolide antibiotic, has bactericidal activity against M. leprae. Given 500 mg daily for 28 days can kill 99% of viable bacilli.

Treatment of Leprosy:

WHO has recommended a combination of drugs in leprosy to:

• Eliminate persisters
• Prevent drug resistance
• Reduce the duration of therapy.

Multidrug regimen for leprosy:

Lepra reactions:

• These are immunologically mediated acute inflammatory reactions that occur in leprosy. They are acute exacerbations triggered by acute infections, stress, anxiety and treatment with dapsone. Lepra reactions need to be suppressed promptly because they can result in permanent neurological changes.
• Early detection and prompt treatment are essential.

Dose: Prednisolone 40–60 mg daily for 2 weeks and gradually tapered over the next 8–10 weeks by reducing 10 mg every 2 weeks.

Type 1 and Type 2 Reactions:

Chemoprophylaxis:

• Only about 1% of contacts develop clinical disease. Dapsone 100 mg daily and rifampicin 600 mg once a month for 6 months or till the contact case becomes noninfectious are recommended for child contacts.
• Acedapsone as a single IM injection every 10 weeks is useful. All contacts should be examined every 6 months.

Source of some antibiotics is described in Table.

Source of some antibiotics:

Antifungal Drugs

Sites Of Action:

Antifungal drugs may act on the fungal cell wall, cell membrane or on the nucleus.

Sites Of Action Classification:

1.  Drugs acting on cell membrane:
   • Polyene antibiotics: Amphotericin B, nystatin, hamycin, natamycin
   • Azoles
     • Imidazoles: Clotrimazole, econazole, miconazole, ketoconazole, butaconazole, oxiconazole, sulconazole, sertaconazole, isoconazole
     • Triazoles: Fluconazole, itraconazole, terconazole, voriconazole, posaconazole, ravuconazole, Isavuconazole
   • Allylamines: Terbinafine, naftifine
2. Drugs acting on cell wall: Pneumocandins/echinocandins–caspofungin, micafungin, anidulafungin
3. Drugs acting on the nucleus: Griseofulvin, flucytosine
4. Other topical agents: Tolnaftate, undecylenic acid, benzoic acid, salicylic acid, naftifine, selenium sulfide, and ciclopirox olamine.