TB Siva Final

Pathophysiology and therapeutics of TUBERCULOSIS: 

Pathophysiology and therapeutics of TUBERCULOSIS Prepared & Presented by Dr. Siva Reddy Challa, M.Pharm,Ph.D Professor & HOD, Dept. of Pharmacology KVSR Siddhartha College of Pharmaceutical Sciences, Siddhartha Nagar, Vijayawada-520010 Andhra Pradesh, INDIA Email: sivareddypharma@gmail.co m

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Mycobacterium tuberculin was first isolated in 1882 by a German physician named Robert Koch who received the Nobel Prize for this discovery.

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Cell wall structure of M. tuberculin

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The cell envelope is extremely hydrophobic and forms an exceptionally strong permeability barrier, rendering mycobacteria naturally resistant to a wide variety of antimicrobial agents. This is due to the unique structure of the mycobacterial cell wall and the presence of long fatty acids, the mycolic acids.

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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.

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Types of T-lymphocytes

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Types of T-lymphocytes

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Innate immunity and Adaptive immunity

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Cell mediated Immunity (Type IV Hypersensitivity) in the pathophysiology of Tuberculosis

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Humoral immunity (Type I Hypersensitivity) in the pathophysiology of Asthma

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Inactive TB (latent TB) TB can remain in an inactive (dormant) state for years without causing symptoms or spreading to other people. Active TB When the immune system of a patient with dormant TB is weakened, the TB can become active (reactivate) and cause infection in the lungs or other parts of the body. Inactive tuberculosis may be treated with an antibiotic, isoniazid (INH), to prevent the TB infection from becoming active. Active TB is treated, usually successfully, with INH in combination with one or more of several drugs, including rifampin , ethambutol ( Myambutol ), pyrazinamide , and streptomycin.

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The risk factors for acquiring TB include Close-contact situations, Alcohol, IV drug use Diabetes Cancer HIV Occupations (for example, health-care workers).

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T Tuberculosis Skin Test At A Glance The tuberculosis skin test is also known as the tuberculin test or PPD test. The PPD test is used to determine if someone has developed an immune response to the bacterium that causes tuberculosis (TB). The standard recommended tuberculin test is the Mantoux test, which is administered by injecting a 0.1 mL volume containing 5 TU (tuberculin units) PPD into the top layers of skin of the forearm. Skin tests should be read 48-72 hours after the injection. The basis of the reading of the skin test is the presence or absence and the amount of induration (localized swelling). A negative test does not always mean that a person is free of tuberculosis. A person who received a BCG vaccine (administered in some countries but not the U.S.) against tuberculosis may also have a positive skin reaction to the TB test.

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A reaction of less than 5 mm is considered negative 5-9 mm is considered positive (+) 10-19 mm is considered positive (++) more than 20 mm is considered positive (+++) A positive tuberculin skin test indicates tuberculous infection, with or without disease

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AFB (Acid fast bacilli test ) (Zeil-neelsen stain) The Ziehl–Neelsen stain, also known as the acid-fast stain, was first described by two German doctors; Franz Ziehl (1859 to 1926), a bacteriologist and Friedrich Neelsen (1854 to 1898), a pathologist. It is a special bacteriological stain used to identify acid-fast organisms, mainly Mycobacteria . It is helpful in diagnosing Mycobacterium tuberculosis since its lipid rich cell wall makes it resistant to Gram stain . It can also be used to stain few other bacteria like Nocardia . The reagents used are Ziehl–Neelsen carbolfuchsin , acid alcohol and methylene blue . Acid-fast bacilli will be bright red after staining.

Antimycobacterials: 

Antimycobacterials

Mycobacteria: 

Mycobacteria Mycobacterium tuberculosis Mycobacterium avium intracellulare complex Mycobacterium leprae

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Why do we have different antibiotics for the treatment of mycobacterial infections ? Because of different cell wall constituent MYCOLIC ACID that makes them acid-fast bacilli and prevents the entry of majority of antibiotics.

Problems with mycobacteria: 

Problems with mycobacteria Other antibiotics are not effective Slow growing bacteria Multidrug resistance emergence (MDR)

To prevent the development of resistance and shorten the duration of therapy, we have…: 

To prevent the development of resistance and shorten the duration of therapy, we have… Multidrug therapy

Antitubercular therapy (ATT): 

Antitubercular therapy (ATT) Primary drugs Secondary drugs

Primary drugs: 

Primary drugs RIPES Rifampin Isoniazid Pyrazinamide Ethambutol Streptomycin

Secondary drugs: 

Secondary drugs Amikacin Capreomycin Cycloserine Ethionamide Para-aminosalicylic acid Ciprofloxacin and ofloxacin Linezolid

Primary drugs: 

Primary drugs

Isoniazid: 

Isoniazid Isoniazid=Isonicotinic acid hydrazide (INH) Bactericidal

Isoniazid: Mechanism of action: 

Isoniazid: Mechanism of action KatG gene in mycobacteria: this enzyme encodes catalase-peroxidase in mycobacteria. Catalase-peroxidase converts INH to active form. activated form of INH inactivate the enzymes involved in mycolic acid synthesis – enoyl acyl carrrier protein reductase (InhA) and beta-ketoacyl-ACP synthease (KasA), resulting in inhibition of call wall synthesis.

Isoniazid: Spectrum: 

Isoniazid: Spectrum Only against mycobacteria. Active against M. tuberculosis and some sensitive strains of Atypical mycobacteria, like M. kansasii Not effective against: Mycobacteriun avium intracellulare complex Mycobacterium leprae

Isoniazid: Narrow spectrum: 

Isoniazid: Narrow spectrum 45

Metabolism: 

Metabolism Isoniazid Acetylisoniazid Isonicotinic acid + Acetylhydrazine (hepatotoxic) Acetyltransferase Acetyl CoA

Pharmacogenetics: 

Pharmacogenetics Slow acetylators Fast acetylators

Isoniazid: Adverse effects: 

Isoniazid: Adverse effects Hepatitis Peripheral neuropathy: It can be prevented/treated by Vitamin B6 CNS: Toxic encephalopathy, seizures Blood: Anemia, Thrombocytopenia

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Role of Vitamin B6 during ATT Peripheral neuritis occurs due to pyridoxine deficiency resulting from isoniazid therapy. Pyridoxine supplements are given for preventing/treating neuropathy due to INH.

Resistance to Isoniazid: 

Resistance to Isoniazid Mediated primarily by mutations of the KatG gene , which result in loss of the catalase-peroxidase enzyme required for the activation of isoniazid. Overexpression of InhA. MDR tuberculosis: Resistance to both, INH and rifampin

Drug interactions: 

Drug interactions Inhibits metabolism of phenytoin and increases its toxicity (Nystagmus, Ataxia)

Rifampin: 

Rifampin Rifamycin derivatives (Rifampin, Rifapentin, Rifabutin) Broad spectrum antibiotic G+, G-, AFB (TB, Leprosy) Mechanism of action : Inhibits transcription by binding to beta subunit of DNA dependent RNA polymerase.

Rifampin: Therapeutic Uses: 

Rifampin: Therapeutic Uses As prophylaxis to prevent several infection As an alternative to INH for the prevention of TB in HIV positive, especially when resistance to INH is known or suspected. To prevent meningococcal disease, in contacts with Neisseria meningitidis Hemophilus influenzae b

Rifampin: Therapeutic Uses: 

Rifampin: Therapeutic Uses For Treatment of: Tuberculosis leprosy In combination with Vancomycin and Gentamicin for the treatment of Staphylococcal endocarditis.

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Uses of Rifampicin For Prophylaxis For Treatment Alternative to INH for the prevention of TB in HIV positive Tuberculosis (in combination with INH, Pyrazinamide ± Ethambutol ) To prevent meningococcal meningitis Leprosy (in combination with Dapsone and Clofazimine) Hemophilus influenza b Staph. endocarditis

Resistance: 

Resistance By decreased affinity of RNA polymerase for rifampin So, always combined with other drugs for the treatment of active infection.

Rifampin: Adverse effects: 

Rifampin: Adverse effects Hepatitis (more with combination with INH) Flu-like illness-chills, fever, fatigue, headache Purpura: if develops, stop the therapy Reddish-orange discoloration of urine, tears and other body fluids

Enzyme induction by Rifampin: 

Enzyme induction by Rifampin Decrease in serum levels of various drugs causes therapeutic failure: OCP failure Failure of Antiepileptic therapy Macrolides Digoxin Sulfonylureas Theophylline Warfarin

Rifapentine: 

Rifapentine Long half life Adverse effects: Rash Marrow suppression Hepatic dysfunction Secretion discoloration

Rifabutin: 

Rifabutin Interferes with DNA synthesis in M. tuberculosis Effective against *MAC Adverse effects Dyspepsia, abdominal pain Uveitis Hepatitis Secretion discoloration

Pyrazinamide: 

Pyrazinamide Nicotinic acid derivative Bactericidal Mechanism of action: Pyrazinamide is converted to pyrazinoic acid (active form of the drug) by the susceptible bacteria.

Pyrazinamide: Therapeutic Uses: 

Pyrazinamide: Therapeutic Uses Administered along with INH and Rifampin for the first 2 months of treatment

Pyrazinamide: Adverse effects: 

Pyrazinamide: Adverse effects Hepatitis Hyperuricemia Gout Hematologic toxicity Fever Increased serum iron concentration Arthralgia

Ethambutol: 

Ethambutol Bacteriostatic Mechanism of action: Ethambutol inhibits the synthesis of Arabinogalactan (component of cell wall), thereby inhibits cell wall formation. Deters resistance to bactericidal drugs in TB therapy

Ethambutol: Adverse effects: 

Ethambutol: Adverse effects Optic neuritis (color blindness) Increased uric acid , Gout Hepatitis Thrombocytopenia

Ethambutol: Therapeutic uses: 

Ethambutol: Therapeutic uses Tuberculosis combined with other drugs (INH, Rifampin, Pyrazinemide) to prevent the development of resistance in case resistance is suspected MAC

Streptomycin: 

Streptomycin It is an aminoglycoside antibiotic Active against extracellular organisms Adverse effects: Nephrotoxicity Ototoxicity Neuromuscular bloakade

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Treatment of Tuberculosis 5 Primary Drugs (RIPES) INH, Rifampin and Pyrazinamide are given together to all patients with pulmonary tuberculosis for the first 2 months, followed by INH and Rifampin for the next 4 months. 1. Isoniazid Bactericidal 2. Rifampin Bactericidal 3. Pyrazinamide Bactericidal 4. Ethambutol Bacteriostatic 5. Streptomycin Bactericidal

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Primary Drug Side Effects Isoniazid Hepatitis, Peripheral neuropathy ( Give Vit . B6 to prevent and Rx), seizures Anemia, Thrombocytopenia Rifampin Hepatitis, Flu like syndrome, Red-orange discoloration of body fluids Pyrazinamide Hepatitis, Hyperuricemia, Gout Hematologic toxicity Ethambutol Optic neuritis, color blindness , Gout , Hepatitis Streptomycin Nephrotoxicity, Ototoxicity Neuromuscular bloakade Hypomagnesemia

Mycobacterium avium-intracellulare complex (MAC): 

Mycobacterium avium-intracellulare complex (MAC) For prevention of MAC infection in HIV+ patients: Rifabutin, Azithromycin or Clarithromycin For treatment in any patient: Rifabutin, Ethambutol, Azithromycin, Clarithromycin, Ciprofloxacin. These all are used in various combinations

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Antimicrobials active against MAC For the prevention of MAC in HIV (+) patient For Treatment of MAC infection in any patient Rifabutin Rifabutin Ethambutol Azithromycin Clarithromycin Ciprofloxacin These drugs are used in various combination to treat MAC infection Azithromycin Clarithromycin

Second line drugs: 

Second line drugs These second line drugs are used for the treatment of MDR tuberculosis. When the Mycobacterium tuberculosis develops resistance to both, INH and Rifampin, it is labeled as Multidrug resistant (MDR) tuberculosis

Secondary drugs: 

Secondary drugs Amikacin: aminoglycoside Capreomycin: is a peptide. Protein synthesis inhibitor Cycloserine: cell wall synthesis inhibitor Ethionamide: analog of isoniazid Para-aminosalicylic acid: analog of PABA Ciprofloxacin and ofloxacin: Fluoroqionolones Linezolid

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Second Line drugs for MDR TB Amikacin Aminoglycoside Capreomycin is a peptide. Protein synthesis inhibitor Cycloserine D- alanine analog; cell wall synthesis inhibitor Ethionamide analog of isoniazid Para-aminosalicylic acid analog of PABA Ciprofloxacin/Ofloxacin Fluoroquinolones Linezolid

Ethionamide: 

Ethionamide Structural analog of isoniazid widely distributed in the body, extensively metabolized and excreted in urine Adverse effects: Intense gastric irritation Hepatotoxicity Peripheral neuropathy Severe postural hypotension Mental depression

Cycloserine: 

Cycloserine It is a Cell wall inhibitor It is structural analog of D-Alanine and inhibits the incorporation of D-Alanine in peptidoglycan pentapeptide. Adverse effects Somnolence Headache Tremors Vertigo Seizures

Leprosy: 

Leprosy Lepromatous leprosy Tubercular leprosy Borderline leprosy

PHARMACOTHERAPEUTICS OF TUBERCULOSIS: 

PHARMACOTHERAPEUTICS OF TUBERCULOSIS

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All TB regimens in use were 18 months or longer until the appearance of rifampicin. In 1953, the standard UK regimen was 3SPH/15PH or 3SPH/15SH 2 . Between 1965 and 1970, EMB replaced PAS. RMP began to be used to treat TB in 1968 and BTS study in the 1970s showed that 2HRE/7HR was efficacious. In 1984, a BTS study showed that 2HRZ/4HR was efficacious, with a relapse rate of less than 3% after two years. In 1995, with the recognition that INH resistance was increasing, the BTS recommended adding EMB or STM to the regimen: 2HREZ/4HR or 2SHRZ/4HR, which are the regimens currently recommended. The WHO also recommend a six-month continuation phase of HR if the patient is still culture positive after 2 months of treatment.

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