Tuberculosis by JITENDRA BHANGALE

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MYCOBACTERIUM, RECENT THERAPY FOR TB, DIFFERENT TYPES OF TB

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Tuberculosis by JITENDRA BHANGALE

  1. 1. 8/16/2012 By- Jitendra Bhangale Assistant Professor & Head, Department of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad 1 © 2010 Delmar, Cengage Learning“Tuberculosis is defined as an infectious disease caused by a bacterium; that most commonly affects the lungs.”It can also be a crippling and deadly disease, and is on the rise in both developed and developing worlds.Globally, it is the leading cause of deaths resulting from a single infectious disease. Currently, it kills “three million people” a year and could claim up to 30 million lives if not controlled. 2 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 1
  2. 2. 8/16/2012TB germs are passed through the air when a person who is sick with TB disease coughs, sings, sneezes, or laughsTo become infected with TB germs, a person usually needs to share air space with someone sick with TB disease (e.g., live, work, or play together)The amount of time, the environment, and how sick the person is all contribute to whether or not you get infectedIn most cases, your body is able to fight off the germs 3 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad Mycobacterium which is carried by humans.  Mycobacterium T.B. can present it self in the human body in different forms effecting any where from “the intestines, bones, joints, skin, and the genitourinary, lymphatic, and nervous systems.” 4 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 2
  3. 3. 8/16/2012 Avian which is carried by birdsTransmitted by ingestion and inhalation of aerosolized infectious organisms from feces. Oral ingestion of food and water contaminated with feces is the most common method of infection. Once ingested, the organism spreads throughout the birds body and is shed in large numbers in the feces.If the bacterium is inhaled, pulmonary lesions and skin invasions may occurTransmission of avian TB is from bird to human not from human to human. 5 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad Bovine tuberculosis is carried by cattle.People contract Bovine TB today,by eating food that has been contaminated by the bacteria or from drinking un-pasteurized milk from cows that are infected with the virus.Bovine TB is most likely going to effect the joints and bones. 6 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 3
  4. 4. 8/16/2012The primary stage of the disease may be symptom-free, or the individual may experience a flu-like illness. This is called the “inactive stage.”Within the active stage of the disease, there might be a slight fever, night sweats, weight loss, fatigue.The symptoms may vary depending on what type of tuberculosis you contract. 7 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badThis is an example of tuberculosis of the skin it is normally referred to as Warty T.B. and someone will only contract this type of tuberculosis if they have had prior exposure to tuberculosis. 8 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 4
  5. 5. 8/16/2012There is a difference between TB “infection” and TB “disease”TB infection: TB germs stay in your lungs, but they do not multiply or make you sick You cannot pass TB germs to othersTB disease: TB germs stay in your lungs or move toother parts of your body, multiply, and make you sick You can pass the TB germs to other people 9 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badTB infection is treated with medicine, usually for 4-9 months.If TB infection is not treated, it can turn into TB disease.It is important to take all your medicine, even though you don’t feel sick. 10 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 5
  6. 6. 8/16/2012TB disease is treated with medicine to kill the TB germs.Usually, the treatment will last for 6-9 months.TB disease can be cured if the medicine is taken as prescribed, even after you no longer feel sick. 11 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badFirst line: These drugs have high antitubercular efficacyas well as low toxicity; are used routinely.Second line: These drugs have either low antitubercularefficacy or high toxicity or both; are used in specialcircumstances only. 12 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 6
  7. 7. 8/16/2012 Second line agentFirst line agent Moxifloxacin Isoniazid Gatifloxacin Rifampin Ethionamide Aminosalicylic acid Ethambutol Cycloserine Streptomycin Amikacin Pyrazinamide Kanamycin Capreomycin 13 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badIsoniazid is the hydrazide of isonicotinic acid.Isoniazid is a prodrug; mycobacterial catalase-peroxidase converts isoniazid into an active metabolite.A primary action of isoniazid is to inhibit the biosynthesis of mycolic acids, branched lipids that are attached to a unique polysaccharide, arabino galactan, to form part of the mycobacterial cell wall.The mechanism of action of isoniazid is complex, with resistance mapping to mutations in at least five different genes (katG [coding for the catalase-peroxidase that activates the prodrug isoniazid], inhA, ahpC, kasA, and ndh). 14 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 7
  8. 8. 8/16/2012The preponderance of evidence points to inhA as the primary drug target. Indeed, the catalase-peroxidase-activated isoniazid, but not the prodrug, binds to the inhA gene product enoyl-ACP reductase of fatty acid synthase II, which converts D2-unsaturated fatty acids to saturated fatty acids in the mycolic acid biosynthetic pathway.Mutations of the katG gene that result in an inactive catalase-peroxidase cause high-level isoniazid resistance, since the prodrug cannot be activated by the catalase-peroxidase.Isoniazid also inhibits mycobacterial catalase-peroxidase (the isoniazid- activating enzyme), which may increase the likelihood of damage to the mycobacteria from reactive oxygen species and H2O2. 15 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badAdverse effect: Fever Jaundice Peripheral neuritis Hypersensitivity Skin eruptions Hepatitis Arthritic symptoms Convulsions 16 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 8
  9. 9. 8/16/2012The rifamycins (rifampin, rifabutin, rifapentine) are a group ofstructurally similar, complex macrocyclic antibiotics produced byStreptomyces mediterranei .Antibacterial Activity:- Rifampin inhibits the growth of mostgram-positive bacteria as well as many gram-negativemicroorganisms such as Escherichia coli, Pseudomonas, indole-positive and indole-negative Proteus, and Klebsiella. Rifampin is veryactive against Staphylococcus aureus and coagulase-negativestaphylococci. 17 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badMechanism of Action. Rifampin inhibits DNA-dependent RNApolymerase of mycobacteria and other microorganisms by forming astable drug-enzyme complex, leading to suppression of initiation ofchain formation in RNA synthesis.More specifically, the β subunit of this complex enzyme is the siteof action of the drug, although rifampin binds only to theholoenzyme. 18 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 9
  10. 10. 8/16/2012Nuclear RNA polymerases from a variety of eukaryotic cells do notbind rifampin, and RNA synthesis is correspondingly unaffected ineukaryotic cells.High concentrations of rifamycin antibiotics can inhibit RNAsynthesis in mammalian mitochondria, viral DNA-dependent RNApolymerases, and reverse transcriptases.Rifampin is bactericidal for both intracellular and extracellularmicroorganisms. 19 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badAdverse effect:- Hepatitis and deaths Chronic liver disease Alcoholism Respiratory syndrome Cutaneous syndrome Flu syndrome Abdominal syndrome 20 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 10
  11. 11. 8/16/2012Antibacetrial spectrum:- M. tuberculosis and M. kansasiiMechanism of action Ethambutol inhibits arabinosyl transferases involved in arabinogalactan synthesis and to intefere with mycolic acid incorporation in mycobacterial cell wall.Mechanism of resistance Bacterial resistance to the drug develops in vivo via single amino acid mutations in the embA gene when ethambutol is given in the absence of other effective agents. 21 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badAdverse effect:- Flu syndrome Abdominal syndrome Hyperuricemia 22 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 11
  12. 12. 8/16/2012It is the oldest aminoglycoside antibiotic obtained fromStreptomyces griseus.It is a narrow spectrum antibiotic that active against aerobic gram-negative bacilli Antibacterial spectrum H. dureyi E. coli Brucella H. influenzae Yersinia pestis V. cholerae Francisella tularensis Shigella Nocardia Klebsiella Calym. granulomatis enterococci M. tuberculosis 23 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad Streptomycin binds to the 30S ribosomal subunit and interferes with initiation of protein synthesis by fixing the 30S-50S ribosomal complex at the start codon (AUG) of mRNA. As 30S-50S complexes downstream complete translation of mRNA and detach, the abnormal initiation complexes, so- called streptomycin monosomes, accumulate, blocking further translation of the message. By Jitendra Bhangale 24 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 12
  13. 13. 8/16/2012 Streptomycin binding to the 30S subunit also causes misreading of mRNA, leading to B. premature termination of translation with detachment of the ribosomal complex and incompletely synthesized protein C. incorporation of incorrect amino acids (indicated by the X), resulting in the production of abnormal or nonfunctional proteins. By Jitendra Bhangale 25 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. PadaliaResistance microorganisms Notable bacilli that are not inhibited are E. coli, H. Influenzae Str. Pneumonine, Str. Pyogens, Staph. aureus 26 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 13
  14. 14. 8/16/2012Streptomycin is highly ionized.It is neither absorbed nor destroyed in the g.i.t.However, absorption from injection site in muscles is rapid.Adverese effect:- Vestibular disturbances, Hypersensitivity reactions are rare; rashes, eosinophilia, fever and exfoliative dermatitis 27 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badMechanism of action:- It inhibits mycolic acid synthesis, but by interacting with a different fatty acid synthase encoding gene.Mechanism of resistanace:- Resistance to pyrazinamide develops rapidly if it is usedalone, and is due to mutation in the pncA gene which encodes forthe enzyme generating the active metabolite of pyrazinamide.Adverse effect:- Hepatotoxicity, Hyperuricaemia, arthralgia, flushing, rashes, fever and loss of diabetes control. 28 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 14
  15. 15. 8/16/2012The C-8-methoxy-fluoroquinolones, such as gatifloxacin andmoxifloxacin are the most active agents.Mechanism of actionThe FQs inhibit the enzyme bacterial DNA topoisomerase IV,which nicks double-stranded DNA, introduces negative supercoilsand then reseals the nicked ends.This is necessary to prevent excessive positive supercoiling of the strands when they separate to permit replication or transcription.The DNA gyrase consists of two A and two B subunits: The A subunit carries out nicking of DNA, B subunit introduces negative supercoils and then A subunit reseals the strands. 29 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badFQs bind to A subunit with high affinity and interfere with its strand cutting and resealing function.Recent evidence indicates that in gram-positive bacteria the major target of FQ action is a similar enzyme topoisomerase IV which nicks and separates daughter DNA strands after DNA replication. 30 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 15
  16. 16. 8/16/2012Mechanism of ActionIn the manner of isoniazid, ethionamide is also an inactive prodrug that is activated by a mycobacterial redux system.EtaA, an NADPH-specific, FAD-containing monooxygenase, converts ethionamide to a sulfoxide, and thence to 2-ethyl-4-aminopyridine.Although these products are not toxic to mycobacteria, it is believed that a closely related and transient intermediate is the active antibiotic.Ethionamide inhibits mycobacterial growth by inhibiting the activity of theinhA gene product, the enoyl-ACP reductase of fatty acid synthase II.This is the same enzyme that activated isoniazid inhibits.Although the exact mechanisms of inhibition may differ, the results are the same: inhibition of mycolic acid biosynthesis and consequent impairment of cell-wall synthesis. 31 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad ParesthesiasAdverse effect Headache Anorexia Restlessness, Nausea and vomiting Tremors Gastric irritation allergic skin rashes Postural hypotension purpura, Mental depression Stomatitis Drowsiness Gynecomastia Olfactory disturbances Impotence Blurred vision Menorrhagia Diplopia Acne Dizziness Alopecia 32 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 16
  17. 17. 8/16/2012Aminosalicylic acid is bacteriostatic.Mechanism of ActionAminosalicylic acid is a structural analog of para-aminobenzoicacid, and its mechanism of action appears to be very similar to thatof the sulfonamides.The sulfonamides are ineffective against M. tuberculosis, andaminosalicylic acid is inactive against sulfonamide-susceptiblebacteria.This differential sensitivity presumably reflects differences in theenzymes responsible for folate biosynthesis in the variousmicroorganisms. 33 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badAdverse effect Gastrointestinal problems Anorexia Nausea Epigastric pain Abdominal distress Diarrhea Hematological abnormalities 34 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 17
  18. 18. 8/16/2012Cycloserine is a broad-spectrum antibiotic produced byStreptococcus orchidaceus.Mechanism of ActionCycloserine and D-alanine are structural analogs; thus, cycloserineinhibits reactions in which D-alanine is involved in bacterial cell-wall synthesis.The use of medium free of D-alanine reveals that the antibioticinhibits the growth in vitro of enterococci, E. coli, S. aureus, Nocardiaspecies, and Chlamydia. 35 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badAdverse effect:- Psychotic states Somnolence Paranoid reactions Headache Twitching Tremor Hyperreflexia Dysarthria Visual disturbances Vertigo Paresis Confusion Tonic-clonic or absence Nervousness seizures. Irritability 36 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 18
  19. 19. 8/16/2012Capreomycin is an antimycobacterial cyclic peptide elaborated by Streptococcus capreolus.It consists of 4 active components¾capreomycins IA, IB, IIA, and IIB.The agent used clinically contains primarily IA and IB.Capreomycin must be given intramuscularly.Adverse effect:-Hearing loss, tinnitus, transient proteinuria, cylindruria, nitrogen retention, leukocytosis, leukopenia, rashes, and fever 37 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad By Jitendra Bhangale 38 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 19

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