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Chemotherapy of Tuberculosis


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Chemotherapy of tuberculosis, Anti-TB Drugs, Anti-Tubercular Drugs, Tuberculosis, Chemistry of Anti-Tubercular Drugs

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Chemotherapy of Tuberculosis

  1. 1. CHEMOTHERAPY OF TUBERCULOSIS S.SEETARAM SWAMY, M.Pharm., Asst. professor, Dept. of Pharmaceutical Chemistry, Chilkur Balaji College of Pharmacy.
  3. 3. INTRODUCTION  Tuberculosis is a chronic granulomatous disease caused by Mycobacterium tuberculosis, which most commonly affects the lungs.  M. tuberculosis organisms are also called tubercle bacilli.  A major health problem in developing countries.  It is currently estimated that 1/2 of the world's population (3.1 billion) is infected with Mycobacterium tuberculosis.  Global Emergency Tuberculosis kills 5,000 people a day.  2.3 million die each year. A. PULMONARY TUBERCULOSIS B. AVIAN TUBERCULOSIS( MICROBACTERIUM AVIUM ;OF BIRDS) C. BOVINE TUBERCULOSIS(MYCOBACTERIUM BOVIS ;OF CATTLE) D. MILIARY TUBERCULOSIS / DISSEMINATED TUBERCULOSIS TYPES 3
  4. 4.  Mycobacterium tuberculosis  Highly aerobic  Gram positive  Non-motile rod  Infects lungs  Divides every 15-20 hours  Unable to be digested by microphages  Very resistant to many disinfectants, acid, alkali, drying, etc.  If not treated properly, TB can be fatal.  Contagious, spread through air by inhalation of airborne bacteria from infected person. 4
  5. 5. Tuberculosis (TB) is one of the most prevalent infections of human beings and contributes considerably to illness and death around the world. It is spread by inhaling tiny droplets of saliva from the coughs or sneezes of an infected person. It is a slowly spreading, chronic, granulomatous bacterial infection, characterized by gradual weight loss. In1882 , Robert Koch discovered a staining technique that allowed him to see the bacteria that cause TB under a microscope. Mycobacterium tuberculosis, the bacteria that causes tuberculosis. 5
  6. 6. TB germs are most commonly found in the lungs, but sometimes they can move to other parts of the body. Common Sites of TB Disease  Lungs  Pleura  Central nervous system  Liver and Spleen  Lymphatic system  Genitourinary systems  Bones and joints  Disseminated (miliary TB) 6
  7. 7. TB infection is caused by the same germs, but it’s less serious. People with TB infection are not sick because they have fewer of the germs in their body, and the germs are latent (sleeping). People with TB infection are not contagious. TB disease occurs when the TB germs are active in a person’s body in large numbers. People with TB disease usually feel sick, and have one or more symptoms of TB disease. They may be infectious, which means they can pass the TB bacteria on to others. If it’s not treated, TB disease can cause serious disability and even death. TB Infection vs. TB Disease Latent TB Infection Active TB Disease TB germs are “asleep” in the body. This phase can last for a very long time – even many years. TB germs are active and spreading. They are damaging tissue in body. Don’t look or feel sick. Chest x-ray is usually normal. Usually feel sick. Doctor will do special tests to find where TB is harming in body. TB infection cannot spread TB to other people. If the TB germs are in lungs, it can spread TB to other people by coughing, sneezing, talking. Usually treated by taking one medicine for 9 months. Treated by taking several TB medicines for at least 6 months. 7
  8. 8.  M. tuberculosis is carried in airborne particles, called droplet nuclei, of 1– 5 microns in diameter. M. tuberculosis is transmitted through the air, not by surface contact.  Its spread from person to person in tiny microscopic droplets. Depending on the environment, these tiny particles can remain suspended in the air for several hours.  M. tuberculosis may be expelled when an infectious person: MODE OF TRANSMISSION  Coughs  Sneezes  Speaks  Sings  laughs 8
  9. 9. The symptoms my vary depending on what type of tuberculosis you contract. Fever  Chills Night sweats Loss of appetite Weight loss and fatigue SIGNS AND SYMPTOMS 9
  10. 10. CAUSES TB is an airborne disease caused by the bacterium Mycobacterium tuberculosis (M. tuberculosis). Mycobacterium tuberculosis complex refers to a group of Mycobacterium species that can cause tuberculosis in humans. Easier to contract with weak immune system. 1. Mycobacterium bovis 2. Mycobacterium africanum 3. Mycobacterium microti 4. Mycobacterium caprae 5. Mycobacterium pinnipedii 6. Mycobacterium canetti 7. Mycobacterium mungi 10
  11. 11.  Drug-resistant strains of TB emerged when an antibiotic fails to kill all of the bacteria it targets.  Some TB bacteria have developed resistance to the most commonly used treatments, such as isoniazid and rifampin. DRUG –RESISTANT TB 11
  12. 12. 1. HIV test 2. Medical history 3. Physical examination 4. Bacteriologic or histologic exam (Chest radiograph if indicated) Evaluation for TB 12
  13. 13.  When someone comes into contact with tuberculosis or feels as if they become infected by tuberculosis, they should call a doctor and order a skin test.  The doctor will inject a small amount of tuberculin under the skin.  If a person has been exposed to tuberculosis a swelling will develop around the spot where the skin test is given. The most commonly used diagnostic tool for tuberculosis is Skin test A false +ve test may happen if you have been vaccinated recently with the Bacille Calmette Guerin (BCG). False –ve results may occur in certain population-including children, older people & with AIDS. Blood test This test use sophisticated technology to measure your immune system’s reaction to TB bacteria. Sputum test Chest X-ray shows signs of TB, your doctor may take sample of your sputum- the mucus that comes up when you cough TEST AND DIAGNOSIS 13
  14. 14. Most TB is curable, but…  Four or more drugs required for the simplest regimen.  6-9 or more months of treatment required.  Person must be isolated until non-infectious.  Directly observed therapy to assure adherence/completion recommended.  Side effects and toxicity common • May prolong treatment • May prolong infectiousness  Other medical and psychosocial conditions complicate therapy •TB may be more severe •Drug-drug interactions common TREATMENT 14
  15. 15. CLASSIFICATION OF ANTI-TB DRUGS BASED ON CHEMICAL MOIETY 1) Salicylic acid derivatives Para amino salicylic acid 2) Pyridine derivatives Isonicotinic acid hydrazide Ethionamide 3) Pyrazine derivatives Pyrazinamide 4) Ethylene Di-amino Butanol derivatives Ethambutol 5) Antibiotics Streptomycin Cycloserine Rifampicin Kanamycin 15
  16. 16. FIRST LINE DRUGS [Have high anti-tubercular efficacy as well as low toxicity] 1. Rifampicin (R) 2. Isoniazid (I) 3. Pyrazinamide (P) 4. Ethambutol (E) 5. Streptomycin (S) R I P E S SECOND LINE DRUGS [Either low anti-tubercular efficacy or high toxicity or Both] 1. Fluroquinolones (F) 2. Amikacin (A) 3. Cyclosporin (C) 4. Ethionamide (E) 5. Para-aminosalicylic acid (Pas) 6. Capreomycin (C) FACE PaC NEWER DRUGS 1. Ciprofloxacin 2. Ofloxacin 3. Clarithromycin 4. Azithromycin 5. Rifabutin COCA - R 16
  17. 17.  Refamycins are a group of macrocyclic antibiotics which are produced by Streptomyces mediterranei.  Eventually 7 rifamycins were developed they are Rifamycin A,B,C,D,E,S,SV.  Refampicin is a semi-synthetic rifamycin made from Rifamycin-B isolated from STREPTOMYCES MEDITERRANEI in 1957.  Among the various rifamycins, rifamycin-B was the first Commercial product. REFAMPICIN
  18. 18.  The first line antibiotic drug Rifampicin(RIF) interferes with RNA transcription in mycobacterium tuberculosis. RIF binds to the β-subunits of the DNA-dependent- RNA- Polymerase enzyme complex and inhibits transcription of messenger RNA (mRNA).  The m-RNA transcripts are essential requirements for protein synthesis.  So they are useful in treating tuberculosis, leprosy, Mycobacterium avium complex (MAC) infection and Staphylococcus infections. MECHANISIM OF ACTION 18
  19. 19. Hepatotoxic - hepatitis, liver failure in severe cases Respiratory – breathlessness Abdominal - nausea, vomiting, abdominal cramps. Flu-like symptoms - with chills, fever, headache. Certain bodily fluids, such as urine and tears, to become orange-red in color. ADVERSE EFFECTES Dose- 10mg/kg >50kg- 600mg
  20. 20.  Refampicin is used as a first line drug in the treatment of tuberculosis. As most of the tubercle bacilli develop resistance to Refampicin. It is used in combination with other anti-tubercular drugs in the MULTIPLE DRUG THERAPY to minimize the problem.  It is also used the treatment of leprosy.  Infection like endocarditis (inflammation of membrane lining the heart.)  Oesteomyelitis(inflammation of bone)  It is used in the first-line therapy of brucellosis in combination with doxycline.  It is also an excellent drug for Pneumonia.  It is also used in combination with dapsone in Treating leprosy. THERAPEUTIC USES 20
  21. 21. - It is tuberculocidal - Structural similarity to Pyridoxine. - First line medication in prevention and treatment of tuberculosis. - Isoniazid is available in tablet, syrup and injectable forms (given I.M or I.V.) -Bacteriostatic at low conc. & bactericidal at high conc. - Especially against actively growing bacteria. MOA Inhibits the biosynthesis of mycolic acids, which are essential constituents of the mycobacterial cell wall. DOSE 5mg/kg > 50 kg- 300mg/kg ISONIAZID (INH) (ISONICOTINIC ACID HYDRAZIDE (H) 21
  22. 22. 1) Hepatitis - loss of appetite, nausea, vomiting, jaundice, and right upper quadrant pain. 2) Peripheral neuropathy (deficiency of pyridoxine ). 3) Fever 4) Skin rashes 5) Arthralgia 6) GI disturbances 7) Psychosis 8) optic neuritis and rarely convulsions ADVERSE EFFECTS 22
  23. 23. Isoniazid is manufactured from isonicotinic acid, which is produced from 4- methyl pyridine. N CH3 Oxidation 4-methyl pyridine N C OHO N C NHNH2O Isoniazide H2N NH2 Hydrazine -H2O SYNTHESIS OF ISONIAZID 23
  24. 24.  Chemically similar to INH.  It is weakly tuberculocidal.  More active in acidic medium.  It is a prodrug and converted into pyrazinoic acid in the body. MOA: It inhibits mycolic acid synthesis, but by interacting with A different fatty acid synthase encoding gene. DOSE: 25mg/kg >50 kg- 1500mg ADVERSE EFFECTS: 1) Hepatotoxicity- major adverse effect. 2) Nausea 3) Vomiting 4) Fever 5) Hyperuricemia PYRAZINAMIDE (PZA) 24
  25. 25. -Tuberculostatic MOA: Inhibits arabinosyl transferases that are involved in mycobacterial cell wall synthesis (It disrupts arabinogalactan synthesis by inhibiting the enzyme arabinosyl transferase). DOSE: 15mg/kg >50 kg- 1000 mg ADVERSE EFFECTS: A) Optic neuritis: red -green color blindness B) Hyperuricaemia C) Skin rashes & joint pain ETHAMBUTOL 25
  26. 26. CH3CH2CH NO2 CH2OH Reduction CH3CH2CH NH2 CH2OH 2-Nitro-1-butanol 2-amino butanol CH3CH2CH NH2 CH2OH (2 moles) ClCH2CH2Cl ethylene dichloride -2HCl CH3CH2CH H N CH2OH H2 C Ethambutol H2 C CHCH2CH3 CH2OH 26
  27. 27. STREPTOMYCIN  Tuberculocidal  It was the first effective drug developed for the treatment of tuberculosis.  Streptomycin is the first aminoglycoside antibiotic which was isolated from the actinomycetes bacteria STREPTOMYCES GRISEUS and several related soil microorganisms.  Streptomycin was first discovered in 1943 by SELMAN ABRAHAM WAKESMAN and received a Nobel prize in 1952. It was introduced primarily for the treatment of tuberculosis.  Dose is reduced to 750mg in patients above 50 yr age 500 mg in above 65 yr age.
  28. 28.  Streptomycin is made up of 3 basic structural units called… 1. Streptidine(a diguanidino compound) 2. Streptose (a aldose sugar) 3. N-methyl-L-glucosamine. O H OH H H CH2OH HOH NHCH3 O OH CHO CH3 H OH H H NH.C.NH2 H H OHH OH HNH.C.NH2 H OH O NH NH N-methyl-L-glucosamine Streptose Streptidine
  29. 29. Aminoglycosides binds to specific 30S – 50S subunit ribosomal proteins. Protein synthesis is inhibited by them in at least three ways: 1.They Block the formation of initiation 70S ribosomal mRNA complex 2.They induce misreading of the code on the mRNA template Causes incorporation of incorrect amino acids into peptide resulting in a nonfunctional or abnormal protein synthesis. 3.Inhibit translocation 29 MECHANISM OF ACTION
  30. 30. A. Ototoxicity  Auditory (Loss of hearing) or vestibular damage(dizziness, vertigo) or both.  Neomycin, kanamycin, and amikacin are the most ototoxic drugs, Streptomycin and gentamicin are the most vestibulo toxic. B. Nephrotoxicity  Aminoglycosides are mainly excreted by glomerular filtration and can be stored up in kidney. It can cause acute renal insufficiency and tubular necrosis.  Neomycin is the most nephrotoxic drug, streptomycin is the least one. C. Neuromuscular blockade D. Skin reactions (Hypersensitivity reactions)  Skin rash, fever, eosinophilia and anaphylactic shock. 30 TOXICITY
  31. 31.  Multiple-drug therapy to treat TB means taking several different antitubercular drugs at the same time.  Drugs are combined to: 1) Delay the development of resistance 2) Reduce toxicity 3) Shorten the course of treatment Most species of bacteria develop resistance to Refampicin.  Use of single drug Refampicin for tuberculosis will not be effective.  That’s why it is used in combination with other anti-tubercular drugs in multidrug therapy.  Drugs used most commonly to treat TB include… Refampicin Isoniazid Pyrazinamide Ethambutol MULTI DRUG THERAPY (MDT)
  32. 32. Two phases of drug therapy are generally used:  Initial phase: In this phase 3 drugs namely Refampicin, isoniazid, Pyrazinamide are used. some times ethambutol drug is used . All these drugs used for 2 months. (e.g: AKT4)  Continuation phase:-Two drugs i.e. Refampicin and isoniazid are to be used for a time period of the next 4months. (e.g: R-Cinex-600) 32
  33. 33. Isolation Ventilate the room Cover the mouth Wear mask Finish entire course of medication vaccinations PREVENTION 33
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  38. 38. World TB day is March 24. This annual event commemorates the date in 1882 when Dr. Robert Koch announced his discovery mycobacterium tuberculosis, the bacteria that cause tuberculosis. HELP PREVENT SPREAD OF TB 38
  39. 39. THANK YOU 39
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