Antitubercular and Antileprotic Agents PDF

Antitubercular And Antileprotic agents: 1 KESHAV 9/19/2024  Tuberculosis 2  Tuberculosis (TB) is an infectious disease caused by the bacte...

Antitubercular And Antileprotic agents: 1 KESHAV 9/19/2024  Tuberculosis 2  Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis (MTB) transmitted among humans which infects macrophages in the lungs.  Tuberculosis generally affects the lungs, but can also affect other parts of the body. Most infections do not have symptoms, known as latent tuberculosis.  About 10% of latent infections progress to active disease which, if left untreated, kills about half of those infected.  If properly treated, tuberculosis caused by drug-susceptible strains is curable in virtually all cases. KESHAV 9/19/2024   Transmission usually takes place through the airborne spread of droplet nuclei produced by patients 3 with infectious pulmonary tuberculosis  This organism usually attacks or affects almost any tissue and lungs, but can also affect the CNS (meningitis), Circulatory system, Genitourinary system, Bone joints.  In 2014, there were 9.6 million cases of active TB which resulted in 1.5 million deaths. More than 95% of deaths occurred in developing countries. KESHAV 9/19/2024  Mycobatcerium tuberculosis 4  It is non motile, acid fast, slow growing, aerobic bacillus, unusual cell wall.  They are weakly Gram-positive bacilli.  The cell wall has high lipid content which shows higher degree of hydrophobicity, resistant to alcohol, acid, alkali, and some disinfectants.  M. tuberculosis is difficult to stain. The structure and function of cell enevlope of M.tuberculosis relies in mycobacterium pathogeneicity, virulence, cell permeability, immunoreactivity, multiple drug resistance. KESHAV 9/19/2024  5 KESHAV 9/19/2024  6 KESHAV 9/19/2024  Tuberculosis Treatment 7  Anti-tubercular drugs are the agents which are used in treatment of tuberculosis.  Because administered of a single drug often leads to the development of a bacterial population resistant to the drug.  Effective treatment of TB must contain multiple drugs to which the organisms are susceptible KESHAV 9/19/2024  Classification 8 Anti-tubercular drugs are classified on the basis of efficacy and safety clinical utility. First-line drugs are those which exhibit high efficacy and less toxicity All first-line anti-tubercular “drug names” have a standard three-letter and a single-letter abbreviation.  Ethambutol is EMB or E,  Isoniazid is INH or H,  Pyrazinamide is PZA or Z,  Rifampicin is RMP or R,  Streptomycin is STM or S.  streptomycin is no longer considered a first line drug because of high rates of resistance KESHAV 9/19/2024  9  Second Line drugs-are found to be more toxic and certain resistance problems.  The second line drugs are only used to treat disease that is resistant to first line therapy (i.e., for extensively drug-resistant tuberculosis (XDR-TB) or multidrug-resistant tuberculosis (MDR-TB)).  Aminoglycosides e.g., amikacin (AMK), kanamycin (KM);  Polypeptides e.g., capreomycin, viomycin, enviomycin;  Fluoroquinolones e.g., ciprofloxacin (CIP), levofloxacin, moxifloxacin (MXF);  thioamides e.g. ethionamide, prothionamide  Cycloserine terizidone (the only antibiotic in its class) KESHAV 9/19/2024  Amino salicylic acid 10  Properties and Use :  It is bacteriostatic and highly specific to M. tuberculosis.  Side effects are anorexia, nausea, epigastric pain, diarrhoea.  It is structurally similar to p-amino benzoic acid (PABA) and the sulfonamides, hence the synthesis of folates in MT.  It is inferior to isoniazid and streptomycin. It is nephrotoxic and hepatotoxic. KESHAV 9/19/2024  11  It is a synthetic 2nd line agent, used in case of resistance, re-treatment and intolerance of first line therapy, used in treatment of Tuberculosis.  It is used in combination with streptomycin and INH and in long term treatment (6-9 months) cause toxic effects on GIT and showed allergic reactions. KESHAV 9/19/2024  Mechanism of action 12  There are two mechanisms responsible for bacteriostatic action against Mycobacterium tuberculosis.  Firstly, para- amino Salicylic inhibits folic acid synthesis. It binds to pteridine synthetase with greater affinity than PABA, effectively inhibiting the synthesis of folic acid.  Secondly, p-aminosalicylic acid may inhibit the synthesis of the cell wall component, mycobactin, thus reducing iron uptake by M.tuberculosis. KESHAV 9/19/2024  Synthesis of Aminosalicylic acid 13 P-Aminosalicylic acid is synthesized in a Koble reaction, which consists of direct interaction of m- aminophenol with potassium bicarbonate and carbon dioxide while heating at a moderate pressure of 5- 10 atom. KESHAV 9/19/2024  Isoniazid (Isonicotinic Acid Hydrazide) 14 KESHAV 9/19/2024  15  Isonicitinic acid hydrazine (INH) is a first –line synthetic anti-tubercular drug. Also known as Isoniazid, INH, Isonicotinohydrazine (Nydrazid, Lanizid).  It is a very simple derivative of pyridine.  It can be used alone or in combination with Refampicin is preferred to prevent development of bacterial resistance and to avoid high dose of isoniazid. KESHAV 9/19/2024  Properties and Use 16  Isoniazid is odorless, and occurs as a white crystalline powder or colourless crystals.  It is freely soluble in water, sparingly soluble in alcohol, and slightly soluble in chloroform and in ether.  Isoniazid is used as an antituberculosis drug. KESHAV 9/19/2024  Mechanism of action 17  Isoniazid is a prodrug that is activated on the surface of M. tuberculosis by KatG enzyme to isonicotinic acid. Isonicotinic acid inhibits the bacterial cell wall mycolic acid, there by making M. tuberculosis susceptible to reactive oxygen radicals.  Isoniazid may be bacteriostatic or bactericidal in action, depending on the concentration of drug attained at the site of infection and susceptibility of the infecting organism.  The drug is active against susceptible bacteria only during bacterial cell division. KESHAV 9/19/2024  18 KESHAV 9/19/2024  Uses 19  Mycobacterial infections  Latent tuberculosis  Prophyalxis against active TB in individuals who are in great risk as very young or immunocomprised individuals. KESHAV 9/19/2024  20 KESHAV 9/19/2024  21 KESHAV 9/19/2024  Properties and Use 22  It’s a white crystalline powder, soluble in water and alcohol.  It is not recommended for use as a single drug but used in combination with other antitubercular drugs in the chemotherapy of pulmonary tuberculosis.  Structurally, it possesses aliphatic diamine and two butanol moieties.  Due to its efficacy and less adverse effects, it is a first line bacteriostatic antimycobacterial drug. KESHAV 9/19/2024  MOA of Ethambutol 23  It is a bacteriostatic drug that targets Arabinosyl transferase and inhibits the polymerization of Arabinogalactan. Hence it inhibits the synthesis of Mycobacterial cell wall. KESHAV 9/19/2024  Pyrazinamide 24 Properties and use : It contains pyrazine ring in its structure, which is a six member heterocyclic ring containing two nitrogen at a distance of 2 carbon atoms. Pyrazinamide has amide group at position 2. It is white crystalline powder, sparingly soluble in water, slightly soluble in alcohol and in methylene chloride. It is the first line antituberculosis drug and is used for the initial treatment in conjunction with INH and RIF. It is used in the treatment of tuberculosis and meningitis. 9/19/2024  MOA 25  Pyrazinamide is a prodrug and is activated by M. tuberculosis amidase enzyme into pyrazine carboxylic acid, which has bactericidal activity. KESHAV 9/19/2024  Ethionamide 26 Properties and Use Ethionamide is yellow crystalline powder or crystals, practically in soluble in water, soluble in methanol and sparingly soluble in alcohol. It is used as antitubercular drug.  Ethionamide is only indicated as a second-line antimycobacterial drug when resistance to or toxicity from first- Isoniazid line drugs has developed. Ethionamide KESHAV 9/19/2024  Mechanism of action 27  It inhibits the synthesis of mycolic acid , the major component of cell wall of bacteria.  It is bacteriostatic against metabolically active M.tuberculosis. KESHAV 9/19/2024  Clofazimine 28  Properties and Use:  Clofazimine is a reddish- brown fine powder, practically insoluble in water, soluble in methylene chloride and very slightly soluble in ethanol.  It is used as antileprotic drug. N,5-bis(4-chlorophenyl)-3- (propan-2-ylimino)-3,5- dihydrophenazin-2-amine KESHAV 9/19/2024  29  It is used in combination with other drugs for leprosy and infections caused by Mycobacterium avium particularly in AIDS patient.  MOA: Clofazimine works by binding to the guanine bases of bacterial DNA, thereby blocking the template function of the DNA and inhibiting bacterial proliferation.  It also increases activity of bacterial phospholipase A2, leading to release and accumulation of lysophospholipids, which are toxic and inhibit bacterial proliferation KESHAV 9/19/2024  30  The mechanisms of its action remains unclear, it may involve in DNA binding and may interfere with template function of DNA.  Clofazimine increases prostaglandin synthesis and the generation of antimicrobial reactive oxidants from neutrophils, which may play a role in the antileprosy effects.  The host cell defense may be stimulated by clofazimine, resulting in the generation of oxidants, such as the super oxide anion, which in turn could have a lethal effect of the organism. KESHAV 9/19/2024  31  Clofazimine, a lipophilic iminophenazine antibiotic, possesses both antimycobacterial and anti-inflammatory activities.  Lipophilicity enables clofazimine to accumulate in skin and nerves, while its anti-inflammatory activities are potentially useful in controlling harmful leprosum and reversal immunity reactions.  However, its efficacy has been demonstrated only in the treatment of leprosy, not in human tuberculosis KESHAV 9/19/2024  Dapsone 32 4-[(4-aminobenzene)sulfonyl]aniline Properties and Use:  It is a white or creamy white, odourless, slightly bitter crystalline, sparingly soluble in alcohol, very slightly soluble in water.  most widely used sulfones.  It is folic acid synthesis inhibitor used in both lepromatous and tuberculoids leprosy.  also known as diaminodiphenyl sulfone (DDS).  is an antibiotic commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. KESHAV 9/19/2024  MOA of Dapsone 33  Dapsone is chemically related to sulfonamides and has the same mechanism of action.  PABA (P amino benzoic acid) Folate synthase  DHFA (Dihydro Folic acid) Dihydrofolate reductase THFA KESHAV 9/19/2024  34 Dapsone KESHAV 9/19/2024  Synthesis of Dapsone 35 KESHAV 9/19/2024  36 Anitubercular Antibiotics  Cycloserine,  Viomycin sulphate,  Capromycin sulphate,  Rifampicin KESHAV 9/19/2024  Cycloserine 37  Is an antibiotic effective against 3 M.tuberculosis. 2 4  It is analogue of an amino acid derivative (serine) with an unusual structure. It exist 1 in cyclic form –a five member ring containing O and N at an adjacent 4-amino-3-isoxazolidinone positions.  Also called isoxazolidine or oxazolidine.  It is classified as a second line drug, i.e, its use only considered if one or more first line drugs can not be used. KESHAV 9/19/2024  Properties and Use 38  Cycloserine is a white crystalline powder, freely soluble in water, slightly soluble in alcohol.  It is used to treat tuberculosis and certain urinary tract infections. KESHAV 9/19/2024  MOA 39  As a cyclic analogue of D-alanine, cycloserine acts against two crucial enzymes important in the cytosolic stages of peptidoglycan synthesis: alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl).  The first enzyme is a pyridoxal 5'-phosphate-dependent enzyme which converts the L-alanine to the D-alanine form. The second enzyme is involved in joining two of these D-alanine residues together by catalyzing the formation of the ATP-dependent D-alanine-D-alanine dipeptide bond between the resulting D-alanine molecules.  If both of these enzymes are inhibited, then D-alanine residues cannot form and previously formed D-alanine molecules cannot be joined together.  This effectively leads to inhibition of peptidoglycan synthesis. KESHAV 9/19/2024  Viomycin sulphate 40  Viomycin is a member of the tuberactinomycin family, a group of nonribosomal peptide antibiotics exhibiting anti- tuberculosis properties.  It is avaible as white powder, soluble in water, insoluble in organic (S)-3,6-Diamino-N-((3S,9S,12S,15S,Z)- solvents like ethanol, ether, and ((2R,4S)-6-amino-4-hydroxy-1,2,3,4- acetone. tetrahydropyridin-2-yl)-9,12- bis(hydroxymethyl)2,5,8,11,14-pentaoxo-6-  The tuberactinomycin family is used (ureidomethylene)-1,4,7,10,13- pentaazacyclohexadecan-15-yl)hexanamide to fight infections of Mycobacterium tuberculosis. KESHAV 9/19/2024  MOA 41  It acts by inhibiting protein synthesis in bacterial cells. Specially it binds to the ribosomal RNA, interfering with peptide chain formation, which is critical for bacterial survival and reproduction. KESHAV 9/19/2024  Capreomycin sulphate 42  It is commonly grouped with the aminoglycosides. It is a cyclic peptide.  Capreomycin is a antibiotic which is given in combination with other antibiotics for MDR-tuberculosis.  Capreomycin is administered intramuscularly and shows bacteriostatic activity.  Capreomycin is frequently used to treat Mycobacterium tuberculosis infections.  Mycobacterium tuberculosis growth has been found to be inhibited at a concentration of 2.5 μg/mL KESHAV 9/19/2024  Properties and use of Capreomycin 43  It is available as white or off white powder.  It is used to treat multi drug resistant form of tuberculosis(Mycobacterium tuberculosis)  MOA:  Capreomycin inhibits protein synthesis in bacteria by binding to the 70s ribosomal unit, thereby interfering with the formation of the bacterial cell wall. KESHAV 9/19/2024  Rifampicin 44 Refmapicins are a group of macrolycic antibiotics. KESHAV 9/19/2024  Properties and Use 45  Rifampicin is a reddish- brown crystalline powder, slightly soluble in water, soluble in methanol.  Rifampicin contain a flat napthalene ring which is attached to a 5 member heterocyclic moiety called furan.  It also has a large aliphatic chain attached at two non adjacent positions of napathalene ring.  Are useful in treating tuberculosis, leprosy and staphylococcus infections.  It is only used in combination with other antitubercular drugs, and it is ordinarily not recommended for the treatment of other bacterial infections when alternative antibacterial agents are available.  It is also used in combination with dapsone in treating leprosy. KESHAV 9/19/2024  Mechanism of Rifampin 46  Rifampin is bactericidal and inhibits Gm +ve bacteria and works by binding non- covalently to DNA-dependent RNA polymerase and inhibiting the start of RNA synthesis.  Rifampicin binds to the Beta subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis and finally inhibit protein synthesis. KESHAV 9/19/2024  47 THANK YOU KESHAV 9/19/2024