5.Antitubercular Agents.pptx bdfjdkkwkdj

Erthjiiokkjhhhjjjjbbjjjhggvvbnbvvbb vvhgcvghhhgff v bbnnbvvbbnnbvvcghnnnvvgggffffffffttttftghjiihg do FYI k in no hgiigjti d ji3uufjfjwjwdjjrekdjjffjkejfjejrjjfjejdijfjfjrjejrrjjrjfjdueudufururufurjeurufurueufuudueurufuuejrurufjrjejejfjfhfhfjejejdjfjdjejejdjfjejejdjdjejejddjfjjeejjddjjeiwudjdfjjeidjfhfhfiwidjfdjjwjejdjfjdjdfjjriedifjrjierjjfjejrfjjrjrkeidfjhfjeieifjfjejfjfjfjejrjfhfhfjejdhfhfjrjdjrieiefjjrjejruffudjfhueurfhfhfhfhdhjfjeiejfjfjfiejrfjfjfjjeejjrieirfjjfjskqkdjcjskskfjfjfieoeowodjfjfjejkwxjjcjsjsjwjdjsjjwksjfjfjfjdkwoworojfjfndjskwkqkqkdjcjjcjfjdkwiwkwkwjdjdjdkwodjcjdjwkeieiidideiifjfjwjjdjfieifjjfjdi3itjtiwiierjieowirkrjrjjejrkeiwnfjfjto3orjfjfnndkskwkdkdkekdkjfjdkekdjfkejfjfjrkrkfkrkkrkfjrjjfcjxhxhjzjxjcjcjskxjfjxjjjzjfgjjsowkfkvowoofkfkskdkjfkdkdkfkkdkfkdkekdkdkdkdkdkdkdkwkkcufireoowjftjrjjekdkfieowjdjfuriejejdjjfiekkdkfuejjwjfjrjjekwjrieiiejfrjrbbdjekwjfjjekwjejejrjrjjeeiieieijejtjfowirkfkjfjekdkdkkdkfkfkrkfkfkkrkrjfjrjrjfjtjtjtjtieifktjfkrjekfkkrkekrkrjdjdjdjdjrjjrjdjdjdjdjrjrjejfjffjjdjdejjejrjrjejejrjrjejejrjrjwkdkrieoeifirieoeoroeoo2irjrjfjfjrjeejudnojsjejekejejjjjjwkwkwoghjjekeowofjjfjwjwjjdjfjsjajjdjfjjejdjfjjsjdjfjnd. F. Djfjfjkekekfjf. Fjieofhrhjrid brieowofjjfjrifidirjriufjejejdjdjejwjebdj. Rjjfriieifjrfjjejjrjfjfjfjfjejjfjfjjejfjfjrirjfjfjfjfjfjeieirjfufieirifjjeifjeiwiidurieidiifufjfjfriruruurjejejfjrjkeieiifiririieiririiriririirieiririrejjwjrkekkrkekkwkrkekkwkefkjdjdjfjdjsjskwiwiieidiwidjeiwififjejejjdjdjeidididieididiieieididididididiidieiwijrjfjdjjdjejejjdjejjejdjeiiwjdjdhvieo2o4oturuu2jrjfjfjririeifjfidififjrjfjruejiwjfjrjejdjfugirieiwiririieiririfufjeieifurueurueieriiriri2ofiufjdiwjwje r fbjwfjgjirujju9ieriwifi4o2iebbj22ke. 2kriekirjeiirhjejrijeirieii2fifjieowoeodioriri2i2iriiriwifoitjjejjwjrjt bjjiijjjrjrjjejwkjrkkekkrkjejkw. Rkkrkekwkkrkdkkkdkekkwkrjkwkkrjjwkkrjdjjjjjkekdjekkwkkdjjejjdfiiirjjdjdjjejrjjejjrjjejjrjjkkwkrjjfjjriieieiirjrjeiijjrjrjejjrjrjrjuieieirkrjjrjjrjjtieijrjrjjejrjrjjejrjrjkejrjjrjjejejrjejjrjrjekjejrjejjejrjrjjejrjrieifjfhehrhrjdiieirjjfj3jirofotoro3tuufuer . Rjririieirifjjrjejrjhfjrjjrjfjjejjfjejjfjeiiriekirifjfbjekeoroo3i4ititiekirrki3iritji5ieiriri4ii4j3jjeiriririririiriririttjjdjeje. Rjrkrk3ktjffnndjdkw3ii55ijrrjrjjtjrjekjffjjr4j. Rkkfkrkekfkkrkekririejfhtjrb3j2kjfb43kkeejj3jrjrjrjtjtjfjtjrjrjjfjrjjrjejrjfjfjrjrjfjjrjfjjrjjeirjfjjrtnntkffkkekrjfjrkrofkekfiiriek3khfgjjtkeifkkfkrifjrjfjjrjeirirkeifijfjekdieidjfbt r 2oeojttjjrjfjrjfkro3ofutujejejfjfjdjekekfkrjfjjejfjfjejfijfjfjfjfjfjeifjgjjgjrjfjekdjfjjtjfjfjjtjkrkfkjtjfjfjjeejotroeooeorortjtjekjrjtjtjejdjfjfjkrkekwiekfjfjtirirjfjfjfkekejfjtjrkfjrjjrjrjfhfhjrjjffjjdjejdjfkwowkftjirii3i4ififjejsnnffjjejrtjjejsjfjtjejdfjjswk2ooefojfjfjekdj3jjdjrjrjjfjfififiriiriririfgu4ifufurufh3h3ruuueururu3ururururururuurufjrkerofj4jirjfjdkejfjfjrjfjrjjejrjrjfuti4i4irjbbbbbd. Rrr t r. Rt 4 t t bjriiririfiroeoitjtjriieieitiriritirieiiittiitiei3i3ittijtirieiiriririirjrieiieieieirjtjejrjrjrieirijtiri33iriirieeiiririro3eoirrirjrjjrejtjrjkrjr

1. Antimycobacterial Agents 1 Antitubercular Agents Antileprotic Agents

2. INTRODUCTION Tuberculosis is the most prevalent infectious disease worldwide and a leading killer caused by a single infectious agent, that is,  Mycobacterium tuberculosis . According to WHO report,  M. tuberculosis,  currently infects over 2 billion people worldwide, with 30 million new cases reported every year. This intracellular infection accounts for at least 3 million deaths annually. Common infection sites of the tuberculosis are lungs (primary site), brain, bone, liver, and kidney. The main symptoms are cough, tachycardia, cyanosis, and respiratory failure.

3. Antitubercular Agents Drugs used in the treatment of tuberculosis can be divided into two major categories 1 .  First-line drugs (Standard Drugs): Isoniazid , streptomycin , rifampicin , ethambutol , and pyrazinamide . 2. Second-line drugs (Reserved Drugs): Ethionamide ,  p -amino salicylic acid, ofloxacin , ciprofloxacin , cycloserine , amikacin , kanamycin , viomycin , and capreomycin .

4. The majority of the patients with TB are treated with first -line drugs and shows excellent results with a 6-month course of treatment . For the first 2 months, isoniazid , rifampicin , and pyrazinamide are given, followed by isoniazid and rifampicin for the remaining 4 months. Second-line drugs are used mainly to treat multidrug resistant  M. tuberculosis (MDR-TB)   infections.

5. A. Standard drugs Isoniazid (INH) It is the most active drug for the treatment of TB It is a prodrug that is activated on the surface of  M. tuberculosis  by katG enzyme to isonicotinic acid A number of structural analogues of INH were synthesized but their activity was lower than the parent compound

6. MoA:- Isoniazid has bacteriostatic and bactericidal activity in vitro against M. tuberculosis and also against strains resistant to other antimycobacterial drugs

7. 2. Pyrazinamide It is a prodrug and is activated by  M. tuberculosis  amidase enzyme into pyrazine carboxylic acid, which has bactericidal activity MoA: Unknown

8. 3. Streptomycin It belongs to the family of aminoglycoside antibiotics Mechanism of Action Inhibit protein synthesis by binding to the 30s ribosomal subunit

9. 4. Ethambutol Chemically N,N’-bis -(1-hydroxy-2 butyl) ethylenediamine Mechanism of Action Not clear but believed to be inhibit the incorporation of mycolic acid in to the bacterial cell wall

10. 5. Rifampin Is a semi-synthetic agent which is derived from rifamycin B, an antibiotic that was originally isolated from Streptomyces mediterranei Rifampin acts by inhibiting the bacterial DNA-dependent RNA polymerase, probably by chelating one of the two zinc atoms required for the activity of this metalloprotease

11. B. Reserve drugs Agents such as ethionamide , p- aminosalisylic acid, cycloserine , capreomycin and kanamycin are considered second-line agents for the treatment of tuberculosis They are usually less well tolerated or have more dramatic side effects than the first line agents They are used for resistant strains, or when first line agents must be discontinued

12. i . Ethionamide A synthetic nicotinamide analogue that may act by inhibiting the incorporation of cysteine and methionine into proteins MoA:  The antimycobacterial action of ethionamide seems to be due to an inhibitory effect on the mycolic acid synthesis.

13. ii. p- Aminosalicylic acid - This agent was once quite popular, until significant resistance to the drug developed. -It interferes with the incorporation of p- aminobenzoic acid into folic acid

14. iii. Cycloserine - this natural product was isolated from Streptomyces orchidaceus as the D-isomer. Interestingly, the L-isomer is also active, and the racemic mixture is more potent than either isomer

15. Antileprotic agents Leprosy is a chronic disease caused due to acid-fast bacillus called  Mycobacterium leprae   and produces nodules on the skin and causes loss of sensation . Once the organism enters into the body, it multiplies and produces antigen–antibody reaction and causes cell-mediated immunity, and produces allergic reaction by the metabolite of the microorganism and finally produces lepra reaction.

16. CLASSIFICATION Antileprotic drugs are classified into the following: I.  Sulphones Sulfones are bacteriostatic and are used only in the treatment of leprosy. Dapsone is the most widely used sulfone for the long-term therapy of leprosy.

17. II.  Benzpyrazine derivatives: Clofazimine is a weakly bactericidal dye that has some activity against M. leprae . It is given to treat sulfone -resistant leprosy or to patients who are intolerant to sulfones . 18

18. Anthelminthic Drugs

19. Antihelminthic Drugs Helminthes are parasitic worms, which infect an estimated 2 billion people worldwide, nearly all in poor developing tropical or semitropical countries Anthelmintics are drugs used to treat parasitic infections due to worms. Worms that are pathogenic to human beings, namely, metazoa are conventionally classified into R ound worms (nematodes ) Trematodes ) and T apeworms ( cestodes ). Anthelmintics act locally either to expel the worms from the gastrointestinal tract or systemically to eradicate the species 20

20. There are only about a dozen or so safe and effective drugs for treating helminth infections, but fortunately many of these are very effective and inexpensive Drugs used 1.Benzimidazoles 2. Praziquantel 3. Pyrantel 4. Piperazine 5. Diethyl Carbamazine Citrate 6. Niclosamide 7. Ivermectin 21

21. 1. Benzimidazoles There are three benzimidazoles that are most commonly used, mebendazole , albendazole and thiabendazole 22 Mebendazole A lbendazole T hiabendazole

22. The first to be introduced in to the market was thiabendazole which had shown broad spectrum activity against a variety of nematodes infecting the gastrointestinal tract This was followed by the discovery and introduction of the benzimidazole carbamates ; mebendazole , albendazole and others Mebendazole and the more recently developed albendazole are widely effective against both intestinal nematodes and most tissue nematodes 23

23. MoA of Benzimidazole Anthelmintics Inhibit the formation of microtubules through binding to beta- tubulin monomers and preventing polymerization Selectivity for parasite toxicity over host toxicity is caused by tighter binding to the parasite tubulin When taken orally, thiabendazole is rapidly absorbed and extensively metabolized by the liver 24

24. 2. Praziquantel Praziquantel is a widely employed anthelmintic initially found to be active against schistosomiasis and subsequently found to widely effective against a variety of trematodes and cestodes Both safe and effective, praziquantel is the drug of choice for treating all forms of schistosomiasis 25

25. Mechanisms of action There are more than one mechanisms of action for PZQ In cases of Helminthes found in the lumen of the host ( cestode infection) the drug leads to muscle contraction and paralysis leading to worm expulsion PZQ has also been shown to inhibit phosphoinisitole metabolism which in an undetermined mechanism leads to the worm paralysis With intravascular dewelling schistosomes PZQ leads to drug induced damage of the tegument of the worm 26

26. As a result antigens in the helminth are subject to attack by immune antibodies of the host, an antigen antibody immunological reaction leads to the death of the parasite 27

27. 3. Pyrantel Pamoate MoA : the Used in treating intestinal nematodes and is currently used for treating pinworm, ( enterobiasis ), roundworm ( ascariasis ), and hookworm ( uncinariasis ) Drug acts on nicotinic acetylcholine receptors to cause spastic paralysis of the worms that detach from the host and are swept out in feces 28

28. 4. Piperazine Only recommended for the treatment of ascariasis cure rate 90% for 2 days treatment. Piperazine is useful as an alternative to mebendazole or pyrantel for treating combined ascariasis and Enterobius infections Available in various salt forms, including the citrate, in syrup and tablet forms piperazin citrate 29 Piperazine citrate Piperazine

29. piperazine blocks the response of ascaris muscle to acetylcholine, causing flaccid paralysis in the worm, Which is dislodged from the intestinal wall and expelled in feces 5. Diethyl Carbamazine Citrate Drug of choice for the treatment of various forms of filariasis and active against ascariasis 30 Diethyl Carbamazine Citrate

30. 6. Niclosamide It is potent taeniacide that causes rapid disintegeration of worm segments and scolex . Second-line drug for treatment of tape worm infections . Penetration of the drug is facilitated by the digestive juices of the host Because very little of the drug is absorbed in to the worm in vitro . 31 Niclosamide

31. 7. Antinematodal Antibiotic Ivermectin 32 R=CH 3 22,23-Dihydroavermectin B 1b R=C 2 H 5 22,23-Dihydroavermectin B 1a

32. Drug of choice for treatment of filaria & strongyloidiasis It is a macrocyclic lactone ring Is a member of structurally complex antibiotics produced by a strain of streptomyces avermitilis Their discovery is the result of an intensive search for anthelmintic agents from natural sources Invermectin is active in low dosage against a wide variety of nematods and arthropods that parasitize animals 33

33. 34 Worms ( helminths ) Drug of choice Tapeworms ( cestodes ) Niclosamide or Praziquantel or Albendazole Roundworms (nematodes) Enterobius vermicularis (pinworm) Ascaris lumbricoides Trichuris trichiura (whipworm) Trichinella spiralis (trichinellosis) Strongyloides stercoralis Necator americanus (hookworm) Ancylostoma duodenale Onchocerca volvulus (Onchocercosis) Wuchereria bancrofti (Elephantiasis) Mebendazole or Pyrantel Mebendazole or Pyrantel Mebendazole or Albendazole Mebendazole and Thiabendazole Thiabendazole Mebendazole or Pyrantel Mebendazole, Pyrantel, or Albendazole Ivermectin Diethylcarbamazine Flukes (trematodes) Schistzoma (Schistozomes) Praziquantel