ANTITUBERCULAR DRUGS and classification,sar,uses of drugs

antitubercular drugs

1. ANT I - TUBE R CU L AR DRUGS (Intro, synthesis, sar…)

2. T U B E R CULOSIS 🠶 An infectious disease caused by the bacterium Mycobacterium tuberculosis. 🠶 Commonly affect the lungs but can also affect other parts of the body. 🠶 Symptoms include: 🠶 Ch r o n ic cough 🠶 H e mopt y sis 🠶 Fever 🠶 Night sweats 🠶 W eight loss 🠶 It is spread through air via cough, sneeze, speak or spit.

3. D R U G S 🠶 1 st line: 🠶 Isoni a z id 🠶 Rifampicin 🠶 Eth a mbutol 🠶 P y ra z in a mide 🠶 St r eptomycin 🠶 2 nd line: 🠶 P a ra a mino salicylic a cid 🠶 Cap r eomycin 🠶 Cip r oflox a cin 🠶 Cycl o se r ine 🠶 Ethi o n a mide 🠶 A m ikacin 🠶 Rifabutin

4. T U B E R CULOSIS Recommended treatment of pulmonary T.B is 6 months of combination of drugs. 🠶 Intensive phase (2 months): 🠶 Rifampicin 🠶 Isoni a z id 🠶 P y ra z in a mide 🠶 Eth a mbutol 🠶 Continuation phase (4 months): 🠶 Isoni a z id 🠶 Rifampin 🠶 Eth a mbutol (Option a l)

5. I S O NIAZ I D 🠶 Also known as isonicotinylhydrazide, 4- Pyridinecarboxylic acid hydrazide. 🠶 Isoniazid was first made in the early 20th century but its activity against tuberculosis was first reported in the early 1950s and was marketed in 1952. 🠶 It is on the World Health Organization's List of Essential Medicines, a list of medicines that constitute the bare minimum for a basic health system.

6. B R ANDS 🠶 NYDRAZIDE (Wilshire) 🠶 ISONIAZID (Unexo) 🠶 FAIRZIDE (Ferro)

7. MECHANISM OF ACTION 🠶 Inhibits synthesis of mycolic acid which is an essential components of mycobacterial cell wall 🠶 Isoniazid is a prodrug that is activated by KatG, the mycobacterial catalase- peroxidase. 🠶 The enzyme inhA, is an NADH- dependent, enoyl (acyl carrier protein) reductase protein thought to be involved in double-bond reduction during fatty acid elongation. 🠶 Isoniazid has bactericidal effect.

8. S Y NT H ESIS 🠶 Step 1: 🠶 4-methyl pyridine is oxidized to obtain Iso-nicotinic acid.

9. S Y NT H ESIS 🠶 Step 2: 🠶 Iso-nicotinic acid upon heating with anhydrous hydrazine form Isoniazid

10. S . A.R 🠶 Pyridine ring is essential for activity. 🠶 Substitution of R-1, R-2 at N-2 leads to variable activity. 🠶 Addition of isopropyl group at position R-2 results in loss of anti-tubercular activity but exhibit psychomotor stimulant activity, while acetyl isoniazid is inactive. 🠶 Any substitution (Alkyl) at R-3 results in loss of activity 🠶 INH is most active derivative.

11. SIDE EFFECT The most frequent reactions are those affecting the nervous system and the liver. 🠶 Peripheral neuropathy (Dose related) Prophylaxis Pyridoxine: Adult: 100-200mg/day orally for 3 weeks or 25 to 100 mg/day for prophylaxis. 🠶 Elevated LFT’s 🠶 Fatal hepatitis 🠶 Aplastic anemia. 🠶 Hypersensitivity reaction 🠶 Dark urine

12. D O S I NG 🠶 Active tuberculosis: 🠶 O r al 🠶 Adult: 5 mg/kg/day in combination with other drugs. 🠶 Children: 10-30mg/kg/day in 2 divided doses 🠶 Prophylaxis: 🠶 O r al 🠶 Adult: 300mg once daily 🠶 Children: 10mg/kg/day 🠶 SIDE EFFECT: 🠶 Peripheral neuritis (Pyridoxine): 🠶 Adult: 100-200mg/day orally for 3 weeks or 25 to 100 mg/day for prophylaxis.

13. RIFAMPICIN 🠶 Also known as Rifampin. 🠶 Rifampicin was discovered in 1957 and first sold as a medication in 1971. 🠶 It’s a semi-synthetic derivative of Rifamycin B, a macrocyclic antibiotic produced by Streptomyces mediteranei. 🠶 It is on the World Health Organization's List of Essential Medicines.

14. B R ANDS 🠶 LEDERRIF (Pfizer) 🠶 UNERIF (Unexo) 🠶 RIFACIN (Pharmawise)

15. MECHANISM OF ACTION 🠶 Rifampin has bactericidal effect. 🠶 Rifampin binds to bacterial DNA-dependent RNA polymerase and thereby inhibits initiation of RNA chain, hence protein synthesis.

16. S Y NT H ESIS 🠶 Rifamycin B is obtained from the fermentation liquid of Streptomyces mediterranei (Amycolatopsis rifamycinica). 🠶 Rifampicin is then obtained by synthetically modifying Rifamycin B.

17. S . A.R 🠶 Intact macro cyclic molecule is essential for activity. 🠶 Saturation of double bonds in macro cyclic ring leads to slightly decreased activity. 🠶 Free hydroxyl (-OH) group present at C- 1, C-8, C-21, C-23 are essential for activity. 🠶 Substitution of hydroxyl group at C-8, C-21, C-23 leads to loss of activity; except C-1 from hydroxyl to carbonyl.

18. S A R 🠶 Modification at the C-3, C-4 often yield compounds with improved physicochemical and P.K properties.

19. SIDE EFFECTS 🠶 Hepatotoxicity 🠶 Flu like symptoms 🠶 Red and orange colored urine, saliva etc. 🠶 Rash

20. D O S I NG 🠶 Active Tuberculosis: Oral or I/V: 10mg/kg OD (Max 600mg/day) for 6 months in combination with other drugs. 🠶 Latent Tuberculosis: Oral or I/V: 10mg/kg OD (Max 600mg/day) for 4 months.

21. PYRAZINAMIDE 🠶 It is a close analog of isoniazid 🠶 It is a pro-drug (Pyrazinoic acid). 🠶 The drug is largely bacteriostatic, but can be bactericidal on actively replicating tuberculosis bacteria. 🠶 It is on the World Health Organization's List of Essential Medicines.

22. B R ANDS 🠶 PYRAZINAMIDE (Pfizer) 🠶 P Z A CIBA 5 00 (No v artis) 🠶 PYRAZID (Schazoo zaka)

23. MECHANISM OF ACTION 🠶 Susceptible organisms produce pyrazinamidase, which is responsible for conversion of pyrazinamide (Prodrug) to Pyrazinoic acid (Active) intracellularly. 🠶 The protonated Pyrazinoic acid can permeate the mycobacterial membrane to lower the pH of the cytoplasm, hence disrupting basic chemical processes especially energy production.

24. S Y NT H ESIS 🠶 Step 1: o-phenylenediamine when reacted with glyoxal; quinoxaline is formed.

25. S Y NT H ESIS 🠶 Step 2: Quinoxaline is then oxidized with potassium permanganate to form pyrazin-2,3- dicarboxylic acid.

26. S Y NT H ESIS 🠶 Step 3: pyrazin-2,3-dicarboxylic acid is then decarboxylated by heating to get pyrazin-2- carboxylic acid.

27. S Y NT H ESIS 🠶 Step 4: pyrazin-2-carboxylic acid is then esterified in presence of methanol and hydrochloric acid to get acetyl ester of pyrazin-2-carboxylic acid.

28. S Y NT H ESIS 🠶 Step 5: acetyl ester of pyrazin-2-carboxylic acid is then treated with ammonia to get pyrazinamide.

29. S . A.R 🠶 The best side chain is amide. 🠶 Another potential side chain is ester which is activated by bacterial esterase. 🠶 Nitrogen (Pyrazinoyl) at P-2 is essential for maximum activity. 🠶 Substitution of “N” with “C” (Nicotinoyl) leads to decreased activity. 🠶 Any other substitution in the ring will lead to loss of activity.

30. SIDE EFFECTS 🠶 Arthralgia, Myalgia 🠶 Gout 🠶 Hepatotoxicity (Dose related) 🠶 Rash

31. D O S I NG 🠶 Active Tuberculosis: Oral: 15 to 30 mg/kg (Max 2g/day) OD in combination with other drugs. 🠶 Latent Tuberculosis: Oral: 15 to 20 mg/kg (Max 2g/day) OD for 2 months

32. ETHAMBUTOL 🠶 Ethambutol was discovered in 1961. 🠶 It possesses bacteriostatic action against Mycobacterium tuberculosis. 🠶 Its (+) enantiomer is used as it is more effective. 🠶 It is on the World Health Organization's List of Essential Medicines.

33. B R ANDS 🠶 M Y AMBU T OL (Pfi z er) 🠶 TUBERCURE (Lowitt) 🠶 ABBU T OL (Ab b ott)

34. MECHANISM OF ACTION 🠶 Ethambutol is bacteriostatic against actively growing TB bacilli. 🠶 It disrupts arabinogalactan (Polymer) synthesis by inhibiting the enzyme arabinosyl transferase leads to increased permeability of the cell wall.

35. S Y NT H ESIS 🠶 Step 1: Nitropropane undergoes hydroxymethylation when treated with Formaldehyde to form 2-nitrobutanol.

36. S Y NT H ESIS 🠶 Step 2: 2-nitrobutanol is then reduced in presence of Raney’s nickel and hydrogen to form 2-aminobutanol.

37. S Y NT H ESIS 🠶 Step 3: (+) 2-aminobutanol is then treated with 2-dichloroethane in presence of sodium hydroxide gives Ethambutol

38. S . A.R 🠶 Increase in ethylene diamine chain length leads to loss of activity. 🠶 Replacement of either of the amino group leads to loss of activity. 🠶 Removal of alcohol groups leads to loss of activity. 🠶 Substitution of hydroxyl groups with methoxy, ethoxy retains activity but with aromatic group (Phenyl, Pyridine) leads to loss of activity. 🠶 Increasing the size of N-substituent lead to loss of activity.

39. SIDE EFFECTS 🠶 Optic neuritis (C.I in children below 6 years) 🠶 Red-green color blindness 🠶 Peripheral neuropathy 🠶 Hyperuricemia

40. D O S I NG 🠶 Active Tuberculosis: Oral: 15 mg/kg OD for 2 months in combination with other drugs.

41. B R ANDS ( M u l t i i n g r e dient) 🠶 MYRIN (Pfizer): 🠶 Isonia z id, Rif a mpi c in, Eth a mbutol 🠶 MYRIN-P (Pfizer): 🠶 Isonia z id, Rifamp i c i n, E th a mbuto l , Pyra z inam i de 🠶 RIMACTAL-INH (Novartis): 🠶 Isonia z id, Rif a mpi c in 🠶 RIFAPIN-H (Schazoo zaka): 🠶 Isonia z id, Rif a mpi c in

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