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Antimycobacterial
The document provides a comprehensive overview of antimycobacterial drugs used to treat mycobacterial infections, including tuberculosis and leprosy. It details the classification, mechanisms of action, side effects, and uses of both first-line and second-line therapies. Key medications discussed include isoniazid, ethambutol, dapsone, and clofazimine, alongside their effects and indications.
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Introduction to antimycobacterial drugs used for infections like tuberculosis and leprosy.
Tuberculosis (TB) is lethal, airborne, typically targeting lungs, spread through coughing.
Common symptoms include chest pain, persistent cough, fever, weight loss, and fatigue.
Standard first-line treatments include isoniazid, rifampicin; combination therapies ensure high cure rates.
Isoniazid inhibits mycolic acid synthesis, has side effects like peripheral neuritis, and is well absorbed.
Ethambutol inhibits cell wall synthesis; used in mycobacterial infections with side effects like optic neuritis.
Used when first-line drugs fail. Includes drugs like ethionamide and fluoroquinolones.
Ethionamide blocks mycolic acid synthesis, poorly tolerated; used in TB and leprosy treatments.
Broad-spectrum antibiotics effective against TB by targeting bacterial DNA processes.
Leprosy, caused by Mycobacterium leprae, leads to nerve damage and is spread via respiratory droplets.
Dapsone and clofazimine are primary medications for treating leprosy.
Dapsone inhibits folate synthesis; side effects include hemolytic anemia and gastrointestinal issues.
Clofazimine is an anti-inflammatory agent with variable absorption, used in resistant cases.
Closing remarks on the presentation.
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Antimycobacterial
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- 3. Definition • An antimycobacterialis a type of drug used to treat mycobacteria infections. • Types include: 1. Tuberculosis treatments 2. Leprostatic agents
- 4. TB • is acommon, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. • Tuberculosis usually attacks the lungs but can also affect other parts of the body.
- 5. TB • It isspread through the air when people who have an active MTB infection cough, sneeze, or otherwise transmit their saliva through the air.
- 6. Symptoms chest pain, coughingup blood, and a productive, prolonged cough for more than three weeks. Systemic symptoms include fever, chills, nigh sweats, appetite loss, weight loss, pallor, and fatigue.
- 8. First line • Allfirst-line anti-tuberculous 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
- 9. Never use asingle drug therapy –Isoniazid –rifampicin combination administered for 9 months will cure 95-98% of cases . –Addition of pyrazinamide for this combination for the first 2 months allows total duration to be reduced to 6 months.
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- 12. MOA –Bacteriostatic at lowconc. & bacteriocidal at high conc. Especially against actively growing bacteria. –Inhibits synthesis of mycolic acid is an essential components of mycobacterial cell wall. –Readily absorbed from GIT.
- 13. MOA –Diffuse into allbody fluids and tissues –Penetrates caseous material and macrophages so it is effective against intra and extracellular organisms. –Metabolized in liver by acetylation –Excreted mainly in urine
- 14. SAR 1-Substitutionof hydrazine portion of INHwith alkyl and ar- alkyl substitution resulted in a series of active and inactive derivatives.
- 15. SAR 2-Substitution on the N2position (R 1,R2=alkyl,R3=H)---- active compounds.
- 16. SAR 2-Substitution on the N2position (R 1,R2=alkyl,R3=H)---- active compounds.
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- 19. Uses –Mycobacterial infections (itis recommended to be given with pyridoxine to avoid neuropathy). –Latent tuberculosis in patients with positive tuberculin skin test –Prophylaxis against active TB in individuals who are in great risk as very young or immunocompromised individuals.
- 20. Side effects –Peripheral neuritis –Opticneuritis. –Allergic reactions ( fever,skin rash,systemic lupus erythematosus ) –Hepatitis –Gastric upset –Haemolytic anaemia –Enzyme inhibitor –CNS toxicity.
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- 22. MOA –Inhibits mycobacterial cellwall synthesis by inhibiting arabinosyl transferase . –Bacteriostatic –Active against intra&extracellular bacilli . –Well absorbed from gut. –20% excreted in feces and 50% in urine in unchanged form. –Crosses BBB in meningitis
- 23. SAR – Ethylene diaminechain --↑this chain length --↓or destroy. – Replacement of either N--↓or destroy. – Increasing the size of Nitrogen substituents--↓or destroy. – Moving the location of alcohol groups--↓or destroy.
- 24. Uses –Used only inmycobacterial infections.
- 25. Side effects –Retrobulbar (optic)neuritis causing loss of visual acuity and red-green colour blindness. –It is relatively contraindicated in children. –GIT .upset . –Hyperuricemia
- 26. 2nd line • Indicationof 2nd line treatment : –Resistance to the drugs of 1st line. –Failure of clinical response –Increase of risky effects. –Patient is not tolerating the drugs first line drugs.
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- 29. MOA –As isoniazid blockssynthesis of mycolic acid . –Available only in oral form. –Metabolized by the liver ,excreted by kidney. –It is poorly tolerated because of : • intense gastric irritation • neurologic symptoms • hepatotoxicity
- 30. Uses Used in TB& leprosy.
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- 33. MOA –Broad spectrum,antibacterial,but also active for M.tuberculosis, –binding to DNA gyrase-DNA complex (gyrA and gyrB ) –inhibiting bacterial DNA replication and transcription, bactericidal.
- 34. SAR –Non fluorinated quinolonesare inactive against mycobacteria. –Different substitution in quinolones improve activity toward Mycobacterium avium intracellular complex(MAC – MAI) known as biophores. •A cyclopropyl ring at N1position. •F atom at position C-6 and C-8 •A C-7 heterocyclic substituents
- 35. SAR –Excessive lipophillicity atN1 can↓activity. –TheN-7 substituents with greatest activity against mycobacteria include substituted piperazines and pyrrolidines.
- 36. Leprosy • Leprosy orHansen's disease (HD) is a chronic disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis. • granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions are the primary external sign.
- 37. Leprosy • Secondary infections,in turn, can result in tissue loss causing fingers and toes to become shortened and deformed, as cartilage is absorbed into the body • usually spread from person to person in respiratory droplets
- 39. Drugs used inleprosy • Dapsone • Clofazimine
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- 41. MOA Inhibits folate synthesis. –Well absorbed orally,widely distributed . – Half-life 1-2 days,tends to be retained in skin,muscle,liver and kidney. – Excreted into bile and reabsorbed in the intestine. – Excreted in urine as acetylated. – It is well tolerated.
- 42. SAR – Relpcemnet of1 benzene ring results in thiazosulfones— less active than DDS – Substitution on benzene ring results in acetosulphone--↓ activity, ↓g.i.t irritation(bz increase solubility) – Substitution by methanesulfinate (CH2SO2)-gives sulfoxone Na, which is water soluble, ↓g.i.t irritation(bz increase solubility) –this drug is preferred who can’t tolerate DDS-but given 3times of DDS bz of its hydrolysis.
- 43. Uses – Tuberculoid leprosy. –Lepromatous leprosy in combination with rifampin & clofazimine. – To prevent & treat Pneumocystis pneumonia in AIDS caused by Pneumocystis jiroveci ( Pneumocystis carinii).
- 44. Side effects – Haemolyticanaemia – Methemoglobinemia – Gastrointestinal intolerance – Fever,pruritus,rashes. – Erythema nodosum leprosum
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- 46. MOA – It isa phenazine dye. – Unknown mechanism of action ,may be DNA binding. – Antiinflammatory effect. – Absorption from the gut is variable. – Given orally , once daily.
- 47. MOA – Excreted mainlyin feces. – Stored mainly in reticuloendothelial tissues and skin. – Half-life 2 months. – Delayed onset of action (6 weeks).
- 48. SAR – Basic nucleus–phenazine – Halogen substitution at P- position of two phenyls at C-3, and C-10-enhance activity but are not essential for activity. – Br > Cl > CH3 >C2H5OH > H >F
- 49. Uses – Multidrug resistanceTB. – Lepromatous leprosy – Tuberculoid leprosy in : • patients intolerant to sulfones – dapsone-resistant bacilli. – Chronic skin ulcers caused by M.ulcerans.
- 50. Side effects – Skindiscoloration ranging from red-brown to black. – Gastrointestinal intolerance. – Red colour urine. – Eosinophilic enteritis
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