Antitubercular Drugs Shahare HV

Classification, Chemistry, SAR, Mechanism of Action . Antitubercular drugs- Isoniazid, Rifampin, Pyrazinamide, Ethambutol, Streptomycin ...

1. ANTI-TUBERCULAR
AGENTS
Prof. Hitesh V. Shahare
Assistant Professor

2. Learners will be able to know;
1. Introduction
2. Classification
3. SAR & MOA
4. Marketed Preparations
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3. Introduction
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Infectiousdiseaseworldwideandaleadingkillercausedbyasingle
infectiousagent
Commoninfectionsites:
Tuberculosis
•Lungs
•Kidney
•Respiratory System

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Dependinguponthesiteofinfection:Diseasecanbecategorizedas;
Respiratory Tract
Pulmonary tuberculosis
Genitourinary Tract
Genitourinary tuberculosis
Nervous System
Tuberculous Meningitis
Throughout Body
Milliary tuberculosis

5. Symptoms
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Mycobacterium Cell Wall

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•ManyPotentAntiTBdrugsdrugsweredevelopedinorder:
Streptomycin
PASA
Isoniazid
Ethambutol
Rifampicin

8. •AccordingtoClinicalUtilityofAntiTBdrugscanbedividedintotwomajor
categories:
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First Line
Agents
Second Line
Agents
Isoniazid,
Streptomycin
Rifampicin
Ethambutol
Pyrazinamide
Ethionamide
p-Amino salicylic acid
Ofloxacin
Ciprofloxacin
CycloserineAmikacin
Kanamycin, Viomycin
Capreomycin
-High Potency
-Low Toxicity
-Low Potency
-High Toxicity

9. Classification
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10. Chemical Nature
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Chemical class Example
1) Salicylic acid derivativesPara amino Salicylic acid
2) Pyridine derivativeIsoniazid, Ethionamide, Prothionamide
3) Pyrazine derivativePyrazinamide
4) Ethylene
diaminobutanolderivative
Ethambutol
5) Antibiotics: Streptomycin, Rifampicin, Kanamycin
6)Miscellaneousclass OfloxacinandCiprofloxacin
AzithromycinandClarithromicin

11. Pyridine derivative
INHisfirstsynthesizedin1952
Firstlinesyntheticanti-tuberculardrug
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Prodrugactivated on the surface of M. tuberculosis by katGenzyme
to Isonicotinic acid.
katGenzyme: Catalase-peroxidase-hemeenzyme
•The major metabolite is N-acetyl isoniazid: Enzyme responsible for
acetylation-CytosolicN-acetyl transferase
•Other metabolites include Isonicotinic acid,which is found in the urine as
a glycineconjugate and hydrazine.

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Isoniazid
[INH]
INH
Prodrug
INH
Active
InhA
KasA
No Further
Mycobacterium Cell
Wall Synthesis
Passive diffusion
MOA
KatG
KatG: Bacterial Catalase-
Peroxidase Enzyme
InhA:AcylProtein
carrier Protein Reductase
Bacterium Cell
KasA:Acyl Protein
Carrier Kinase
Enzymes Inhibited
NoSynthesis of
Mycolic acid
Bactericidal

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•IsoniazidmaybeBcteriostaticorBactericidalinaction,dependingonthe
concentrationofthedrugattainedatthesiteofinfectionandthe
susceptibilityoftheinfectingorganism.
Bcteriostatic
Against resting cell
Bactericidal
Against rapidly multiplying organism

15. SAR
1.N-1nitrogeninhydrazinesidechain
shouldbeunsubstituted.
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2.N-2Nitrogencanbesubstitutedwithalkyl
groupstogetactivecompounds.
3.Replacementofpyridinenucleuswithotheraromaticring
suchasbenzeneorpiperidineorthiazoleringdiminishedthe
anti-tubertcularactivity.

16. 4.IsopropylgroupissubstitutedatN2:Isopropylderivativenamed
Iproniazid.
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5.Numerousderivativeshavebeendevelopednoneofthemhaveexhibited
activitysuperiortothatoftheparentdrug.
But not having Anti-tubercular activity.
It exhibit Psychomotor Stimulantactivity.
N'-Isopropylisonicotinohydrazide

17. Isoniazid: Side effects
1.Clumsiness or unsteadiness
2.Dark urine
3.Loss of appetite
4.Nausea and vomiting
5.Numbness, Tingling, Burning or pain in hands or feet
6.Unusual tiredness or weakness
7.Yellow eyes or skin
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18. Ethambutol
•Thedextroenantiomer(+)isalmost200-
500timesmorepotentthanthemeso(-)–
enantiomer
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•EthambutolabbreviatedasEMB
EMBinhibitenzymeArabinosylTransferase
EnzymerequiredforsynthesisofArabinogalactan
Required for Synthesis of Mycolic acid
component of Mycobacterium Cell wall
MOA
Bcteriostatic

19. SAR
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1.Thepresenceoftwoaminomoieties:Essential,ReplacementofAminomoieties
byAcetyl,SulphonylorNitrosoylmoieties:Inactive
2.Presenceofsmallbranchedalkyl
groupsonthenitrogenatomalso
influencestheactivity
3. HeteroatomsOxygen,
Sulphur in Ethylene moiety:
Inactive derivatives
4.IncreaseorDecreaseinethylene
chainlength:Destroytheactivity

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Opticneuritisresultingindecreasedvisionandloss
ofabilitytodifferentiatered,greencolour
Nausea
Anorexia
Rashes
Fever
Hyperuracaemia
Side
Effects

21. Pyrazinamide
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•ChemicallysimilartoINH
•ItisweaklyTuberculocidal
•Moreactiveinacidicmedium

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•Hepatotoxicity
•Hyperuricaemia
•Abdominal distress
•Arthralgia
•Flushing
•Rashes, fever
•Loss of diabetes control: repeated blood glucose
monitoring is warranted in diabetics.
Side
Effects

23. Rifampicin
•Bactericidal to M. tuberculosis.
•Both extra-and intracellular organisms are affected.
•It can kill organisms that are poorly accessible to many other drugs, such
as intracellular organisms and those sequestered in abscesses and lung
cavities.
•Rifampin binds to bacterial DNA-dependent RNA polymerase and
thereby inhibits RNA synthesis.
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AntibioticobtainedfromStreptomycesmediterranei

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MOA
Inhibits DNA-dependent RNA polymerase of mycobacterium by
forming a stable drug enzyme complex
Leading to suppression of initiation of chain formation in RNA
synthesis
Bactericidal DNA-dependent
RNA polymerase
Double stranded DNA Single stranded mRNA
Rifampicin

26. Ethionamide
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Nicotinamidederivative, with antibacterial activity
Inhibit the synthesisof mycolic acid, a saturated fatty acid found in the
bacterial cell wall, thereby inhibiting bacterial cell wall synthesis
Second line drug in the therapy of Tuberculosis used
only in combination
SE: Hepatotoxicity, GI distress

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Para-amino-salicylic acid
•Hematological
•(Megaloblastic anemia)
•Hypothyroidism
•Hepatitis
•Hypokalemia
•Hypersensitivity
Inhibitor of bacterial folate metabolism in a
manner similar to the sulphonamide
Side
Effects

28. Rifabutin
1.SemisyntheticstructurallysimilartoRifampicin
2.AgainstM.avium,-causesofdisseminatedinfections,withpatients
sufferingwithHumanImmunodeficiencyVirus(HIV).
3.Rifabutinlipophilicinnatureandpenetratecellwalloforganismmore
effectivelythanotheragents.
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29. Streptomycin
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1943 from Streptomyces griseus
Given in combination with Isoniazid, Rifampicin, and Pyrazinamide
Intramuscularly
Act by binding to the 30S ribosomal subunit of susceptible organisms and
disrupting the initiation and elongation steps in Protein Synthesis.
SE: Ototoxicity & Nephrotoxicity
BACTERICIDAL

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34. 5 September
2020
SNJB's SSDJ College of Pharmacy, Chandwad (Nasik) 34
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