Anti tubercular drugs

1. ANTI- TUBERCULAR DRUGS
SAIYAD ARSH ZIA
M.PHARAM (PHARMACOLOGY)

2. Tuberculosi is an infectious disease caused by
Mycobacteria; Mycobacterium tuberculosis &
Mycobacterium bovis.

3. Classification of anti-TB drugs:
1) first line drugs:
• F Field defects causing drug i.e. Ethambutol
• I Isoniazid (INH)
• R Rifampicin
• S Streptomycin
• T Twice a day given drug i.e. Pyrazinamide (All other first line
antituberculars are given once a day)

4. 2) second line drugs:
• S Salicylates like Para-amino salicylate
• E Ethionamide
• C Cycloserine
• O Old drug: Thiacetazone
• N Newer Drugs:
• D Drugs rarely used: Aminoglycosides e.g. Capreomycin, Kanamycin,
Amikacin
Quinolones e.g. Ciprofloxacin, Levofloxacin, gatifloxacin and Moxifloxacin
Macrolides e.g. Clarithromycin, Azithromycin
• Rifabeutin

5. first line drugs:
ISONIAZID
Mechanism of resistance:
Resistance can emerge rapidly if the drug is used alone.
Resistance can occur due to either
1. High-level resistance is associated with deletion in the katG gene
that codes for a catalase peroxidase involved in the bioactivation of
INH.
2. Low-level resistance occurs via deletions in the inhA gene that
encodes ―target enzyme‖ an acyl carrier protein reductase.

6. MOA: MECHANISM OF ACTION
The activated form of isoniazid - forms a covalent complex with an inh-A (Acyl
carrier protein -AcpM) and KasA, a ß-ketoacyl carrier protein synthetase, which
mycolic acid synthesis and kills the cell.

7. PHARMACOKINETICS:
ADME:Absorption, Distribution, Metabolism, Elimination:
• Absorption
Rapid and complete; rate can be slowed with food
Peak Plasma Time: 1-2 hr
• Distribution
All body tissues and fluids including CSF; crosses placenta; enters breast milk
Protein Bound: 10-15%
• Metabolism
Hepatic ( fast, slow acetylators)
• Elimination
Half-life elimination: fast acetylators: 30-100 min; slow acetylators: 2-5 hr; may
be prolonged with hepatic or severe renal impairment
Excretion: Urine (75-95%); feces

8. Adverse Effects:
>10%: Mild incr LFTs (10-20%), Peripheral neuropathy (doserelated incidence, 10-
20% incidence with 10 mg/kg/d), Loss of appetite, Nausea,Vomiting, Stomach
pain,Weakness.
1-10%: Dizziness, Slurred speech, Lethargy, Progressive liver damage (increases
with age; 2.3% in pts > 50 yrs), Hyperreflexia.
<1%: Agranulocytosis, Anemia, Megaloblastic anemia,Thrombocytopenia, SLE,
Seizure.
Contraindications:
Previous INH (isonicotinic acid hydrazide) hepatic injury or reaction; acute liver
damage
Hypersensitivity.

9. SECOND LINE ANTI-TB DRUGS:
These are less effective and/or less well tolerated anti-TB drugs that are used only in
case the bacilli are resistant to one or more 1st line drugs or when these are not
tolerated/are contraindicated.
Uses :
Anti-tuberculosis.

10. Ethionamide:
It is an antitubercular drug of moderate efficacy, introduced in 1956, which acts on
both extra- and intracellular bacilli.
Mechanism of Resistance:
Ethionamide is a derivative of isonicotinic acid structurally similar to isoniazid. It is also
a pro-drug requiring activation by a monooxygenase encoded by the ethA gene. It
interferes with the mycolic acid synthesis by forming an adduct with NAD that inhibits
the enoyl-ACP reductase enzyme. EthA is regulated by the transcriptional repressor
EthR. Resistance to ethionamide occurs by mutations in etaA/ethA, ethR and also
mutations in inhA, which cause resistance to both isoniazid and ethionamide.
Moreover, studies with spontaneous isoniazid- and ethionamide-resistant mutants
of M. tuberculosis found that they map to mshA, encoding an enzyme essential for
mycothiol biosynthesis.

11. MOA:
Ethionamide, like pyrazinamide, is a nicotinic acid derivative related to Isoniazid.
Ethionamide is a prodrug which is activated by the enzyme ethA, a mono-
oxygenase in Mycobacterium tuberculosis, and then binds NAD+ to form an
which inhibits InhA in the same way as isoniazid. The mechanism of action is
thought to be through disruption of mycolic acid.

12. Pharmacokinetics:
Absorption: completely absorbed following oral administration
Bioavailability approximately 100%.
Volume of distribution 93.5 L.
Protein binding :Approximately 30% bound to proteins.
Metabolism: Hepatic . Metabolized to the active metabolite
sulfoxide, and several inactive metabolites.
The sulfoxide metabolite has been demonstrated to have
antimicrobial activity against Mycobacterium tuberculosis.
Route of elimination: Less than 1% of the oral dose is excreted
as ethionamide in urine.

13. Adverse effects:
Half life2 to 3 hours
Disorder of gastrointestinal tract
Postural hypotension
Dizziness
Drowsiness
Headache
Peripheral neuropathy
Psychosis
Contraindications
Hypersensitivity to ethionamide
Severe hepatic dysfunction
Uses :
Anti-tuberculosis

14. THANK YOU
SAIAYD
ARSH ZIA