1. Unit III: Chemotherapy
a. Antitubercular agents
Presented by: Mirza Anwar Baig
M.Pharm (Pharmacology)
Anjuman I Islam's Kalsekar Technical Campus,
School of Pharmacy.
New Panvel,Navi Mumbai
2. What is tuberculosis?
Tuberculosis is a chronic granulomatous disease.
About 1/3rd of the world’s population is infected with Mycobact.
tuberculosis.
As per WHO statistics for 2010, there were 9.4 million active TB cases
globally.
India was the highest contributor with 2.3 million cases.
About 1000 people die from TB every day in india.
India has a large load of HIV infected subjects, and these patients are
especially vulnerable to severe forms of tubercular.
3. Classification:
1) First line: These drugs have high antitubercular efficacy as well as low
toxicity; are used routinely.
1. Isoniazid (H) 4. Ethambutol (E)
2. Rifampin (R) 5. Streptomycin (S)
3. Pyrazinamide (Z)
2) Second line: These drugs have either low antitubercular efficacy or higher
toxicity or both; and are used as reserve drugs.
• Ethionamide (Eto) Fluoroquinolones
• Prothionamide (Pto) • Ofloxacin (Ofx)
• Cycloserine (Cs) • Levofloxacin (Lvx/Lfx)
• Terizidone (Trd) • Moxifloxacin (Mfx)
• Para-aminosalicylic acid (PAS) • Ciprofloxacin (Cfx)
Injectable drugs
• Kanamycin (Km)
• Amikacin (Am)
• Capreomycin (Cm)
4. Group I: are the most potent and best tolerated oral drugs used routinely.
Group II: are potent and bactericidal, but injectable drugs.
Group III: includes FQs which are well tolerated bactericidal oral drugs; all
patients with drug resistant TB should receive one FQ.
Group IV: are less effective, bacteriostatic/more toxic oral drugs for resistant
TB.
Group V: are drugs with uncertain efficacy; not recommended for MDR-TB;
may be used in extensively resistant TB (XDR-TB).
5. Isoniazid (Isonicotinic acid hydrazide, H)
• It is primarily tuberculocidal.
• Fast multiplying organisms are rapidly killed.
• Acts on extracellular as well as on intracellular TB (bacilli present within
macrophages).
• Equally active in acidic or alkaline medium.
Mechanism of action:
• Inhibition of synthesis of mycolic acids which are unique fatty acid
components of mycobacterial cell wall.
6. Mechanism of action contd..
1. Highly selective for mycobacteria (it is not active against any other
microorganism).
2. Reduce the lipid content of mycobacteria
3. Target genes (InhA’ and ‘KasA’), which function in mycolic acid synthesis.
4. Mycobacteria convert INH to a reactive metabolite by catalase-peroxidase
5. This then forms complex with NAD that inhibits InhA and KasA.
6. Forms complex with NADP as well which inhibits mycobacterial DHFRase
resulting in interruption of DNA synthesis.
7. Resistance:
1. Mutation of the catalase-peroxidase so that the bacilli do not generate the
reactive metabolite of INH.
2. Mutation in the inhA or kasA genes.
3. Efflux of INH from the bacterial cell.
4. Loss of the active INH concentrating process.
• No cross resistance with other antitubercular drugs occurs.
8. Pharmacokinetics:
• Completely absorbed orally and penetrates all body tissues, tubercular cavities,
placenta and meninges.
• Extensively metabolized in liver; most important pathway being N-acetylation
by NAT2.
• The acetylated metabolite is excreted in urine.
• Induced peripheral neuritis is more common in slow acetylators.
• A hepatotoxic minor metabolite is produced by CYP2E1 from acetylhydrazine.
9. Adverse effects:
• Peripheral neuritis and a variety of neurological manifestations
(paresthesias, numbness, mental disturbances, rarely convulsions).
• Hepatitis, a major adverse effect of INH, is rare in children, but more
common in older people and in alcoholics (chronic alcoholism induces
CYP2E1 which generates the hepatotoxic metabolite).
• INH hepatotoxicity is due to dose-related damage to liver cells, but is
reversible on stopping the drug.
• Other side effects are lethargy, rashes, fever, acne and arthralgia
10. Rifampin
• Semisynthetic derivative of rifamycin B obtained from Streptomyces
mediterranei.
• Bactericidal to M. tuberculosis and many other gram-positive and gram-
negative bacteria .
• Against TB bacilli, it is as efficacious as INH and better than all other
drugs.
• M. leprae is highly sensitive.
• Both extra- and intracellular organisms are affected.
11. • Interrupts RNA synthesis by binding to β subunit of mycobacterial DNA-
dependent RNA polymerase.
• The basis of selective toxicity is that mammalian RNA polymerase does not
avidly bind rifampin
• Rifampin resistance is nearly always due to mutation in the rpoB gene
reducing its affinity for the drug.
• No cross resistance with any other antitubercular drug, except rifampin
congeners, has been noted.
12. Pharmacokinetics
• It is well absorbed orally, but food decreases absorption; rifampin is to be
taken in empty stomach.
• Widely distributed in the body: penetrates intracellularly, enters tubercular
cavities, caseous masses and placenta.
• Though it crosses meninges, it is largely pumped out from CNS by P-
glycoprotein.
• It is metabolized in liver to an active deacetylated metabolite which is
excreted mainly in bile, some in urine also.
• Rifampin and its desacetyl derivative undergo enterohepatic circulation.
The t½ of rifampin is variable (2–5 hours).
13. Adverse effects: The incidence of adverse effects is similar to
INH.
Other uses of rifampin
1. Leprosy
2. Prophylaxis of Meningococcal and H.influenzae meningitis and carrier
state.
3. Second/third choice drug for MRSA, diphtheroids and Legionella infections.
4. Combination of doxycycline and rifampin is the first line therapy of
brucellosis
14. Pyrazinamide (Z)
• Weakly tuberculocidal and more active in acidic medium.
• More lethal to intracellularly located bacilli and to those at sites showing an
inflammatory response.
Mechanism of action:
• Converted inside the mycobacterial cell into an active metabolite
pyrazinoic acid by an enzyme (pyrazinamidase) encoded by the pncA gene.
• Probably inhibits mycolic acid synthesis by interacting with a different
fatty acid synthase.
• Pyrazinoic acid also appears to disrupt mycobacterial cell membrane and its
transport function.
• Resistance develops rapidly if it is used alone, and is mostly due to
mutation in the pncA gene.
16. • Absorbed orally, widely distributed, has good penetration in CSF.
• extensively metabolized in liver and excreted in urine; plasma t½ is 6–10
hours.
Adverse effects:
• Hepatotoxicity (dose related adverse effect).
• Hyperuricaemia (due to inhibition of uric acid secretion in kidney: gout can
occur).
• Abdominal distress, arthralgia, flushing, rashes, fever and loss of diabetes
control: repeated blood glucose monitoring is warranted in diabetics.
18. • About 3/4 of an oral dose of E is absorbed.
• Penetrates meninges incompletely and is temporarily stored in RBCs.
• Less than ½ of E is metabolized.
• Excreted in urine by glomerular filtration and tubular secretion; plasma t½
is ~4 hrs.
• Caution is required in its use in patients with renal disease.
Adverse Effects:
• Loss of visual acuity/colour vision
• Nausea, rashes, fever, rarely peripheral neuritis.
• Hyperuricemia
19. Streptomycin (S):
• Tuberculocidal
• Less effective than INH or rifampin
• Acts only on extracellular bacilli (because of poor penetration into cells).
• Penetrates tubercular cavities, but does not cross to the CSF, and has poor
action in acidic medium.
Mechanism of action:
20. SECOND LINE ANTI-TB DRUGS
1. Kanamycin (Km), Amikacin (Am)
2. Capreomycin (Cm)
3. Fluoroquinolones (FQs)
4. Ethionamide (Eto)
Assignment:
Discuss mechanism of action, adverse effects and uses of
drugs second line anti TB drugs.
21. The goals of antitubercular chemotherapy
(a) Kill dividing bacilli:
To reduce bacillary load in the patient and achieve quick sputum negativity so
that the patient is non- contagious to the community: transmission of TB is
interrupted.
(b) Kill persisting bacilli
To effect cure and prevent relapse. This depends on sterilizing capacity of the
drug.
(c) Prevent emergence of resistance
So that the bacilli remain susceptible to the drugs.
