Pharmacology of Anti-TB Drugs

1. PHARMACOLOGY
ANTI-TUBERCULAR DRUGS
Nem Kumar Jain
MS (Pharm.) Pharmacology & Toxicology
Assistant Professor, School of Pharmacy
ITM University Gwalior

2. TUBERCULOSIS(TB)
Chronic granulomatous inflammatory
disease and a major health problem in
developing countries.
Primarily affects lungs, other organs such
as brain, liver, kidney, spleen, bone etc.
As per WHO reports(2010), approx. 9.4
million active TB cases globally
India: 2.3 million cases
Other common names included “wasting
disease” and the “white plague”.
Etiology: TB is caused by Mycobacterium
species mainly by Mycobacterium
tuberculosis which is aerobic atypical
slender, rod shaped bacteria.
• Other strains which causes TB are
 M. Avium Complex (MAC): M. avium & M.
intracellulare
• Less common strains which causes TB
are
 M. africanum
 M. microti
 M. pinnipeddi
 M. cannetti
• Less pathogenic strains are
 M. abscessus
 M. fortuitum
 M. chelonae
 M. ulcerans
• Non pathogenic strains are M. smegmatis
• M.tuberculi also called as Koch’s bacilli or Acid
Fast bacilli (with lipid-rich cell walls that stain poorly with
the Gram stain, but once stained, the walls cannot be easily
decolorized by treatment with acidified organic solvents).
– Stained by carbofuscine

3. TYPES AND SOME FACTS OF TUBERCULOSIS
• Based on anatomical side:
Pulmunary TB (lungs)
Milliary (Spleen, kidney, liver, brain etc)
• Based on presence of signs and
symptom:
 Active TB (only shows signs and
symptoms).
 Latent TB (Signs and symptoms
absent, Dormant)
• Based on type of tissue response
 Primary TB: First time, Childhood TB
No Immunization or infection
Secondary TB: Re-infection
sp. which makes resultant disease
Chronic and necessitates prolong
treatment
 Slow growing
Intracellular infection
Formation of slow growing granuloma
results in destruction of host tissue
• Biology of Mycobacterium: distinct
populations
Rapidly growing with high bacillary
load
Slow growing
Spurters
Dormant

4. UNIQUE CELL WALL
Mycobacterial cell wall
• Presence of Mycolic acid (90’c’
atoms arranged in a ring like
structure) in Mycobacterium
species.
• Mycolic acids
 Prevents ,resists against
hydrophilic and lipophilic
antibiotics, loss of water,
transport of various
substances
 Helps in evading from
immune system.
• High potential to become
Resistant

5. PREVENTION OF TB
22
• Prevention strategies include BCG vaccination
and treatment of persons with latent
tuberculosis infection who are at high risk of
developing active disease.
• BCG was derived from an attenuated strain of M.
bovis.
• Efficacy is between 0-80%.
• BCG vaccine is recommended for routine use at
birth in countries with high tuberculosis
prevalence.
• Bacillus Calmette-Guérin (BCG)

6. • Mycobacteria are intrinsically
resistant to most antibiotics
– Grows more slowly than other
bacteria – antibiotics active
against rapidly growing cells
– lipid-rich mycobacterial cell
wall is impermeable to many
agents
– It grows inside macrophage –
poorly penetrated by drugs
– Excellent ability to develop
resistance – Multiple Drug
Resistant (MDR)
• Combinations of two or more drugs
– to overcome these obstacles
– to prevent emergence of
resistance during the course
of therapy
• The response of mycobacterial
infections to chemotherapy is slow
- treatment must be administered
for months to years, depending on
which drugs are used

7. • Drugs used in the treatment of tuberculosis can be
divided into two major categories
- First Line : high antitubercular efficacy as well as
low toxicity – routinely used: - HRZES
Isoniazid (H) , Rifampin (R),
Pyrazinamide (Z), Ethambutol (E),
Streptomycin (S)
– Second Line : low antitubercular efficacy or high
toxicity
• Paraminosalicylic Acid (PAS), Cycloserine,
ethionamide, prothionamide, Rifabutin,
thiacetazone
• Flouroquinolones: Ciprofloxacin, Olfloxacin,
levofloxacine, moxifloxacine Kanamycin,
Amikacin, capreomycine
• Macrolides:Clarithromycin,Azithromycin
• First Line Drugs
• Isoniazide
• Synthetic analogue of pyridoxine
• Primary tubercilocidal
• bacteriostatic for resting bacilli, but is
bactericidal for rapidly dividing
microorganisms
• inhibits synthesis of mycolic acids -
essential components of mycobacterial
cell walls, not active against other
microorganism
• Highly selective for mycobacterium
• Resistance
 Its prodrug – activated by enzyme catalase-
peroxidase
 Mutation causes inhibition of this enzyme
 No cross resistance occurs with other
antitubercular drug
 Always given in combination

8. MECHANISM OF ACTION AND RESISTANCE
Resistance
– Mycobacteria may develops resistance towards
H due to change in genes coding for catalase
peroxidase (katG).
– Alteration in KasA and InhA and in structure of
efflux pumps of bacteria.
• Pharmacokinetics:
– Orally well absorbed
– Well distributed
– Metabolized in Liver by N-acetylation (NAT2)
– Based on acylation
• Slow acetylators (Half life- 3h)
• Fast acetylators( Half life-1h)
– Excreted through urine
• Adverse effects:
– GI disturbances,
– Hepatotoxicity
– Peripheral Neuritis
– Hypersensitivity reactions
• Interaction: alluminium hydroxide inhibits
absorption, Potent enzyme inhibitor (cyp2c19,
cyp3a4)
Isoniazide
Mycobacterial Catalase peroxidase (katG)
activates
Aducts with
NAD NADP
Mycobacerial
Dihydrofolate
reductase
Type II fatty acid synthase (FAS)
system
Inhibition of Mycolic acid
Inhibition of
DNA synthesis
Bactericidal action
Active
metabolite
beta-ketoacyl
ACP synthase
(kasA)
Enoyl acyl
carrier protein
reductase (inhA)

9. RIFAMPICIN/ RIFAMPIN (R)
• Derived from the soil mold Streptomyces
mediterranei
• Bactericidal to M. tuberculosis and other
gram positive and gram negative bacteria
including M. leprae
• Both extracellular and intracellular
organisms are affected
• Against TB bacilli, it is as efficacious as
INH and better than all other drugs
• Mechanism of action: Rifampin inhibits
DNA dependent RNA synthesis. Probably,
the basis of selective toxicity is that
mammalian RNA polymerase does not
avidly bind rifampin
• Resistance: nearly always due to
subunit of RNA polymerase-the target of
rifampin action) reducing its affinity for the
drug.
• No cross resistance with any other
antitubercular drug has been noted.
• Pharmacokinetics: well absorbed orally,
• widely distributed in the body: penetrates
cavities, caseous masses, placenta and
meninges.
• 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
t1/2 of rifampin is variable (2-5 hours).

10. • Interactions: microsomal enzyme
inducer-increases several CYP450
isoenzymes, including CYP3A4, CYP2D6,
CYP1A2 and CYP2C subfamily.
• It thus enhances its own metabolism as
well as that of many drugs including
warfarin, oral contraceptives,
corticosteroids, sulfonylureas, digitoxin,
steroids, HIV protease inhibitors, non-
nucleoside reverse transcriptase inhibitors
(NNRTis), theophylline, metoprolol,
fluconazole, ketoconazole, etc.
• Contraceptive failures have occurred
• Adverse Effects: similar to INH.
• Hepatitis, a major adverse effect, generally
occurs in patients with preexisting liver
disease and is dose-related
• 'Respiratory syndrome': breathlessness
• Purpura, haemolysis, shock and renal
failure.
Minor reactions usually not requiring drug
withdrawal are:
• 'Cutaneous syndrome': flushing, pruritus +
rash (especially on face and scalp),
redness and watering of eyes
• 'Flu syndrome': with chills, fever,
headache, malaise and bone pain.
• 'Abdominal syndrome': nausea, vomiting,
abdominal cramps with or without
diarrhoea.
• Urine and secretions may become orange-
redbut this is harmless.

11. PYRIZINAMIDE (Z)
• Chemically similar to INH
• It is weakly tuberculocidal but more active in acidic
medium
• It is more lethal to Slow Growing, intracellularly
located bacilli and to those at sites showing an
inflammatory response (pH is acidic at both these
locations.
• highly effective during the first 2 months of therapy
• PHARMACOKINETICS:
– Rapidly absorbed from GI tract
– It is widely distributed in the body and achieves a
concentration in the CSF equal to the plasma
levels.
– Deaminated in the liver.
– Degradation products and he free drug are
eliminated in urine
• ADVERSE EFFECTS:
– Hyperuricemia (precipitating gout)
– Hepatotoxicity
– Arthralgia, nausea,vomiting, anorexia, malaise,
– Rarely photosensitivity reaction
– Loss of diabetes control
• Used in both Extrapulmonary and pulmonary
TB
• Resistance: mutation of pncA geneMECHANISM OF ACTION
PYRAZINAMIDE
PYRAZINOIC ACID
mycolic acid synthesis Disrupts
cell
membrane
integrity
Tuberculocidal effect
Pyrizinamidase (pncA
gene)

12. ETHAMBUTOL
• Ethambutol is selectively tuberculostatic
• Active against MAC as well as other mycobacteria but
not other types of bacteria
• Fast multiplying bacilli are more susceptible
• Added to three drug regimen RHZ, primarily to prevent
resistance development
• Mechanism of Action: inhibits embAB gene encoded
Arabinoacyl transferase
Resistance: mutation of embAB gene
• PHARMACOKINETICS:
– 70% is absorbed
– Penetrates into erythrocytes, gets deposited,
and released into circulation
– 50% of oral dose excreted unchanged in
urine with in 24h
– 15% excreted in the form of two metabolites
– Accumulates in presence of renal damage
• ADVERSE EFFECTS:
– Retrobulbular optic neuritis on prolonged
therapy which results in decrease visual
acuity.
– Others are
Nausea,headache,anorexia,allergic
reactions,and confusion
– Hyperuricimia and Gout (Urate excretion
decreased)
• If any visual disturbances are seen in the
patient,Ethambutol should be removed from
patient’s regimen
• Safe in pregnancy
Ethambutol
Inhibits Arabinosyl transferase
Inhibits Synthesis of ARABINO
GLYCANS
Inhibits cell wall synthesis

13. STREPTOMYCIN
• First anti-tubercular drug
• Tuberocidal but less effective than isoniazide or rifampicine
• Acts only on extracellular bacilli
Pharmacokinetics:
– Not absorbed orally and must be given in IM.
Well absorbed when instilled in intrapleurally
– It doesn’t cross BBB. However, high
concentrations are seen in CSF during
meningeal inflammation.
– It is mainly concentrated in kidneys, liver,
and skeletal tissues.
– It crosses Placental barrier,
– Excreted unchanged by GFR. And
approximately 50-60% of drug is eliminated in
urine in active form within 24h.
• ADVERSE EFFECTS:
– Pain at the site of injection
– 8th cranial nerve damage
– Neuromuscular blockade
– Nephrotoxicity and ototoxicity
– Super infections with Staphylococcus
aureus and candida
Contraindication: Elderly and in those with
impaired renal functions
MECHANISM OF ACTION
STREPTOMYCIN
Binds to 30S subuint of
ribosomes
Which results in production
Abnormal proteins
Accumulates in
mycobacterium
Destruction of
mycobacterium

14. SECOND LINE DRUGS
• These are less effective and/or less well tolerated
• Used only in case the bacilli are resistant to one or more
first line drugs or when they are not well tolerated and/or
contraindicated
1. Kanamycin and Amikacin:
• Tuberculocidal aminoglycosides
• Pharmacological profile similar to Streptomycin
• Part of Regimen for S-resistant or MDR-TB
• AM is less toxic
• Cross resistance common
• Equally nephrotoxic
2. Capreomycin:
• Cyclic peptide antibiotic
• Chemically different from aminoglycode but similar anti-
tb effect and ototoxicity and nephrotoxicity
• Used against Aminoglycosides resistant and MDR –TB
strains
3. Flouroquinolones: useful new addition to the
antitubercular drugs
• Ofloxacin(Ofx), levofloxacin (Lfx),ciprofloxacin (Cfx)and
moxifloxacin (Mfx)
• Alternative to first line drugs
• Active against MAC, M. fortuitum, other atypical
mycobacteria
• Anti- mycobacterial tuberculosis Activity Mfx> Lfx> Ofx &
Cfx
• Anti atypical mycobacteria activity Cfx> Lfx
• FQs penetrate macrophages too
• Cfx not used now because of its extensive use against
other bacteria too
• Primary indication is for treatment of MDR-TB
• Resistance against Mfx is slow to develop

15. SECOND LINE DRUGS
3. Ethionamide: chemically resembles Isoniazid
• MECHANISM OF ACTION: Blocks the synthesis of
mycolic acids and it is a tuberculostatic drug.
• PHARMACOKINETICS: ABSORPTION is similar to H,
Metabolized in liver and only 1% excreted
unchanged in urine
• Because of its Intense gastric irritation and neurological
toxicity(optic and peripheral neuritis) and
hepatotoxicity, it is rarely used,
• Used only for Drug Resistant TB, MDR-TB regimen. MAC
infection in AIDS
• Also reserved drug for Leprosy.
4. Prothionamide: congener of Ethionamide and
resembles pharmacologically in all aspects to
ethionamide Interchangiable to Ethionamide in use
5. Cycloserine: MECHANISM OF ACTION :It is D-alanine
analogue and hence inhibits bacterial cell wall synthesis
by inactivating the enzyme which racimize the L-alanine
and link two D-alanine residues.
tuberculostatic
• PHARMACOKINETICS: Rapidly absorbed from
gut,distributed through out the body (csf and plasma
concentrations are equal in meningitis condition).50%
of orally administered dose gets excreted in urine in
unchanged form and 65% is excreted by kidneys within
72h.
• Broad spectrum antibiotic and it is tuberculostatic.
• It is effective against tubercle bacilli resistant to H or S
and against atypical mycobacterium.
• ADVERSE EFFECTS:
– Peripheral neuropathy,
– Delusions, Nervousness etc.
– Contanindicated in patients with seizures
Uses: MDR-TB
NO cross resistance with any anti-TB drugs.
6. Terizidone: contains two molecules of Cycloserine
• properties MOA similar to cycloserine
• less Neurotoxic
• interchangeable in use

16. 7. Para amino salicylic acid (PAS)
• Sulphonamide derivative
• Inhibits Folate synthase
• Selective Mycobacterial Folate synthase inhibitor
• Tuberculostatic
• Resistance poor to develop
• Adverse effects: Epigastric Pain, anorexia, nausea, rashes,
goiter, liver dysfuction etc. poor patient tolerability
• Uses: only in resistant TB, MDR-TB
8. Thiacetazone: not used nowadays due to questionable
efficacy
9. Rifabutin:
• chemically and pharmacologically similar to Rifampicine
• Less active against M. Tuberculosis
• R-resistant strains exhibit cross resistance
• Rifabutin is weak enzyme inducer
• Specially used in HIV –TB Infection who receive
protease inhibitors and NNRTI
• Prophylaxis and treatment of MAC-TB

17. TREATMENT REGIMEN FOR TB
FOR NEWLY INFECTED PATIENTS
FOR PREVIOUSLY TREATED PATIENTS WITHLOW
RESISTANCE TO DRUGS
INTENSIVE PHASE
(2months)
H,R,Z,E+VitB6
CONTINUOUS
PHASE
(4months)
H,R+VIT B6
INTENSIVE PHASE
(3months)
HRZES HRZE
+
Pyridoxine 100mg/day
CONTINUOUS PHASE
(5months)
HRZ + Pyridoxine
100mg/day

18. MULTI DRUG RESISTANT OR
HIGHLY RESISTANT
CONTINUOUS PHASE
(12-18months)
E
OFLOXACIN/LEVOFLOXA
CIN
CYCLOSERINE
ETHIONAMIDE+
PYRIDOXINE
• INTENSIVE PHASE
• (6months)
Z
•E
AMIKACIN/KANAMYCIN
• OFLOXACIN/
• LEVOFLOXACIN
• CYCLOSERINE
ETHIONAMIDE+
• PYRIDOXINE For H resistance: R+Z+E for 12Months
For R resistance: H+Z+E for 12Months
For both H+R resistance: Z+E+S(Et)+CIROFLOXACIN(OR OFLOXAC
OR LEVOFLOXACIN),for 12-18 Months