This document provides information on first and second line antitubercular drugs. It lists the main first line drugs as isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin and describes their mechanisms of action, pharmacokinetics, uses, doses and side effects. Second line drugs discussed include fluoroquinolones, macrolides, ethionamide and cycloserine. Details are provided on individual drug properties like absorption, metabolism and toxicity risks.

1. 1

2. First Line Drugs
 Isoniazid (H)
 Rifampin (R)
 Pyrazinamide (Z)
 Ethambutol (E)
 Streptomycin (S)
ANTITUBERCULAR DRUGS

3. Second line drugs
 Ethionamide (Etm)
 Prothionamide
 Para amino salicyclic acid (PAS)
 Cycloserine (Cys)
 Kanamycin (Kmc)
 Amikacin (Am)
 Capreomycin
 Thiacetazone (tzn)
ANTITUBERCULAR DRUGS

4. Second Line Drugs
Quinolones
 Ciprofloxacin
 Ofloxacin
Macrolides
 Clarithromycin
 Azithromycin
Other Drugs:
 Rifabutin
 Rifapentin
 Linezolid
 ? Ifn - γ

5. INH
Salient features:
(1) Most active anti TB drug
(2) Important assets are
-potency
-infrequent toxicity
-low cost
(3) Bactericidal for rapid growers
(4) Useful for TB meningitis
(5) Effective for both extra cellular &intracellular TB
(6) If combined with other drug it has good
resistance preventing action
5

6. Structure of INH
 Hydrazide of isonicotinic acid
INH PYRIDOXINE
 It has structural similarity with Pyridoxine
6

7. Mechanism of Action
ISONIAZID
Kat G(catalase peroxidase
in mycobacteria)
Active INH
AcpM & Kas AcpM- Acyl Carrier protein Reductase.
Kas A (ß ketoAcyl Carrier protein synthetase)
Inhibits Mycolic Acid Synthesis. –Mycobacterial Cell Wall.
7

8. Pharmacokinetics
 Abs: Complete orally. Oral dose=Parenteral dose
 Dist: penetrate all body tissue
Placenta
Meninges
Caseous lesion of TB
Meta: in liver
INH
N acetyl transferase(NAT2)
N-Acetyl Isoniazid
Isonicotinic Acid Acetyl Hydrazine
1st ACETYLATION(Phase II), then HYDROLYSIS (Phase I)
8

9. Acetylation of INH is genetically determined
FAST SLOW
Eskimos, Egyptians,
Japanese Mediterin Jews
Indians(30-40%), Indians(60-70%
HIGH N-Acetyl transferase LOW
Autosomal Inherited as Autosomal
Dominant Recessive
70 mins T½ 2-3 hrs
Occurs Peripheral neuritis More frequent
Also occurs Hepatitis More
9

10. Pharmacokinetics
 Excretion:-75-95% excreted in urine
-Dose adjustment is not required in Renal Failure
-INH & Acetyl Hydrazine are not bound to
plasma protein, thus dialyzable.
 C/I - KNOWN HYPERSENSITIVITY
-ACUTE HEPATIC DISEASE
10

11. Clinical Use
 Therapeutic: Essential component of all
Anti TB Regimen
 Prophylactic:
-Transmission to close contact
-Baby born to infected mother
-Development of active TB in
immune deficient individuals
Doses of INH
I. 5mg/kg/day
II. 10mg/kg/A.D
III. 10mg/kg/day –in serious infection
-If malabsorbtion is a problem
IV. Prophylactic: 5mg/kg/day
11

12. Adverse Effects:-
I. Rash
II. Peripheral Neuropathy
III. Hepatitis
IV. Transient loss of Memory
V. Seizure
VI. Pleural effusion
HEPATOTOXICITY
-Acetyl Hydrazine cause the damage
-↑in Serum Transaminase
-Clinical Hepatitis
-Can be fatal if not withdrawn promptly
12

13. PERIPHERAL NEUROPATHY
-Parasthesia,numbness
-Due to relative deficiency of Pyridoxine
Pyridoxine Kinase
1)Pyridoxine Pyridoxal phosphate
INH having strong similarity with Pyridoxine competes with
Pyridoxine
2)INH ↑ Pyridoxine excretion –Thus causing deficiency
13

14. Pyridoxine:-
Prophylaxis:
10mg once daily
 Malnourished Patient
 Elderly,
 Pregnant & lactating mother,
 Diabetics
 Alcoholics
T/t of established neuropathy:
100-200mg/once daily
14

15. RIFAMPIN(R)
 Semisynth. deri of Rifamycin B-from
St.meditarranei
 Bactericidal ,affect all subpopulation of M. TB.
 Acts best on Spurters &slow growing
 Acts both extra &intracellularly
 Good sterilizing property.
 Resistance preventing action.
 Bactericidal efficacy ≈ INH
 &>any other 1st line drug
 Analogue of RIFAMPIN is RIFABUTIN
 Obtained from Rifamycin S
15

16. RIFAMPIN(R) Bactericidal Efficacy
 Inhibits - Gm+ve
-Gm-ve
-Mycobact.inf
-M. TB, M.leprae,M.kansassi
 Important ones are
-H. influenzae
-N. meningitis
-Legionella
-Brucella
-M.R.S.A
16

17. M.O.A OF Rifampin
 D.N.A

 DNA dependent RNA Polymerase
R.N.A

Protein Synthesis

Cell multiplication
Rifampin bind to β S.U of D.D.R.P

Drug –Enz Complex

Suppression of chain initiation
RIFAMPIN
17

18. Pharmacokinetics
Abs: -Well absorbed from G.I tract
-PAS interferes with abs.
-Food also interferes with abs.
Dist:-wide. Penetration to •Cavities
•Meninges
•Caseous Mass
•Placenta
Rifampicin causes an orange red
coloration of body secretion
due to various aspect of
Rifampin metabolism
18

19. P/K Metabolism
Following abs. from G.I. Tract

Eliminated rapidly in the bile
&undergoes Enterohepatic Circulation

Rifampin is progressively
deacetylated

This metabolite is bactericidal
 T1/2 varies from 1.5-5 hrs
 EXCRETION: Urine-30%
Faeces 60-65%
Recycling through liver by excretion in bile, reabsorption from intestines
into portal circulation, passage back into liver, and re-excretion in bile.
19

20. Doses of Rifampin
 Doses- 10mg/kg/day
10mg/kg/Alt.day
 C/I –k/c/o history of hypersensitivity to Rifamycin
-Hepatic Dysfunction
 Precaution –Careful monitoring of L.F.T.
-In elderly
- In alcoholics
-Pts. having hepatic disease
20

21. Side Effects:
1) Hepatitis: i)Mod - bilirubin
-S.G.O.T/S.G.P.T
which are common at the outset
ii)Transient
2) Haemolytic Syn: Purpura,Haemolysis,Shock
& Renal failure
3) Exfoliative Dermatitis in H.I.V +ve
4) Temp.oliguria, Dyspnoea, Haemolytic anemia-
Thrice/week
5) Flu like Syndrome –Twice/ week
21

22. Drug Interactions of Rifampin
Strongly induces CYTP450 isoforms
CYP1A2
CYP2C9
CYP2C19
CYP2D6
CYP3A4
 Own metabolism &also other drugs like
22

23. Drug Interactions of Rifampin
OC Pill –contraceptive failure,Estrogen to be /
nonhormonal methods to accept.
Oral anticoagulant
Oral hypoglycemic drugs
Corticosteroid drugs
Anti arrhythmic drugs -Digitoxin, Quinidine
Antiretroviral drugs –PI &NNRTI except EFAVIRENZ
Antifungal Drugs –Ketoconazole
23

24. USES OF RIFAMPIN
 1)Mycobacterial infection
☻M.tb
☻M.leprae
☻Atypical mycobacteria
-M. kansassi
-M. intracellulare
-M. marinum
24

25. 2) Other indications
 a) meningococcal meningitis-carrier state
600mg B.D for 2 days
 b) H.influenzae meningitis –close contact
20mg/kg/dayfor 4days
 c) Legionella infection-Along with Erythromycin
 d) Serious staphylococcal infection like
- osteomyelitis
-prosthetic Valve Surgery
 e) Brucellosis –Along with Doxycycline
 f) MRSA
 g) T/t of meningitis caused by highly penicillin
resistant strain
25

26. PYRAZINAMIDE (Z)
 Synthetic analogue of Nicotinamide
 Though weakly tuberculocidal

More active in acidic medium
 Highly effective during 1st 2months
 More effective against Slow Growing
 Active both intra & extracellularly
 Combination therapy Including Z
 - Duration of t/t is ↓
- Potent sterilizing action
- Risk of relapse is reduced
26

27. 3.4%
10.3%
0
20
40
60
80
100
Pyrazinamide No Pyrazinamide
Relapses
(%)
Pyrazinamide is essential for the first two months of 6/8-month treatment
Relapses
27

28. 96
90 92
0
20
40
60
80
100
2 months PZA 4 months PZA 6 months PZA
Pyrazinamide does not give any
additional benefit if given beyond two
months in short-course treatment
Cure
Rate
(%)
28

29. MOA OF PYRAZINAMIDE
 Pyrazinamide
Mycobacterial Pyrazinamidase
Pyrazinoic Acid
Inhibits Mycolic Acid Synthesis
 Resistance due to mutation of gene pncA
29

30. Pharmacokinetics: PYRAZINAMIDE
Abs: Well absorbed from G.I.tract.
Dist: good penetration to all body tissues &
CSF
Meta: Pyrazinamide
Pyrazinoic Acid
5-OH pyrazinoic Acid
T1/2  6-10hrs
Dose: 25mg/D
35mg/A.D
30

31. Side Effects: PYRAZINAMIDE
1)Hepatotoxicity: Most hepatotoxic
 SGOT &SGPT
Serum Bilirubin
C/I-Not to be given with any degree of
hepatic dysfunction.
2)Inhibits the excretion of ureates

Hyper uracemia

Acute episodes of Gout
3)Joint pain , Arthralgia
31

32. Management of ATT induced Hepatitis
Patient developing hepatitis during t/t of T.B
 Rule out any probable cause of jaundice
 If the diagnosis is ATT induced hepatitis:
 Drugs prone for hepatitis must be stopped
 T/t must be withheld until LFT is normal
 Wait for 2 wks after disappearance of
jaundice
 Seriously ill TB pt. with ATT induced hepatitis may
die without t/t
T/t- { 2SHE/10HE} (WHO Guidelines,2003)
As hepatitis is resolved, usual Anti TB to be started
32

33. ETHAMBUTOL (E)
Tuberculostatic ,active against
M. tb
M.A.C
M. intracellularae
Rapid Growers are more susceptible
Hastens the rate of sputum conversion
Prevents the emergence of Resistant bacilli
33

34. M.O.A of Ethambutol
Ethambutol


Mycobact. Arabinosyl Transferase


Polymerisation reaction of
Arabinoglycan

Essential component of Myco.Cellwall
E inhibits the enz. Myco. Arabin. Trans., which is required
for polymerisation reaction of Arabinoglycan
34

35. Pharmacokinetics: Ethambutol
 Abs: Well absorbed from g.i.t.
 Dist: Wide,penetrates the meninges
 T1/2 ~ 4hrs
 Excretion :-unchanged in urine(3/4th)
-Excreted by G.F& T.S
-Dose to be reduced in Renal failure
 C/I ; Cr. Clearance <50ml/min
Doses of Ethambutol : 15mg/kg/day
30mg/kg/A.D
35

36. Side Effects: Ethambutol
1)RETROBULBAR NEURITIS :causing
-Loss of V.A
- Red Green Color blindness
-Field Defect
Early recognition &stoppage of drug-
visual toxicities is largely reversible
Contra-indication ;In children <6yrs
a) they are unable to report early.
b) may not permit the assessment of V.A
&red green color blindness discrimination
2) Renal uric acid excretion > Hyperuricemia
3)Pruritus, Joint Pain
36

37. STREPTOMYCIN(S)
 Aminoglycoside from Str.griseus
 1st clinically active against Mycobact.
 Limitation of its use
i)dose related toxicity
ii) devlopment of resistant org.
iii)pt compliance is poor due to i.m
 Present status:
-Least used 1st line A.T.D
-More active against extracellular bacilli
- Inactive against intracellular bacilli.
37

38. Mechanism of Action STREPTOMYCIN(S):
 -Drug actively transported across Cell membrane by O2
dependent process.
 - Binds with specific 30s S.U of ribo protein(s12)
 -Protein Syn . Is hampered
*Interferes with chain initiation
*Induce misreading of mRNA
* Incorporation of incorrect A.A into peptide

Formation of Nonfunctional /toxic protein
*Cause break up of polysomes into monosomes
IRREVERSIBLE & LETHAL FOR CELL
38

39. Pharmacokinetics: STREPTOMYCIN(S)
 Neither absorbed / destroyed in G. I. Tract.
 Absorption from inj site is rapid (30-60min)
 Distributed to Extracellular TB cavities.
 Not metabolized, Excreted unchanged in urine
39

40. Side Effects: STREPTOMYCIN(S)
i)OTOTOXICITY-drugs get conc. In labrynthine fluid,both vestibular
& cochlear damage
ii)NEPHROTOXICITY
iii)N.M PARALYSIS -Ach release,
sensitivity of post.syn. receptors.
iv)Sterile abscess at the inj. site
Contra Indication:
- Not to be given in pregnancy
-Avoid use with other ototoxic drug eg; High ceiling diuretics,
Minocycline, Cisplatin
-Avoid use of other nephrotoxic drug eg; Amphotericin B,
Vancomycin, Cyclosporin, Cisplatin
-Pts with renal disease.
-Cautious use with muscle relaxant.
40

41. Uses: STREPTOMYCIN(S)
 Sensitive to M.tb
M.A.C
M.kansassi
 Remains as an imp drug when inj. form is
needed- espcially with severe &life threatening
condition.
-TB meningitis
-Miliary TB
 Other uses:
- Tularemia
- Plague
 Dose:15mg/kg/D
15mg/kg/A.D
41

42. DRUGS ADULT CHILD INTERMITTENT
INH
Rifampin
ETB
PYZ
SM
300 mg
< 50 kg – 450 mg
>50 kg – 600 mg
25 mg / kg – 2months
15 mg / kg
< 50 kg – 1.5g
50 – 74 kg – 2g
>75 kg – 2.5g
< 3o kg – 750mg
> 30 kg – 1 gm
5-10 mg/kg
10 mg / kg
--
15-30mg/kg
20 mg / kg
15 mg / kg
600- 900 mg
600- 900 mg
30 mg / kg
Thrice wkly 2g
3 g
3.5 g
1g
42

43. II LINE DRUGS
DRUGS TYPE OF
ACTION
MECHANIS
M
DOSAGE
DOSAGE ADVERSE
EFFECTS
Thiacetazone
PAS
Ethionamide
Prothionamide
Cycloserine
Capreomycin
Amikacin
Kanamycin
static
static
static
static
CIDAL
Cell wall syn.
Folate syn.
Cell wall syn.
Cell wall syn.
Protein syn.
150 mg /d
300 mg / kg
750 – 1gm /d
500-1000 mg
-
GIT
Hepatotoxicity.
GIT symtoms
Cutaneous reactions,
fever, GOITRE.
Metallic taste
CNS – Mental
distrubances.
CNS toxicity
C/I epilepsy.
OTO &
NEPHROTOXICY
43

44. NEWER DRUGS
DRUGS TYPE OF
ACTION
MECHANISM
DOSAGE
DOSAGE ADVERSE
EFFECTS
1.Macrolides
Azithromycin
Clarithromycin
2. Quinolones
Ciprofloxacin
Ofloxacin
3. Rifabutin
Cidal
Cidal
Cidal
Protein syn.
DNA gyrase
DNA depedent
RNA Polymerase
500 mg OD
500 mg BD
750 -1500mg
400 -800 mg
< 50 kg –150mg
> 50 kg –300 mg
GIT Symptoms
GIT symptoms
CNS Symptoms
Hepatotoxicity
44

45. Principles of Tuberculosis Treatment
• Regimens Must Contain Multiple Drugs
• Drugs Must be Taken Regularly
Treatment Must be Continued for Sufficient Time
(Minimal Acceptable Duration of Treatment = 6
Months)
45

46. Principles of Tuberculosis Treatment
The World health Organization Advocates
Directly Observed Therapy
(DOT)
46

47. 47

48. 48

49. Aim of therapy
 Speedy elimination of large population –
 Rapidly dividing organisms - in cavities
 Sterilization of slowly dividing organisms.
- In cells & slowly dividing organisms
(Per sisters)
49

50. Actively multiplying Slowly multiplying IC &
EC bacilli in caseous lesions
indadequate R
Adequate R Adequate R Late growth of ‘Persisters’
Inadequate Bactericidal action Sterilizing action
R
Elimination of Elimination of
EC bacilli ‘PERSISTERS’
Treatment RELAPSE
failure
Lasting cure of
TUBERCULOSIS
PRINCIPLES OF MODERN CHEMOTHERAPY OF TB
INH
RIF
SM
RIF
INH
PYZ
50

51. REVISED NATIONAL TB CONTROL PROGRAMME(RNTCP)
DRECTLY OBSERVED THERAPY – SHORT COURSE
(DOTS)
TB CATEGORY
I. New smear positive pulmonary TB
New smear negative pulmonary TB
New severe extra pulmonary TB
II. Smear positive failure / relapse / default
cases.
III. New smear negative pulmonary TB – less
parenchymal involvement.
51

52. 52

53. REVISED NATIONAL TB CONTROL PROGRAMME (RNTCP) –
DRECTLY OBSERVED THERAPY – SHORT COURSE
(DOTS)
TB
CATEGORY
INITIAL PHASE CONTINUATION
PHASE
TOTAL
DURATION
I
II
III
2H3R3Z3E3
2H3R3Z3E3S3 +
1H3R3Z3E3
2H3R3Z3
4H3R3
5H3R3E3
4 H3 R3
6 MONTHS
8 MONTHS
6 MONTHS
53

54. H - resistance R Z E -- 12 months
H + R resistance Z+ E + S / Km / Am /Cpr
+ Copro / Ofl ± Etm.
MDR -TB
TB – PREGNANCY
LACTATING MOTHERS
54

55. HIV PATIENTS
M. TB
H + R + Z+ E -- 2months
H + R -- 7months
H+ R+ Z -- 4months
MAC
Clari / azi + rifabutin + ETB + FQ /
clofazamine /
ethionamide
2- 6 months.
Clari /azi + rifabutin / FQ/ETB
> 12 months (or)
LIFELONG
55

56. ROLE OF STEROIDS ?
NOT USED ROUTINELY
 Seriously ill patients
 Hypersensitivity reactions to ATT.
 TB in serous cavities - pleural effusion,
 pericarditis, peritonitis
 TB Meningitis
 Genitourinary TB
 AIDS patients with severe manifestations.
C/I : Intestinal TB.
Dose - Predinisolone 40mg/d - 6wks.
Then reduce the dose.
56

57. MYCOBACTERIA I LINE THERAPY ALTERNATIVE
AGENTS
M. AVIUM Clarithro/ Rifabutin
COMPLEX Azithro + etb Rafampin
+ rifabutin Ethinonamide
Cycloserine
Moxi / Gati
M. KANSASII INH + RIFA + ETB Ethionamide
Cycloserine,
Clari, ami, sm
Moxi / Gati
57