Give idea about pharmacology of anti-TB & anti-leprosy

1. Anti-Tuberculous
Drugs
Dr. Sameh Ahmad Muhamad abdelghany
Lecturer Of Clinical Pharmacology
Mansura Faculty of medicine

2. A G E N D A
2
1
Overview for TB
2 FIRST LINE ANTI-
TUBERCULOUS DRUGS
3 SECOND LINE ANTI-
TUBERCULOUS DRUGS
4 REGIMEN OF TB
THERAPY
5
Anti-LEPROSY Drugs

3. Mycobacterium
tuberculosis

4. Overview
4
 Mycobacterium tuberculosis, one of a number of
mycobacteria, can lead to serious infections of the
lungs, genito-urinary tract, skeleton, and meninges.
 Worldwide estimations record 9 million new cases
every year, and approximately 2 million die of the
disease each year.

5. PULMONARY TB

6. 6

7. Overview
7
 Properties of Mycobacterium tuberculosis:
o Cell wall -- high lipid content.
o Mycolic acid a major component.
o Slow growth.
o Survive within phagocytes..

8. Mycobacteria
Mycobacterium cell wall

9. Mycobacteria
Slow-growing bacillus Dormant forms in macrophages

10. Overview
 Treatment of TB (and other mycobacteria) presents
therapeutic problems because:
i. Tubercle bacilli are either extracellular (metabolically
active), intracellular (metabolically inactive) or inactive
inside necrotic caseous material.
ii. Bacterial resistance is common.
iii. The organism grows slowly and may require 6-24 months
of treatment
10

11. General rules during TB therapy:
11
 Never treat TB by a single drug.
 Never add a single drug to a failing regimen!
 Treatment must be continued for long period (6-24 months)
to eradicate bacilli.
 Poor patient compliance.
 Followed up of patient is a must for detection of adverse
effects of drugs and/or therapeutic failure.

12. FIRST LINE ANTI-TUBERCULOUS DRUGS
12
 Isoniazide
 Rifampicin (Rifampin)
 Ethambutol
 Pyrazinamide
 Streptomycin

13. I- Isoniazid (INH)
13
Chemistry
 isonicotinylhydrazide (INH).

14. Isoniazid (INH)
14
Pharmacokinetics
 Good absorption after oral administration.
 It penetrates most body fluids including the CSF.
 It accumulates in caseated lesions and can attack both extra- and
intracellular bacilli.
 INH is acetylated in the liver. The rate of acetylation is
genetically determined (“rapid acetylators” and “slow
acetylators”).

15. Isoniazid (INH)
15
Mechanism of action
 is an analog of pyridoxine (vitamin B6).
 is a prodrug that is activated inside M. tuberculosis into active
metabolite which inhibits the synthesis of mycolic acid, an
essential component of the mycobacterial cell wall (bactericidal).
 Mycolic acid is present only in M. tuberculosis, so INH has no
activity on other bacteria or atypical mycobacteria.
 Resistance is due to mutations in the enzyme responsible for
conversion of INH into the active metabolite.

17. Isoniazid (INH)
17
Therapeutic uses
1. Treatment of TB: INH is administered in combination with
one or more other first-line drugs to minimize the
development of resistance.
2. For prophylaxis (close contacts), INH is used alone.

18. Isoniazid (INH)
18
Adverse effects
1. Inhibition of CYP450.
2. Neurotoxicity:
 High levels of INH compete with pyridoxine at the enzyme
pyridoxal kinase leading to peripheral neuropathy.
 more common in slow acetylators.
 minimized by co-administration of pyridoxine (vitamin B6).

19. Isoniazid (INH)
19
Adverse effects
3. Hepatotoxicity with jaundice (3%):
 due to accumulation of toxic metabolites in the liver.
 more common in rapid acetylators and in individuals > 35
years.
4. Hypersensitivity reactions with rash and fever (2%).
5. Hemolytic anemia in patients with G-6PD deficiency

20. II- Rifampin (Rifampicin)
20
Chemistry

21. Rifampin (Rifampicin)
21
Pharmacokinetics
 is absorbed orally and can reach all body tissue and fluids
including the CSF, pleural and ascetic fluids.
 can reach TB cavities, sputum and penetrate macrophage
killing intra- and extracellular TB bacilli.

22. Rifampin (Rifampicin)
22
Pharmacokinetics(cont.)
 enters enterohepatic circulation
 induces hepatic microsomes to decrease the half-lives of
other drugs.
 excreted through the bile and urine.
 Its metabolites cause orange-red discoloration of urine, stool,
tears, and sweat; the patient should be warned.

23. Rifampin (Rifampicin)
23
Mechanism of action
 selectively inhibits bacterial DNA-dependent RNA polymerase
enzyme leading to ↓ RNA synthesis (human enzyme is not affected).
 is bactericidal for both intra- and extracellular M. tuberculosis, and
atypical mycobacteria.
 effective against many Gram-positive and Gram-negative bacteria.
 Resistance develops rapidly if the drug is used alone. It is due to a
change in the polymerase enzyme.

25. Rifampin (Rifampicin)
25
Therapeutic uses
1. Treatment of TB in combination with INH and pyrazinamide.
2. Although rifampin has activity against many Gram positive and
negative bacteria but should be used only against TB to prevent
development of resistance.
3. Treatment of leprosy in combination of dapsone and
clofazemine.
4. Prophylactic for individuals exposed to meningitis caused by
Meningococci or H. influenzae

26. Rifampin (Rifampicin)
26
Adverse effects
1. Hepatotoxicity (rare):
 abnormal liver enzymes, jaundice, etc. especially in old patients and
patients with chronic liver disease.
2. Microsomal enzyme induction leading to decrease half-lives of other
drugs.
3. Flu-like symptoms: with intermittent therapy.
4. Red tears and urine: harmless, but can stain contact lenses.
5. GIT upset (nausea and vomiting) and skin rash

27. III- Ethambutol
27
Mechanism of action
 inhibits arabinosyl transferase involved in cell wall
biosynthesis.
 specific bacteriostatic for M. tuberculosis. It is active
against intra- and extracellular TB bacilli.
 Relatively less toxic and resistant strains develop slowly.

28. Ethambutol
28
Therapeutic uses
1. Treatment of TB in combination with INH and rifampin to
minimize resistance.
2. Treatment of TB during pregnancy because it is the least
toxic.

29. Ethambutol
29
Adverse effects
1. Peripheral neuropathy and Visual disturbances (1-5%):
 Optic neuropathy manifested by field defects and red-green
color blindness.
 These effects are reversible on stopping the drug.
2. Hyperuricemia and gout: due to ↓ uric acid excretion.
3. GIT disturbance & hypersensitivity reactions.

30. IV- Pyrazinamide
30
Mechanism of action
 Taken up by the macrophages and is converted into the
active product by the acidic medium of the lysosomes inside
the macrophages.
 It inhibits mycobacterial cell wall functions.

31. Pyrazinamide
31
Therapeutic uses
 In combination with INH and rifampin to minimize
resistance
Adverse effects
1. Hepatotoxicity is the major side effect.
2. Hyperuricemia and gout: due to ↓ uric acid excretion

32. V- Streptomycin
32
 It is one of the aminoglycosides.
 It is bactericidal for extracellular bacilli but it is ineffective
against intracellular bacilli.

33. Streptomycin
33
Therapeutic uses
 in combination with INH & rifampin to treat resistant
pulmonary TB and renal TB
 given by IM injections.
Adverse effects
1. Nephrotoxicity
2. Ototoxicity (8th nerve damage)
3. Neuromuscular block.

34. SECOND LINE ANTI-TUBERCULOUS DRUGS
34
 Para aminosalicylic acid
 Ethionamide
 Cycloserine
 Fluoroquinolones
 Capreomycin

35. Para aminosalicylic acid (PAS)
35
 is an analog of PABA
 Works similar to sulfonamides but only against mycobacteria

36. Ethionamide
36
 It blocks the synthesis of mycolic acids (like INH).
 Resistance develops rapidly.
 Commonly produces severe GI disturbances.

37. REGIMEN OF TB THERAPY
37
Patients with active TB:
 Initial phase (first 2-4 months): 4 drugs are used (RIPE):
(Rifampin + INH + Pyrazinamide + Ethmabutol).
 Continuation phase (next 4-6 months): at least 2 drugs are
used (INH + rifampin).

38. REGIMEN OF TB THERAPY
38
Patients with latent TB:
 Latent TB (i.e. patients with +ve Tuberculin skin test and had
history of contact to a person proved to have TB)
 INH alone for 6 months or dual Rifampicin + INH for 3
months.

39. REGIMEN OF TB THERAPY
39
Patients with meningeal TB:
 are treated for a prolonged period (12-18 months) with the
addition of steroids.

40. REGIMEN OF TB THERAPY
40
TB during pregnancy:
 The only anti-TB drug which is absolutely contraindicated
is streptomycin because of the high risk of congenital
deafness.
 other first line anti-TB drugs are safe for use in pregnancy.

41. REGIMEN OF TB THERAPY
41
TB with liver disease
 INH, rifampin, and pyrazinamide are hepatotoxic but
because of their effectiveness, they should be used depending
on monitoring of liver function tests.
 In severe liver damage, only one drug can be used.

42. CHEMOTHERAPY OF LEPROSY
42
 Dapson
 Clofazimine
 Rifampicin (Rifampin)

43. I- Dapson
43
 Structural analogue of PABA and chemically related
to sulfonamides.
 Mechanism of action:
o similar to sulfonamides (bacteriostatic).
 Therapeutic uses:
o treatment of leprosy with rifampin for 2-5 years.

44. Dapson
44
 Adverse effects:
1. Nausea, vomiting, skin rash
2. Hemolysis and methemoglobinemia,
3. Exacerbation of skin lesion of lepromatous leprosy.

45. II-Clofazimine
45
 Mechanism of action:
o inhibit mycobacteria DNA synthesis (bactericidal).
 Therapeutic uses:
o in combination with dapson and rifampin to prevent
resistance.

46. Clofazimine
46
 Adverse effects:
1. Abdominal pain
2. Brown urine
3. Atropine-like actions.

47. III- Rifampin
47
 is the most active antilepromatous drug available.

48. T H A N K Y O U !
A N Y Q U E S T I O N S ?