Pharmacology Antimycobacterial drugs.ppt

Antimicrobial Drugs
Classification
Mechanism of Action
Pharmacokinetic
Pharmacodynamic
Adverse effects
Examples and Uses

1. Chemotherapy of Tuberculosis
Medically important mycobacteria
Mycobacterium Tuberculosis
A typical Mycobacterium
Mycobacterium Leprae

2. Tuberculosis
Common sites of infections
Apical areas of lung
Renal parenchyma
Growing ends of bones
Where oxygen tension is high

3. Transmission
Through air ( air borne transmission )
Active tuberculosis kill about two of every three
people if left untreated .

4. Latent tuberculosis
The inhaled bacilli are taken into alveolar
macrophages and remain viable & multiplying
within the cells for extended period of time.
The person is clinically asymptomatic
Positive tuberculin test is the only indication
Individuals with latent TB are not infectious & can
not transmit organisms.

5. Active tuberculosis
The goals for the treatment :
- Cure the individual patient
- Minimize the transmission of TB to others
-Kill the tubercle bacilli
- Prevent drug resistance

6. Treatment Of Tuberculosis
Tuberculosis remains the primary cause of
death due to infectious disease.
Periods of treatment ( minimum 6 months)
Drugs are divided into :
First line Second line
Third line

7. Antimycobacterial drugs
First line of drugs:
Isoniazid (INH)
Rifampin
Ethambutol
Streptomycin
Pyrazinamide

8. Never use a single drug therapy
The standard “short “ course
treatment for TB is isoniazid ,
rifampin , pyrazinamide , and
ethambutol for two months, then
isoniazid and rifampin alone for a
further four months .

9. Continue
For latent tuberculosis , the standard treatment is
six to nine months of isoniazid alone.

10. Isoniazid
Bacteriostatic for resting bacilli.
Bactericidal for rapidly
dividing bacilli.
Is effective against intracellular
as well as extracellular bacilli

11. Mechanism Of Action
Is a prodrug, activated by
mycobacterial catalase -peroxidase
Cell wall synthesis inhibitor
Inhibits synthesis of mycolic acids----
Which are essential components of
Mycobacterial cell walls.

12. Pharmacokinetics
Readily absorbed when given either
orally or parenterally.
Aluminum containing antacids
interfere with absorption.

13. Distribution
Diffuse rapidly into all body fluids and
cells.
Highly concentrated in pleural fluids.
Its concentration in CSF is significant in
inflammed meninges.
Penetrates well into caseous material.

14. Metabolism & Excretion
Metabolized in the liver by acetylation
.
Excreted in urine mainly as
metabolites.

15. Clinical uses
Mycobacterial infections (it is recommended
to be given with pyridoxine to avoid
neuropathy).
Latent tuberculosis
Prophylaxis against active TB in individuals
who are in great risk as very young or
immunocompromised individuals.

16. Adverse effects
Peripheral neuritis
Optic neuritis &atrophy.
Allergic reactions ( fever,skin
rash,systemic lupus erythematosus )
Hepatitis

17. Adverse effects (cont.)
Hematological reactions
Gastrointestinal upset
Arthritic symptoms

18. Adverse effects (cont.)
CNS toxicity include ;
Lack of mental concentration , memory
loss.
Excitability & seizures
Psychosis
( Respond to pyridoxine)

19. Drug Interactions of INH
Inhibits the hepatic microsomal enzymes,
cytochrome P450 & decrease metabolism
of other drugs ( especially , Phenytoin )and
increase their toxicity .

20. Rifampin
Bactericidal
Inhibits RNA synthesis-by inhibiting
bacterial DNA- dependent RNA
polymerase enzyme.

21. Site of Action
Intracellular bacilli
Extracellular bacilli
Bacilli in caseous lesions

22. Pharmacokinetics
Well absorbed orally.
Aminosalicylic acid delay the absorption
of rifampin, (They should be given
separately at an interval of 8-12 hour ).

23. Metabolism & Excretion
Metabolized in liver by acetylation &
enters enterohepatic circulation.
Half-life 1.5-5 hours & increased in
hepatic dysfunction.
Eliminated in bile & feces( 60-65% ) &
30% in urine.

24. Distribution
Distributed throughout the body organs &
fluids . Adequate CSF concentration is
achieved in meningeal inflammation.

25. Clinical uses
Mycobacterial infections
Prophylaxis of active tuberculosis.
Treatment of deep –seated staphylococcal
infections .
Prophylactic agent following exposure to
Neisseria meningitids & H .influenzae

26. Adverse effects
Harmless red-orange discoloration of body
secretions( urine, sweat, tears) & contact
lenses ( soft lenses may be permanently
stained ).
Skin rash
Fever

27. Adverse Effects ( cont.)
Nausea & vomiting
 Hepatitis, cholestatic jaundice
Flu-like syndrome
 Hemolytic anemia, thrombocytopenia & acute
tubular necrosis.

28. Drug Interactions
Potent inducer of hepatic microsomal
enzymes ( cytochrome P450)
Increase elimination of other drugs
including :
Anticoagulants
Anticonvulsants
Contraceptives

29. Ethambutol
Bacteriostatic
Inhibits mycobacterial arabinosyl
transferase ( inhibits polymerization of
arabinoglycan an essential component of
mycobacterial cell wall )

30. Site Of Action
Intracellular & Extracellular bacilli

31. Phrmacokinetics
Well absorbed orally
Half-life 3-4 hours
75% of the drug is excreted unchanged in
the urine, 15% as metabolities.

32. Clinical uses
In combination therapy for :
Ttreatment of tuberculosis
Mycobactrium avium complex
in patients with or without HIV

33. Adverse effects
Retrobulbar (optic) neuritis causing loss of
visual acuity and red-green color
blindness.
Relatively contraindicated in
children( under 5 years).
GIT .upset .
Hyperuricemia

34. Pyrazinamide
Prodrug( converted to pyrazinoic acid ,the
active form .
Bacteriostatic
Mechanism : unknown
May act through inhibition of
mycobacterial fatty acid synthase I gene

35. Site Of Action
 More active at an acidic pH ( within
macrophages ) and active against
Intracellular Bacilli

36. Phrmacokinetics
Well absorbed from GIT
Widely distributed including CSF
Half-life 9-10 hours
Excreted primarily by renal route.

37. Clinical uses
Mycobacterial infections mainly in
multidrug resistance cases.
It is important in short –course (6 months)
regimens with isoniazid and rifampin.
Prophylaxis of TB in combination with
ciprofloxacin.

38. Adverse effects
Hepatotoxicity
Hyperuricemia( provoke acute gouty
arthritis )
Nausea & vomiting
Drug fever & skin rash

39. Streptomycin & Amikacin
Bactericidal
Inhibitors of protein synthesis by biding to
30 S ribosomal subunits.
Active mainly on extracellular bacilli

40. Clinical uses
Severe , life-threating form of T.B. as
meningitis, disseminated disease,
infections resistant to other
drugs( Multidrug resistance tuberculosis).
In aerobic gram –ve bacterial infections.

41. Adverse Effects
Ototoxicity
Nephrotoxicity
Neuromuscular block

42. Contraindications
Myasthenia gravis
Pregnancy

43. Indication of 2
nd
line treatment
Resistance to the drugs of 1
st
line.
Failure of clinical response
There is contraindication for first line
drugs.
Patient is not tolerating the drugs first
line drugs.

44. Ethionamide
Blocks synthesis of mycolic acid .
Prodrug
Is converted to active form (sulfoxide ).

45. Pharmacokinetics
Absorbed from GIT, Given only orally
Rapidly & widely distributed
Half-life 2 hours
Metabolized in liver, less than 1% is
excreted in active form in urine
Inhibits the acetylation of INH

46. Clinical uses
Is a secondary agent , to be used
concurrently with other drugs when
therapy with primary agents is ineffective
or contraindicated.

47. Adverse Effects
Anorexia, nausea, vomiting, intense
gastric irritation.
 Poorly tolerated (About 50% of patients
are unable to tolerate a single dose more
than 500 mg ).

48. Adverse Effects (cont.)
Neurological adverse effects relieved by
pyridoxine ( vit.B6 ) .
Hypotension
Alopecia
Metallic taste

49. Capreomycin
Aminoglycosides
It is an important injectable agent for
treatment of drug-resistant tuberculosis.
It is nephrotoxic and ototoxic.
Local pain & sterile abscesses may occur.

50. Cycloserine
Inhibitor of cell wall synthesis
Cleared renally
The most serious side effects are peripheral
neuropathy and CNS side effects.
Pyridoxine should be given.
Contraindicated in epileptic patients.

51. Amikacin
Used as alternative to streptomycin.
Used in multidrug- resistance tuberculosis.
No cross resistance between streptomycin
and amikacin.

52. Ciprofloxacin & levofloxacin
Effective against typical and atypical
mycobacteria.
Used against multidrug- resistant
tuberculosis.
Used in combination with other drugs.

53. Rifabutin
As rifampin , it is RNA polymerase
inhibitor.
Cross resistance with rifampin
Enzyme inducer of cytochrome p450.
Effective against typical and atypical
mycobacteria.

54. Phrmacokinetics
Absorbed from GIT

Excreted in urine & bile
Adjustment of dosage is not necessary in
patients with impaired renal function.

55. Clinical uses
Treatment of T.B. in HIV- infected
patients ( received concurrent
antiretroviral therapy)
Prevention of tuberculosis
Prevention & treatment of disseminated
atypical mycobacterial infections in AIDS
patients

56. Adverse Effects
Skin rash
GIT intolerance
Neutropenia
Orange-red discoloration ( skin, urine,
-----as rifampin ).

57. Drug Interactions
Enzyme inducer of cytochrome P450
enzymes (Less potent than rifampin ).

58. Aminosalicylic Acid (PAS).
Similar in structure to sulfonamide and p-
aminobenzoic acid.
Bacteriostatic
Folate synthesis inhibitor.

59. Pharmacokinetics
Well absorbed from GIT
Best given after meals
High concentration in pleural fluid & caseous
tissues.
Excreted mainly in urine as metabolites.

60. Clinical uses
Treatment of pulmonary & other forms of
tuberculosis.

61. Adverse effects
GIT upset
Hypersensitivity reactions
Hematological troubles
Crystalluria

62. Third line
Arginine
Vitamin D
Thioridazine
Macrolides as clarithromycin
Corticosteroids is proven for TB meningitis and
pericarditis

63. TB & Pregnancy
Untreated TB represents a far greater risk to a
pregnant woman and her fetus than treatment.
Rifampin makes hormonal contraception less
effective , so additional precautions to be taken
for birth control .
Streptomycin is used as a last alternative

64. TB& Breast Feeding
It is not a contraindication to receive drugs ,
but caution is recommended

65. Leprosy ( Hansen
,
s disease)
Deforming disease caused by Mycobactrium
leprae.
Affect cooler areas of the body in humans ( skin ,
nerve segments near to skin , mucous membranes
of the upper respiratory tract )

67. Transmission
Respiratory route

68. Drugs used in leprosy
Dapsone
Inhibits folate synthesis.
Well absorbed orally,widely distributed .
Half-life 1-2 days,tends to be retained in
skin,muscle,liver and kidney.
Excreted into bile and reabsorbed in the intestine.
Excreted in urine as acetylated.
It is well tolerated.

69. Clinical uses
Tuberculoid leprosy.
Lepromatous leprosy in combination with rifampin
& clofazimine.
To prevent & treat Pneumocystis jiroveci
pneumonia in AIDS .

70. Adverse effects
Haemolytic anaemia
Methemoglobinemia
Gastrointestinal intolerance
Fever,pruritus,rashes.
Erythema nodosum leprosum
Peripheral neuropathy

71. Clofazimine
It is a phenazine dye.
Unknown mechanism of action ,may be DNA binding.
Antiinflammatory effect.
Absorption from the gut is variable.
Given orally , once daily.
Excreted mainly in feces.
Stored mainly in reticuloendothelial tissues and skin.
Half-life 2 months.
Delayed onset of action (6 weeks).

72. Clinical uses
Multidrug resistance TB.
Lepromatous leprosy
Tuberculoid leprosy in :
patients intolerant to sulfones
dapsone-resistant bacilli.
Chronic skin ulcers caused by M.ulcerans.

73. Adverse effects
Skin discoloration ranging from red-brown to
black.
Gastrointestinal intolerance.
Red colour urine.
Eosinophilic enteritis