Transcript Antimycobacterial drugs

Chemotherapy of Tuberculosis
 Medically
important mycobacteria
 Mycobacterium Tuberculosis
 A typical Mycobacterium
 Mycobacterium Leprae
Treatment Of Tuberculosis
 Tuberculosis
remains the primary cause of
death due to infectious disease.
 Organs involved --------- primarily lungs
 Drugs are divided into two groups:
 First line
 Second line
Antimycobacterial drugs
First
line of drugs:
 Isoniazid
(INH)
 Rifampicin
 Ethambutol
 Streptomycin
 Pyrazinamide
Never use a single drug therapy
–rifampicin combination
administered for 9 months will cure
95-98% of cases .
Addition of pyrazinamide for this
combination for the first 2 months
allows total duration to be reduced to
6 months.
Isoniazid
Isoniazid
Bacteriostatic
for resting bacilli.
Bactericidal for rapidly
dividing bacilli.
Is effective against intracellular
as well as extracellular bacilli
Mechanism Of Action
Is
a prodrug
Cell wall synthesis inhibitor
Inhibits synthesis of Mycolic acids---Which are essential components of
Mycobacterial cell walls.
Pharmacokinetics
Readily
absorbed when given either
orally or parenterally.
Aluminum
containing antacids
interfere with absorption.
Distribution
 Diffuse
rapidly into all body fluids and
cells.
 Detected in significant concentrations in
pleural & ascitic fluids.
 Its concentration in CSF is significant in
inflammed meninges.
 Penetrates well into caseous material.
Metabolism & Excretion
75%
to 95% of a dose of INH is
excreted in urine within 24 hours.
Mostly as metabolities.
The main excretory products in
human result from enzymatic
acetylation.
Clinical uses
 Mycobacterial
infections (it is recommended
to be given with pyridoxine to avoid
neuropathy).
Latent tuberculosis in patients with
positive tuberculin skin test
 Prophylaxis against active TB in individuals who
are in great risk as very young or
immunocompromised individuals.
Adverse effects
Peripheral
neuritis
Optic neuritis &atrophy.
Allergic reactions ( fever,skin
rash,systemic lupus erythematosus )
Hepatitis
Adverse effects (cont.)
Hematological
reactions
Vasculitis
Arthritic
symptoms
Adverse effects (cont.)
 CNS
toxicity include ;
 Lack of mental concentration , memory
loss.
 Excitability & seizures
 Psychosis
 ( Respond to pyridoxine)
Drug Interactions of INH
 Inhibits
the hepatic microsomal enzymes,
cytochrome P450 & decrease metabolism
of other drugs ( especially , Phenytoin )and
increase their toxicity .
Rifampicin
 Bactericidal
 Inhibits
RNA synthesis----- by binding to
the beta –subunit of bacterial DNA
dependent RNA polymerase.
Site of Action
 Intracellular
bacilli
 Extracellular bacilli
 Bacilli in caseous lesions
Pharmacokinetics
 Well
absorbed orally.
 Aminosalicylic acid delay the absorption
of rifampicin, (They should be given
separately at an interval of 8-12 hour ).
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.
Distribution
 Distributed
throughout the body organs &
fluids including CSF in effective
concentration.
Clinical uses
 Mycobacterial
infections
 Prophylaxis of active tuberculosis.
 Treatment of serious staphylococcal
infections as osteomyelitis and
endocarditis.
 Meningitis by highly resistant penicillin
pneumococci
Adverse effects
 Harmless
red-orange discoloration of body
secretions( urine, sweat, tears) & contact
lenses ( soft lenses may be permanently
stained ).
 Skin rash
 Fever
Adverse Effects ( cont.)
 Nausea
& vomiting
 Hepatotoxicity
 ( Hepatitis, cholestatic jaundice)
 If administered less than twice weekly causes a
flu-like syndrome( fever , chills, myalgias,
hemolytic anemia, thrombocytopenia & acute
tubular necrosis.
Drug Interactions
 Potent
inducer of hepatic microsomal
enzymes ( cytochrome P450)
 Increase elimination of other drugs
including :
 Anticoagulants
 Anticonvulsants
 Contraceptives
Ethambutol
 Bacteriostatic
 Inhibits
mycobacterial arabinosyl
transferase ( inhibits polymerization
reaction of arabinoglycan an essential
component of mycobacterial cell wall )
Site Of Action
 Intracellular
& Extracellular bacilli
Phrmacokinetics
 Well
absorbed orally
 Half-life 3-4 hours
 75% of the drug is excreted unchanged in
the urine, 15% as metabolities.
Clinical uses
 Treatment
of tuberculosis in combination
with other drugs.
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
Pyrazinamide
 Prodrug( converted
to pyrazinoic acid ,the
active form .
 Bactericidal
 Acting on mycobacterial fatty acid
synthase I gene involved in mycolic acid
biosynthesis.
Site Of Action

Intracellular Bacilli
Phrmacokinetics
 Well
absorbed from GIT
 Widely distributed including CSF
 Half-life 9-10 hours
 Excreted primarily by renal route.
Clinical uses
 Mycobacterial
infections (TB) mainly in
multidrug resistance cases.
 It is important in short –course (6 months)
regimens with isoniazid and rifampicin.
 Prophylaxis of TB in combination with
ciprofloxacin.
Adverse effects
 Hepatotoxic
 Hyperuricemia(
provoke acute gouty
arthritis )
 Nausea & vomiting
 Drug fever & skin rash
Streptomycin & Amikacin
 Bactericidal
 Inhibitors
of protein synthesis by biding to
30 S ribosomal subunits.
 Acting on extracellular bacilli
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.
Adverse Effects
 Ototoxicity
 Nephrotoxicity
 Neuromuscular
block
Contraindications
 Myasthenia
 Pregnancy
gravis
Indication of 2nd line treatment
to the drugs of 1st line.
 Failure of clinical response
 There is contraindication for first line
drugs.
 Patient is not tolerating the drugs first
line drugs.
 Resistance
Ethionamide
Blocks
synthesis of mycolic acid .
 Prodrug
 Is
converted to active form (sulfoxide ).
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
Clinical uses
 Is
a secondary agent , to be used
concurrently with other drugs when
therapy with primary agents is ineffective
or contraindicated.
Adverse Effects
 Anorexia,
nausea, vomiting, gastric
irritation.
 About 50% of patients are unable to
tolerate a single dose more than 500mg.
Adverse Effects (cont.)
 CNS
symptoms include :
 Mental depression
 Drowsiness
 Convulsions & peripheral neuropathy
 Headache
 ( Pyridoxine relieves the neurologic
symptoms)
Adverse Effects(cont.)
 Severe
hypotension
 Allergic skin reactions
 Hepatitis
 Alopecia
 Metallic taste
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.
Cycloserine
 Inhibitor
of cell wall synthesis
 Cleared renally
 The most serious side effects are peripheral
neuropathy and CNS dysfunction, including
depression & psychotic reaction.
 Pyridoxine should be given.
 Contraindicated in epileptic patients.
Amikacin
 Used
as alternative to streptomycin.
 Used in multidrug- resistance tuberculosis.
 No cross resistance between streptomycin
and amikacin.
Ciprofloxacin & levofloxacin
 Effective
against typical and atypical
mycobacteria.
 Used against multidrug- resistant
tuberculosis.
 Used in combination with other drugs.
Rifabutin
As
rifampicin , it is RNA polymerase
inhibitor.
 Cross resistance with rifampicin but not to
all microorganisms.
 Enzyme inducer of cytochrome p450.
 Effective against typical and atypical
mycobacteria.
Phrmacokinetics
 Absorbed
from GIT
 Lipophilic drug
 Excreted in urine & bile
 Adjustment of dosage is not necessary in
patients with impaired renal function.
Clinical uses
 Treatment
of T.B. in HIV- infected patients
( replaced rifampicin, because it is less
potent enzyme inducer)
 Prevention of tuberculosis
 Prevention & treatment of disseminated
atypical mycobacterial infections in AIDS
patients
Adverse Effects
 Skin
rash(4%)
 GIT intolerance (3%)
 Neutropenia (2%)
 Arthralgia
 Orange-red discoloration ( skin,urine, ----as rifampicin ).
Drug Interactions
 Enzyme
inducer of cytochrome P450
enzymes.
Aminosalicylic Acid (PAS).
 Similar
in structure to sulfonamide and paminobenzoic acid.
 Bacteriostatic
 Folate synthesis inhibitor.
Pharmacokinetics
 Well
absorbed from GIT
 Best given after meals
 Distributed throughout the total body water &
reaches high concentration in pleural fluid &
caseous tissues.
 CSF levels are low
 Half-life one hour
 80% of the drug is excreted in urine as
metabolities.
Clinical uses
 AS
a second line agent is used in the
treatment of pulmonary & other forms of
tuberculosis.
Adverse effects
 GIT
upset ( anorexia, nausea, epigastric
pain , diarrhea ).
 Hypersensitivity reactions
 Hematological troubles ( leukopenia,
agranulocytosis, eosinophilia)
 Crystalluria
Clofazimine
Drug Regimens
6
months duration
 A) First 2 months:
 INH+ Rifampin + Pyrazinamide +
Ethambutol or Streptomycin
 B) Last 4 months
 INH + Rifampin
2- Drug Regimens
 2-
9 months duration:
 A) First 2 months:
 INH + Rifampicin + Ethambutol
 B)
Last 7 months:
 INH + Rifampicin
Drug Regimens(cont.)
 If
there is possibility of drug resistance,
Ethambutol or Streptomycin or even
second line drugs is added
 Depending on :
 Type of resistance
 Sensitivity of microorganisms
Drug Regimens (cont.)
 We
give drug combination to :
 1- Avoid the emergence of resistance
 2- Increase therapeutic efficacy
 3- Decrease : Dose, Frequency of dose
administration, adverse effects
Treatment Of Tuberculosis In Pregnant
Women
 AS
previously mentioned , but
streptomycin is contraindicated because it
can cause congenital ototoxicity
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.
Clinical uses
 Tuberculoid
leprosy.
 Lepromatous leprosy in combination with rifampin
& clofazimine.
 To prevent & treat Pneumocystis pneumonia in
AIDS caused by Pneumocystis jiroveci (
Pneumocystis carinii).
Adverse effects
 Haemolytic
anaemia
 Methemoglobinemia
 Gastrointestinal intolerance
 Fever,pruritus,rashes.
 Erythema nodosum leprosum
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).

Clinical uses
 Multidrug
resistance TB.
 Lepromatous leprosy
 Tuberculoid leprosy in :

patients intolerant to sulfones
dapsone-resistant bacilli.
 Chronic skin ulcers caused by M.ulcerans.

Adverse effects
 Skin
discoloration ranging from red-brown to black.
 Gastrointestinal intolerance.
 Red colour urine.
 Eosinophilic enteritis
Treatment of TB in pregnant women
 INH
( pyridoxine should be given ),
 Rifampicin , ethambutol
 Pyrazinamide is given only if :
 Resistant to other drugs is documented
 Streptomycin is contraindicated.
 Breast feeding is not contraindication to receive
drugs , but caution should be observed.