Download 05. Antimycobacterial drugs

Chemotherapy of Tuberculosis
 Medically
important mycobacteria
 Mycobacterium Tuberculosis
 A typical Mycobacterium
 Mycobacterium Leprae
Tuberculosis
 Common
sites of infections
 Apical areas of lung
 Renal parenchyma
 Growing ends of bones
 Where oxygen tension is high
Transmission
 Through
air ( air borne transmission )
 Active tuberculosis kill about two of every three
people if left untreated .
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.
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
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
Antimycobacterial drugs
First
line of drugs:
 Isoniazid
(INH)
 Rifampin
 Ethambutol
 Streptomycin
 Pyrazinamide
Never use a single drug therapy
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 .
The
Continue
 For
latent tuberculosis , the standard treatment is
six to nine months of isoniazid alone.
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, activated by
mycobacterial catalase -peroxidase
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.
 Highly concentrated in pleural fluids.
 Its concentration in CSF is significant in
inflammed meninges.
 Penetrates well into caseous material.
Metabolism & Excretion
Metabolized
in the liver by acetylation
.
Excreted in urine mainly as
metabolites.
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.
Adverse effects
Peripheral
neuritis
Optic neuritis &atrophy.
Allergic reactions ( fever,skin
rash,systemic lupus erythematosus )
Hepatitis
Adverse effects (cont.)
Hematological
reactions
Gastrointestinal upset
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 .
Rifampin
 Bactericidal
 Inhibits
RNA synthesis-by inhibiting
bacterial DNA- dependent RNA
polymerase enzyme.
Site of Action
 Intracellular
bacilli
 Extracellular bacilli
 Bacilli in caseous lesions
Pharmacokinetics
 Well
absorbed orally.
 Aminosalicylic acid delay the absorption
of rifampin, (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 . Adequate CSF concentration is
achieved in meningeal inflammation.
Clinical uses
 Mycobacterial
infections
 Prophylaxis of active tuberculosis.
 Treatment of deep –seated staphylococcal
infections .
 Prophylactic agent following exposure to
Neisseria meningitids & H .influenzae
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
 Hepatitis, cholestatic jaundice
 Flu-like syndrome
 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 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
 In
combination therapy for :
Ttreatment of tuberculosis
Mycobactrium avium complex
in patients with or without HIV
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 .
 Bacteriostatic
 Mechanism : unknown
 May act through inhibition of
mycobacterial fatty acid synthase I gene
Site Of Action

More active at an acidic pH ( within
macrophages ) and active against
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 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.
Adverse effects
 Hepatotoxicity
 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.
 Active mainly 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, intense
gastric irritation.
 Poorly tolerated (About 50% of patients
are unable to tolerate a single dose more
than 500 mg ).
Adverse Effects (cont.)
 Neurological
adverse effects relieved by
pyridoxine ( vit.B6 ) .
 Hypotension
 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 side effects.
 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
rifampin , it is RNA polymerase
inhibitor.
 Cross resistance with rifampin
 Enzyme inducer of cytochrome p450.
 Effective against typical and atypical
mycobacteria.
Phrmacokinetics
 Absorbed
 Excreted
from GIT
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 ( received concurrent
antiretroviral therapy)
 Prevention of tuberculosis
 Prevention & treatment of disseminated
atypical mycobacterial infections in AIDS
patients
Adverse Effects
 Skin
rash
 GIT intolerance
 Neutropenia
 Orange-red
discoloration ( skin, urine, ----as rifampin ).
Drug Interactions
 Enzyme
inducer of cytochrome P450
enzymes (Less potent than rifampin ).
Aminosalicylic Acid (PAS).
 Similar
in structure to sulfonamide and paminobenzoic acid.
 Bacteriostatic
 Folate synthesis inhibitor.
Pharmacokinetics
 Well
absorbed from GIT
 Best given after meals
 High concentration in pleural fluid & caseous
tissues.
 Excreted
mainly in urine as metabolites.
Clinical uses
 Treatment
of pulmonary & other forms of
tuberculosis.
Adverse effects
 GIT
upset
 Hypersensitivity reactions
 Hematological troubles
 Crystalluria
Third line
 Arginine
 Vitamin
D
 Thioridazine
 Macrolides as clarithromycin
 Corticosteroids is proven for TB meningitis and
pericarditis
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
TB& Breast Feeding
 It
is not a contraindication to receive drugs , but
caution is recommended
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 )
Transmission
 Respiratory
route
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 jiroveci
pneumonia in AIDS .
Adverse effects
 Haemolytic
anaemia
 Methemoglobinemia
 Gastrointestinal intolerance
 Fever,pruritus,rashes.
 Erythema nodosum leprosum
 Peripheral neuropathy
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