05. Antimycobacterial drugs
Download
Report
Transcript 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