Transcript Drugs used in Tuberculosis

Presented by:Professor Dr. Imad A-J
Thanoon
Department of Pharmacology
College of Medicine-University of
Mosul
Mycobacterium Infections
Common Infection Sites
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lung (primary site)
brain
bone
liver
kidney
Difficult to treat:
1.
Most antibiotics are effective against rapidly growing
organism in contrast to M.tb slow growing
2.
Mycobacterium Cell can be dormant, thus completely
resistant to many antibiotics or killed very slowly by few
drugs
The lipid rich mycobacterium Cell wall is impermeable to
many drugs.
A substantial proportion are intracellular &chemotherapeutic
agents penetrate poorly
Mycobacterium develop resistance to any single drug
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Caseation &fibrosis block the blood vessels supplying
necrotic area thus penetration of antitubercular drug
difficult
• Isoniazid (INH), Rifampicin, Pyrazinamide,
Ethambutol, and Streptomycin are five first line
agents for treatment of tuberculosis.
• Isoniazid and Rifampicin are the two most active
drugs. An Isoniazid – Rifampicin combination
administrated for 9 months will cure 95-98% of
cases of TB. The addition of Pyrazinamide to an
Isoniazid –Rifampicin combination for the first 2
months allow the total duration of therapy to be
reduced to 6 months without loss of efficacy.
• In practice, therapy is initiated with a four drug
regimen of Isoniazid–Rifampin , Pyrazinamide,
and either Ethambutol or Streptomycin
Antitubercular Therapy
Effectiveness depends upon:
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Type of infection
Adequate dosing
Sufficient duration of treatment
Drug compliance
Selection of an effective drug combination
Isoniazid (INH)
• INH introduced in 1952, is the most active drug for
the treatment of tuberculosis caused by susceptible
strains.
• INH is the hydrazine of Isonicotinic acid .It is
bactericidal for effectively growing tubercle bacilli.
• INH able to penetrate into phagocytic cells .
• Metabolised in the liver by acetylation ( watch for
slow acetylator).
• Diabetic patients taking INH should monitor their
blood glucose levels because hyperglycemia
may occur.
Mechanism of action of INH:
• INH is a pro-drug that is activated in the body,
the activated form of INH exerts its lethal
effect by blocks mycolic acid synthesis, an
essential components of mycobacterial cell
walls.
• It is an enzyme inhibitors for drug
metabolism, it inhibit meta. Of
warfarin,diazepam,CBZ and phenobarbitone.
Adverse reactions :
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2.
allergic reactions : fever and skin rashes .
direct toxicity : INH induced hepatitis is the most frequent
major toxic effect , caused by the acetyl hydrazine
metabolite.
3. clinical hepatitis with loss of appetite, nausea, vomiting,
jaundice, and right upper quadrant pain occurs in 1% of INH
recipients and can be fatal.
4. Peripheral neuropathy by ↑vitamin B6 excretion. More
frequent in slow acetylators
5. CNS toxicity: memory loss, psychosis, and seizures.
6. Miscellaneous : hematological abnormality provocation of
B6 deficiency, anemia, tinnitus, & GI discomfort .
No dose modification in R-F
C/I acute liver disease.
Rifampicin :
Mechanism of action of Rifampicin :
• Rifampicin binds strongly to the B-subunit of bacterial
DNA-dependant RNA polymerase and there by inhibit
RNA synthesis, it is bactericidal.It act both intra &
extracellular,and its bactericidal efficacy is about that of
INH.
• Food interfere with the absorption, wide penetration to
tissues(placenta, meninges,cavities, caseous mass)
• Eliminated in bile & undergo enterohepatic circulation.
Adverse reactions of Rifampicin :
• Rifampicin in part a harmless orange color to urine, sweat,
tears, and contact lenses (soft lenses may be permanently
stained ).
• Occasional adverse effects include rashes, nephritis, and
thrombocytopenia.
• It may cause cholestatic jaundice and occasionally hepatitis.
• Rifampin causes a flu-like syndrome characterized by fever,
chills, myalgias, anemia, thrombocytopenia and some times is
associated with acute tubular necrosis.
• Note: rifampicin cause oral contraceptives to become
ineffective
Ethambutol :
• Is a synthetic drug
Mechanism of action :Ethambutol is an inhibitor
an essential component of the mycobacterial
cell mall( by inhibiting the enzyme mycolic
arabin transfersae required for polymerization
reaction of arabinoglycan).
Note: Dose to be reduced in RF ,C/I < 6 years
Adverse reactions :
• The most common serious adverse events is
retrobulbarneuritis causing loss of visual acuity
and red-green color blindness.
• This dose–related side effect is more likely to
occur at dosage of 25mg/kg/d visual acuity
testing is desirable if the 25mg/kg/d dosage is
used.
• Ethambutol is relatively contraindicated in
children too young to permit assessment of
visual acuity and red-green color discrimination .
Pyrazinamide :
• Pyrazinamide is a weak tuberculocidal, more active
in the first 2 months of therapy, active against intra &
extracellular bacilli
• Mechanism of action :Act by inhibiting mycolic
acid synthesis
• It is distributed throughout the body after oral use and
excreted mainly by GF. It reduce the relapse rate
from 10.3% to 3.4%
Adverse reactions of
Pyrazinamide:
• Major adverse effects of Pyrazinamide
include hepatatotoxixity ( in 1-5% of
patients ), it is the most hepatotoxic drug,
nausea, vomiting, drug fever and
hyperuricemia , the latter occurs uniformly
and is not a reason to half therapy .
hyperuricemia may provoke acute gouty
arthritis . ( it inhibit the excretion of urates).
Streptomycin :
• Is aminoglycosides group, which are group
of bactericidal antibiotics and sharing
chemical , antimicrobial, pharmacologic
and toxic characteristics . More active
against extracellular bacilli, absorption
from IM site 30-60 minutes excreted
unchanged in the urine.
Adverse effects of Streptomycin
• Streptomycin is ototoxic and nephrotoxic. vertigo
and hearing loss are the most common side
effects, and may be permanent. ototoxicity is
dose related, and the risk is increased in elderly,
as with all aminoglycosides, the dose must be
adjusted according to renal function toxicity can
be reduced by limiting therapy to no more than
6 months whenever possible .It can cause
sterile abscess at the injection site.
Alternative second-line drugs in
treatment of tuberculosis :
• The alternative drugs listed below are
usually considered only :• in the case of resistance to the drugs of
first choice ( which occur with increasing
frequency )
• in case of failure of clinical is available to
deal with toxic effects.
Ethionamide :
• Ethionamide is chemically related to INH and
also block the synthesis of mycolic acids .
available only in oral form it is metabolized by
the liver .
Although effective in the treatment of tuberculosis,
is poorly tolerated because of the intense gastric
irritation and neurologic symptoms that
commonly occur. Ethionamide is also
hepatotoxic. neurologic symptoms may be
alleviated by pyridoxine.
Capreomycin :
• Capreomycin (a peptide) is an important
injectable agent for treatment of drug resistant
tuberculosis. strains of m. tuberculosis that are
resistant to streptomycin or amikacin.
• Capreomycin is nephrotoxic and ototoxic
tinnitus, deafness, and vestibular disturbances
occurs the injection causes significant local
pain , and sterile abscessed may occur .
Cycloserine :
• Cycloserine is an inhibitor of cell wall synthesis,
inhibit many gram negative and gram positive
organisms, but it is used almost exclusively to
treat tuberculosis resistant to first line agents .
• The most serious adverse effects are peripheral
neuropathy ,depression and psychotic reactions.
pyridoxine 150mg /d should be given with
Cycloserine.
Kanamycin and Amikacin :
The pharmacology, mode of action, toxicity
and antibacterial properties of kanamycin
and Amikacin are similar to streptomycin ,
but prevalence of drug –resistant, strains
is low
Ciprofloxacin and Levofloxacin :
• Quinolones are bactericidal . Floroquinolones are an
important recent addition to the therapeutic regimens
against tuberculosis, specially strains that are
resistant to first –line agents.
• The drug most be used in combination with two or
more other active agents. A floroquinolone plus
Pyrazinamide may also be used to prevent disease
following contact to active case of multi drug –
resistant tuberculosis .