Transcript Antimycobacterial drugs

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
at low conc. & bacteriocidal at high
conc. Especially against actively growing bacteria.
 Inhibits synthesis of mycolic acid is an essential
components of mycobacterial cell wall.
Pharmacokinetics
 Readily
absorbed from GIT.
 Diffuse into all body fluids and tissues
 Penetrates caseous material and macrophages so it
is effective against intra and extracellular
organisms.
 Metabolized in liver by acetylation
 Excreted mainly in urine
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.
 Allergic reactions ( fever,skin rash,systemic lupus
erythematosus )
 Hepatitis
 Gastric upset
 Haemolytic anaemia
 Enzyme inhibitor
 CNS toxicity.

Rifampicin
 Bactericidal
,binds strongly to β subunit of
bacterial DNA-dependent RNA polymerase
leading to inhibition of RNA synthesis .
Pharmacokinetics
 Well
absorbed orall.
 Excreted mainly through liver into bile.
 Highly protein bind .
 Penetrates macrophages so affect extra and
intracellular organisms.
 Adequate CSF conc. Only in meningeal
inflammation.
Clinical uses
 Mycobacterial
infections
 Prophylaxis in contacts of children with
Haemophilus influenzae type b disease.
 Treatment of serious staphylococcal infections as
osteomyelitis and endocarditis.
 Meningitis by highly resistant penicillin
pneumococci
Adverse effects
Harmless red-orange colour to urine,sweat,tears,contact
lenses.
 Rashes
 Thrombocytopenia
 Nephritis
 Cholestatic jaundice,hepatitis
 Flu-like syndrome
 Induce cytochrome p-450

Ethambutol
Inhibits mycobacterial cell wall synthesis by inhibiting
arabinosyl transferase .
 Bacteriostatic
 Active against intra&extracellular bacilli .
 Well absorbed from gut.
 20% excreted in feces and 50% in urine in unchanged
form.
 Crosses BBB in meningitis
 Used only in mycobacterial infections.

Adverse effects
 Retrobulbar
(optic) neuritis causing loss of visual
acuity and red-green colour blindness.
 It is relatively contraindicated in children.
 GIT .upset .
 Hyperuricemia
Pyrazinamide
 It
is converted to pyrazinoic acid ,the active form
(prodrug)
 Mechanism is unknown.
 Bactericidal
 Acting on intracellular organisms.
 Well absorbed orally ,metabolized in liver
,excreted mainly through kidney .
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
 Life
threating forms of TB ( meningitis,
dissiminated disease).
 Resistant cases (Multidrug resistance tuberculosis
at least to INH & rifampicin ) .
 Amikacin
can be used as alternative to
streptomycin.
 Both active mainly against extracellular bacilli.
Indication of 2nd line treatment
to the drugs of 1st line.
 Failure of clinical response
 Increase of risky effects.
 Patient is not tolerating the drugs first line drugs.
 Resistance
Ethionamide
As isoniazid blocks synthesis of mycolic acid .
 Available only in oral form.
 Metabolized by the liver ,excreted by kidney.
 It is poorly tolerated because of :
 -intense gastric irritation
 -neurologic symptoms
 -hepatotoxicity
 Used in TB & leprosy.

Capreomycin
 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 resistant strains.
 Used in combination with other drugs.
Rifapentine
 As
rifampicin , it is RNA polymerase inhibitor.
 Cross resistance with rifampicin.
 Potent inducer of cytochrome p450.
 Effective against typical and atypical
mycobacteria.
Aminosalicylic Acid (PAS).
Similar in structure to sulfonamide and p-aminobenzoic
acid.
 Folate synthesis inhibitor.
 Well absorbed from GIT.
 Widely distributed in tissues except CSF.
 Excreted in urine as active and as metabolic products.
 Causes crystalluria,anorexia,nausea,diarrhea,epigastric
pain.
 Peptic ulcer and haemorrhage can occur.
 Hypersensitivity reactions.

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.