Download 13th Lecture 1436

PHL 424
Antimicrobials
13th Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Anti-tuberculous drugs
Anti-tuberculous drugs, Overview
 Mycobacterial organisms cause Tuberculosis, Mycobacterium avium complex (MAC)
disease, and leprosy
 These diseases are chronic and necessitate prolonged treatment
 Tuberculosis is the primary worldwide cause of death due to infectious disease
 Nowadays , there is an increased incidence of tuberculosis due to HIV associated
Mycobateria
 A number of characteristics of mycobacteria make these diseases chronic and
necessitate prolonged treatment:
1. Mycobacteria grow slowly and may be dormant in the host for long periods; thus,
they are relatively resistant to the effects of antibiotics
2. Many antibacterial agents do not penetrate the cell walls of mycobacteria, and a
portion of mycobacteria can reside inside macrophages, adding another permeability
barrier that effective agents must cross
3. Mycobacteria are agile in developing resistance to single chemotherapeutic agents
 As a consequence, the essential elements of the treatment of mycobacterial disease
are to always treat with at least two different drugs to which the organism is
susceptible and to treat for sufficient duration (months to years) to prevent relapse
Anti-tuberculous drugs, Individual drugs
First-line
– Isoniazid
– Rifampicin
– Ethambutol
– Pyrazinamide
Second-line
– Clarithromycin
– Ciprofloxacin
– Capreomycin
– Cycloserine
– Kanamycin
– Amikacin
– streptomycin
Anti-tuberculous drugs, Isoniazid
 Isoniazid (INH) is still considered the primary drug for the
chemotherapy of tuberculosis
 All patients with disease caused by isoniazid-sensitive
strains of the tubercle bacillus should receive the drug if
they can tolerate it
 Isoniazid is the hydrazide of isonicotinic acid. It is synthetic
analog of pyridoxine
 It is a small (MW 137), simple molecule freely soluble in
water
Mycobacterial cell wall
Isoniazid, Mechanism of Action
 Mechanism of Action
 INH passes freely through mammalian cell wall, that is why it is effective for
intracellular organism
 A primary action of isoniazid is to inhibit the biosynthesis of mycolic acids,
which are long, branched lipids that are attached to a unique
polysaccharide, arabino galactan, to form part of the mycobacterial cell wall
 Mycolic acids are unique to mycobacteria, explaining the high degree of
selectivity of the antimicrobial activity of isoniazid
 Isoniazid is a prodrug; mycobacterial catalase-peroxidase (KatG) converts
isoniazid into an active metabolite
 Its main targets are the two mycolic acid synthetic enzymes:
1.
2-trans-enoyl-acyl carrier protein reductase (InhA)
2.
β-ketoacyl-acyl carrier protein synthase (KasA)
 Isoniazid also inhibits mycobacterial catalase-peroxidase (the isoniazidactivating enzyme), which may increase the likelihood of damage to the
mycobacteria from reactive oxygen species and H2O2
Isoniazid, Resistance & Pharmacokinetics
 Resistance
 The most common mechanism of isoniazid resistance is mutations in catalaseperoxidase (katg) gene, preventing conversion of the prodrug isoniazid to its
active metabolite
 Mutation in the mycobacterial inhA and KasA genes involved in mycolic acid
biosynthesis
 Cross-resistance between isoniazid and other agents used to treat tuberculosis
(except ethionamide, which is structurally related to isoniazid) does not occur
 Pharmacokinetics
 Isoniazid is readily absorbed when administered either orally or parenterally
 Fatty food & aluminum-containing antacids may reduce absorption
 Isoniazid diffuses readily into all body fluids and cells. It is detectable in
significant quantities in pleural and ascitic fluids; concentrations in the CSF
with inflamed meninges are similar to those in the plasma and 20% of
plasma concentration with non-inflamed meninges
 Penetrate well into macrophages so it is effective against intra and
extracellular organisms
 Metabolized in liver by acetylation
Isoniazid, Pharmacokinetics, contd. & Uses
 Metabolism by enzymatic acetylation is genetically determined:
1.
Slow acetylation – better response (Scandinavians, Jews, and North
African Caucasians)- t½: 2-5h
2.
Fast acetylation(Japanese) – t ½: 70 min
 The half-life of the drug may be prolonged by hepatic insufficiency
 Because isoniazid is relatively nontoxic, a sufficient amount of drug can be
administered to fast acetylators to achieve a therapeutic effect equal to that
seen in slow acetylators
 Excreted mainly in urine within 24 hours, mostly as metabolites
 Uses
 Mycobacterial infections. It is recommended to be given with pyridoxine to
avoid peripheral and CNS toxicity in malnourished patients and those
predisposed to neuropathy (e.g., elderly, pregnant women, HIV-infected
individuals, diabetics, alcoholics and uremics)
 Latent tuberculosis in patients with positive tuberculin skin test
 Prophylaxis against active TB in individuals who are in great risk such as
very young or immunocompromised individuals
Isoniazid, Adverse Effects
 Adverse Effects
 Peripheral neuritis (most commonly paresthesias of feet and hands). Neuropathy
is more frequent in slow acetylators and in individuals with diabetes mellitus, poor
nutrition, or anemia
 Optic neuritis
 Allergic reactions ( fever, skin rash, systemic lupus erythematosus)
 Hepatitis (the most frequent major toxic effect)
 Gastric upset
 Haemolytic anaemia
 CNS toxicity (memory loss, psychosis and seizures)