Download Chapter 44 Antituberculosis Drugs

Chapter 44 Antituberculosis
Drugs
Department of pharmacology
Liu xiaokang(刘小康）
2010,3
• Therapeutic Goals:
• (1) Prevention or prophylaxis.
• (2) Cure of clinical disease.
• (3) Requirements: a) Prolonged therapy.
b)Combined therapy. c) Compliance. d)
Prevention of development of drug
resistance. e) Cures, ideally, 95-100%.
• Properties of Mycobacterium
tuberculosis:
• a) Cell wall -- high lipid (60% dry weight)
content.
• b) Mycolic acid a major component.
• c)Slow growth.
• d) Survive within phagocytes.
Isoniazid (INH)
• General comments:
• (1) Prophylaxis as single agent.
• (2)Cure -- ALWAYS in combination:
Slows development of resistance (to INH
alone -- 1 mutation in 106 cell divisions; to
2nd drug -- 1 mutation in 106 to 108 cell
divisions; Combination -- Odds of
resistance = 1 in 106 x 106 = 1 in 1012!!).
• Antibacterial activity:
• Bacteriostatic at most concentrations (is
bactericidal
to
actively
growing
organisms)
• Mechanism of action:
• Inhibits mycolic acid synthesis.
• Resistance:
• 1998 - 8-10% of isolates in US are
resistant (10-20% in Caribbean and
Southeast Asia). Organisms may be
Multidrug-resistant.
• Pharmacokinetics:
• PO, Well absorbed, Widely distributed
(intracellular,
CSF,
Necrotic
material).
Elimination mainly acetylation - liver Nacetyltransferase.
• Fast and slow acetylators:
Plasma
concentration in fast acetylators may be 1/3 to
1/2 that of slow acetylators. Elimination halflife (Fast = 70 min, Slow = 180 min, Fast/Slow =
50:50 Western countries (whites and blacks),
Fast/Slow = 90/10 Eskimos and Japanese.
• Adverse Effects:
• (1) Allergic, Including fever, skin
eruptions, hepatitis, and various kinds of
rashes. Hematological reactions, e.g.,
thrombocytopenia, agranulocytosis,
eosinophilia, and anemia may occur.
Reversible vasculitis may occur and
arthritic symptoms at various joints may
be observed.
• (2) Most frequent -- Hepatitis -- 2 types:
a)minor increase in liver
aminotransferases -- not have to stop
drug, 10-20% of cases, Not symptomatic.
b) Clinical hepatitis in 1% can be fatal -Stop drug. loss of appetite, nausea,
vomiting, jaundice, and upper right
quadrant pain.
• (3) Most notable -- peripheral neuritis
(including optic neuritis): in 10-20% if
given > 5 mg/kg/d, but infrequent in
standard dose of 300 mg/adult (Assuming
70 kg as standard, 300 is 4.3 mg/kg).
Predisposing conditions: slow acetylators,
malnutrition, alcoholism, diabetes, AIDS,
uremia.Supplement with pyridoxine
(Vitamin B6)
Rifampin
• Mechanism of Action:
• Binds
to
DNA-dependent
RNA
polymerase, Inhibits initiation -- not
elongation.
• Antibacterial Spectrum:
• M. tuberculosis, Bactericidal, Broad
spectrum of bacteria, Many Gram–
bacteria and many chlamydia.
• Pharmacokinetics:
• PO -- Well absorbed, Broadly distributed
-- even CSF. Orange-red color stains
tissues / secretions / urine. Enterohepatic
cycling and partially biotransformed in
liver. Drug and metabolites eliminated in
feces. Autoinduction of metabolism
( Half-life shortens 40% first 14 days of
Rx, Hepatic microsomal induction).
• Clinical uses:
• (1) Tuberculosis, Never used alone for
Therapy of TB.
• (2) Leprosy.
• (3) Various bacterial infections, e.g., with
a beta-lactam or vancomycin for
staphylococcal endocarditis.
Meningococcal and staphylococcal
carrier states.
• Adverse reactions:
• Relatively safe, less than 4% in TB
patients have significant reactions.
• Drug interaction:
• Hepatic microsomal induction, Shortens
half-life of many drugs.
• Resistance:
• Frequency of resistance is 1:106
organisms (M. tb). Develops quickly, due
to changes in the beta subunit of DNAdependent RNA polymerase. Not use
drug alone for TB or other bacteria
Ethambutol
• Activity:
• No effect on bacteria other than
mycobacteria. Suppresses growth (static)
of organisms resistant to streptomycin
and isoniazid, i.e., no cross resistance.
• Resistance to ethambutol develops.
• Mechanism:
• Not clear. May be interfering RNA
synthesis or inhibits synthesis of
component of mycobacterial cell wall –
arabinogalactan(阿拉伯半乳糖 ) (This
may increase penetration of other drugs
into the organisms).
• Clinical use: Always used in combination.
• Adverse reactions: Minimally toxic (<2%) at
15 mg/kg per day (usual dose), decreased visual
acuity, rash, drug fever. Optic neuritis
(reversible) -- most important adverse effect
and Dose related: Occurs in 15% of patients
receiving 50 mg/kg per day and 5% of those
receiving 25 mg/kg per day and <1% 15 mg/day.
Decreased visual acuity and red/green color
blindness.
Pyrazinamide
• Activity: Bactericidal to tubercle bacilli
within monocytes at 12.5 μg/ml. (requires
slightly acidic pH), Resistance develops
rapidly when used alone.
• Mechanism: unknown.
• Pharmacokinetics:
• Orally administered at 1 gram gives 45
μg/ml at 2 h and 10 μg/ml at 15 h
(Normal dose is 20-30 mg/kg po). Broadly
distributed. Eliminated primarily by
glomerular
filtration;
also
biotransformed.
• Adverse reactions: most common and
serious side effect is liver injury.
• Other antituberculosis dugs:
Streptomycin, rifapentine, rifandin, paraaminosalicylic acid, ethionamide,
amikacin, fluoroquinolones.
•
(The end)