DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Mechanisms of Resistance. Mutations involved in cycloserine
resistance to pathogenic Mycobacteria are currently unknown.
However, resistance in clinical isolates of M. tuberculosis has been
detected in 10-82% of isolates (Anonymous, 2008b).
Absorption, Distribution, and Excretion. Oral cycloserine is
almost completely absorbed. The population pharmacokinetics are
best described using a one-compartment model with first-order
absorption and elimination (Zhu et al., 2001). The drug’s t 1/2
is
9 hours. C max
in plasma is reached in 45 minutes in fasting subjects,
but is delayed for up to 3.5 hours with a high-fat meal. See
Table 56–2 for PK values. Cycloserine is well distributed throughout
body. There is no appreciable barrier to CNS entry for
cycloserine, and cerebrospinal fluid (CSF) concentrations are
approximately the same as those in plasma. About 50% of
cycloserine is excreted unchanged in the urine in the first 12 hours;
a total of 70% is recoverable in the active form over a period of
24 hours. The drug may accumulate to toxic concentrations in
patients with renal failure. About 60% of it is removed by
hemodialysis, and the drug must be re-dosed after each hemodialysis
session (Malone et al., 1999a).
Therapeutic Uses. Cycloserine is available for oral administration.
The usual dose for adults is 250-500 mg twice daily.
Untoward Effects. Neuropsychiatric symptoms are common and
occur in 50% of patients on 1 g/day, so much so that the drug has
earned the nickname “psych-serine.” Symptoms range from
headache and somnolence to severe psychosis, seizures, and suicidal
ideas. Large doses of cycloserine or the concomitant ingestion of
alcohol increases the risk of seizures. Cycloserine is contraindicated
in individuals with a history of epilepsy and should be used with
caution in individuals with a history of depression.
Capreomycin
Capreomycin (CAPASTAT) is an antimycobacterial cyclic peptide. It
consists of four active components: capreomycins IA, IB, IIA, and
IIB. The agent used clinically contains primarily IA and IB.
Antimycobacterial activity is similar to that of aminoglycosides as
are adverse effects, and capreomycin should not be administered
with other drugs that damage cranial nerve VIII.
Bacterial resistance to capreomycin develops when it is given
alone; such microorganisms show cross-resistance with kanamycin
and neomycin. The adverse reactions associated with the use of capreomycin
are hearing loss, tinnitus, transient proteinuria, cylindruria,
and nitrogen retention. Severe renal failure is rare. Eosinophilia is
common. Leukocytosis, leukopenia, rashes, and fever have also been
observed. Injections of the drug may be painful. Capreomycin is a second-line
antituberculosis agent. The recommended daily dose is 1g
(no more than 20 mg/kg) per day for 60-120 days, followed by 1 g
two to three times a week.
Macrolides
The pharmacology, bacterial activity, resistance mechanisms
of macrolides are discussed in Chapter 55.
Azithromycin and clarithromycin are used for the treatment
of MAC.
Dapsone
Dapsone (DDS, diamino-diphenylsulfone) or 4′-
diaminodiphenylsulfone, was synthesized by Fromm and
Wittman in 1908, and its similarity to sulphonamides led
to the establishment of anti-streptococcal effects by
Buttle et al. and Forneau et al. in 1937.
DAPSONE
Mechanism of Action. Dapsone is a structural analog of paraaminobenzoic
acid (PABA) and a competitive inhibitor of dihydropteroate
synthase (folP1/P2) in the folate pathway, shown in
Figure 56–5. The effect on this evolutionarily conserved pathway
also explains why dapsone is a broad-spectrum agent with antibacterial,
anti-protozoal, and antifungal effects.
The anti-inflammatory effects of dapsone occur via inhibition
of tissue damage by neutrophils (summarized by Wolf et al.,
2002). First, dapsone inhibits neutrophil myeloperoxidase activity
and respiratory burst. Second, it inhibits activity of neutrophil lysosomal
enzymes. Third, it may also act as a free radical scavenger,
counteracting the effect of free radicals generated by neutrophils.
Fourth, dapsone may also inhibit migration of neutrophils to
inflammatory lesions (Wolf et al., 2002). Dapsone is extensively
used for acne, but this therapy is not recommended.
Antimicrobial Effects. Antibacterial. Dapsone is bacteriostatic
against M. leprae at concentrations of 1-10 mg/L. More than 90% of
clinical isolates of MAC and M. kansasii have an MIC of ≤8 mg/L,
but the MICs for M. tuberculosis isolates are high. It has little activity
against other bacteria.
Inhibitors:
Dapsone
PAS
Sulfonamides
Thymidylate
synthase X (thyX)
dUMP
Thymidylate
synthase A
5,10-methylene
tetrahydrofolate
dTMP
Pteridine + PABA
Dihydropteroic acid
Dihydrofolic acid
Tetrahydrofolic acid
Dihydropteroate
synthase (folP1/P2)
Dihydrofolate
synthase (folC)
Dihydrofolate
reductase (dfrA)
Figure 56–5. Effects of antimicrobials on folate metabolism and
deoxynucleotide synthesis.
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CHAPTER 56
CHEMOTHERAPY OF TUBERCULOSIS, MYCOBACTERIUM AVIUM COMPLEX DISEASE, AND LEPROSY