Antituberculosis drugs: Drug interactions, adverse effects, and use in special situations. Part 1: First-line drugs
J Bras Pneumol. 2010;36(5):626-640
Adverse reactions that are more severecontribute to changes in the therapeuticregimen and lead to the use of drugs thatare less active and occasionally more toxic,
substantially increasing treatment costs, as wellas the number of home visits, outpatient visits,and hospitalizations.
These reactions can leadpatients to interrupt or abandon treatment,
resulting in higher rates of treatment failure andacquired resistance, as well as an increase in thenumber of tuberculosis cases
and, more rarely,in the number of deaths.
According to the Brazilian National Ministryof Health, the incidence of minor or mildadverse reactions in patients treated with theformer regimen I (2RHZ/4RH) ranged from 5%to 20% and did not result in immediate changein the standard regimen. Major or severe adversereactions were less common (occurring inapproximately 2% of the cases, reaching 8% inspecialized clinics) and led to the discontinuationor alteration of the treatment. Minor adverseeffects include nausea, vomiting, epigastric pain,abdominal pain, arthralgia, arthritis, peripheralneuropathy, cutaneous pruritus, headache,and changes in behavior (insomnia, anxiety,decreased libido, and euphoria). Major adverseeffects include exanthema, vertigo, psychosis,and hepatotoxicity (vomiting, alteration in liverfunction tests, and hepatitis). However, a recentstudy investigating 329 medical charts of patientsfrom a teaching hospital reported that 41.1%of the patients presented with minor adversereactions and 12.8% presented with majoradverse reactions.
The difference betweenthe results suggests that, during the everydaymonitoring in clinical practice, not all possibleside effects are investigated. Perhaps these effectsoccur in such a mild or even transitory way thatpatients do not consider them relevant enoughto be reported to the physicians.
In addition,it is often difficult to evaluate the effectivenessor toxicity of a given drug, since antituberculosisdrugs are usually administered as a combinationregimen of various drugs, which requires thathealth care workers have a thorough knowledgeof the pharmacodynamics and possible sideeffects of the drugs used in combination, as wellas of the interactions among those drugs.In this review article, we describe theprincipal characteristics of each of the drugs thatconstitute the basic regimen for tuberculosistreatment proposed by the Brazilian National Ministry of Health and the Brazilian ThoracicA number of treatments have been proposedfor cases of intolerance to one of the first-linedrugs and for other clinical situations, such asliver disease.
Patients with bacilli that are resistant toisoniazid and rifampin, patients with bacillithat are resistant to isoniazid, rifampin, andanother first-line drug, and patients in whomthe basic regimen fails constitute a groupof patients classified as having multidrug-resistant tuberculosis. For cases such as these,a combination regimen of streptomycin,ethambutol, terizidone, pyrazinamide, and onequinolone (levofloxacin or ofloxacin) has beenproposed.
If streptomycin cannot be used, itshould be replaced with amikacin.
Patients with extensively drug-resistant tuberculosisshould be referred to a tertiary referral center,and individualized salvage drug regimens(which include capreomycin, moxifloxacin, para-aminosalicylic acid, and ethionamide) should beused.
Chart 1 shows the recommended doses of the aforementioned drugs according to the Brazilian National Ministry of Health/BrazilianThoracic Association,
the American ThoracicSociety (ATS)/Centers for Disease Control and Prevention (CDC)/Infectious Diseases Societyof America (IDSA),
and the World HealthOrganization (WHO).
Although the therapeutic regimens areextremely effective, studies have shownthat undesirable drug interactions (amongthe antituberculosis drugs or between theantituberculosis drugs and other drugs used bypatients) can occur, as can adverse reactions of varying degrees of severity.
Drug interactions can be defined as reciprocalreactions among drugs, resulting in undesirableor unexpected effects. Drug interactions can alterthe serum concentrations of the drugs involved,thereby reducing their effectiveness.
Adverse reactions to antituberculosis drugsare related to various factors, and the principaldeterminants of such reactions are the doseand time of day at which the medicationis administered, as well as patient age andnutritional status, together with the presenceof preexisting diseases or dysfunctions, such asalcoholism, impaired liver function, impairedkidney function, and HIV coinfection.