Clinical Pharmacology of Antitubercular Drugs

Symposium on Anti-Infective Therapy

Clinical Pharmacology of Antitubercular Drugs Michael D. Reed,* Pharm.D ., and Jeffrey L. Blumer, Ph.D., M.D.t

Although no new antitubercular medications have become available within the past 10 years, the approach to the chemotherapy of tuberculosis has changed substantially. Numerous two and three drug combinations have been evaluated as have shortened hospitalizations and intermittent chemotherapeutic regimens.s. 39, 62, 66• m, 122, 123, 128 These advances, however, have been primarily derived from studies performed in adult patients. Only recently have these expanded studies, including pharmacokinetic evaluations, been performed in children. Since most pediatric studies have involved the "first-line" antitubercular drugs isoniazid, rifampin, and ethambutol, this paper will emphasize these agents. The clinical management of children with tuberculosis will be presented in Part II of this symposium. ISONIAZID Since its discovery in 1952, isoniazid (INH) has become the most important antitubercular medication available today. Most authorities agree that all patients with disease caused by isoniazid-sensitive strains of tubercle bacillus should receive the drug. The effectiveness of isoniazid both in the treatment of tuberculosis disease and as a prophylactic agent is well established. Chemistry Isoniazid (Fig. 1) is the hydrazine of isonicotinic acid.l6 The drug is water-soluble and relatively stable. Owing to their toxicity, no congeners *Assistant Professor of Pediatrics, Case Western Reserve University; Co-Director, Greater Cleveland Poison Control Center; Division of Pediatric Pharmacology and Critical Care, Rainbow Babies and Childrens Hospital, Cleveland, Ohio tAssistant Professor of Pediatrics and Pharmacology, Case Western Reserve University, Chief, Division of Pediatric Pharmacology and Critical Care, Rainbow Babies and Childrens Hospital, Cleveland, Ohio

Pediatric Clinics of North America-Vol. 30, No. 1, February 1983

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Figure 1.

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Chemical structure of isoniazid.

CONHNH~

of isoniazid are currently employed in human medicine. In the United States, isoniazid is available in scored tablets of 100 and 300 mg, as a syrup containing 50 mg/5 ml, and as an injectable solution containing 100 mg/ml. Mechanism of Action Although extensively studied, the exact mechanism of the mycobactericidal activity of isoniazid is unknown. Investigations have suggested that drug interaction with nucleic acid biosynthesis, membrane lipids, and/ or glycolysis of the mycobacterium bacillus may be important. 36 Recent data have shown that isoniazid inhibits the synthesis of mycolic acids (important constituents of the mycobacterial cell wall) by interfering with the enzyme mycolase synthetase. 42 This enzyme, which appears unique to mycobacteria, is inhibited by concentrations similar to the minimal inhibitory concentration for the drug against M. tuberculosis. Absorption, Distribution, Metabolism, and Excretion Isoniazid is well absorbed from the intestine following oral administration.43· 1!9 The coadministration of antacids, however, diminishes the absorption of isoniazid; thus the drug should be given one hour before or two hours after antacid administration. 61 In clinically stable patients, serum concentrations following intramuscular administration are comparable to those observed with oral dosing. 97 Peak serum concentrations in children ranging from 6 to 20 mg/1 usually occur within one to two hours following drug administration. 94· 97 Serum concentrations in adults are usually lower, ranging from 3 to 5 mg/1. 43· 86 This discrepancy in serum concentrations appears to be a result of the greater dosage of isoniazid per unit of body weight administered to children, in contrast to adults. The need for these higher serum concentrations in children for the treatment of non-central nervous system tuberculosis is suspect and requires further study. Once absorbed, isoniazid is well distributed throughout body fluids and tissues. liS, 154 The drug diffuses readily into pleural, ascitic, and cerebrospinal fluids; caseous material; skin; muscle; sputum; and saliva. 43, ss, 1!5 Isoniazid concentrations in the cerebrospinal fluid of patients with or without tuberculous meningitis appear similar to those in serum. 43· 47 In addition, the drug easily crosses the placenta and is excreted in human milk. 76, 154 M ycobactericidal activity has also been demonstrated against intracellular tubercule bacilli.140 The metabolism of isoniazid has been extensively studied in both animals and humans. 43· 60 • 119· 154 The drug undergoes hepatic acetylation by the enzyme N-acetyltransferase, producing acetylisoniazid. This undergoes further hydrolysis to yield isonicotinic acid and acetylhydrazine. 146 Both active drug and metabolities are excreted in the urine, and the quantity of

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active, unmetabolized drug in the urine is dependent upon the individual's rate of hepatic acetylation. The rate of isoniazid acetylation is genetically controlled. 88• 102 Patients may be subdivided phenotypically into one or two groups-slow or rapid acetylator. The acetylator phenotype may be ascertained by determining the time-dependent excretion of acetylisoniazid in urine or by evaluation of the bimodal distribution in the serum concentration versus time curve. Acetylator status shows an autosomal mode of inheritance in which slow acetylators appear to be homozygous recessives and rapid acetylators are either heterozygotes or homozygous dominants. 53 The frequency distribution of acetylator phenotype is dependent upon race, but is not influenced by sex or age. Clinically, there appears little need to determine an individual patient's rate of acetylation, as studies have shown that the clinical results following therapy with isoniazid are not influenced by the patient's rate of acetylation. 94 • 128• 145 The status of an individual patient's acetylation phenotype may, however, be important when considering intermittent (twice weekly) chemotherapeutic regimens. Adverse Effects The extensive experience with the use of isoniazid either alone or in combined chemotherapeutic regimens has revealed a low order of toxicity. 86, ns Gastrointestinal side effects, including nausea, vomiting, and diarrhea, are uncommon following the administration of usual recommended dosages.ns The frequency of these adverse effects appears to increase with doses greater than 20 mg/kg/day.ns Rare hypersensitivity reactions to isoniazid may be manifest by fever, hepatitis, and by maculopapular, morbilliform, purpuric, and urticarial rashes. 3• 24· 35 Isoniazid therapy has also been associated with arthritic symptoms (arthralgias of knees, elbows, and wrists) and lupus erythematosus. 38 • 53• 101 In conjunction with the latter, an increased incidence of antinuclear antibodies has been reported in patients receiving isoniazid, though resolution occurs following discontinuation of isoniazid therapy. 35, 86, m Less frequent side effects include rare hematologic reactions (agranulocytosis eosinophilia, thrombocytopenia, anemia)44 • n 4 acne, psychosis, and central nervous system depression or stimulation. 17• 83 • 147 Central nervous system toxicity with isoniazid occurs more frequently following excessive dosages of the drug. It may precipitate convulsions in patients with underlying seizure disorders, but convulsions rarely occur in patients with no prior history of seizures. 52• 86 Patients receiving concomitant phenytoin therapy should be monitored closely for signs of phenytoin toxicity, such as excessive sedation or incoordination. Isoniazid has been shown to interfere with the metabolism of phenytoin, resulting in increased serum phenytoin concentrations. 77• 78 This potentially serious drug interaction is usually significant in patients who are slow acetylators, and they may require a reduction in the daily phenytoin dosage. 78 Pyridoxine (vitamin B6) deficiency, resulting in peripheral neuropathy has also been associated with isoniazid therapy. This toxicity is a result of isoniazid competitively combining with pyridoxal or pyridoxal phosphate, forming hydrazones, thus inhibiting the activity of pyridoxal kinase. 18 Per-

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ipherial neuropathy rarely occurs when usual recommended doses of isoniazid are employed (5 mg/kg/day in adults), although it has been reported in as many as 20 per cent of patients receiving higher dosages. 52 Alcoholics and patients with malnutrition appear more susceptible to this drug interaction. In contrast, children receiving isoniazid therapy appear less susceptible to developing pyridoxine deficiency or peripheral neuritis than adults. 93 · 115 Discontinuation of isoniazid or concurrent pyridoxine administration will reverse pyridoxine deficiency, with no effect on the antimycobacterial activity or serum concentration of isoniazid. 112 The most serious adverse reaction associated with isoniazid therapy is a drug-induced hepatitis. Although early studies implicated isoniazid as a potential hepatotoxin, the clinical importance of this adverse effect was not fully appreciated until 1969.124 Isoniazid-associated hepatitis is clinically, biochemically, and histologically similar to viral hepatitis. 92 The exact mechanism of hepatotoxicity has not been fully elucidated. Data derived primarily from studies in animals suggest than an acetylated metabolite of isoniazid, acetylhydrazine, is converted to a potent acylating agent capable of inducing hepatic necrosis. 90• 92 • 132 Early investigators believed that rapid acetylators of the drug produced greater amounts of acetylhydrazine and thus were more prone to the development of isoniazid-hepatitis than slow acetylators. 19• 71 • 91 However, numerous investigators have shown no difference in the incidence of isoniazid-hepatitis between rapid and slow acetylators. 42 • 113• 128 These data suggest that, although rapid acetylators may produce greater amounts of acetylhydrazine, these patients also produce more deacetylhydrazine, a nontoxic metabolite of acetylhydrazine. From these data and others, a causal relationship between the acetylator phenotype and the development of isoniazid-associated hepatitis cannot be made. The true incidence of isoniazid-associated hepatitis is not known. Depending upon the authors definition of "hepatitis" and the population studied, literature estimates range from 1 to 38 per cent of patients receiving isoniazid developing evidence of hepatocellular toxicity. 4 In addition, increasing age and the concurrent use of alcohol appears to predispose patients to an increased risk of toxicity. From these data, it appears that approximately 20 per cent of the patients will develop mild changes in serum liver function tests but that only a small percentage of patients will develop a true "hepatitis." Much less data is available on the incidence of INH-associated hepatotoxicity in children. Previous data suggested that this adverse drug reaction was rare in patients under the age of 20 years.33, 71 • 76, 12o However, case reports have appeared describing hepatocellular toxicity and death following isoniazid therapy in children. 25• 29• 120· 135• 149 In the series reported by Spyrides et al., 7. 5 per cent of 239 children developed elevations in SCOT and SGPT during isoniazid chemoprophylaxis; only two of these children developed serum enzyme concentrations high enough to require discontinuation of drug therapy. 134 Other investigators have reported similar findings. 11 As a result of these data and the potential for decreased compliance in follow-up visits, most clinicians do not recommend the routine monitoring of serum liver function tests in children receiving isoniazid therapy. 9, 11, 131, 135

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RIFAMPIN Unlike isoniazid and ethambutol, rifampin is active against many nonmycobacterial organisms. Rifampin is a potent tuberculocidal agent. Combination therapy with rifampin and isoniazid are currently considered the most effective antitubercular regimen for the treatment of tuberculosis. 7• 48 • 95 Many clinicians, however, prefer to limit the use of rifampin for advanced or difficult-to-treat cases because of the expense of the drug and the potential development of resistant mycobacterium.121 Chemistry The rifamycins are a group of complex macrocyclic antibiotics that were isolated from Streptomyces mediterranei in Italy in the early 1960s. Rifampin (Fig. 2), the semisynthetic hydrazine derivative of rifamycin B, is a zwitterion and is soluble in organic solvents and water at an acidic pH.86 In the United States, the drug is available in 300 mg capsules. An intravenous preparation is currently under investigation. Outside of the United States, rifampin is available in combination with isoniazid. Mechanism of Action Rifampin is bacteriocidal against many gram-positive and gram-negative bacteria. The drug's bacteriocidal activity against M. tuberculosis in vitro is well documented and appears to be comparable to that of isoniazid. 31, 59 , 126· 150, 155 Although the M. kansasii are often sensitive to rifampin, other species of myocobacterium, including M. fortuitum, M. avium, and M. intracellulare are generally resistant. 155 Rifampin inhibits the growth of susceptible bacteria and mycobacteria by interfering with RNA synthesis. The drug avidly binds to DNA-dependent RNA polymerase, thus interfering with the transfer of genetic information from DNA to mRNA. 70 RNA-polymerase activity in mammalian cells, however, does not appear to be affected by rifampin. 86 Absorption, Distribution, Metabolism, and Excretion Following oral administration, rifampin is well absorbed, achieving peak serum concentrations within 1 to 3 hours. 1 The coadministration of

Figure 2.

Chemical structure of rifampin.

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para-aminosalicylic acid may delay the absorption of rifampin, resulting in blunted peak serum concentrations. 23 In addition, the presence of food in the stomach has been shown to diminish both the amount of drug absorbed and the peak serum concentration. 1 Thus, most investigators recommend administration of the drug before meals. McCracken et al. studied three extemporaneous formulations of rifampin in 38 fasted infants and children. 89 Adequate and comparable absorption was observed when rifampin was administered as either an 85 per cent sucrose suspension or rifampin powder mixed in applesauce. When the rifampin sucrose suspension was also mixed in applesauce, the amount of drug absorbed was decreased as reflected in a 32 per cent decrease in the drugs area under the serum-concentration time curve. In this study, peak serum concentrations occurred within two hours of drug administration. The concentration of rifampin in various tissues has been determined either through direct sampling or evaluation of surgically removed samples. The drug is well distributed throughout the body, which is reflected by the orange-red discoloration of the urine, feces, saliva, sputum, tears, and sweat. Concentrations of the drug in the lung, fat tissue, and breast milk often exceed serum concentrations. 1• 30• 126 Rifampin concentrations in bile and urine can exceed serum concentrations by as much a 10- and 20-fold respectively. 110 The drug penetrates phagocytic cells and is capable of killing intracellular microorganisms. 84• 85 In addition, therapeutic concentrations of rifampin are achieved in the cerebrospinal fluid of patients with tuberculous meningitis. 37, 129 The metabolism of rifampin is primarily hepatic via deacetylation.I, 75, 86 The deacetylated metabolite, however, retains most, if not all, of the parent compound's antimicrobial activity. 86 Thirty to 40 per cent of the drug is excreted in bile. Within four to six hours of administration, the concentration of rifampin in bile plateaus, with nearly all of the drug in the deacetylated form . 1 Although deacetylated rifampin undergoes biliary excretion, minimal amounts are reabsorbed because of its polarity. 75 The half-life of rifampin in blood ranges from 1.5 to 5 hours and appears to be dose related. 2 Single large doses of rifampin (600 and 900 mg) appear to saturate the hepatic capacity for drug clearance and thus disproportionately prolong the half-life. 2 In the study by McCracken et al., the half-life of rifampin, after a single dose, averaged 2. 9 hours in children ranging in age from 6 to 58 months. 89 With continuous therapy the half-life of rifampin shortens. This decrease in half-life of rifampin appears to plateau after six days and is a result of the drug's ability to induce the hepatic enzymes responsible for its own metabolism. 2 In the presence of hepatic dysfunction, dosage adjustments are necessary to reduce drug accumulation and the potential for toxicity. 28 • 63 In contrast, dosage adjustments do not appear necessary in the presence of renal dysfunction. 1 Adverse Effects The incidence of adverse reactions associated with rifampin, when employed in usual therapeutic dosage schedules, is estimated to be 4 per cent. 86 It appears that this incidence may increase when the drug is administered in larger doses or on an intermittent chemotherapeutic

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regimen. 45· 50• 109 The most common side effects are rash (0.8 per cent), fever (0.5 per cent), and nausea and vomiting (1.5 per cent). 51 • 109 One of the more frequent hypersensitivity reactions occurring early in the course of rifampin therapy is the "cutaneous syndrome."6· 50 This syndrome consists of flushing and/or itching of the skin (with or without a rash) usually involving the face and scalp. Watering of the eyes may also occur. The symptoms associated with this reaction usually occur within two to three hours of a dose of rifampin and are generally self-limiting requiring only symptomatic treatment. Other hypersensitivity reactions that occur rarely during rifampin therapy include hemolysis, 51 • 156 thrombocytopenia, 20• 106 interstitial nephritis, 49· 136 and acute renal failure. 34• 45• 69 These hypersensitivity reactions appear to occur more frequently during intermittent antitubercular dosage regimens, or when patients prescribed daily therapy interrupt their medication for several days. 34, 45, 49, 69, 118 Liver disease following the use of rifampin has been reported, though it is difficult to determine whether this is due to rifampin alone or to other, coadministered drugs. 79--S2, 125 Many patients will develop slight elevations of serum transaminase, particularly upon initiation of rifampin therapy. However, these patients are generally asymptomatic, and serum transaminase concentrations often normalize despite the continuance of rifampin therapy. 51 • 96 The concomitant administration of rifampin and isoniazid (or other potentially hepatotoxic drugs) may predispose patients to hepatotoxicity. Reports describing serious but reversible "toxic hepatitis" have been reported in both children and adults during combined rifampin-isoniazid therapy. This toxic reaction appears rare in children and may be associated with excessive dosages of isoniazid. 29 Preexisting liver disease, alcoholism, and old age appear to increase the hepatic complications related to either rifampin alone or when coadministered with isoniazid. 56, 144 The ability of rifampin to affect the immune system remains controversial. Numerous investigators have reported suppression of cutaneous hypersensitivity to tuberculin and T-cell function following rifampin administration in both animals and humans. 55• 57 Most studies, however, have not demonstrated a consistent alteration in humoral immune responses during rifampin therapy, and the clinical relevance of these observations are unknown. Rifampin has been shown to interfere with the metabolism of a number of substances and drugs. 1· 26 The drug competes with, and thus reduces, the biliary excretion of bilirubin, sulfobromophthalein, and certain cholecystography contrast media. 1 The increase in serum bilirubin concentrations appears to occur at the initiation of rifampin therapy, but normalizes after two to three weeks of continuous therapy. This phenomenon is believed to be a result of the drug's ability to induce hepatic enzyme systems, and thus, compensate for any competition in biliary excretion. 1 This increase in hepatic metabolic capability has been associated with hepatocellular proliferation of smooth endoplasmic reticulum. 65 In addition to causing increases in the rate of its own metabolism, the accelerated metabolism of oral contraceptives, 22 • 130 corticosteroids, 27 • 157 tolbutamide, 141 oral anticoagulants, 86· 99 methadone, 14• 73 and digitoxin1 has also been reported.

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ETHAMBUTOL Ethambutol is a bacteriostatic antitubercular medication commonly combined with other agents in the treatment of tuberculosis. This drug is infrequently used in children under the age of five primarily because of its potential for ocular toxicity. The drug, however, remains an important component of regimens used in older children and adults.m. 131 Chemistry Ethambutol, an effective antitubercular congener of N, NLdiisopropyl-ethylenediamine, is the dextrorotatory isomer of 2,2'-(ethylenediimino-di-1-butanol dihydrochloride (Fig. 3). Studies have shown that the dextro form possesses approximately 200 times more activity against tubercule bacilli than the levo-isomer.l 43 The d-isomer, ethambutol, is a water-soluble and heat-stable compound. Commercially, the drug is available in scored tablets containing 100 or 400 mg of ethambutol. Mechanism of Action Unlike isoniazid and rifampin, ethambutol is tuberculostatic, thus incapable of killing mycobacterium. 12• 64 In vitro, ethambutol is rapidly taken up by mycobacteria during the exponential growth phase, though growth is not significantly inhibited before approximately 24 hours. Most strains of M. tuberculosis and M. kansasii are sensitive to ethambutol, whereas the sensitivity to other atypical mycobacterium are variable. 68, us, 150 The precise mechanism of action of ethambutol is unknown, but the drug is believed to exert its tuberculostatic activity as an antimetabolite inhibiting mycobacterial RNA synthesis. 6 Maximal inhibition of mycobacteria appears to occur at a neutral pH. 46 Absorption, Distribution, Metabolism, and Excretion Approximately 75 to 80 per cent of an orally administered dose of ethambutol is absorbed from the gastrointestinal tract. 100 Co-administration of ethambutol with food does not appear to impair absorption of the drug. Four hours post dose, peak serum concentrations of about 5 mg/1 are achieved after a 25 mg/kg dose in adults. 100 Doubling the dose of ethambutol appears to double serum concentrations, implying that the drug follows a first-order pharmacokinetic process. 104 Detailed analysis of the body distribution of ethambutol is unavailable. Based upon clinical efficacy of the drug, it is presumed to achieve therapeutic concentrations in vital organs and tissue. Ethambutol has been shown to accumulate within the erythrocyte, which may serve as a depot from which the drug re-enters the plasma. 100 In patients with tuberculous

TH~OH

T2H5

H--C-NH-CH"--CH --HN--C-H

I

C2 Hb

.

2

I

CH 20H

Figure 3.

Chemical structure of ethambutol.

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meningitis, cerebrospinal fluid concentrations ranging from 1 to 2 mg/1 following 25 mg/kg/day have been reported,21· 105 but the drug does not appear to enter the spinal fluid·in patients with normal meninges.l05 Once absorbed into systemic circulation, approximately 80 per cent of ethambutol is excreted as the active, unchanged drug by the kidney. 104 About 10 to 15 per cent of the drug is metabolized to either an aldehyde or dicarboxylic acid derivative, and both appear to be inactive.l00 • 104 The half-life of the drug in plasma ranges from three to four hours.lOO, 104 Hepatic insufficiency does not appear to alter the disposition of ethambutol, whereas proportional dosage adjustments are necessary in the presence of renal insufficiency. Is, 72

Adverse Effects In general, ethambutol is well tolerated when administered in usual therapeutic dosages. In a series evaluating over 1900 patients, the overall incidence of reactions to ethambutol 15 mg/kg/day were less than 2 per cent. 103 In these patients, 0.8 per cent developed diminished visual acuity, 0.5 per cent experienced a rash, and 0.5 per cent developed what was believed to be a drug fever. Other adverse effects that have been observed in patients receiving ethambutol include gastrointestinal upset, malaise, headache, mental confusion, disorientation, and joint pain. 86 Ethambutol may decrease the renal elimination of uric acid and may increase serum urate concentrations by as much as 50 per cent.l07 Peripheral neuritis has also been reported in patients receiving ethambutol but appears to be very rare.l48 The most important adverse effect associated with ethambutol therapy is a retrobulbar neuritis, which results in decreased visual acuity and redgreen color blindness. This effect may be either unilateral or bilateral and its incidence appears to be dose related. It is estimated to occur in 15 per cent, 5 per cent, and less than 1 per cent of patients receiving dosages of 50, 25, and 15 mg!kg/day respectively. 83 Using current dose recommendations of 25 mg/kg/day for two months with a dosage reduction to 15 mg/kg/ day, ocular toxicity is infrequent, and when it occurs it is generally mild. 74 The ocular toxicity observed in patients receiving ethambutol is usually reversible upon discontinuation of drug therapy, although color blindness may persist for some time. 32· 82 The time necessary to recovery is generally dependent on the degree of visual impairment. 104 Continued therapy with ethambutol after the onset of symptoms may result in optic atrophy with irreversible impairment of vision. 74 Because of the difficulties inherent in visual acuity testing of young children, this complication of ethambutol therapy limits the usefulness of the drug to children older than five years.

OTHER ANTITUBERCULAR MEDICATIONS Other drugs less frequently used as adjuvants in the treatment of tuberculosis today include streptomycin, paraminosalicylic acid, pyrazinamide, cycloserine, ethionamide, viomycin, kanamycin, capreomycin, and thiacetazone. For the most part, these drugs have limited utility in the

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modern treatment of tuberculosis and are used only in specific cases, dealing primarily with multi-drug resistant mycobacteria. Streptomycin. This is an aminoglycoside antibiotic that was the first clinically effective drug available for the treatment of tuberculosis. 86· 115 Following its widespread use in the late 1940s, streptomycin-resistant organisms developed rapidly. With the availability of other antituberculous drugs, it was found that their co-administration with streptomycin reduced the rate at which mycobacteria developed drug-resistance. 115 The potential toxic effects of streptomycin are those inherent to aminoglycoside antibiotics in general (see following article), although auditory and vestibular toxicity appear to occur more frequently following streptomycin therapy than with newer aminoglycoside antibiotics. Because of difficulties associated with parenteral therapy as well as its potential toxicity, most clinics today reserve the use of streptomycin to the more resistant cases or those who may require a three-drug regimen. Para-Aminosalicylic Acid (PAS). Para-aminosalicylic acid is a well absorbed, orally administered mycobacteriostatic agent that appears to inhibit the growth of M. tuberculosis by interfering with folic acid metabolism.86, n5 The drug exerts minimal to no effect against other mycobacteria. 74 The half-life of para-aminosalicylic acid in plasma is about one hour.152 Approximately 85 per cent of the drug is excreted in the urine; up to as much as 30 per cent of the total dose is excreted as the unchanged active drug. 151 · 152 The remainder is hepatically metabolized primarily via acetylation. 58 The drug appears to be well distributed in most body fluids and tissues but does not penetrate into the cerebrospinal fluid even in the presence of inflammation. 152 The co-administration of isoniazid and paraaminosalicylic acid may result in increased serum concentration of isoniazid owing to competition in hepatic metabolism. 87 In addition, the concomitant administration of probenecid may decrease the renal excretion of para-aminosalicylic acid.n5 The most common adverse effects associated with para-aminosalicylic acid include gastrointestinal irritation and allergic, hypersensitivity reactions. Nearly all patients experience some degree of gastrointestinal upset, primarily nausea, vomiting, and abdominal cramping. Hypersensitivity reactions occur in approximately 5 to 10 per cent of patients receiving paraaminosalicylic acid and include fever, rash, and conjunctivitis. 86· 127 These reactions usually occur within the first five weeks of initiating para-aminosalicylic acid. Also, allergic hepatitis that can be fatal has been reported. 80, 116, 127 This adverse drug reaction generally occurs within the first three months of therapy and is usually preceded by other allergic manifestations. Pyrazinamide. This drug is a bacteriostatic synthetic pyrazine analog of nicotinamide. Gastrointestinal absorption of the drug is rapid and complete, producing peak serum concentrations within two hours of oral administration. 41 The half-life of the drug in serum is approximately 9 to 10 hours, 41 though adequate pharmacokinetic studies have not been performed. Pyrazinamide and its major metabolite, pyrazionic acid, are excreted in the urine primarily via glomerular filtration. The drug appears to

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distribute well into tissue, particularly liver, lungs, and kidneys. 138 In one patient with tuberculous meningitis, simultaneous five-hour post-dose serum and cerebrospinal fluid concentrations were identical, averaging 50 mg/1. 47 The major limitations to the clinical use of pyrazinamide have been its relatively low in vitro activity against mycobacterium tuberculosisus. 138 and its hepatotoxic potential. Cycloserine. Cycloserine is a structural analog of n-alanine, which appears to competitively antagonize enzymes responsible for linking n-alanine in the bacterial cell wall. 58 Most strains of M. tuberculosis, M. kansasii, and atypical mycobacteria are sensitive to cycloserine, including strains resistant to other antitubercular drugs. 8• 40 Available only for oral administration, the drug is well absorbed and achieves peak serum concentrations within three to four hours. 115• 137 Partially metabolized in the liver (approximately 35 per cent), cycloserine is well distributed throughout the body, including the central nervous system.1 15• 137 The most important toxicities associated with cycloserine therapy are neurologic and include somnolence, headache, tremor, nervousness, irritability, seizures, and psychosis. These toxicities appear to occur within the first few weeks of therapy. 86• 137 Because of these, most clinicians avoid the use of cycloserine, especially in patients with seizure disorders or mental disabilities.

SUMMARY Isoniazid, rifampin, and ethambutol are the three major drugs used in the modern treatment of patients with tuberculosis. Data on these drugs in children have been derived primarily fro.m their clinical use in pediatrics and extrapolation from experiences in adults. A number of questions remain concerning the clinical pharmacology and appropriate use of these drugs in children. Additional pediatric pharmacokinetic studies are necessary to confirm the current dosage recommendation and use of these agents in the pediatric patient.

Table I.

Daily Dosage and Route of Elimination of Antitubercular Medication

DRUG

Isoniazid Rifampin Ethambutol Cycloserine Para-aminosalicylic acid Pyrazinamide Streptomycin

MAJOR ROUTE OF ELIMINATION

CHILDREN

ADULTS

10-15 mg/kg (maximum, 500 mg) 10-20 mglkg (maximum, 600 mg) 10-15 mg/kg 5-15 mglkg 200 mglkg

5 mglkg (or 300 mg) 600 mg

Liver

15 mg/kg 0.5-1.0 gm 9-12 gm

Kidney Kidney Kidney

20-30 mglkg 20-40 mglkg

1.5-2.25 gm 1000 mg

Kidney Kidney

Liver

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