The Side Effects and Interactions of Antituberculosis Drugs

The Side Effects and Interactions of Antituberculosis Drugs WhitneyW. Addington, M.D., F.C.C.P.o

A ntituberculosis drugs may produce side effects varying from unimportant to life-threatening. The side effects of drugs prescribed for a patient must be known, as well as whether it is necessary to monitor for such effects. Table I lists the side effects and recommendations for monitoring of antituberculosis drugs used in the United States; only the most commonly used drugs, the so-called first-line drugs, will be reviewed in the text. ISONIAZID

(isOniazid has been associated with a number of central nervous system symptoms such as dizziness, muscular twitching and, rarely, convulsions. Such central nervous system side effects due to isoniazid are uncommon and cease after discontinuing the drug. Not uncommon is a feeling of excitement if the entire 300 mg of isoniazid is taken at one time and usually follows approximately eight hours after ingestion. Ihis is alleviated by dividing the dose throughout the day Pyridoxine hydrochloride prevents peripheral neuritis that has been observed following isoniazid therapy, and while probably unnecessary in most patients, it is recommended that all patients, including children who receive isoniazid, also take pyridoxine. Very rarely there are elude h sitivi reactions · oni i " By far the most important side e ct of isoniazid is iver disease. The clinical features of isoniazidinduced liver disease are clinically, biochemically and histologically indistinguishable from viral hepatitis. 1 In mild cases, histologic examination of the liver has demonstrated focal areas of hepatocellular necrosis. In more severe cases, the syndrome resembles typical viral hepatitis and begins with malaise, anorexia and nausea, with or without vomiting, be{pre the development of jaundice. Some patients m~plain initially of a viral-like illness, while others are asymptomatic until the onset of jaundice. Biochemical tests yield the pattern of aCute hepatocellular necrosis with high transaminase and mod~tely elevated alkaline phosphatase values Some patients demonstrate a mixed pattern of hepatocellular and cholestatic jaundice. The histologic pattern °Professor of Medicine and Head, Pulmonary Section, The University of Chicago, Chicago. Reprint requests: Dr. Addington, 950 East 59th Street, Box

75, Chicago60637

782 WHITNEY W. ADDINGTON

characteristic of viral he Mild or more severe liver injury may occur from one week to many months after the initiation of isoniazid therapy; however, the majority of cases of isoniazid-associated hepatitis occur withjn the first three months of treatment. In most patients, -improvement occurs shortly after isoniazid has ~ discontinued and is almost always complete. Monitoring liver enzymes has not proved useful in detecting isoniazid-associated hepatitis except in those patients who report gastrointestinal symptoms such as anorexia, nausea, vomiting or jaundice. It is essential that the patient understand the potential toxic side effects and be instructed to both discontinue his isoniazid and to seek medical care when such symptoms occur. Prompt cessation of the drug causes a return toward normal of the bilirubin and enzymes. Indeed, a rapid improvement of liver function tests is often more characteristic of drug-associated hepati~ than of viral hepatitis or alcoholic liver diseasel Rapid acetylation of isoniazid theoretically shouIt be associated with increased liver disease because the metabolites of isoniazid degredation are considered to be toxic to the liver. However, it remains controversial whether rapid acetylators are more susceptible to iso~zid-induced liver disease] It also is not known whyWle incidence of isoniazid-induced liver disease increases with advancing age of the patien~ It is this unexplained finding that has caused the recommendation tha[preventive therapy not be administered to patients over the age of 35, except for well-defined risk groups

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3

DRUG 1NTERAcnONS

Both isoniazid and rifampin have been demonto participate in important drug interactions. l Isoniazid has been shown to interfere with the metabolism of diphenylhydantoin (Djla ntin ) and patients r.eceiving both isoniazid and Dilantin should be instructed about the potential for Dilanti:n overdosage In such patients, the Dilantin dose should be lowered while the patient is receiving isoniazid, and the Dilantin dose increased after the isoniazid has been. discontinued Bifampin has been shown to be a potent jnducer of dru~ metabolism, as it causes a proliferation of the smooth endoplasmatic reticulum and an increase of cytochrome P450 content in the

~ated

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Side Effects

leoniuid Hepatitis Central nervous syatem eonvulsions optic neuritis with atrophy mURIe twitching disaineaa ataxia toxk encephalopathy Hypenenaitivity: fever, rub Druc iDtervtions: DipbenylhydantoiD 8O~ce Ethambutol

Optic neuritis

Rifampin

Oranae urine,

Monitorilll Pyridoxine: 10 InK for prophylaxill; 50 to tOOJIll- for treatment SOOT, SGPT (if symptomatic) _~tln_~.i.f.!Y~2!o.rn!titijQ.(JW:r enaymes more than twice normal

Obeerve for overdose Visual acuity and red-green color diacrimination

SkiD ruh

Unreported at 1& JIlI/kc d08f!; OCCUJ'll at 26 JIlI/Itc. Uee with caution in pl'ftleDce of renal inaufticiency

lean, ll&1iva

Flu-like syndrome Hepatitis

SGOT, SGPT

Thrombocytopenia

Platelet count (if suspected)

(if

symptomatic) -

Hemolysis

Renal failure I>ruIlnteraetlona: Warfarin

Prothrombin time

Rifampin deereuee the hypoprotbrombiDemic dect of warfarin; warfarin do8e may need to be redueed when rifampin diacontinued Prepaney reported in women on rifampin and oral contraceptivM wbich may bave accelerated eatabolism eaused by enayme induction Rifampin may be .-ociated with withdrawal symptoms in pati~nte on a methadone maintenance procram; aJ.o probably relaWd to arcelented cataboliam caueed by ea.yme induction Copeomittant ~min"tration of PAS aDd rifampin may &ead to deueued. abeorption of rifama Apparently not cbn lyaipiJicant

Audiogram VMtibular function BUN, ereatiniDe

Use with eaution in preeence of renal iuuftieiency

Oral contraceptiVe8

Methadone

PAS

I" "lTo immUDOllUppI"M8ion Streptomycin

8th cranial oerve damap Nephrotoxicity Neuromuscular junction blockade

8eeD in patieDte al80 receivinl mU8C1e relaxante

Hypenen.aitivity reaetionerub, dermatiiia. aoalypbyluia

Pyraainamide

Hyperuricemia-aeute lOut Hepatotoxicity

Reu8ure patient Need not discontinue rifampin aDd may restart if do dieeontinue DiIcontinue if jaundice~r ensymee more than twice normal Anti=rifampin anhbocbee ai*NG!ld on platelets, fix complement, results in platelet damap; diecoDtinue rifampin I>ru« related antibody fixee and activates complement; diecontinue Probably on immunololic buia

Uric acid

SOOT, BGPT (if symptomatic)

Hyperurieemia common; acute lOUt rare ClOIDIDOD with hiP doup

More

Gutrointeetinal--aDorn Daueea Diabete8 mel1itis more diftieult to manace

PAS

Gutrointe8tinal-anorexia, nauaea Hypenenaitivity reaetionefever, ruh, arthritis Hepatotoxicity Bodium load

Ethionamide

Gastrointe8tinal-anorexia, DaU8ea, vomitinc Postural hypotenaion, depnleaioo, asthenia, droWIIineM Skin rash, pyrpura. lYDeeomama, impotence Hepatotoxicity

Cyc10eerine

Central nervous system IOmnolence headache

Gastrointestinal intolerance extremely COIDJDOll in adult, ... 10 in children Diecontinue

SGOT, BOPT (if symptomatic) Divided dc.e may help controlpatrointeetinalGde-electa

BOOT, SGPT

More common witb hilber doup and in preeenceof ethanol; eerum left.. may help; aDticoovuJeante have been ueed to COIltrollleisuna

tremor

dyurthria

vertigo abnormal behavior peychoeis eeiaures Hypenenaitivity-ruh Kanamycin

8th cranial nerve damage Nephrotoxicity Vestibular toxicity HypeneD8itivity reaetioneruh, pruritus Neuromuscular junction blockade

Capreomycin

8th cranial nerve

da.ma«e

Nephrotoxicity Hypokalemia Hypel'lleDAitivity reactioneruh, urticaria, eosinophilia Neuromuscular junction blockade

CHEST, 76: 6, DECEMBER, 1979 SUPPLEMENT

Audiocram veetibular function BUN, creatinine

Should be pftD with care to receiYinc muaele retaxante Audiogram

BUN, creatinine, urinalysis

patinte

Uee with caution in older patiente aDd in preeenee of renal insufficiency

Serum potuBium

Uee with eaution in patienta receivinc

mUKIe relaxanta

SIDE EFFECTS AND INTERACnONS OF DRUGS 783

liver which may even increase the rate of desaeetvlation of rifampin. 2 There is a selectivity in the enzyme induction effect of rifampin for anticoagulants such as warfarin sodium oral hypoglycemic aients, corticosteroids, methadone and oral contraceptives. Pregnancy has occurred in women receiving .oral contraceptives, withdrawal has been experienced in gatients on methadone maintenance and warfarin spdium requirements for anticoagulation have inrifampin. Concreas.ed in patients also receiyin~ versely, these effects are reversed after the discontinuation of rifampin; overcoagulation, for example, has occurred following the discontinuation of rifampin in patients maintained on warfarin sodium.] fuFAMPIN

[A - flu.like syndrome may be produced by ri£ampin. Also, the patient's urine, tears and saliva max-tum orange following the initiation of rifampin and this requires only patient reassurance and not discontinuation of the drug. However, more serious side effects of rifampin include renl,l failure, hemolysis and thrombocytopenia. The thrombocytopenia· results from the absorbtion of antiri£ampin antibodies onto platelets which, after fixin~ complement, result in platelet damage Such reactions require immediate discontinuation of rifampin. Rifampin associated hepatitis is similar to that observed following administration of isoniazid and should be watched for with careful instruction of the patient and prompt discontinuation of the drug at the onset of suspicious symptoms. As with isoniazid, routine monitoring of liver function tests is not fruitful. The liva" toxicity of isoniazid and ri£ampin appears to be additive, not synergistic, and does n2t necessarily preclude the administration of either or both drugs to alcoholic patients with or without liver disease. However, considerable caution should be exercised in the care of patients with pre-existent liver disease and efforts made to limit the number of potentially hepatotoxic drugs (! os res ion .' · has been demonstrated in vitro with suppressed secretion of migration~inhibition factor and blastic response by lymphocytes and with reduced antibody production by lymph node cells." The reactivity to PPD has been of patients after found to be reduced in a ~roup receiving ri£ampin. The occurrence of light chain pzateinuria in the majority of patients receiving ri£ampin has been established. However, no clinically apparent deleterious effects of the immunosuppression evoked by rifampin has been observed in p~ents receiving it for treatment of tuberculosisj LStreptomycin has long been known to be neophro~and to cause eighth cranial nerve dama~e. It 784 WHITNEY W. ADDINGTON

should be used with caution in the presence of renal insufficiency. Audiograms, tests of vestibular function and renal function are indicated as a base-line and later if symptoms occur. Neuromuscular junction blockade rarely has been observed in patients receiving both streptomycin and muscle relaxants or with pre-existing myasthenia gravis.

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E1HAMBUTOL

[The only important toxic effect of ethambutol is retrobulbar neuritis. 4 There are two types. The..most common jnvolves the central fibers of the optic nerve; vision becomes blurred. there is decreased visual acuity" central .scotoma and often loss of ability to see green and sometimes red. Less commonly the peripheral fibers are involved, with constriction of peripheral visual fields but no loss of visuaJ acujty; this type seems to occur only with v~ high dosa~e. With neither type is there any abnormality on ophthalmoscopy. Symptoms most often occur after more than two months of theragy and usually reverse after stoPpinK the drug Toxicity js dose-related. A regimen of 25 mg/kg of ethambutol orally in a single daily dose for two months followed by 15 mg/kg results in virtually no ocular toxicity. With a dose of 25 mg/kK the incidence of retrobulbar neuritis has been as high as 6 percent. Tests for visual acuity do not give early warning of retrobulbar neuritis and may be normal in spite of subjective symptoms. It is best, therefore, to warn the patient to stop his drugs at once if he has any ocwar symptoms. The use of ethambutol requires base-line visual

acuity and red-green color discrimination tests but no further monitoring is necessary in the absence of eye symptoms if a dose of 15 mg/kg is being used. Routine .monitoring is indicated if the dose· is 25 mg/kg.

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PAS

Ghe gastrointestinal side effects of PAS are .$0 frequent that PAS is no longer used as a primary drug in adults. Children. appear to tolerate PAS hypersensitivity much. better than adults althou~h reactions such as feyer, rash and arthritis have been reported. ] REFERENCES

1 Mitchell JR, Zimmerman HI, Ishak KG, et al: Isoniazid liver injury. Ann Intern Med 84:181-192, 1976 2 Sanders WE: Rifampin. Ann Intern Med 85:82-86, 1976 3 Paunescu E: In vivo and in vitro suppression of humoral and cellular immunological response by Rifampicin. Nature 228:1188-1190, 1970 . 4 Citron KM: Ethambutol: A Review with special reference to ocular toxicity. Tubercle 50:32-42, 1969

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