Letters
doses on the development of tolerance to isosorbide dinitrate. N Engl 1
is 4.2 ± 2.1 (SD) hours and the clearance of tizanidine is 2.0 ± 0.8
Med 1987;316:1440-4.
1)kg/h.4.5 No reports have been published conceming tizanidine-drug in-
7. ABRAMS J. A reappraisal of nitratetherapy. lAMA 1988;259:396-401. 8. PACKER M. What causes tolerance to nitroglycerin? The 100 year old mysterycontinues. 1 Am Coli Cardioll990;16:932-5. 9. DUPUIS J. LALONTE G, LEMIEUX R,et aI. Toleranceto intravenous nitroglycerin in patients with congestiveheart failure: role of increasedintravascular volume, neurohumoral activation and lack of prevention withN-acetylcysteine. 1 Am Coli Cardioll990;16:923-31.
teractions.' Therefore, it may be that the mechanism of the phenytoin--tizanidine interaction is competitive inhibition of metabolic enzymes in the liver. Coadministration of phenytoin and tizanidine probably should be avoided, or patients receiving both drugs should receive careful monitoring of serum phenytoin concentrations. Further studies are needed to determine the underlying mechanism of this interaction. KAzuYUKl VENO, B.S.
Pharmacist
Phenytoin-tizanidine interaction
KAZUYOSHI MIY AJ, B.S.
TO THE EDITOR: Phenytoin is the most frequently prescribed anticonvulsant in the management of seizures, and is eliminated primarily by metabolism via hepatic enzyme systems. A number of drugs are reported to cause increases in serum phenytoin concentrations by inhibiting its metabolism.v" Tizanidine is used to improve muscle tone in shoulderarm-neck syndrome or low back pain, and is almost entirely metabolized by the liver.r" We report on a patient in whom the steady-state serum phenytoin concentration was apparently increased by the addition of tizanidine therapy. A 59-year-old manweighing 59 kg hadexperienced a cerebral infarction about sixmonths earlier and wascurrently experiencing convulsions on a frequent basis. Atthistime, therapy wasbegun with phenytoin (fme granules) 300mg/dfor three months. Trough serum concentrations (thefraction of unbound drugto total) 5, 8, and 12weeks afterstarting phenytoin therapy were 78.09(7.65), 74.9(7.37), and 75.7(7.53) urnol/L, respectively. At thisdose,his seizures werewellcontrolled andthere wasnoevidence of adverse effects. Nootheranticonvulsant medication wasadded, nordidthepatient receive anyothermedication thatmayhavealtered theserum phenytoin concentration-dose relationship. Hepatic and renal functions wereevaluated throughout this time period,and wereconsistently maintained within normal limits. Laboratory findings were: totalprotein 0.067 gIL, albumin 0.041 gIL, blood urea nitrogen 4.28mmol/L, andserum creatinine 53.041!ID01/L. Three months afterstarting phenytoin therapy, the patient complained of painin oneshoulder, andwasdiagnosed withshoulder-arm-neck syndrome. Concomitant therapy with tizanidine 2 mg tid wasbegun. Oneweeklaterthepatient developed drowsiness. His serumphenytoin (unbound fraction) concentration was 100.7 (9.91) umol/l; The administration of phenytoin wasstopped for three days,and thedosewasthenreduced to 240mg/d. Oneweek later, theserum phenytoin concentration was 45.6 (4.28); three weeks later it was 81.2 (8.32) umol/L. The drowsiness haddisappeared, but recurred about three weeks afterphenytoin was restarted. Therefore, thetizanidine therapy wasstopped. Oneweek latertheserum phenytoin concentration was57.9(5.79), and three weeks laterit was55.5(5.59) umol/l., Thedrowsiness disappeared anddidnotrecur. The trough serum phenytoin concentration of the patient increased from 75.5 to 100.7 llIDol/Lone week after phenytoin and tizanidine were coadministered, and despite the reduction of the phenytoin dose, the concentration continued to increase. Unbound percentage of serum phenytoin was unchanged. Phenytoin exhibits nonlinear pharmacokinetics in clinical pracrice.P Accordingly, a small increase in the dose can result in disproportional increases in the steady-state phenytoin concentration and time to achieve steady-state. Therefore, it is likely that the serum phenytoin concentration had not achieved steady-state one week after coadministration of phenytoin and tizanidine and three weeks after the phenytoin dose was reduced. Consequently, serum phenytoin concentrations gradual1y increased. His drowsiness appeared to correspond to the increased serum phenytoin concentrations; however, one adverse effect of tizanidine is drowsiness." The albumin was consistently within normal limits and the protein binding was approximately ten percent. Therefore, the drowsiness may have been caused by phenytoin or the combination of phenytoin and tizanidine. Phenytoin is eliminated from the body mainly by biotransformation in the liver to inactive metabolites. The major pathway is parahydroxylation and, to a lesser extent, metahydroxylation of one of the phenyl rings.>' Tizanidine is a new antispasticity agent with a novel chemical structure' and a pharmacologic profile different from that of myotonolytic drugs (e.g., diazepam, baclofen, dantrolene),"The absorption oftizanidine after oral administration (6-mg) tablets to normal adults is rapid and above 70 percent, and first-pass hepatic metabolism of oral tizanidine is about 80 percent. Time to peak concentration is one to two hours. The major pathway of tizanidine metabolism is hydroxylation of the imidazoline ring or phenyl ring fol1owedby conjugation. Tizanidine is almost entirely metabolized by the liver and more than 70 percent of the metabolites are excreted in the urine. The elimination beta-phase half-life
Director ofPharmacy National Sengokuso Hospital 1191 Nagose, Kaizuka-shi Osaka, 597 Japan KlYOSHl MITSUZANE, M.D.
Physician Department ofInternal Medicine
REFERENCES I. WINTER ME, TOZEN TN. Phenytoin. In: Evans WE, Schentag n, Jusko
2. 3. 4. 5.
Wl Appliedpharmacokinetics: principles of therapeutic drug monitoring. 2nd ed. Spokane, WA: AppliedTherapeutics, 1986:493-539. LEVINE M,CHANG T. Therapeuticdrug monitoringof phenytoin.Rationale and currentstatus. Clin Pharmacokinet 1990;19;341-58. NATION RL, EVANS AM, MILNE RW. Pharmacokinetic drug interactions with phenytoin (part 2). Clin Pharmacokinet 1990;18:131-50. Tizanidine. Drug interview-form sheet. Tokyo, Japan: Sandos Yakuhin, 1989;13-4. HEAZLEWOOD V,SYMONIW P, MARUFF P,EADIE MJ. Tizanidine-initial pharmacokinetic studies in patients with spasticity. Eur 1 Clin PharmacoI1983;25:65-7.
6. SAYERS AC, BURKI HR, EICHENBERGER E. The pharmacology of 5chloro-4-(2-imidazolin-2-yl-amino)-2,I,3-benzothiadiazole(DS 103282), a novel myotonolytic agent. Arzneimittelforschung 1980;30:793803.
Comment: tluoxetine adverseeffectsand drug interactions TO THE EDITOR: We read with interest the timely review article by Levinson et al. regarding adverse effects and drug interactions associated with fluoxetine (DIep 1991;25;657-61). We would like to report an interaction between fluoxetine hydrochloride and imipramine hydrochloride that occurred after fluoxetine was discontinued. A 35-year-old white woman wasadmitted to ourfacility aftershethrew herself down a flight of stairs in a suicide attempt. She had a history of twoprevious suicideattempts (oneby ingestion of pillsandalcohol, theotherbyhaving a caraccident whileintoxicated) sinceher husband'sdeathin 1988. She reported feeling "blue"constantly since thedeath of herhusband. Shehadbeentreated withan antidepressant andcounseling, butdidnotfeel these measures were helpful. Shealso began to drink alcohol heavily. Shewasplaced on fluoxetine hydrochloride 20mg poqamin August 1990 byherfamily physician. Apparently, hercondition continuedto deteriorate. On admission to our facility, shehadmultiple neurovegetative symptoms of depression, including feelings of helplessness, hopelessness, guilt, and decreased libido. Shewasdiagnosed by thewardpsychiatrist as having major depression, single episode. Upon admission, laboratory findings revealed hematology to be within normal limits andbiochemistry remarkable onlyforan alkaline phosphatase level of 121 units/L. Her BPwas 120/80 mm Hg.Enalapril maleate 10mg qam,which shereportedly had beentakingpriorto admission, wascontinued and fluoxetine was discontinued. Imipramine wasstarted three dayslaterat an initial dosage of 50 mg qpm;the dosage was increased by 50 mg everynightto a dosage of 200mg po qhs.Hercombined imipramine/desipramine (I/D)concentration on day4 of imipraminetherapy at the dosageof 200 mg/d was516 ng/mL(therapeutic range 150-3(0). The patient'sonlycomplaint wasof feeling verytired. Vitalsigns includedBP 84/64 mm Hg and pulse80 beats/min. Imipramine andenalapril were heldfor 72 hours. A repeat I/D concentration 72 hours afterthe initial concentration was225 ng/mL. The patient wasrestarted on imipramine 75 mgqhs;repeat I/D concentrations remained between 220and269ng/mL. Enalapril wasrestarted at a dosage of 5 mg qam.At the timeof discharge three weeks later, she wasno longer having feelings of hopelessness, helplessness, or guilt. Shewasdischarged on imipramine 75 mgqhs with a serum I/Dconcentration of 269ng/mL. Levinson et al. stated that a drug-free period or a reduction in tricyclic antidepressant (TCA) dosage of up to 50 percent is recommended if a
Dlep, The Annals ofPharmacotherapy
•
1991 November. Volume 25 •
1273
doses on the development of tolerance to isosorbide dinitrate. N Engl 1
is 4.2 ± 2.1 (SD) hours and the clearance of tizanidine is 2.0 ± 0.8
Med 1987;316:1440-4.
1)kg/h.4.5 No reports have been published conceming tizanidine-drug in-
7. ABRAMS J. A reappraisal of nitratetherapy. lAMA 1988;259:396-401. 8. PACKER M. What causes tolerance to nitroglycerin? The 100 year old mysterycontinues. 1 Am Coli Cardioll990;16:932-5. 9. DUPUIS J. LALONTE G, LEMIEUX R,et aI. Toleranceto intravenous nitroglycerin in patients with congestiveheart failure: role of increasedintravascular volume, neurohumoral activation and lack of prevention withN-acetylcysteine. 1 Am Coli Cardioll990;16:923-31.
teractions.' Therefore, it may be that the mechanism of the phenytoin--tizanidine interaction is competitive inhibition of metabolic enzymes in the liver. Coadministration of phenytoin and tizanidine probably should be avoided, or patients receiving both drugs should receive careful monitoring of serum phenytoin concentrations. Further studies are needed to determine the underlying mechanism of this interaction. KAzuYUKl VENO, B.S.
Pharmacist
Phenytoin-tizanidine interaction
KAZUYOSHI MIY AJ, B.S.
TO THE EDITOR: Phenytoin is the most frequently prescribed anticonvulsant in the management of seizures, and is eliminated primarily by metabolism via hepatic enzyme systems. A number of drugs are reported to cause increases in serum phenytoin concentrations by inhibiting its metabolism.v" Tizanidine is used to improve muscle tone in shoulderarm-neck syndrome or low back pain, and is almost entirely metabolized by the liver.r" We report on a patient in whom the steady-state serum phenytoin concentration was apparently increased by the addition of tizanidine therapy. A 59-year-old manweighing 59 kg hadexperienced a cerebral infarction about sixmonths earlier and wascurrently experiencing convulsions on a frequent basis. Atthistime, therapy wasbegun with phenytoin (fme granules) 300mg/dfor three months. Trough serum concentrations (thefraction of unbound drugto total) 5, 8, and 12weeks afterstarting phenytoin therapy were 78.09(7.65), 74.9(7.37), and 75.7(7.53) urnol/L, respectively. At thisdose,his seizures werewellcontrolled andthere wasnoevidence of adverse effects. Nootheranticonvulsant medication wasadded, nordidthepatient receive anyothermedication thatmayhavealtered theserum phenytoin concentration-dose relationship. Hepatic and renal functions wereevaluated throughout this time period,and wereconsistently maintained within normal limits. Laboratory findings were: totalprotein 0.067 gIL, albumin 0.041 gIL, blood urea nitrogen 4.28mmol/L, andserum creatinine 53.041!ID01/L. Three months afterstarting phenytoin therapy, the patient complained of painin oneshoulder, andwasdiagnosed withshoulder-arm-neck syndrome. Concomitant therapy with tizanidine 2 mg tid wasbegun. Oneweeklaterthepatient developed drowsiness. His serumphenytoin (unbound fraction) concentration was 100.7 (9.91) umol/l; The administration of phenytoin wasstopped for three days,and thedosewasthenreduced to 240mg/d. Oneweek later, theserum phenytoin concentration was 45.6 (4.28); three weeks later it was 81.2 (8.32) umol/L. The drowsiness haddisappeared, but recurred about three weeks afterphenytoin was restarted. Therefore, thetizanidine therapy wasstopped. Oneweek latertheserum phenytoin concentration was57.9(5.79), and three weeks laterit was55.5(5.59) umol/l., Thedrowsiness disappeared anddidnotrecur. The trough serum phenytoin concentration of the patient increased from 75.5 to 100.7 llIDol/Lone week after phenytoin and tizanidine were coadministered, and despite the reduction of the phenytoin dose, the concentration continued to increase. Unbound percentage of serum phenytoin was unchanged. Phenytoin exhibits nonlinear pharmacokinetics in clinical pracrice.P Accordingly, a small increase in the dose can result in disproportional increases in the steady-state phenytoin concentration and time to achieve steady-state. Therefore, it is likely that the serum phenytoin concentration had not achieved steady-state one week after coadministration of phenytoin and tizanidine and three weeks after the phenytoin dose was reduced. Consequently, serum phenytoin concentrations gradual1y increased. His drowsiness appeared to correspond to the increased serum phenytoin concentrations; however, one adverse effect of tizanidine is drowsiness." The albumin was consistently within normal limits and the protein binding was approximately ten percent. Therefore, the drowsiness may have been caused by phenytoin or the combination of phenytoin and tizanidine. Phenytoin is eliminated from the body mainly by biotransformation in the liver to inactive metabolites. The major pathway is parahydroxylation and, to a lesser extent, metahydroxylation of one of the phenyl rings.>' Tizanidine is a new antispasticity agent with a novel chemical structure' and a pharmacologic profile different from that of myotonolytic drugs (e.g., diazepam, baclofen, dantrolene),"The absorption oftizanidine after oral administration (6-mg) tablets to normal adults is rapid and above 70 percent, and first-pass hepatic metabolism of oral tizanidine is about 80 percent. Time to peak concentration is one to two hours. The major pathway of tizanidine metabolism is hydroxylation of the imidazoline ring or phenyl ring fol1owedby conjugation. Tizanidine is almost entirely metabolized by the liver and more than 70 percent of the metabolites are excreted in the urine. The elimination beta-phase half-life
Director ofPharmacy National Sengokuso Hospital 1191 Nagose, Kaizuka-shi Osaka, 597 Japan KlYOSHl MITSUZANE, M.D.
Physician Department ofInternal Medicine
REFERENCES I. WINTER ME, TOZEN TN. Phenytoin. In: Evans WE, Schentag n, Jusko
2. 3. 4. 5.
Wl Appliedpharmacokinetics: principles of therapeutic drug monitoring. 2nd ed. Spokane, WA: AppliedTherapeutics, 1986:493-539. LEVINE M,CHANG T. Therapeuticdrug monitoringof phenytoin.Rationale and currentstatus. Clin Pharmacokinet 1990;19;341-58. NATION RL, EVANS AM, MILNE RW. Pharmacokinetic drug interactions with phenytoin (part 2). Clin Pharmacokinet 1990;18:131-50. Tizanidine. Drug interview-form sheet. Tokyo, Japan: Sandos Yakuhin, 1989;13-4. HEAZLEWOOD V,SYMONIW P, MARUFF P,EADIE MJ. Tizanidine-initial pharmacokinetic studies in patients with spasticity. Eur 1 Clin PharmacoI1983;25:65-7.
6. SAYERS AC, BURKI HR, EICHENBERGER E. The pharmacology of 5chloro-4-(2-imidazolin-2-yl-amino)-2,I,3-benzothiadiazole(DS 103282), a novel myotonolytic agent. Arzneimittelforschung 1980;30:793803.
Comment: tluoxetine adverseeffectsand drug interactions TO THE EDITOR: We read with interest the timely review article by Levinson et al. regarding adverse effects and drug interactions associated with fluoxetine (DIep 1991;25;657-61). We would like to report an interaction between fluoxetine hydrochloride and imipramine hydrochloride that occurred after fluoxetine was discontinued. A 35-year-old white woman wasadmitted to ourfacility aftershethrew herself down a flight of stairs in a suicide attempt. She had a history of twoprevious suicideattempts (oneby ingestion of pillsandalcohol, theotherbyhaving a caraccident whileintoxicated) sinceher husband'sdeathin 1988. She reported feeling "blue"constantly since thedeath of herhusband. Shehadbeentreated withan antidepressant andcounseling, butdidnotfeel these measures were helpful. Shealso began to drink alcohol heavily. Shewasplaced on fluoxetine hydrochloride 20mg poqamin August 1990 byherfamily physician. Apparently, hercondition continuedto deteriorate. On admission to our facility, shehadmultiple neurovegetative symptoms of depression, including feelings of helplessness, hopelessness, guilt, and decreased libido. Shewasdiagnosed by thewardpsychiatrist as having major depression, single episode. Upon admission, laboratory findings revealed hematology to be within normal limits andbiochemistry remarkable onlyforan alkaline phosphatase level of 121 units/L. Her BPwas 120/80 mm Hg.Enalapril maleate 10mg qam,which shereportedly had beentakingpriorto admission, wascontinued and fluoxetine was discontinued. Imipramine wasstarted three dayslaterat an initial dosage of 50 mg qpm;the dosage was increased by 50 mg everynightto a dosage of 200mg po qhs.Hercombined imipramine/desipramine (I/D)concentration on day4 of imipraminetherapy at the dosageof 200 mg/d was516 ng/mL(therapeutic range 150-3(0). The patient'sonlycomplaint wasof feeling verytired. Vitalsigns includedBP 84/64 mm Hg and pulse80 beats/min. Imipramine andenalapril were heldfor 72 hours. A repeat I/D concentration 72 hours afterthe initial concentration was225 ng/mL. The patient wasrestarted on imipramine 75 mgqhs;repeat I/D concentrations remained between 220and269ng/mL. Enalapril wasrestarted at a dosage of 5 mg qam.At the timeof discharge three weeks later, she wasno longer having feelings of hopelessness, helplessness, or guilt. Shewasdischarged on imipramine 75 mgqhs with a serum I/Dconcentration of 269ng/mL. Levinson et al. stated that a drug-free period or a reduction in tricyclic antidepressant (TCA) dosage of up to 50 percent is recommended if a
Dlep, The Annals ofPharmacotherapy
•
1991 November. Volume 25 •
1273
