NONCOMPLIANCE LEADING TO DRUG ACCUMULATION RESULTING IN PHENYTOIN TOXICITY Ravi Akula, MD; Syed Hasan, MD, FABHP; Rao Pipalla, PhD; and Clifford Ferguson, MD Washington, DC
Phenytoin is effective in suppressing tonic-clonic and partial seizures, and is widely used for initial therapy, particularly in adults. Ninety percent of phenytoin is protein bound and entirely eliminated by hepatic metabolism. The major metabolite of phenytoin, 5-(p-hydroxyphenyl)-5phenylhydantoin (5HPPH) is excreted in the urine. Higher phenytoin levels for a given dose of phenytoin can be seen in alcohol intoxication, hepatic and renal failures, hypoalbuminemia, nephrotic syndrome, trauma, and AIDS. Noncompliance can lead to accumulation of the drug-causing toxicity. We present a patient with acute alcohol intoxication who developed phenytoin toxicity due to noncompliance with the drug. (J Natl Med Assoc. 2003;95:1201-1203.)
Key words: phenytoin * metabolism * toxicity
INTRODUCTION Phenytoin is a widely used antiepileptic medication. First introduced in 1938, it is the oldest sedative antiepileptic drug. It is a relatively safe medication when the blood level is maintained within the therapeutic range. Phenytoin follows nonlinear kinetics and as such, minor increases in the dose may lead to toxic concentrations. Excessive dosing is one of the more common causes of toxicity. We present a patient with acute alcohol intoxication who developed phenytoin toxicity due to noncompliance with the prescribed dosing regimen. A 58-year-old African-American man was admitted to the hospital for witnessed seizure. Medical history was significant for asthma dating back to childhood and tonic-clonic seizures due to alcohol abuse. There was no family history of ( 2003. From the Center for Sickle Cell Disease, Washington, DC. Send correspondence and reprint requests for J Natl Med Assoc. 2003;95:1201-1203 to: Syed P. Hasan, MD, FABHP, Center for Sickle Cell Disease, 2121 Georgia Avenue NW, Washington, DC 20059; phone: (202) 865-6100; fax: (425) 9638879; e-mail:
[email protected]
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seizure disorder. He was prescribed phenytoin 100 mg by mouth three times a day but admitted to taking phenytoin 100 mg by mouth apparently two to three times a day for the last three years. He denied using any over-the-counter or herbal preparations. Admission vital signs were as follows: temperature 97.7°F, heart rate 77/min and regular, respiratory rate 22/min, supine blood pressure 100/60 mmHg. The admission physical examination revealed a drowsy, moderately built and nourished man. He had coarse facial features with marked supraorbital prominence, gingival hyperplasia, nystagmus on lateral gaze, mild ataxia, and slightly decreased deep tendon reflexes. Chest examination was significant for bilateral wheezing. He had a normal chest x-ray and EKG. Significant initial laboratory values on admission were as follows: phenytoin level 52.3gg/mL and alcohol 103 mg/dL. The complete blood count and comprehensive metabolic panel (including liver function tests), prothrombin time, and activated partial thromboplastin time were normal. He also had a normal urinalysis and negative urine toxicology screen. Arterial blood gases: PH 7.38, PCO2 43.4, P02 54.2, HCO3 25.5, 02 saturation 87.4%. Hypoxia was attributed to asthma exacerbation. Gastric VOL. 95, NO. 12, DECEMBER 2003
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Figure 1. Phenytoin Levels Obtained During Hospital Admission
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lavage was not performed in the emergency room. The patient was admitted to a telemetry unit, managed conservatively, and remained stable throughout the hospitalization. Intravenous normal saline was used for hydration. Other medication included diclofenac sodium for generalized body ache. He also received multivitamin and thiamine daily during this hospitalization for prophylaxis against delirium tremens. Repeated tests showed gradually but slowly declining phenytoin levels. Phenytoin levels were drawn serially to monitor the rate of decline. Although there are no reports of interaction between diclofenac and phenytoin, diclofenac was discontinued in the event it may have contributed to slow decline of the phenytoin level. After reviewing the literature for possible causes of slow decline in phenytoin level, 24-hour urine for 5-(p-hydroxyphenyl)-5phenylhydantoin (5HPPH) concentration was first collected on the seventh day of the hospitalization. The 5HPPH level was low (20 mg/ml). Subsequent alcohol levels obtained on the second and third day of the hospitalization were 24.5 mg/dL and 4.7 mg/dL respectively. Subsequent phenytoin levels obtained on the second, fourth, and sixth days were JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
46.5 jg/mL, 34.7 gg/mL and 23.9 ,ug/mL respectively (Figure 1). By the eighth day the phenytoin level had declined to 15.8 gg/mL, and the patient was discharged. No other interventions were done.
DISCUSSION Phenytoin, a hydantoin, suppresses the seizure activity and propagation of electric discharge by decreasing sodium transport and blocking calcium channels at the cellular level. Primary mode of metabolism of phenytoin is by parahydroxylation in the liver and is subsequently conjugated with glucoronic acid to form 5HPPH'. The metabolite is clinically inactive and is excreted in the urine2. Approximately 1-5% of phenytoin is excreted unchanged in the urine. Saturation of the enzyme responsible for hydroxylation of phenytoin occurs at doses needed to achieve therapeutic effect. Therefore, it shows firstorder kinetics at low doses, but this changes to zeroorder kinetics once the enzyme becomes saturated. As blood levels rise within the therapeutic range, the maximum capacity of the liver to metabolize the drug is achieved. Further increase in the dose, even though relatively small, may produce very large changes in VOL. 95, NO. 12, DECEMBER 2003 1202
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phenytoin concentrations. At higher concentration, the half-life of the drug increases significantly, because it follows zero-order kinetics. Steady state is not achieved in normal fashion. At high levels, sometimes, patients quickly develop symptoms oftoxicity. At low blood levels, it takes 5-7 days to achieve steady state blood levels after each dosage change; at higher levels it may be 4-6 weeks before blood levels are stable. The rate ofmetabolism is affected by intrapatient and interpatient variations (race, gender, genetics, age), interacting drugs and concomitant diseases. Blacks and Japanese populations show slower phenytoin metabolism, compared to caucasians'. Pitner et al. reported in their study of patients aged 60-79, a 21% lesser amount of medication to achieve the same level as compared to younger patients3. Tobacco and alcohol stimulate phenytoin metabolism, so lower levels are seen in these patients4. Acute alcohol intoxication can cause transient hepatic insufficiency resulting in elevation of the phenytoin level, which normalizes with the return of liver functions. In general hypoalbuminemia, renal and hepatic dysfunctions result in decreased protein binding that causes a rise in the percent of unbound phenytoin, but a decline in the total serum concentration of phenytoin due to altered distribution of phenytoin from the blood to peripheral sites. Our patient had two of the characteristics of hypometabolism-black and elderly man-leading to toxicity, as reported in the literature. Though alcohol could cause transient elevation of phenytoin level, it seems unlikely in this case, as hepatic functions were normal. As per his history, our patient was not compliant with the medication. Physical examination suggested the presence of both acute and chronic signs of phenytoin toxicities. Genetic defects in the metabolism of phenytoin causing a delay in clearance has been reported in the literature. The mode of inheritance was suggested to be autosomal dominant5'6. One study reported that three out of four generations of family members showed defective metabolism5. There is a good correlation between the amount of 5HPPH excreted and the rate of metabolism5'7. Although our patient had a low level of 5HPPH in the urine, one sample does not allow us to ascertain that this patient had genetic basis for elevated levels of phenytoin. Clinicians should be aware of the rare possibility of genetic hypometabolism as a reason for phenytoin toxicity. Pharmacogenetic variation in phenytoin metabolism involving mutations of hepatic CYP2C9*3 1203 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
shows that pharmacogenetic variation may contribute to phenytoin toxicity89. Genetic counseling should be offered to the family members of the individual who is found to be the hypometabolizer ofphenytoin. This will enable the earlier detection of individuals at risk for toxicity. Free phenytoin has also been shown to be a marker of clinical efficacy and adverse effects. The level in saliva and erythrocytes correlates closely to the free phenytoin level, but their use in clinical practice is limited. Because 7-28 days or more are needed to achieve steady level, close monitoring is required during the initiation of phenytoin therapy.
CONCLUSION Many clinical conditions can lead to high phenytoin levels and toxicity. Genetic defects, pharmacogenetic variation in phenytoin metabolism involving mutations of hepatic CYP2C9*3, hepatic, and renal impairment can cause phenytoin toxicity. Elderly and black patients should have close monitoring of the phenytoin levels, as these groups may develop toxic symptoms more readily. It seems probable that chronic inappropriate dosing led to a very high drug level in our patient. Once an individual is identified to have high levels and/or toxic symptoms, close monitoring of phenytoin level for several days may be necessary before returning to normal.
REFERENCES 1. Watanabe M, Iwahashi H, Suwahi H, et al. Phenytoin kinetics in Japanese adult epileptics: Phenotype of phenytoin slow metabolizers. Clinical Neuropharmacology. 1997;20:346-35 1. 2. Arnold K, Gerber N. The rate of decline of diphenylhydantoin in human plasma. Clinical Pharmacol Ther. 1969; 1 1: 121-134. 3. Pitner J, Long LD, Meyer RP, et al. Phenytoin toxicity in an older patient with slow metabolism and atypical presentation. Pharmacotherapy. 1998; 18:218-225. 4. Kutt H, Haynes J, McDowell. Some causes of ineffectiveness of diphenylhydantoin. Arch Neurolo. 1996; 14:489-492. 5. Vasko MR, Bell RD, Daly DD, et al. Inheritance of phenytoin hypometabolism: A kinetic study of one family. Clinical Pharmacol Ther. 1979;27:96-103. 6. Evans DAP, et al. Pharmacogenetics. American Journal of Medicine. 1963;34:639-662. 7. Kutt HI, Wolk M, Scherman R, et al. Insufficient parahydroxylation as a cause of diphenylhydantoin toxicity. Neurology. 1964; 14:542-548. 8. Kidd RS, Curry TB, Gallagher S, et al. Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. Pharmacogenetics. 2001; 11:803-808. 9. Brandolese R, Scordo MG, Spina E, et al. Severe phenytoin intoxication in a subject homozygous for CYP2C9*3. Clinical Pharmacol Ther. 2001;70:391-394.
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