Essay: Diagnosis and use of Phenytoin

R.S., a 34 year old African American male, presented to the walk-in clinic with a red, itchy rash and an overall feeling of ‘lousiness’ for the past week. While obtaining his past medical history, it was documented that the patient had sustained a subdural hematoma three months prior during a football game. A surgical procedure was performed to resolve the traumatic brain injury. Post-surgery the patient developed complex partial seizures that secondarily developed into generalized tonic-clonic seizures. Phenytoin was initiated, and the patient has been taking 200 mg twice daily for the past 6 weeks. During the physical exam, it was found that the maculopapular scaly erythematous rash was on his torso and upper extremities. He also had a fever, an enlarged, tender liver, slightly inflamed mucus membranes, and cervical lymphadenopathy. Further questioning revealed the patient had been experiencing dark urine and light colored stools over the past couple of days. We are not aware of any other medications that the patient is taking or any additional past medical, familial, or surgical history. A social history revealed that our patient is employed at a custom automobile shop and makes his living painting vehicles.
Phenytoin is an older AED commonly used to prevent seizures. Its mechanism of action is blocking sodium channels in neurons and increasing the release of GABA (an inhibitory neurotransmitter), thus increasing the stimulus required as well as reducing the frequency of neuronal stimulation resulting in reduced seizure/epileptic activity. Phenytoin, along with many of the other classical AEDs, has a narrow therapeutic window. Close monitoring is necessary to keep the patients plasma drug levels within range. It also displays non-linear pharmacokinetics and its metabolism may become saturated at clinical doses. Phenytoin and similar AEDs, like carbamazepine and phenobarbital, are metabolized in the liver by CYP450 enzymes to produced reactive metabolites called arene epoxide metabolites. These metabolites are further metabolized to unreactive products for excretion by epoxide hydrolase enzymes. Genetic deficiency of the hydrolase enzyme, environmental factors and or toxic levels of the toxic substrates can potentially lead to a buildup of the intermediary reactive metabolites which can cause hepatotoxicity. Toxicity and adverse drug reactions like cardiovascular complications, CNS changes, rash, hepatitis, and blurred vision need to be taken into consideration when using phenytoin. Due to his work history, we can additionally note the paint fumes may have potentiated further hepatic damage, but his lack of symptoms to previous exposure allows us to assume the main offender was the phenytoin unless further information is given. Additionally, R.S.’s inflamed mucosal membranes may be due to inhalation the paint fume chemicals.
The darkened urine (hematuria) and overall lousiness can possibly be attributed to a renal issue like acute kidney failure. It does not explain many of the other symptoms being experienced by our patient. To rule out any kidney involvement, we recommend a 24 hour urine collection and serum creatinine labs be done to make a ruling on the hypothesis.
The likelihood of a drug induced reaction, as well as other unclear causative factors, aided in the decision to admit R.S. on a precautionary basis. Once hospitalized, labs were drawn. Phenytoin was discontinued and the patient was treated with oral prednisone and topical corticosteroids to help alleviate the rash. Oral and topical steroids have anti-inflammatory properties and an indication for drug reactions. Initiation of corticosteroids is an appropriate therapy for the patient’s presumed hypersensitivity symptoms. Lab results showed elevated liver enzymes (ALT/AST) and elevated serum bilirubin. A high ALT/AST indicates inflammation, injury or disease of the liver, supporting our drug induced hepatitis hypothesis. Elevated serum bilirubin occurs when there is a large amount of bilirubin in the blood (bilirubinemia) or when hepatic injury is present and therefore the liver cannot clear bilirubin efficiently. Heptaic injury can result in cholestasis which could explain the pale stools and dark urine.
The elevated serum bilirubin, elevated liver enzymes and enlarged, tender liver confirm hepatic involvement, but at this stage, it remains unclear whether drug-induced hepatitis is a causative factor or a symptom. Because the patient is an African American male, had dark urine, bilirubinemia, felt lousy and was taking phenytoin, glucose-6-phosphate dehydrogenase (G-6-PD) deficiency was another possible hypothesis. G-6-PD deficiency is an X-linked genetic disorder. It results in a buildup of oxidative radicals due to the reduced amount of active glutathione causing an inability to neutralize the radicals. This normally presents with hemolytic anemia due to red blood cells lacking another anti-oxidation method. The patient’s CBC results were within normal limits so we rejected this hypothesis. In a patient experiencing hemolytic anemia the RBC count would be decreased and reticulocyte count would be increased.
An elevated white blood cells count with exaggerated eosinophils was also revealed by the lab results. These figures, along with the patient’s fever, painted a scenario of possible infection. Secondary bacterial peritonitis (SBP) could be indicated by the upper right quadrant pain(enlarged, tender liver), fever, cervical lymphadenopathy and elevated WBC count, but without further administration of antibiotics, the patient’s fever dissipated and WBC count normalized and thus SBP was ruled out. Eosinophilia could indicate a parasitic infection or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). We would recommend getting a stool sample to help rule out the possibility of a gastrointestinal parasitic infection. Ultimately, we ruled out a parasitic infection because of the patient’s resolution of fever and eosinophils without antiparasitic drugs. On the other hand, DRESS was found to be a promising conclusion.
On the second day of admission the resident remarked that all other illnesses of concern were ruled out by procedures and labs. This allowed us to rule out many of our hypotheses including drug induced systemic lupus erythematous (SLE). Phenytoin has been found to trigger SLE in some patients. R.S.’s maculopapular scaly red rash, dark urine (hemolytic anemia), occupation as a car painter (environmental trigger), escalation of seizures and medication (phenytoin) made this a promising hypothesis. A definitive ruling out of this hypothesis requires performing of an anti-nuclear antibody (ANA) titer. ANAs are present in 98% of SLE patients.
On day three, R.S.’s fever resolved and his maculopapular scaly erythematous rash became exfoliative without infectious complications. Furthermore, lab parameters began to normalize on the fourth day. Resolution of R.S.’s signs and symptoms with the discontinuation of phenytoin, strengthen our thoughts that phenytoin was the causative agent. With no AED’s on board, later that afternoon the patient relapsed into tonic-clonic convulsions and was treated with IV lorazepam. Additionally, R.S. had two more tonic-clonic seizures on day 5 in which lorazepam was also used. Lorazepam is a benzodiazepine acting on GABAA receptors inhibiting/reducing neuronal activity. While this stop-gap measure is effective in acute treatment, chronic use can lead to tolerance. At this point, the doctor would like to initiate another AED. Because he is less familiar with newer AEDs, he prefers the classical drug agents like oxcarbazepine and phenobarbital. Oxcarbazepine has a MOA similar to phenytoin. Phenobarbital works by binding to GABAA receptors, decreasing the release of glutamate and blocking sodium and calcium channels when present at high concentrations. Like phenytoin, oxcarbazepine and phenobarbital become arene epoxide metabolites. Therefore, these AEDs should not be used in our patient.
Newer AED agents are more diverse in their chemical structures and are unrelated to the classical heterocyclic ring of old AEDs that can form toxic metabolites. After analyzing the newer AEDs, we recommend the doctor prescribes topiramate for the patient. Topiramate works by blocking sodium channels. This changes phosphorylation of voltage and ligand gated channels by targeting kinases. Topiramate is indicated as a monotherapy in epileptics experiencing partial-onset and primary generalized tonic-clonic seizures. In order for a patient to have epilepsy, they must experience multiple seizures with a 24 hour time frame in between. R.S. qualifies as an epileptic with his seizure history. According to Lexicomp, there are immediate and extended release tablets. Both recommend increasing the dose weekly until they have tapered up to the recommended dose. If the patient starts on the immediate release, he should start with topiramate IR 25 mg by mouth twice daily, and increase by 50-100 mg each week until he reaches 200 mg twice daily. If he starts on the extended release, then the initial dose is topiramate ER 50 mg by mouth once daily and increase by 50-200 mg each week until he reaches 400 mg daily. No dose adjustments are recommended by the manufacturer for hepatic impairment, but it is noted that topirimate’s clearance may be reduced. Upon discharge, R.S. should be counseled on how to take topiramate. Depending on whether he starts on the IR or ER formulation, R.S. should take this drug twice or once daily, respectively. The ER formulation is contraindicated with alcohol. CNS changes (confusion, psychomotor slowing, depression), metabolic acidosis, changes in vision, and allergic reactions are all side effects that could occur. The patient should also be instructed to not abruptly discontinue the medication as it could increase the frequency of seizures.’