Phenytoin chemical structure
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Dilantin

Phenytoin sodium (marketed as Dilantin® in the USA and as Epanutin® in the UK, by Parke-Davis, now part of Pfizer) is a commonly used antiepileptic. It was approved by the Food and Drug Administration in 1953 for use in seizures. Phenytoin acts to damp the unwanted, runaway brain activity seen in seizure by reducing electrical conductance among brain cells. more...

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History

Phenytoin (diphenylhydantoin) was first synthesized by a German physician named Heinrich Biltz in 1908. Biltz sold his discovery to Parke-Davis, which did not find an immediate use for it. In 1938, outside scientists including H. Houston Merritt and Tracy Putnam discovered phenytoin's usefulness for controlling seizures, without the sedation effects associated with phenobarbital. There are some indications that phenytoin has other effects, including anxiety control and mood stabilization, although it has never been approved for those purposes by the FDA.

Jack Dreyfus, founder of the Dreyfus Fund, became a major proponent of phenytoin as a means to control nervousness and depression when he received a prescription for Dilantin in 1966. Dreyfus' book about his experience with phenytoin, A Remarkable Medicine Has Been Overlooked, sits on the shelves of many physicians courtesy of the work of his foundation. Despite more than $70 million in personal financing, his push to see phenytoin evaluated for alternative uses has had little lasting effect on the medical community. This was partially due to Parke-Davis's reluctance to invest in a drug nearing the end of its patent life, and partially due to mixed results from various studies.

Dilantin made an appearance in the 1962 novel One Flew Over the Cuckoo's Nest by Ken Kesey, both as an anticonvulsant and as a mechanism to control inmate behavior.

Side-effects

At therapeutic doses, phenytoin produces horizontal gaze nystagmus, which is harmless but occasionally tested for by law enforcement as a marker for drunkenness (which can also produce nystagmus). At toxic doses, patients experience sedation, cerebellar ataxia, and ophthalmoparesis, as well as paradoxical seizures. Idiosyncratic side effects of phenytoin, as with other anticonvulsants, include rash and severe allergic reactions.

There is some evidence that phenytoin is teratogenic, causing what Smith and Jones in their Recognizable Patterns of Human Malformation called the fetal hydantoin syndrome. There is some evidence against this. One blinded trial asked physicians to separate photographs of children into two piles based on whether they showed the so-called characteristic features of this syndrome; it found that physicians were no better at diagnosing the syndrome than would be expected by random chance, calling the very existence of the syndrome into question. Data now being collected by the Epilepsy and Antiepileptic Drug Pregnancy Registry may one day answer this question definitively.

Phenytoin may accumulate in the cerebral cortex over long periods of time, as well as causing atrophy of the cerebellum when administered at chronically high levels. Despite this, the drug has a long history of safe use, making it one of the more popular anti-convulsants prescribed by doctors, and a common "first line of defense" in seizure cases. Phenytoin may also cause gingival hyperplasia.

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Diary: from a week in practice
From American Family Physician, 8/1/05 by John O'Handley

Monday

Estella, a middle-aged Hispanic patient, visited the mobile clinic for exudative tonsillitis four days ago. The result of her rapid strep test was positive, but her type I allergy to penicillin precluded the use of a beta-lactam antimicrobial for treatment. I was left with azithromycin (Zithromax) because our pharmacy on the mobile clinic is limited, but I warned Estella that if she was unable to swallow the pills or if her condition did not improve, she would have to go to the emergency department. Estella took the medication but did not improve, and the swelling in her neck became more pronounced. A friend took her to the emergency department today, and a computed tomography scan confirmed the presence of loculated fluid in the right tonsil. She was given intravenous clindamycin (Cleocin) and underwent local incision and drainage of the tonsillar abscess. Estella was fortunate. We sometimes complain about the disarray of our medical system, but in the mobile clinic, at least, emergency patients are not turned away for lack of resources.

Tuesday

"The thing that hangs down in my throat hurts," Idel, a young Somali woman, said. Idel speaks some English, but we still need an interpreter. Her chief complaint, sore throat, had been bothering her for three years. Her uvula was almost atrophic but was slightly inflamed on its tip--certainly not consistent with the symptoms she described. I was surprised by the duration of symptoms. She had been to the clinic several times in the past year for various complaints, but never seemed to improve. "None of the medicines helped," said Idel. Looking through the chart, I found that antibiotics, antihistamines, analgesics, and decongestants had been no help. Testing for the streptococcal antigen had been a dead end. "I also have a cough," Idel further explained. At this point, the medical student and I looked at each other and realized the diagnosis had been there all along. "Do you have any heartburn?" I asked. "Yes," she affirmed, pointing to her chest. Gastroesophageal reflux disease seemed so obvious now. In this instance, the process of diagnosing took a circuitous route. It was not until I probed a little deeper that everything fell into place.

Wednesday

Success stories happen even on the streets, but it is rare for patients to return to the mobile clinic to give thanks for the care they received. George came to the mobile clinic two weeks ago "ready to die." Weakness and abdominal pain had been increasing for two weeks, and he knew something had to be done. He had curtailed his daily intake of four 40-oz beers, but even abstinence did not improve the symptoms that drove him to seek medical help. By the time he reached the mobile clinic, his pallor, hypotension, and pained expression forced me to opt for immediate transfer to the emergency department. From there, he was admitted after examination and tests revealed he had a hemoglobin of 9.8 g and an ulcer two thirds the circumference of the duodenum. A transfusion and initiation of a proton pump inhibitor did wonders for his condition. George felt like a new man, and today his gratitude for the help he received knew no bounds. The nurses and staff who previously had been so solicitous of his welfare were overjoyed at his new appearance. Whether George would follow through on his abstinence from alcohol was hard to say, but if his resolve was anything like the gratitude he was expressing, he would be successful in his struggle.

Thursday

Monty is from a good family, but his bipolar disorder severely affected his integration into society. Formerly homeless, he now lives in a small room in a low-income housing project. He came to the mobile clinic today after five days of rib pain on his left side. Monty is normally a quiet, reserved individual, but today the floodgates opened and he talked about everything except his immediate problem. I redirected the conversation to his rib pain. It had begun when he was trying to reach some chocolate pudding in a dumpster behind a grocery store. Monty had successfully procured the chicken wings and spareribs that recently had been disposed of, but dessert was a little deeper inside the dumpster. As he strained against the metal side to reach the pudding, he felt something "pop." The point tenderness and irregularity of his left sixth rib indicated a fracture. I reassured him it would heal in four to six weeks and gave him something for the pain. I didn't need to warn him about the dangers of his hunting and gathering methods: Monty had learned his lesson.

Friday

Michael, a tall, strapping, middle-aged man, had lost his construction job and had been living in a shelter for two days. He came to the mobile clinic because of pain and swelling in his right knee. Two weeks earlier, he had been playing basketball when a sudden pivot caused knee pain and a loud "pop." A visit to a local emergency department had followed, and Michael told us that yellow fluid was drained from his knee after a radiograph showed no bony injury. I was somewhat skeptical of the color of the effusion; because it was associated with an acute injury, I would have expected bloody fluid. The effusion had now returned and was causing him a good deal of pain. T.B., the fourth-year medical student with me this month, examined Michael and reported a medial effusion, tenderness over the medial collateral ligament (MCL), and no warmth or redness. Michael wanted the fluid removed, believing it was the main cause of his pain, and T.B. aspirated 18 mL of yellow serous fluid from the medial aspect of the knee. In discussing the case with an orthopedic surgeon later, I was told that a tear of a cruciate ligament or bony injury within the joint would give a bloody effusion, but a tear of the MCL, because it is extra-articular, could result in a sympathetic serous effusion. This information clarified my thinking on knee effusions and also reinforced my confidence in Michael's ability to provide an accurate history. Michael felt much relief with his smaller knee and promised to follow up with the orthopedic clinic to ensure a satisfactory resolution of his problem.

Saturday/Sunday

Salme has had seizures since her childhood in Somalia. She was running low on her supply of phenytoin (Dilantin) and had developed a headache over the past two days. "This warns me that I may have a seizure," she said through our interpreter. Neurologically, she was intact. Because she had had no recent medical care, I examined her abdomen and found what felt like a 20-week-sized fetus. "Have you felt this before?" I queried. "I haven't noticed anything different," she replied. "Could you be pregnant?" I asked. Salme attested to the fact that she was not married and had regular periods, the last one 10 days ago. Could it be a fibroid, a solid tumor, or a cyst? I thought, trying to make sense of the opposing information from the history and physical examination. Would a urine pregnancy test be an insult to her veracity? I went ahead and ordered one, and she complied without objection. The test confirmed what I had suspected. Salme seemed nonplussed and did not acknowledge how the conception came about. My thoughts went back to other patients who presented with a headache as the sole symptom of pregnancy. For Salme, it was a harbinger of a seizure. The unexpected outcome of the visit was accepted with a quiet resignation.

After years spent in private family practice and in academia, John O'Handley, M.D., is medical director of the Mount Carmel Outreach Program in Columbus, Ohio. The program provides free medical care to uninsured and homeless patients throughout the city on a mobile coach clinic. Dr. O'Handley continues to see private patients two mornings a week.

Address correspondence to John O 'Handley, M.D., 6150 East Broad Street, Columbus, OH 43213 (e-mail: johandley@mchs.com).

To preserve patient confidentiality, the patients' names and identifying characteristics have been changed in each scenario. Any resemblance to actual persons is coincidental.

COPYRIGHT 2005 American Academy of Family Physicians
COPYRIGHT 2005 Gale Group

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