|Volume 7, Issue 6 June 2011
One of the most commonly prescribed antiepileptic drugs is phenytoin, otherwise known as the brand name of Dilantin®. This medication which was discovered in 1938 was found to be one of the earliest agents with a potential to stop seizures, yet without causing sedation. As a result and because there were very few drugs in the early 20th century, phenytoin became one of the most popular seizure agents in the world, and to this date is still one of the most highly prescribed medications. This month’s epilepsy.com monthly column takes a closer look at this medication.
Despite its popularity, phenytoin is rather complicated . This drug exerts its effect by impacting sodium channels on the membranes of neurons in the brain. By interacting with the sodium channels it is able to suppress abnormal firing which can lead to seizures. Phenytoin is available in both an oral and an IV form. For years phenytoin, which is a very difficult compound to dissolve in water, required a complicated solution to make it solvent. Thus, it is and was mixed with propylene glycol and ethanol in order for the medication to be able to be delivered via an intravenous route. However, the propylene glycol and ethanol created a series of problems including painful infusion and serious allergic reactions which led to a new version of the intravenous formulation of the drug to be created. This new drug called fosphenytoin is specifically derived to basically make the compound more soluble in water and therefore it is converted from what is known as a prodrug to the actual drug phenytoin, which is responsible for its main effects.
Pharmacology and Blood Levels
Despite the fact that phenytoin is available in new forms which make it more water soluble, the compound is actually rather difficult to get in the brain. In humans the rate of absorption for this drug is quite variable and prolonged and influenced by a number of different factors. In fact, it is difficult to have a rather consistent or stable concentration of the medication as judged by serum levels based on simple ingestion of phenytoin. Many factors can affect phenytoin levels in your blood stream, including drug interactions and how well one’s liver is functioning.
In addition to the brand name version of the medication, there have been several generic phenytoin preparations that have been approved by the Food and Drug Administration and available for use in the United States. Only one, a 100 mg generic extended release product manufactured by Mylan Pharmaceuticals, is approved as bioequivalent to Dilantin Kapseals™. The reason for this is that most of the generic medications tend to result in a rather high immediate jump in phenytoin level when taken. In order to obtain stable concentrations an extended release form of this medication is typically recommended.
There are rather complex pharmacological properties associated with Dilantin, which includes the fact that it is highly bound to plasma protein, such as albumin in healthy adults. The problem is that medications that are highly bound to these proteins cannot cross the barrier to the brain so only the unbound or free phenytoin distributes passively between the spinal fluid that bathes the brain and one’s circulatory system. As a result, it is not uncommon to have a very high phenytoin level yet the lab tests will show a normal level for phenytoin in the blood because the blood levels measure only the free portion or unbound portion of the medication. Most laboratories assume that the therapeutic range for phenytoin is between 10 to 20 mcg/ml, yet clinical experience proves that this level does not guarantee seizure protection. In some individuals seizures have been well controlled with concentrations lower than 10 mcg/ml, although at times more than 20 mcg/ml is needed for others. This variability in seizure control may be due to the underlying disorder, the seizure type or genetic determinants. There is no consistent significant association between the serum phenytoin concentration and any measures of toxicity or effectiveness. Therefore, it is essential that you always evaluate the patient and not pay as much attention to the phenytoin level.
Phenytoin is metabolized through the liver in a rather complex and competitive pathway involving what is known as the cytochrome P450 system. As a result there can be a lot of different interactions associated with phenytoin as many medications are metabolized through this system. Phenytoin can interact with the following medications:
This listing is not complete and other interactions exist. It is important to check with your physician or healthcare practitioner if you are taking a medication while on phenytoin as phenytoin may impact the other drug and visa versa.
Phenytoin is approved for a number of different conditions. It is effective in the treatment of acute seizures, particularly acute repetitive seizures, and status epilepticus. It can also be used for chronic maintenance therapy to prevent seizure recurrence. It is effective against partial onset seizures and generalized tonic-clonic seizures, but has very limited use for more generalized seizure types, including absence, clonic, myoclonic, tonic or atonic seizures. In juvenile myoclonic epilepsy it may be effective for treating tonic-clonic seizures if that is the main seizure type that is occurring. In Lennox-Gastaut Syndrome the agent is only helpful for the tonic-clonic seizures. Most studies that have looked at the effectiveness of phenytoin have primarily found that it is useful for acute repetitive seizures and status epilepticus.
There are many side effects related to phenytoin use. Those most commonly encountered are those related to increasing doses of the medication. Typically, signs of phenytoin toxicity include things such as unusual eye movements, imbalance, incoordination, double-vision, and drowsiness. One may appear as though they are effectively drunk. Nausea, vomiting, abdominal pain can also be seen. Less common adverse effects related to the use of this drug include unusual movements of the face, sedation; and an inability to process information.
Rash can occur in 8.5% of patients, particularly children and adolescents. Rash can be fairly serious, and therefore if one notes a rash with the onset of phenytoin use it is important that one let their physician or healthcare professional know so the appropriate action can be taken.
Long term therapy with phenytoin can result in effects which are somewhat concerning. Long term use of the drug has been associated with what is known as gingival hyperplasia, or overgrowth of the gums. Other changes may include unwanted facial hair and acne. In one recent study it was found that folic acid taken in children who are exposed to phenytoin may help to diminish the gum overgrowth.
Even more problematic is cerebellar atrophy, which occurs after long term use of this medication in some patients. Cerebellar atrophy is an overt finding on imaging studies such as MRIs or CT scans and can result in imbalance or chronic ataxia. Phenytoin can also suppress immunoglobulin production, white blood cells and platelet counts.
Recent findings have found that long term phenytoin use may lead to osteoporosis after one to two years of consistent use. It is suggested that people who take phenytoin be supplemented with a minimum of 1000 milligrams of calcium in order to prevent or mitigate the risk of osteoporosis.
In women who are of childbearing years there is a teratogenic effect associated with the use of phenytoin. There is a small but increased risk for cleft palate in offspring with phenytoin use during pregnancy. A recently published study “The Neurodevelopmental Effect of Antiepileptic Drugs, A Prospective Observational Study” found that on average the IQ of children exposed to phenytoin was seven points better than the ones exposed to valproic, but not different from the ones exposed to carbamazepine or lamotrigine. Three earlier studies have shown that phenytoin use carries a higher risk of poor cognitive outcome compared to unexposed controls.
Things to Remember
As one can see there are a number of issues associated with the use of phenytoin. Despite its overwhelming popularity by emergency room staff, geriatricians, and other primary care physicians, there are a number of adverse effects, drug interactions, and other concerns which renders phenytoin as a suboptimal choice.
- For the individual who presents with an acute seizure emergency in the hospital or status epilepticus, phenytoin is certainly an appropriate and effective agent. But for chronic long term use outside of the hospital, phenytoin is probably not the best first choice for most.
- It is not appropriate to use this agent in women of childbearing years, given its risk of teratogenicity and the fact that there are other alternative choices that may be somewhat safer.
- Its cosmetic effects are not the best for children.
- In the elderly, phenytoin use may cause problems with balance and therefore may not be appropriate for use in that group. Moreover, phenytoin has an extensive drug interaction profile, increasing the risk of an unwanted or potentially serious adverse side effects.
- Lastly, serum blood levels are often misleading.
How can the Epilepsy Therapy Project help
The Epilepsy Therapy Project is committed to advancing promising new therapies. By investigating newer agents we hope to offer better drug alternatives to phenytoin. Moreover, our educational tools, such as My Epilepsy Diary, can help keep track of your use of phenytoin, potential complications, drug interactions, and whether phenytoin is working in controlling seizures.
AED XI CONFERENCE PRESENTATIONS ARE NOW ONLINE:
For those of you who want to know more about the Epilepsy Pipeline and could not attend the recent AED XI Conference in Miami, we can now bring the conference to you. We are proud to offer the slides and audio presentations of the conference lectures on epilepsy.com.
For a more summarized view of the proceedings, listen to the recent Hallway Conversation with Dr. Jackie French discussing the Conference with epilepsy.com editor, Dr. Joseph Sirven. Follow the link in the Hallway Conversations section below.
INSTITUTE OF MEDICINE IS CURRENTLY ADDRESSING THE PUBLIC HEALTH ASPECTS OF EPILEPSY AND EPILEPSY CARE IN THE UNITED STATES:
The Institute of Medicine, an independent national advisory group of the National Academy of Sciences, is currently addressing the topic of epilepsy and how best to advise government and other agencies on what should be done regarding this condition. There are several workshops that are being arranged around the work of this committee and another one will soon be occurring at the Institute's headquarters in Washington, DC. Epilepsy Therapy Project's Chairman and Co-Founder, Warren Lammert, will be testifying at the next meeting regarding his personal dealings with the healthcare system and epilepsy.
The IOM Committee on the Public Health Dimensions of the Epilepsies' Workshop on Public Health Dimensions of the Epilepsies: Health Care Quality and Access and Education of Health Care Providers, Patients, and the Public will take place on June 28-29, 2011, at the National Academies' Keck Center (500 Fifth Street NW, Washington, DC 20001).
If you are interested in attending or finding out more about this workshop, please see the link below for registration and other information.
Register for this workshop
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TAKE THE EIGHT QUESTION SURVEY NOW
Hallway Conversations, a series of audio podcasts in which Dr. Joseph Sirven, Editor-in-Chief of epilepsy.com, has the pleasure of having a brief conversation with thought leaders and newsmakers in the field of epilepsy on a range of seizure related topics. The series is intended as a second opinion to help clinicians understand the latest research as explained by the investigator or perhaps focus on a clinical issue with the help of a leading epilepsy authority on the topic. The purpose is to frame the latest epilepsy news in the right context so as to better manage patients with seizures and improve quality of life. We hope that you find the series informative and helpful and that you join us in listening on a regular basis.
Listen to the latest podcasts in the Hallway Conversations series from:
June 3, 2011
Jacqueline French, MD
President Epilepsy Study Consortium
Epilepsy Therapy Project,
Board of Directors; Chair, Scientific Advisory Board
Professor of Neurology
NYU School of Medicine
Topic: Highlights from the AED Xi Pipeline Conference
May 18, 2011
Avani Modi, Ph.D.
Assistant Professor in Pediatrics
Division of Behavioral Medicine and Clinical Psychology
Center for Treatment Adherence and Self Management
Cincinnati Children's Hospital Medical Center
Topic: Taking Your Medications: Following Doctors Orders and Seizures
May 11, 2011
Yu-tze Ng, MD, FRACP
Director of Clinical & Drug Research
Pediatric Neurology & Epilepsy
Barrow Neurological Institute
Associate Clinical Professor, Creighton University
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ETP has made an investment in ICVrx. ICVrx will start clinical studies of three generic drugs reformulated for implanted pump delivery to provide the medically refractory epilepsy community a "first choice" treatment option.
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