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.
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.
Joseph Sirven, M.D.
Last Reviewed: 6/15/11
Article from the June 2011 Epilepsy.com Spotlight Newsletter. Other articles in this issue inclue:
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