Introduction
Phenytoin was first synthesized as a derivative of barbiturates by German professor Heinrich Biltz in 1908. In 1923, an American chemist working for Parke-Davis pharmaceutical company resynthesized Phenytoin in Detroit. During the initial screening, it was found that Phenytoin did not produce sedative side effects similar to barbiturates and was, therefore, considered an unimportant drug by Parke-Davis. Later, in 1936, Putnam and Merritt identified the anticonvulsive properties of Phenytoin by using a new animal model for convulsive disorders. Subsequently, between 1937 and 1940, they evaluated its clinical value in a number of patients. Phenytoin is a medication commonly used to treat seizures and epilepsy. The alternative name of Phenytoin is 5,5-diphenylhydantoin.
What Is Phenytoin Toxicity?
Phenytoin toxicity refers to the side effects that can occur when the level of Phenytoin in the body becomes too high. Phenytoin is a medication used to treat seizures and epilepsy, but if the dose is too high or if the body is unable to process the medication properly, the level of Phenytoin in the blood can rise to toxic levels. An overdose of Phenytoin can happen when an individual takes more medication than prescribed, either intentionally or accidentally.
What Are the Risk Factors for Phenytoin Toxicity?
Several risk factors can increase the likelihood of Phenytoin toxicity, which include:
- Higher Dose: Taking too much Phenytoin can result in toxicity. This can occur if a person takes a higher-than-prescribed dose or if the dose is not adjusted appropriately based on changes in the person's weight, kidney function, or other factors.
- Drug Interactions: Certain medications can interact with Phenytoin and increase the risk of toxicity. These may include other anticonvulsant medications, antibiotics, and medications used to treat heart conditions.
- Age: Elderly patients may be more susceptible to toxicity due to changes in metabolism and kidney function that can occur with age.
- Kidney Disease: The kidneys are responsible for removing Phenytoin from the body; if they are not functioning properly, the medication can build up to toxic levels.
- Liver Disease: The liver is responsible for metabolizing Phenytoin, and if it is not functioning properly, the medication can accumulate in the body and cause toxicity.
- Genetic Factors: Some individuals may have genetic variations that affect how their bodies process Phenytoin, which can increase the risk of toxicity.
- Malnutrition: Malnutrition can affect the body's ability to process Phenytoin, which can increase the risk of toxicity.
What Are the Clinical Manifestations of Phenytoin Toxicity?
There are several clinical manifestations of Phenytoin toxicity depending on the route and duration of drug exposure. Phenytoin toxicity affects the nervous system and cardiovascular systems. Oral Phenytoin overdose primarily results in neurotoxicity, whereas cardiovascular toxicity is a rare occurrence. Conversely, parenteral administration of this medication is associated with significant cardiovascular toxicity as its major side effect.
- Neurotoxic Effects: The neurotoxic effects of Phenytoin are concentration dependent and can range from mild symptoms to more severe symptoms. Symptoms include nystagmus (an involuntary rhythmic movement of the eyes), ataxia (a neurological disorder that affects coordination, balance, and movement control), tremor (an involuntary rhythmic movement of a body part), slurred speech, vomiting, lethargy, hyperactivity, and confusion. Phenytoin can cause coma and seizures, which are rare and usually only occur when serum concentrations are extremely high. While unbound plasma Phenytoin concentration is a reliable predictor of neurotoxicity, this laboratory value is not commonly obtained.
- Cardiovascular Effects: Although Phenytoin is an antiarrhythmic drug, it is almost never used for this purpose anymore. Its effects on the cardiac voltage-gated sodium channels can lead to dysrhythmias (abnormal heart rhythms) and SA (sinoatrial) and AV (atrioventricular) nodal blocks. Still, these effects are rare when the drug is taken orally. However, the intravenous form of Phenytoin contains propylene glycol, which is a cardiac depressant. Rapid infusions of intravenous Phenytoin can cause bradycardia (decrease in heart rate), low blood pressure, and absence of heartbeat, so it is important to administer this formulation at a rate of 50 mg per minute or less.
- Phenytoin-Induced Gingival Enlargement (PIGE): Gingival hyperplasia is a frequently observed result of prolonged use of Phenytoin. The enlargement of the gingival tissues associated with Phenytoin is thought to be caused by the drug's direct impact on gingival fibroblasts and their metabolites. In addition to this, other contributing factors to PIGE can include changes in calcium metabolism, low levels of folic acid in the bloodstream, and suppression of the immune system.
- Phenytoin Hypersensitivity: This allergic reaction can occur between one week to one month after starting the therapy, presenting with fever, rash, and various internal organ involvement such as hepatitis, myocarditis, and pneumonitis. Hepatitis, myocarditis, and pneumonitis are inflammatory conditions affecting the liver, heart muscle, and lungs, respectively.
What Are the Syndromes Associated With Phenytoin Toxicity?
The syndromes associated with Phenytoin toxicity include:
- DRESS Syndrome: The syndrome known as DRESS (Drug reaction with eosinophilia and systemic symptoms) has been linked to long-term use of the anticonvulsant drug Phenytoin, as well as other aromatic anticonvulsants like Carbamazepine and Lamotrigine. Although it is rare, occurring in only 1 in 1000 to 10,000 individuals, it can be serious and may manifest within two months of starting treatment. The symptoms of DRESS typically involve a high fever, a rash on the skin, and inflammation of the pharynx, which can be mistaken for streptococcal pharyngitis. The syndrome can also cause damage to multiple organ systems, such as the liver and kidneys, as well as lymph node enlargement and even encephalitis. To prevent further progression of the syndrome, it is crucial to discontinue Phenytoin immediately and start steroid treatment. A skin biopsy may be necessary to confirm the diagnosis, and an alternative non-aromatic anticonvulsant should be used in place of Phenytoin.
- Stevens-Johnson Syndrome (SJS): Phenytoin has also been linked to two other serious skin conditions, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening. While once thought to be idiopathic, genetic variations in the human leucocyte antigen system and CYP (cytochrome P450) genes have been found to increase the risk of developing these conditions. If a skin and mucosal rash are observed, discontinuing Phenytoin immediately is necessary. Genetic testing may be advised before switching to another aromatic anticonvulsant.
- Purple Glove Syndrome: Intravenous administration of Phenytoin can lead to a rare side effect called ‘Purple Glove Syndrome’. This syndrome is characterized by the worsening of distal limb edema and discoloration, which can progress to extensive skin necrosis (a localized death or decay of skin tissue), and limb ischemia (a condition that arises due to restricted blood flow to the extremities).
What Is the Treatment for Phenytoin Toxicity?
The treatment options for Phenytoin toxicity include:
- Stopping Phenytoin: If the patient is experiencing severe symptoms of Phenytoin toxicity, the doctor may stop the medication immediately to prevent further buildup of the drug in the body.
- Supportive Care: Patients with Phenytoin toxicity may require supportive care, such as intravenous fluids to maintain hydration, oxygen therapy to help with breathing, and monitoring of vital signs.
- Activated Charcoal: It is an effective agent that binds to Phenytoin and prevents its absorption. In cases of acute Phenytoin ingestion, a single dose of activated charcoal may be helpful. In cases of large overdoses, Phenytoin can slow down gastrointestinal motility, leading to delayed absorption. Moreover, activated charcoal can be useful in cases of acute ingestion of extended-release tablets. However, in situations where there is a decreased level of consciousness, activated charcoal is not recommended.
- Medications: In some cases, medications may be prescribed to help manage the symptoms of Phenytoin toxicity, such as Benzodiazepines to control seizures or antipsychotics to control agitation or hallucinations.
- Dialysis: In severe cases of Phenytoin toxicity, dialysis may be necessary to remove the drug from the patient's bloodstream.
- Adjusting Phenytoin Dose: Once the patient has stabilized, the healthcare professional may adjust the dose of Phenytoin or switch to an alternative medication to prevent further toxicity.
Conclusion:
Phenytoin toxicity can occur due to a variety of reasons. Follow the guidance of the doctor when taking Phenytoin, as they can monitor for potential side effects and adjust the dose as needed. Careful monitoring of the patient's dose and regular testing of blood levels helps to prevent toxicity to a certain extent.
