Ever since it has been discovered at the beginning of the 20th century, in 1908, Phenytoin has remained among the most commonly used and well-studied anticonvulsants in the world. It is listed in the WHO’s (World Health...
Ever since it has been discovered at the beginning of the 20th century, in 1908, Phenytoin has remained among the most commonly used and well-studied anticonvulsants in the world. It is listed in the WHO’s (World Health Organization) List of Essential Medicines.
So, what are anticonvulsant medicines?
Anticonvulsants are a diverse set of drugs used in treating epileptic seizures in patients. These drugs are also widely used to address bipolar disorder and borderline personality disorder. This is because many of these drugs seemingly act as mood stabilizers. These medicines are also helpful in the treatment of neuropathic pain.
However, due to its narrow therapeutic index and all-pervasive daily use by people, there is always a potential threat of Phenytoin overdose or toxicity from chronic use. Hence, it is imperative to have early detection, management, and also prevention of further toxicity among the masses.
Different risk factors for Phenytoin toxicity
There is a slew of risk factors leading to Phenytoin toxicity. Some of them are as follows:
Altering medications
Phenytoin toxicity can take place when there is an increase in the daily dose of Phenytoin, alterations in the formulations or brands in addition to modification in the frequency of dosage administration. It is also likely to occur when patients are given new medications that interfere with the binding capacity of Phenytoin to plasma proteins or metabolism. Due to its metabolism by CYP450 liver enzymes, many drug interactions can happen.
Transformation in Physiology
New diseases can bring about changes in the Phenytoin plasma concentration. For instance, liver cirrhosis can cause a decrease in serum albumin apart from a decreased metabolism of Phenytoin by the CYP450 pathway. As a result of these two phenomenons Phenytoin in the serum would increase. On the other hand, kidney-related ailment can also lead to hypoalbuminemia and uremia which leads to a decrease in the percentage of bound Phenytoin in the plasma. Other reasons for Phenytoin toxicity in a patient (who is on chronic therapy with no changes in the dosage) are malnutrition, malignancy, and pregnancy.
Acute Ingestion
Acute ingestion is a very common cause leading to toxicity of Phenytoin. An overdose could be intentional or inadvertent. People also mix crack cocaine with Phenytoin, which can cause an unintentional overdose, compromising the safety of the user.
Unremitting Toxicity
Gingival hyperplasia is frequent in people who have been taking Phenytoin for a long period. This condition, known as Phenytoin-induced gingival enlargement (PIGE), is believed to be primarily triggered by the direct impact of the drug and its byproducts on the gingival fibroblasts. Other factors that may cause PIGE include the suppression of the adrenocortical axis, disruptions in calcium metabolism, decreased levels of serum folic acid, and immune system suppression.
Signs of Phenytoin toxicity
Toxicity is governed by various factors and basic pharmacologic principles. It is influenced by the route of exposure, the duration of the exposure (whether it is acute or long-term), dosage, and metabolism.
As far as Phenytoin is concerned it displays its main toxicity signs on the cardiovascular and nervous systems. When there is an overdose of oral Phenytoin it leads to mainly neurotoxicity and only very rarely manifests in cardiovascular toxicity. Alternatively, cardiovascular toxicity remains the main side effect of parenteral administration.
Neurotoxicity
The neurotoxic effects of Phenytoin depend on concentration. Some of the signs include mild nystagmus to ataxia, vomiting, slurred speech, lethargy, and in extreme conditions coma and death. Paradoxically, when there is a very high concentration of Phenytoin it can lead to seizures.
The symptoms faced by people are closely associated with the concentration of unbound Phenytoin in the bloodstream. Unfortunately, the measurement of this specific laboratory value is not conducted frequently.
Seizures are very uncommon in this and they usually happen when the serum concentrations are very high. When a patient, suspected of Phenytoin overdose has seizures, it should prompt the search for other co-ingestants.
Cardiac Toxicity
Phenytoin belongs to the category of antiarrhythmic medicines, although it is now rarely used as an agent. It mainly impacts the voltage-gated sodium channels in the heart, which can cause abnormal heart rhythms and disruptions in the functioning of the sinoatrial (SA) and atrioventricular (AV) nodes.
However, such effects are not seen when Phenytoin is given orally. When administered intravenously, the main concern is the toxicity associated with propylene glycol, which (Propylene glycol) acts as a cardiac depressant, and if rapidly infused, it can lead to bradycardia, hypotension, and even asystole. Hence, it is very important to administer intravenous Phenytoin formulations at a rate not exceeding 50 mg per minute for the patient’s safety.
Other Toxicities
When Phenytoin is administered intravenously there could be a very rare side effect called “Purple Glove syndrome.” It is marked by deteriorating distal limb edema and discoloration. This, in turn, can cause extensive skin necrosis and limb ischemia.
Some reports come up occasionally of Phenytoin hypersensitivity that occurs one week to one month after starting the therapy. Its symptoms are fever, rash, hepatitis, myocarditis, pneumonitis, etc. When someone takes Phenytoin for a long period, it can lead to folate deficiency, peripheral neuropathy, or a lupus-like syndrome. However, these effects are not common with acute overdoses.
Treatment interventions
Maintaining serum Phenytoin level is very important. When evaluating patients suspected of a potential Phenytoin overdose, doctors must consider a wide range of possibilities and adopt a comprehensive approach. They should conduct a fingerstick glucose test on all patients to assess their blood sugar levels. Moreover, in the case of female patients (of child-bearing age), a pregnancy test should also be conducted as part of the diagnostic process.
An ECG is also compulsory on all suspected Phenytoin overdose patients, especially those who have received parenteral Phenytoin. In laboratory modalities, there should be a host of tests conducted such as a complete blood count (CBC), liver function test (LFT), basic metabolic panel (BMP), total serum Phenytoin concentration, and serum albumin. Also, the doctors should conduct urine toxicology, acetaminophen, alcohol levels, and salicylic to complete the toxicologic workup.
It is important to note that Phenytoin toxicity has no specific treatment and the hallmark is supportive care. Managing Phenytoin toxicity should initially follow the accepted treatment of general overdoses. The physicians should assess the airway, and initiate advanced airway management in patients who cannot maintain their airway or respiratory drive. They should also assess the circulation and address any abnormalities in vital signs.
Conclusion
To prevent Phenytoin toxicity, one should focus on prevention, which can be best done by a professional team. It is necessary that both, the nurse and the chemist educate the patient on the lethality of a drug overdose and the importance of not altering the dose.
Patients who intentionally ingest Phenytoin (for self-harm) must be referred to a mental health expert before discharging from the facility. In case of an older patient is unable to read the label on the vial or incapable of maintaining good hydration while on Phenytoin, should be given support via a social worker. Most importantly, the chemist should ensure that there is no polypharmacy and minimum risk of drug interactions.
FAQs
What are the signs of Phenytoin toxicity?
Symptoms of Phenytoin toxicity are coma, confusion, dizziness, seizures (occasionally), low blood pressure, fever, muscle rigidity or spasms, side-to-side eye movement (nystagmus), sleepiness, slurred speech, tremor (unintentional trembling), swollen gums, unsteadiness, etc.
What is Phenytoin used for?
Phenytoin is used to manage and treat epilepsy, complex partial seizures, and status epilepticus. It belongs to the anticonvulsants class of drugs.
What is the antidote for Phenytoin?
As of now, there is no known antidote for Phenytoin. Moreover, there is no proof that any method of gastrointestinal decontamination or enhanced elimination has a positive outcome on Phenytoin toxicity.
What is a normal Phenytoin level?
The normal beneficial range for children & adults is 10 to 20 μ/mL (8 to 15 μ/mL in newborns). Results are in micrograms per milliliter (μ/mL).
What are the three types of Phenytoin?
The three types of Phenytoin are an extended-release (long-acting) capsule, a suspension (liquid) to be taken by mouth, and a chewable tablet.
What is the main action of Phenytoin?
Phenytoin plays a vital role in preventing seizures by disrupting the positive feedback loop that allows high-frequency action potentials to propagate through neurons. Because of its narrow therapeutic index, it is important to closely monitor the drug's levels in the body to guide appropriate dosing. It is imperative to have monitoring so that Phenytoin is given at the right dosage. This can help in achieving better seizure control and minimize the risk factors.
How serious is Phenytoin toxicity?
Phenytoin toxicity is fortunately rarely fatal. However, it can lead to neurologic symptoms ranging from nystagmus to ataxia to coma. Giving Phenytoin intravenously may rarely become complicated as a result of Purple Glove Syndrome.
What to avoid when taking Phenytoin?
One should not drink alcohol while taking Phenytoin because it may alter the effects of the medication. It could lead to serious side effects. In case of experiencing worsening or new side effects one should contact the doctor immediately.
Can Phenytoin cause brain damage?
The anti-seizure drug Phenytoin has been linked to changes in the cerebellum, cerebellar signs, and permanent cerebellar damage.
Does Phenytoin affect memory?
Phenytoin has been linked to weakening concentration, memory, visuomotor functions, and mental speed.
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