Phenytoin

For most adults, the goal of Phenytoin therapy is to achieve a steady-state serum concentration between 10 and 20 mcg/mL. Healthcare providers typically initiate therapy with a loading dose or a gradual titration.

• Maintenance Dose: The standard adult maintenance dose is 300 mg to 400 mg per day. This is often started as 100 mg taken three times daily. Some patients may eventually be transitioned to a single 300 mg extended-release dose once daily if their seizures are well-controlled.
• Status Epilepticus: In emergency settings, a loading dose of 10 mg/kg to 15 mg/kg is administered intravenously at a rate not exceeding 50 mg per minute to avoid cardiovascular collapse.
• Neurosurgery: 100 mg to 200 mg every 4 hours during and after surgery may be utilized as a temporary prophylactic measure.

Phenytoin is approved for use in children, but dosing is highly individualized based on weight and age.

• Initial Dose: Typically starts at 5 mg/kg/day, divided into two or three equal doses.
• Maintenance Range: Most children require 4 mg/kg/day to 8 mg/kg/day. Because children often metabolize Phenytoin faster than adults, they may require more frequent dosing (e.g., every 8 hours) to maintain stable blood levels.
• Infants: Neonates may have unpredictable absorption and metabolism, requiring extremely close monitoring by a pediatric neurologist.

Renal Impairment

In patients with significant kidney disease, the protein binding of Phenytoin is often reduced. This means a higher percentage of the drug remains "free" and active. While the total Phenytoin level might look low, the active level could be toxic. Doctors often use the "Sheiner-Tozer" formula to adjust and interpret levels in these patients.

Hepatic Impairment

Since Phenytoin is primarily cleared by the liver, patients with cirrhosis or hepatitis are at a high risk of drug accumulation. Lower starting doses and slower titration are mandatory to prevent toxicity.

Elderly Patients

Older adults often have lower albumin levels and decreased liver clearance. Clinical guidelines suggest starting at the lower end of the dosing range and monitoring for early signs of ataxia (unsteadiness) or confusion.

Consistency is the most important factor when taking Phenytoin.

• With or Without Food: You may take Phenytoin with food to reduce stomach upset, but you must do it the same way every time. Changing how you take it relative to meals can change your blood levels.
• Swallow Whole: Extended-release capsules must be swallowed whole. Do not crush, chew, or open them, as this can release the entire dose at once, leading to toxicity.
• Suspension Care: If using the liquid form, shake the bottle vigorously for at least 60 seconds. If not shaken properly, the medication settles at the bottom, leading to under-dosing at the start of the bottle and over-dosing at the end.
• Tube Feedings: If you are on a feeding tube, Phenytoin must be separated from the feeding formula by at least 2 hours before and 2 hours after the dose.

If you miss a dose, take it as soon as you remember. However, if it is almost time for your next scheduled dose, skip the missed dose and return to your regular schedule. Never take two doses at once to "make up" for a missed one, as this can trigger toxic side effects or cardiac issues.

Phenytoin overdose is a medical emergency. Early signs include nystagmus (involuntary eye movement), ataxia (loss of coordination), and dysarthria (slurred speech). Severe overdose can lead to coma, dangerously low blood pressure, and respiratory depression. If an overdose is suspected, contact a poison control center or emergency services immediately.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop taking this medication without medical guidance, as sudden discontinuation can trigger severe, continuous seizures.

Phenytoin is associated with several side effects that occur frequently, especially during the initiation of therapy or when doses are adjusted.

• Central Nervous System Effects: Dizziness, drowsiness, and a general feeling of mental cloudiness are very common. Patients often describe a "brain fog" or slowed thinking.
• Gingival Hyperplasia: This is a unique side effect where the gum tissue overgrows the teeth. It occurs in up to 50% of long-term users. Maintaining meticulous oral hygiene and regular dental cleanings can help manage this.
• Nystagmus: This is a rhythmic, involuntary jerking of the eyes. While common, an increase in nystagmus often indicates that the drug level in the blood is becoming too high.
• Gastrointestinal Upset: Nausea, vomiting, and constipation may occur, particularly if the medication is taken on an empty stomach.

• Hirsutism: Increased growth of hair on the face or body, which can be distressing for some patients.
• Coarsening of Facial Features: Long-term use can lead to a thickening of the lips and skin on the face.
• Coordination Issues: Mild tremors or a slight unsteadiness when walking (ataxia).
• Skin Rashes: A mild morbilliform (measles-like) rash may appear. Any rash must be reported to a doctor immediately to rule out more serious conditions.

• Blood Dyscrasias: Phenytoin can rarely cause a decrease in white blood cells (leukopenia), red blood cells (anemia), or platelets (thrombocytopenia).
• Peyronie's Disease: A rare connective tissue disorder affecting the penis has been reported in association with phenytoin use.
• Lymphadenopathy: Swelling of the lymph nodes that can mimic lymphoma.

> Warning: Stop taking Phenytoin and call your doctor or emergency services immediately if you experience any of the following:

• Severe Skin Reactions: Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN). Symptoms include skin pain, a red or purple rash that spreads, and blistering or peeling of the skin and mucous membranes.
• DRESS Syndrome: Drug Reaction with Eosinophilia and Systemic Symptoms. This presents as a rash, fever, and swollen lymph nodes, and can lead to organ failure (liver, kidneys, or lungs).
• Hepatotoxicity: Signs of liver damage include yellowing of the eyes or skin (jaundice), dark urine, and severe upper abdominal pain.
• Suicidal Ideation: Like all anti-epileptic drugs, Phenytoin may increase the risk of suicidal thoughts or behaviors. Monitor for changes in mood, anxiety, or depression.
• Cardiac Arrhythmias: Particularly with IV use, Phenytoin can cause life-threatening heart rhythm changes or a severe drop in blood pressure.

With prolonged use (years), Phenytoin can impact various body systems:

• Bone Health: Phenytoin interferes with Vitamin D metabolism, which can lead to osteomalacia (softening of the bones) or osteoporosis (brittle bones), increasing the risk of fractures.
• Cerebellar Atrophy: Chronic toxicity or long-term high-dose use has been linked to permanent shrinkage of the cerebellum, the part of the brain responsible for balance.
• Peripheral Neuropathy: Numbness or tingling in the hands and feet due to nerve damage.
• Vitamin Deficiencies: Specifically Folate (Vitamin B9) deficiency, which can lead to a specific type of anemia.

Cardiovascular Risk with Rapid Infusion: The FDA has issued a Black Box Warning for intravenous Phenytoin. If the drug is infused too quickly, it can cause severe hypotension (low blood pressure) and fatal cardiac arrhythmias. The rate of infusion must not exceed 50 mg per minute in adults or 1-3 mg/kg/min in children. Continuous heart monitoring (ECG) is required during IV administration.

Report any unusual symptoms or persistent side effects to your healthcare provider immediately. Regular blood tests are necessary to ensure the drug remains at a safe and effective level.

Phenytoin is a potent medication that requires careful management. One of the most critical warnings involves the risk of "Status Epilepticus" if the drug is stopped suddenly. Abrupt discontinuation can cause continuous, life-threatening seizures. Patients must never stop taking Phenytoin or change their dose without the direct supervision of a neurologist. Additionally, Phenytoin has a very narrow therapeutic window, meaning the difference between a dose that works and a dose that is toxic is very small.

Cardiovascular Risk Associated with Rapid Intravenous Administration: The FDA mandates a Black Box Warning for Phenytoin regarding its administration via injection. Rapid intravenous administration of phenytoin is associated with severe cardiovascular events, including atrial and ventricular conduction depression, ventricular fibrillation, and severe hypotension. Deaths have been reported. The rate of administration should not exceed 50 mg per minute in adults. In pediatric patients, the rate should not exceed 1 to 3 mg/kg/min or 50 mg/min, whichever is slower. Close monitoring of cardiac function and blood pressure is essential during and immediately after infusion.

• Serious Dermatologic Reactions: There is a high risk of life-threatening skin reactions (SJS/TEN) in patients with the HLA-B*1502 genetic allele. This allele is most common in people of Asian descent (including Han Chinese, Filipinos, Malaysians, and South Asians). The FDA recommends genetic testing for these patients before starting Phenytoin.
• Hepatotoxicity: Phenytoin can cause acute liver failure. If a patient develops a fever, rash, or jaundice, the drug may need to be discontinued immediately.
• Suicidality: Anti-epileptic drugs, including Phenytoin, increase the risk of suicidal thoughts or behavior in about 1 in 500 patients. This can occur as early as one week after starting the medication.
• Hyperglycemia: Phenytoin can inhibit the release of insulin, leading to high blood sugar levels. Patients with diabetes must monitor their glucose levels closely.

Because of its complex nature, patients on Phenytoin require regular laboratory testing:

• Serum Phenytoin Levels: Initially checked weekly, then every 3-6 months once stable. The target range is typically 10-20 mcg/mL.
• Liver Function Tests (LFTs): To monitor for hepatotoxicity.
• Complete Blood Count (CBC): To monitor for rare blood disorders.
• Albumin Levels: Especially in the elderly or those with kidney disease, to calculate the "free" phenytoin level.

Phenytoin may cause dizziness, coordination problems, and blurred vision. Patients should not drive or operate heavy machinery until they know how the medication affects them. Furthermore, most jurisdictions have specific laws regarding driving for individuals with a history of seizures.

Alcohol has a complex interaction with Phenytoin. Acute alcohol consumption (a single night of drinking) can increase Phenytoin levels, leading to toxicity. Conversely, chronic alcohol use can decrease Phenytoin levels, increasing the risk of breakthrough seizures. It is best to avoid alcohol entirely while taking this medication.

If Phenytoin must be stopped, it should be tapered (gradually reduced) over several weeks or months. Sudden withdrawal is only performed in the event of a severe allergic reaction, and even then, an alternative anticonvulsant is usually started immediately.

> Important: Discuss all your medical conditions, especially heart, liver, or kidney problems, with your healthcare provider before starting Phenytoin.

Certain medications should never be used with Phenytoin because the interaction is too dangerous or renders the other drug useless.

• Delavirdine: Phenytoin significantly reduces the levels of this HIV medication, leading to treatment failure and viral resistance.
• Certain Azole Antifungals: While some can be used with monitoring, others may lead to extreme Phenytoin toxicity.

Phenytoin is a "potent inducer" of liver enzymes. This means it speeds up the metabolism of other drugs, making them less effective.

• Warfarin: Phenytoin can either increase or decrease the blood-thinning effects of warfarin. Frequent INR (blood clotting) tests are required.
• Oral Contraceptives: Phenytoin makes birth control pills, patches, and implants less effective. Women of childbearing age should use a non-hormonal form of contraception (like a copper IUD or condoms) to prevent unplanned pregnancy.
• Corticosteroids: Phenytoin reduces the effectiveness of steroids like prednisone.
• Valproic Acid: This is a complex interaction. Valproic acid can displace Phenytoin from protein binding sites, increasing the risk of toxicity even if the "total" Phenytoin level looks normal.

• Amiodarone: Can increase Phenytoin levels by inhibiting its metabolism.
• Omeprazole: May increase Phenytoin levels in some patients.
• Tricyclic Antidepressants: May lower the seizure threshold, making Phenytoin less effective at preventing seizures.

• Enteral Feedings (Tube Feeding): Feeding formulas (like Ensure or Jevity) bind to Phenytoin in the gut and prevent it from being absorbed. Doses must be separated from feedings by at least 2 hours.
• Calcium and Antacids: Taking Phenytoin at the same time as calcium supplements or antacids can reduce its absorption. Separate these by at least 2 to 3 hours.

• St. John’s Wort: This herbal supplement is a potent inducer and can significantly lower Phenytoin levels, leading to breakthrough seizures.
• Folic Acid: While Phenytoin causes folate deficiency, taking high doses of folic acid supplements can actually lower Phenytoin levels in the blood.
• Ginkgo Biloba: May lower the seizure threshold and interfere with Phenytoin's efficacy.

Phenytoin can interfere with certain medical tests, potentially leading to inaccurate results:

• Thyroid Function Tests: It may lower T4 levels, although the patient is not actually hypothyroid.
• Dexamethasone Suppression Test: Phenytoin may cause a false-positive result in this test for Cushing's syndrome.
• Blood Glucose: It may cause elevated readings on blood sugar tests.

For each major interaction, the mechanism usually involves the induction of Cytochrome P450 enzymes (reducing other drug levels) or competition for albumin binding (increasing active drug levels). The clinical consequence is either a loss of therapeutic effect for the other drug or a sudden spike in Phenytoin toxicity. Management always involves frequent blood level monitoring and dose adjustments by a healthcare professional.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, as Phenytoin interacts with more drugs than almost any other medication.

Phenytoin must NEVER be used in the following circumstances:

• Hypersensitivity to Hydantoins: If a patient has ever had a severe allergic reaction to Phenytoin, Ethotoin, or Fosphenytoin, they must not take this drug. The risk of anaphylaxis or severe skin reactions is extremely high.
• Sinus Bradycardia: Because of its effects on cardiac sodium channels, Phenytoin can dangerously slow the heart rate in patients who already have a slow heart rhythm.
• Sinoatrial (SA) Block or Second/Third-Degree AV Block: These are specific types of heart block. Phenytoin can interfere with the heart's electrical conduction, potentially leading to cardiac arrest in these patients.
• Adams-Stokes Syndrome: A condition characterized by sudden fainting spells due to a change in heart rhythm.
• Co-administration with Delavirdine: Due to the risk of loss of virologic response in HIV patients.

In these cases, the doctor must weigh the benefits of seizure control against significant risks:

• Porphyria: Phenytoin is considered "porphyrinogenic" and can trigger an acute attack of this rare metabolic disorder.
• Liver Disease: Because the liver is the only way the body clears Phenytoin, patients with severe hepatic impairment are at extreme risk of toxicity.
• Diabetes: Phenytoin's effect on blood sugar may make diabetes management significantly more difficult.
• Pregnancy: While not an absolute contraindication (seizures themselves are dangerous to the fetus), the risk of birth defects is high, and alternative medications are usually preferred.

Patients who are allergic to other anticonvulsants, such as Carbamazepine or Phenobarbital, may also be allergic to Phenytoin. This is known as "aromatic anticonvulsant hypersensitivity syndrome." If a patient has a history of a drug-induced rash with any seizure medication, Phenytoin should be started with extreme caution, if at all.

> Important: Your healthcare provider will evaluate your complete medical history, including your heart health and genetic background, before prescribing Phenytoin.

Phenytoin is classified as FDA Pregnancy Category D. This means there is clear evidence of human fetal risk based on adverse reaction data. Use of Phenytoin during pregnancy can cause "Fetal Hydantoin Syndrome," which includes symptoms such as cleft lip and palate, heart defects, and developmental delays. However, having a seizure during pregnancy can also harm the baby by cutting off oxygen. If a woman becomes pregnant while taking Phenytoin, she should not stop the medication abruptly but should contact her neurologist immediately. High-dose folic acid is often recommended for these patients.

Phenytoin is excreted into breast milk in small amounts. Most experts consider it "probably compatible" with breastfeeding, but the infant must be monitored for signs of drowsiness or poor feeding. The decision to breastfeed should be made after a risk-benefit discussion with a pediatrician.

Phenytoin is used in children for the same indications as adults. However, children often have a much faster metabolism, requiring higher mg/kg doses and more frequent administration. Long-term use in children is a concern due to the risk of coarsening facial features and gingival hyperplasia, which can affect a child's self-esteem and dental health.

Elderly patients (65+) are at a significantly higher risk for Phenytoin toxicity. Age-related declines in liver function and lower levels of albumin (the protein that binds the drug) mean that more active drug stays in the system. Geriatric patients are also more susceptible to the balance-related side effects of Phenytoin, which can lead to dangerous falls and hip fractures.

In patients with end-stage renal disease (ESRD) or significant kidney impairment, the drug's ability to bind to protein is reduced. This results in an increased fraction of "free" phenytoin. Standard blood tests may show a "normal" level, but the patient may be experiencing toxicity. Doctors must monitor "free phenytoin levels" specifically in this population.

Since the liver is the primary site of Phenytoin metabolism, any degree of liver failure (Child-Pugh Class A, B, or C) requires a dose reduction. In severe liver disease, the half-life of the drug can extend from 24 hours to over 100 hours, leading to rapid accumulation.

> Important: Special populations require individualized medical assessment and more frequent blood monitoring.

Phenytoin is a primary membrane stabilizer. Its main molecular target is the voltage-gated sodium channel in the neuronal membrane. Specifically, it binds to the channel in its inactive state, preventing it from reverting to the resting state. This action limits the repetitive firing of action potentials in hyper-excitable neurons. Unlike other drugs, Phenytoin does not interfere with the normal conduction of electrical signals at normal frequencies, which is why it does not cause general anesthesia or profound sedation at therapeutic levels.

The therapeutic effect of Phenytoin is closely related to its concentration in the plasma. The "therapeutic window" is narrow, typically 10 to 20 mcg/mL. Concentrations below this range often fail to prevent seizures, while concentrations above 20 mcg/mL are associated with dose-related toxicity (nystagmus, ataxia, and lethargy). Because the drug's metabolism is saturable, the relationship between dose and plasma concentration is not linear; a 10% increase in dose can lead to a 50% or greater increase in blood levels.

| Parameter | Value |

|---|---|

| Bioavailability | 90% to 95% (Oral) |

| Protein Binding | 90% (primarily to Albumin) |

| Half-life | 7 to 42 hours (average 24h; dose-dependent) |

| Tmax | 1.5 to 12 hours (formulation dependent) |

| Metabolism | Hepatic (CYP2C9 and CYP2C19) |

| Excretion | Renal (<5% unchanged), Fecal (minimal) |

• Molecular Formula: C15H11N2NaO2 (Sodium Salt)
• Molecular Weight: 274.25 g/mol
• Solubility: Soluble in water (sodium salt form); poorly soluble in water (acid form).
• Structure: A hydantoin derivative related to the barbiturates but with a five-membered ring structure.

Phenytoin is the prototypical member of the Hydantoin class of anti-epileptic drugs. Related medications include Fosphenytoin (an injectable prodrug) and Ethotoin. It is distinct from other classes like Carbamazepine (iminostilbenes) or Valproate (carboxylic acids).