Introduction to Phenytoin and Its Narrow Therapeutic Window
Phenytoin, sold under brand names like Dilantin and Phenytek, is a cornerstone medication for managing and preventing certain types of seizures [1.2.1]. Its effectiveness hinges on maintaining a steady concentration in the bloodstream. The clinically effective serum level, known as the therapeutic range, is quite narrow, typically between 10 and 20 micrograms per milliliter (mcg/mL) [1.8.2]. Levels below this range may be insufficient to control seizure activity, while levels above it can lead to significant toxicity [1.6.1].
Phenytoin's metabolism is complex. It is primarily broken down in the liver by the cytochrome P450 enzyme system, specifically the enzymes CYP2C9 and CYP2C19 [1.5.1, 1.5.4]. Because this metabolic pathway is saturable, small changes in dosage or the introduction of an interacting substance can cause disproportionately large shifts in blood concentrations [1.6.4]. This makes phenytoin particularly vulnerable to drug interactions. Many substances can alter its concentration, but this article focuses specifically on what drugs decrease phenytoin levels, a critical interaction that can compromise its efficacy and lead to breakthrough seizures.
The Primary Mechanism: Hepatic Enzyme Induction
The most common reason for decreased phenytoin levels is a process called enzyme induction [1.3.4]. Certain drugs and substances, known as 'inducers,' stimulate the liver to produce more CYP450 enzymes [1.3.1]. When a patient taking phenytoin starts an enzyme-inducing drug, their liver becomes more efficient at metabolizing phenytoin. This accelerated breakdown causes phenytoin to be cleared from the body more quickly, resulting in lower, and potentially subtherapeutic, plasma concentrations [1.4.2].
Phenytoin itself is a potent inducer of other CYP enzymes, such as CYP3A4, which explains why it affects the levels of many other medications [1.3.1, 1.3.3]. However, it is also a victim of this process when co-administered with other potent inducers.
Drugs That Decrease Phenytoin Levels
A wide array of medications can lower phenytoin levels, primarily through enzyme induction or, less commonly, by reducing its absorption from the gut.
Antiepileptic Drugs (AEDs)
It is common for patients with epilepsy to be on polytherapy, but some AEDs can unfortunately reduce the effectiveness of phenytoin.
- Carbamazepine (Tegretol): This is a well-known, potent enzyme inducer that can significantly decrease phenytoin concentrations [1.2.5, 1.3.5].
- Vigabatrin (Sabril): This medication is also known to lower phenytoin levels [1.2.5].
- Phenobarbital: This older AED can have unpredictable effects, but it often acts as an inducer and may decrease phenytoin levels [1.2.1, 1.2.5].
Antibiotics and Antivirals
Infections requiring treatment can complicate seizure management.
- Rifampin (Rifadin): A powerful enzyme inducer used to treat tuberculosis and other infections. It accelerates phenytoin metabolism, which can lead to lower levels and an increased risk of seizures [1.2.1, 1.2.3]. The interaction can also make rifampin less effective [1.2.1].
- Antiviral Agents: Certain drugs used to treat HIV, such as ritonavir and nelfinavir, can decrease plasma phenytoin levels, posing a risk for loss of seizure control [1.2.5].
Antineoplastic Agents
Cancer chemotherapy regimens can present significant interaction challenges.
- Drugs such as bleomycin, carboplatin, cisplatin, and doxorubicin, often used in combination, have been shown to decrease phenytoin serum levels [1.2.5].
Other Prescription Medications
- Theophylline: Used for respiratory diseases like asthma, theophylline can decrease phenytoin levels [1.2.3, 1.2.5].
- Fosamprenavir: An antiviral that can lower phenytoin concentrations [1.2.5].
Alcohol and Supplements
- Chronic Alcohol Abuse: While acute alcohol intake can inhibit metabolism and raise levels, chronic heavy drinking induces liver enzymes and can lead to decreased phenytoin levels over time [1.2.5, 1.4.2].
- St. John's Wort: This popular herbal supplement for depression is a known inducer of CYP enzymes and can significantly reduce phenytoin concentrations [1.2.5, 1.7.2].
- Folic Acid: While phenytoin can lower folate levels, high-dose folic acid supplementation can, in turn, increase phenytoin clearance and lower its serum concentration [1.4.5, 1.7.5].
Mechanism 2: Reduced Absorption
Some substances interfere with phenytoin's ability to be absorbed from the gastrointestinal tract.
- Antacids: Antacids containing calcium carbonate, aluminum hydroxide, or magnesium hydroxide (e.g., Tums, Mylanta) can decrease the absorption of phenytoin, making it less effective. It is recommended to space out the administration of phenytoin and antacids [1.2.5, 1.4.1].
- Sucralfate: This medication used for ulcers can also reduce phenytoin absorption [1.2.5, 1.4.4].
- Enteral Nutrition (Tube Feedings): Administering phenytoin with enteral tube feedings can significantly decrease its absorption. It is often recommended to stop the feeding for a period before and after the phenytoin dose [1.4.5].
Comparison of Interacting Substances
| Interacting Agent | Class | Primary Mechanism | Clinical Management/Consideration |
|---|---|---|---|
| Carbamazepine, Phenobarbital | Antiepileptics | Enzyme Induction [1.2.5] | Frequent therapeutic drug monitoring (TDM) and potential phenytoin dose adjustment are necessary. |
| Rifampin | Antibiotic | Potent Enzyme Induction [1.2.1] | Requires close monitoring of phenytoin levels and likely dose increases. Consider alternative antibiotics if possible. |
| Ritonavir, Nelfinavir | Antivirals | Enzyme Induction [1.2.5] | TDM is critical. This interaction can also make the antiviral less effective. |
| Bleomycin, Carboplatin | Antineoplastics | Enzyme Induction [1.2.5] | Monitor phenytoin levels closely during and after chemotherapy cycles. |
| St. John's Wort | Herbal Supplement | Enzyme Induction [1.2.5, 1.7.2] | Patients should be strongly advised against using this supplement while on phenytoin. |
| Chronic Alcohol Use | Lifestyle Factor | Enzyme Induction [1.2.5] | Counsel patients on the risks of chronic alcohol consumption. Monitor levels. |
| Antacids (Calcium, etc.) | GI Agents | Reduced Absorption [1.2.5] | Do not take at the same time. Separate doses by at least 2-3 hours [1.4.1, 1.4.4]. |
| Enteral Tube Feedings | Nutrition | Reduced Absorption [1.4.5] | Withhold feedings for 1-2 hours before and after phenytoin administration. |
Clinical Implications and Management
The primary consequence of a subtherapeutic phenytoin level is the increased risk of breakthrough seizures, which can have devastating personal and public safety implications [1.2.1]. Therefore, managing these interactions is paramount.
- Therapeutic Drug Monitoring (TDM): Regular monitoring of serum phenytoin concentrations is essential, especially when a potentially interacting drug is started, stopped, or has its dose changed [1.4.3]. Trough levels, drawn just before the next scheduled dose, are generally preferred for monitoring maintenance therapy [1.4.3].
- Dose Adjustment: If an inducing agent is added, the phenytoin dose may need to be increased. Conversely, if an inducer is discontinued, the phenytoin dose will likely need to be reduced to prevent toxicity as its metabolism returns to its baseline rate [1.3.7].
- Patient Education: Patients must be educated about these interactions, including over-the-counter products and supplements like antacids and St. John's wort. They should be advised to consult their healthcare provider before starting any new medication [1.7.2].
- Strategic Dosing: For interactions involving absorption, separating the administration times of phenytoin and the offending agent (e.g., antacids, calcium supplements) by several hours can often mitigate the effect [1.4.1, 1.7.5].
Conclusion
Many common drugs, as well as some supplements and lifestyle factors, can decrease phenytoin levels, primarily by inducing the liver enzymes responsible for its metabolism or by impairing its absorption. This can lead to a loss of efficacy and put patients at risk for seizures. Vigilant monitoring, proactive dose adjustments, and thorough patient education are the cornerstones of managing these clinically significant interactions and ensuring the continued effectiveness of phenytoin therapy.
For further detailed information, consult authoritative sources such as the FDA's prescribing information for Phenytoin [1.2.4].
