Phenytoin

Mechanism of Action

Anticonvulsants do not correct the underlying cause of epilepsy; instead, they inhibit abnormal neuronal activity. Phenytoin affects membrane excitability by blocking voltage-dependent sodium channels which carry inward membrane current necessary for the generation of an action potential. 

Phenytoin preferentially blocks cells that are firing repetitively – the higher the frequency of firing the greater the block. 

Created in BioRender. Boucher, M. (2026) https://BioRender.com/kchhgyn

Fig 1: Mechanism of Action of Phenytoin, via blockade of sodium channels

Pharmacokinetics

Formulations

Phenytoin is available as extended-release capsules, chewable tablets, oral suspension, and intravenous formulations. Fosphenytoin is a pro-drug which is a water-soluble form of phenytoin and given intravenously, after administration it is rapidly converted into phenytoin mole for mole.

Phenytoin is a class one MHRA medicine, meaning that patients should be maintained on a specific manufacturer’s preparation. Therefore, when switching between preparations, care must be taken as phenytoin sodium is not bioequivalent to phenytoin base (e.g. EpanutinⓇ Infatabs and EpanitunⓇ suspension). 

• 100mg of phenytoin sodium is approximately equivalent to 92mg phenytoin base
• There is an active MHRA Alert from 2017 about bioequivalence and antiepileptic drugs

Absorption

• Oral phenytoin is well absorbed in the small intestine. Readily crosses cell membranes.

Distribution

• 80-90% plasma protein binding to albumin 
• Steady state (Css) is reached in approximately 7-10 days 

Metabolism 

• Phenytoin undergoes saturable (capacity-limited) metabolism in the liver and is a substrate for CYP2C9 (major), CYP2C19 (major), and CYP3A4 (minor)

Elimination

• Phenytoin exhibits non-linear (zero-order) kinetics at higher concentrations, where elimination becomes constant regardless of concentration.
• Small dose increases can lead to disproportionately large increases in plasma concentration.
• Clearance is reduced in the elderly.
• Half-life is approximately 24 hours but increases with higher doses.

Contraindications

Acute porphyrias, second- and third-degree heart block; sino-atrial block; sinus bradycardia and Stokes-Adams syndrome are all listed contraindications for use of phenytoin. 

Cautions and Adverse Effects

Hepatic and Renal Impairment

As phenytoin is highly bound to albumin (the liver makes albumin) and extensively metabolised in the liver, in cases of liver impairment a dose reduction may be required. 

Furthermore, in renal impairment, protein binding is reduced, which will lead to an increase in free phenytoin levels. 

In both circumstances:

• Unbound (free) phenytoin levels are more clinically useful in these patients.
• If measuring total phenytoin levels, a lower level may be clinically effective

Blood Disorders

Thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression have occasionally been reported in patients treated with phenytoin. 

Purple Glove Syndrome

Soft tissue irritation and inflammation can occur at the site of injection with IV phenytoin use, this may be alongside extravasation of IV phenytoin. 

Risk of Suicidal Thoughts and Behaviour

MHRA Alert for all antiepileptics was issued in 2008 after a meta-analysis of placebo controlled trials showed a small increased risk of suicidal thoughts and behaviour. 

Vitamin D Deficiency 

Phenytoin, alongside other anticonvulsants, can increase metabolism of vitamin D3 via induction of the CYP450 enzyme. This may lead to a vitamin D deficiency, hypocalcaemia and hypophosphataemia. As a result of this, patients treated with phenytoin are at higher risk of osteopenia, osteoporosis and fractures in long term therapy. 

Folate Deficiency 

Phenytoin can cause folate deficiency leading to megaloblastic anaemia. Folate levels should be checked every 6 months and supplementation started if required. 

Serious cutaneous adverse reactions (SCARs) 

SCARs can occur such as the following:

• generalised exanthematous pustulosis (AGEP)
• exfoliative dermatitis
• Stevens – Johnson syndrome (SJS)
• toxic epidermal necrolysis (TEN)

Hypersensitivity Syndrome or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 

Both syndromes have been reported in patients treated with phenytoin, presenting with fever and rash, which can lead to multi-organ involvement such as hepatitis, nephritis, pneumonitis and myocarditis. This reaction usually occurs within 2-4 weeks of starting phenytoin. 

Laboratory Test Interactions 

Phenytoin may reduce total and free thyroxine levels, however this does not lead to clinical hypothyroidism nor affect circulating levels of thyroid stimulating hormone (TSH). 

Pharmacogenomics

Patients from Han Chinese or Thai origin should have screening for the HLA-B*1502 allele genotype prior to starting phenytoin, due to an increased risk of Stevens-Johnson syndrome. 

Case-control genome-wide association studies in Taiwanese, Japanese, Malaysian, and Thai populations have shown that carriers of the reduced-function CYP2C9*3 variant have an elevated risk of SCARs. Furthermore, individuals carrying the reduced-function CYP2C92 or CYP2C93 variants (i.e., intermediate or poor metabolisers of CYP2C9 substrates) may have an increased risk of elevated phenytoin plasma levels and resulting toxicity.

Pregnancy

Phenytoin exposure during pregnancy may cause foetal malformation such as cleft palate, microcephaly and mental retardation, due to effects on folate metabolism thereby inhibiting DNA synthesis. Phenytoin should only be prescribed to women of childbearing potential if, after careful evaluation of other appropriate treatment options, the expected benefits are considered to outweigh the potential risks.

Women of childbearing potential should use effective contraception during treatment and for one month after discontinuation. Phenytoin induces enzymes, therefore it may reduce the effectiveness of hormonal contraceptives; women should be advised to use alternative reliable methods of contraception.

Monitoring 

Phenytoin has a narrow therapeutic window and displays non-linear pharmacokinetics, meaning that small dose increases can produce large increases in exposure to phenytoin and vice versa (missed doses can quickly reduce exposure). Blood levels can be measured to ensure therapeutic dosing, with a range of 10–20 μg/mL often aimed for. Regular monitoring helps prevent toxicity and ensures seizure control.

Signs and symptoms of toxicity include:

• Nystagmus
• diplopia
• slurred speech
• ataxia
• confusion
• Hyperglycaemia – phenytoin affects glucose metabolism and inhibits insulin release 

Phenytoin is highly bound to plasma proteins, therefore for patients with hypoalbuminemia e.g. pregnancy and the elderly, it is more accurate to adjust phenytoin levels for albumin as there will be an increase in unbound phenytoin levels. Plasma phenytoin levels do not distinguish between bound (inactive) and free phenytoin.

If free phenytoin concentrations cannot be measured, predictive equations can be used in adult patients to estimate unbound phenytoin levels.

Other baseline and periodic thereafter monitoring to be considered includes full blood count, liver function tests, urea and electrolytes, vitamin D and folate. Phenytoin should be withdrawn in cases of acute hepatotoxicity and in severe/progressive leucopenia. 

Created in BioRender. Boucher, M (2026) https://BioRender.com/m585807

Fig 2: Binding of phenytoin to albumin

Interactions

Oral phenytoin interacts with enteral feed by binding to the protein in the feed, reducing the efficacy of phenytoin. Usual practise is to interrupt feeding for 2 hours before and after phenytoin administration; more frequent phenytoin level monitoring may be necessary

When phenytoin is administered alongside drugs which displace phenytoin from albumin, there will be more free phenytoin which could lead to toxicity however this will be excreted faster leading to a lower phenytoin concentration. This effect therefore may enhance or reduce the action of phenytoin in an unpredictable way. Examples include salicylates, phenylbutazone and valproate. 

Phenytoin is metabolised by CYP2C9 (major), CYP2C19 (major) and CYP3A4 (minor). Therefore is susceptible to drug interactions with enzyme inhibitors due to its saturable metabolism; inhibition of CYP enzymes may lead to proportionally significant increases in free phenytoin levels. 

Examples of inhibitors include the following:

• CYP3A4 inhibitors: clarithromycin, isoniazid, diltiazem 
• CYP2C9 inhibitors: amiodarone, fluoxetine
• CYP2C19 inhibitors: omeprazole, fluconazole 

Enzyme inducers of CYP2C9 and CYP2C19, such as St John’s Wort and rifampicin, will reduce phenytoin levels. St John’s Wort is not recommended to be taken alongside phenytoin due to this effect. Theophylline and folic acid can also reduce phenytoin levels.

Some drugs may increase or decrease phenytoin levels including ciprofloxacin, carbamazepine, phenobarbital, sodium valproate and diazepam. 

Phenytoin itself is also an inducer of CYP1A2 (weak), CYP3A4 (strong) and P-glycoprotein, therefore has the potential to reduce the levels of drugs that are substrates.

Examples of substrates include the following:

• P-glycoprotein substrates: edoxaban, digoxin, dabigatran, apixaban 
• CYP3A4 substrates: clarithromycin, oral contraceptives and oestrogens, apixaban 
• CYP1A2 substrates: warfarin, theophylline

Phenytoin can also reduce methotrexate clearance due to reduced renal excretion.

References

1. Phenytoin monitoring – NHS SPS – Specialist Pharmacy Service – The first stop for professional medicines advice Published 22 June 2021 · Last updated 10 March 2026. Accessed 24/03/26.
2. Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019. 
3. Phenytoin 100mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc) | 4225 Accessed 25/03/26
4. Phenytoin Sodium 50mg/ml Solution for Injection – Summary of Product Characteristics (SmPC) – (emc) | 4326 Accessed 26/03/26
5. Antiepileptic drugs: new advice on switching between different manufacturers’ products for a particular drug – GOV.UK Accessed 26/03/26
6. Phenytoin: Drug information, available from: https://www.uptodate.com/contents/phenytoin-drug-information?search=phenytoin&selectedTitle=1~150&usage_type=panel&display_rank=1&kp_tab=drug_general&source=search_result Accessed 26/03/26