Peringatan Keamanan

The experience of phenytoin toxicity is not limited to situations of acute ingestion, but may also occur due to drug interactions or due to physiological circumstances that impact serum albumin (ie. kidney disease) or drug metabolism.A188751 Other changes that may result in phenytoin toxicity include pregnancy, malnutrition and malignancy.A188751

Phenytoin toxicity most often affects the cardiovascular and nervous systems.A188751 The most common presentation of toxicity depends on the route of administration.A188751 Cardiovascular adverse effects are most commonly linked to intravenous phenytoin administration, whereas neurological adverse effects are more common with oral phenytoin administration.A188751

Neurotoxicity is usually dependent on serum concentrations.A188751 When concentrations range from 10-20 mg/L, mild nystagmus and lateral gaze may occur, while more significant nystagmus is associated with concentrations ranging from 20-30 mg/L.A188751 At concentrations of 30-40 mg/L, slurred speech, tremor, nausea, vomiting and ataxia have been reported.A188751 In more serious cases where serum levels range from 40-50 mg/L patients are at risk of lethargy, confusion and hyperactivity, and at levels beyond 50 mg/L, coma and seizures may occur.A188751

Phenytoin is classified as an antiarrhythmic and can cause SA and AV nodal blocks as well as dysrhythmias due to its effect on voltage-gated sodium channels.A188751 Further, since phenytoin is poorly soluble, the parenteral form is administered with propylene glycol, which is a cardiac depressant.A188751 The infusion rate of parenteral phenytoin should not exceed 50 mg per minute due to the risk of hypotension, bradycardia, and asystole.A188751

Treatment for phenytoin toxicity is non-specific and centres around supportive care.A188751 One dose of activated charcoal may be used to prevent phenytoin absorption in cases of acute ingestion.A188751

Although hemodialysis is moderately effective at removing phenytoin, it is not normally recommended due to the risks associated with the procedure, and the general effectiveness of supportive care.A188751

Phenytoin

DB00252

small molecule approved vet_approved

Deskripsi

Phenytoin is classified as a hydantoin derivative and despite its narrow therapeutic index, it is one of the most commonly used anticonvulsants.A33595,A188832,A189219 Since it's introduction about 80 years ago, phenytoin has not only been established as an effective anti-epileptic, but has also been investigated for several other indications such as bipolar disorder, retina protection, and wound healing.A188826,A188832

Clinicians are advised to initiate therapeutic drug monitoring in patients who require phenytoin since even small deviations from the recommended therapeutic range can lead to suboptimal treatment, or adverse effects.A189219,A35884 Both parenteral and oral formulations of phenytoin are available on the market.A189219

Struktur Molekul 2D

Berat 252.268
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) Oral administration: The half-life of phenytoin ranges from 7 to 42 hours, and is 22 hours on average.[A189282,L9362] Intravenous administration: The half-life of phenytoin ranges from 10-15 hours.[L10941]
Volume Distribusi The volume of distribution of phenytoin is reported to be approximately 0.75 L/kg.[A189282]
Klirens (Clearance) The clearance of phenytoin is non-linear.[A35884] At lower serum concentrations (less than 10 mg/L), elimination is characterized by first order kinetics.[A188751] As plasma concentrations increase, the kinetics shift gradually towards zero-order, and finally reach zero-order kinetics once the system is saturated.[A188751]

Absorpsi

Given its narrow therapeutic index, therapeutic drug monitoring is recommended to help guide dosing.A189219,A35884 Phenytoin is completely absorbed.A189219 Peak plasma concentration is attained approximately 1.5-3 hours, and 4-12 hours after administration of the immediate release formulation and the extended release formulation, respectively.A188751,A189219 It should be noted that absorption can be markedly prolonged in situations of acute ingestion.A189219

Metabolisme

Phenytoin is extensively metabolized and is first transformed into a reactive arene oxide intermediate.A33595 It is thought that this reactive intermediate is responsible for many undesirable phenytoin adverse effects such as hepatotoxicity, SJS/TEN, and other idiosyncratic reactions.A33595 The arene oxide is metabolized to either a hydroxyphenytoin or phenytoin dihydrodiol metabolite, although the former accounts for about 90% of phenytoin metabolism.A33595 Interestingly, two stereoisomers of the hydroxyphenytoin metabolite are formed by CYP2C9 and CYP2C19: (R)-p-HPPH and (S)-p-HPPH.A33595 When CYP2C19 catalyzes the reaction, the ratio of stereoisomers is roughly 1:1, whereas when CYP2C9 catalyzes the reaction, the ratio heavily favours the "S" stereoisomer.A33595 Since the metabolism of phenytoin is in part influenced by genetic polymorphisms of CYP2C9 and CYP2C19, this ratio can be utilized to identify different genomic variants of the enzymes.A188772,A188832,A33595 EPHX1, CYP1A2, CYP2A6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 are responsible for producing the phenytoin dihydrodiol metabolite.A33595 Hydroxyphenytoin can be metabolized by CYP2C19, CYP3A5, CYP2C9, CYP3A4, CYP3A7, CYP2B6 and CYP2D6 to a phenytoin catechol metabolite or undergo glucuronidation by UGT1A6, UGT1A9, UGT1A1, and UGT1A4 to a glucuronide metabolite that can be eliminated in the urine.A33595 On the other hand, the phenytoin dihydrodiol entity is only transformed to the catechol metabolite.A33595 The catechol metabolite can undergo methylation by COMT and be subsequently eliminated in the urine, or can spontaneously oxidize to a phenytoin quinone (NQO1 can transform the quinone back to the catechol metabolite).A33595 Of note, although CYP2C18 is poorly expressed in the liver, the enzyme is active in the skin and is involved in the primary and secondary hydroxylation of phenytoin.A33595,A189312 This CYP2C18 mediated bioactivation may be linked to the manifestation of adverse cutaneous drug reactions associated with phenytoin.A33595

Rute Eliminasi

The majority of phenytoin is excreted as inactive metabolites in the bile.L9362,L10941 An estimated 1-5% of phenytoin is eliminated unchanged in the urine.A189219

Farmakogenomik

2 Varian
CYP2C9 (rs1057910)

Patients with this genotype have reduced metabolism of phenytoin.

HLA-B (None)

The presence of this genotype in HLA-B is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis when treated with phenytoin.

Interaksi Makanan

3 Data
  • 1. Avoid alcohol. Alcohol may increase or decrease serum levels of phenytoin.
  • 2. Take separate from antacids. Take at least 2 hours before or after antacids. Taking this medication with antacids can reduce absorption.
  • 3. Take with food. Food reduces irritation and increases bioavailability.

Interaksi Obat

2006 Data
Cyclosporine The serum concentration of Cyclosporine can be decreased when it is combined with Phenytoin.
Aripiprazole The metabolism of Aripiprazole can be increased when combined with Phenytoin.
Pyridoxine The metabolism of Phenytoin can be increased when combined with Pyridoxine.
Azithromycin The metabolism of Azithromycin can be increased when combined with Phenytoin.
Methysergide The metabolism of Methysergide can be increased when combined with Phenytoin.
Chlorpromazine The metabolism of Chlorpromazine can be increased when combined with Phenytoin.
Cephalexin The metabolism of Cephalexin can be increased when combined with Phenytoin.
Doxazosin The metabolism of Doxazosin can be increased when combined with Phenytoin.
Cisapride The metabolism of Cisapride can be increased when combined with Phenytoin.
Astemizole The metabolism of Astemizole can be increased when combined with Phenytoin.
Norethisterone The metabolism of Norethisterone can be increased when combined with Phenytoin.
Fenofibrate The metabolism of Fenofibrate can be increased when combined with Phenytoin.
Rosuvastatin The metabolism of Rosuvastatin can be increased when combined with Phenytoin.
Pimozide The metabolism of Pimozide can be increased when combined with Phenytoin.
Fosphenytoin The metabolism of Fosphenytoin can be increased when combined with Phenytoin.
Drospirenone The metabolism of Drospirenone can be increased when combined with Phenytoin.
Allylestrenol The metabolism of Allylestrenol can be increased when combined with Phenytoin.
Zuclopenthixol The metabolism of Zuclopenthixol can be increased when combined with Phenytoin.
Roflumilast The metabolism of Roflumilast can be increased when combined with Phenytoin.
Cobimetinib The serum concentration of Cobimetinib can be decreased when it is combined with Phenytoin.
Fosaprepitant The metabolism of Fosaprepitant can be increased when combined with Phenytoin.
Lomitapide The metabolism of Lomitapide can be increased when combined with Phenytoin.
Linagliptin The metabolism of Linagliptin can be increased when combined with Phenytoin.
Vorapaxar The metabolism of Vorapaxar can be increased when combined with Phenytoin.
Netupitant The metabolism of Netupitant can be increased when combined with Phenytoin.
Idelalisib The metabolism of Idelalisib can be increased when combined with Phenytoin.
Ceritinib The metabolism of Ceritinib can be increased when combined with Phenytoin.
Tasimelteon The metabolism of Tasimelteon can be increased when combined with Phenytoin.
Nintedanib The metabolism of Nintedanib can be increased when combined with Phenytoin.
Tenofovir alafenamide The serum concentration of Tenofovir alafenamide can be decreased when it is combined with Phenytoin.
Dihydroergocornine The metabolism of Dihydroergocornine can be increased when combined with Phenytoin.
Ebastine The metabolism of Ebastine can be increased when combined with Phenytoin.
Duvelisib The metabolism of Duvelisib can be increased when combined with Phenytoin.
Dacomitinib The metabolism of Dacomitinib can be increased when combined with Phenytoin.
Gilteritinib The metabolism of Gilteritinib can be increased when combined with Phenytoin.
9-aminocamptothecin The metabolism of 9-aminocamptothecin can be increased when combined with Phenytoin.
Methylprednisone The metabolism of Methylprednisone can be increased when combined with Phenytoin.
Dihydroergocristine The metabolism of Dihydroergocristine can be increased when combined with Phenytoin.
Dihydroergocryptine The metabolism of Dihydroergocryptine can be increased when combined with Phenytoin.
Medical Cannabis The metabolism of Medical Cannabis can be increased when combined with Phenytoin.
Isavuconazole The metabolism of Isavuconazole can be increased when combined with Phenytoin.
Tazemetostat The metabolism of Tazemetostat can be increased when combined with Phenytoin.
Pretomanid The serum concentration of Pretomanid can be decreased when it is combined with Phenytoin.
Fluvoxamine The serum concentration of Phenytoin can be increased when it is combined with Fluvoxamine.
Buprenorphine Phenytoin may increase the central nervous system depressant (CNS depressant) activities of Buprenorphine.
Doxylamine Doxylamine may increase the central nervous system depressant (CNS depressant) activities of Phenytoin.
Dronabinol The serum concentration of Dronabinol can be increased when it is combined with Phenytoin.
Droperidol Droperidol may increase the central nervous system depressant (CNS depressant) activities of Phenytoin.
Hydroxyzine Hydroxyzine may increase the central nervous system depressant (CNS depressant) activities of Phenytoin.
Magnesium sulfate The therapeutic efficacy of Phenytoin can be increased when used in combination with Magnesium sulfate.
Methotrimeprazine Phenytoin may increase the central nervous system depressant (CNS depressant) activities of Methotrimeprazine.
Metyrosine Phenytoin may increase the sedative activities of Metyrosine.
Minocycline Minocycline may increase the central nervous system depressant (CNS depressant) activities of Phenytoin.
Mirtazapine Phenytoin may increase the central nervous system depressant (CNS depressant) activities of Mirtazapine.
Nabilone Nabilone may increase the central nervous system depressant (CNS depressant) activities of Phenytoin.
Orphenadrine Phenytoin may increase the central nervous system depressant (CNS depressant) activities of Orphenadrine.
Paraldehyde Phenytoin may increase the central nervous system depressant (CNS depressant) activities of Paraldehyde.
Pramipexole Phenytoin may increase the sedative activities of Pramipexole.
Rotigotine Phenytoin may increase the sedative activities of Rotigotine.
Sodium oxybate Phenytoin may increase the central nervous system depressant (CNS depressant) activities of Sodium oxybate.
Suvorexant Phenytoin may increase the central nervous system depressant (CNS depressant) activities of Suvorexant.
Tapentadol Tapentadol may increase the central nervous system depressant (CNS depressant) activities of Phenytoin.
Thalidomide The risk or severity of somnolence and peripheral neuropathy can be increased when Thalidomide is combined with Phenytoin.
Zolpidem Phenytoin may increase the central nervous system depressant (CNS depressant) activities of Zolpidem.
Amphetamine The therapeutic efficacy of Phenytoin can be decreased when used in combination with Amphetamine.
Phentermine The therapeutic efficacy of Phenytoin can be decreased when used in combination with Phentermine.
Pseudoephedrine The therapeutic efficacy of Phenytoin can be decreased when used in combination with Pseudoephedrine.
Benzphetamine The therapeutic efficacy of Phenytoin can be decreased when used in combination with Benzphetamine.
Diethylpropion The therapeutic efficacy of Phenytoin can be decreased when used in combination with Diethylpropion.
Lisdexamfetamine The therapeutic efficacy of Phenytoin can be decreased when used in combination with Lisdexamfetamine.
Mephentermine The therapeutic efficacy of Phenytoin can be decreased when used in combination with Mephentermine.
MMDA The therapeutic efficacy of Phenytoin can be decreased when used in combination with MMDA.
Midomafetamine The therapeutic efficacy of Phenytoin can be decreased when used in combination with Midomafetamine.
2,5-Dimethoxy-4-ethylamphetamine The therapeutic efficacy of Phenytoin can be decreased when used in combination with 2,5-Dimethoxy-4-ethylamphetamine.
4-Bromo-2,5-dimethoxyamphetamine The therapeutic efficacy of Phenytoin can be decreased when used in combination with 4-Bromo-2,5-dimethoxyamphetamine.
Tenamfetamine The therapeutic efficacy of Phenytoin can be decreased when used in combination with Tenamfetamine.
Chlorphentermine The therapeutic efficacy of Phenytoin can be decreased when used in combination with Chlorphentermine.
Methylenedioxyethamphetamine The therapeutic efficacy of Phenytoin can be decreased when used in combination with Methylenedioxyethamphetamine.
Dextroamphetamine The therapeutic efficacy of Phenytoin can be decreased when used in combination with Dextroamphetamine.
Metamfetamine The therapeutic efficacy of Phenytoin can be decreased when used in combination with Metamfetamine.
Iofetamine I-123 The therapeutic efficacy of Phenytoin can be decreased when used in combination with Iofetamine I-123.
Ritobegron The therapeutic efficacy of Phenytoin can be decreased when used in combination with Ritobegron.
Mephedrone The therapeutic efficacy of Phenytoin can be decreased when used in combination with Mephedrone.
Methoxyphenamine The therapeutic efficacy of Phenytoin can be decreased when used in combination with Methoxyphenamine.
Gepefrine The therapeutic efficacy of Phenytoin can be decreased when used in combination with Gepefrine.
2,5-Dimethoxy-4-ethylthioamphetamine The therapeutic efficacy of Phenytoin can be decreased when used in combination with 2,5-Dimethoxy-4-ethylthioamphetamine.
Phendimetrazine The therapeutic efficacy of Phenytoin can be decreased when used in combination with Phendimetrazine.
Halazepam The serum concentration of Phenytoin can be increased when it is combined with Halazepam.
Camazepam The serum concentration of Phenytoin can be increased when it is combined with Camazepam.
Delorazepam The serum concentration of Phenytoin can be increased when it is combined with Delorazepam.
Ethyl loflazepate The serum concentration of Phenytoin can be increased when it is combined with Ethyl loflazepate.
Cloxazolam The serum concentration of Phenytoin can be increased when it is combined with Cloxazolam.
Fludiazepam The serum concentration of Phenytoin can be increased when it is combined with Fludiazepam.
Cinolazepam The serum concentration of Phenytoin can be increased when it is combined with Cinolazepam.
Pinazepam The serum concentration of Phenytoin can be increased when it is combined with Pinazepam.
Medazepam The serum concentration of Phenytoin can be increased when it is combined with Medazepam.
Loprazolam The serum concentration of Phenytoin can be increased when it is combined with Loprazolam.
Doxefazepam The serum concentration of Phenytoin can be increased when it is combined with Doxefazepam.
Lormetazepam The serum concentration of Phenytoin can be increased when it is combined with Lormetazepam.
Nordazepam The serum concentration of Phenytoin can be increased when it is combined with Nordazepam.

Target Protein

Sodium channel protein type 5 subunit alpha SCN5A
Sodium channel protein type 1 subunit alpha SCN1A
Voltage-gated inwardly rectifying potassium channel KCNH2 KCNH2
Voltage-dependent L-type calcium channel CACNA1C
Sodium channel protein type 2 subunit alpha SCN2A
Sodium channel protein type 8 subunit alpha SCN8A
Nuclear receptor subfamily 1 group I member 2 NR1I2
Sodium channel regulatory subunit beta-1 SCN1B
Sodium channel protein type 3 subunit alpha SCN3A
GABA(A) Receptor GABRA1

Referensi & Sumber

Synthesis reference: Mahdi B. Fawzi, Anne K. Taylor, "Parenteral phenytoin preparations." U.S. Patent US4642316, issued April, 1981.
Artikel (PubMed)
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    Fischer JH, Patel TV, Fischer PA: Fosphenytoin: clinical pharmacokinetics and comparative advantages in the acute treatment of seizures. Clin Pharmacokinet. 2003;42(1):33-58. doi: 10.2165/00003088-200342010-00002.
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    Dagenais R, Wilby KJ, Elewa H, Ensom MHH: Impact of Genetic Polymorphisms on Phenytoin Pharmacokinetics and Clinical Outcomes in the Middle East and North Africa Region. Drugs R D. 2017 Sep;17(3):341-361. doi: 10.1007/s40268-017-0195-7.
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    Silvado CE, Terra VC, Twardowschy CA: CYP2C9 polymorphisms in epilepsy: influence on phenytoin treatment. Pharmgenomics Pers Med. 2018 Mar 29;11:51-58. doi: 10.2147/PGPM.S108113. eCollection 2018.
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    Keppel Hesselink JM: Phenytoin: a step by step insight into its multiple mechanisms of action-80 years of mechanistic studies in neuropharmacology. J Neurol. 2017 Sep;264(9):2043-2047. doi: 10.1007/s00415-017-8465-4. Epub 2017 Mar 27.
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