Describe the pharmacology of phenytoin
Many candidates scored well in this question by using a standardised approach such as:
Pharmacoceutics, Pharmacokinetics and Pharmacodynamics. This topic is well covered in
the reference texts and a high degree of content was expected.
Surely with a heading like "Pharmacoceutics" the candidates would not have gotten far.
| Class | Antiepileptic |
| Chemistry | Hydantoin |
| Routes of administration | Oral and IV |
| Absorption | 50-90% bioavailability; erratic absorption because poor solubility in stomach acid and intestinal fluids. |
| Solubility | pKa 8.0-9.2; extremely poor water solubility. |
| Distribution | VOD = 1.6-2.5L; highly protein bound (90%, mainly to albumin). |
| Target receptor | Voltage-gated sodium channels are thought to be the main therapeutic drug target |
| Metabolism | Hepatic metabolism (CYP450) into an inactive hydroxyphenytoin, which is then excreted into the urine |
| Elimination | Non-linear elimination kinetics: first order at low concentrations, zero-order at high concentrations. Metabolic enzymes are saturated at normal therapeutic concentrations |
| Time course of action | Half life is about 22 hours, but within a wide range (7 to 42hrs) because of unpredictable metabolism |
| Mechanism of action | By binding to voltage gated sodium channels and stabilising them in their inactive state, phenytoin decreases the excitability of excitable tissues and prevents the generation and propagation of action potentials |
| Clinical effects | Antiepileptic effects, as well as a host of side-effects: Acute toxic effects: Ataxia, nystagmus and tremor, slurred speech, cardiac toxicity Toxicity with chronic use: Gingival hyperplasia, hypersensitivity rash, folate deficiency, peripheral neuropathy, drug-induced lupus, bone marrow suppression. Also: DRESS syndrome, toxic epidermal necrolysis, Stephens-Johnson syndrome |
| Single best reference for further information | DBL phenytoin product data sheet |
Jones, Gary L., Gary H. Wimbish, and William E. McIntosh. "Phenytoin: basic and clinical pharmacology." Medicinal research reviews 3.4 (1983): 383-434.
Bialer, Meir. "Chemical properties of antiepileptic drugs (AEDs)." Advanced drug delivery reviews 64.10 (2012): 887-895.
Hesselink, Jan M. Keppel, and David J. Kopsky. "Phenytoin: 80 years young, from epilepsy to breast cancer, a remarkable molecule with multiple modes of action." Journal of neurology 264.8 (2017): 1617-1621.
Gugler, Roland, Carl V. Manion, and Daniel L. Azarnoff. "Phenytoin: pharmacokinetics and bioavailability." Clinical Pharmacology & Therapeutics 19.2 (1976): 135-142.
Lindow, John, and Eelco FM Wijdicks. "Phenytoin toxicity associated with hypoalbuminemia in critically ill patients." Chest 105.2 (1994): 602-604.
Richens, Alan. "Clinical pharmacokinetics of phenytoin." Clinical pharmacokinetics 4.3 (1979): 153-169.
Richens, Alan, and Andrew Dunlop. "Serum-phenytoin levels in management of epilepsy." The Lancet 306.7928 (1975): 247-248.
Cuttle, Leila, et al. "Phenytoin metabolism by human cytochrome P450: involvement of P450 3A and 2C forms in secondary metabolism and drug-protein adduct formation." Drug Metabolism and Disposition 28.8 (2000): 945-950.
Gill, M. A., et al. "Phenytoin overdose. Kinetics." Western Journal of Medicine 128.3 (1978): 246.
Poupaert, Jacques H., et al. "Structure-activity relationships of phenytoin-like anticonvulsant drugs." Journal of medicinal chemistry 27.1 (1984): 76-78.
Tunnicliff, G. "Basis of the antiseizure action of phenytoin." General Pharmacology: The Vascular System 27.7 (1996): 1091-1097.
Atkinson Jr, Arthur J., and R. Davison. "Diphenylhydantoin as an antiarrhythmic drug." Annual review of medicine 25.1 (1974): 99-113.
Gupta, Arjun, Christina Yek, and Robert S. Hendler. "Phenytoin toxicity." Jama 317.23 (2017): 2445-2446.