Question 3

Describe the pharmacology of phenytoin 

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College Answer

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


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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.