Describe the pharmacology of Phenytoin
A structured approach was expected addressing both the mechanism of action and pharmacokinetics. Candidates were expected to outline relevant mechanisms of action (such as sodium channel blockade) and how they relate to its use as an anticonvulsant agent. Additional credit was given for discussing other potential mechanisms and other uses such as pain management and antiarrhythmic properties. Phenytoin is illustrative of several key concepts in pharmacology and mention of these was expected. Failure to address these key concepts or provide sufficient detail was a common omission. Candidates were expected to discuss that phenytoin is highly protein bound, changes from first to zero order kinetics with escalating doses and is metabolised by the cytochrome p450 enzyme system. Some discussion of the significance of these points was expected and extra credit was awarded for more detailed explanations, comments on enzyme induction and examples of drug interactions that are well known and clinically relevant. Candidates were expected to comment on the mode of delivery and compare oral and intravenous dosing. It was expected that the need for a loading dose followed by maintenance dosing would be mentioned and extra credit was given for highlighting the potential hazards of rapid intravenous administration. Additional credit was given for mentioning the importance of a narrow therapeutic index and the need for clinical monitoring. Well organized answers such as those with an ordered list of subheadings were rewarded.
|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.