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.
|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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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.