Question 2

Describe the pharmacology of Phenytoin

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College Answer

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.

Discussion

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

References

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