Describe the pharmacology of Phenytoin (75% of marks) and Levetiracetam (25% of marks).
The knowledge of phenytoin was often superficial and many answers were too brief and didn’t
adequately cover the required material. The knowledge around levetiracetam seemed very
limited with many candidates guessing (incorrectly) what the pharmacokinetics might be. Most
answers demonstrated a structured approach to this type of question.
Better answers were able to distil major issues such as the narrow therapeutic window for
phenytoin or the potential clinical impact of differing ordered kinetics or altered metabolism.
Candidates are reminded to read each question carefully; levetiracetam should not be confused
|Routes of administration||Oral and IV||Oral and IV|
|Absorption||50-90% bioavailability; erratic absorption because poor solubility in stomach acid and intestinal fluids.||Almost 100% oral bioavailability; rapidly and completely absorbed when given orally (96%)|
|Solubility||pKa 8.0-9.2; extremely poor water solubility.||pKa -2.0; highly acid drug, and very water soluble.|
|Distribution||VOD = 1.6-2.5L; highly protein bound (90%, mainly to albumin).||VOD=0.5-0.7 L/kg; mainly distriubuted into total body water. Minimally protein bound (less than 10%)|
|Target receptor||Voltage-gated sodium channels are thought to be the main therapeutic drug target||Multiple potential targets (calcium channels, potasium channels, AMPA and GABA receptors), with what appears to be some selectivity for epileptogenic foci|
|Metabolism||Hepatic metabolism (CYP450) into an inactive hydroxyphenytoin, which is then excreted into the urine||Minimally metabolised; about 30% of the drug is excreted in the urine as an inactive metabolite, the origins of which are unclear and almost certainly non-hepatic|
|Elimination||Non-linear elimination kinetics: first order at low concentrations, zero-order at high concentrations. Metabolic enzymes are saturated at normal therapeutic concentrations||70% of the drug is excreted unchanged in the urine|
|Time course of action||Half life is about 22 hours, but within a wide range (7 to 42hrs) because of unpredictable metabolism||Half life is about 7-8 hours in healthy volunteers|
|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||Multiple effects on multiple excitatory and inhibitory neurotransmitters and ion channels. Appears to have some selectivity for abnormally firing tissue, i.e. this drug is selective for epileptic brain tissue. The precise mechanism of its effect remains unknown|
|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
|Main side-effects are neurocognitive and behavioural. These may include a change in mood, eg. depression, anixety, restlessness or fatugue, personality changes, cognitive decline, and an increased risk of suicide.|
|Single best reference for further information||DBL phenytoin product data sheet||Wright et al (2013)|
Patsalos, P. N. "Pharmacokinetic profile of levetiracetam: toward ideal characteristics." Pharmacology & therapeutics 85.2 (2000): 77-85.
Stockis, Armel, et al. "Clinical pharmacology of levetiracetam for the treatment of epilepsy." Expert review of clinical pharmacology 2.4 (2009): 339-350.
Surges, Rainer, Kirill E. Volynski, and Matthew C. Walker. "Is levetiracetam different from other antiepileptic drugs? Levetiracetam and its cellular mechanism of action in epilepsy revisited." Therapeutic Advances in Neurological Disorders 1.1 (2008): 13-24.
Wright, Chanin Clark, et al. "Clinical pharmacology and pharmacokinetics of levetiracetam." Frontiers in neurology 4 (2013): 192.
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.