Targets for anti-seizure medications are generally at either the excitatory (glutamatergic) synapse, or the inhibitory (GABAergic) synapse. Which one is the target for most drugs? Give some examples of drugs acting at this more common target.
Most act by blocking actions of the excitatory (glutamatergic) synapse. Examples include phenytoin, carbamazepine, lamotrigine, gabapentin, pregabalin, phenobarbitone and topiramate.
Name two important anti-seizure drugs that are highly protein-bound.
How are most anti-seizure drugs cleared?
Of the anti-seizure drugs available before 1990, there were five major chemical groups: barbiturate, hydantoins, oxazolidinediones, succinimides, and acetylureas. Which group does phenytoin belong to?
Name three ions whose transport across membranes is altered by phenytoin.
K+, Na+, Ca2+
Phenytoin acts by multiple different pharmacologic mechanisms. What is perhaps the most important mechanism, which doesn’t directly act on GABA or glutamate?
Phenytoin blocks Na+ channels in the presynaptic neuron, thereby preventing the generation of rapidly repetitive action potentials.
What is fosphenytoin? What is its usefulness, and how is it administered?
Fosphenytoin is a prodrug, which is rapidly converted to phenytoin in the plasma. It can be given intramuscularly (or IV), with much better absorption IM than phenytoin IM.
What is the average half-life of phenytoin, assuming it is in the therapeutic range?
24hrs (but note that the half-life is highly variable at different doses)
What is the therapeutic range of phenytoin in plasma for most patients?
What is often the earliest clinical sign of a patient approaching toxic levels of phenytoin?
Nystagmus (but this rarely requires dose adjustment).
What are the most common adverse effects of phenytoin that would prompt dose reduction?
Diplopia and Ataxia
What are some cosmetic adverse effects of long-term phenytoin use?
Gingival hyperplasia, Hirsutism.
What is the basic chemical structure of carbamazepine?
Tricyclic, with a ureide moiety (-N-CO-NH2). Its chemical structure resembles that of the tricyclic antidepressants.
Carbamazepine has many pharmacologic actions – how is it similar to phenytoin?
It also blocks Na+ channels, preventing the generation of rapidly repetitive action potentials.
How does the half-life of carbamazepine change as a patient uses the drug more long-term?
Half life is initially approx. 36hrs, but this will gradually reduce to as low as 8 hrs.
How is carbamazepine administered?
What are the most common dose-related adverse effects of carbamazepine?
Diplopia and Ataxia.
What are the most concerning, and possibly fatal, adverse effects of carbamazepine?
Blood dyscrasias such as agranulocytosis and aplastic anaemia.
What is the basic description of the chemical structure of valproic acid?
It is a fatty acid.
What are some clinical uses of sodium valproate?
Absence seizure, Myoclonic seizures, Generalized tonic-clonic seizures, Migraine prevention, Bipolar disorder.
Sodium Valproate: Bioavailability? Half-life?
Half-life: 9-18 hours.
Valproate vs. Carbamazepine: Which has a greater volume of distribution, and what property is this related to?
Carbamazepine has a greater Volume of distribution, and this is related to the fact that Carbamazepine is 70% protein-bound, but Valproate is 90% protein-bound.