Anti-Epileptics (General, Phenytoin and Phenobarbitol) Flashcards
Define a “Seizure?”
A seizure is a paroxysmal (or sudden) event due to abnormal or excessive synchroous neuronal activity in the brain.
What is “Epilepsy?”
Recurrent seizures due to some underlying chronic process .
What is thought to be the mechanism behind epilepsy?
Disturbances of neuronal excitability, such as direct activation of glutamate or antagonizing the effects of GABA.
What part of the brain is it thought that seizures arise from?
Thought to be from the cerebral cortex.
Two general concepts of a seizure are:
Partial (focal) seizures. in which the seizure begins focally at a cortical site, and generalized (diffuse) seizures, where the seizures begins in both hemispheres from the outset.
How does the Na channel blocker mechanism generally work with anti-epileptics?
It will promote the inactive state of the voltage gated Na channels, thus it will reduce the time of the sustained, repeated firing of the neurons.
How does the Glutamate/GABA MOA work in terms of anti-epileptics?
The idea is to diminish glutamate (excitatory) and enhance GABA (inhibitory) synaptic inhibition.
How does the T-type Ca channel inhibition work for MOA of anti-epileptics? What kind of seizures are these used for?
It’s used for tx of absence seizures, idea is to shut down the voltage gated Ca 2+ channels so that the T-type Ca currents are shut down
Name the 4 drugs that block the voltage gated Na channels?
Phenytoin, Carbamazepine, Lamotrigine, and Valproate.
Name the 4 voltage gated Ca channel blockers (pre-synaptic, NOT the T type?)
Ethosuximide, Lamotrigine, Gabapentin and Pregabalin.
Name the 12 anti-epileptic drugs?
Benzodiazapine, Carbamazepine, Oxcarbamazepine, Ethosuximide, Felbamate, Gabapentin, Pregabalin, Lamotrigine, Levetiracetam, Phenobarbitol (Primidone), Phenytoin (Phosphenitoin), Topiramate, Valproate (Divalproex).
Which are the 2 anti-epileptics that ARE highly protein bound?
Phenytoin and Valproic acid, the rest are NOT highly bound to plasma.
What is special about Phenobarbitol administration?
Comes oral, IV and IM, the IV formulation is useful in tx of status epilepticus.
How is Phenobarbitol metabolized? Half life?
25% excreted unchanged, but 75% metabolized by 2C9. Long half life (1-5 days in adults, less in infants).
How does Primidone compare to Phenobarbitol?
Primidone is oral only, it’s hepatically metabolized to phenobarbitol and PEMA both of which have anti seizure effects. Half life is much shorter (5-16 hrs).
What is the MOA of Phenobarbitol?
Basically to hyperpolarize the cell. It does this through potentiating the effects of GABA receptors. Phenobarbitol binds to the allosteric sites of the GABA receptors, and when GABA binds and opens the receptor, Phenobarbital KEEPS THE GABA RECEPTOR OPEN, allowing more Cl- to pour into the channel and inducing hyperpolarization.
In order for Phenobarbitol to work, what neurotransmitter is essential to be present?
Phenobarbitol is binds to an allosteric site of the GABA receptor, it REQUIRES GABA to bind to its receptor to open the channel. Phenobarbitol just keeps the channel open longer.
What are the 3 uses for Phenobarbitol in terms of Tx?
Used for Partial (focal) seizures, generalized tonic-clonic seizures (esp in children), and alternative tx for status epilepticus.
AE’s of phenobarbitol? AE’s of IV phenobarbitol?
HS rxns (rash, hepatotox and bone marrow tox). Sedation (phenobarbitol is used in some sleeping meds), depression, memory loss (cognitive impairment), hyperactivity in kids and pt's in acute pain, agitation and confusion in the elderly. IV: Respiratory depression ESP when used after BENZO's. Also hypotension.
What is the first and second line tx of status epilepticus and what is a potential DDI of these 2 drugs?
Benzo’s are first line, Phenobarbitol (IV) is second line. If PhenoB is administered after Benzo’s this increases the risk of resp depression. Phenytoin is also a first line for status epilepticus.
CYP’s and Phenobarbitol?
Metabolized by 2C19, and POTENT CYP INDUCER!
What is the difference between Phenytoin and Fosphenytoin?
Fosphenitoin is formulated so that it can be administered in a soluble form IV, once in the blood it turns into phenytoin. Phenytoin also can be IV but very prone to precipitate out, hence Fosphenytoin. Also, IM variant of Phenytoin (not recommended, unpredictable absorption). Fosphenytoin is $$$$$ so IV Phenytoin still used in hospital.
What is the kinetics of phenytoin and what are 2 other drugs that share this kinetics? What is special about this kind of kinetics? How is half life determined for this kind of kinetics?
Phenytoin display 0 order kinetics, alcohol and asprin also demonstrate this. Zero order kinetics means it is non-linear, that once the enzymes that metabolize the drug is saturated, the level of the drug in the body will spike dramatically because until the enzyme finishes the metabolism one molecule it won’t move onto the next. Half life therefore is determined by the conc in the plasma.
What is special to note about Phenytoin in terms of Bioavailability and distribution?
Wide range of bioavailibility 20-90%, highly plasma bound so patient’s albumin levels become important, as well as hyperbilirubenimia (will decrease available albumin).
