Pharmacology of Seizure and Epilepsy Flashcards
Acquired or inherited malfunction of neuronal ion channels or neurotransmitters systems disrupting normal electrical activity in the brain is known as _
epilepsy
What drug is commonly used for generalized onset absence seizures?
Ethosuximide is the most common. Others that can be used are valproate, and lamotrigine
What is the MOA of ethosuximide?
Blocks T-type Ca channels
Phenytoin, carbamezephine, Lamotrigine, oxcarbazepine and zoniscamide all are AEDs that antagonize what channels?
voltage-gated Na channel. They prolong fast inactivation state of the Na ion channel
What AED acts by enhancing slow inactivation of Na channels?
Lacosamide
Na Channels are target for drugs used to treat epilepsy, seizures and pain and cardiac arrhythmias. They exhibit little or no selectivity for Na channel subtypes. How then does AED target specific Na channels?
Under normal condition, the drug has very finite window when it can work. At the normal dose level it is nearly impossible for the drugs to have effect. However, during a seizure, when AP are firing continuously, the window to have an effect increases and thus increases the chance of the drug to work. In other words, the probability of a Na channel blockade is proportional to the frequency of Na channel opening and closing. In epileptic seizures where neurons are firing at higher frequency than normal, the NaV blockers act preferentially on the neurons involved in the disease
1 and 2 are AED. They are state dependent agents that slow the recovery of Na ion channels from inactivation. 1 is most effective at depolarized membrane potential and high frequency action potential firing and ha minimal effects on cognitive function. 2 binds Na less effectively, but with a much faster rate than 1, making 2 more effective in blocking high frequency of firing.
- phenytoin
2. carbamezepine
Like Phenytoin and carbamezepine, Lamotrigine can act on Na channels similarly in that they all block fast-inactivated Na channels. However, it’s anti-epitelptic tion is not identical to carbamzepine and phenytoin. Why?
Lamotrigine also acts on other molecular targets such as N and P type voltage-gated Ca channels in cortical neurons and neocortical potassium currents.
What is the MOA of Lacosamide and what does it treat?
Treats partial seizures. Lacosamide stabilizes the slow-inactivated state. It’s effective in reducing amplitudes and frequency of sustained repetitive firing spikes when the stimulus was prolonged to tens of seconds. Other AEDS like phenytoin, carbamezpine and lamotrigine exert their action over substantially shorter time scale.
A. What are the hallmarks of Absence seizures and channels are involved? B. What drug is used?
A. T-type Ca channels mediate 3Hz spike and wave activity int he thalamus. AEDs that inhibit these T type Ca channels are useful for controlling absence seizures.
B. Ethosuximide
What was valproate considered first line therapy for?
Valproate is a broad specturm AED for generalized onset seizures
What are some common AE seen with valproate?
- Wt gain
- tremor
- hair loss
- lethargy
- neural tube defect
- GI distress
- hepatotoxicity and pancreastitis
Which AED is chemically and structurally unrelated to other anticonculsants, and its primary MOA appears to be blocking voltage gated Na channels and T-Type Ca channels?
Zonisamide
_ is a AED adjunct that works by blocking GABA re-uptake (transporters), thus keeping GABA around longer and thus inhibitory signal is around longer.
Tiagabine
_ is an AED adjunct that prevents GABA from being turned into something else, i.e. glutamate, and thus amount of GABA that is in vesicle increases and thus amount that is released is also increased.
Vigabatrin
What group of AED works by post-synaptic modulation of GABA-receptors and enhance the post-synaptic GABAergic neuronal transmission.
- Phenobarbital and related barbs
- Primidone
- Benzodiazapines
What are some common complications of phenobarbital and related barbs?
- powerful, non-specific CNS depression
- Significant sedation
- Lethal respiratory depression
- Abuse and addiction potential
What on the GABA receptor do Benzodiazepines bind to?
Binds to an allosteric site and cause a change such to potentiate GABA binding leading to Cl-channels opening with greater frequency. In other words, increase the duration of the Cl- channeling opening
With increased dose of benzodiazepine and barbiturate, which one has a greater lethality?
Barbiturate. Lethality is GABA independent.
_ is indicated for treatment of status epilepticus.
Benzos (IV lorazepam/diazepam) and maintained with phenytoin
Which benzo is the drug of choice for myoclonic seizures and subcortical myoclonus and is very effective in emergency treatment of status epilepticus and can be given IV or rectally given after the patient has been stabilized.
Clonazepam
What is the best treatment option for someone with intractable difficulty in controlling epilepsy?
Topirimate due to it’s ability to work in many receptors, namely: voltage gated Na channels, Ligand gated Na channels (AMPA/glutamate receptor), Increase GABA and potentiates GABA-A receptors.
What are some AE associated with phenytoin?
Phenytoin has zero-order PK, therefore doubling dose does not double serum level making it difficult to adjust dose.
- induces hepatic CYP450 enzymes
- Gingival hyperplasia
- Hirsutism
- Hypocalcemia
- Osteoporosis
- drug induced lupus
What AE are associated with Carbamezepine?
- inducer of hepatic CYP450 enzymes
- aplastic anemia (rare but often fatal) -
- Leukopenia, neutropneia, thrombocytopenia
- hypocalcemia, osteoporosis (due to vit D catabolism)
- neural tube defect
- diplopia
- drug induced lupus
- SIADH
