Drugs for Epilepsy Flashcards
define seizures
periods of self sustained neural hyper excitation
what happens during a seizure, in terms of neurons
the forebrain neurons cease their normal activities and begin to fire in massive, synchronized bursts
after seconds or minutes, when the inhibitory mech of the brain regain control, the seizure ends
spreading depression?
a time when the inhibitory neurons take over
during a seizure: blood flow to the brain is _________, and there is a greater use of ________ & ________
increased, glucose, oxygen
causes of seizures (7)
- high fever (esp in children)
- brain infection
- meningitis
- head injury or trauma
- alcohol or benzodiazepine withdrawal
- drug infection (cocaine, amphetamine, antidepressants (buproprion)) - “at high doses can cause seizures, but medically it’s all g
- stroke or cvd event: anything that reduces blood to the brain (stroke = brain blood vessel burst)
define epilepsy (aka seizure disorder)
GROUP of neurological disorders characterized by spontaneous, recurrent seizures
people with epilepsy have a ____ seizure threshold - and explain what it is
low
every brain has one, every brain will generate a seizure if it is subjected to a high enough level of excitatory stimulation
how are seizures triggered in non-epileptic people
during electroconvulsive therapy (ECT)
what is the prevalence of epilepsy in the population at point prevalence vs lifetime prevalence
point prevalence: prevalence at any given time
lifetime prevalence: prevalence at a point during their lifetimes
it’s 1% and 4% respectively
what are the two main causes of epilepsy (and which one has a higher causation)
70% bc of genetics: due to a mutation in a gene that controls neuron excitability
30% bc of structural/metabolic causes
what was the old understanding in the cause of epilepsy and how did they figure it out
Used to be idiopathic but they started to sequence people’s genomes and they find misspellings
what are common structural causes of epilepsy (4)
scar, cancer or benign tumor, vascular malformation
essentially something in the brain that is causing the seizure: tumor, cancers, even benign brain tumors, vascular malformation (the way our arteries are in the brain, there is a kink = area that doesn’t get blood easily = when hungry for blood it may cause a seizure, head trauma
what is the onset of epilepsy
at any time during life - many begin in childhood, often before 15 y/o
can you “outgrow seizures”?
sometimes, or they may have reduced freq of seizures in adulthood
what is an onset phenomenon seen recently (maybe bc people are living longer)
an increased onset of seizures after age 65 - many of these are thought to be the result of small strokes
what are the comorbidities with epilepsy (6)
esp with uncontrolled seizures, you can get other seizures
- cognitive, memory problems
- psychiatric; anxiety, depression, adhd, psychosis
- asthma
- migraine
- stroke
- ulcers
main types of seizures (2) and describe them
- generalized seizures: occur throughout the cortex
- partial seizures: occur just in one location of the cortex (1-2 electrodes = localized)
what are the two types of generalized seizures and distinguish between them
absence (petit mal): briefly unconscious, blank stare, no memory of attack , less than 30 sec (3 per sec spike and wave throughout whole brain)
tonic clonic (grand mal): unconscious, dramatic convulsions, no memory of attack, lasts less than 5 min, constant spiking throughout the whole brain
^status epilepticus
what are the two types of partial seizures and distinguish between them
simple partial: conscious, memory of attack, sensory/motor/emotion symptoms, varied duration, burning toast smell, localized spiking in neocortical or limbic areas of the brain
complex partial (temporal lobe): conscious but non-responsive, automatisms, no memory of attack, duration varies, localized then spreading spiking in 1 or both temporal lobes
describe the differences you might see between a normal eeg pattern vs during absence seizure vs tonic-clonic seizure
normal eeg pattern: Only some firing and many others are quiet = very small changes in the amp of the waves
absence seizure: Regular and synchronized pattern - almost looks like very deep sleep
tonic-clonic seizure: After the peak, the post-ictal state is invoked and the lines get very straight (kinda wavy, wavy w short periods and high amp, short periods w short amp, short periods w high amp)
in which part of the brain can we measure the neuron activity
only the cortex - neurons closest to the skull
through what device are seizures detected
electroencephalogram
the _____ neurons fire, the higher the peaks and valleys
more
ps: irregular are short and stubbly and synchronized and long and wave
list the consequences if epilepsy is not managed (7)
- difficulty learning
- aspiration pneumonia (if breathing in food or saliva into lungs during seizure)
- permanent brain damage
- seizure worsening (death)
- death from suicide
- injury from falls/bumps/self inflicted bites/driving/operating machinery during a seizure
- excitotoxicity
what is excitotoxicity
excessive neuron firing leading to cell death (everything gets stored up and released at once) - allowing too much calcium in and using too much energy because of seizures
list the common sized effects of anti-seizure medications (5)
- sleepiness
- memory impairments
- nausea/GI upset
- dependence/withdrawal
- cognitive issues
t/f and explain: all the side effects are different for the anti-seizure medication
true: act on basic parts of neuron function (gaba, voltage gated sodium channels)
_____ night sleep may cause worse seizures
poor
explain the significance of a ketogenic diet
People who were starving - seizures went away = found that if you gave diet high in fat and low in sugar = ketosis (production of ketones) and used that as energy source instead of carbs and sugars - lets you get your nutrient requirements but no seizures. HARD TO MAINTAIN. You need fat and protein consistently, no sugars and no carbs (growing children need carbs)
how do anti-seizure meds generally act (moa)
by promoting (agonist) gaba signaling or reducing (antagonists) the function of voltage gated ion channels - many have more than one moa
anti seizure meds are _______ of gaba / _________ of voltage gated ion channels
agonists, antagonists
what are the moa of ketogenic diet
ketone bodies, medium chain triglycerides, anti-inflammatory effects, mitochondrial function improvements, epigenetics, gut microbiome
what is the importance of voltage-dependent sodium and calcium channels
Changes voltage, the voltage is the trigger for other neurons to open (the electricity) = gate is opened (domino effect)
Glutamate starts it, voltage gated sodium channels spread it. With enough glutamate and sodium channels = only sodium channels by the axon. If this is blocked = neuron will never release NT.
Majority of cells in the brain are glutamate releasing.
Another channel opens up, calcium channel - calcium comes in when the gate opens up and you need this to release the NT. Without calcium, no NT released (same as if silent) .
list the 5 classic drugs of epilepsy
- phenobarbital (luminal)
- phenytoin (dilantin)
- ethosuximide (zarontin)
- carbamazepine (tegretol)
- valproate (valproic acid)(depakene)
what are the features of grin1 encephalopathy
- all patients have intellectual disability
- approximately 70% of grin1 patients have childhood epilepsy
- motor impairments: hypotonia, dystonia, hyperkinesis
- cortical visual impairment (CVI) is reported for many patients
what are structural mri indications for grin1 encephalopathy
minor changes - reduced brain volume, reduced white matter volume
what are features of first diagnosis grin1 encephalopathy
developmental delay, intellectual disability, autism, epilepsy
describe what they saw in mice with grin1 encephalopathy
mice w a mutation in grin1 gene have spon seizures, eeg recordings of their cortex and hippocampus show these seizure events. number of seizures (ictal events) were recorded with drug treatment (vehicle), with a low dose of cbd, with a high dose of cbd, and w a low dose of lamotrigine (anti seiz med). high dose cbd caused more seizure events in this mouse, even though it has been beneficial for one form of childhood epilepsy (dravet syndrome). the patient with this mutation also had increased seizures when given cbd.
what are the first drug discovered for tonic clonic and partial seizures (oldest drug still in use)
phenobarbital (luminal)
features and side effects of phenobarbital (luminal)
- cheap and safe, long half-life
- side effects: sedation/sleepiness, memory impairment, gi upset
moa of phenobarbital (luminal)
a barbiturate: enhances gaba-a system - keeps the gaba channel open longer - increases the inhibitory effect of gaba
what was the second drug for tonic-clonic and part seizures (second oldest still in use)
phenytoin (dilantin)
compare phenobarbital and phenytoin
less sedating than phenobarbital, also has long half life
list the side effects of phenytoin (dilantin)
- headache
- nausea
- dizziness
- sleepiness
- acne
- gingival hyperplasia
- hirsutism (growing facial hair)
Caused by off target effects (when the drug has a different target)
what is the moa for phenytoin (dilantin)
blocks voltage dependent sodium channels (antagonist) - these are the channels that allow the action potential to travel down the axon. phenytoin blocks the channels and reduces the number of action potentials that a neuron can fire
name the drug of choice for absence seizures
ethosuximide (zarontin)
why is ethosuximide good for absence seizures
Works on SPECIFIC calcium channels = localized = side effects less problematic
list the side effects of ethosuximide
- upset stomach
- diarrhea
- weight loss
- hiccups
describe the moa of ethosuximide
blocks voltage dependent calcium channels (antagonist) - these are the channels that trigger the release of nt when the ap reaches the axon terminal. ethosuximide blocks one specific type of these calcium channels that is found in the thalamus and reduces the amt of glutamate nt that is released in that brain region
what is the treatment for tonic clonic partial seizures
carbamazepine (tegretol)
list the side effects of carbamazepine
- dizziness
- nausea
- problems w coordination
- reduces numbers of wbc
what is the moa of carbamazepine
blocks voltage dependent sodium channels (antagonist) - these are the channels that allow the ap to travel down the axon
what does carbamazepine have a similar moa to ((same/different) __________ side effects)
phenytoin (and the first moa of valproate), different
what was the first broad spectrum drug
valproate (valproic acid)(depakene)
what does a broad spectrum drug do
be effective for absence, tonic clonic, partial seizures
what are the side effects for valproate
- tremor
- weight gain
- hair loss
- bruising and bleeding
what does teratogen mean
should not be used during pregnancy
t/f valproate be used during pregnancy
FALSE it is a teratogen
is the moa for valproate known
there are multiple and not fully understood
possible: Turns on a gene that in turn will produce the GABA NT = every time that the GABA neuron fires it releases more = increases the effect
Valproic acid can decrease the runaway excitation process
(but there is another flashcard with more depth)
describe the first and second moa of valproate
1st: blocks voltage dependent sodium channels (antagonist) - similar to phenytoin and carbamazepine
2nd: opens up chromatin/dna structure to allow more gene expression = epigenetics. one of genes that is expressed is for enzyme that makes gaba - more gaba = more inhibition of neuron firing
