Lecture 19: Drugs Used To Treat Seizure Disorders Flashcards
What is the definition of a seizure?
seizures are a transient alteration of behavior due to abnormally excessive and synchronous neuronal activity in the brain
seizures can be provoked (i.e., by chemical agents or electrical stimulation) or unprovoked
What is the definition of epilepsy?
epilepsy is a disorder of brain function characterized by the periodic and unpredictable occurrence of seizures
epilepsy can be symptomatic (occur due to a known event such as head trauma or cancer) or asymptomatic (generally due to poorly defined genetic factors
not everyone who has experienced seizures have epilepsy
the condition of epilepsy denotes the occurrence of spontaneous, unprovoked seizures
What is the mechanism of seizures?
normally, neurons fire asynchronously in the brain
spread of electrical activity is maintained by changes in membrane potential following depolarization (refractory period) and surround inhibition
What is surround inhibition?
is the physiological mechanism that focuses neuronal activity in the central nervous system
the primary afferent fiber whose receptive field center is closest to the point of stimulation will produce more action potentials than those on the periphery
action potentials in the second order neurons whose receptive fields are toward the periphery of the stimulus field are more strongly inhibited, and therefore produce fewer action potentials, than the cell with its receptive field in the center
What are the three steps of seizures?
initiation, propagation, and termination
What are the two events that characterize seizure initiation?
- high frequency bursts of action potentials
- hyper synchronization of a neuronal population
this sustained neuronal depolarization results in a burst of action potentials driven by calcium influx through NMDA receptors
How do seizures the overcome barriers of intact hyperpolarization and surround inhibition?
increasing extracellular potassium which blunts the hyper polarizing outward potassium currents
accumulation of calcium in presynaptic terminals leading to enhanced neurotransmitter release
depolarization induced activation of the NMDA receptor, which causes more calcium influx and neuronal activation
this leads to loss of surround inhibition and propagation of seizure activity across the brain
What is the mechanism of seizure resolution?
seizures resolve generally resolve spontaneously, and the mechanisms that terminate a seizure are not well known, but likely involve:
loss of ionic gradients
depletion of ATP
depletion of neurotransmitters (e.g. glutamate)
activation of inhibitory circuits (GABA)
What is status epilepticus?
a seizure lasting longer than 5 minutes or if you have more than 1 seizure within a 5 minute period is called status epilepticus and is a life-threatening condition
What is the postictal period after a seziure?
lasts 5-30 minutes after a seizure and is characterized by drowsiness, confusion, depression/anxiety, and sometimes psychosis (including hallucinations and delusions)
What are the classes of seizures?
there are different types of seizures depending on where in the brain they initiate and how widely they propagate
can vary from uncontrolled shaking movements with loss of consciousness, to shaking movements involving only part of the body with variable levels of consciousness, to subtle momentary loss of awareness
seizure classes include focal seizures, generalized seizures, and non-convulsive (absence) seizures
What are focal seziures?
diverse manifestations depending on where in the brain it originates (may include visual psychic, autonomic, olfactory, or motor phenomena)
may be simple (retain consciousness) or complex (loss of consciousness)
jerking activity may start in a specific muscle group and spread to surrounding muscle groups
automatisms are unusual activities that are not consciously created, like smacking the lips
focal seizures may become generalized over time
What are generalized seizures?
several types including tonic-clonic and myoclonic
all involve loss of consciousness and typically happen without warning
tonic-clonic seizures involve sustained contractions (tonic) of muscles throughout the body followed by periods of alternating muscle contraction and relaxation (clonic) (used to be called grand mal seizures)
myoclonic seizures involve a brief (~1s) shock like contraction of muscle that may be localized or generalized
What are non-convulsive seizures?
include absence and atonic seizures
What are absence seizures?
absence seizures are characterized by an abrupt onset of impaired consciousness
can be subtle, with only a slight turn of the head or staring
while there is a loss of consciousness, the person does not fall over and may return to normal right after the seizure ends, though there may be a period of postictal disorientation
What are atonic seizures?
atonic seizures are characterized by sudden loss of muscle strength
usually consciousness is maintained, though the person may fall down
What are the characteristics of drugs used to treat seizures?
the anti-seizure drugs are usually used chronically to prevent the occurrence of seizures in people with epilepsy
they are also, on occasion, used in people who do not have epilepsy to prevent seizures that may occur as part of an acute illness such as meningitis or in the early period following either neurosurgery or traumatic brain injury
other anti-seizure drugs are used to terminate ongoing seizures such as in status epilepticus or prolonged febrile seizures or following exposure to seizure-inducing nerve toxins
seizures are occasionally caused by an acute underlying toxic or metabolic disorder, such as hypocalcemia, in which case appropriate therapy should be directed toward correcting the specific abnormality
What are the mechanisms through which anti-seizure drugs act?
anti-seizure drugs act by either enhancing inhibitory (GABAergic) neurotransmission or diminishing excitatory (glutamatergic) neurotransmission
they do this by: blocking ionic conductance (particularly sodium, calcium, and potassium), blocking neurotransmitter release, and inhibiting/activating the postsynaptic membrane
one drug may have multiple targets that reduce likelihood of seizures
How do drugs used to treat seizures enhance inhibitory neurotransmission?
several different anti-seizure drugs enhance GABAergic inhibitory transmission by targeting various elements on the pre- or post-synaptic inhibitory neuron
What are benzodiazepine and barbiturates?
benzodiazepines and barbiturates are positive allosteric modulators at the GABAa receptors - they enhance the activity of GABA by binding to an allosteric site
benzodiazepines have no effect on the GABA receptor in the absence of GABA, while barbiturates can act as GABA agonists at higher concentrations
benzodiazepines increase the frequency at which the GABAa receptor opens (this increases the potency of GABA), whereas barbiturates increase the duration at which the GABAa receptor is open (this increases the efficacy of GABA)
What are the symptoms of overdose on benzodiazepines and barbiturates?
risk of overdose possible for both benzodiazepines and barbiturates (but riskier for barbiturates because of direct gating at the GABA receptor)
symptoms of overdose include sluggishness, incoordination, faulty judgement, and death
addictive risk when taken with other CNS depressants (like alcohol or opioids)
What is vigabatrin?
inhibits GABA aminotransaminase (GABA-T), an enzyme involved in degradation of GABA
What is tiagabine?
inhibits the GABA transporter (GAT-1 located in neurons and glia), which prolongs the action of the neurotransmitter
How do some anti-seizure drugs block voltage gated sodium channels?
they do so by causing a conformational change of the inactivation gate
action is rate dependent (block increases with increased frequency of neuronal discharge) and results in prolongation of the inactivated state of the sodium channel and the refractory period of the neuron
What is gabapentin?
gabapentin consists of a GABA molecule covalently bound to a lipophilic cyclohexane ring; it was developed as a centrally active GABA agonist with high lipid solubility that facilities crossing the blood brain barrier
in fact, gabapentin has little activity at the GABA receptor; rather, it inhibits voltage gated calcium channels
gabapentin binds to the alpha2delta subunit of the calcium channel; not a direct block, but disrupts the regulatory function of the alpha2delta subunit
blocking calcium influx reduces neurotransmitter release (particularly in glutamatergic neurons)
How do drugs used to treat seizures cause the diminution of excitatory neurotransmission?
other anti-seizure drugs act as antagonists at glutamate receptors (AMPA and NMDA)
for example, perampanel is a non-competitive antagonist at the AMPA receptor
may cause serious psychiatric and behavioral changes, including mood disorders and suicidal/homicidal ideation
What are the pharmacokinetic considerations regarding anti-seizure medication?
typically anti-seizure drugs are used for long period of time to prevent recurrence of seizures, so consideration of pharmacokinetic properties important for avoiding toxicity and drug interactions
despite the wide diversity of anti-seizure drugs, most exhibit very similar pharmacokinetic properties; drugs are generally well-absorbed, have good bioavailability, and cross the blood brain barrier
anti-seizure drugs are cleared mostly by the liver, but have low extraction ratios (can be long acting); potential for drug-drug interactions are common
most anti-seizure drugs have serious side effect risks associated with depression of central nervous system activity (depression, suicidal thoughts, death)
