Lecture 19: Drugs Used To Treat Seizure Disorders

Question 1

What is the definition of a seizure?

Answer 1

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

Question 2

What is the definition of epilepsy?

Answer 2

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

Question 3

What is the mechanism of seizures?

Answer 3

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

Question 4

What is surround inhibition?

Answer 4

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

Question 5

What are the three steps of seizures?

Answer 5

initiation, propagation, and termination

Question 6

What are the two events that characterize seizure initiation?

Answer 6

1. high frequency bursts of action potentials
2. hyper synchronization of a neuronal population

this sustained neuronal depolarization results in a burst of action potentials driven by calcium influx through NMDA receptors

Question 7

How do seizures the overcome barriers of intact hyperpolarization and surround inhibition?

Answer 7

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

Question 8

What is the mechanism of seizure resolution?

Answer 8

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)

Question 9

What is status epilepticus?

Answer 9

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

Question 10

What is the postictal period after a seziure?

Answer 10

lasts 5-30 minutes after a seizure and is characterized by drowsiness, confusion, depression/anxiety, and sometimes psychosis (including hallucinations and delusions)

Question 11

What are the classes of seizures?

Answer 11

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

Question 12

What are focal seziures?

Answer 12

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

Question 13

What are generalized seizures?

Answer 13

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

Question 14

What are non-convulsive seizures?

Answer 14

include absence and atonic seizures

Question 15

What are absence seizures?

Answer 15

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

Question 16

What are atonic seizures?

Answer 16

atonic seizures are characterized by sudden loss of muscle strength

usually consciousness is maintained, though the person may fall down

Question 17

What are the characteristics of drugs used to treat seizures?

Answer 17

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

Question 18

What are the mechanisms through which anti-seizure drugs act?

Answer 18

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

Question 19

How do drugs used to treat seizures enhance inhibitory neurotransmission?

Answer 19

several different anti-seizure drugs enhance GABAergic inhibitory transmission by targeting various elements on the pre- or post-synaptic inhibitory neuron

Question 20

What are benzodiazepine and barbiturates?

Answer 20

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)

Question 21

What are the symptoms of overdose on benzodiazepines and barbiturates?

Answer 21

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)

Question 22

What is vigabatrin?

Answer 22

inhibits GABA aminotransaminase (GABA-T), an enzyme involved in degradation of GABA

Question 23

What is tiagabine?

Answer 23

inhibits the GABA transporter (GAT-1 located in neurons and glia), which prolongs the action of the neurotransmitter

Question 24

How do some anti-seizure drugs block voltage gated sodium channels?

Answer 24

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

Question 25

What is gabapentin?

Answer 25

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)

Question 26

How do drugs used to treat seizures cause the diminution of excitatory neurotransmission?

Answer 26

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

Question 27

What are the pharmacokinetic considerations regarding anti-seizure medication?

Answer 27

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)