Lecture 23 - Anti-Seizure Drugs Flashcards
a transient alteration of behaviour due to abnormally excessive and synchronous neuronal activity in the brain
seizures
a disorder of brain function characterized by the periodic by the periodic and unpredicatable occurance of seizures
epilepsy
true of false: everyone with seizures will be diagnosed with epilepsy
false
epilepsy can be _____ or _____
symptomatic (occur due to known event such as head trauma), asymptomatic (generally due to poorly defined genetic factors)
can seizures be provoked by things like chemical agents or electrical stimulation?
yes
can seizures be unprovoked (occur spontaneously)?
yes
the condition of epilepsy denotes the occurence of:
spontaneous, unprovoked seizures
neurons fire by generating:
action potentials
action potentials are driven by sequential opening of ___ and ___
voltage gated sodium channels, and voltage gated potassium channels
what are the four phases of an action potential?
1) rest
2) depolarization
3) repolarization
4) hyperpolarization
where do action potentials propogate?
down the axon to the terminal
at the terminal, action potentials evoke:
voltage gated Ca++ channels to open
an increase in intracellular calcium at the nerve terminal stimulates:
neurotransmitter release
normally, neurons fire ____ in the brain
asynchronously (not all at once)
the spread of electrical activity is maintained by:
the refractory period and surround inhibition
the physiological mechanism that focuses neuronal activty in the central nervous system
surround inhibition
will a primary afferent fibre whose receptive field is closest to the point of stimulation produce more or less action potentials than those on the periphery?
more action potentials
action potentials in the second order neurons whose receptive fields are toward the periphery of the stimulus are more strongly:
inhibited (produce fewer APs) than those in the centre of the receptive field
what are the three steps/phases of a seizure?
1) initiation
2) propogation
3) termination
seizure initiation is characterized by two events:
1) high-frequency bursts of APs
2) hyper-synchronization of a neuronal population
sustained neuronal depolarization in a seizure results in a burst of APs driven by:
Ca++ influx through NMDA receptors (loss of Mg++ block)
propogation of bursting activity is normally prevented by:
intact hyperpolarization and surround inhibition
what are the three major mechanisms where hyperpolarization and surround inhibition can be overcome?
- increasing extracellular K+ (blunts the hyperpolarizing outward K+ currents)
- accumulation of Ca++ in the presynaptic terminals leads to enhanced neurotransmitter release
- depolarization induced activation of the NMDA receptor (causes more Ca++ influx and neuronal activation)
how do seizures resolve?
spontaneously
the mechanisms that terminate a seizure are not well known, but likely involve:
- loss of ionic gradients
- depletion of ATP
- depletion of neurotransmitters
- activation of inhibitory circuits (GABA)
a life threatening condition where seizures last longer than 5 minutes or have more than 1 seizure within a 5 minute period
status epilepticus
lasts 5-30 minutes after a seizure and is characterized by drowsiness, confusion, depression/anxiety, and sometimes psychosis (low neuronal activity)
postictal period
true or false: there are different seizures depending on where in the brain they initiate and how widely they propogate
true
what are the three major seizure classes?
- focal seizures
- generalized seizures
- non-convulsant/absent seizures
focal seizures can have diverse manifestations depending on:
where in the brain they originate
focal seizures can be classified as either ____ or ____
simple (maitains consciousness), complex (loss of consciousness)
focal seizures in the motor cortex may be characterized by jerking activity which may start in one muscle group and spread to others known as:
Jacksonian March
unusual activities of focal seizures that are not consciously created, like smacking the lips
automatisms
can focal seizures become generalized over time?
yes
what are the major types of generalized seizures?
- tonic-clonic
- myoclonic
type of seizure that involves loss of consciousness and typically happen without warning
generalized seizures
type of generalized seizures involved in sustained contractions of muscles throughout the body followed by periods of muscle relaxation
tonic-clonic seizures
type of generalized seizures which involve a brief (~1s) shock like contraction of muscles that may be local or generalized
myoclonic seizures
what are the two major types of non-convulsive seizures
absence or atonic
seizures characterized by an abrupt onset of impaired consciousness (can be subtle); while there is loss of consciousness, the person doesn’t fall over and may return to normal right after the seizure ends, though there may be a period of posticatal disorientation
absence seizures
seizures that are caracterized by sudden loss of muscle strength; usually consciousness is maintained, though the person may fall down
atonic seizures
anti-seizure drugs act by either enhancing _____ or diminishing _____
inhibitory (GABAergic) neurotransmission, diminishing excitatory (glutamatergic) neurotransmission
what three major mechanisms do anti-seizure drugs use?
- blocking ion conductance
- blocking neurotransmitter release
- inhibiting/activating the postsynaptic membrane
true or false: one drug may have multiple targets that reduce the likelihood of seizures
true
benzodiazepines and barbituates are both _____ at the _____ receptors
positive allosteric modulaters, GABAa
enhance the activity of GABA by binding to an allosteric site
benzodiazepines and barbituates
which drug has an effect on the GABA receptor in the absence of GABA: barbituates or benzodiazepines?
barbituates (can act as GABA agonists at higher concentrations)
what effect do benzodiazepines have on GABAa receptors?
increase the frequency at which the GABAa receptors open (increases the potency of GABA)
what effect do barbituates have on GABAa receptors?
increase the duration at which the GABAa receptor is open (increases the efficacy of GABA)
is it possible to overdose on barbituates or benzodiazepines?
yes (riskier for barbituates because of direct gating at the GABA receptor)
what are the symptoms of an overdose from barbituates and/or benzodiazepines?
sluggishness, incoordination, faulty judgement, death
the risk of overdose by barbituates/benzodiazepines increases when taken with:
other CNS depressants (like alcohol or opioids)
a drug which inhibits the GABA transporter (GAT-1), which prolongs that action of the neurotransmitter
tiagabine
a drug which inhibits GABA aminotransferase (GABA-T), an enzyme involved in degredation of GABA
vigabatrin
how do certain anti-seizure drugs block voltage gated Na+ channels in neruonal membranes?
by causing a conformational change in the inactivation gate
the action of drugs which block voltage gated Na+ channels is:
rate dependent and results in prolongation of the inactivated state/refractory period
what is gabapentin made of?
a GABA molecule covalently bound to a lipophillic cyclohexane ring
a drug developed as a centrally active GABA agonist with high lipid solubility that facilitates crossing the blood brain barrier
gabapentin
what is the function of gabapentin?
it inhibits voltage gated Ca++ channels
gabapentin binds to the:
alpha-2-delta subunit of the calcium channel
what is the effect of blocking calcium influx?
reduces neurotransmitter release (particularly in glutamatergic neurons)
a non-competitive antagonist at the AMPA receptor
perampanel
what are the negative side effects of perampanel?
may cause serious psychiatric and behavioural changes, including mood disorders and suicidal/homicidal ideation
list the major pharmacokinetic properties of anti-seizure drugs?
- well-absorbed
- good bioavailability
- cross the blood brain barrier
why is it important to consider the pharmacokinetic properties of anti-seizure drugs?
important for avoiding toxicity and drug interactions
anti-sezuire drugs are cleared mostly by the:
liver
do anti-seizure drugs have a high or low extraction ratio?
low, so they can be long acting
most anti-seizure drugs have serious side effect risks associated with:
depression of CNS activity (depression, suicidal thoughts, death)
