Lecture 23 - Anti-Seizure Drugs

Question 1

a transient alteration of behaviour due to abnormally excessive and synchronous neuronal activity in the brain

Answer 1

seizures

Question 2

a disorder of brain function characterized by the periodic by the periodic and unpredicatable occurance of seizures

Answer 2

epilepsy

Question 3

true of false: everyone with seizures will be diagnosed with epilepsy

Answer 3

false

Question 4

epilepsy can be _____ or _____

Answer 4

symptomatic (occur due to known event such as head trauma), asymptomatic (generally due to poorly defined genetic factors)

Question 5

can seizures be provoked by things like chemical agents or electrical stimulation?

Answer 5

yes

Question 6

can seizures be unprovoked (occur spontaneously)?

Answer 6

yes

Question 7

the condition of epilepsy denotes the occurence of:

Answer 7

spontaneous, unprovoked seizures

Question 8

neurons fire by generating:

Answer 8

action potentials

Question 9

action potentials are driven by sequential opening of ___ and ___

Answer 9

voltage gated sodium channels, and voltage gated potassium channels

Question 10

what are the four phases of an action potential?

Answer 10

1) rest
2) depolarization
3) repolarization
4) hyperpolarization

Question 11

where do action potentials propogate?

Answer 11

down the axon to the terminal

Question 12

at the terminal, action potentials evoke:

Answer 12

voltage gated Ca++ channels to open

Question 13

an increase in intracellular calcium at the nerve terminal stimulates:

Answer 13

neurotransmitter release

Question 14

normally, neurons fire ____ in the brain

Answer 14

asynchronously (not all at once)

Question 15

the spread of electrical activity is maintained by:

Answer 15

the refractory period and surround inhibition

Question 16

the physiological mechanism that focuses neuronal activty in the central nervous system

Answer 16

surround inhibition

Question 17

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?

Answer 17

more action potentials

Question 18

action potentials in the second order neurons whose receptive fields are toward the periphery of the stimulus are more strongly:

Answer 18

inhibited (produce fewer APs) than those in the centre of the receptive field

Question 19

what are the three steps/phases of a seizure?

Answer 19

1) initiation
2) propogation
3) termination

Question 20

seizure initiation is characterized by two events:

Answer 20

1) high-frequency bursts of APs
2) hyper-synchronization of a neuronal population

Question 21

sustained neuronal depolarization in a seizure results in a burst of APs driven by:

Answer 21

Ca++ influx through NMDA receptors (loss of Mg++ block)

Question 22

propogation of bursting activity is normally prevented by:

Answer 22

intact hyperpolarization and surround inhibition

Question 23

what are the three major mechanisms where hyperpolarization and surround inhibition can be overcome?

Answer 23

• 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)

Question 24

how do seizures resolve?

Answer 24

spontaneously

Question 25

the mechanisms that terminate a seizure are not well known, but likely involve:

Answer 25

- loss of ionic gradients - depletion of ATP - depletion of neurotransmitters - activation of inhibitory circuits (GABA)

Question 26

a life threatening condition where seizures last longer than 5 minutes or have more than 1 seizure within a 5 minute period

Answer 26

status epilepticus

Question 27

lasts 5-30 minutes after a seizure and is characterized by drowsiness, confusion, depression/anxiety, and sometimes psychosis (low neuronal activity)

Answer 27

postictal period

Question 28

true or false: there are different seizures depending on where in the brain they initiate and how widely they propogate

Answer 28

true

Question 29

what are the three major seizure classes?

Answer 29

- focal seizures - generalized seizures - non-convulsant/absent seizures

Question 30

focal seizures can have diverse manifestations depending on:

Answer 30

where in the brain they originate

Question 31

focal seizures can be classified as either ____ or ____

Answer 31

simple (maitains consciousness), complex (loss of consciousness)

Question 32

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:

Answer 32

Jacksonian March

Question 33

unusual activities of focal seizures that are not consciously created, like smacking the lips

Answer 33

automatisms

Question 34

can focal seizures become generalized over time?

Answer 34

yes

Question 35

what are the major types of generalized seizures?

Answer 35

- tonic-clonic - myoclonic

Question 36

type of seizure that involves loss of consciousness and typically happen without warning

Answer 36

generalized seizures

Question 37

type of generalized seizures involved in sustained contractions of muscles throughout the body followed by periods of muscle relaxation

Answer 37

tonic-clonic seizures

Question 38

type of generalized seizures which involve a brief (~1s) shock like contraction of muscles that may be local or generalized

Answer 38

myoclonic seizures

Question 39

what are the two major types of non-convulsive seizures

Answer 39

absence or atonic

Question 40

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

Answer 40

absence seizures

Question 41

seizures that are caracterized by sudden loss of muscle strength; usually consciousness is maintained, though the person may fall down

Answer 41

atonic seizures

Question 42

anti-seizure drugs act by either enhancing _____ or diminishing _____

Answer 42

inhibitory (GABAergic) neurotransmission, diminishing excitatory (glutamatergic) neurotransmission

Question 43

what three major mechanisms do anti-seizure drugs use?

Answer 43

- blocking ion conductance - blocking neurotransmitter release - inhibiting/activating the postsynaptic membrane

Question 44

true or false: one drug may have multiple targets that reduce the likelihood of seizures

Answer 44

true

Question 45

benzodiazepines and barbituates are both _____ at the _____ receptors

Answer 45

positive allosteric modulaters, GABAa

Question 46

enhance the activity of GABA by binding to an allosteric site

Answer 46

benzodiazepines and barbituates

Question 47

which drug has an effect on the GABA receptor in the absence of GABA: barbituates or benzodiazepines?

Answer 47

barbituates (can act as GABA agonists at higher concentrations)

Question 48

what effect do benzodiazepines have on GABAa receptors?

Answer 48

increase the frequency at which the GABAa receptors open (increases the potency of GABA)

Question 49

what effect do barbituates have on GABAa receptors?

Answer 49

increase the duration at which the GABAa receptor is open (increases the efficacy of GABA)

Question 50

is it possible to overdose on barbituates or benzodiazepines?

Answer 50

yes (riskier for barbituates because of direct gating at the GABA receptor)

Question 51

what are the symptoms of an overdose from barbituates and/or benzodiazepines?

Answer 51

sluggishness, incoordination, faulty judgement, death

Question 52

the risk of overdose by barbituates/benzodiazepines increases when taken with:

Answer 52

other CNS depressants (like alcohol or opioids)

Question 53

a drug which inhibits the GABA transporter (GAT-1), which prolongs that action of the neurotransmitter

Answer 53

tiagabine

Question 54

a drug which inhibits GABA aminotransferase (GABA-T), an enzyme involved in degredation of GABA

Answer 54

vigabatrin

Question 55

how do certain anti-seizure drugs block voltage gated Na+ channels in neruonal membranes?

Answer 55

by causing a conformational change in the inactivation gate

Question 56

the action of drugs which block voltage gated Na+ channels is:

Answer 56

rate dependent and results in prolongation of the inactivated state/refractory period

Question 57

what is gabapentin made of?

Answer 57

a GABA molecule covalently bound to a lipophillic cyclohexane ring

Question 58

a drug developed as a centrally active GABA agonist with high lipid solubility that facilitates crossing the blood brain barrier

Answer 58

gabapentin

Question 59

what is the function of gabapentin?

Answer 59

it inhibits voltage gated Ca++ channels

Question 60

gabapentin binds to the:

Answer 60

alpha-2-delta subunit of the calcium channel

Question 61

what is the effect of blocking calcium influx?

Answer 61

reduces neurotransmitter release (particularly in glutamatergic neurons)

Question 62

a non-competitive antagonist at the AMPA receptor

Answer 62

perampanel

Question 63

what are the negative side effects of perampanel?

Answer 63

may cause serious psychiatric and behavioural changes, including mood disorders and suicidal/homicidal ideation

Question 64

list the major pharmacokinetic properties of anti-seizure drugs?

Answer 64

- well-absorbed - good bioavailability - cross the blood brain barrier

Question 65

why is it important to consider the pharmacokinetic properties of anti-seizure drugs?

Answer 65

important for avoiding toxicity and drug interactions

Question 66

anti-sezuire drugs are cleared mostly by the:

Answer 66

liver

Question 67

do anti-seizure drugs have a high or low extraction ratio?

Answer 67

low, so they can be long acting

Question 68

most anti-seizure drugs have serious side effect risks associated with:

Answer 68

depression of CNS activity (depression, suicidal thoughts, death)