Exam 3 lecture 6 Flashcards
Define myoclonic, tonic, clonic, atonic, tonic-clonic seizures
Myoclonic- shock-like contraction of muscles, isolated jerking of head, trunk and body
tonic- these seizures occur in children. involve rigidity as a result of increased tone in exterior muscle.
clonic- these seizures occur in babies and young children. Involve rapid, repetitive motor activity
Atonic- Sudden loss of muscle tone. Pt fall (drop attacks)
tonic-clonic- life threatening
Define seizure, epilepsy, convulsion (!!!)
Seizure- abnormal neuronal discharge with or without loss of consciousness
Epilepsy- repeated seizure due to damage, irritation, and/or chemical imbalance in the brain which leads to a sudden excessive, synchronous electrical discharge
Convulsion- specific seizure type where the attack is manifested by involuntary muscle contractions.
What are seizures a result of (!!!)
Seizures are a result of disordered, synchronous, and rhythmic firing of populations of brain neurons (synchronized hyperexcitability)
Prolonged seizure can lead to _______. Why?
Ischemia.
During a seizure, the brain uses more energy than it can manufacture, so prolonged seizure can result in cell eschemia.
Classify seizures (!)
focal onset
generalized onset
unknown onset
Define the types of seizures (!!!)
Focal onset- known spot where neurons fire to cause seizures. Classified into either aware or impaired awareness. Has motor onset and non motor onset. May progress to focal to bilateral tonic-clonic
Generalized onset- Classified to either motor (tonic clonic) or non motor (abscence seizures)
unknown onset- Classified into motor or non motor
compare focal and generalized seizures
focal- starts in temporal lobe. May progress to bilateral tonic clonic.
generalized- most are assumed to be genetic
difference in propagation between focal seizure and primary generalized seizures
focal- frequently progress to secondary generalized seizures via projections to the thalamus (focal to bilateral)
Primary generalized seizures- propagate via diffuse interconnections between thalamus and cortex. (no discrete focus) (involves both hemispheres of the brain)
focal seizures can be either ______ or _______
Focal seizures can be aware or impaired awareness
describe aware and impaired awareness focal seizures
Aware- 25% of focal seizures
no loss of consciousness
impaired awareness- most common focal seizure.
Clouding of consciousness, staring
Aura
postictal state due to impaired awareness
What is Postictal state? symptoms.
postictal state- After a seizure, a patient will not recover a normal level of consciousness immediately. May last seconds to hours depending on (area of brain affected, length of seizure, use of antiepileptic drugs, age)
symptoms- confusion, disorientation, anterogate amnesia
Describe generalized seizures (absence types)
Can be typical or atypical
typical- No convulsions, aura, or postictal period
atypical- slower onset than typical
Describe the generalized seizures
Generalized tonic-clonic-
1st phase- tonic phase- no aura
2nd phase- clonic phase
Focal-to-bilateral tonic-clonic seizures start out as a focal seizure
(this type of seizure was previously referred to as a ‘secondarily
generalized attack’). In this case there can be a brief aura.
Understand the characteristic properties of status epilepticus and the therapeutic goals in treating this state.
repetitive seizure activity in which the patient does not regain consciousness between seizures or a continous single seizure episode lasting >30 mins. could be life threatening.
Therapeutic goal is to bring seizures under control wiyhin 60 mins.
What is PDS? understand the electrophysiological basis of
depolarization and hyperpolarization.
The PDS consists of a large depolarization that triggers a burst of action potential
Depolarization- Involves activation of AMPA and NMDA channels by excitatory neurotransmitter glutamate and voltage gated calcium channels leading to an influx of cations.
depolarization if followed by hyperpolarization
Involving the activation of GABA receptors (influx of Cl- ions) and voltage and calcium dependent K channels leading to an efflux of K+
Neuronal signaling (depolarization) is normally dampened by
feed forward and feedback inhibition.
Does one seizure make an epilepsy? When can we dx therapy for epilepsy
No!
Drug therapy can be gradually withdrawn in
patients who have been clinically-free of
seizures for 2-5 years.
Which of the following types of convulsions can be preceded by
an aura phase?
(A) typical absence (petit-mal)
(B) primary generalized tonic-clonic (grand-mal)
(C) focal to bilateral (secondary generalized) tonic-clonic
(D) all of the above
Focal to bilateral (secondary generalized) tonic clonic
Define inhibitory surround
Electrical discharge spreads through the seizure focus but is contained as a result of inhibition in a neighboring zone called inhibitory surround.
What does the the evolution of focal seizure to generalized (bilateral) involve
Involves a loss of hyperpolarization and surround inhibition.
understand the electrophysiological basis for tonic phase and clonic phase
In tonic phase- GABA mediated inhibition disappears where as glutamate mediated AMPA and NMDA receptor activity increases
In clonic- GABA mediated inhibition disappears gradually returns leading to a period of oscilliation.
What happens as GABA mediated inhibition breaksdown during tonic phase
Action potentially propagate to a distant neurons, leading to spread of seizure activity from focus to distant sites in the brain.
Describe underlying conditions or environmental perturbations that can trigger epileptic seizures
Pre natal injury
CVD
Brain tumors
Head trauma
infection
hemorrhage
drugs
metabolic disturbances (hyperventilation, blood gas, PH, hypoglycemia)
sleep deprivation
stress
withdrawal from AEDs
Identify drugs that aggrevate or increase seizure risk
-alcohol
-theophyline
-CNS stimulants
-bupropion
-oral contraceptive
-withdrawals from depressants
-clonzapine
What happens during hyperpolarization phase of a PDS
Influx of Cl- ions resulting from GABA a receptor activation
MOA of anticonvulsant drugs
- reduce Na influx, prolong activation of Na channels
- reduce Ca influx (critical for absence seizures)
- enhance GABA mediated neuronal inhibition
- antagonism of excitatory transmitters (glutamine)
- Other targets (levetiracetam)
What is a bad thing about carbamezapine and oxcarbezapine
They are dirty drugs, not selective at all. Affect NaV in heart
Molecular targets of excitatory synapse
presynaptic- Na channels
Ca channels
post synaptic- NMDA recpeorts
AMPA receptor
molecular targets at inhibitory synapse
presynaptic- GABA transporter (GAT-1)
GABA transaminase (GABA-T)
postsynaptic- GABA a receptor
GABA b receptor
MOA of hydantoins: phenytoin (dilantin) (!!)
MOA- binds and stabilizes inactive state if Na+ channels (not isoform selective so can target Na channels in brain aswell as other parts of the body)
fosphenytoin has similar MOA but is a prodrug
phenytoin, carbamezapine and valproate MOA
binds and stabilizes the inactivated state of Na channels
phenytoin elimination kinetics
Dose dependents. Leads to non linear PK
drug interactions of phenytoins
Can be displaced from plasma protein by other drugs (valproate) leading to increase in plasma concentrations
Phenytoin induces cytochrome P450 enzymes thereby increases rate of metabolism of the other drugs
side effects/toxicity of Phenytoin
arrhythmia
visual
ataxia
GI sx
Gingival hyperplasia hirsutism
hypersensitivity rn (skin rash)
What are the iminostilbenes used to treat? what are the drugs? MOA? (!!)
anticonvulsants.
Carbamezapine (tegretol)
Oxcarbamezapine (trileptal)
MOA of carbmezapine - binds and stabilizes inactive stateof Na channels
MOA of oxcarbamezapine- enhances inactivation of voltage gated Na channels
toxicity and drug/ia of carbamezapine and oxcarbezapine
drug i/a of carbamezapine- induces liver cytochrome P450 enzymes,
toxicity of carbamezapines- blurred vision, ataxia, GI disturbances; sedation at
high doses, serious skin rash (Stevens-Johnson
Syndrome/toxic epidermal necrolysis); Drug reaction with
eosinophilia and systemic symptoms (DRESS)
hypersensitivity reaction
drug i/a of oxcarbezapine- enhances inactivation of voltage-gated
Na+ channels
toxicity- dermatological reactions, cardiac risks (PR interval
prolongation), visual disturbances
Pharmacology of anticonvulsant drugs
Lacosamide (Vimpat)
oxcarbezapine has reduced toxicity compared to carbamezapine
molecular targets at the excitatory (glutaminergic) synapse (ALL with drug name) (!!!!!)
presynaptic
Na channels- (phenytoin, carbamezapine, lacosamide, lamotrigine, valproate)
Ca channels- (Ethosuximide, lamotrigine, levetriacetam, valproate)
Postsynaptic- NMDA receptors (felbamate)
AMPA receptors (topiramate)
molecular targets at inhibitors at GABAergic synapse
presynaptic targets
GABA transporter (GAT)- tiagabine
GABA transaminase (GABA T)- vigabatrine
post synaptic targets- GABA a receptors- phenobarbital, benzodiazepines
lacosamide use, MOA and toxicity
Anticonvulsant
MOA- enhances inactivation of voltage gated Na channels
toxicity- dermatological reasons, cardiac risks (PR interval prolongation), visual dsturbances.
Be able to identify the chemical structures of phenytoin,
phenobarbital, ethosuximide, and valproate (!!!!!)
What are the barbiturate drugs? MOA? Drug I/A? (!!!)
Phenobarbital (luminal) and primidone (mysoline)
phenobarbital- drug of choice in infants up to 2 months of age
MOA- binds to allosteric site on GABA receptor, increases duration of Cl channel- opening events ( and thus enhances GABA inhibitory signalling)
Primidone- more similar MOA to phenytoin than phenobarbital
drug i/a- induces P450 enzymes, sedation, physical dependence (potential abuse)
What are the benzodiazepine drugs? MOA? toxicity? (!!!)
Diazepam (valium) and clonazepam (klonopine)
diazepam- especially useful in tonic-clonic epilepsy.
MOA- binds to allosteric regulatory site on GABA recpetor, invcreases frequency of Cl channel opening events (and thus enhances GABA inhibiting signalling)
toxicity- sedation, physical dependence (tolerance), not useful for chronic tx
clonazepam- useful for acute tx of epilepsy and absence seizures
Name anticonvulsant drug categories (!!!)
Hydantoins (phenytoin)
Iministilbenes (mezapines)
lacosamide
barbiturates
benzodiazepines
Gabapentin/pregabalin
vigabatrine/tiagabine
felbamate/topiramate
succinamides
Gabapentin and pregabalin use, MOA, toxicity
Gabapentin used as adjunct anti-seizure therapy (also used for neuropathic pain and migraine)
MOA- increase GABA release
reduce presynaptic Ca2+ influx, thereby reducing glutamate release
toxicity- sedation, ataxia, behavioral changes
pregabalin-similar
Vigabatrin and tiagabine MOA and toxicity (!!)
vigabatrin MOA- irreversible inhibitor of GABA transaminase (GABA-T), the enzyme responsible for regrading GABA
toxicity- sedation, depression, visual field defects
Tiagabine MOA- inhibits GAT-1
toxicity- sedation, ataxia
Felbamate (felbatol) and topiramate (topamax) MOA and toxicity (!!)
felbamate MOA- NMDA receptor agonist
toxicity- severe hepatitis (which is why it is 3rd line)
topiramate (topamax) MOA- AMPA and kainate receptor antagonist
toxicity- nervousness, confusion, cognitive dysfunction, sedation, vision loss
succinimides drug, MOA, toxicity- (!!)
MOA- blocks T type Ca2+ channels in thalamic neuron
toxicity- GI distress, sedation
What are T type Ca channels
T type calcium channels are thought to be involved in generating the rhythmic discharge of an absence attack
Gabapentin effect on postsynaptic neurons
increases Cl influx
What kind of drug is topiramate
AMPA receptor antagonist
tiagabine targets
GABA transporter
Lamotrigine MOA and toxicity
MOA- inhibits Na and Ca channels
toxicity- sedation, ataxia, serious skin rash (steven johnson syndrome/ toxic epidermal necrolysis)
Valproate MOA, toxicity and drug i/a
MOA- inhibits Na and Ca channels
increases GABA levels
toxicity- GI distress, hyperammonemia, hepatotoxicity, (careful monitoring necessary)
drug i/a- displaces phenytoin from plasma protein and inhibits metabolism of phenytoin, cerbamezapine, phenobarbital, lamotrigine)
levetiracetam MOA (!!!)
binds the synaptic vesicular protein SV2A, and thus interferes
with synaptic vesicle release and neurotransmission.
* also appears to interfere with calcium entry through Ca2+
channels and with intraneuronal calcium signaling.
* because of its unique mechanism of action, it is a candidate for
treatment of status epilepticus cases that are refractory to other
therapies
Drugs used to treat all 3 seizures (absence, myoclonic, partial and generalized tonic-clonic)
lamotrigine
levetiracetam
valoroate
zonisamide
Drugs used to treat absence seizures
ethosuximide, methosuximide, trimethadione
drugs used to treat myoclonic seizures
topiramate
drugs that treat both absence and myoclonic
clonazepam
drug that treats both absence and partial and generalized tonic clonic
gabapentin
drug that treats both myoclonic and partial and generalizd tonic clonic
felbamate
