23 - Anti-seizure Drugs Flashcards
What are seizures? What are they caused by?
Transient alteration of behaviour due to abnormally excessive and synchronous neuronal activity in the brain
What is epilepsy?
Disorder of brain function characterized by periodic and unpredictable occurrences of seizures
Epilepsy can be symptomatic or asymptomatic. What causes each?
Symptomatic: occur due to head trauma or cancer
Asymptomatic: due to poorly defined genetic factors
Can seizures be provoked?
Yes, seizures can be provoked, or unprovoked
Does everyone who has experienced seizures have epilepsy?
No, not everyone who has experienced seizures have epilepsy
At the terminal of an action potential, which channels open? What increases NT release?
An action potential evokes voltage gated calcium channels to open.
An increase in intracellular calcium stimulates NT release
Normally, neurons fire (blank) in the brain.
Asynchronously
Spread of electrical activity is maintained by (2)
Changes in membrane potential following depolarization (refractory period) and surround inhibition
Seizures can be divided into 3 steps: initiation, propagation, and termination What are the 2 events in seizure initiation?
What drives the burst of action potentials?
1) high frequency bursts of action potentials
2) hyper synchronization of a neuronal population
Driven by calcium influx through NMDA receptors
What is seizure propagation of bursting activity usually prevented by? How can sufficient activation overcome these barriers?
Prevented by hyperpolarization (makes neurons less likely to fire) and surround inhibition (when a group of neurons fire, nearby neurons are inhibited to localize the signal so it does not spread)
With sufficient activation, barriers can be overcome by:
1) increasing extracellular potassium
(normally, potassium leaves the neuron to hyperpolarize it. But if too much potassium is outside neuron, neurons stay depolarized, making it easier for neurons to fire)
2) accumulation of calcium encourages more NT release
3) depolarization activates NMDA receptors which causes more calcium influx and neuronal activation
once excitatory signaling becomes too widespread, inhibitory neurons can’t keep up, and electrical activity spreads across the brain
Seizures usually resolve of their own (termination). How does this occur?
What is it called when a seizure lasting longer than 5 minutes or have more than one seizure in a 5 minute period called?
1) loss of ionic gradients (without proper gradients, neurons can’t keep firing, and activity slows)
2) ATP depletion. Seizures are energy-intensive, and they can burn itself out
3) depletion of NT (especially glutamate, the main excitatory chemical)
4) activation of inhibitory circuits (GABA). As the seizure builds, GABA inhibition kicks in
Status epilepticus is a seizure that than > 5 minutes, and it life threatening
What is the name of the period that comes after the seizure?
Postictal period. Lasts 5-30 minutes, characterized by drowsiness, confusion, depressed mood, anxiety, sometimes psychosis
What the seizure classes? How are seizure classes separated by?
Focal seizures, generalized seizures, non-convulsive/absence seizures
Different seizure types depend on where in the brain they initiate and how widely they propagate
Describe focal seizures
May be simple or complex, and start in one specific area of the brain
Jacksonian March: Jerking activity may start in a specific muscle group and spread to surrounding muscle groups
Automatisms are unusual activities that are not consciouses created, like smacking the lips
Focal seizures may become generalized over time
Describe generalized seizures
several types such as tonic-clonic and myoclonic
All involve loss of consciousness and occur without warning
Tonic-clonic seizures involve sustained contractions (tonic) of muscles throughout the body followed by periods of muscle relaxation (clonic)
Myoclonic seizures involve a break shock like contraction of muscles that may be localized or generalized
Describe non-convulsive seizures
Include absence and atonic seizures
Absence seizures are characterized by an abrupt onset of impaired consciousness. There is loss of consciousness, but the person does not fall over and may return to normal right after the seizure ends
Atonic seizures are characterized by sudden loss of muscle strength. Usually consciousness is maintained, though the person may fall down
How do drugs used to treat seizures generally work?
Either enhance inhibitory (GABAergic) neurotransmission or diminish excitatory (glutamatergic) neurotransmission
This is done by:
1) blocking ionic conductance (sodium, calcium, potassium)
2) blocking NT release
3) inhibiting/activating the postsynaptic membrane
One drug may have multiple targes that reduce likelihood of seizures
What seizure treating drugs enhance inhibitory neurotransmission?
benzodiazepines and barbiturates are positive allosteric modulators at the GABAa receptors (enhance GABA activity by binding to an allosteric site)
benzodiazepines have no effect on the GABA receptor in the absence of GABA. They increase the frequency at which the GABA receptor opens (increasing the potency of GABA)
barbiturates can act as GABA agonists at higher concentrations. They increase the duration at which the GABA receptor is open (increasing efficacy of GABA)
What is the risk of taking benzodiazepines and barbituates?
Overdose. Riskier for barbiturates because of direct gating at GABA receptor. Additive risk when taken with other CNS depressants
What do tiagabine and vigabatrin do?
Anti-seizure drugs that enhance GABAergic inhibitory neurotransmission in the synapse of presynaptic cell
tiagabine inhibits the GABA transporter which prolongs action of NT
vigabatrin inhibits GABA aminotransaminase (enzyme involved in degradation of GABA)
Some anti-seizure drugs block voltage gated sodium channels in neuronal membranes. How do they do this?
Cause a conformational change of the inactivation gate. Action is rate dependent (block increases with increased frequency of neuronal discharge)
Describe 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 facilitates crossing the blood brain barrier
Gabapentin has little activity at the GABA receptor. It inhibits voltage gated calcium channels.
Binds to the alpha 2 delta subunit of the calcium channel. Blocking calcium influx reduces NT release
Other anti seizure drugs act as antagonists at glutamate receptors (AMPA and NMDA). What is perampanel?
Non competitive antagonist at the AMPA receptor. May cause serious psychiatric and behavioral changes, including mood disorders and suicidal ideation
What is extraction ratio? So anti-seizure drugs have low or high extraction ratios?
Extraction ratio: fraction of drug that is eliminated from circulation by the eliminating organ (eg liver)
Anti-seizure drugs are cleared mostly by the liver, but have low extraction ratios
