16 Antiseizure drugs Flashcards
Seizures are transient alterations in behaviour due to __________ and ____________
Seizures are transient alterations in behaviour due to abnormally excessive and synchronous neuronal activity in the brain
What does it mean that epilepsy can be symtomatic or asymptomatic?
Symptomatic: occur due to a known event (eg head trauma or cancer)
Asymptomatic: unknown, but believed to be due to genetic factors
Normally, neurons fire _______ in the brain.
Whereas seizures are:
Normally, neurons fire asynchronously in the brain
Seizures are: an extreme form of synchronous brain activity
What is surround inhibition?
The physiological mechanism that focuses neuronal activity in the CNS
What are the three ‘steps’ that a seizure can be divided into?
- initiation
- propogation
- termination
What two events characterize Seizure initiation?
- high frequency bursts of action potentials (recruit NMDA receptors)
- hyper synchronization of a neuronal population
*This sustained neuronal depolarization results in a burst of AP’s driven by Ca2+ influx through NMDA receptors
What normally prevents propagation of bursting activity
Hyperpolarization and surround inhibition
What are three ways that propagation/bursting activity can occur (ie how to overcome hyperpolarization and surround inhibition)?
- increasing extracellular K+
- blunts the hyperpolarizing outward potassium currents
- Accumulation of Ca2+ in presynaptic terminals leading to enhanced NT release
- Depolarization induced activation of NMDA receptor
- causes more Ca2+ influx and neuronal activation
Seizures generallly resolve _______ and the mechanisms that terminate a seizure are not well known but likely involve what 4 processes?
Seizures generallly resolve spontaneously and the mechanisms that terminate a seizure are not well known but likely involve what 4 processes?
- loss of ionic gradients (eg Na+ depleted = can’t maintain AP)
- depletion of ATP (low cell. resp.)
- depletion of NT’s (eg glutamate)
- Activation of inhibitory circuits (GABA)
Define status epilepticus
A seizure lasting longer than 5 minutes
or
if you have more than 1 seizure in a 5-minute period
Life-threatening
What is the postictal period and how long does it last?
The postictal period lasts 5-30 minutes after a seizure and is characterized by drowiness, confusion, depression/anxiety, and sometimes psychosis
What are two determining factors of seizure classification?
Different types of seizures depending on where in the brain they initiate and how widely they propagate
What are three classes of seizures?
- focal seizures
- simple
- complex
- generalized seizures
- several types including
- tonic clonic
- myoclonic
- several types including
- non-convulsive (absence) seizures
- absence
- atonic
What are focal seizures and what are the two types?
- Activation in a specific area of the brain (focussed)
- Diverse manifestations depending on where in the brain it originates (visual, psychic, auditory, autonomic, olfactory, or motor)
- Two types:
- simple (retain consciousness)
- complex (loss of consciousness)
What is jacksonian march?
Associated with focal seizures; jerking activity that starts in a specific muscle group and then spreads to surrounding muscle groups
What are automatisms?
Associated with Focal seizures; unusual activities that are not consciously created (eg smacking the lips)
What are generalized seizures? What are the two type mentioned in lecture?
- Seizure that migrates/propogates throughout entire brain
- All involve loss of consciousness and typically happen without warning
- Two types:
- tonic-clonic
- myoclonic
What type of seizure involves sustained muscle contraction throughout the body (15-20 seconds) followed by periods of alternating muscle cotnraction and relaxation?
Tonic-clonic
(used to be called grand mal)
What is a myoclonic seizure?
Brief (~1sec) shock-like contraction of muscles that may be localized or generalized
What are non-convulsive seizures and what are the two types mentioned in lecture?
No shaking or motor response at all
- Absence Seizures:
- abrupt onset of impaired consciousness
- can be subtle (look like “zoning out”)
- may return to normal right after seizure ends or have period of postictal disorientation (petit mal)
- Atonic Seizures:
- sudden loss of muscle strength
- usually consciousness is maintained, though the person may fall down
What are three situations that might warrant the use of antiseizure drugs?
- chronic use to prevent the occurrence of seizures in individuals with epilepsy
- used in people who do not have epilepsy to prevent seizures that may result as part of an acute illness (eg meningitis) or in early period following either neurosurgery or traumatic brain injury
- 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 ________. Would antiseizure drugs be effective tx?
Seizures are occasionally caused by an acute underlying toxic or metabolic disorder such as hypocalcemia. Would antiseizure drugs be effective tx?
- no, in cases like this it would be more appropriate to treat the specific abnormality
How do antiseizure drugs act?
Antiseizure drugs act by either enhancing inhibitory (GABAergic) neurotransmission or diminishing excitatory (glutamatergic) neurotransmission
What are three ways in which antiseizure drugs either enhance GABAergic neurotransmission (inhibitory) or diminish glutamatergic (excitatory) neurotransmission?
- blocking ionic conductance (particularly sodium, calcium, and potassium)
- Blocking NT release
- Inhibiting/activating the postsynaptic membrane
One drug may have multiple targets that reduce liklihood of seizures
_________ and ________ are positive allosteric modulators at the GABAa receptors - they enhance the activity of GABA by binding to an allosteric site
Benzodiazepines and barbiturates are positive allosteric modulators at the GABAa receptors - they enhance the activity of GABA by binding to an allosteric site
What do Benzodiazepines and barbiturates target?
Benzodiazepines and barbiturates are positive allosteric modulators at the GABAa receptors - they enhance the activity of GABA by binding to an allosteric site
- enhance inhibitory neurotransmission
What are two major differences between benzodiazepine and barbiturates?
- Action with/without GABA
- Benzodiazepines have no effect on the GABA receptor in the absence of GABA
- Barbiturates can act as GABA agonists at higher concentrations
- Mechanism:
- Benzodiazepines increase the frequency at which the GABAa receptor opens thus increasing the potency of GABA
- Barbiturates increase the duration at which the GABAa receptor is open (increases efficacy of GABA)
Between Benzodiazepines and Barbiturates, which drug has a higher risk for overdose?
While overdose is possible for both drugs, it is riskier for barbiturates because of direct gating at the GABA receptor = push inhibition beyond physiological threshold
What are four symptoms of overdose on benzodiazepines or barbiturates?
What increases overdose risk?
- sluggishness
- incoordination
- faulty judgement
- death
*Depressed CNS activity because increase GABA = Increase inhibition*
Additive risk when taken with other CNS depressants (like alcohol or opioids)
What are two antiseizure drugs that work by enhancing GABAergic inhibitory neurotransmission in the synapse or presynaptic cell
- Vigabatrin
- Tiagabine
What are two antiseizure drugs that act post-synaptically to enhance the activity of GABA
- Benzodiazepines
- Barbiturates
What drug inhibits GABA aminotransaminase (GABA-T)
* GABA-T is an enzyme involved in the degradation of GABA = inhibition of GABA breakdown therefore increases the effects of GABA
- Vigabatrin
What drug inhibits the GABA transporter (GAT-1)?
Tiagabine
- GAT-1 located in neurons and glia clears GABA
- Inhibition of GAT-1 prolongs the action of the NT (GABA)
What does vigabatrin do?
Vigabatrin acts presynaptically to inhibit GABA aminotransaminase (GABA-T) an enzyme involved in degradation of GABA to enhance GABAergic inhibitory neurotransmission
What does tiagabine do?
Inhibits the GABA transporter (GAT-1) located in neurons and glia which prolongs the action of GABA
Some anti-seizure drugs block _________ in neuronal membranes (eg carbamazepine)
Some anti-seizure drugs block voltage-gated sodium channels in neuronal membranes (eg carbamazepine)
- Lipophilic (in order to enter the cell)
- bind intracellularly causing a conformation change
How does carbamazepine work?
- Blocks voltage gated sodium channels in neuronal membranes by causing a conformational change of the inactivation gate (image on slide 22)
- Action is rate-dependent (targets active neurons)
- Results in prolongation of the inactivated state of the sodium channel and the refractory period of the neuron
The action of drugs that block voltage gated sodium channels (eg _______) is rate dependent. What does this imply?
The action (ie the blocking) increases with increased frequency of neuronal discharge.
Ie the more active a neuron is, the more drawn to it the drug will be. This results in prolongation of the inactivated state of the Sodium channel and the refractory period of the neuron
What is Gabapentin?
Drug consisting of GABA molecule covalently bound to a lipophilic cyclohezan ring
- Centrally active GABA agonist with high lipid solubility that facilitates crossing the BBB
- Inhibits Voltage-gated calcium channels by binding to the alpha 2 delta (δ) subunit of the Ca2+ channel and disrupting the regulatory function of that subunit
- blocks influx of Ca2+ which reduces NT release particularly at glutamatergic neurons
How does gabapentin inhibit voltage-gated Ca2+ channels?
Gabapentin binds to the alpha2delta subunit of the calcium channel and disrupts its regulatory function thereby blocking the influx of Ca2+ and reducing NT release (particularly in glutamatergic (excitatory) neurons)
Drugs such as _________ act as antagonists at glutamate receptors (AMPA and NMDA)
Drugs such as perampanel act as antagonists at glutamate receptors (AMPA and NMDA)
What is perampanel?
Drug that acts as a non-competitive antagonist at the AMPA receptor
What are some averse effects of perampanel?
Perampanel may cause serious psychiatric and behavioural changes including mood disorders and suicidal/homicidal ideation because it’s not selective to active receptors (ie not rate dependent) and blocks ALL AMPA receptors
Despite the wide variety of anti-seizure drugs, most exhibit very similar pharmacokinetic properties:
- ________
- ________
- ________
- Cleared mostly by the ______
- Extraction ratio?
Despite the wide variety of anti-seizure drugs, most exhibit very similar pharmacokinetic properties:
- generally well-absorbed
- good bioavailability
- cross the BBB
- Cleared mostly by the Liver
- Extraction ratio? low = can be long acting
- potential for drug-drug interactions are common
- Extraction ratio? low = can be long acting
What are the serious side effects of most anti-seizure drugs?
Most anti-seizure drugs have serious side effect risks associated with depression of CNS activity (depression, suicidal thoughts, death)
