Lecture 47 - Pharmacology of Anticonvulsant Drugs Flashcards
Mechanism of action of anticonvulsant drugs:
stabilize and reduce neuronal excitability (reduce E/I balance)
1. Decrease sodium influx, prolong inactivation of Na+ channels (following the opening and subsequent closing of the channel)
2. Reduction of calcium influx (this is critical for absence seizures)
3. Enhance GABA-mediated neuronal inhibition
4. Antagonism of excitatory transmitters (i.e., glutamate)
5. Other targets (i.e., Levetiracetam)
Decrease sodium influx, prolong inactivation of Na+ channels examples
carbamazepine oxcarbazepine
phenytoin
lacosamide
lamotrigine
valproate
Reduction of calcium influx (this is critical for absence seizures)
ethosuximide
lamotrigine
valproate
Enhance GABA-mediated neuronal inhibition
barbiturates (activate the GABAA receptor)
benzodiazepines (activate the GABAA receptor)
valproate (increases GABA levels)
gabapentin (increases GABA release)
vigabatrin (inhibits GABA transaminase)
tiagabine (inhibits GAT-1)
Antagonism of excitatory transmitters (i.e., glutamate)
felbamate (antagonist of NMDA receptors)
topiramate (antagonist of kainate/AMPA receptors)
Why there are few drugs targeting K channels to treat seizures?
because HERG is also targeted –> heart problems
Molecular targets at the excitatory (glutamatergic) synapse
Presynaptic targets
§ Na+ channels
§ Ca2+ channels
Post-synaptic targets
§ NMDA receptors
§ AMPA receptors
Molecular targets at the inhibitory (GABAergic) synapse
Presynaptic targets
§ GABA transporter (GAT-1)
§ GABA transaminase (GABA-T)
Post-synaptic targets
§ GABAA receptors
§ GABAB receptors (?)
Drugs used to treat focal seizures and generalized tonic-clonic seizures
phenytoin, carbamazepine, oxcarbazapine, lacosamide, phenobarbital, primidone, diazepam, clonazepam, gabapentin, pregabalin, vigabatrin, tiagabine, felbamate, topiramate
A number of antiseizure drugs have a common
heterocyclic ring structure.
X group:
-N- hydantoin derivatives (phenytoin)
-C-N- barbiturates (phenobarbital)
-C- succinimides (ethosuximide)
Hydantoins
phenytoin (Dilantin)
– oldest non-sedative antiseizure drug (introduced in 1938)
– mechanism of action: binds and stabilizes the inactivated state of Na+ channels (not isoform selective thus can target sodium channels in the brain as well as other parts of the body)
– other drugs in this class with a similar mechanism of action:
* fosphenytoin (Cerebyx): injectable phosphate prodrug
* ethotoin (fewer side effects, but less effective than phenytoin)
* mephenytoin (more toxic than phenytoin)
Mechanism of sodium channel activation
Phenytoin and other anticonvulsants (e.g., carbamazepine, valproate) act by binding and stabilizing the inactivated state of Na+ channels.
Hydantoins: phenytoin (Dilantin): pharmacokinetics
- Phenytoin elimination kinetics are dose-dependent. This leads to non- linear pharmacokinetics.
- As blood levels of phenytoin increase, the liver enzymes responsible for metabolizing the drug become saturated.
- Small increases in the drug dose can lead to dramatic increases in the drug concentration in the blood.
- Therapeutic plasma level: 7.5-20 μg/mL (a higher level can be toxic).
Hydantoins: phenytoin (Dilantin): drug interactions
- Phenytoin can be displaced from plasma proteins by other drugs (e.g., Valproate), leading to an increase in its plasma concentration.
- Phenytoin induces liver cytochrome P450 enzymes, thereby increasing the rate of metabolism of other drugs (e.g., carbamazepine).
Hydantoins: phenytoin (Dilantin): toxicity
- arrhythmia
- visual: nystagmus (involuntary eye movements), diplopia (blurred vision)
- ataxia
- GI symptoms
- sedation (only at high doses)
- gingival hyperplasia, hirsutism (growth of facial hair)
- hypersensitivity reactions (skin rash)
Iminostilbenes
carbamazepine (Tegretol) and oxcarbazepine (Trileptal)
Carbamazepine
– structure: tricyclic compound (used to treat bipolar depression)
– 3D structure is very similar to that of phenytoin
– mechanism of action: binds and stabilizes the inactivated state of Na+ channels
– drug interactions: induces liver cytochrome P450 enzymes, thereby increasing the rate of metabolism of itself and other drugs (e.g., phenytoin, ethosuximide, valproate, clonazepam)
– toxicity: 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
Oxcarbazepine
– reduced toxicity compared to carbamazepine
Lacosamide (Vimpat)
– mechanism of action: enhances inactivation of voltage-gated Na+ channels
– toxicity: dermatological reactions, cardiac risks (PR interval prolongation), visual disturbances
Barbiturates and benzodiazepines bind
an allosteric regulatory site on the GABAA receptor.
Barbiturates
phenobarbital (Luminal) and primidone (Mysoline)
Phenobarbital
drug of choice in infants up to 2 months of age
– structure: 3D structure similar to that of phenytoin
– oldest anti-seizure drug other than the bromides
– mechanisms of action:
* binds to an allosteric regulatory site on the GABAA receptor, increases duration of Cl- channel-opening events (and thus enhances GABA inhibitory signaling).
– drug interactions: induces liver cytochrome P450 enzymes
– toxicity: sedation, physical dependence (potential of abuse)
Primidone
– mechanism of action: may be more similar to that of phenytoin than phenobarbital
Benzodiazepines
diazepam (Valium) and clonazepam (Klonopin)
Diazepam
especially useful for tonic-clonic status epilepticus; often administered as a rectal gel for acute control of seizure activity
– mechanisms of action:
* binds to an allosteric regulatory site on the GABAA receptor, increases frequency of Cl- channel-opening events (and thus enhances GABA inhibitory signaling).
– toxicity: sedation, physical dependence (tolerance); therefore, not useful for chronic treatment.
Clonazepam
useful for acute treatment of epilepsy and absence seizures
– similar properties as for diazepam
Gabapentin
used as an adjunct anti-seizure therapy (also used for neuropathic pain and migraine)
– structure: analog of GABA
– mechanisms of action:
* increases GABA release
* decreases presynaptic Ca2+ influx, thereby reducing glutamate release
– toxicity: sedation, ataxia, behavioral changes
Pregabalin
– similar properties as for gabapentin
Vigabatrin
used as an adjunct therapy for refractory patients
– structure: analog of GABA (γ-vinyl-GABA)
– mechanism of action:
* irreversible inhibitor of GABA transaminase (GABA-T), the enzyme responsible for degrading GABA
– toxicity: sedation, weight gain, agitation, psychosis, depression, visual field defects
Tiagabine
also used as an adjunct therapy
– mechanism of action: inhibits GABA transporter (GAT-1)
– toxicity: nervousness, depression, tremor, sedation, ataxia
Drugs targets at the inhibitory (GABAergic) synapse
Presynaptic targets
§ GABA transporter (GAT-1) (tiagabine)
§ GABA transaminase (GABA-T) (vigabatrin)
Post-synaptic targets
§ GABAA receptors (phenobarbital, benzodiazepines)
Molecular targets at the excitatory, glutamatergic synapse
NMDA and AMPA (and kainate) receptors
NMDA receptor
glutamate binding triggers an influx of Na+ and Ca2+ and an efflux of K+.
AMPA receptor
glutamate binding triggers an influx of Na+ and an efflux of K+. This is also true of a 3rd type of ionotropic glutamate receptor, the kainate receptor.
Felbamate
used as a 3rd line drug for refractory cases (especially for focal seizures)
– mechanism of action:
* NMDA receptor antagonist
– toxicity: severe hepatitis (which is why it’s a 3rd line drug)
Topiramate
used as a monotherapy or an adjunct therapy
– structure: substituted monosaccharide (unique structure compared
to that of other anticonvulsants)
– mechanism of action:
* AMPA and kainate receptor antagonist
– toxicity: nervousness, confusion, cognitive dysfunction, sedation, vision loss
Drugs used to treat absence seizures
ethosuximide
Succinimides
ethosuximide (Zarontin)
– introduced in 1960 as a ‘pure petit-mal’ drug
– mechanism of action: blocks T-type Ca2+ channels (low-threshold
current) in thalamic neurons
– T-type Ca2+ channels are thought to be involved in generating the rhythmic discharge of an absence attack. (Remember from Lecture 47 that generalization involves thalamocortical signaling).
– Toxicity: GI distress, sedation, psychiatric disturbances
T/F Gabapentin increases Cl- influx in postsynaptic neurons
True
Drugs used to treat focal seizures, generalized tonic-clonic seizures, and absence seizures
clonazepam, lamotrigine, valproate, levetiracetam,
Lamotrigine (Lamictal)
– uses: primary or adjunct therapy for focal and primary generalized seizures, including absence; also used for bipolar disorder
– structure: phenyltriazine
– mechanisms of action:
* inhibits Na+ and voltage-gated Ca2+ channels
* disrupts synaptic glutamate release
– toxicity: sedation, ataxia, serious skin rash (Stevens-Johnson Syndrome/toxic epidermal necrolysis)
Valproate (Depaken)
– uses: focal and generalized seizures, including absence; bipolar disorder, migraine headache
– structure: fatty acid (note: ionized at physiological pH)
– mechanisms of action:
* inhibits Na+ and Ca2+ channels
* increases GABA levels (by stimulating glutamic acid decarboxylase or inhibiting GAT-1 or GABA-T)
– drug interactions:
* displaces phenytoin from plasma proteins
* inhibits the metabolism of phenytoin, carbamazepine, phenobarbital, lamotrigine
– toxicity: GI distress, hyperammonemia, hepatotoxicity (can be fatal – careful monitoring necessary), sedation, weight gain; tremor (at high doses)
Levetiracetam (Keppra)
– uses: focal and generalized seizures, myoclonic seizures, status epilepticus
– mechanisms of action:
* 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.
Brivaracetam (briviact)
analog of levetiracetam that acts via a similar mechanism, but with a higher affinity for SV2A.
Drug targets at excitatory (glutamatergic) synapse
Presynaptic targets:
Na+ channels (phenytoin, carbamazepine, lacosamide, lamotrigine, valproate)
Ca2+ channels (ehtosuximide, lamotrigine, levetiracetam, valproate)
Post-synaptic targets:
NMDA receptors (felbamate)
AMPA receptors (topiramate)
