Exam 3 - Lecture 23 and 25, Anticonvulsants Flashcards
Epilepsy
Greek “to be seized”
A group of syndromes characterized by recurrent, unprovoked seizures
Seizure
Latin “to take possession of”. An abnormal, excessive hyper synchronous discharge of a population of (cortical) neurons
Focal = partial
Convulsion
Sudden, irregular, involuntary muscle contraction
Epileptogenesis
The process by which a “normal” brain becomes epileptic
Refractory epilepsy
Epilepsy remains uncontrolled following prescription of 2 different drugs. Also called intractable or pharmacoresistant
Symptomatic epilepsy
Results from a known/ suspected CNS disorder
Idiopathic epilepsy
No known cause, possibly genetic
Cryptogenic epilepsy
The disease etiology is unknown
Generalized tonic-clonic seizure
(classic seizure phenotype)
~20-30% of patients
Tonic Phase -> Clonic Phase -> Post-ictal confusional Fatigue
Ictal State
The seizure
Postictal State
State of altered consciousness after a seizure. Lasts 5 - 30 min, characterized by drowsiness, confusion, nausea, hypertension, headache or migraine and other disorienting symptoms
Simple Partial seizures
~ 10 to 15% of patients
Auditory - Hiss or ringing in ears
Visual - See flashes of light, blurring etc
Somatosensory - Tingling of face, side of body
Focal Motor - Tonic-clonic movements of upper/lower limb
Autonomic - Sweating, flushing
Grimacing
Head and eyes turned opposite sides
Complex Partial Seizures
~20 - 50% of patients “Grand Mal”
Dysphasia
Olfactory Hallucinations
Formed visual hallucinations - seeing a tree that’s not there
Formed auditory hallucinations - hearing music etc
Dreamy state, blank face
Psychomotor phenomena - chewing movement, wetting lips
Impairment of consciousness - cognitive, affective symptoms
Sudden unexpected death in epilepsy
SUDEP
Defined as the sudden and unexpected, non-traumatic and non-growing death of a person with epilepsy, without a toxicological or anatomical cause of death detected during the post-mortem examination
SUDEP Risk Factors
Males, mostly younger because don’t survive to older age
Severe refractory seizures Poor compliance Young age and early age of seizures onset Biologically male Being asleep during seizure
SUDEP mechanism
Seizure in brain causes a chain reaction, causing issues with heart rate and breathing.
Causes apnea (stop breathing), Arrhythmia and Asystole (No contraction) of heart
How is epilepsy treated
Anti-convulsant/seizure/epileptic drugs
Surgery - specific focal lesions vs corpus callostomy
Ketogenic diet - no carbs, burn fat release ketones
Implanted device - Vagus nerve or deep brain stimulator
Properties of an ideal anti epileptic drug
Highly effective, low incidence of toxicity
Effective against more than one seizure type
Long lasting, long half life
Non-sedating
Inexpensive
No tolerance, particularly to anticonvulsant effect
Categories of AED
SV40 binders Ion channel ligands Barbiturate Benzodiazepines Novel AEDs
Carbamazepine (Tegretol)
MoA: Sodium Channel Blocker, state dependent
Low efficacy inhibitor of 5HT reuptake
FDA approved for: Partial seizures, Generalized tonic-clonic seizures, Mixed seizures, Trigeminal neuralgia, Mania in bipolar disorder
Side effects: DRESS syndrome (Drug reaction with eosinophilia and systemic systems) or DIHS (drug-induced hypersensitivity syndrome). Suicidal tendency, hyponatremia, Spina bifida
Lamotrigine (Lamictal)
MoA: Sodium channel blocker, state dependent binds when channel is moving between closed-open-inactive
Indications: Focal seizures, Tonic-clonic seizures, Lennox Gastaut syndrome, Recurrent depressive episodes in bipolar disorder
Side effects: in >10% of patients, Nav1.7 channels activate nerves, leading to a rash. Arrhythmias rare but possible in case of OD. Long list of side effects
Valproic Acid (Depakene)
MoA:
Enhances Na channel inactivation (state dependent, likes to hold in inactive state), Low efficacy block of Cav3 channels, No effect on GABAA receptor function
Side effects:
Frequent GI (16%), anorexia, nausea, vomiting
CNS: sedation, ataxia, tremor (not common)
Toxicity:
Rare, fulminant hepatits (liver death) often fatal
Combo with clonazepam has caused absence status epileptics (rare)
Effective in many seizure models and clinical seizure types
Lacosamide (Vimpat)
MoA:
Enhances Na inactivation, state dependent…likes to hold in inactive state.
Binds to collapse-in response mediator protein 2 (crmp-2)
Approved for: adjunct partial onset seizures in 17yr + Patients with diabetic neuropathic pain oral or injectable dosage forms effective as add on in refractory partial seizures
Side effects: headache, drowsiness, blurred vision and tremor
Levetiracetam (Keppra)
Novel MoA:
Binds Vesicle protein SV2A, stereoselective
Pyrrolidine s-enantiomer of a protest nootropic agent
FDA approved for:
Partial-onset seizure, Myclonic seizure, Tonic-clonic seizure
Side effects:
Psychosis, Suicidal ideation, somnolence (drowsiness), Asthenia (lack of strength), Dizziness….low incidence of side effects
Dose not interact metabolically with other AEDs
3D printing drugs
Keppra first FDA approved
cool because you could potentially make a tablet of any dose using this method
Target: Voltage-gated sodium channels
Carbamazepine, lamotrigine, lacosamide
Target: Voltage-gated calcium channels (T-type)
Ethosuximide
Target: Voltage-gated potassium channels
Retigabine (ezogabine)
Target: SV2A
Levetiracetam
Brivaracetam
Target: a2d
Gabapentin, gabapentin enacarbil, pregabalin
Target: AMPA receptor
Perampanel
Sodium Channel structure
24 transmembrane domains
Channels made up of Alpa and Beta subunits
Voltage sensing domain is responsible for opening and closing channel
Hodgkin-Huxley Model
Closed - Open - Activated
Closed when some domains of subunits are “down” and open when domains move “up”
Most common Sodium channels in CNS
Nav 1.2 also 1.1, and 1.6
1.3 is only in development, not much in adults
Pathophysiology of Nav channels
You want drug to target specific sodium channel, since there are sodium channels all over the body
Ex… targets 1.2 and also 1.7 (expressed in bunch of other spots) or 1.5 (which is in heart)
Brivaracetam (Briviact)
MoA:
Binds to vesicle protein SV2A; stereoselective, reducing neurotransmitter release
FDA approved for:
Partial seizures
Alternative to levetiracetam if adverse effects observed
Adverse effects: Somnolence (drowsiness) Asthenia (lack of strength) Dizziness Nausea Coadmin with carbamazepine or phenytoin increase their efficacy, potentially reducing tolerance
Gabapentin (Neurontin)
MoA:
Binds to a2d subunit of voltage-gated Ca2+ channels to inhibit channel function
Subunits of pre-synaptic P/Q type Ca2+ channels
Reduces presynaptic neurotransmitter release
DOES NOT INTERACT WITH GABA-PHYSIOLOGY
FDA approved for: Partial seizures Neuropathic pain Trigeminal neuralgia RLS
Adverse effects: Dizziness Fatigue Ataxia Suicidal Tendency Addiction
Perampanel (Fycompa)
MoA:
Non-competitive antagonist at post-synaptic AMPA receptors
AMPA-receptors are glutamatergic ion channels
FDA approved for:
Partial seizures
Tonic-clonic seizures
Patients over 12 years old
Adverse effects:
Fetal Damage
Black box warning - homicidal ideation (have to monitor in hospital first before being sent home)
OD can cause euphoria
Negative allosteric Modulators
Bind to allosteric site and LOWER THE POTENCY AND/OR EFFICACY of the agonist that binds at the orthosteric site
NAM
Positive allosteric Modulators
Bind to the allosteric site and INCREASE THE POTENCY AND/OR EFFICACY of the agonist that binds at the orthosteric site
PAM
Silent allosteric Modulators
Also called neutral allosteric ligands, bind to the allosteric site of a receptor and have NO effect on efficacy/potency of the orthostric ligand.
They prevent NAMS and PAMS from interacting with receptor
Retigabine (Ezogabine, Potiga, Trobalt)
MoA:
Activates M-current (mediated by Kv7 [KCNQ] voltage-gated potassium channels)
Activation of channels increases K flux and stabilizes the resting potential of the neurons below the firing threshold. RTG activates the channels and inhibits the seizures.
FDA approved:
Partial seizures
Off-label use:
Migraine
Trigeminal neuralgia
Neuropathic pain
Adverse effects: Dizziness and vertigo Fatigue Blue skin discoloration Slurred speech
Barbiturates
Effective agents partial and generalized seizures, easy to OD
Ex. Phenobarbital, primidone, mephobarbital
Benzodiazepines
Effective against limited forms of partial or generalized seizures and status epilepticus.
Ex. Clonazepam, lorazepam, diazepam, midazolam, clorazepate, clobazam
Most widely prescribed and used
Chlordiazepoxide (Librium)
First Benzo
Sedative, hypnotic, anxiolytic, anti-convulsant effects
Subject to abuse and has many side effects
Clonazepam
Fewest side effects, best tolerated
MoA benzos:
Allosteric modulators GABA Rs
Low efficacy block of Cav3 channels
Suppresses seizure focus and enhances surround inhibition
Side effect:
related to CNS depression
Effective for:
Absence and myoclonic seizures
Issues:
Extensive anticonvulsant tolerance
Cannabidiol (Epidiolex)
MoA:
Low affinity for CB- receptors
Antagonist at GPR55, inverse agonist at GPR3,6,12
Allosteric modulator at mu and d opioid receptors
Blocks Nav channels
FDA approved for:
Lennox Gaustaut Syndrome
Dravet Syndrome
Epilepsy in tuberous sclerosis complex
Adverse reactions: Somnolence (drowsiness) Decreased appetite Diarrhea Sleep distrurbance
Stiripentol (Diacomit)
MoA:
Increases GABAergic signaling (Unclear if it is a direct effect on GABAA-Rs, increased release of GABA or maintenance of GABA levels in synaptic cleft)
FDA approved for:
Dravet Syndrome, particularly as add on to valproate
Not known if useful in adolescents or adults
Adverse effects: Somnolence Decreased appetite Ataxia Sleep disturbance Neutopenia Aggressive, irritable behavior (in children)
GABAa receptor channels
Need Alpha and Beta together to make GABA site.
Need 5 subunits to make a receptor, different combos have different properties
Benzodiazepines mechanism of action
Allosteric modulators at GABAA receptors
Barbiturates mechanism
Positive allosteric modulators,
Agonist at GABAA receptors
Antagonist at AMPA/Kainate receptors
Minor effects on CAv channels, glycine and nAChRs
First line Anti-seizure
Clobazem and valproic acid
Second line Anti-seizure
stiripentol, topiramate, ketogenic diet
Third line Anti-seizure
clonazepam, levetiracetam, zonisamide, ethosuximide, VNS
Contraindicated
carbamazepine, oxcarbazepine, lamotrigine, phenytoin, and vigabatrin
How does decreased Na+ current lead to disease?
These channels cause changes in inhibitory neurons, by decreasing inhibition it makes it impossible to bring excitatory signals under control
KCNQ
6 transmembrane proteins
Mutations in KCNQ2 or 3:
can lead to pediatric epilepsies or deafness…unsure if its due to loss or gain of function
can also lead to SUDEP
Hm1a toxin
comes from a spider
decreases seizure frequency and improves survival in mice. reduce seizures and live longer
Binds to voltage sensing domain Na channel
Considerations for development of future AEDs
Considerations:
Experimental models
Druggable targets
Alternatives to pharmacological intervention?
How to design clinical trial….. hard to do tests if you need to keep patient on whatever AED they are already taking
Possibilites
Computational approach to SAR based on structural biology
Completely novel drug scaffolds
GABA synthesis
Glutamine -> Glutamate -> GABA
Vigabatrin inhibits GABA conversion into Succinate Semialdehyde, increasing GABA levels
M- current (KCNQ channels)
Chanel needs PIP2 for activation
Hydrolysis of PIP2 decreases M-current, resting membrane potential depolarizes (voltage goes up)
Acetylcholine inhibits channels, by acting on PIP2
K+ current helps regulate excitability, reducing K+ current makes it easier for action potentials to fire…making it easier for seizures to start
Benzodiazepine binds to….
Between alpha/gamma subunits GABAa receptor
Barbiturate binds to…
Between alpha/beta subunits GABAa receptor
Most common risk factors epilepsy
No identified risk factors followed by family history related
How to terminate action potentials
Block Nav channels
Block neurotransmitter release
Blocks postsynaptic receptor activation
Increase opening of Kv channels
