New anti- epileptics Flashcards
Pharmacology of antiepileptics
1.Sodium channels inhibitors
2.Calcium channels inhibitors
3.Enhancers/inducers of GABA pathway
4.Inhibitors of the release of excitatory neurotransmitters
The aim of anti- epilepsy meds
The main aim is
therapeutic interventions is to simply lower neuronal excitability and
or enhance neuronal inhibition one way antiepileptic drugs may prevent
excessive firing of an action potential in neurons
Sodium channels inhibitors
Voltage-gated sodium channels antiepileptics that block sodium channels and thus reduce the amount of sodium that enters the neuron include Carbamazepine Oxcarbazepine Lamotrigine Phenytoin Topiramate Valproic acid and Zonisamide, phenytoin, sodium valproate
Blocking Calcium Channels
another way antiepileptics can slow
down hyperactive neurons is by blocking calcium channels this task gets done by drugs that inhibit high-voltage-activated calcium channels such as
Lamotrigine and Topiramate and drugs that inhibit low-voltage-activated t-type calcium channels such as Valproic acid and Zonisamide as a side note here keep in mind that many of the antiepileptic drugs act on multiple targets so as you can see Lamotrigine Topiramate Valproic acid and Zonisamide can inhibit both calcium channels and sodium channels
Enhancers/inducers of GABA pathway
Benzodiazipines,barbiuates,Valportate,gabapentin
Inhibitor of the release of excitatory neurotransmitters
eg phenytoin
Barbituates
Prolong Gaba mediated chloride ion channels
BDZ
Increase frequency of GABA mediated chloride ion channels
Newer anti-epileptics - regular ones
APPLY TO ALL
Felbamate,Topiramate,Lamotrigine
SV2A
SV2A isa synaptic vesicle membrane protein expressed in neurons and endocrine cells and involved in the regulation of neurotransmitter release. Although the exact function of SV2A still remains elusive, it was identified as the specific binding site for levetiracetam, a second generation antiepileptic drug
Why do we need new drugs? - 4
Lack of efficacy: approximately 30% of cases are estimated to be resistant (intractable epilepsy)
Safety profile: wide range of side effects such as: drowsiness, cognitive impairment, lack of energy, tremors, swollen gum, cardiac side effects, hair loss, teratogenicity
Drug-drug interactions: phenytoin and carbamazepine: hepatic metabolic enzyme inducers
Risk of misuse: benzodiazepines and other drugs exerting GABAergic effect
Challenges against discovery
The discovery of antiepileptics started with potassium bromide then barbiturates
Phenytoin in 1936, was the first non-sedative antiepileptic
Until 1950s, the era of 1st generation (barbiturates derivatives)
1960-1975: 2nd generation: cyclic ureides free
1980s: rational drug development based on mechanism of action (3rd generation)
In 2022, the US FDA approved 37 new drugs, non of them for epilepsy!
Such crowded market of antiepileptics has compromised the R&D interest of giant pharmaceutical companies
Glutamate pathway
(NMDA)
Soticlestat : in Phase 3 trials
In the brain, an enzyme CYP46A1 induces the hydroxylation of cholesterol to (24HC)
24HC is a positive allosteric modulator of N-methyl-D-aspartic acid (NMDA) receptors which mediate excitatory glutamatergic signaling
Hyperactivation of glutamatergic signaling leading to neuronal dysfunction and damage, also known as excitotoxicity
Soticlestat works as a cholesterol 24-hydroxylase inhibitor (CH24H, also known as CYP46A1)
Radiprodil
Radiprodil is a subtype-selective NMDA receptor subtype 2B (NR2B) antagonist currently undergoing clinical evaluation
It was shown to have preclinical efficacy in seizure models in rats, and more recently was tested in a Phase 1b study in infantile spasm syndrome
Terminated(After reviewing the feasibility and projected completion date of the study, UCB has made the decision to stop the study)
AV101
(KP) links excitatory amino acid transmission and neuroinflammation
KP pathway produces quinolinic acid (QUIN) that activates NMDAR and exerts neurotoxic effect
AV-101 is an oral prodrug of 7-chlorokynurenic acid ), which is
Converted by kynurenine aminotransferase (KAT)-rich astrocytes into NMDAR competitive antagonist
Converted by kynurenine 3-monooxygenase-rich microglia to an inhibitor of QUIN
Phase 1 clinical trials
Glutamate pathway
(mGluR)
Glutamate is released in the synaptic cleft via calcium-dependent exocytosis, to bind:
Excitatory postsynaptic ionotropic receptors (NMDA, AMPA or Kainate)
Modulatory metabotropic receptors(mGluRs) that change the excitation rate of postsynaptic ion channels leading to either inhibition or excitation
The mGlu2 receptor functions as a presynaptic autoreceptor that, upon activation, decreases the release of the excitatory neurotransmitter glutamate
JNJ-1813 is another class of compounds, metabotropic glutamate receptor 2 (mGluR2) agonist (PAM: positive allosteric modulator)
Currently in phase 2 clinical trials
Potassium channels
XEN1101: Kv7 potassium channels opener (PIII)
XEN496 in PIII, is a Kv7.2 potassium channel opener, is a proprietary paediatric formulation of the active ingredient ezogabine being developed for the treatment of KCNQ2 developmental and epileptic encephalopathy (KCNQ2-DEE)
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STK-001
Dravet syndrome is a severe and progressive genetic epilepsy characterized by frequent, prolonged and refractory seizures, beginning within the first year of life
Dravet syndrome is difficult to treat and has a poor long-term prognosis
One of the most common channelopathy affects theα1 subunit of a neuronal voltage‐gated sodium channel that is coded by the SCN1A gene (Chromosome 2q24.3)
In approximately 85% of cases, DS is caused by spontaneous, heterozygous loss of function mutations in the SCN1A gene
DS patients have two copies, one wild-type and the other is mutant
STK-001 is an oligonucleotide that has the potential to be the first disease-modifying therapy to address the genetic cause of Dravet syndrome
Oligonucleotides are short synthetic polymers of nucleotides that are complementary to specific regions of mutant –pre- mRNA
STK-001 is designed to upregulate NaV1.1 protein expression by leveraging the non-mutant (wild-type) copy of theSCN1Agene to restore physiological NaV1.1 levels, thereby reducing both occurrence of seizures and significant non-seizure comorbidities
Glycolysis pathways
Numerous studies were published in late 1990s supporting the ketogenic diet as a therapeutic approach for intractable epilepsy
A ketogenic diet should be applied under a specialist supervision and broadly consists of a low carbohydrate, high fat diet
Ketogenic diet will lead to higher proportion of ketones in the bloodstream which seems to reduce the frequency of seizures
Treatment would usually begin with only one medicine, if this is ineffective, a different drug may be tried
2-deoxy-D-glucose (2.DG)Inhibits glycolysis in response to neural activity (PII) in University of Virginia
Tonic Clonic and Partial Seizures
Carbamazepine,Phenytoin
Absence Seizures
Ethosuzemide
Broad spec
Valproic acid
Adjunct
Lamotrigine,gabapentin
