L48. Pharmacology - Ion Channels & Ionotropic Receptors- Use in Seizure Disorders & Beyond
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Questions and Answers

Levetiracetam and brivaracetam are believed to exert their antiseizure activity through which primary target?

  • GABAA receptors
  • GluA (AMPA) receptors
  • Voltage-gated sodium channels
  • Synaptic Vesicle protein 2A (SV2A) (correct)

Perampanel's therapeutic effect is based on its action on which receptor?

  • GluA (AMPA) receptors, non-competitively antagonizing them and reducing synaptic transmission (correct)
  • GABAA receptors, enhancing inhibitory neurotransmission
  • Voltage-gated sodium channels, prolonging their inactivation
  • T-type calcium channels, blocking calcium influx

Valproic acid's broad spectrum of action is most likely attributed to:

  • Selective inhibition of histone deacetylase
  • Multiple mechanisms of action including sodium channel inactivation, increased GABA levels, T-type Ca channel modulation, and histone deacetylase inhibition (correct)
  • Its action on a single molecular target within the brain
  • Its high specificity for T-type calcium channels alone

Topiramate is known to act on which of the following targets?

<p>GABAA receptors, voltage-gated sodium channels and GluA receptors (C)</p> Signup and view all the answers

What opportunities have arisen in cases where epilepsies emerge from specific genetic mutations?

<p>Unique opportunities for treatment based on the defined pathophysiology of these epilepsies (A)</p> Signup and view all the answers

Which characteristic distinguishes absence seizures from focal seizures, influencing their respective treatment strategies?

<p>The primary origin of absence seizures in the thalamus versus the cortical origin of focal seizures. (D)</p> Signup and view all the answers

Considering the interconnectedness of brain regions, which structure's recruitment is most critical in the progression of a focal seizure to a generalized tonic-clonic seizure?

<p>The thalamus, given its extensive connections to the entire cortex. (A)</p> Signup and view all the answers

If a new drug were designed to selectively target the pathophysiology of epilepsy by modulating neuronal excitability, which mechanism of action would be least likely to be effective, given the classification and origins of seizures discussed?

<p>Modulating thalamic neuronal activity without affecting cortical excitability. (A)</p> Signup and view all the answers

Given that epilepsy, neuropathic pain, and bipolar disorder can be conceptualized as disorders of aberrant excitability, what common pharmacological strategy might be effective across all three conditions?

<p>Modulating ion channel function to stabilize neuronal firing. (D)</p> Signup and view all the answers

A patient presents with recurrent seizures localized to the motor cortex, primarily affecting the right arm. What type of seizure is the patient most likely experiencing, and what would be the most appropriate initial treatment approach?

<p>Focal seizures; initiate treatment with a drug that selectively dampens cortical excitability. (B)</p> Signup and view all the answers

Considering the heterogeneity of epilepsy and its potential secondary causes, which diagnostic step is most critical in determining the appropriate long-term management strategy for a newly diagnosed patient?

<p>Neuroimaging to rule out structural lesions such as tumors or stroke. (A)</p> Signup and view all the answers

Which of the following best explains why similar pharmacotherapeutic approaches might be used to treat both epilepsy and bipolar disorder?

<p>Epilepsy and bipolar disorder are both characterized by disturbances in neuronal excitability. (A)</p> Signup and view all the answers

Which of the following best explains why many antiseizure drugs (ASDs) have multiple mechanisms of action?

<p>Many ASDs were identified through animal screenings rather than target-driven design, leading to the discovery of various effects. (A)</p> Signup and view all the answers

A researcher is developing a novel drug to treat epilepsy. Which of the following strategies would be most consistent with current approaches in antiseizure drug development?

<p>Developing a drug that selectively modulates synaptic vesicle protein SV2A to reduce synaptic release. (B)</p> Signup and view all the answers

A patient with epilepsy is taking an antiseizure drug that enhances GABAergic neurotransmission. Which of the following is the most likely mechanism of action of this drug?

<p>Positive modulation of $GABA_A$ receptors (A)</p> Signup and view all the answers

Why are available antiseizure drugs (ASDs) described as 'antiseizure' rather than 'antiepileptic'?

<p>ASD's primarily focus on preventing seizures without addressing underlying disease progression. (A)</p> Signup and view all the answers

A new antiseizure drug is being developed to target voltage-gated sodium channels. Which of the following mechanisms would be most consistent with its intended action?

<p>Prolonging the inactivated state of voltage-gated sodium channels. (C)</p> Signup and view all the answers

A pharmaceutical company is developing a novel drug designed to minimize synaptic excitation by targeting ionotropic glutamate receptors. Which of the following strategies would align with this goal?

<p>Selectively blocking AMPA receptors to reduce postsynaptic depolarization. (C)</p> Signup and view all the answers

Considering the mechanisms by which antiseizure drugs (ASDs) reduce network excitability, which of the following targets would be most likely to cause widespread central nervous system (CNS) depression as a side effect?

<p>Positive modulation of $GABA_A$ receptors. (D)</p> Signup and view all the answers

Despite the availability of numerous antiseizure drugs (ASDs), a significant portion of patients still experience poor seizure control. Which of the following factors contributes most significantly to this challenge?

<p>The development of drug-resistant seizures in some patients. (B)</p> Signup and view all the answers

A researcher aims to develop a novel antiseizure drug with minimal side effects. Which of the following strategies would be most promising in achieving this goal?

<p>Designing a drug that selectively targets a specific subtype of glutamate receptor in a localized brain region. (D)</p> Signup and view all the answers

Which characteristic of GABAA receptor subunit composition MOST accurately determines benzodiazepine binding?

<p>The specific combination of α and γ subunits present in the receptor. (C)</p> Signup and view all the answers

How does Tiagabine enhance GABAergic inhibition in the brain?

<p>By blocking the reuptake of GABA, increasing ambient GABA concentrations. (C)</p> Signup and view all the answers

What is the MOST direct mechanism by which Vigabatrin increases extracellular GABA concentrations?

<p>Inhibiting GABA metabolism, which leads to GABA efflux via reversed GABA transporters. (A)</p> Signup and view all the answers

Why is Vigabatrin's clinical use limited despite its effectiveness in treating refractory seizures?

<p>Because it can lead to irreversible vision loss in some patients. (A)</p> Signup and view all the answers

What is the established mechanism of action for Gabapentin and Pregabalin in treating seizures?

<p>Binding to the α2δ-1 subunit of voltage-dependent calcium channels. (A)</p> Signup and view all the answers

Besides calcium channels, what other potential role has been suggested for α2δ proteins, regarding synaptic function?

<p>Acting as scaffolding proteins at the synapse. (C)</p> Signup and view all the answers

Levetiracetam interacts with the synaptic vesicle protein SV2A. Which downstream action MOST directly contributes to its antiseizure effects?

<p>Altered neurotransmitter release probability. (C)</p> Signup and view all the answers

Which of the following strategies would MOST selectively enhance extrasynaptic GABAA receptor activity without directly affecting synaptic receptors?

<p>Using a GABA reuptake inhibitor in conjunction with a GABA metabolism inhibitor. (D)</p> Signup and view all the answers

A novel drug is developed that enhances GABA's affinity for the α5 subunit-containing GABAA receptors. What is the MOST likely primary effect of this drug?

<p>Reduced excitability of neurons, particularly in the hippocampus. (C)</p> Signup and view all the answers

A patient with refractory epilepsy is being treated with Vigabatrin. If the patient begins to experience visual field defects, what is the MOST appropriate course of action?

<p>Discontinue Vigabatrin treatment immediately and consider alternative therapies. (A)</p> Signup and view all the answers

Which characteristic of action potentials is directly influenced by the inactivation of sodium channels?

<p>The repolarization phase and refractory period. (B)</p> Signup and view all the answers

How does facilitating sodium channel inactivation lead to the selective suppression of seizures?

<p>By preferentially suppressing the high-frequency spiking associated with seizures while sparing normal neuronal activity. (D)</p> Signup and view all the answers

Why is ethosuximide primarily used in the treatment of absence seizures?

<p>It selectively blocks T-type calcium channels in the thalamus, which are crucial in the generation of absence seizures. (A)</p> Signup and view all the answers

What is the primary mechanism through which Kv7 channels (KCNQ) regulate neuronal excitability?

<p>By modulating the resting membrane potential and controlling membrane excitability via potassium efflux. (B)</p> Signup and view all the answers

Why was Retigabine (ezogabine) removed from distribution despite its effectiveness as an ASD?

<p>It was associated with retinal toxicity, leading to visual impairment. (C)</p> Signup and view all the answers

How do barbiturates and benzodiazepines enhance inhibitory GABAergic transmission?

<p>By acting as positive allosteric modulators of GABAA receptors, increasing GABA-induced chloride fluxes. (D)</p> Signup and view all the answers

Which of the following mechanisms describes how certain antiseizure drugs reduce neuronal excitability by prolonging the inactivated state of sodium channels?

<p>Stabilizing sodium channels in the inactivated state, thus decreasing the availability of channels to open during depolarization. (D)</p> Signup and view all the answers

Considering the role of T-type calcium channels in neuronal function, what effect would a selective antagonist of these channels likely have on thalamocortical oscillations?

<p>Disrupt the normal rhythmic pattern of thalamocortical oscillations, potentially affecting sleep-wake cycles. (D)</p> Signup and view all the answers

What is the most likely reason that the development of potassium-channel-targeting drugs for epilepsy treatment has been limited, despite the potential for these channels to dampen neuronal excitability?

<p>Potassium channel modulators often lack the necessary specificity, leading to unacceptable off-target effects and toxicity. (C)</p> Signup and view all the answers

How do benzodiazepines affect the frequency and amplitude of inhibitory postsynaptic potentials (IPSPs) mediated by GABAA receptors?

<p>They increase the frequency and amplitude of IPSPs by enhancing the affinity of GABAA receptors for GABA and prolonging chloride channel opening. (C)</p> Signup and view all the answers

Flashcards

SV2A

The primary target through which Levetiracetam and brivaracetam exert their antiseizure activity.

Perampanel

A noncompetitive antagonist of GluA (AMPA) receptors that reduces synaptic transmission. Has a narrow therapeutic window.

Valproic Acid (Depakene)

A widely used ASD with multiple targets, including sodium channels, GABA levels, and T-type Ca channels. Also used for bipolar disorder and migraines.

Topiramate (Topamax)

An ASD with likely multiple targets, including sodium channels, GABAA receptors, and GluA receptors. Also used to treat migraines.

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Disease-Specific ASDs

Epilepsies arising from specific genetic mutations offer unique treatment opportunities due to defined pathophysiology.

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Nervous System Disorders

Disorders of the nervous system that involve disturbances of thought, mood, or emotion, often linked to aberrant neuronal excitability.

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Epilepsy

A chronic neurological disorder characterized by recurrent seizures due to abnormal electrical activity in the brain.

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Focal Seizures

Seizures originating in a specific area of the cortex, with symptoms depending on the affected region.

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Generalized Tonic-Clonic Seizures (progression from focal)

A specific type of seizure that starts as a focal seizure, then spreads to involve the entire brain, often via the thalamus.

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Thalamus (in Seizures)

A brain structure strongly interconnected with the cortex, playing a key role in the generalization of seizures.

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Absence Generalized Seizures

Seizures thought to originate in the thalamus, rather than the cortex.

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Seizures

Abnormal electrical activity in the central nervous system that manifests as seizures.

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Antiseizure Drugs (ASDs)

Drugs that reduce the frequency or severity of epileptic seizures.

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Standard Drug Therapies

Control seizures for ~2/3 of patients, but don't strongly prevent or reverse the underlying epilepsy.

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ASDs Mechanism of Action

The intended action of drugs is to reduce hyper-excitability in neuronal networks to stop seizures.

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Multiple Sites of Action (ASDs)

A common occurrence among ASDs due to being identified through animal screenings rather than target specific design.

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Na+ Channel Modulation

Reducing network excitability by prolonging the inactivated state of voltage-gated Na+ channels.

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Enhancement of GABA Transmission

Enhancing the effect of your primary inhibitory neurotransmitter to reduce network excitability.

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Inhibition of Ca2+ Channels

Reducing Calcium influx at the presynaptic terminal to reduce network excitability.

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Diminishing Synaptic Excitation

Reducing the effect of your primary excitatory neurotransmitter to reduce network excitability.

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Voltage-Dependent Sodium Channels

Fundamental for generating action potentials in neurons; modulate to reduce network excitability.

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Voltage gated Sodium Channels

Open in response to depolarization, allow Na+ influx, and cause the action potential upstroke.

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Sodium Channel Inactivation

The process where Na+ channels stop passing current after opening, helping repolarize the cell and causing a refractory period.

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ASD Mechanism: Na+ Channel Inactivation

Carbamazepine, phenytoin, lamotrigine, oxcarbazepine and zonisamide work primarily by prolonging the inactivation of sodium channels.

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T-Type Calcium Channels

These channels are important in thalamus firing, thus the drug ethosuximide is effective against absence seizures.

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Low Threshold Calcium Channels

A type of calcium channel that plays a key role in thalamic firing.

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Potassium Channels

Channels that dampen neuronal excitability.

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Retigabine (Ezogabine)

Enhances the activity of Kv7 (KCNQ) potassium channels, reducing neuronal excitability.

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Inhibitory GABAergic Transmission

A key mechanism for controlling hyperexcitation in the brain.

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Barbiturates & Benzodiazepines

Drugs that modulate GABAA receptors to enhance inhibitory chloride flux.

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Positive Allosteric Modulators

Increase the effect of GABA by binding to GABAA receptors, leading to increased chloride influx and hyperpolarization.

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GABAA Receptors

Heteropentameric receptors in the brain that bind GABA, mediating inhibitory neurotransmission. Subunit composition dictates drug selectivity.

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Benzodiazepines' Action

These drugs enhance GABA's effect at GABAA receptors containing specific α subunits and the γ subunit, increasing the frequency of channel opening.

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Tiagabine

Drug that inhibits GABA reuptake transporters (GAT), increasing extracellular GABA levels.

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Vigabatrin

Drug that inhibits GABA metabolism, increasing cytoplasmic GABA and its release, ultimately raising extracellular GABA.

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Gabapentin & Pregabalin

Drugs initially designed as GABA agonists but are actually α2δ-1 subunit ligands of calcium channels.

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Levetiracetam

Originally identified through screening, this drug targets the synaptic vesicle protein SV2A.

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α2δ Subunits

Proteins that are the binding site for gabapentin and pregabalin. They are subunits of voltage-dependent calcium channels, and play broader roles in synaptic function.

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Effect of Blocking GABA Metabolism

Blocking GABA metabolism leads to a rise in cytoplasmic GABA, causing its efflux from terminals and activation of extrasynaptic GABAA receptors.

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Tiagabine's Mechanism

The mechanism by which tiagabine increases ambient GABA levels, leading to activation of extrasynaptic GABAA channels.

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Study Notes

  • Nervous system disorders range from paralysis/seizures to complex disturbances.
  • Mechanistic substrates may be less varied than expected across disorders.
  • Epilepsy, neuropathic pain, and bipolar disorder are treated with similar pharmacological approaches due to aberrant excitability.
  • The study of epilepsy pharmacotherapy gives insight into controlling aberrant excitability for other disorders.
  • Epilepsy is a chronic disorder with recurrent seizures due to abnormal CNS electrical activity.
  • Epilepsy affects ~1% of the worldwide population and is a common neurological disorder after stroke.
  • Epilepsy can be genetic or result from insults like trauma, stroke, tumors, or neurodegenerative diseases.
  • Epileptic seizures are of two main types: focal and primary generalized seizures.

Focal Seizures

  • Symptoms depend on the location of abnormal brain activity.

Without altered mental status

  • Consciousness is preserved.
  • Spread to ipsilateral regions within cortex.

With altered mental status

  • Symptoms typically arise from abnormal activity in the temporal or frontal lobe.
  • Altered consciousness occurs.
  • Involuntary automatisms are often present.
  • Memory impairment of ictal phase occurs.
  • Classically is preceded by an aura.

Focal seizure with secondary generalization

  • Begins with focal seizure symptoms with or without altered mental status.
  • Evolves into a tonic-clonic seizure with sustained contraction followed by rhythmic movements of all limbs.
  • Loss of consciousness occurs.
  • Is Preceded by aura.

Primary Generalized Seizures

Absence seizure (petit mal)

  • Brief interruption of consciousness occurs.
  • Blank stare occurs.
  • Occasional motor symptoms occur, such as lip smacking or rapid blinking
  • Not preceded by an aura.

Myoclonic seizure

  • Brief muscle contraction may occur in individual muscles or generalize.
  • Can cause falling if muscles generalize.
  • Associated with systemic diseases like uremia, hepatic failure, hereditary degenerative conditions, or Creutzfeldt-Jakob disease.

Tonic-clonic (grand mal) seizure

  • Symptoms are as described above, but the onset is abrupt.
  • Not preceded by symptoms of a focal seizure.
  • Focal seizures are localized to a patch of cortex.

Pharmacotherapy of Epileptic Seizures

  • Origins can be traced to the discovery of potassium bromide in the late 19th century and barbiturates in the early 20th century.
  • Subsequent efforts identified many compounds with antiseizure activity.
  • More recent work has focused on specific molecular targets.
  • Standard drug therapies control seizures for only ~2/3 of patients.
  • Newer drugs may have fewer side effects but haven't changed the prevalence of drug-resistant seizures.
  • Available drugs are antiseizure, not antiepileptic.

Mechanism Of Action Of Antiseizure Drugs

  • Drugs suppress epileptic seizures by reducing network excitability through four mechanisms.
  • Multiple sites of action are common among antiseizure drugs (ASDs) due to identification through animal screenings.

Modulation of Cation Channels

  • Na+, K+, and Ca2+ channels.
  • Prolongs the inactivated state of voltage-gated Na+ channels.
  • Positively modulates of K+ channels.
  • Inhibits Ca2+ channels.

Enhancement of GABA Neurotransmission

  • Through actions on GABAA receptors.
  • Modulates GABA metabolism.
  • Inhibits GABA reuptake into the synaptic terminal.

Modulation of Synaptic Release

  • Through actions on the synaptic vesicle protein SV2A or Ca2+ channels containing the a28 subunit.

Diminishing Synaptic Excitation

  • Mediated by ionotropic glutamate receptors (e.g., AMPA receptors).
  • Action potentials are mediated by voltage-dependent sodium channels.
  • Channels open in response to suprathreshold depolarizations, allowing sodium influx into the cell.
  • After a time period, they inactive, which contributes to the decay of the action potential, cell/axon enters a refractory period.
  • ASDs facilitate sodium channel inactivation suppressing high-frequency spiking while sparing ongoing activity.

T-Type Calcium Channel Inhibition

  • Low threshold (T Type) calcium channels play a key role in the firing of the thalamus.
  • Ethosuximide is effective in treating generalized absence seizures, but not other seizure types.

Facilitation of Inhibitory GABAergic Synaptic Transmission

  • GABAergic transmission is a key mechanism controlling runaway excitation.
  • GABA acts on ionotropic GABAÄ€ receptors and on metabotropic GABAB receptors.
  • Barbiturates and benzodiazepines facilitate GABA-induced chloride fluxes through GABAA receptors.
  • These drugs are positive allosteric modulators of GABAA channels.

Other Methods

  • Inhibition of synaptic transmission via GABApentin and pregabalin.
  • The ASD drug Levetiracetam was originally identified through a screening and subsequently was found to target the synaptic vesicle protein SV2A.
  • Blockade of Excitatory Postsynaptic Receptors: Glutamate is a excitatory neurotransmitter in the brain.

Compounds

  • Valproic acid and Topiramate: are widely used and effective ASDs.
  • Valproic acid (Depakene): effective against focal seizures, generalized tonic-clonic and combination seizures, bipolar disorder and migraine.
  • Topiramate (Topamax): effective against focal and generalized tonic-clonic seizures.

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Description

Nervous system disorders range from paralysis and seizures to complex disturbances. Epilepsy, neuropathic pain, and bipolar disorder are treated with similar drugs. The study of epilepsy pharmacotherapy gives insight into controlling aberrant excitability for other disorders.

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