Exam 3 Review

NMDA receptors are permeable to which of the following ions? Select all that apply.

1. sodium

2. chloride

3. calcium

4. potassium

NMDA receptors are permeable to which of the following ions? Select all that apply.

1. sodium

2. chloride

3. calcium

4. potassium

1,3,4

Opening of NMDA receptors will allow for entry of sodium and calcium ions to exit the cell; NMDA receptors don’t allow for entry of chloride ions; GABAa receptors allow for entry of chloride ions into the cell; AMPA and 5HT3 receptors usually allow for entry of sodium and exit of potassium ions

Exit in potassium ions from a neuron results in

1. depolarization

2. hyperpolarization

3. refractoriness

4. repolarization

4

Remember potassium ions are positive; positive iions leaving the cell will make the cell potential more negative and less likely to fire;thus piotassium ions exiting the cell will result in repolarization

Opening of ligand gated GABAA receptors allows the entry of which ions

a) Sodium

b) Potassium

c) Calcium

d) Chloride

d

GABAa receptor is a ligand-gated ion channel and the ligand being the neurotransmitter GABA; opening of the GABAa receptor results in entry of chloride ions; chloride ions are negative ions and thus their entry makes the cell potential negative and less likely to fire; thus, GABA is an inhibitory neurotransmitter; NMDA and receptors allow for entry of sodium and calcium and exit of potassium; AMPA and 5HT3 receptors usually allow for entry of sodium and exit of potassium ions

A neuron is most likely to fire when it is

a) Hyperpolarized

b) Depolarized

c) In the refractory phase

d) Repolarized

b

Depolarization usually occurs when sodium enters the cells; sodium is a positively charged ion; entry of sodium makes the cell potential more positive and this increases the likelihood of the cell firing and transmitting its signals; a neuron is unlikely to fire during the refractory phase, repolarization and hyperpolarization phases

Entry of sodium ions into a neuron results in

a) Repolarization

b) Hyperpolarization

c) Depolarization

d) Refractoriness

c

Depolarization usually occurs when sodium enter the cells; sodium is a positively charged ion; entry of sodium makes the cell potential more positive and this increase the likelihood of the cell firing and transmitting its signals

Entry of chloride ions into a neuron will make its potential

a) Negative

b) Positive

c) No change

a

Chloride is a negatively charged ion and thus entry of chloride ions into the cell makes the cells more negative

Which neurotransmitter is involved in allowing entry of chloride ions into a neuron?

a) Dopamine

b) Serotonin

c) GABA

d) Glutamate

c

GABAa receptor is a ligand-gated ion channel and the ligand being the neurotransmitter GABA; opening of the GABAa receptor results in entry of chloride ions; chloride ions are negative ions and thus their entry makes the cell potential negative and less likely to fire; thus, GABA is an inhibitory neurotransmitter; NMDA and receptors allow for entry of sodium and calcium and exit of potassium; AMPA and 5HT3 receptors usually allow for entry of sodium and exit of potassium ions

Which of the following can be used to decrease chemical neurotransmission? (SELECT ALL THAT APPLY)

a) Blockade of postsynaptic receptors

b) Blockade of neurotransmitter reuptake transporter

c) Blockade of calcium entry into the presynaptic membrane

d) Blockade of the synaptic vesicle from merging with the presynaptic membrane

a,c,d

Chemical neurotransmission can be decreased by all of the following mechanisms: blockade of postsynaptic receptors, blockade of calcium entry into the presynaptic membrane,and blockade of the synaptic vesicle from merging with the presynaptic membrane. Blockade of the neurotransmitter reuptake transporter increases levels of the neurotransmitter in the synapse and thus increases chemical neurotransmission; while the question was asking for ways to decrease chemical neurotransmission

9. Which type of calcium ion channel is responsible for release of neurotransmitter from the presynaptic nerve terminal?

a) T-type

b) N-type

c) L-type

b

Remember L-type calcium channels are found on blod vessels and are acted on by calcium channel blockers like verapamil which are used to treat hypertension; t-type are transient type of calcium channels which are important in absence seizures and acted on by drugs like ethosuximide and valproate; n-type are neuronal type of calcium channels that play a role in synaptic neurotransmitter release

Of the following sites on the GABAA receptor, which one can actually cause convulsions

a) GABA site

b) Benzodiazepine site

c) Picrotoxin

d) Steroid site

e) Barbiturate site

c

[Learn the various sites on the GABAA receptor; Remember GABA is an inhibitory neurotransmitter; Picrotoxin is a GABAA receptor antagonist and binding of picrotoxin to its site blocks the GABAA receptor and can cause seizures; this is actually a model used in the laboratory to discover new antiepileptic medications; benzodiazepine and barbiturates are actually used to treat seizure/convulsions/epilepsy; The steroid site is the site of binding of neurosteroids, alcohol and anesthetics. These agents usually cause sedation and not convulsions]

Epileptogenesis is associated with conversion of normal circuits into chronically hyperexcitable one.

a) True

b) False

a

[Learn the concept of epileptogenesis; epileptogenesis is the reason for treating patients with epilepsy because every seizure lays the foundation for the next seizure]

Loss of GABAergic neurons can lead to epileptogenesis

a) True

b) False

a

[Learn the mechanisms that underlie epileptogenesis: Loss of inhibitory GABA neurons; Decrease in GABA transmission; Increase in glutamate (excitatory neurotransmitter) transmission; Reorganization of surviving neurons that leads to hyperexcitable neuronal networks; Alteration in expression of ion channels which makes neurons more excitable]

Epilepsy is defined as recurrent and predictable occurrence of muscular spasms

a) True

b) False

b

[Epilepsy is not predictable and need not be only restricted to muscle spasms; muscle spasms could be one of the manifestations but may not be present in every form of epilepsy]

A focal seizure originates in a network in one hemisphere and rapidly engages both hemispheres

a) True

b) False

b

[The question describes a generalized seizure; a focal seizure is limited to a particular part of the brain; You should know how to differentiate a generalized seizure from a focal seizure; Some drugs can be used in both generalized and focal seizures, but some drugs can be used in only one form of seizures]

If a seizure involves only ringing in the ears and occurs for a brief period, what type of seizure will it be

a) Focal

b) Generalized

c) Complex

d) Status epilepticus

a

This is an example of focal seizure

Clonic phase of the tonic-clonic seizure involves

a) Sustained contraction of muscles

b) Rhythmic contraction and relaxation of muscles

c) Constant ringing in the ears

d) Inability to maintain posture

b

During the clonic phase there is rhythmic contraction and relaxation; sustained contraction occurs in the tonic phase of the seizure; constant ringing in the ears is called focal seizure; inability to maintain posture occurs in a type of seizures known as ‘atonic seizures’

Epileptogenesis is associated with increased glutamate transmission

a) True

b) False

a

See also answer for PQ#12; epileptogenesis is associated with increased glutamate transmission due to loss of inhibitory GABAergic neurons

Epilepsy should be treated because

a) Each seizure results in damage to the brain

b) Seizures are an embarrassment if they occur in public

c) Seizures make finding a job difficult

d) Seizures can result in super intelligent human beings

a

see answers for PQ# 11 and 12; Epilepsy should be treated as each seizure lays the foundation for the next seizure due to loss of inhibitory GABAergic neurons

Which neurons are most susceptible to repeated seizures?

a) Glutamate

b) Dopaminergic

c) GABAergic

d) Serotoninergic

e) Noradrenergic

c

Remember GABAergic neurons are inhibitory; During seizures, GABA neurons are very susceptible; Loss of GABA neurons result sin loss of inhibitory input and makes an individual more susceptible to seizures

The anti-epileptic drug Rufinamide (Banzel® ) acts via

a) Competitive inhibition of the AMPA receptors

b) Activation of chloride channels

c) Blockade of glutamate release

d) Activation of potassium channels

e) Inactivation/blockade of voltage-gated sodium channels

e

Rufinamide acts via blockade of voltage-gated sodium ion channels; Remember sodium is a positive ion and entry of sodium into a neuron causes depolarization and makes a neuron more likely to fire; thus an effective strategy to decrease occurrence of seizures is to block sodium channels; Perampanel is a non-competitive inhibitor/blocker of the AMPA receptors; In contrast, topiramate is a competitive inhibitor/blocker of the AMPA receptor; benzodiazepines (e.g. clonazepam), stiripentol, Primidone, cannabidiol, barbiturates (e.g. phenobarbital) activate GABAA receptors, which results in opening of the chloride ion channels; Levetiracetam an SV2A synaptic vesicle protein inhibits release of glutamate; Ezogabine activates potassium ion channels

The mechanism of action of the antiepileptic drug topiramate (Topomax® ) is explained by which of the following? (SELECT ALL THAT APPLY)

a) Blockade of ionotropic glutamate receptors (AMPA/Kainate)

b) Blockade of voltage-gated Na+ channels

c) Enhancement of GABAA currents

d) Activation of a hyperpolarizing K+ current e) Inactivation of T-type calcium channels

a, b, c, d

This is a difficult question; topiramate does have multiple targets and a complex mechanism of action; blockade of glutamate transmission is one of the main mechanism; however, topiramate is a competitive antagonist of AMPA receptors; In contrast, perampanel (Fycompa) is a non-competitive antagonist of the AMPA and thus is an advance over a previously available drug. Additional mechanism of topiramate include: Blockade of voltage-gated Na+ channels, enhancement of GABAA currents, activation of a hyperpolarizing K+ current; Inactivation of T-type calcium channels is not one of the mechanisms of topiramate; Sodium valproate and Ethosuximide that are used in the treatment of ‘Absence seizures’ inactivate T-type calcium channels

Which of the following drugs act via blocking glutamate neurotransmission? (SELECT ALL THAT APPLY)

a) Felbamate

b) Ezogabine

c) Topiramate

d) Perampanel

a, c, d

Felbamate, topiramate and perampanel- all act on glutamate receptors; Felbamate blocks NMDA receptors; topiramate is a competitive antagonist of the AMPA receptors; while perampanel is selective non-competitive antagonist of the AMPA receptors; Felbamate and topiramate also bind to other targets, which help in their antiepileptic action; Ezogabine is potassium channel activator which is available in Europe but the drug has been withdrawn from all markets due to visual adverse effects associated with it

Which of the following statements regarding adverse events associated with antiepileptic medications is true?

a) Idiosyncratic events can be fully explained based on the mechanism of action

b) Acute adverse effects are dose-dependent

c) Chronic effects are not usually seen with antiepileptic medications

d) Drug interactions are extremely rare with antiepileptic medications

b

Acute side effects (e.g. nausea, vomiting, ataxia, drowsiness) are dose-dependent and patients develop tolerance over a period of time; Idiosyncratic side effects of anti-epileptic medications cannot be explained; Chronic side effects such as gum hyperplasia with phenytoin, osteoporosis and behavioral changes in children are also common and thus require patient education through counselling, regular monitoring and follow-up

Which of the following drugs increase GABA transmission by targeting the presynaptic GABA terminal? (SELECT ALL THAT APPLY)

a) Tiagabine

b) Midazolam

c) Gabapentin

d) Stiripento

a, c

Tiagabine inhibits reuptake of GABA and thus acts on the presynaptic terminal; Gabapentin increases GABA synthesis and thus acts on the presynaptic terminal; Midazolam is a positive allosteric modulator (sometimes called agonist) of GABAA receptor and these receptors are postsynaptic and not presynaptic; Similarly, Stiripentol acts on GABAA receptors, which are postsynaptic'; the question specifically asked for drugs that act on presynaptic GABA terminal

Barbiturates act by increasing the

a) Duration of opening of the GABAA receptor

b) Frequency of opening of the GABAA receptor

c) Duration of opening of the NMDA receptor

d) Frequency of the opening of the AMPA receptor

a

This question is important to differentiate mechanism of action of barbiturates vs. benzodiazepines; Barbiturates increase duration of opening of the GABAA receptor and thus overdose deaths are more common with barbiturates; In contrast, benzodiazepines increase frequency of opening of the GABAA receptor and this results in less chance of overdose death; benzodiazepines were a significant advance over barbiturates in terms of drug development; Always ask yourself why was new a drug class developed; it is usually to overcome limitations of an existing drug

Seizures can occur because of which of the following? (SELECT ALL THAT APPLY)

a) Hypoglycemia

b) Hypoxia

c) Listening to Gregorian chants

d) Meningitis

a, b. d

Infection, hypoglycemia, ischemia, stroke, and hypoxia at high altitudes can all cause seizure; Gregorian chants will be soothing and unlikely to cause seizures

Which of the following drugs can lead to seizures? (SELECT ALL THAT APPLY)

a) Benzodiazepine withdrawal

b) Cocaine intoxication

c) Alcohol withdrawal

d) Phenytoin sodium

e) Ephedra supplement

a, b, c, e

Drug withdrawal is a major cause of seizures; If a young patient is brought to the emergency room with history of sudden onset seizures and no previous medical or family history of seizures- the first diagnosis to rule out is use of drugs of abuse and withdrawal; alcohol withdrawal, cocaine intoxication/overdose, benzodiazepine withdrawal can cause seizures; Phenytoin sodium is used to treat seizures and hence cannot cause seizures

SD, a 66 year old man, has been started on Phenytoin Na for the treatment of seizures he has been experiencing after he experienced a head injury last week. After starting Phenytoin Na, he has been feeling drowsy, confused, and unable to balance himself. On examination of his eyes, nystagmus has been observed. In addition to phenytoin Na, Sam also takes aspirin and omeprazole. These symptoms are most likely due to

a) Poor seizure control

b) Aura associated with impending seizure

c) Adverse effects of phenytoin

d) Subdural hematoma

c

Antiepileptics suppress neuronal excitation; they are supposed to suppress excitation in the area of seizure focus but they suppress neurons all over the brain; the signs and symptoms described in this patient are due to suppression of the cerebellum and caused by administration of phenytoin sodium; hence the answer is adverse effects of phenytoin sodium

Assume you are in the year 2030. A patient walks into the clinic with a report which states that he has a genetic polymorphism which allows for prolonged opening of his neuronal sodium channels. Which of the following drugs will be most effective in this patient?

a) Lamotrigine

b) Ezogabine

c) Gabapentin

d) Perampanel

a

The only drug in the list that binds to sodium ion channel is lamotrigine. Hence that is the answer; Perampanel binds to AMPA receptors; Ezogabine opens potassium channels; Gabapentin increases GABA synthesis

Assume you are in the year 2030. A patient walks into the clinic with a report which states that she has a genetic polymorphism which delays opening of his neuronal potassium channels. What effect do you think it will have on his neuronal activity?

a) Neurons will be hyperpolarized

b) No effect on neuronal excitability

c) Neurons will have prolonged depolarization phase

d) Neurons will show faster repolarization

c

The opening of potassium channels results in repolarization of the neurons; thus delay in opening of potassium channels will prolong the depolarization phase of the neurons and in relation to epilepsy the seizure will continue

Which of the mechanisms of action explains the effects of cannabidiol (Epidolex® ) in epilepsy? (SELECT ALL THAT APPLY)

a) Blockade of NMDA receptors

b) Blockade of AMPA receptors

c) Blockade of voltage-gated potassium channels

d) Blockade of voltage-gated sodium channels

e) Activation of GABAA receptors

d, e

Cannabidiol [Epidolex® ] has several mechanism of action. These include: Activation of GABAA receptors, Blockade of voltage-gate sodium channels, blockade voltage-gate Ttype calcium channels and blockade GPR55 (Orphan G-protein-coupled receptor). In addition, cannabidiol inhibits CYP450 isoenzymes like CYP3A4 and CYP2C19 enzymes. These enzymes are necessary for the degradation of benzodiazepine like clobazam leading to an increase in their Tmax values and plasma half-life; Cannabidiol has no action on NMDA, AMPA or chloride channels

In all voltage-gated ion channels, which of the following transmembrane segments usually serves as the voltage-sensor?

a) S4 segment

b) S5 segment

c) S1 segment

d) S6 segment

a

In all voltage-gated ion channels, the S4 transmembrane segment serves as the voltage sensor; The pore consists of the ion-selectivity filter, a narrow re-entrant loop between segments S5 and S6

Which of the following statements is true about the T-type calcium channels? (SELECT ALL THAT APPLY)

a) They are involved in absence seizures

b) Ethosuximide blocks this type of calcium channels

c) Composed of alpha, beta, delta and gamma subunits

d) They are high voltage activated calcium channels

e) S4 segment serves as the voltage sensor

a, b, e

T-type calcium channels are involved in absence seizures; Ethosuximide and blocks this type of calcium channels; Composed of only alpha 1 subunits. They lack beta, delta and gamma subunits; They are low (not high) voltage activated calcium channels; S4 segment like in all other ion channels serves as the voltage sensor

Which of the following statements are true about voltage-gated potassium ion channels? (SELECT ALL THAT APPLY)

a) They are simple ion channels and contain only one subunit

b) S4 harbors the voltage sensor

c) The pore for the voltage-gated ion channel exists between S2 and S3 segments

d) Ezogabine blocks voltage-gated potassium ion channels

e) Voltage-gated potassium ion channels are involved in absence seizures

a, b, d

Voltage-gated potassium ion channels are simple ion channels and contain only one subunit; S4 harbors the voltage sensor; The pore for the voltage-gated ion channel exists between S5 and S6 segments and not S2 and S3 segments; Ezogabine blocks voltage-gated potassium ion channels; Voltage-gated potassium ion channels are not Epilepsy Prac Qs_D’souza_2024 involved in absence seizures; it is the T-type calcium channels are involved in absence seizures

The best descriptor to classify Drug Z is

• iminostilbene

• benzodiazepine

• diaminotriazine

• barbiturate

• hydantoin

Barbiturate

The metabolic pathway that terminates the effects for Drug W is

• reduction of the carbonyl group

• para-aromatic oxidation

• hydrolysis of the terminal amide

• ring opening by N-N reduction

• phase II glucuronidation

hydrolysis of the terminal amide

What drug class is this?

Benzodiazepine

How does this drug produce its pharmacological effects?

Modulation of Na+ flux

What complex does this drug alter?

GABAa receptor and Cl- channel complex

What drug class is this?

Barbiturate

How is this compound deactivated?

Direct phase II conjugation

How is this drug activated?

Its target of action activates the latent functional group

What does this drug target?

A synaptic neurotransporter