Drugs Affecting Gaba System

Summary

This educational module delves into anti-epileptic drugs targeting the GABA system, focusing on enhancing inhibitory neurotransmission. It covers four main drug groups: GABA agonists like benzodiazepines and barbiturates, GABA analogs such as gabapentin and pregabalin, GABA transporter inhibitors exemplified by tiagabine, and GABA transaminase inhibitors like vigabatrin. Each group's mechanism, clinical uses, and side effects are discussed, providing a comprehensive understanding of managing seizures through GABA modulation.

Takeaways

• 🧠 GABA (gamma-aminobutyric acid) is a crucial inhibitory neurotransmitter in the brain, and its imbalance can lead to conditions like epilepsy.
• 💊 Anti-epileptic drugs targeting the GABA system aim to increase inhibitory synaptic activity, thereby reducing the frequency of seizures.
• 🔑 There are two main types of GABA receptors: GABA A, which is concentrated in the brain and opens chloride channels, and GABA B, found in the spinal cord and involved in muscle relaxation.
• 💡 Drugs affecting the GABA system can be categorized into four groups: GABA agonists, GABA uptake inhibitors, GABA transaminase inhibitors, and GABA analogs.
• 💼 GABA agonists, such as benzodiazepines and barbiturates, enhance GABA's effect by increasing the frequency or duration of chloride channel opening.
• 🚫 Barbiturates like phenobarbital have multiple mechanisms, including blocking AMPA receptors and voltage-gated sodium and calcium channels, but can cause sedation and behavioral abnormalities.
• 🌱 Benzodiazepines are used for emergency control of seizures but have drawbacks like sedative effects and tolerance development with long-term use.
• 🌐 GABA analogs like gabapentin and pregabalin increase GABA concentration in the brain and are also used for neuropathic pain and anxiety disorders.
• 🚫 Tiagabine, a GABA uptake inhibitor, increases GABA concentration in the synaptic cleft by inhibiting its reuptake, but can cause side effects like dizziness and tremor.
• 🛑 Vigabatrin, a GABA transaminase inhibitor, irreversibly inhibits the enzyme responsible for GABA metabolism, leading to increased GABA levels, but can cause visual side effects and weight gain.

Q & A

What is the primary function of GABA in the nervous system?

GABA, or gamma-aminobutyric acid, is an important inhibitory neurotransmitter that plays a crucial role in decreasing neuronal excitability throughout the nervous system.

How do GABA A receptors contribute to the inhibitory synaptic activity?

GABA A receptors are concentrated in the brain and contribute to inhibitory synaptic activity by opening chloride channels, leading to hyperpolarization of the neuron and thus inhibiting its activity.

What are the two main types of GABA receptors discussed in the script?

The two main types of GABA receptors discussed are GABA A receptors and GABA B receptors. GABA A receptors are mainly found in the brain and are involved in inhibitory synaptic activity, while GABA B receptors are primarily located in the spinal cord and are involved in muscle relaxation.

How does the drug vigabatrin affect the GABA system?

Vigabatrin is an irreversible inhibitor of the GABA transaminase enzyme, which is responsible for the metabolism of GABA. By inhibiting this enzyme, vigabatrin increases the concentration of GABA in the brain.

What are the adverse effects associated with the use of phenobarbital?

Phenobarbital can cause sedation, behavioral abnormalities, impairment in learning and memory, hyperactivity in children, and mental confusion. These adverse effects are particularly relevant in clinical settings.

Which drug is commonly used as a first-line treatment for emergency control of convulsions?

Diazepam is commonly used as a first-line treatment for emergency control of convulsions, particularly in status epilepticus.

What is the mechanism of action of benzodiazepines in the context of epilepsy treatment?

Benzodiazepines act as GABA agonists, increasing the frequency of GABA-mediated chloride channel opening, which enhances inhibitory synaptic activity and helps control seizures.

How do GABA analogs like gabapentin and pregabalin affect the GABA system?

GABA analogs like gabapentin and pregabalin do not directly act as GABA agonists. Instead, they modulate the release of GABA by binding to the alpha2delta subunit of voltage-gated calcium channels, thereby increasing GABA concentration in the brain.

What is the primary use of tiagabine, a GABA transporter inhibitor?

Tiagabine is primarily used in the treatment of complex partial seizures, with or without generalization, by inhibiting the GABA transporter and increasing the concentration of GABA in the synaptic area.

What are the visual side effects associated with vigabatrin?

Vigabatrin is known to cause visual side effects, which is a significant drawback of the drug. These effects are commonly asked about in entrance exams and are a clinical consideration when prescribing the medication.

Outlines

00:00

💊 Introduction to GABA-Affecting Anti-Epileptic Drugs

This paragraph introduces the module on anti-epileptic drugs that target the GABA system, which plays a crucial role in inhibitory neurotransmission. The paragraph explains the imbalance between excitatory and inhibitory neurotransmitters as a key factor in epilepsy. The learning objectives include understanding drugs that affect GABA levels, their adverse effects, and contraindications. GABA acts through two main receptors: GABA A, concentrated in the brain and involved in chloride channel opening, and GABA B, present in the spinal cord and related to muscle relaxation. The synthesis of GABA from glutamate by glutamic acid decarboxylase is discussed, along with its termination through action on postsynaptic receptors, metabolism by GABA transaminase, or reuptake by GABA transporters. Four groups of drugs affecting the GABA system are mentioned: GABA agonists (e.g., benzodiazepines, barbiturates, tiagabine, stiripentol), GABA uptake inhibitors (e.g., tiagabine), GABA transaminase inhibitors (e.g., vigabatrin), and GABA analogs (e.g., gabapentin, pregabalin). The paragraph also discusses the mechanism of phenobarbital, which enhances GABA receptor-mediated synaptic inhibition and blocks AMPA receptors at higher doses.

05:00

💊 Benzodiazepines and Barbiturates as GABA Agonists

This paragraph delves into the specifics of benzodiazepines and barbiturates as GABA agonists. Benzodiazepines increase the frequency of GABA-mediated chloride channel opening, leading to a sedative effect, while barbiturates like phenobarbital increase the duration of opening. The paragraph discusses the drawbacks of benzodiazepines, such as sedation and tolerance to anti-convulsant action over the long term. Specific drugs like diazepam, clobazam, and lorazepam are highlighted for their use in emergency seizure control, absence seizures, and status epilepticus, respectively. The adverse effects of benzodiazepines, including behavioral abnormalities and motor disturbances, are mentioned, along with their availability in tablet and injection forms. The paragraph concludes with a discussion of GABA analogs, which do not directly act as GABA agonists but modulate GABA release by binding to calcium channels.

10:03

💊 GABA Analogs and Their Clinical Applications

The final paragraph focuses on GABA analogs, such as gabapentin and pregabalin, which are used not only for epilepsy but also for neuralgias, migraine prophylaxis, and anxiety disorders. These drugs increase GABA concentration in the brain and inhibit certain types of calcium channels, modulating neurotransmitter release. The paragraph addresses the common side effects of drowsiness and dizziness associated with these drugs. Gabapentin is used as a second-line treatment for partial seizures and is available as a tablet, often started at night to manage side effects. Pregabalin, a newer congener with less sedation, is also used for neuropathic pain. The paragraph concludes with a mention of tiagabine, which inhibits the GABA transporter, leading to increased GABA concentration in the synaptic area and facilitating inhibitory neural transmission. The side effects of tiagabine include dizziness, fatigue, tremor, and confusion. Vigabatrin, which inhibits GABA transaminase, is also discussed, with its side effects such as visual disturbances, weight gain, and psychiatric symptoms. The paragraph summarizes the module on drugs affecting the GABA system, covering GABA agonists, analogs, transporter inhibitors, and metabolism enhancers.

Keywords

💡GABA

GABA, or gamma-aminobutyric acid, is an inhibitory neurotransmitter that plays a crucial role in reducing neuronal excitability throughout the nervous system. In the context of the video, GABA is central to understanding the drugs discussed, as they either enhance or modulate GABAergic activity to prevent seizures. The script mentions that GABA acts through two main receptors, GABA A and GABA B, and imbalances in GABA levels can lead to conditions like epilepsy.

💡GABA A receptor

The GABA A receptor is predominantly found in the brain and is associated with the opening of chloride channels, which leads to the inhibition of neuronal firing. The video script explains that anti-epileptic drugs often target the GABA A receptor to enhance inhibitory synaptic activity, thereby reducing the frequency of seizures. This receptor is a primary target for drugs like benzodiazepines and barbiturates.

💡GABA B receptor

The GABA B receptor is mainly present in the spinal cord and is involved in muscle relaxation through its connection with G-protein coupled receptors. While the script does not delve deeply into GABA B receptor drugs, it is mentioned in the context of centrally acting muscle relaxants, which are not the primary focus of the video but highlight the diversity of GABA's roles in the body.

💡Anti-epileptic drugs

Anti-epileptic drugs are medications used to treat epilepsy by reducing the frequency and severity of seizures. The video script discusses various classes of these drugs, including GABA agonists, GABA analogs, GABA transporter inhibitors, and GABA transaminase inhibitors. Each class works through different mechanisms to increase inhibitory neurotransmission and prevent epileptic seizures.

💡Benzodiazepines

Benzodiazepines are a class of drugs that act as GABA agonists, enhancing the effect of GABA at the GABA A receptor. The script mentions that benzodiazepines increase the frequency of chloride channel opening, leading to increased inhibitory neurotransmission. Examples given include diazepam, clobazam, and lorazepam, which are used for different seizure types and have varying side effects and durations of action.

💡Barbiturates

Barbiturates, such as phenobarbital, are another class of GABA agonists discussed in the video. They enhance GABA receptor-mediated synaptic inhibition, and at higher doses, they can block voltage-gated sodium and calcium channels. The script notes that phenobarbital is used for various seizure types but has fallen out of favor for long-term use due to its sedative effects and potential for behavioral abnormalities in children.

💡GABA analogs

GABA analogs, such as gabapentin and pregabalin, do not directly act as GABA agonists but modulate the release of GABA by binding to specific subunits of calcium channels. The script explains that these drugs are used for resistant partial seizures and various types of neuralgia, highlighting their broad application beyond epilepsy.

💡GABA transporter inhibitor

The script mentions tiagabine as a GABA transporter inhibitor, which works by inhibiting the reuptake of GABA, thus increasing its concentration in the synaptic cleft and enhancing inhibitory neurotransmission. This drug is used for complex partial seizures and is highlighted for its unique mechanism of action among the drugs affecting the GABA system.

💡GABA transaminase inhibitors

GABA transaminase inhibitors, such as vigabatrin, irreversibly inhibit the enzyme responsible for GABA metabolism, leading to increased GABA levels in the brain. The video script points out that vigabatrin can cause distinctive visual side effects, which are a notable clinical consideration. It is used for partial seizures and is an example of a drug with a specific metabolic effect on GABA.

💡Pharmacokinetics

Pharmacokinetics refers to the movement of drugs within the body, including absorption, distribution, metabolism, and excretion. The script briefly touches on the pharmacokinetic properties of phenobarbital, noting that it is a potent enzyme inducer, which can lead to tolerance with long-term use. Understanding pharmacokinetics is essential for dosing and managing the effects and side effects of anti-epileptic drugs.

Highlights

Introduction to anti-epileptic drugs affecting the GABA system.

GABA is an inhibitory neurotransmitter with two main receptors: GABA A and GABA B.

GABA A receptors are concentrated in the brain and are the primary target for anti-epileptic drugs.

GABA B receptors are involved in muscle relaxation and are used in centrally acting muscle relaxants.

GABA is synthesized from glutamate by glutamic acid decarboxylase.

GABA's action is terminated by acting on postsynaptic receptors or by being metabolized or re-uptaken.

There are four groups of drugs affecting the GABA system: GABA agonists, uptake inhibitors, transaminase inhibitors, and analogs.

Benzodiazepines and barbiturates act as GABA agonists, enhancing chloride channel opening frequency or duration.

Phenobarbital enhances GABA receptor-mediated synaptic inhibition and blocks AMPA receptors.

Phenobarbital is a potent enzyme inducer and can develop tolerance with long-term use.

Adverse effects of phenobarbital include sedation, behavioral abnormalities, and cognitive impairments.

Benzodiazepines are used for emergency control of seizures but have drawbacks like sedative effects and tolerance.

GABA analogs like gabapentin and pregabalin increase GABA concentration and inhibit certain calcium channels.

GABA analogs are used for resistant partial seizures and neuralgic pain, but can cause drowsiness and dizziness.

Tiagabine inhibits the GABA transporter, increasing GABA concentration in the synaptic area.

Vigabatrin irreversibly inhibits GABA transaminase, leading to increased GABA levels and potential visual side effects.

Vigabatrin is used for partial seizures and is known for its unique side effect profile, including visual disturbances.

Module conclusion summarizing the key points on drugs affecting the GABA system.

Transcripts

welcome students to the next module of

anti-epileptic drugs that is the drugs

affecting gaba system

so we have already discussed the drugs

affecting calcium channels drugs

affecting sodium channels and now we are

discussing the drugs affecting gaba

system as we all know it is mainly the

imbalance between the anxiety chain

inhibitory neurotransmitter so in this

we are going to concentrate mainly how

to you know increase the inhibitory

synaptic activity or inhibit increase

the inhibitory transmissions so learning

objectives will be enumerated drugs

which acts by affecting gaba levels and

discuss the user's adverse effect and

contraindications as we all know gaba is

an important inhibitory neurotransmitter

it mainly acts by two receptor gaba a

receptor and gaba b receptor gaba a

receptor is mainly concentrated in the

brain which mainly acts through chlor

you know chloride channel opening and

that is the one which is the main target

for our anti-epileptic drugs whereas the

gaba b receptors are mainly present in

the spinal cord and they belong to a g

protein couple type of receptors and

they are mainly involved in muscle

relaxation so which we use it as a

centrally acting muscle relaxants

so before we start up what is the drugs

affecting gaba

let's uh see how the gaba is synthesized

and how it is transported as we all know

it is the glutamate which is a precursor

molecule for gaba which gets converted

to gaba by glutamic acid decarboxylase

once this gaba is synthesized it is

stored in the vesicles and it is

released whenever there is a

depolarization or there is a impulse

conduction in the pre-synaptic neuron

the released gaba has two ways for its

action to gets terminated one is it acts

on the postsynaptic receptor

after that either it will get

metabolized by

gaba trans a minus enzyme or it will be

re-uptaken back by

a gaba transporter so when we are

talking of the drugs which are affecting

the gaba system

there are mainly four groups of drugs

one group which are acting as gaba

agonist we have mainly drugs like

benzodiazepine barbiturates genocide and

stirripintol

gabari uptake inhibitors like tiago bean

gaba trans aminos inhibitors like vigor

battery and gaba analogs like

gabapentine and pregabal here gaba

analogs may not be directly acting as

gaba agonist or gaba mimetics they

mainly act by modulating the release of

gaba how is it we will discuss later

now as i discussed s it is the vigor

battery which inhibits the gaba

transient mnas along with that sodium

valproate which i said a broad spectrum

anti-epileptic can also inhibit the

gamma transaminase

and tiago bean is a drug which inhibits

the gaba transporters you see in the

picture benzodiazepine and barbiturates

act as gaba agonist

now discussing on each group mainly

phenobarbitone and

benzodiazepine let's discuss first

phenobabatone enhances the gaba receptor

mediated synaptic inhibition along with

that it has a

other mechanism of blocking ampa

receptor

but when you give it a high dose it also

has other mechanisms like blocks

voltage-gated uh sodium channels and

calcium channels so there are multiple

mechanisms for phenobarbital but the

main mechanism is enhancement of gaba

receptor mediated synaptic inhibition

and coming to pharmacokinetic property

it is a potent enzyme inducer which

develops tolerance to sedative action on

a long term usage

and adverse effects yes phenobabatone

you all know it is one of the drugs

which is used as a sedative and hypnotic

yes the common adverse effect is

sedation but the important adverse

effect mainly which comes in into

clinical relevance is a behavioral

abnormalities if you are using in a

children that is a reason the use of

phenobarbitone in febrile seizure as a

prophylaxis treatment has been abandoned

nowadays

impairment in the learning and memory

hyperactivity in children and mental

confusion

where do we use this drug we use this

drug in all types of seizures you see

generalized on a clonic seizure simple

partial seizure complex partial seizure

and profile axis of febrile seizure yes

it was being used for the prophylaxis of

febrile seizure but nowadays we have

reduced the use and it is only the

diazepam which is being used because of

its

behavioral abnormality and impairing the

learning and memory in children and it

is the second line drop in the status

epileptic what is it we will discuss in

the next module

it's available as injections and in the

tablet form so depending on whether it's

adult or children the dose can be

adjusted

the next group of drugs which act as

gabo against so we said two groups of

drugs which act as gaba agonist one is

benzodiazepine the other one is

barbiturates otherwise phenobarbitude so

we discussed phenobarbitude now coming

to the benzodiazepine how does this drug

act it this drug acts mainly by you can

see in the picture

increasing the frequency of gaba

mediated chloride channel opening see in

the picture it increases the frequency

of gaba mediated chloride channel

opening whereas the phenobarbital

increases the duration of opening

whereas the benzodiazepine increases the

frequency of opening but what is the

drawback the drawback is that it has a

sedative effect yes because this is one

of the sedative drugs which is being

used for anti-epileptic purpose

tolerance to anti-convulsant action so

this is one of the main drawback when

you are using it for a long term that's

the reason the use of benzodiazepine for

long-term use in anti-epileptic purposes

come down

because of its tolerance action in

benzodiazepine we have different drugs

but what is used for anti-epileptic

purpose we have

four drugs that is dizzy power clan as

the pack clobazam and laura zepa now

dicey pump

it's a first line draw for emergency

control of conversion any patient you

say convulsing diazepam can be given 10

milligram intravenously in status

epilepticus the first choice is

larizepam nowadays but previously it was

diazipa

tetanus patient is convulsing because of

tetanus you can give diazepam

eclampsia eclampsia is

a state in pregnancy where the pregnancy

induced hypertension will

lead to a seizure manifestation their

diazepam can be given and drug poisoning

if a there is a epilepsy due to drug

poisoning we can give the diazepa the

second use is the febrile seizures

febrile's teacher yes diazepam is a drug

of choice and it is given per rectally

in a child and febrile suture is nothing

but seizure in the children below the

five years of age when there is a

episode of fever

but what are the adverse effects when we

give it an emergency obviously we give

it through intravenous route it causes

falling blood pressure it causes

respiratory depression and it leads to

thrombophlebitis

it is available as tablets and induction

yes we don't use it for a long term view

so most of the time what we use for

emergency is in an injection form the

next drug is clobaza so it is a potent

long-acting drug which can be used in

absence seizures and even as an adjuvant

in myoclonic and

a kinetic epilepsy that is atonic

epilepsy

but what are the adverse effects lack of

concentration irritability behavior

abnormality motor disturbance ataxia

salivation this is the reason that's the

reason why benzodiazepines are not being

preferred that commonly as the other

drugs because of their central nervous

system adverse effects yes it's

available as capsules and it can be you

know

those can be titrated depending on the

response

clonazepam

it's less sedative compared to other

drugs long acting

again used in partial secondary

generalized tonic cloning seizures

secondary generalized tonic-clonic

seizure that means it is

where the onset was a partial seizure

later seizure activity progressed to

become a secondary generalized

tonoclonal seizures absences or atomic

seizures it is mainly used as an

adjuvant drug so it's not a wastelander

it's used as an adjuvant drug

it is also available in different

strains and the dose can be adjusted

depending on the response the another

important and the life-saving drug in

benzodiazepine group which is the drug

of choice in status epilepticus that is

lorazepam so larazepam is a drug of

choice for status epilepticus and

emergency control of convulsion what's

the advantage compared to diazepam there

is a less thrombophlebitis and the

action is sustained so it is available

in tablets and injection form what we

use is the injection form what we give

is four milligram iv whenever there is a

seizure episode

so that completes one group of drugs

that is gaba agonist which two drugs

there that's benzodiazepines and

phenobarbital the next group of drugs is

gaba analogues now what do we understand

by gaba analogs are they really acting

like gaba no as i said

see here in the picture

uh they are mainly trying to bind to a

calcium channel where there is alpha to

delta subunit in the calcium channel you

can see in the enlarged picture in the

box there

the drug tries to bind to that alpha to

delta subunits and tries to modulate the

release of the neurotransmitter

so the drugs are gabapentine and

pregabalin so coming to the easter these

drugs most commonly nowadays not just

use for anti-epileptic purpose they are

the one of the drugs used in the

neuralgias also so how do they act they

increase the gaba concentration in the

brain by increasing the release and

synthesis along with that it

inhibits the end type of calcium channel

that's what i was telling and it

modulates the release of

neurotransmitters

but

the problem with this drugs is

drowsiness

and dizziness this is one of the main

problem majority of the patient starts

facing when you start the patient on

gabapentin and they try to discontinue

it

where do we use this gaba pentane i said

it is used in resistant partial seizure

that means we have already tried the

first line drugs like carbamazepine and

other drugs and the patient is not

responding then we can try gabapentine

otherwise this drugs that is both gaba

pentene and priy gabalin are a first

line drugs in neuralgic pain especially

in diabetic neuropathy

the other use is prophylaxis in migraine

alternative to phobic state and it is

used in generalized anxiety disorders

and

postherpetic neuralgia available as

tablet most of the time this tablet is

started in the night time so that if the

dizziness all that effects is taken care

but might need to increase the dose

depending on the response

the second drug again pregabalin which

is the newer congenital same mechanism

of action advantage compared to gaba

pentane is less sedation and uses in

neuropathic pain

so we finished uh the second group of

drugs which affect the gaba system that

is the gaba analogues gabapentine and

pregabalin coming to the third which

inhibits the gaba transporter you can

see in the picture tiago bean is

inhibiting the gaba transporter mainly

highlighted in the orange there so it

inhibits the gaba uptake in the neuronal

and glial cells through gaba so what

happens the concentration in the gaba in

the synaptic area is increased which

facilitates the inhibitory neural

transmission so advanced effect is

dizziness fatigue tremor and confusion

so where do we use we use it in complex

partial seizures with or without

generalization

the last group of drugs in gaba uh drugs

affecting gaba system is the drugs which

inhibits the gaba transaminase enzyme

that is vigor battering so it is an

irreversible inhibitor of gaba

transaminase so it irreversibly inhibits

so for the metabolism of the gaba then

the fresh synthesis of enzyme has to

happen

the problem with vigor pattern is it has

a particular type of side effect which

is the most commonly asked in your all

entrance exam that is a visual side

effect which is an anti-epileptic drug

which has a visual side effect as its

drawback that is vigor battery other

than that it causes weight gain

behavioral changes depression and

psychosis most of the time these drugs

are used in partial seizures with or

without generalization

so that ends the module on the drugs

affecting gaba system so we have studied

four drugs gaba agonist gaba analogs

gaba transporter inhibitor and

drugs which increases the metabolism of

gaba that is vigor bacteria

i think that completes the whole module

on the drugs affecting gaba and thank

you all