Anticonvulsants and anxiolytics: Benzodiazepines

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Introduction0:00–0:32

Benzodiazepines are a class of medications that act as a central nervous system depressant. They have a wide variety of uses including anxiolytic effects, or to relieve anxiety; as anticonvulsants, or to manage seizure disorders; as a hypnotic for insomnia; as an anesthetic; and to treat withdrawal syndromes.
They act by enhancing the main inhibitory neurotransmitter gamma-aminobutyric acid, or GABA, by binding to its receptor.
It’s pretty well-established that your brain’s really important. It controls your feelings, your movements, your sleep, your memory… It controls everything, whether you’re aware of it or not.

Physiology0:32–1:47

The cells that make up our brain are called neurons. Neurons communicate with each other through neurotransmitters.
When one neuron is stimulated, it’ll release excitatory neurotransmitters like glutamate which bind to receptors on the next neuron.
This causes the next neuron to depolarize and release its own excitatory neurotransmitters, propagating the signal throughout the brain.
Now, we also have inhibitory neurons that will shut down this chain of events. These neurons release the main inhibitory neurotransmitter gamma-aminobutyric acid, or GABA, which binds to GABA receptors on other neurons.
These receptors are large, multi unit complexes that form ligand-gated ion channels that open up to let Cl- ions into the cell.
The influx of negatively charged ions causes hyperpolarization, where the cell’s membrane potential becomes more negative, which means it’s much more difficult for it to depolarize and fire off an action potential, meaning it’s less responsive to stimuli.
Alright, now there are cases where neurons in the brain start sending out more excitatory signals than normal. This can occur due to either too much excitation by the excitatory neurotransmitters, or too little inhibition by the inhibitory neurotransmitters like GABA.

Pathology1:47–2:12

Excessive excitatory signals can cause psychiatric disorders like anxiety, and neurological disorders like seizures and epilepsy.
Okay, so one way we can decrease the excitatory signals is by enhancing the effect of inhibitory neurons through medication like benzodiazepines.

Mechanism of Action2:12–4:38

They are composed of a benzene ring that consists of six carbon atoms fused to a diazepine ring that is made up of 5 carbon atoms and two nitrogen atoms.
Now, based on the overall duration of action, these medications can be subdivided into short-acting benzodiazepines, like ALPRAZolam, Triazolam, Oxazepam, and Midazolam; intermediate-acting benzodiazepines, such as Temazepam, LORazepam, and ClonazePAM; and finally, long-acting benzodiazepines, like ChlordiazePOXIDE, DiazePAM, and Flurazepam.
So, to remember short-acting benzodiazepines think of “ATOM”; for intermediate-acting, remember that these medications are tender, loving, and caring, or short TLC; and finally for long-acting benzodiazepines, think of alphabet and it’s order CDeF.
These medications target the BZ site of GABAA receptors, which is located between ⍺1 and 2 subunits of the receptor. When both benzodiazepine and GABA bind to their separate sites on the receptor, benzodiazepines increase the frequency of Cl- channels opening, thereby increasing the influx of Cl- ions.
As a result, high intracellular concentrations of Cl- ions cause membrane hyperpolarization, which means it’s much more difficult for neuron to depolarize and fire off an action potential.
Now, a similar group of medications called barbiturates also function by binding to GABAA receptors. The important distinction is that barbiturates work by increasing the duration of Cl- channels opening and unlike benzodiazepines, they can cause the channels to open even in the absence of GABA.
Now, let’s draw a chart of the dose-dependent effects of benzodiazepines. On the left side of the chart, let’s place central nervous effects and on the bottom, let’s place dose.
Low doses of benzodiazepines cause sedation, disinhibition, and anxiolysis; but as the dose increases, benzodiazepines cause hypnosis and anesthesia.
Since they don’t have GABA mimetic effect, benzodiazepines reach the plateau; therefore they are not associated with medullary depression and coma.
Alright, so benzodiazepines are indicated when the neurons get “super excited” and we want to calm them down like in anxiety disorders, or during a panic attack.

Indications4:38–6:16

It’s important to note that preferred medications for the long-term treatment of panic attacks are selective serotonin reuptake inhibitors, or short SSRIs, due to abuse potential, dependence, and tolerance of benzodiazepines.
Benzodiazepines are also very effective anticonvulsants and are considered the treatment of choice for status epilepticus, which is when a person has over 5 minutes of ongoing seizures or multiple seizures without returning to normal in between.
Certain benzodiazepines are also used for anesthesia since we basically want to depress the function of the patient’s nervous system.
For the same reason, they are an effective treatment for insomnia, but they decrease REM sleep. Moreover, because they decrease REM sleep, they can also be used to treat night terrors, which is a sleep disorder similar to nightmares but far more dramatic as it’s associated with screaming and crying.
Since alcohol and barbiturates also work by targeting GABAA receptors, benzodiazepines can be used to manage their withdrawal symptoms by decreasing their severity.
DiazePAM can also be used as the second-line treatment for eclampsia, which is a life-threatening complication of pregnancy that is associated with seizures.
But, it’s important to note that diazePAM should be used only if seizures recur after giving magnesium sulfate (MgSO4), which is the first-line treatment for eclampsia.
Finally, they are sometimes used as muscle relaxants to treat spasms, like those caused by cerebral palsy. Moving on to side effects!

Side Effects6:16–7:45

Benzodiazepines can have some adverse effects even when used at therapeutic levels, but since they are more selective than barbiturates, these side effects are less severe.
They can cause drowsiness, as well as a decrease in concentration, problem solving abilities, and reaction time. Due to this, they should not be taken before driving.
Despite being a central nervous system depressant, benzodiazepines can cause paradoxical stimulation in certain parts of the brain, leading to symptoms such as fast speech, excitement, and restlessness.
Another side effect is anterograde amnesia, which is defined as an inability to form new memories after the administration of the medication.
In some cases, this can be useful to eliminate unpleasant perioperative memories and the most common benzodiazepine used for anterograde amnesia is midazolam!
Next, benzodiazepines should be used with caution in the elderly because they can cause ataxia and precipitate falls. Also when combined with alcohol or other medications that depress the central nervous system, like barbiturates, the depressive effects are additive and can get severe to the point of respiratory depression and coma.
The good news is that overdose can be managed with flumazenil, which acts as a competitive antagonist for benzodiazepines, which means that it binds to the same site as benzodiazepine and blocks its action.
But, it’s important to note that flumazenil can’t be used to treat barbiturate overdose! Alright, switching gears and moving on.

Metabolism7:45–8:22

Most of these medications are metabolized in the liver by CYP450 enzymes into active metabolites; therefore they should be avoided in individuals with liver impairment.
But, it’s important to note that these individuals can use LORazepam, Oxazepam, and Temazepam because they are primarily metabolized by a process known as glucuronidation.
This process is not associated with active metabolites and therefore is safe. So remember, individuals that drink a LOT, can use LORazepam, Oxazepam, and Temazepam.
When used chronically, a person can develop tolerance to benzodiazepines, and their effectiveness decreases, which means that they’ll need to increase the dose to get the same effects.

Tolerance and Dependence8:22–9:09

This is problematic because benzodiazepines are habit forming and could lead to addiction. Moreover, short-acting benzodiazepines are associated with a higher addiction potential since they have a shorter half life!
Chronic use also leads to dependence, which means, when the medication is discontinued, the person experiences withdrawal symptoms like insomnia, anxiety, and seizures.
This is less likely to happen when compared to barbiturates, making benzodiazepines the preferred choice. Surprisingly, the treatment of choice for people with benzodiazepine withdrawal is more benzodiazepines, but with lower doses!
As far as contraindications go, benzodiazepines should be avoided in individuals with myasthenia gravis since they can exacerbate myasthenic symptoms.

Contraindications9:09–9:34

Other contraindications include respiratory insufficiency, severe liver impairment, acute narrow-angle glaucoma, and untreated open-angle glaucoma.
Finally, these medications should be avoided during pregnancy and breastfeeding. Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharmacology facts!

Memory Palace9:34–12:13

So first, let’s start with a large dorm room, and hanging from the ceiling are two interlocked rings which represent the benzene and diazepine ring that make up benzodiazepines.
Now six students live here, which means there’s a lot of people coming and going, so the door representing the chloride channel opens frequently.
Each of these guys represents one of the indications for benzodiazepines. First, there’s a three level bunk bed, and the student sleeping soundly on the top bunk represents their effect as a hypnotic.
On the next level, there’s a student who’s undergoing surgery, which represents their anesthetic effects. The student on the bottom bunk is having a seizure to help you remember they are anticonvulsants.
Let’s put a poster of the dose-dependent chart by the bed to help you remember that concept. Now there’s also a long desk with five students.
One student is having an anxiety attack as he studies for his test, so benzodiazepines can be used as an anxiolytic. His buddy is getting a massage, which represents their muscle relaxant properties.
The next student fell asleep and is dreaming about a horrible ghost to help you remember they are used to treat night terrors.
The next student is trying to stay awake by putting a giant clamp on his head, which represents eclampsia. And finally his other buddy is tossing away all his alcohol, since benzodiazepines can be used to treat withdrawal symptoms.
On the wall in front of him is his old poster that says “drink a LOT” on it with a picture of a sad liver. LOT stands for Lorazepam, Oxazepam and Temazepam which are safe to use in individuals with liver impairment.
Okay, now these guys have some lady friends over, which represents the side effects. First, there’s a girl dozing on the sofa, representing drowsiness.
Next to her is a girl having trouble with a rubik's cube which represents the cognitive effects like decreased problem solving abilities and concentration.
Another girl standing next to her is trying to remember her name and this represents amnesia. The next girl is talking quickly and excitedly on her phone, which represents paradoxical stimulation.
She’s trying to get a taxi to go home which represents ataxia. The last girl is hanging up anti drug posters since benzodiazepines can lead to addiction.
In case of overdose, flumazenil is the medication of choice so let’s have a flying maze next to her like a guardian angel.
There’s a whisky bottle surrounded by barbed wires in the trash can to help you remember these medications should not be taken with alcohol or barbiturates since their depressant effects are additive.
All right, as a quick recap. Benzodiazepines are central nervous system depressants that function by enhancing the actions of GABA by increasing the frequency of Cl- channels opening.

Review12:13–12:52

They are widely used as anxiolytics, anticonvulsants, anesthetics, and for the treatment of: sleep disorders, muscle spasticity, and withdrawal syndromes.
Benzodiazepine overdose is relatively safe when compared to barbiturates and can be managed with flumazenil, which is a competitive antagonist for benzodiazepines.
When used for a long period of time, they cause tolerance and addiction. If they’re discontinued, it could trigger withdrawal symptoms.
But wait, there's more: Here's a mind map with all of the mnemonics from the video. Go ahead and pause the video so you can test yourself to see what you remember.

Mind Map12:52–13:01