Sedatives and Hypnotics

❖ Introduction and definitions:

Sedatives: are drugs that decrease general activity and moderate excitement. These
drugsare used to calm the patient.
Hypnotics: are drugs that put the patient into sleep (induce sleep). They produce
drowsiness and facilitate the onset and maintenance of sleep. This is done by decreasing
the latency after he goes to sleep, decreasing the number of times during which the
patientwakes up at night or increasing the sleeping time in general.
Anxiolytics: are drugs used to manage anxiety.
Anxiety: is a medical condition where the patient has an unpleasant state accompanied
bynervous behaviour.
Fear: is a normal common life experience that happens after a stressful condition
(example: fear resulting from entering the exams room, fear resulting from visiting a
physician…etc.). Fear doesn’t warrant treatment.

❖ Signs and symptoms:

It is easy to diagnose a patient with anxiety if he has these symptoms.
These symptoms are noticed on both anxious and fearful people. If there is a direct reason for
thesefeelings and symptoms → fear. If there isn’t direct reason for these feelings and symptoms
→ anxiety. If the reason for these feelings is in the future → anxiety. Example: a second year
university student who is anxious about not finding a job after he graduates. The student in this
example will suffer from anxiety that will affect his physiological function as well as his mental
thinking (this condition needs to be addressed and treatment should be given to the patient).

These symptoms include:

1. Mind racing.
2. Sleep disturbances.
3. Breathlessness.
4. Nausea and loss of appetite.
5. Restlessness.
6. Jelly-like legs.
7. Dizzy disorientated lightheaded.
8. Vision strange blurry.
9. Swallowing difficulty.
10. Heart racing and palpitations.
11. Trembling.
12. Sweating and shivering.
13. Wanting to run.
 ❖ Degrees of activity:
A normal individual might have an increase in stress
and activity, resulting in anxiety or fear, or a decrease
in them,resulting in sedation and calmness. A further
decrease in activity results in sleep and hypnosis. If the
decrease in activity continues, the patient will be
anesthetized.
In the sedated phase, there won’t be any motor
impairmentnor any cognitive impairment. So, when a
patient is given sedatives, he will sense calmness and
sedation (while he is awake and can function normally).
The next stage of activity inhibition is Hypnosis.
Then the next stage of activity inhibition is surgical anesthesia, which is only produced by
giving the patient anesthetic drugs. When someone is surgically anesthetized, his muscles will
relax and hewon’t feel pain. So, he will actually lose the motor function, the cognitive function as
well as the general sensation.
With further inhibition, and as the patient won't be able to breathe alone if there is no
mechanical ventilation, the patient may die (because all muscles, including the
diaphragm,are going to be relaxed).
According to this, any drug that moves the patient from the anxious state to the normal
state is an anxiolytic. Any drug that moves the patient from the normal state to a little
bitcalmer state is a sedative. Any drug that moves the patient from the normal state to
the sleep and hypnosis state is a hypnotic. Any drug that moves the patient from the
normal state to the surgical anesthesia state is a general anesthetic.
Note that as we increase the dose of sedatives/ hypnotics (dose dependent), we move the
patientfrom higher degrees of activity (anxiety) to lower ones (sedation → hypnosis →
surgical anesthesia → death).

❖ Drugs:
1- Benzodiazepines (the most common).
2- Barbiturates (old generation).
3- Non-Benzodiazepines (z-class).

4- OTC Medications (over the counter: you don’t need a prescription to buy them).

1. Benzodiazepines (BDZ):
➢ They have largely replaced barbiturates in the treatment of anxiety and insomnia because
benzodiazepines are generally considered safer (they have a high therapeutic index) and
moreeffective.
➢ The most widely used anxiolytics.
➢ Drugs names usually end with -zolam or -zepam
 ➢ MOA: They target GABA (A) receptors and increase their affinity to GABA.
➢ Pharmacokinetics of BDZ:
1. Lipophilic; which means that they are absorbed orally (easily absorbed by the GIT), can cross the
BBB (to produce their effects of sedation) and can cross the Placenta (not recommended during
pregnancy).
Note: they can be given IV or IM in cases of status epilepticus.

2. Metabolism: benzodiazepines are metabolized by the liver microsomal enzymes. One subtype of
these medications can produce active metabolites that will result in a longer half-life. Final metabolism
of these medications happens through conjugation and then excretion.

MOA of benzodiazepine: GABA receptors are receptors

Benzodiazepines target GABA A receptors, which consist of 5 to which the endogenous
subunits; 2 α, 2 β and 1 γ, and a channel in the middle. If we take a neurotransmitter GABA bind.
cross section of a GABA A receptor, we can see that the binding site There are two types of GABA
for GABA is between the α and β subunits. However, BDZs don’t
receptors:
bind to the same binding site of GABA. So, they are neither agonists
nor antagonists. BDZs are considered to be positive allosteric GABA A: ionotropic receptors
modulators that binds to a different site other than the binding site of where ions (specifically chloride
the ligand (at the interface of the α and γ subunits). ions) can enter the cell.
GABA B: metabotropic
receptors (G protein coupled
receptor), there is no channel
that opens directly because of
the binding of GABA to the
receptor or an agonist of it.
They are mostly found as
dimers. Once the ligand binds
→ G-protein will be activated.

Note that there are two binding sites for GABA.

From the figure in the previous page:
A. The GABA receptor is inactive and the chloride ion channel is closed.
B. Once the GABA binds to the receptor, the channel will open and chloride ions will go inside the cell
and produce hyperpolarization of the neuron (because they are negative in charge).

C. If GABA binds in the presence of BDZ (both should be binding as BDZs alone can’t make the
action), there will be an enhancement in the function of the GABA. Therefore, there will be more entry
of chloride ions → leading to more hyperpolarization (inhibition) and making it more difficult for the
cell to depolarize. Therefore, reducing neural excitability and producing sedative and hypnotic effects.

So, BDZs increase the affinity of GABA Receptors to its ligand and GABA starts to bind more
frequently to its receptor per unit of time. When we study Barbiturates, we will find that they will
increase the binding duration (time) of GABA to the receptor. So, both of them target GABA A
receptors to enhance the function of GABA, but with a different MOA.

Remember:
Allosteric modulators: are substances that bind to a receptor to change the receptor’s response to
a stimulus. They don’t bind at the same active site of the receptor. They bind to another adjacent
site on the receptor. This will lead to either increasing or decreasing the affinity of the receptor to
the primary ligand.
If it increases (enhances) the effect, we call it “positive allosteric modulator”. If it decreases
(reduces) the effect, we call it “negative allosteric modulator”.

Therapeutic uses of BDZs:

1. Anxiety disorders:
➢ For continued severe anxiety.
➢ Try to use for short periods of time (because they are prone for addiction (the patient will be
calm only when he takes these medications)).
➢ Diazepam, Clonazepam and Lorazepam are preferred drugs.
2. Muscular disorders: such as skeletal muscle spasms in multiple sclerosis and cerebral palsy.
These drugs will decrease spasms and pain felt by the patient.
3. Amnesia:
➢ They are often employed as preanesthetic medications for anxiety-provoking and unpleasant
procedures, such as upper and lower GI endoscopy and bronchoscopy. These drugs enhance
the action of anesthetic drugs and also cause a form of conscious sedation (the patient won’t go
into complete general anesthesia and he will be aware and normal during the procedure). The
patient will be receptive to instructions during these procedures and able talk to the surgeon. But
once the procedure is finished, he won’t remember anything.
➢ We prefer the short acting BDZs such as Midazolam (DOC).
4. Epilepsy and seizures:
➢ DOC for grand-mal seizures and status epilepticus (in the hospital setting).
➢ Lorazepam or Diazepam.
5. Sleep disorders (insomnia):
➢ Either because of increased latency to sleep (you go to sleep but you can’t sleep. You stay in the
bed for 5-6 hours and then sleep) or because of (frequent and early awakening).
➢ Taking benzodiazepines will increase stage II of non-REM sleep (REM = Rapid Eye
Movement).
➢ The problem of using these medications for a long period is rebound insomnia (if the patient
took these drugs for a long period of time then suddenly stopped taking them).
➢ Giving these drugs to elderly might cause harm in an indirect way. When they go to the
bathroom for example at night after taking these drugs, they will be sedated. This sedation will
increase their chances of falling down resulting in fractures and injuries that might exacerbate
their medical conditions (so we have to advise the patients and tell them what to do).
➢ Commonly prescribed benzodiazepines for sleep disorders include:
A- Flurazepam: Long-acting.
B- Temazepam: Intermediate acting (given orally 1-2 hours before going to bed).
C- Triazolam: Shortest half-life. This drug has the highest chance to produce rebound insomnia.

Rebound insomnia:
BZDs (especially short acting ones) can produce rebound insomnia (which means
that when the patient stops the drug, he will have insomnia again (that may be
worse than the first insomnia).

This is a study conducted on patients using BZDs to sleep to see the effect after
stopping the drug.

You can see that in the case of Triazolam, which is a short acting BDZ, the patient
stays awake for the longest period of time after stopping the drug (he suffered
from insomnia again). He stays awake for almost 50% increase in total wake time
from baseline. On the other hand, if the patient stops taking Flurazepam, which is
long- acting BZD, he will continue to experience its effects of inducing sleep.
So, the highest risk of having rebound insomnia is usually associated with short-
acting drugs.

Side effects of BDZs:

1- Paradoxical effect:
After taking BDZs, some patients become more active, more excited and mare
awake than usual (the patient experiences opposite effects). It is not known why these effects happen
(however, they affect only a small percentage of patients).

2- Tolerance and dependence:

• The patient with time will need to increase the dose so that drug can be effective.
• Also, if the patient stopped taking these medications, he would suffer from rebound insomnia
and other side effects. These withdrawal symptoms are more common with short acting
benzodiazepines compared with long acting ones. These withdrawal symptoms include:
Confusion, anxiety, agitation, restlessness, insomnia, tension, convulsions and seizures (the
opposite of indications).
3- Drowsiness and sedation:
Although that sedation is one of the therapeutic advantages of using these medications, it can be also
considered as a side effect. This is important to note for patients who drive to work (as these drugs
induce sleep → accidents), patients who have an important meeting in the following day or patients who
have exams (as these drugs cause cognitive impairment).

4- Combination with other sedatives (and other brain function inhibitors) concurrently:
• Alcohol, barbiturates, anesthetics.
• Produce very toxic side effects that may result in death.

5- Anterograde amnesia:
Impaired cognitive function and ability to learn new information after the drug starts producing its
effects.

Classification of benzodiazepines:
– Usually, BDZs are classified according to their duration of action into:
1. Long acting BDZs:
➢ Diazepam (Valium) is the prototype.
➢ Other long acting medications are: Flurazepam, Clonazepam, Chlordiazepoxide.
➢ These drugs are said to be long acting because their metabolism in the liver produces active
metabolites, so longer duration of action.
➢ Uses:
1- Anxiolytic.
2- Anticonvulsant (DOC in status epilepticus).
3- Sedative/hypnotic.
4- Muscle relaxant (in cerebral palsy for example).
➢ Side effects:
1- Anterograde amnesia
2- Can produce tolerance, dependence and withdrawal symptoms.

➢ Pharmacokinetics:
• Oral, IM, IV
• It has a good oral bioavailability (100%).
• Protein bound in the plasma (to albumin).
• Very lipid soluble; they can easily cross the BBB and can accumulate within the organs
(resulting in a long duration of action (because after the drug is cleared from the blood, the
drug can go to the blood from its accumulations within organs)).
• It has active metabolites such as desmethyldiazepam (nordazepam) and oxazepam.
• Glucuronidation in the liver and excretion by the kidney.
• Half-life may reach 100 hours (with active metabolites).
2. Intermediate acting BDZs:
➢ Lorazepam, Temazepam and Alprazolam.
➢ Intermediate duration of action (9-20 hours).
➢ Uses: Anxiety – Epilepsy - Nausea and vomiting - Muscle spasms - Insomnia.
➢ They have faster tolerance and dependence compared to long acting BDZs. So, it is not preferred
to use these medication for more than 4 weeks.
3. Short acting BDZs:
➢ Midazolam, Triazolam and oxazepam
➢ Half-life is 2-6 hours.
➢ Uses:
• Pre-anesthetic medication (the main use)
• Preoperative sedation
• Endoscopic (upper and lower) and bronchscopic procedures (to produce conscious sedation)
• Anticonvulsant (if diazepam is not found)
• In short-term treatment for insomnia (but if you use it for a long period, it may produce huge
dependence and rebound insomnia).

BDZ Overdose:
• Risk of BDZ overdose is enhanced if combined with other depressants like: Alcohol, opioids,
TCAs (Tricyclic antidepressants), anesthetics and barbiturates.
• Toxidrome of BDZ:
o drowsiness, slurred speech and loss of
consciousness
o hypotension and ataxia Toxidrome: is a group of signs
o respiratory and cardiovascular depression (very low and symptoms that is very
RR) suggestive of a particular drug
o there is no miosis (pin-point pupil) and this is how intoxication.
you can differentiate between opioids overdose and
BDZs overdose.

If a patient with BDZ overdose arrived to the hospital, we have to maintain his respiration. They are
going to intubate him directly to maintain a normal respiratory rate and normal O2 and CO2 levels.
• Antidote: Flumazenil. but its use is controversial, why?
o In long term users, this drug might be not effective.
o It may cause epilepsy (so you have to make a good judgement of the dose to be given to
the patient alongside monitoring him).
o It may cause cardiac arrhythmias.
o Re-sedation occurs because flumazenil has a very short duration of action compared to
BDZs. So, you have to re-administer the drug repeatedly till all the BDZ is excreted.
2. Barbiturates:
➢ Older than BDZs.
➢ Barbiturates were replaced with BDZs due to the side effects of barbiturates, which include:
1- toxicity, especially liver toxicity.
2- induction of liver enzymes, producing a lot of drug-drug interactions (these hypnotics are used
commonly by elderly. Elderly take a lot of medications → barbiturate in this case will cause a lot of
drug to drug interactions).
3- higher and stronger dependence and tolerance.
4- more lethal.
5- withdrawal symptoms are more severe.
➢ MOA: They target GABA (A) receptors. Barbiturates binding
site is near the ion channel (chloride pore). It increases the
duration during which the chloride channel is open. So, it is
also a positive allosteric modulator. Another difference
between barbiturate and BDZs is that barbiturates can activate
the channel when they are at a high concentration even in the
absence of GABA (so they can be considered as GABA
agonists).
➢ Barbiturates are much more dangerous than BDZs.
The therapeutic index of barbiturates is much
narrower than that of BDZ. So, barbiturates reach
lethal doses at a much lower dose.
➢ Examples:
1- Thiopental: induction of anesthesia (short acting).
2- Phenobarbital: anticonvulsant (long acting). DOC in status epilepticus of
BDZ didn’t work.
3- Pentobarbital: sedative/hypnotic (intermediate acting).

Looking at this picture: you can see that benzodiazepines have the highest
therapeutic index (lethal dose / effective dose) so it is considered the safest. You
can see Barbiturates having a lower therapeutic index and Morphine (an opioid)
having the lowest therapeutic index thus considered the most dangerous.

3. Z-class:
➢ Zolpidem is the prototype.
➢ Other drugs include: zaleplon and eszopiclone.
➢ These drugs are non-benzodiazepines. However, they have the same MOA. They bind to the
same binding site and have the same effect (increase the affinity).
➢ They have a short half-life (2-3 hours) and a rapid onset of action.
➢ Effect may last for one week after discontinuation.
➢ These drugs decrease sleep latency. However, they have no effect on sleep stages. They are the
most commonly prescribed sleep pills in the United States (because they are safer than BDZ,
very efficacious, have a short duration of action and their rebound insomnia compared to BDZ is
less).
➢ They can be given through multiple routes of administration.
 ➢ Side effects:
1- Impaired performance and cognition especially in the morning. The patient should be careful
upondriving.
2- It might produce dependence.
➢ In case of overdose, we use the same antidote; namely Flumazenil. Flumazenil is an
antagonistthat binds to the same binding site of both BDZs and Zolpidem.

4. OTC medications:
1- Ramelteon:
➢ Melatonin agonist (MT 1+2 receptor agonist). Once melatonin binds to its receptor, it
induces sleep. Melatonin is a hormone (secreted by the pineal gland) that controls the
circadian rhythm. Its highest concentration in the body is between midnight and 8 AM. So, if
we have an agonist,such as Ramelteon, we can induce sleep.
➢ It is a very safe drug. It has no dependence or tolerance. For this reason, these drugs are over
thecounter (but not in Jordan).
➢ It is taken 30 minutes before bedtime.
➢ It is indicated for insomnia as it decreases sleep latency. It is good also for patients who travel
all the world as it decreases the jet-lag problems that patients may suffer from during their
travels.
➢ Side effects:
Dizziness, fatigue and somnolence.

2- First generation Antihistamines:

➢ Indicated for mild insomnia.
➢ Diphenhydramine is the prototype.
➢ Other drugs include chlorphenamine (Allerfin).
3- alcohol:
➢ They are not prescribed to induce sleep. But it can also be anxiolytic and produce sedation.
➢ They can produce disulfiram like reactions.
➢ Naltrexone is the DOC in alcohol addiction.

Summary:
Anxiety: (intermediate/long) BDZ drugs are preferred like:
• Alprazolam
Status epilepticus:
• Diazepam, Lorazepam IV (the patient can’t eat or drink during convulsions).
In anesthesia induction (preanesthetic): we usually use short acting drugs like:
• Midazolam
Insomnia: (intermediate acting BDZ, or short acting for short period then switch
intointermediate acting)
Temazepam, Oxazepam (a short acting drug