7 - Anxiolytics-Sedatives-Hypnotics

Dr Nancy Safwat Younis
(PhD, BCPS)
Nyounis@kfu.edu.sa
Neurophysiology Overview
GABA controls the excitability of neurons by binding to

the GABAA receptor.
All GABAA receptors contain an ion channel that
conducts chloride ions across neuronal cell membranes and two
binding sites for the neurotransmitter GABA.
Chloride ions entering the cell stabilize the membrane and
make it more difficult for excitatory transmitters to fire the
neurons.
All sedatives-hypnotics are positive GABAA modulators.
They increase the ability of GABA to open the chloride (Cl-)
ion channel.
At low doses, Benzodiazepines enhance the effect of GABA.
Drugs used in anxiety, sleep disorders or hypnotics all have the

capacity to depress the function of the CNS producing calming or
drowsiness (sedation).
They do this in a dose-dependent fashion which progressively

leads to death.
Now, drugs like antidepressant, antiepileptic and antipsychotic

drugs) or 5-hydroxytryptamine (5-HT)1A receptor agonists (e.g.
buspirone) that have no hypnotic effect are in use.
Neurophysiology Normal
Overview
Anxiolytic
Drowsiness/Decreased
reaction time
Hypnosis
Confusion, Delirium
and Ataxia
Surgical Anaesthesia
Coma and Death

General Definitions
Anxiolytic: Reduce anxiety, physical, emotional, cognitive.
Sedative: Calm effect, reduce and treat agitation.
Hypnotic: Induce sleep fast in insomnia.

General Definitions: Anxiety disorders
Anxiety is an unpleasant state of tension, apprehension, or
uneasiness
The physical symptoms of severe anxiety: tachycardia,

sweating, trembling, and palpitations) and involve sympathetic
activation.
Episodes of mild anxiety are common life experiences and do

not warrant treatment. However, severe, chronic, debilitating
anxiety may be treated with antianxiety drugs (sometimes
called anxiolytics) and/or some form of psychotherapy.
Anxiety disorders as recognized clinically include:
Generalised anxiety disorder (an ongoing state of excessive

anxiety lacking any clear reason or focus)
Social anxiety disorder (fear of being with and interacting with

other people)
Panic disorder (sudden attacks of overwhelming fear occur in

association with marked somatic symptoms, such as sweating,
tachycardia, chest pains, trembling and choking).
Anxiety disorders as recognized clinically include:

Generalised anxiety disorder
Social anxiety disorder
Panic disorder
Phobias (strong fears of specific objects or situations, e.g.
snakes, open spaces, flying)
Post-traumatic stress disorder (anxiety triggered by recall of

past stressful experiences)
Obsessive compulsive disorder (compulsive ritualistic behavior

driven by irrational anxiety, e.g. fear of contamination).
Drugs used in anxiety disorders
Treatment = psychological + drug treatment.
Because many of the antianxiety drugs also cause some sedation,

the same drugs often function clinically as both anxiolytic and
hypnotic (sleep-inducing) agents. (Anxiolytics, Sedative and
Hypnotic agents)
Treatment changed from using traditional anxiolytic/ hypnotic

agents (i.e. BZD and barbiturates) to drugs treat other CNS
disorders (e.g. antidepressant, antiepileptic and antipsychotic)
Benzodiazepines (BZD) is effective anxiolytic drugs, but produce

unwanted side effects such as amnesia, and tolerance and physical
dependence, drugs of abuse, ineffective in treating any depression
that may occur along with anxiety.
Antidepressants and buspirone do, however, require three or more

weeks to show any therapeutic effect and must be taken
continuously, whereas BZD can be useful for patients who need
acute treatment as they reduce anxiety within 30 min, and can be
taken on an as needed basis.
Anxiolytics
Antidepressants
Antiepileptic
-Adrenoceptor antagonists
Buspirone
Benzodiazepines
Antidepressants
Selective serotonin (5-HT) reuptake inhibitors (SSRIs; e.g.

escitalopram, sertraline and paroxetine) and
serotonin/noradrenaline reuptake inhibitors (SNRIs; e.g.
venlafaxine and duloxetine)
Effective in the treatment of generalised anxiety disorder,

phobias, social anxiety disorder and post-traumatic stress
disorder; Effective against most forms of anxiety.
Antidepressants
Antidepressants are now the main drugs used to treat anxiety.
Their effects are slow in onset (> 2 weeks).
These agents have the additional advantage of reducing any

depression that may be associated with anxiety.
Antiepileptic
Gabapentin, pregabalin, tiagabine and valproate, antiepileptic

drugs, are effective in treating generalised anxiety disorder.
-Adrenoceptor antagonists (propranolol)
These are used to treat some forms of anxiety, particularly where

physical symptoms such as sweating, tremor and tachycardia are
troublesome.
Their effectiveness depends on block of peripheral sympathetic

responses rather than on any central effects.
Buspirone
Effective in generalized anxiety disorder
ineffective in controlling panic attacks or severe anxiety states

or phobias or social anxiety disorder.
Potent partial agonist at 5-HT1A receptors
binds to 5-HT receptors to relieve anxiety suppression.
Its effect is slow in onset (> 2 weeks); takes days to weeks to

produce its anxiolytic actions just like antidepressants.
Buspirone
Unlike benzodiazepines, it does not cause sedation, motor

incoordination, tolerance and withdrawal effects.
Has wide margin of safety.
drug appears to be safe in pregnancy.
Side Effects
Include nausea, dizziness, headache and restlessness.
No sedation or loss of coordination (less troublesome than with

BDZ)
Antidepressants
Antiepileptic
-Adrenoceptor antagonists
Buspirone
Benzodiazepines
Benzodiazepines
Mechanism of action
Pharmacological Effects
Classification
Pharmacokinetics
Effects on the CNS
Therapeutic Uses
Side Effects
Abuse Potential
Benefits
Effects in Overdose
Adverse effects
Benzodiazepines
Benzodiazepines are a class of mild tranquilizers that

prevent or reduce anxiety symptoms by affecting the
inhibitory neurotransmitter gamma-aminobutyric acid
(GABA).
Could be classified as either: Anxiolytic, or Sedative-

hypnotic.
They have potential abuse.

Benzodiazepines
Mechanism of action:
Act selectively on GABAA receptors which mediate inhibitory
synaptic transmission throughout the central nervous system,
facilitating the opening of GABA-activated chloride channels
Benzodiazepines
Anxiolytic: reduction of anxiety and aggression
Sedative and hypnotic: induction of sleep and sedation
Anticonvulsant effect
Muscle relaxant: reduction of muscle tone and
coordination; at high doses, BDZ relax skeletal muscle,
probably by increasing presynaptic inhibition in the spinal
cord, where the 2 GABAA receptors are largely located.
Anterograde amnesia: temporary impairment of memory.
The ability to learn and form new memories is also impaired.
(not the retrograde amnesia)
Benzodiazepines
Effects on the CNS
With increasing doses, benzodiazepines can progressive cause

sedation, then hypnosis and then stupor (a condition in which
someone is not able to think normally).
Can not produce general anesthesia since awareness persists.
Have anti-anxiety / sedative-hypnotic properties.
The muscle relaxants property is centrally controlled.

Benzodiazepines
Pharmacokinetics
Absorption: Well absorbed when given orally. (intravenously, and
intramuscular injection, buccally and rectally)
Distribution:
They bind strongly to plasma protein.
High lipid solubility SO accumulate gradually in body fat.
Persist longer in obese, elderly.
Fast across blood-brain-barrier: rapid onset of action.
Distribution volumes is large.
Metabolism: metabolized by hepatic microsomal system
Elimination: eventually excreted as glucuronide conjugates in the
urine.
Benzodiazepines
Classification:
Classification is based on duration of action.
o Short acting : Midazolam, Triazolam, Oxazepam, Lorazepam,

Temazepam,
More rapid-acting agents that provide quicker symptom

control.
However, tolerance of the hypnotic effect develops rapidly,

withdrawal problems are common.
Benzodiazepines
Classification:
o Long acting: Alprazolam, Chlordiazepoxide, Diazepam,
Clonazepam and Flurazepam.
Longer-lasting effects throughout the day
Less pronouncedwithdrawal symptoms may be
More hangover symptoms occur in the morning
Accumulate in older adult patients
Benzodiazepines duration of action influences their use: Short-

acting compounds being useful hypnotics with reduced
hangover effect on wakening, long-acting compounds being
more useful for use as anxiolytic and anticonvulsant drugs.
Benzodiazepines
Therapeutic Uses
1. Major indication is for anxiety (because of their anxiolytic

properties); acute anxiety.
2. Panic attacks (used in combination with antidepressants

particularly in panic disorders has better prognosis) and phobias.
Useful in treating anxiety related to depression and schizophrenia.
Reserved for severe anxiety only and not used to manage the stress
of everyday life (addiction potential) .
Benzodiazepines
Therapeutic Uses
3. Effective as sedative/hypnotics: useful in treatment of
a. Insomnia
b. Effective muscle relaxants
c. Generate anterograde amnesia
Commonly prescribed benzodiazepines for sleep disorders include
intermediate-acting temazepam and short-acting triazolam.
Long-acting flurazepam is rarely used, due to its extended half-
life, which may result in excessive daytime sedation and
accumulation of the drug, especially in the elderly.
Benzodiazepines
Therapeutic Uses
4. Treatment of alcohol withdrawal
5. Effective anticonvulsant: Clonazepam is occasionally used as

an adjunctive therapy for certain types of seizures, whereas
lorazepam and diazepam are the drugs of choice in terminating
status epilepticus.
6. Muscular disorders: Diazepam is useful in the treatment of

skeletal muscle spasms.
Benzodiazepines
Side Effects (during therapeutic use)
Most Common: mental confusion, disorientation, drowsiness,
lethargy.
Benzodiazepines enhance the depressant effect of other drugs,
including alcohol
Less common: Muscular incoordination, ataxia (a lack of muscle
control during voluntary movements), short term anterograde
amnesia, slurred speech, dementia and seizures may occur if
drug is discontinued abruptly.
Tolerance develops with rebound insomnia; a gradual
escalation of dose needed to produce the required effect.
Benzodiazepines
Tolerance and dependence
Tolerance : gradual escalation of dose needed to produce the

required effect.
Psychological and physical dependence can develop if high doses

are given over a prolonged period.
Abrupt discontinuation results in withdrawal symptoms, including

confusion, anxiety, agitation, restlessness, insomnia, tension, and
rarely, seizures (abstinence syndrome).
Benzodiazepines
Tolerance and dependence
Benzodiazepines with a short elimination half-life, such as

triazolam, induce more abrupt and severe withdrawal reactions than
those seen with drugs that are slowly eliminated, such as
flurazepam.
Because of the long half-lives of some BDZ, withdrawal symptoms

may occur slowly and last a number of days after discontinuation of
therapy.
Benzodiazepines
Abuse Potential
There is a low incidence of abuse and
dependence if taken for a short time.
However, prolonged use can lead to
dependence and result in withdrawal.
Withdrawal symptoms include:
Return of anxiety state
increases in rebound insomnia
restlessness
agitation
irritability
Benzodiazepines
Benefits
They have high therapeutic index and therefore large margin of

safety.
Does not affect respiration or cardiovascular functions, but only

in patients with respiratory insufficiency (COPD) & cardiac
abnormalities.
BZDs have practically no action on other body system .

Benzodiazepines
Effects on pregnancy
They can cross the placental barrier freely and accumulate in

fetal circulation.
Usage during the first trimester can result in fetal abnormalities.
Also usage in third trimester can result in fetal dependence, or

floppy-infant syndrome
Benzodiazepines are also excreted in the breast milk

Benzodiazepines
Effects in Overdose
CNS depression
Unconsciousness
Not being able to take full, deep, normal breaths.
Shallow breathing
Respiratory depression
Collapse of heart and heart functions; decrease blood
pressure and increase heart rate.
Walking difficulty
Flumazenil is used as an effective antagonist of BDZ
Benzodiazepines
Effects in Overdose
Flumazenil
Flumazenil is a benzodiazepine antagonist, which also binds the

same receptors as benzodiazepines.
Has high affinity for benzodiazepine receptor
It behaves as a Competitive antagonist.
It is used as antidote to benzodiazepine overdose.
The sedative effects of benzodiazepines are antagonized.
Onset of action is fast when given parentally for symptomatic
treatment, producing immediate effects with very short half-life.
Sedatives and hypnotics drugs
Agents used in insomnia
Benzodiazepine-like drugs / Z-drugs (e.g. zaleplon,
zolpidem and zopiclone).
Although chemically distinct, these short-acting hypnotics act

at the benzodiazepine site on GABAA receptors containing
the 1 subunit.
They lack appreciable anxiolytic activity.
Eszopiclone is the active stereoisomer of zopiclone.

Clomethiazole:
It acts as a positive allosteric modulator of GABAA receptors

acting at a site distinct from the benzodiazepines.
Melatonin receptor agonists:
Melatonin, ramelteon and tasimelteon are agonists at MT1

and MT2 receptors.
They are effective in treating insomnia in the elderly and

autistic children as well as in totally blind individuals
Ramelteon
Melatonin is a hormone secreted by the pineal gland to maintain the
circadian rhythm underlying the normal sleep wake cycle.
Ramelteon is a selective agonist at the MT1 and MT2 subtypes of
melatonin receptors to induce and promote sleep.
Ramelteon is indicated for the treatment of insomnia characterized
by difficulty falling asleep (increased sleep latency).
Minimal potential for abuse, and no evidence of dependence or
withdrawal effects has been observed. Therefore, ramelteon can be
administered long term.
Orexin receptor antagonist:
Orexin are peptide transmitters in the CNS that are important

in setting diurnal rhythm.
Neuropeptide orexin promotes wakefulness
Orexin levels are normally high in daylight and low at night,

so the drug reduces wakefulness.
Suvorexant is an antagonist of OX1 and OX2 receptors which

mediate the actions of the orexins. Suvorexant decreases sleep
latency and promotes sleep maintenance
Antihistamines (e.g. diphenhydramine and promethazine)

can be used to induce sleep.
Included in various over-the-counter preparations.
Effective in treating mild types of situational insomnia.
However, they have undesirable side effects (such as

anticholinergic effects) that make them less useful than the
benzodiazepines and the nonbenzodiazepines.
Doxepin is an SNRI antidepressant with histamine H1- and

H2-receptor antagonist properties
Quetiapine is an antipsychotic drug with a wide spectrum

of activity including H1 antagonism; both are used to treat
insomnia.
Miscellaneous other drugs (e.g. chloral hydrate and

meprobamate): no longer recommended, but occasionally
used.
Chloral hydrate
Relatively safe hypnotic, inducing sleep in a half hour and
lasting about 6h.
Used mainly in children and the elder, and the patients
when failed to other drug.
MOA: general CNS depressant, can exert barbiturate-like
effects on GABAA-receptor channels
Indication: Insomnia
Pharmacokinetics: prodrug: converted to trichloroethanol
Adverse effects:
is irritating to the gastrointestinal tract and causes epigastric
distress.
It also produces an unusual, unpleasant taste sensation.
Antihistamines
Some antihistamines with sedating properties, such as

diphenhydramine, hydroxyzine, and doxylamine, are effective
in treating mild types of situational insomnia.
However, they have undesirable side effects (such as

anticholinergic effects) that make them less useful than the
benzodiazepines and the nonbenzodiazepines.
Some sedative antihistamines are marketed in numerous over-

the-counter products.

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Dr Nancy Safwat Younis

GABA controls the excitability of neurons by binding to

Drugs used in anxiety, sleep disorders or hypnotics all have the

They do this in a dose-dependent fashion which progressively

Now, drugs like antidepressant, antiepileptic and antipsychotic

Coma and Death

Sedative: Calm effect, reduce and treat agitation.

Hypnotic: Induce sleep fast in insomnia.

The physical symptoms of severe anxiety: tachycardia,

Episodes of mild anxiety are common life experiences and do

Anxiety disorders as recognized clinically include:

Generalised anxiety disorder (an ongoing state of excessive

Social anxiety disorder (fear of being with and interacting with

Panic disorder (sudden attacks of overwhelming fear occur in

Anxiety disorders as recognized clinically include:

Post-traumatic stress disorder (anxiety triggered by recall of

Obsessive compulsive disorder (compulsive ritualistic behavior

Treatment = psychological + drug treatment.

Because many of the antianxiety drugs also cause some sedation,

Treatment changed from using traditional anxiolytic/ hypnotic

Benzodiazepines (BZD) is effective anxiolytic drugs, but produce

Antidepressants and buspirone do, however, require three or more

Selective serotonin (5-HT) reuptake inhibitors (SSRIs; e.g.

Effective in the treatment of generalised anxiety disorder,

Antidepressants are now the main drugs used to treat anxiety.

Their effects are slow in onset (> 2 weeks).

These agents have the additional advantage of reducing any

Gabapentin, pregabalin, tiagabine and valproate, antiepileptic

-Adrenoceptor antagonists (propranolol)

These are used to treat some forms of anxiety, particularly where

Their effectiveness depends on block of peripheral sympathetic

Effective in generalized anxiety disorder

ineffective in controlling panic attacks or severe anxiety states

Potent partial agonist at 5-HT1A receptors

binds to 5-HT receptors to relieve anxiety suppression.

Its effect is slow in onset (> 2 weeks); takes days to weeks to

Unlike benzodiazepines, it does not cause sedation, motor

Has wide margin of safety.

drug appears to be safe in pregnancy.

Include nausea, dizziness, headache and restlessness.

No sedation or loss of coordination (less troublesome than with

Benzodiazepines are a class of mild tranquilizers that

Could be classified as either: Anxiolytic, or Sedative-

They have potential abuse.

Effects on the CNS

With increasing doses, benzodiazepines can progressive cause

Can not produce general anesthesia since awareness persists.

Have anti-anxiety / sedative-hypnotic properties.

The muscle relaxants property is centrally controlled.

Classification is based on duration of action.

o Short acting : Midazolam, Triazolam, Oxazepam, Lorazepam,

More rapid-acting agents that provide quicker symptom

However, tolerance of the hypnotic effect develops rapidly,

Benzodiazepines duration of action influences their use: Short-

1. Major indication is for anxiety (because of their anxiolytic

2. Panic attacks (used in combination with antidepressants

4. Treatment of alcohol withdrawal

5. Effective anticonvulsant: Clonazepam is occasionally used as

6. Muscular disorders: Diazepam is useful in the treatment of

Side Effects (during therapeutic use)

Tolerance and dependence

Tolerance : gradual escalation of dose needed to produce the

Psychological and physical dependence can develop if high doses