Anxiolytics

Sedatives
Hypnotics

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 Anxiety
• INTRODUCTION: Anxiety word was derived from the Latin root
‘anxieta’ meaning trouble in the mind about some uncertain
event and it has a Greek root ‘anxo’ meaning to squeeze,
strangle or press tight.
• Anxiety is the state of fear, apprehension (worries
about the future), uneasiness . The cause of which is
not known.
• According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-5) , anxiety disorders include disorders that share features of excessive
fear and anxiety and related behavioral disturbances.
•

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 Anxiety
• Occasional anxiety is a normal part of life.
• We might feel anxious when faced with a problem at work, before taking a test,
or making an important decision.
• Anxiety disorders involve more than temporary worry or fear. For a person with
an anxiety disorder, the anxiety does not go away and can get worse over time.
• These feelings can interfere with daily activities such as job performance, school
work, and relationships.
• Individuals with anxiety disorders develop cardiovascular, cerebrovascular,
gastrointestinal, and respiratory disorders at a rate significantly higher than the
general population. 

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• Many sensations occurs in human body during anxiety as it prepares for danger. The
sensations, which occur in human body, when the natural Alarm System of human body
(the “fight-flight-freeze” response) has been activated, are known as “alarm reactions”. 
• According to multiple-systems, symptoms of anxiety are (a) Cognitive, (b) Physiological
and (c) Behavioral. 
• Cognitive component of anxiety is related to the cognitive distortions in the
components of attention, interpretation, and memory for information processing.
• Physiological component of anxiety consists of the autonomic or somatic sensations. It
also includes avoidance related to the sleep, insomnia, nightmares, and
refusal/reluctance to sleep alone. Accelerated heart rate, heart palpitations, chest pain,
shortness of breath, difficulty in swallowing and nausea are other symptoms. 
• Behavioral component of anxiety refers to the action that is taken by an individual to
prevent feared stimuli exposure. Behavioral symptom associated with the anxiety
disorders includes avoidance, in which specific stimuli was avoided by the individual(e.g.
bridges) or situations (e.g. public speaking) to prevent anticipated harm. Due to
avoidance, there will be impairment in maintaining daily routines or in family, academic
and/or social functions by the individual.

symptoms of anxiety
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• Symptoms vary depending on the type of anxiety disorder, but general symptoms
include:
• Feelings of panic, fear, and uneasiness
• Problems sleeping
• Cold or sweaty hands and/or feet
• Shortness of breath
• Heart palpitations
• An inability to be still and calm
• Dry mouth
• Numbness or tingling in the hands or feet
• Nausea
• Muscle tension
• Dizziness
• Hot flashes
• paresthesia

Symptoms of anxiety
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 Types of Anxiety
Some of these disorders include
• separation anxiety disorder,
• selective mutism (is a complex childhood anxiety disorder characterized by
a child's inability to speak and communicate effectively in select social
settings, such as school. These children are able to speak and
communicate in settings where they are comfortable, secure, and
relaxed.),
• social anxiety disorder,
• panic disorder
• Agoraphobia (in this the patient fears when in an open spaces, shopping
mall, public spaces).
• Obsessive-compulsive disorder and posttraumatic stress disorder are no
longer considered anxiety disorders as they were in the previous version
of the DSM.

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 Types of anxiety disorder
• Panic disorder : People with this condition have feelings
of terror that strike suddenly and repeatedly with no
warning. Other symptoms of a panic
attack include sweating, chest pain, palpitations
(unusually strong or irregular heartbeats), and a feeling
of choking, which may make the person feel like he or
she is having a heart attack or "going crazy."

• Social anxiety disorder /social phobia: it involves

overwhelming worry and self-consciousness about
everyday social situations. The worry often centers on a
fear of being judged by others, or behaving in a way
that might cause embarrassment or lead to ridicule.
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 Types of anxiety disorder
• Specific phobias:
• A specific phobia is an intense fear of a specific object or
situation, such as snakes, heights, or flying. The level of fear is
usually inappropriate to the situation and may cause the
person to avoid common, everyday situations.

• Generalized anxiety disorder :

• This disorder involves excessive, unrealistic worry and tension,
even if there is little or nothing to provoke the anxiety.

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Table 5.1 Summary of Major Anxiety
Disorders

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 Pathophysiology
• In the central nervous system (CNS), the major
mediators of the symptoms of anxiety disorders
appear to be are neurotransmittors for eg:
norepinephrine, serotonin, dopamine, and
orexin/hypocretin, gamma-aminobutyric acid (GABA).
• Other neurotransmitters and peptides, such as
corticotropin-releasing factor, may be involved.
• Peripherally, the autonomic nervous system, especially
the sympathetic nervous system, mediates many of
the symptoms.
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• Studies suggest that an imbalance of
certain neurotransmitters (chemical messengers in
the brain) may contribute to anxiety disorders.
• The neurotransmitters targeted in anxiety disorders
are gamma-aminobutyric acid (GABA), serotonin
(5HT), dopamine(DA) , and epinephrine (AD).
• Serotonin appears to be specifically important in
feelings of well being, and deficiencies/rise are
highly related to anxiety and depression. Stress
hormones such as cortisol also play a role.

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 Anatomical sites
• The brain parts that are involved and play
important role in anxiety are:
• Amygdala, other limbic system( hippocampus ,
hypothalamus, cingulate gyrus, limbic cortex,
limbic midbrain), Prefrontal cortex.
• In anxiety usually the size of above mentioned
areas are found to be decreased as compared
to normal.

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 ETIOLOGIES
• Etiologies involved are:
• Biochemical factor: Neurotransmitters etc
• Genetic factor
• Social factor
• Traumatic events
• Medical conditions: epilepsy, hypoglycemia,
recurrent pulmonary emboli, adrenal gland
tumor.
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 BIOCHEMICAL FACTORS
• In anxiety the major NTs involved are
• NAD- increased
• DA-increased
• 5HT-increased
• GABA- decreased
• OTHERS ARE CORTICOTROPHIN RELEASING
HORMONE (CRH)
• CORTISOL
• TSH
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Role of Neurotransmitters in anxiety

15
• Cholecystokinnin: CCK, a neuropeptide, was, like 5-HT, discovered originally
in the digestive tract and found in the CNS later.  CCK‐immunoreactive fibers
and CCK (2) receptors are most abundantly present in anatomical locations
like periaqueductal gray (PAG), which mediate anxiety.  The CCK2 receptor
regulates the fear-related behaviours in humans and animals . CCK-4 injection
triggers the panic attacks in patients with a history of panic disorder. 
• Adenosine: Adenosine results due to hydrolysis of 5‐adenosine
monophosphate and is transformed to inosine, which is then stored as
adenosine triphosphate.  Adenosine is also involved in the regulation of
anxiety-related behavior. High doses of caffeine, which is the nonselective
adenosine receptor antagonist, induce fear in healthy people and trigger
panic attacks in anxiety disorder patients. 
•  Adenosine through A1 and A2A receptors exert anxiolytic effect through its
fascilitatory influence on release of GABA in the septum and
hippocampus.  On treatment with caffeine, rats were more anxious in the
elevated plus-maze test (X-maze)  and a free exploratory paradigm,  while an
adenosine-1 receptor agonist had an anxiolytic effect in the X-maze. 
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• Acetylcholine: Acetylcholine plays a pivotal role in learning and memory
processes. Acetylcholine levels can be modulated by stress in several brain
regions. Acetylcholinesterase present in the CNS catalyzes the hydrolysis of
acetylcholine to choline thus leads to cognitive impairment. Cholinergic input to
hippocampus is enhancing in response to anxiogenic and stressful stimuli.
Muscarinic receptors presynaptically inhibit GABA release in striatal neurons
BOTH Muscarinic M1 and M4 receptors induce anxiety Nicotine facilitates
GABAergic neuron and increase GABA release. 
• Cannabinoids: Cannabinoid receptor is widely distributed in the CNS present in
the brain areas related to stress responses such as the central amygdala and the
paraventricular nucleus of the hypothalamus and in the limbic system.
Cannabinoid-1 agonist can induce both anxiolytic and anxiogenic responses in
animal studies.  Low doses of the cannabinoid produce anxiolytic effects,
whereas higher doses result in anxiety. Acute administration of the selective CB1
receptor antagonist SR141716A induced anxiety-like responses in the elevated
plus maze and the defensive withdrawal tests. CB1 knockout mice showed
anxiogenic-like response in the light/dark box. 136

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• Corticotrophin-Releasing Factor: Corticotrophin-Releasing Factor is made
up of peptide containing 41 amino acids. This neurotransmitter in CNS
acts as a key mediator of autonomic, immune, behavioral and endocrine
stress responses. The peptide appears to be anxiogenic, proinflammatory
and leads to increase pain perception. Corticotrophin-Releasing Factor is
an essential component, which mediates endocrine and behavioral
anxiety-like responses, and stimulation of CRF2 may produce anxiolytic-
like effects. 
• Melatonin: Melatonin is synthesized by the pineal gland during night and
acts through G-protein coupled receptors (GPCRs), MT1 (MEL1a) and
MT2(MEL1b). Melatonin is involved in numerous physiologic processes
including circadian rhythms, mood regulation, anxiety, sleep, appetite,
immune responses and cardiac functions. Preoperative anxiolytic effects
of melatonin found a significant reduction in anxiety. MT2 receptors
modulate anxiety levels and consequently this receptor may become a
novel target for the treatment of anxiety.

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• Substance P: Substance P neurotransmission has been associated with aversion
and anxiety behavioral model. Substance P act primarily at the neurokinnin-1
(NK1) receptor. NK-1 antagonists are mediated by the dorsal raphe nucleus. NK-1
receptor exhibit anxiolytic effects in several models including elevated plus maze
and social interaction tests. Disruption of NK-1 receptor results in 5-HT 1A-receptor
desensitization and anxiolytic behavior and the effect of substance P play a role in
anxiogenic behavior. 14
• Neuroactive Steroids (NAS): GABA-A receptor is a direct binding site for the
neuroactive steroids. Enzymes involved in the biosynthesis of these NASs, such as
5α- reductase and 3α-hydroxy-steroid oxidoreductase are found in key
neuroanatomic structures involved in the anxiety such as the amygdala and the
hippocampus. Positive modulation of the GABA-A receptor has been associated
with anxiolytic activity whereas anxiogenic activity in animals models of anxiety in
association with negative modulation. The potential role of NAS analogues is in
the treatment of anxiety disorders.
• NAS eg are allopregnanolone, epiallopregnanolone, pregnanolone , vitamin D is
categorized as NASs as it affects the brain of younger children and adult
population 

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• A 2015 study looked at mental illnesses and twins and found
that the RBFOX1 gene may make someone more likely to
develop generalized anxiety disorder. A 2016 review showed
that social anxiety disorder, panic disorder, and generalized
anxiety disorder are all linked to specific genes.
• More recently, a 2017 review of studies concluded that
generalized anxiety disorder (GAD) can be inherited, with GAD
and associated conditions being linked to a number of
different genes.

Genetic factor
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• Sedative/ anxiolytic/ tranquilizer:
• Are substances that induces sedation by reducing
irritability or excitement and it exert calming effect

• Hypnotic are agents that produces drowsiness and

encourage onset and maintenance of state of sleep. It
produces a more pronounced depression of CNS than
sedation. This can be achieved with most drugs in this
class by increasing the dose.
• the difference in sedative and hypnotics is the dose and
level of CNS depression.
• Lower dose causes calmness
• Higher dose induces sleep.
• There are certain agents that can decrease anxiety
without causing sedation.
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 Anxiolytics/ sedative /hypnotics
• Mild anxiety may not need treatment but
chronic anxiety requires treatment.
• Classification:
• Benzodiazepines.
•  Barbiturates.
•  Miscellaneous drugs.

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 Other anxiolytics
• Choice and mode of use of anxiolytic agents:
• BZD- ARE FIRST CHOICE
• Beta blocker- when somatic symptoms are
observed
• Sedative antidepressant- when there is
depression with anxiety-eg TCA
• Buspirone can be used when 2 week delay in
effect is acceptable.
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BENZODIAZEPINES (BDZ)

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• Benzodiazepines (BZDs) are sedative-hypnotic agents commonly used
for a variety of situations that include seizure control, anxiety, alcohol
withdrawal, insomnia, control of drug-associated agitation, as muscle
relaxants, and as preanaesthetic agents (Abdelmajeed, 2009).
• Because of their widespread use, these drugs have propensity for
abuse either alone or in association with other substances.
Benzodiazepines (BDZs) are non toxic in a wide range of doses but the
incidence of intoxication with them including abuse and attempts to
suicide are not rare
• They can be classified on the basis of their pharmacological action as
well as on the basis of duration of action .i.e.
• Hypnotics/anxiolytic/anticonvulsant/muscular relaxant.
• Short acting, intermediate acting, long acting.

Benzodiazepine
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Therapeutic indication of Benzodiazepine

Muscular Pre anesthetic

anxiety
spasm agent

For alcohol
convulsions
withdrawl

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 27
Classification OF BENZODIAZEPINES
• 2-Keto compound On the basis of
• 3-Hydroxy compound chemical structure
• 7-Nitro compound
• Triazolo compound
• Imidazo compound
• Long acting On the basis of
• duration of action
Intermediate acting
• Short acting
• Ultra short acting
On the basis of
• Sedative, hypnotic , anxiolytics pharmacological
action
• Anticonvulsant, MUSCULAR RELAXANT
• Preanesthetic agents
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• Common types of benzodiazepine:
• 2-keto compounds:
clorazepate, diazepam, flurazepam, halazepam, 
prazepam, and others.
• 3-hydroxy compounds:
lorazepam, lormetazepam, oxazepam, temazepam
7-nitro compounds:
clonazepam, flunitrazepam, nimetazepam, nitrazepam
Triazolo compounds:
adinazolam, alprazolam, estazolam, triazolam
Imidazo compounds
• climazolam, loprazolam, midazolam

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Classifications
According to Duration of Action :

ultrashort acting drugs: (6 hrs)

Triazolam.
  Midazolam.
chlorazepate

- Short acting: (12-18 hours).

Lorazepam
Oxazepam
Temazepam
-  Intermediate: (24 hours).
Alprazolam
nitrazepam
Estazolam
clonazepam
- Long acting: ( 24-72 hours)

Chlordiazepoxide
Diazepam
Flurazepam.
Quazepam
Prazepam
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31
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the
CNS. Benzodiazepines potentiate GABAergic neurotransmission at all levels
including the spinal cord, hypothalamus, hippocampus, substantia nigra, cerebellar
cortex, and cerebral cortex.
GABAA receptors are ionotropic, regulating chloride channels. The receptors are
pentameric, although there are 19 different subunits within the GABAA receptor
family; α1–6, β1–3, γ1–3, δ, ϵ, π, ρ1–3, and θ, the minimum requirement for an
active receptor are an α and β subunit (Whiting, 2003). 
GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel.
Benzodiazepines bind to specific benzodiazepines receptors which is associated
with postsynaptic GABAA receptors.
This binding would cause an increase in the efficiency of GABAergic synaptic
inhibition by increasing the ability to open chloride channels and increasing the
chloride influx causing membrane hyperpolarization, which leads to a decrease in
the firing rate of critical neurons in many regions of the brain. Therefore,
benzodiazepines act by augmenting GABA inhibitory action.

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• Five subunits can combine in different ways to form GABA A channels.
The minimal requirement to produce a GABA-gated ion channel is the
inclusion of both α and β subunits, but the most common type in the
brain is a pentamer comprising two α's, two β's, and a γ (2α 1 2β 1γ2).
• The receptor binds two GABA molecules, at the interface between an
α1 and a β2 subunit.
• In order for GABAA receptors to be sensitive to the action of
benzodiazepines they need to contain an α and a γ subunit, between
which the benzodiazepine binds, increasing the frequency of opening
of the associated chloride ion channel and hyperpolarizing the
membrane. This potentiates the inhibitory effect of the available
GABA leading to sedative and anxiolytic effects.

GABAA RECEPTOR
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34
 Possible arrangements in a pentamer of subunits taken from three different types, α (yellow),
β (red), and γ (green).

Erwin Sigel, and Michael E. Steinmann J. Biol. Chem.

2012;287:40224-40231

© 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
 Anticlockwise
composition of
BDZ RP
GAMMA ,ALPHA
,BETA,ALPHA,
BETA

GABAA RECEPTOR 36
Synthesis of GABA

37
 Synthesis and metabolism of GABA
• Succinate is the re-entry point for the gamma-aminobutyric acid (GABA) shunt into the TCA
cycle, a closed cycle which synthesizes and recycles GABA.
• The GABA shunt serves as an alternate route to convert alpha-ketoglutarate into succinate,
bypassing the TCA cycle intermediate succinyl-CoA and instead producing the intermediate
GABA. Transamination and subsequent decarboxylation of alpha-ketoglutarate leads to the
formation of GABA.
• GABA is then metabolized by GABA transaminase to succinic semialdehyde. Finally, succinic
semialdehyde is oxidized by succinic semialdehyde dehydrogenase (SSADH) to form succinate,
re-entering the TCA cycle and closing the loop.
• Enzymes required for the GABA shunt are expressed in neurons, glial cells, macrophages and
pancreatic cells.

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GABA shunt

39
• The binding site for benzodiazepines is distinct from the binding
site for barbiturates and GABA on the GABAA receptor, and also
produces different effects on binding, with the benzodiazepines
causing increase bursts of chloride channel opening to occur
more often.
• while the barbiturates cause the duration of bursts of chloride
channel opening to become longer. At higher dose they can
produce effects in absence of GABA.  
• Since these are separate modulatory effects, they can both take
place at the same time, and so the combination of
benzodiazepines with barbiturates is strongly synergistic,
barbiturate can increase the binding of Benzodiazepine with BDZ
receptors and can be dangerous if dosage is not strictly
controlled.

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 Affinity of BDZ with different isoforms of
subunits
• diazepam and midazolam (i.e., classical non-selective
BDZs which act at α1-/α2-/α3- and α5-containing
GABAARs), zolpidem (a non classical BDZ site ligand
that exerts higher affinity for α1-containing GABA ARs
as compared to α2-/α3-/α5-containing GABA ARs) and
L-838,417 (a positive BDZ site modulator of α2-/α3-
and α5-containing GABAARs but an antagonist at α1-
containing GABAARs). each of these compounds had
reinforcing properties.  

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BDZs  facilitation of GABA action on GABA
receptors  chloride channels opening 

chloride influx to the cell  cell membrane

hyperpolarization  inhibition of
propagation of action potential  inhibitory
effect on different sites of the brain
especially motor cortex, and limbic system.

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• Benzodiazepine Receptor Ligands:
• Three types of ligand benzodiazepine receptor interactions have
been reported. This includes:
• (1) Agonists facilitate GABA action. These effects are typically
produced by benzodiazepines, which exert anxiolytic and
anticonvulsant effects.
• (2) Antagonists are typified by the synthetic benzodiazepine
derivative flumazenil, which blocks the actions of benzodiazepines
but does not affect the actions of barbiturates or ethanol.
• (3) Inverse agonists produce anxiety and seizures, an action that
has been demonstrated for several compounds, especially the B-
carbolines, e.g. n-butyl-B-carboline-3-carboxylate (Beta-CCB). In
addition to their direct actions, these molecules can block the
effect of benzodiazepines.
 

43
• BDZs are not general CNS depressants. a general CNS
depressant can cause any degree of depression, ranging from
the slightest sedation to anesthesia, coma, and death. 
• BDZs will not cause anesthesia, and in fact have extensively
replaced the barbiturates and other sedative hypnotics
because they are much less likely to cause fatal CNS
depression.
• at high concentration BDZ are capable of potentiating the
action of adenosine
• BDZ lack any effect in absence of GABA,THEY ARE NOT
GABAmimetic means unlike GABA.
• five shorter acting are capable of producing Sedative-
hypnoticactivity,estazolam,flurazepam,quazepam,temazepam,t
riazolam.

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• Absorption:
• They are usually given orally. Benzodiazepines are weakly basic drugs that
absorbed most effectively at the high pH found in the duodenum. Oral
absorption of triazolam is extremely rapid.
• Ditribution:
• Lipid solubility plays a major role in determining the rate at which a particular
sedative-hypnotic enters the central nervous system. Diazepam and triazolam
are more lipid-soluble than chlordiazepoxide and lorazepam; thus, the central
nervous system actions of the latter drugs are slower in onset.
• Administration of benzodiazepines during pregnancy should be done with the
recognition that the placental barrier to lipid-soluble drugs is incomplete and
that all of these agents are capable of reaching the fetus.
• Benzodiazepines and most other sedative-hypnotics bind extensively to plasma
proteins.

Pharmacokinetics of Benzodiazepines
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46
BDZ indication dose Adverse effect DOSE ADJUSTMENTS

alprazolam Panic attack, anxiety 6-10 mg/day, Rebound anxiety after

0.25-0.5 mg tid not abrupt discontinuation
exceed 4 mg

clonazepam anticonvulsant and panic disorders, should be Doesnot cause rebound

anxiolytic effects initiated at a dose of 0.25 anxiety
mg tablets, taken orally
twice a day for 3 days,
after which the dose
should be increased to 0.5
mg tablets twice daily. The
maximum daily dose
should not exceed 1-4 mg.
For treating seizure
disorders, adults should
start with 0.5 mg tablets
taken orally 3 times per
day. For this indication,
the maximum daily dose
should not exceed 20 mg.

47
diazepam anxiolytIc , muscle Both intramuscular and Oversedation,
relaxant, intravenous forms are anterograd amnesia
also available for
anxiolysis and should be
given in doses of 2-10 mg
every 3-4 hours,
depending on symptom
severity and age
considerations.
As an adjunct to
antiseizure therapy or for
muscle relaxation, 2-10
mg orally up to 4 times
per day is recommended.
For status epilepticus,
physicians initially
administer 5-10 mg
intravenously every 15
minutes up to a
maximum dose of 30 mg.
If needed, this dose may
be repeated in 2-4 hours

lorazepam anticonvulsant and also For anxiolysis, dosing peripheral vasodilation patients with hepatic or
works well as an adjunct begins with 2-3 mg/d and a subsequent renal dysfunction 
to antipsychotics in the orally, divided into 3 decrease in arterial blood
treatment of acute doses per day. Maximum pressure.
agitation and mania daily doses should not
exceed 10 mg.
midazolam preoperatively as an sedation/anxiolysis is usually 1-5 mg intravenously up
anxiolytic and sedative to 1 hour before surgery in otherwise healthy patients.
hypnotic agent  In higher-risk patients, such as those older than 60
years or those with chronic obstructive pulmonary
disease, no more than 3 mg intravenously up to 1 hour
before surgery is recommended.

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PHARMACOKINETICS
1. most of them are well absorbed orally,
Rapid absorption
e.g. triazolam & Alprazolam
diazepam & chlorazepate
Slow absorption
e.g. lorazepam & oxazepam, temazepam

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2. Chlorazepate is a prodrug converted by
acid hydrolysis in stomach to form
nordiazepam (desmethyldiazepam).

3. Can be given parenterally

Diazepam-Chlordiazepoxide (IV
only NOT IM)
Midazolam – Lorazepam (IV or IM)

50
4. Bzs are lipid soluble and widely distributed
5. Redistribution from CNS to skeletal muscles,
adipose tissue) (termination of action).
6. Cross placental barrier during pregnancy
and are excreted in milk (Fetal & neonatal
depression).

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Pharmacokinetics of Benzodiazepines
• Biotransformation:
• Hepatic metabolism accounts for the clearance or
elimination of all benzodiazepines. The patterns and
rates of metabolism depend on the individual drugs.
• Most benzodiazepines undergo microsomal oxidation
(phase I reactions), including N-dealkylation and
aliphatic hydroxylation.
• The metabolites are subsequently conjugated (phase
II reactions) by glucuronosyl transferases to form
glucuronides that are excreted in the urine. However,
many phase I metabolites of benzodiazepines are
active, with half-lives greater than the parent drugs.
•       

52
53
NORDIAZEPA
M

54
 Pharmacokinetics of Benzodiazepines
• Desmethyldiazepam, which has an elimination half-life 40-140 hours, is an active
metabolite of chlordiazepoxide,prazepam,fosazepam, diazepam, and clorazepate.
• While diazepam is metabolized mainly to desmethyldiazepam, it is also converted to
temazepam which is further metabolized in part to oxazepam. The alprazolam and
triazolam undergo alpha-hydroxylation, and the resulting metabolites appear to
exert short-lived pharmacological effects since they are rapidly conjugated to form
inactive glucuronides.

• EXCEPT No active metabolites are formed for Lorazepam, Estazolam, Oxazepam

• Those benzodiazepines for which the parent drug or active metabolites have long
half-lives are more likely to cause cumulative effects with multiple doses.
Cumulative and residual effects such as excessive drowsiness appear to be less of a
problem with such drugs as oxazepam and lorazepam, which have shorter half-lives
and are metabolized directly to inactive glucuronides.

55
56
 Pharmacokinetics of Benzodiazepines

• Excretion:
• The water-soluble metabolites of
benzodiazepines and other sedative-hypnotics
are excreted mainly via the kidney.
•  

57
Pharmacological Effects of Benzodiazepines
• Enhancing GABA action by benzodiazepines would decrease
the firing rate of many neurons in the brain. The most
important effects of the benzodiazepines on the central
nervous system are:
•  Reduction of anxiety and aggression
•   Sedation and induction of sleep
•  Reduction of muscle tone and coordination
• anticonvulsant effect.
• They do not produce any analgesic or antipsychotic activity.

58
Reduction of anxiety and aggression

• Benzodiazepines show activity and exert a

marked 'taming‘ effect, allowing animals to be
handled much more easily.
• benzodiazepines do not have specific
antidepressant effects, though the relief of
anxiety may be beneficial in depressed
patients.

59
• Benzodiazepines decrease the time taken to get to sleep, and
increase the total duration of sleep, though the latter effect occurs
only in subjects who normally sleep for less than about 6 hours each
night. Both effects tend to decline when benzodiazepines are taken
regularly for 1-2 weeks.

• The use of sedative-hypnotics for more than a week may lead to

tolerance to their effects on sleep patterns. Withdrawal after
continued use can result in a rebound increase in the frequency of
occurrence and duration of REM sleep.

Sedation and induction of sleep

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• Normal sleep consists of two major stages:
• non-rapid eye movement (NREM) sleep, (which represents approximately
70-75% of total sleep); and rapid eye movement (REM) sleep.
• REM and NREM sleep occur cyclically over an interval of about 90
minutes.
• The effect of sedative-hypnotics on patterns of normal sleep are as
follows:
• The latency of sleep onset is decreased (time to fall asleep).
•   The duration of NREM sleep is increased.
•   The duration of REM sleep is decreased.
•   The duration of slow-wave sleep is decreased.

NORMAL SLEEP CYCLE

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• Benzodiazepines appear to reduce muscle tone by a
central action that is independent of their sedative
effect. A reduction of muscle tone appears to be possible
without producing appreciable in-coordination.
• Bdz 2 RP ARE RESPONSIBLE TO CAUSE MYORELAXANT
EFFECT AND ARE PRESENT IN ABUNDANCE IN MOTOR
NEURONS AND DORSAL HORN OF SPINAL CORD.

Reduction of muscle tone and Coordination:

62
• All benzodiazepines have anticonvulsant activity in
experimental animal tests. They are generally more
effective against chemically induced convulsions caused by
leptazol, bicuculline than against electrically induced
convulsions, and are among the most potent agents known
in preventing leptazol-induced convulsions.
• Several benzodiazepines, including clonazepam and
diazepam are clinically useful in the management of seizure
states. Diazepam, given intravenously, is effectively used in
controlling the repeated seizures of status epilepticus.
• Anticonvulsant effect: especially diazepam, lorazepam, clorazepate,
clonazepam, nitrazepam.

Anticonvulsant effects

63
 Anesthesia
• Certain benzodiazepines, including diazepam
and midazolam, are used intravenously in
anesthesia but have not proved to be very
successful.
•     

64
 • Sedative-hypnotics even at therapeutic doses can produce significant
respiratory depression in patients with obstructive pulmonary disease.
• Effects on respiration are dose-related, and depression of the medullary
respiratory center is the usual cause of death due to overdose of
sedative-hypnotics.
• At toxic doses, myocardial contractility(diazepam, lorazepam) and
peripheral resistance (nitrazepam) may both be depressed by central
and peripheral effects, leading to circulatory collapse.
• Benzodiazepines produce less respiratory and cardiovascular
depression compared to barbiturates.
•  
Effects on Respiration and Cardiovascular Function:

65
 •        Tolerance, a decrease in responsiveness to a drug following
continuous exposure, is a common feature of sedative-hypnotic
use. The changes in responsiveness of the central nervous system
(pharmacodynamic tolerance) may explain tolerance to
benzodiazepines.    
•        The consequences of abuse of these agents can be defined in
both psychologic and physiologic terms. When the pattern of
sedative-hypnotic use becomes compulsive, more serious
complications develop, including physical dependence and
tolerance.
•        Physical dependence can be described as an altered
physiologic state that requires continuous drug administration to
prevent the appearance of an abstinence or withdrawal syndrome.
This syndrome is characterized by states of increased anxiety,
insomnia, and CNS excitability that may progress to convulsions.
Tolerance; Dependence of Benzodiazepines

66
• All sedative-hypnotics are capable of causing physical
dependence when used on a chronic basis. However, the
severity of withdrawal symptoms differs between
individual drugs and depends also on the magnitude of
the dose used immediately prior to cessation of use.
• Differences in the severity of withdrawal symptoms
between individual sedative-hypnotics relate in part to
half-life, since drugs with long half-lives are eliminated
slowly enough to accomplish gradual withdrawal with few
physical symptoms. Therefore, benzodiazepines produces
less intense withdrawal symptoms after stopping of
therapy due to the long plasma half-life and their active
metabolites.

67
 Clinical Indications of Benzodiazepine
 
• Hypnotics for insomnia.
•  Anxiety.
•  Panic attacks.
•  For acute alcohol withdrawal.
•  Anticonvulsants in treatment of epilepsy.
•  Muscle relaxants in chronic muscle spasm and spasticity.
• Adjunct to analgesics For preoperative sedation

68
Therapeutic Uses
Anxiety disorders:   alprazolam
• General anxiety disorders ,
• Panic attack
• major depressive disorders
• Schizophrenia
Diazepam, clonazepam and lorazepam is
useful in patients that need prolong
treatments.

69
Sleep disorders (Insomnia).
Triazolam: initiate sleep
Estazolam - Lorazepam - temazepam: sustain
sleep
Flurazepam - Quazepam
Long acting drugs can cause hangover.

70
To control withdrawal symptoms of alcohols
diazepam- chlordiazepoxide.

Treatment of epilepsy
Diazepam – Lorazepam: Status epilepticus
Clonazepam-Clorazepate: absence , myoclonic
seizures.

Muscle relaxation: in spastic states (Diazepam)

71
In anesthesia
 Preanesthetic medication diazepam
 Induction of balanced anesthesia
(Midazolam)
 Adjunct therapy during minor surgery
(endoscopy, bronchoscopy, dental surgery).
 

72
73
• Drugs that used as anxiolytics and sedatives:
•  Diazepam: 5-10mg twice daily.
 Chlordiazepoxide: 10-20mg 2-3 times daily.
•  Alprazolam: 0.25-0.5mg 2-3 times daily.
•  Lorazepam: 1-2mg twice daily.
•  Oxazepam: 15-30mg 3 times daily.
•  
• Drugs that used as hypnotics: taken at bedtime.
•  Flurazepam: 15-30mg daily.
•  Lorazepam: 2-4mg twice daily.
•  Temazepam: 10-30mg daily.
•  Triazolam: 0.125-0.5mg daily.
•  

Dosage of Benzodiazepines
74
Side Effects of Benzodiazepines

• Drowsiness, confusion, amnesia and impaired motor coordination, which

considerably impairs manual skills such as driving performance. 
• An interaction with alcohol is often claimed, whereby a low plasma
concentration of benzodiazepines can enhance the depressant effect of
alcohol.
• The long and unpredictable duration of action of many benzodiazepines is
important in relation to side effects. Drugs such as nitrazepam that are used
as hypnotics have been shown to produce a substantial day-after
impairment of job performance and driving skill.
•  BZDs impair episodic memory but semantic memory is not affected by BDZ.
• Implicit memory is also impaired by BZDs, but not in the same manner as
explicit memory.

75
 Adverse effects:
1.Ataxia (motor incoordination), cognitive impairment.
2.Hangover Sleep tendency, drowsiness, confusion especially in
long acting drugs.
3. tolerance.
4. Physical and Psychological dependence.
5. Withdrawal symptoms.(Rebound Insomnia, anorexia,
anxiety, agitation, tremors and convulsion).

76
Dose reduction in
1. Liver disease
2. Elderly people.
3. Contraindicated: don’t combine BDZ
with Alcohol and other CNS depressants,
antihistaminics. 

77
Acute Toxicity of Benzodiazepines

• Benzodiazepines in acute overdose are considerably less dangerous

than other anxiolytic/hypnotic drugs.
• The effect of an overdose is to cause prolonged sleep, without
serious depression of respiration or cardiovascular function.
• However, in the presence of other CNS depressants, particularly
alcohol, benzodiazepines can cause severe, even life-threatening,
respiratory depression. 
• The availability of an effective antagonist, flumazenil, means that
the effects of an acute overdose can be counteracted, which is not
possible for most CNS depressants.
•  

78
 • They potentiate the CNS depressant effect of alcohol
as well as the other CNS depressant drugs.
• Concurrent administration of benzodiazepines with
liver microsomal enzyme inhibitors such as cimetidine
would lead to excessive sedation and drowsiness due
to the increase in benzodiazepine’s plasma levels.
Lorazepam, temazepam and oxazepam are
Drug Interactions
metabolized of Benzodiazepine
by a different metabolic pathway involving
glucuronidation which is not affected by cimetidine.
•  

79
• Benzodiazepine Antagonists:
• Flumazenil:
•        Flumazenil is one of several 1,4-benzodiazepine derivatives with
high affinity to Benzodiazepines receptors that act as competitive
antagonists. It blocks many of the actions of benzodiazepines but does
not antagonize the CNS effects of other sedative-hypnotics, ethanol,
opioids, or general anesthetics.
• Flumazenil is used in reversing the CNS depressant effects of
benzodiazepines overdose and following use of these drugs in
anesthetic and diagnostic procedures.
• When given intravenously, flumazenil acts rapidly but has a short half-
life (0.7-1.3 hours) due to rapid hepatic clearance. Adverse effects of
flumazenil include agitation, confusion, dizziness, and nausea.
•  PHARMACOKINETICS of flumazenil
 Has short duration of action T 1 /2 = 1 hour
 Absorbed orally , Undergoes extensive first pass metabolism
 no active metabolites, Should be used IV, (Repeated doses are
necessary).
80
Therapeutic Uses
1.  Acute BZD toxicity (comatose patients).
2. Reversal of BZD sedation after endoscopy,
dentistry.

Side Effects
  Nausea

 Dizziness

 Precipitate withdrawal symptoms.

81
• Barbiturates are drugs that act as central nervous system depressants, and can therefore
produce a wide spectrum of effects, from mild sedation to total anesthesia.
• They are also effective as anxiolytics, hypnotics, and anticonvulsants.
• Barbiturates also have analgesic effects; however, these effects are somewhat weak,
preventing barbiturates from being used in surgery in the presence of other analgesics
(opioids or volatile anesthetics such as halothane)
• barbiturates are still used as anticonvulsants, as para-operative sedatives (ex. sodium
thiopental), and analgesics for cluster headaches/ migraines (ex. Fioricet)
• Barbituric acid was first created in 1864 by a German scientist named Adolf von Baeyer. It was a combination of urea
from animals and malonic acid from apples.
• urea +malonic acid------ barbituric acid
• Its first derivative utilized as medicine was used to put dogs to sleep but was soon produced by Bayer as a sleep aid in
1903 called Veronal

Barbiturates
82
 Types

Barbituric Acid

Amobarbital Phenobarbital Pentobarbital

83
 GABA biding
Barbiturates act as positive allosteric modulators, and at site
higher doses, asagonists of GABAA receptors. GABA is the
principal inhibitory neurotransmitter in
the mammalian central nervous system (CNS). BBT
Barbiturates bind to the GABAA receptor at multiple binding site
homologous transmembrane pockets located at subunit
interfaces, which are binding sites distinct
from GABA itself and also distinct from the
benzodiazepine binding site.
Like benzodiazepines, barbiturates potentiate the effect
of GABA at this receptor. In addition to this GABAergic
effect, barbiturates also block AMPA and kainate
receptors, subtypes of ionotropic glutamate receptor.
The Cl ion channel may open in burst of approx 1 milisec,
5 milli sec and 10 millisec.

Phenobarbitals blocks sodium channels thus producing

anesthesia.

Mechanism of action

84
 Classification of barbiturates
• They are classified according to their duration of
action:
• Ultra short acting: thiopental that acts within
seconds and has duration of action of about 30
min,
• Short acting: OOA within 5-15 mins,
pentobarbital, secobarbital, amobarbital. DOA IS
3-8 hrs
• Long acting: phenobarbital has a doa of >1 day
85
 Pharmacological action
• CNS depression:
• BBT may produce CNS depression calming effect
and decreases excitement.
• At higher doses may produce hypnosis, followed by
anesthesia and finally coma and death.
• They don’t increase the pain threshold neither
have analgesic activity.
• They may exacerbate pain
• Chronic use leads to tolerance.
86
 Therapeutic uses
• Anesthesia: thiopental is used IV for anesthesia.
• Anticonvulsant: phenobarbital is used for the treatment
of tonic clonic seizures
• They may decrease cognitive development in children in
children and decrease cognitive performance in adults.
• Also used in treatment of refractory status epilepticus.
• In status epilepticus that occur in children it
significantly decrease of oxygen utilization by the brain,
protecting cerebral edema and ischemia

87
• Sedative/ hypnotics:
• They are used as mild sedative to treat anxiety.
• They suppress REM sleep more than any other stages.
• Their use as hypnotic is not advocated due to tolerance, but butalbital is used in
combination with acetaminophen and caffeine or aspirin and caffeine in management of
tension type or migraine headache.
• They decrease the latency to sleep.
• It decrease the nightmare awakening.
• It increases the total sleep time.
• For the treatment of insomnia they are used for short period of time.

• Memory and cognition:

• BBT decrease the cognitive performance and memory.

• Their withdrawl may result in convulsions of excitable cell and can lead to respiratory
spasms.
• They have narrow therapeutic margins so a mild increase in dose ,may lead to toxicity.

88
• They are well absorbed after oral administration and distributed throughout
the body.
• they redistribute from brain to splanchnic areas, skeletal muscle, adipose
tissues.
• This is important in causing short duration of action of thiopental and
similar short acting drugs.
• They readily can cross the placental barrier and fetus may suffer withdrawal
symptoms and depress the fetus.
• The DOA of short acting & intermediate acting may be 3-8 hrs and10-16 hrs
for longer acting drugs.
• Phenobarbital is the least lipophillic in nature resulting in its prolong action
• These are metabolized by liver and capable of inducing CYP 450 enzyme,
and eliminated via kidney.

pharmacokinetics

89
• Respiratory depression : at higher doses causes hypnosis, followed
by anesthesia, then coma and death.
• Drowsiness
• Impaired concentration.
• Mental and physical sluggishness.
• Hangover
• Nausea and vomiting.
• Cyp450 enzyme induction.
• Contraindicated in acute porphyria, COPD patient, hepatic failure.
• Abrupt withdrawal may induce anxiety, tremors, weakness,
restlessness, N & V, seizures, delirium and cardiac arrest.
• Severe depression of respiration is coupled with cardiovascular
depression.

Adverse effect

90
 Other drugs
• Zolpidem
• Zaleplon
• Eszopiclone
• Ramelteon
• Antihistamine
• antidepressant

91
• It is short-acting non benzodiazepine hypnotic of the imidazopyridine class
that potentiates GABA, an inhibitory neurotransmitter, by binding to
GABAA receptors at the same location as benzodiazepines. It works quickly,
usually within 15 minutes, and has a short half-life of two to three hours.
• MECHANISM OF ACTION:
• Zaleplon and zolpidem(ambien) both are agonists at the GABA A α 1 subunit.
Due to its selective binding, zolpidem has very weak anxiolytic, myorelaxant,
and anticonvulsant properties but very strong hypnotic properties. Zolpidem
binds with high affinity and acts as a full agonist at the α1-
containing GABAA receptors, about 10-fold lower affinity for those containing
the α2- and α3- GABAA receptor subunits, and with no appreciable affinity
for α5 subunit-containing receptors.
• zolpidem has a preferential binding for the GABA A-benzodiazepine receptor
complex in the brain but a low affinity for the GABA A-benzodiazepine receptor
complex in the spine

Imidazopyridine class zolpidem

92
• ZOLPIDEM increases the duration of sleep
in healthy and insomnia patient
•  zolpidem may increase slow wave
sleep but cause no effect on stage 2 sleep.
• the decreases night awakening and no
residual morning sedation, confusion, or
memory impairment

Pharmacological action
93
• Night eating syndrome (also commonly known as sleep-eating)
• Headaches (mostly withdrawal symptom)
• Nausea (mostly withdrawal symptom)
• Vomiting (mostly withdrawal symptom)
• Dizziness
• Hallucinations, through all physical senses, of varying intensity
• Altered thought patterns
• Ataxia or poor motor coordination, difficulty maintaining balance
• Euphoria or dysphoria
• Impaired judgment and reasoning
• Uninhibited extroversion(talkative , interactive) in social or interpersonal settings
• Increased impulsivity (mostly withdrawal symptom)
• When stopped, rebound insomnia may occur
• May interact negatively with the effects of alcohol consumption .

Adverse effect
94
•  long-term use of zolpidem is associated with drug
tolerance, substance dependence, rebound
insomnia, and CNS-related adverse effects.
• It was recommended that zolpidem be used for
short periods of time using the lowest effective
dose.
• Zolpidem 10 mg is effective in treating insomnia
when used intermittently no fewer than three and
no more than five pills per week for a period of 12
weeks. The 15-mg zolpidem dosage provided no
clinical advantage over the 10-mg zolpidem dosage.

Adverse effect
95
 Adverse effects

• Alcohol has cross tolerance with GABAA receptor

positive modulators such as the benzodiazepines and
the nonbenzodiazepine drugs.For this reason,
alcoholics or recovering alcoholics may be at
increased risk of physical dependency on zolpidem.
Also, alcoholics and drug abusers may be at
increased risk of abusing and or becoming
psychologically dependent on zolpidem.

96
 Adverse effect
• Zolpidem has been assigned to pregnancy category C by the
FDA. Animal studies have revealed evidence of incomplete
ossification and increased postimplantation fetal loss at doses
greater than seven times the maximum recommended human
dose or higher; however, teratogenicity was not observed at any
dose level.
• There are no controlled data in human pregnancy. In one case
report, zolpidem was found in cord blood at delivery. Zolpidem
is recommended for use during pregnancy only when benefits
outweigh risks. 

97
• An overdose of zolpidem may cause excessive sedation,
pin-point pupils, or depressed respiratory function, which
may progress to coma, and possibly death.
• Combined with alcohol, opiates, or other CNS depressants,
it may be even more likely to lead to fatal overdoses.
• Zolpidem overdosage can be treated with the
benzodiazepine receptor antagonist flumazenil, which
displaces zolpidem from its binding site on the
benzodiazepine receptor to rapidly reverse the effects of
the zolpidem.

overdose
98
 Pharmacokinetic data

Bioavailability 70% (oral)

Protein binding 92%

Metabolism Hepatic through CYP3A4

Biological half-life 2–3 hours

Excretion renal (56%)
fecal (34%)

Administration with food decrease the peak concentration by

30%

99
• Zaleplon (marketed under the brand names Sonata, Starnoc, and Andante) is
a sedative-hypnotic, almost entirely used for the management/treatment
of insomnia.

• It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class.
Zaleplon is effective in the management/treatment of insomnia, primarily
characterized by difficulty falling asleep. Due to its ultrashort elimination half-
life, zaleplon may not be effective in reducing premature awakenings.

• It may result in an impaired ability to drive the next day, though it has proven
promising when compared to other sedative/hypnotics and next-day residual
sedation. It may have advantages over benzodiazepines with fewer adverse
effects.

Pyrazolopyrimidine class : zaleplon

100
• Zaleplon, like zolpidem, zopiclone, or eszopiclone, are
all specific agonists at the
benzodiazepine GABAA α1 sub-receptor site.
• It also modulates the GABAA sub-sites, α2 and α3, to a
lesser degree. It has no statistical significance as
an anticonvulsant.
• However, as a pyrazolopyrimidine, zaleplon has served
as a novel chemical platform from which new
anxiolytics will hopefully arise.
• Much like zolpidem, as an imidazopyridine and also a
full agonist at the GABAA α1 sub-receptor site, has been
reviewed considerably with some novel contributions.

101
• Zaleplon selectively binds with high efficacy to the benzodiazepine
site (ω1) on the α1-containing GABA-A receptors than as compared
to α2 and α3 -containing  subunits,which help produce the primary
therapeutic hypnotic properties
• The ultrashort half-life gives zaleplon a unique advantage over
other hypnotics because of its lack of next-day residual effects on
driving and other performance-related skills.
•  Unlike nonselective benzodiazepine drugs and zopiclone, which
distort the sleep pattern, zaleplon appears to induce sleep without
disrupting the natural sleep architecture.

Mechanism of action of Z drugs

102
 Pharmacokinetic data

Bioavailability 30% (oral)

Metabolism Hepatic

Biological half-life 1–1.5 h

Excretion Renal

103
• The side effects of zaleplon are similar to the side effects of benzodiazepines, although
with less next-day sedation, and in two studies zaleplon use was found to not cause an
increase in traffic accidents, as compared to other hypnotics currently on the market.

• A common effect of zaleplon abuse is the occurrence of (typically short-

lived) hallucinations. Fewer visual and auditory hallucinations/disruptions with the use of
zaleplon than with other drugs in the nonbenzodiazepine class (e.g. zolpidem and the
“Ambien Walrus”).

• Anterograde amnesia can occur and can cause one to lose track of the amount of
zaleplon already ingested, prompting one to ingest more than originally
planned. However, continuous ingestion is extremely unlikely precisely because of
zaleplon's quick onset of action.

Adverse effect
104
• it is a non benzodiazepine hypnotic which is slightly effective
for insomnia. It is apyrrolopyrazine cyclopyrrolone agent.
• Eszopiclone is the active dextro rotatory stereoisomer
of zopiclone, and belongs to the class of drugs known as
cyclopyrrolones. Its S-enantiomer separation results in less
adverse effect.
• It has no potential of developing tolerance on chronic dosing.
• It increases the time spent in stage 3 and 4, and
recommended to be used for insomnia upto 6 months.

Eszopiclone
105
• Common side effects can include:
• unpleasant bitter or metallic taste
• headaches
• chest pain
• cold-like symptoms
• pain
• dry mouth
• daytime drowsiness
• lightheadedness
• dizziness
• upset stomach
• decreased sexual desire
• painful menstruation (periods)
• heartburn
• Sedation, drowsiness, and sleepiness

106
 Pharmacokinetic data
Protein binding 52–59%
Metabolism Hepatic oxidation and
demethylation (CYP3A4and 
CYP2E1-mediated)
Biological half-life 6 hours
Excretion Renal

107
• Melatonin, chemically N-acetyl-5-methoxy tryptamine,is a substance found in animals,
plants, fungi and bacteria. In animals it is a hormone that anticipates the daily onset of
darkness.
• In animals, melatonin is involved in the entrainment (synchronization) of the circadian
rhythms of physiological functions including sleep timing, blood pressure regulation,
seasonal reproduction and many others. Many of melatonin's biological effects in
animals are produced through activation of melatonin receptors.MT1 and
MT2receptors are present in high concentration in suprachiasmatic nucleus of
hypothalamus.
• Melatonin has been studied for insomnia in the elderly. Prolonged- release melatonin
has shown good results in treating insomnia in older adults.
•  Short-term treatment (up to three months) of prolonged-release melatonin was found
to be effective and safe in improving sleep latency, sleep quality and daytime alertness.
• Melatonin can be used to reset the circadian sleep clock.
•  Melatonin supplementation has been shown to improve sleep duration, sleep onset
latency, and night-time awakenings.

Melatonin receptor agonist

108
 Melatonin receptors
• The melatonin receptors are G protein-coupled
receptors and are expressed in various tissues
of the body.
• There are two subtypes of the receptor in
humans, melatonin receptor 1 (MT1)
and melatonin receptor 2 (MT2). Melatonin and
melatonin receptor agonists , on market or
in clinical trials, all bind to and activate both
receptor types
109
110
• The binding of melatonin to melatonin receptors activates a few signaling
pathways.
• MT1 receptor activation inhibits the adenylyl cyclase and its inhibition
causes a rippling effect of non activation; starting with decreasing
formation of cyclic adenosine Monophosphate (cAMP), and then
progressing to less protein kinase A (PKA) activity, which in turn hinders
the phosphorylation of cAMP responsive element-binding protein (CREB
binding protein) into P-CREB.
• MT1 receptors also activate phospholipase C (PLC), affect ion channels
and regulate ca++ ion flux inside the cell.

•  The binding of melatonin to MT2 receptors inhibits adenylyl cyclase

which decreases the formation of cAMP. As well it hinders guanylyl
cyclase and therefore the forming of cyclic guanosine monophosphate
(cGMP). Binding to MT2 receptors probably affects PLC which
increases protein kinase C (PKC) activity. Activation of the receptor can
lead to ion flux inside the cell

111
 MELATONIN RECEPTOR AGONIST.
RAMELTEON
• It is (S)-enantiomer of a tricyclic indan derivative.
• IT IS AN AGONIST OF MT1,MT2 RECEPTOR used in treating
insomnia particularly delayed onset of sleep. It improves total
sleep time.
• it does not possess abuse potential& does not cause
tolerance and dependence.
• It does not produce withdrawal symptoms and rebound
insomnia.
• MT1 rp activation improves sleep induction thru inhibition of
firing rate from SCN neuros while MT2 rp activation affects
the circadian rhythmsetting related to our centeral clock.

112
 Adverse effect
• Somnolence
• Dizziness
• Nausea
• Fatigue
• Headache
• High doses may produce testicular and liver
tumors in mice.

113
 Pharmacokinetic data
bioavailabilty 1.8%
Protein binding 82%
metabolism CYP1A2
Biological half life 1-2.6 hrs
excretion Renal 84% and fecal 4 %

114
 Agomelatine
It is MT1, MT2 rp agonist and 5HT2C RP antagonist.
It synchoronize the circadian rhythm.
Antagonism of 5-HT2C receptors by agomelatine results in
an increase of dopamine and norepinephrine activity in
the frontal cortex. Conversely, many SSRIs (but
not fluoxetine, which is a 5-HT2C antagonist) indirectly
stimulate 5-HT2C activity by increasing levels of serotonin
in the synapse although the delayed mood elevation
that is usually typical of SSRIs is usually paralleled by the
downregulation of the 5-HT2C receptors

115
• H1 receptor antagonist diphenhydramine and doxylamine both act
on tubero mammilary nucleus(TMN) of posterior hypothalamus.
• TMN regulates normal release of histamine and regulates normal
arousal and its decrease release at night reduces arousal response.
• H1 RP antagonist at TMN promotes sleep by inhibiting TMN outflow
to other brain parts for eg dorsal raphe nuclei, paraventricular
nucleus, locus ceruleus.
• Thus they decrease sleep latency and increases total sleep time.

Anti histamines
116
• Doxylamine can be used by itself as a sleep aid or combined with other
drugs for cold and allergy relief (usually in a night-time formula). It is
sometimes used along with Vitamin B6 to stop morning sickness during
pregnancy. Doxylamine is one of the most powerful OTC sedatives in the
U.S., more so than some prescription hypnotic drugs. Many patients taking
doxylamine encounter dry mouth, nausea, and drowsiness.

• Doxylamine succinate is a potent anticholinergic and has a side-

effect profile common to such drugs, including dry mouth, ataxia, urinary
retention, drowsiness, memory problems, inability to concentrate,
hallucinations, psychosis, and a marked increased sensitivity to external
stimuli. Like many hypnotics, it should not be combined with other
antihistamines, such as cetirizine (Zyrtec) or diphenhydramine (Benadryl),
as this combination can increase the risk of serious side effects. Using
doxylamine over a long period of time is not recommended.

117
• Diphenhydramine was the first antihistamine approved by the FDA (in the 1940s)
and is widely used in OTC sleeping pills. Many generic sleep aids consist solely of
one active ingredient - diphenhydramine. It is one of the oldest antihistamines
available (classified as a first-generation antihistamine), but for many patients
surpasses the efficacy of even new prescription drugs.
• Medical professionals seek out diphenhydramine when a substantial histamine
release demands a fast, effective reversal, and is therefore often the drug of choice
for allergic rhinitis, motion sickness, insect bites and stings, and hives.
• Profound drowsiness is a very common side effect, as is dizziness, difficulty
concentrating, and urinary retention.  It is also used for insomnia, symptoms of
the common cold, tremor in parkinsonism, and nausea.
•  It is used by mouth, injection into a vein, and injection into a muscle. Maximal
effect is typically around two hours after a dose and effects can last for up to seven
hours.
• Common side effects include sleepiness, poor coordination, and an upset
stomach. Its use is not recommended in babies. There is no clear risk of harm when
used during pregnancy; however, use during breastfeeding is not recommended.

118
Niaprazine was invented in France, and is used mainly in the European
Union. The main use for niaprazine is its intense sedative effect (as
opposed to its antihistamine effects). Vertigo and daytime sedation are
frequently encountered with the use of this drug.
• Originally believed to act as
an antihistamine and anticholinergic,niaprazine was later discovered to
have low or no binding affinity for the H1 and mACh receptors, and was
instead found to act as a potent and selective 5-HT2A and α1-adrenergic
receptor antagonist . It possesses low or no affinity for the 5-HT1A, 5-
HT2B, D2, and β-adrenergic, as well as at SERT and VMAT , but it does
have some affinity for the α2-adrenergic receptor  likely acting as an
antagonist there as well.

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• Pyribenzamine is another first-generation antihistamine; today it is used
much less frequently as newer antihistamines arrive on the market. It is
indicated for the treatment of hay fever, asthma, urticaria, and rhinitis,
and is a mild sedative. Pyribenzamine is known to be abused
recreationally with the opiate pentazocine. Common side effects of
pyribenzamine use are dry mouth, nausea, gastrointestinal irritation, and
dizziness.
• Clemastine is indicated for the treatment of allergy symptoms, including
rhinitis and pruritus (itching or hives). Although it is a sedative
antihistamine, its effects are less intense than many other drugs of this
nature. The side effects of clemastine are greatly dependent on the dose,
and sometimes can produce contradictory responses. The most
commonly reported side effects of clemastine use are dizziness,
drowsiness, blurred vision, and dry mouth.

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 ANTIDEPRESSANT
DOXEPIN
• Doxepin (HCl) is a tricyclic antidepressant of the dibenzoxepine
class, also having significant anxiolytic activity. Doxepin (HCl) is
effective in treating depression and to treat nerve pain, and
insomnia. Two to three weeks are required to observe the full
effects of drug. Doxepin (HCl) is administered orally.
• Oral absorption of Doxepin (HCl) is found to be 50% ±50. Volume
of distribution is found to be 9.1-33.3 l/kg and plasma protien
binding is high. Presystemic metabolism is noted to be 71% ±16
and metabolism is reported extensive by liver. Renal Excretion
accounts for major and plasma half life is 8.2-24.5 hr.

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 Adverse effects
• The signs and symptoms that are produced after the
acute overdosage of Doxepin (HCl) include Cardiac
arrhythmias, Convulsions, Coma, Hyperthermia,
Drowsiness, Blurred vision, Drowsiness, Dry mouth,
Urinary retention, Respiratory depression,
Respiratory depression, Mydriasis, Hypertension,
Stupor, Decreased GI motility, Hyperreflexia,
Respiratory depression, hyperreflexia.

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 DOXEPIN
Dose Single Dose Frequency Route Instructions
Adult Dosage
0.142 to 1.428 0.78 (0.785) 8 hourly PO Maintenance
mg/kg
1.071 mg/kg 1.1 (1.071) 24 hourly PO Initial

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 SUVOREXANT
• Mechanism of action
• Suvorexant exerts its therapeutic effect in insomnia through antagonism of orexin receptors.
The orexin neuropeptide signaling system is a central promoter of wakefulness. Blocking the binding of wake-
promoting neuropeptides orexin A and orexin B to receptors orexin receptor type 1 (OX1) and orexin receptor
type 2(OX2) is thought to suppress wake drive. Animal studies report the binding affinities for OX1 (0.55 nM) and
OX2 (0.35 nM).
• Pharmacokinetics
• The bioavailability of suvorexant is at 82%. It is highly protein-bound. Food delays the time to max concentration.
The primary route of elimination is through the feces, with approximately 66% of radiolabeled dose recovered in
the feces compared to 23% in the urine. The elimination half-life is reported to be 12 hours.
• Abuse liability
• According to the U.S. Drug Enforcement Administration (DEA), suvorexant produces similar reinforcing effects to
those of zolpidem in humans and thus may have a similar abuse liability. As such, suvorexant has been
designated a schedule IV controlled substance in the U.S. under the Controlled Substances Act.

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 SLEEP CYCLE
• People experience two forms of sleep: rapid eye movement (REM) and nonrapid eye movement (NREM).
Sleep typically begins with the NREM phase, which is followed by the REM phase. NREM sleep is
subdivided into three stages in which brain activity, eye movement, and skeletal muscle tone progressively
decrease, placing the individual in a deeper state of sleep. Later in the cycle, when the individual enters
REM sleep, electrical activity in the brain increases, contributing to increased blood flow to the brain,
changes in respiratory and cardiac rates, and dreaming.1 REM sleep correlates with activities of the
hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system in healthy humans. 2
• Sleep is regulated by a variety of chemicals in the body. In the forebrain and hypothalamus, neurons
release gamma-aminobutyric acid (GABA) and histamine. These neurotransmitters have opposing actions
on the sleep–wake cycle. Increased GABA and decreased histamine release induce NREM sleep by
deactivating the cortex and thalamus. The sleep–wake cycle is also affected by neurotransmitters released
by reticular activating system (RAS) neurons, such as norepinephrine, acetylcholine, and serotonin. These
neurotransmitters contribute to maintaining wakefulness and significantly decrease during REM sleep.
Orexin, which is produced in the hypothalamus, is a neuropeptide that plays an important role in
maintaining wakefulness. It is hypothesized that the action of orexin changes the activity of the
neurotransmitters involved in the regulation of sleep/wake states. Melatonin is a hormone that plays an
integral role in diurnal rhythms. It synchronizes the body with the environment’s light–dark cycle, peaking
during the night and dipping during the day, to stabilize the body’s natural circadian rhythm. 1,3

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