Sedative-hypnotics &

Anxiolytics
Kennedy Edem Kukuia, PhD
Neuropharmacologist/Senior Lecturer
Department of Medical Pharmacology

1
• A sedative drug decreases activity, moderates excitement,
and calms
• A hypnotic drug produces drowsiness and facilitates the
onset and maintenance of a state of sleep resembling natural
sleep and from which the recipient can be aroused easily.
• Anxiety states and sleep disorders are common problems,
and sedative-hypnotics are widely prescribed drugs
worldwide.

DrKen Kukuia 2
 SLEEP
• Sleep is divided into two phases:
– nonrapid eye movement (NREM) sleep
– rapid eye movement (REM) sleep
• Humans typically experience 4 to 6
cycles of NREM and REM sleep,
each cycle lasting between 70 and
120 minutes.
• There are 4 stages of NREM sleep.
• Healthy sleep will typically progress
through the 4 stages of NREM sleep
prior to the first REM period.
DrKen Kukuia 3
 SLEEP
• From wakefulness, sleep typically
progresses quickly through stages 1 and 2.
• Stage 1 of NREM sleep: between
wakefulness and sleep, and individuals feel
they are awake, drowsy, or asleep.
• Stages 3 and 4 NREM: both metabolic
activity and brain waves slow.
– This slow-wave sleep occurs most frequently
early in the sleep period.
– Stage 3 and stage 4 sleep are called delta sleep, as
the sleep is characterized by high-amplitude
slow activity known as delta waves (0.5–3 Hz).
– In this stage eye movements are absent, and
muscle tone is atonic.

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 SLEEP
• The neurochemistry of sleep is complex as
sleep cannot be localized to either a specific
area of the brain or a neurotransmitter.
• NREM sleep is controlled by the basal
forebrain, the area surrounding the solitary
tract in the medulla and the dorsal raphe
nucleus, which is primarily serotonergic.
• Sleep is reduced when there are decreases in
5-HT or destruction of the dorsal raphe
nucleus in the brainstem, which contains
most of the brain’s serotonergic bodies.

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 SLEEP
• REM sleep is turned on by cholinergic cells in the mesencephalic,
medullary, and pontine gigantocellular regions.
• It is turned off by the dorsal raphe nucleus, the locus coeruleus, and the
nucleus parabrachialis lateralis, the latter two of which are primarily
noradrenergic.
• The ascending reticular activating system and the posterior hypothalamus
facilitate arousal and wakefulness.
• Dopamine has an alerting effect; decreases in dopamine promote
sleepiness.
• Neurochemicals involved in wakefulness include ACh and NA in the cortex
and histamine and neuropeptides such as substance P and CRF in the
hypothalamus .
DrKen Kukuia 6
 SLEEP
• Sleep is typically measured and observed in sleep laboratories using
an EEG, electro-oculograms of each eye, ECG, electromyogram, air
thermistors, abdominal and thoracic strain belts, and oxygen saturation
monitor.
• This study is named polysomnography (PSG) and is used to assess and
record variables that characterize sleep and aid in diagnosis of sleep
disorders.
• Variables obtained during PSG include sleep onset, arousals, sleep stages,
eye movements, leg and jaw movements, arrhythmias, airflow during sleep,
respiratory effort, and oxygen desaturations.

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 INSOMNIA
• Insomnia is subjectively characterized as a complaint of difficulty falling
asleep, difficulty maintaining sleep, or experiencing nonrestorative sleep.
• Insomnia lasting two or three nights because of jet lag, eg, is considered to
be transient insomnia, whereas short-term insomnia usually resolves in less
than 3 weeks.
• Insomnia is considered to be chronic when it lasts longer than 1 month

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COMMON ETIOLOGIES OF SLEEP DISORDERS

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DrKen Kukuia
 ANXIETY
• A vague unpleasant emotion that is experienced
in anticipation of some future misfortune
• A state of apprehension, uncertainty or fear,
resulting from the anticipation of a realistic or
imaginary threatening event or situation
• May have emotional, behavioural, cognitive and
physical components

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• Anxiety is a normal adaptive function
• Anxiety disorders are extremes of normal anxiety
– Occur when normal anxiety system becomes
dysregulated - excessive, inappropriate or deficient
• Specific disorders
– Generalised anxiety disorder
– Panic disorder
– Phobias
– Post Traumatic Stress Disorder
– Obsessive compulsive disorder (OCD)
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Generalized anxiety disorder

❑ Characterized by
excessive,
uncontrollable &
often irrational
worry.

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Panic disorder
❑Characterized by unexpected &
repeated episodes of intense fear
accompanied by physical reaction

❑Physical symptoms during an attack

include:
❑a pounding or racing heart
❑Sweating
❑breathing problems
❑weakness or dizziness
❑feeling hot or a cold chill
❑tingly or numb hands
❑chest pain, or stomach pain. 13
 Phobia

❑ A type of anxiety disorder, usually defined as a

persistent fear of an object or situation
14
 Post-traumatic stress disorder

❑PTSD develops after a terrifying ordeal that involved physical harm or the
threat of physical harm.

❑Patient might have gone through the ordeal or witnessed it 15

Obsessive Compulsive Disorder
• Repetitive unwanted obsessions or compulsive acts
• Compulsions are stereotyped behaviours repeated again
and again
– Cleaning, checking, tidying, counting,
– Sometimes marked indecision or slowness
– Not enjoyable or useful
– May be thought of as protective in some way and can reduce
anxiety
• Autonomic symptoms present
• Close links with depression
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 AETIOLOGY
• Genetic
• Neurotransmitter abnormalities
– 5-HT, NA, GABA
• HPA axis dysregulation
• Social factors
– Early life adversity
– Stressful events especially those involving threat
– Lack of support network
• Personality factors
– Some personality traits predispose to certain anxiety disorders
: avoidant, perfectionist
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• CNS depression is responsible for the action of
sedative-hypnotics
– Older drugs cause sedation, hypnosis, anaesthesia and coma
e.g. alcohol and barbiturates
– Newer drugs may need extremely large doses to cause effects
beyond hypnosis

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 Drug A: older sedative-
hypnotics

Drugs B: newer sedative-

hypnotics

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• An ideal anxiolytic drug should:
– calm the patient without causing too much daytime sedation
– Devoid of physical or psychological dependence.

• An ideal hypnotic drug should:

– allow the patient to fall asleep quickly and
– maintain sleep of sufficient quality and duration so that the patient
awakes refreshed without a drug hangover.
• Both types of drugs should have very low toxicity
• Should not interact with other medications in such a way as to
produce unwanted or dangerous effects.
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 Drugs/ Classes of drugs used
• Benzodiazepines
• Barbiturates: now confined to epilepsy & anaesthesia
• Non-benzodiazepine benzodiazepine receptor
agonists: Zaleplon, Zopiclone, Eszopiclone and Zolpidem
• Melatonin receptor agonists: Ramelteon
• Sedative antihistamines e.g. diphenhydramine,
hydroxyzine, promethazine
• Herbals- Valerian
• Miscellaneous drugs e.g. chloral hydrate, meprobamate,
methaqualone
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 BENZODIAZEPINES

DrKen Kukuia 22
• Basic structure consist:
– benzene ring
– coupled to a 7-member heterocyclic structure containing 2
nitrogens at positions 1 & 4
• A substituent in the 7 position, such as a halogen or a nitro
group, is required for sedative-hypnotic activity.
• The structures of triazolam and alprazolam include the
addition of a triazole ring at the 1,2-position.
DrKen Kukuia 23
 PHARMACOKINETICS-BDZ
Absorption & Distribution
• Usually given orally and are well absorbed by this route
– Rate of absorption varies with drugs
– Lipophilicity plays a role in rate of absorption
• The absorption of triazolam is extremely rapid, and that of
diazepam and the active metabolite of clorazepate is more
rapid than other commonly used BDZs.

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• BDZs are weak bases
– Implication for absorption in small intestines??
• Lipid solubility plays a major role in determining the rate
at which a particular BDZ enters the CNS.
– This property is responsible for the rapid onset of CNS effects of
triazolam
• All sedative-hypnotics cross the placental barrier during
pregnancy
– given in the predelivery period, they may contribute to the
depression of neonatal vital functions
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• Sedative-hypnotics are detectable in breast milk and may
exert depressant effects in the nursing infant

• Protein binding x’tics results in only few clinically

significant interactions .

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 Biotransformation & Excretion
• Hepatic metabolism accounts for the clearance of all BDZs
• Tissue redistribution also plays a role
• Elimination half life is dependent on hepatic metabolism
– microsomal oxidation (phase I reactions), including N-
dealkylation and aliphatic hydroxylation.
– The metabolites are conjugated (phase II reactions) to form
glucuronides

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• Alprazolam and triazolam undergo α-hydroxylation
– the resulting metabolites are rapidly conjugated to form inactive
glucuronides
– appear to exert short-lived pharmacologic effects
• Repeated administration with long acting drugs could
cause cumulative effects
– Metabolites have long half lives
• This appears to be less of a problem with estazolam,
oxazepam and lorazepam
– shorter half-lives and are metabolized directly to inactive
glucuronides
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DrKen Kukuia 29
• The water-soluble metabolites of BDZs and other sedative-
hypnotics are excreted mainly via the kidney.
– Usually changes in renal function do not have a marked effect on the
elimination of parent drugs.
– Only trace amounts of the BDZs appear in the urine unchanged.
• The biodisposition of sedative-hypnotics can be influenced by:
– alterations in hepatic function resulting from disease
– drug-induced increases or decreases in microsomal enzyme activities.

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• In very old patients and in patients with severe liver disease, the
elimination half-lives of these drugs are often increased
significantly.
– In such cases, multiple normal doses of these sedative hypnotics can
result in excessive CNS effects.

• The activity of hepatic microsomal drug-metabolizing enzymes

may be increased in patients exposed to certain older sedative
hypnotics on a long-term basis.

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• Barbiturates (especially phenobarbital) and meprobamate are
most likely to cause this effect
– may result in an increase in their own hepatic metabolism as well as that
of other drugs.

• In contrast, BDZs and the newer hypnotics do not change hepatic

drug-metabolizing enzyme activity with continuous use.

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PHARMACODYNAMICS

DrKen Kukuia 33
 GABA A RECEPTOR

• The GABAA receptor has a pentameric

structure assembled from 5 subunits (each
with 4 membrane-spanning domains)
selected from multiple polypeptide classes
(α, β, γ, δ, ε, π, ρ, etc).
• Multiple subunits of several of these classes
have been characterized, among them 6
different α (eg, α1 - α6), 4 β, and 3 γ.
• A major isoform of the GABAA receptor that
is found in many regions of the brain
consists of two α1, two β2, and one γ2
subunits.
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• In this isoform, the 2 binding sites
for GABA are located between
adjacent α1 and β2 subunits,
• The binding pocket for
benzodiazepines (the BDZ site of the
GABAA receptor) is between an α1
and the γ2 subunit.

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• GABAA receptors in different areas of the CNS consist of
various combinations of the essential subunits, and the
BDZs bind to many of these, including receptor isoforms
containing α2, α3, and α5 subunits.

• Barbiturates also bind to multiple isoforms of the GABAA

receptor but at different sites from those with which BDZs
interact.

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• Zolpidem, zaleplon, and eszopiclone bind more selectively
because these drugs interact only with GABAA receptor
isoforms that contain α1 subunits.
• The heterogeneity of GABAA receptors may constitute the
molecular basis for the varied pharmacologic actions of
BDZs and related drugs.
• In contrast to GABA itself, BDZs and other sedative
hypnotics have a low affinity for GABA B receptors, which
are activated by the spasmolytic drug, baclofen

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DrKen Kukuia 38
 MODE OF ACTION-BDZs
• BDZs potentiate GABAergic inhibition at all levels of the neuraxis,
including the spinal cord, hypothalamus, hippocampus, substantia
nigra, cerebellar cortex, and cerebral cortex.
– GABA is a major inhibitory neurotransmitter in the CNS.

• The BDZs do not substitute for GABA but enhance GABA’s effects
allosterically without directly activating GABAA receptors or opening the
associated chloride channels.

• Interaction of BDZs with GABA enhances chloride ion conductance

induced by increasing in the frequency of channel-opening events.

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Organ level effects
• Sedation
• Hypnosis
• Anticonvulsant effect
• Muscle relaxation

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CLINICAL USES
• Treatment of anxiety states
• Treatment of insomnia
• Skeletal muscle relaxation
• Premedication in anaesthesia
• Treating status epilepticus and acute seizures
• Anterograde amnesia
• Alcohol and sedative-hypnotic withdrawal
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ADVERSE EFFECTS
• Toxic effects from acute overdosage
• Unwanted effects during normal therapeutic use
• Tolerance and dependence

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Side effect during therapeutic use
• Drowsiness
• Confusion
• Amnesia
• Impaired coordination

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Acute overdosage
• In overdosage, BDZs are considerably less toxic
compared to other sedative-hypnotics
• Cause prolonged sleep without serious depression of
respiratory and CV fxn
– in presence of other CNS depressants, BDZs can
cause life threatening respiratory depression

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CHLORDIAZEPOXIDE (Librium)
• Long-acting BDZ
• Used mainly in
– Anxiety disorders
– Anaesthetic premedication
– Management of alcohol withdrawal
– Muscle relaxation

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 CLONAZEPAM (Clonopin)
• Long-acting BDZ
• Used mainly in
– seizure disorders- TOLERANCE DEVELOPS
– adjunctive treatment in acute mania
– certain movement disorders such as Tourette’s syndrome

NB: Tourette syndrome is a neurological disorder

characterized by repetitive, stereotyped, involuntary
movements and vocalizations called tics.
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DIAZEPAM (Valium)
• Prototype BDZ
• It is a long-acting BDZ
• Used mainly in
– anxiety disorders
– Seizure disorders- Status epilepticus
– Anaesthetic premedication
– Skeletal muscle relaxation

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FLURAZEPAM (Dalmane)
• It is a long-acting BDZ
• Used mainly in
– Insomnia
– Anxiety disorders

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ALPRAZOLAM (Xanax)
• It is a medium-acting BDZ
• Withdrawal symptoms may be especially
severe
• Used mainly in
– Anxiety disorders
– Depression

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NITRAZEPAM
• It is a medium-acting BDZ
• Used mainly in
– Anxiety disorders
– Insomnia

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LORAZEPAM (Ativan)
• It is a short-acting BDZ
• Metabolized solely by conjugation
• Used mainly in
– Anxiety disorders
– Insomnia
– Preanaesthetic medication

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OXAZEPAM (Serax)
• It is a short-acting BDZ
• Metabolized solely by conjugation
• Used mainly in
– Anxiety disorders
– Insomnia

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TEMAZEPAM (Restoril)
• It is a short-acting BDZ
• Metabolized solely by conjugation
• Used mainly in
– Anxiety disorders
– Insomnia

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MIDAZOLAM (Versed)
• It is an ultrashort-acting BDZ
• Metabolized solely by conjugation
• Used mainly in
– Anxiety disorders
– Insomnia
– Preanaesthetic medication

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TRIAZOLAM (Halcion)
• It is an ultrashort-acting BDZ
• Undergoes α-hydroxylation before conjugation
• Used mainly in insomnia

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CLORAZEPATE (Tranxene)
• It is a pro-drug
• Converted to nordazepam by decarboxylation in GIT
• Used mainly in
– anxiety disorders
– Seizure disorders

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 FLUMAZENIL

• Flumazenil (ROMAZICON) is an
imidazobenzodiazepine that behaves as a specific BDZ
antagonist.

• Flumazenil binds with high affinity to specific sites on

the GABAA receptor, where it competitively antagonizes
the binding and allosteric effects of BDZs and other
ligands.
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• The drug antagonizes both the electrophysiological and
behavioural effects of agonist and inverse agonist- BDZs and
β-carbolines respectively.

• Administration of flumazenil may precipitate seizures

under certain circumstances

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• Flumazenil is available only for i.v administration.
• Although absorbed rapidly after oral administration, <25%
of the drug reaches the systemic circulation owing to
extensive first pass hepatic metabolism
– effective oral doses are apt to cause headache and dizziness.
• On i.v administration, it is eliminated almost entirely by
hepatic metabolism to inactive products with a t1/2 of about
1 hour
• Duration of clinical effects usually is only 30–60 minutes.

DrKen Kukuia 59
• The primary uses of flumazenil are:
– the management of suspected BDZ overdose and
– the reversal of sedative effects produced by BDZs
administered during either general anaesthesia or
diagnostic and/or therapeutic procedures.

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BARBITURATES

DrKen Kukuia 61
• The barbiturates are derivatives of 2,4,6-
trioxohexahydropyrimidine that reversibly depress
the activity of all excitable tissues
• Considered the prototype sedative-hypnotic
• Induce psychological and physical dependence
• E.g. Phenobarbital, secobarbital, thiopental,
methohexital, pentobarbital, amobarbital

DrKen Kukuia 62
MODE OF ACTION- BARBITURATES
• Barbiturates also facilitate the actions of GABA at multiple
sites in the CNS, but—in contrast to benzodiazepines—they
appear to increase the duration of the GABA-gated chloride
channel openings.
• At high concentrations, the barbiturates may also be GABA-
mimetic, directly activating chloride channels.
• These effects involve a binding site or sites distinct from the
BDZ binding sites.

DrKen Kukuia 63
• Barbiturates are less selective in their actions than BDZs,
because they also depress the actions of the excitatory
neurotransmitter glutamic acid via binding to the AMPA
receptor.

• Barbiturates also exert nonsynaptic membrane effects in

parallel with their effects on GABA and glutamate
neurotransmission.

DrKen Kukuia 64
• This multiplicity of sites of action of barbiturates may be
the basis for their ability to induce full surgical
anaesthesia and for their more pronounced central
depressant effects (which result in their low margin of
safety) compared with BDZs and the newer hypnotics.

DrKen Kukuia 65
• Increased biotransformation of other pharmacologic
agents as a result of enzyme induction by
barbiturates is a potential mechanism underlying
drug interactions.

DrKen Kukuia 66
PHARMACOKINETICS
• Weakly acidic
– Absorbed in the stomach and small intestine
• Lipophilicity determines rate of CNS entry
– Thiobarbiturates are very lipid soluble hence has a high
entry and rapid onset of action
• Redistribution leads to termination of major CNS
effects

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• Clearance is dependent on metabolic transformation
to more water soluble metabolites
– Oxidation to alcohols, acids and ketones
– ROH, RCOOH, RCO are converted to glucuronides

• Excreted by the kidneys

– Phenobarbital: elimination rate can be increased
significantly by alkalinization of the urine.

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CLINICAL USES
• Insomnia
• Epilepsy
• General Anaesthesia

DrKen Kukuia 69
ADVERSE EFFECTS
• Dizziness, lightheadedness, sedation, headache
• Nausea and abdominal pain.
• Tolerance
• Dependence
• Cardiovascular depression
• Respiratory depression

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ZOLPIDEM
• An imidazopyridine derivative structurally unrelated to
BDZs, with hypnotic actions.

• Binds selectively to the BDZ(1) subtype of BDZ receptors

and facilitates Gaba-mediated neuronal inhibition.

• The actions of zolpidem are antagonized by flumazenil.

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• Zolpidem has minimal muscle relaxant and
anticonvulsant effects.

• However, amnestic effects have been reported with

use of doses greater than recommended.

• The drug has a rapid onset of action, and its

duration of hypnotic action is close to that of
triazolam.

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• Zolpidem causes minor effects on sleep patterns at the
recommended hypnotic dose but can suppress REM
sleep at higher doses.

• Rebound insomnia may occur on abrupt discontinuance

of higher doses.

• Respiratory depression occurs if large doses are ingested

with other CNS depressants, including ethanol.

• The risk of tolerance and dependence with extended use

of zolpidem is less
DrKen Kukuia 73
• Zolpidem is rapidly metabolized to inactive
metabolites by the liver via oxidation and
hydroxylation.

• The elimination half-life of the drug is 1.5–3.5 hours,

with clearance decreased in elderly patients.

• Dosage reductions are recommended in patients

with hepatic dysfunction, in elderly patients, and in
patients taking cimetidine.

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ZALEPLON
• Zaleplon binds selectively to the BDZ1 receptor subtype,
facilitating the inhibitory actions of GABA.

• Zaleplon is rapidly absorbed from the GIT and has an

elimination half-life of about 1 hr.

• Metabolized to inactive metabolites mainly by hepatic

aldehyde oxidase and partly by the CYP3A4.
• Dosage should be reduced in patients with hepatic
impairment and in the elderly.
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• Metabolism of zaleplon is inhibited by cimetidine

• Drugs that induce hepatic CYP3A4 increase the

clearance of zaleplon.

• Zaleplon decreases sleep latency but has little effect on

total sleep time or on sleep architecture.

• Rapid onset and short duration of action are favourable

properties for those patients who have difficulty falling
asleep.
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• Amnestic effects and next-day impairment of
psychomotor performance occurs

• The risk of tolerance and physiologic dependence appears

to be low

• High doses(2X recommended dose) can cause rebound

insomnia.

• Zaleplon potentiates the CNS depressant effects of

ethanol and other sedative-hypnotics.
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RAMELTEON

DrKen Kukuia 78
• Ramelteon (Rozerem), a novel hypnotic drug, is an
agonist at MT 1 and MT 2 melatonin receptors located in
the suprachiasmatic nuclei of the brain.
– It is specifically useful for patients who have difficulty in
falling asleep.

• Melatonin receptors are thought to be involved in

maintaining circadian rhythms underlying the sleep-
wake cycle.

• The drug has no direct effects on GABAergic

neurotransmission in the CNS.
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• The drug is rapidly absorbed after oral administration

• Undergoes extensive first-pass metabolism, forming an

active metabolite with longer half-life (2–5 hours) than
the parent drug.

• The CYP1A2 isoform is mainly responsible for its

metabolism, but the CYP2C9 isoform is also involved.

• The drug should not be used in combination with

inhibitors of CYP1A2 (eg, ciprofloxacin, fluvoxamine,
tacrine, zileuton) or CYP2C9 (eg, fluconazole)

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• In patients with chronic insomnia ramelteon
– reduced the latency of persistent sleep
– with no effects on sleep architecture
– no rebound insomnia or significant withdrawal symptoms.

• Ramelteon has minimal potential for abuse, is not a

controlled substance, and regular use does not result in
dependence.

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• Should be used with caution in patients with liver
dysfunction.
• The CYP inducer rifampicin markedly reduces the plasma
levels of both ramelteon and its active metabolite.
• Adverse effects of ramelteon include:
– dizziness, somnolence, fatigue
– endocrine changes as well as decreases in testosterone and increases in
prolactin.

DrKen Kukuia 82
H1 RECEPTOR ANTAGONISTS
• Histamine acts on at least three types of receptor (H1–3)
in the brain
• They occur in most brain regions and are all G-protein
coupled. H3 receptors are inhibitory autoreceptors on
histamine-releasing neurons.
• Like other monoamine transmitters, histamine is
involved in many different CNS functions.

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• Histamine release follows a distinct circadian
pattern, the neurons being active by day and silent
by night.

• H1 receptors in the cortex and reticular activating

system contribute to arousal and wakefulness, and
H1 receptor antagonists produce sedation

DrKen Kukuia 84
• E.g.
– Diphenhydramine
– Chlorpheniramine
– Hydroxyzine
– Promethazine

DrKen Kukuia 85
 HERBAL REMEDIES
• Valerian is an herbal sleep remedy that has been studied for its sedative-
hypnotic properties in patients with insomnia.
• The mechanism of action is not fully understood but may involve
increasing concentrations of GABA.
• The recommended dose for insomnia ranges from 300 to 600 mg.
• An equivalent dose of dried herbal valerian root is 2 to 3 g soaked in 1 cup
of hot water for 20 to 25 minutes.

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 ANXIOLYTICS

DrKen Kukuia 87
 DRUGS
Anxiety disorder First line drugs Second line drugs Alternatives
Generalized anxiety • Duloxetine • Benzodiazepines- • Antihistamines-
disorders • Escitalopram alprazolam, clonazepam, hydroxyzine
• Imipramine chlordiazepoxide, • Anticonvulsants-
• Paroxetine clorazepate, diazepam, pregabalin
lorazepam, oxazepam
• Sertraline • Atypical
• Venlafaxine • Buspirone Antipsychotic-
• Imipramine Quetiapine XR

Panic disorder SSRIs- citalopram, • Alprazolam Phenelzine

escitalopram, • Citalopram
fluoxetine, paroxetine, • Clomipramine
fluvoxamine, sertraline • Clonazepam
• Venlafaxine XR • Imipramine

DrKen Kukuia 88
Anxiety disorder First line drugs Second line drugs Alternatives
Social anxiety disorder Escitalopram Clonazepam Clonazepam
Fluvoxamine CR Citalopram Gabapentin
Paroxetine Mirtazapine
Sertraline Phenelzine
Venlafaxine XR Pregabalin
*β-blockers-
propranolol, atenolol
Post traumatic stress SSRI- citalopram, Venlafaxine XR α1 antagonists
disorder escitalopram, TCAs- amitriptyline, Atypical antipsychotics
fluoxetine, sertraline imipramine MAO inhibitors-
fluvoxamine, paroxetine phenelzine

DrKen Kukuia 89
Anxiety disorder First line treatment Second line treatment Third line treatment
Obsessive compulsive CBT alone • Switch to another SSRI • Switch to another
disorder SSRI alone or clomipramine antipsychotic
CBT + SSRI • Augmentation with augmenting agent
antipsychotic
• Augmentation of
SSRI with
clomipramine

DrKen Kukuia 90
AZAPIRONES
• Buspirone is the first e.g of a class of anxiolytic agents
– Can relieve some symptoms of anxiety in doses that do not cause
sedation.
• Clinically relevant effects are mediated via 5-HT1A
receptors, where it acts as a partial agonist.
• Inhibit activity of noradrenergic nucleus ceruleus neurons
and thus interferes with arousal reactions
• Well absorbed from the GIT

91
• >95% bound to plasma proteins.
• Buspirone is extensively metabolized, with less than 1%
of the parent drug excreted into the urine unchanged.
• At least one of the metabolic products of buspirone is
biologically active.
• The parent drug has an elimination half-life of 4 to 6
hrs.

92
• Buspirone is as effective as the BDZs in the treatment of
general anxiety.
– The full anxiolytic effect of buspirone takes several weeks to
develop

• In therapeutic doses, buspirone has little or no sedative

effect

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• Lacks the muscle relaxant and anticonvulsant properties

• Buspirone does not potentiate CNS depression caused by

sedative–hypnotic drugs or by alcohol

• It does not prevent the symptoms associated with BDZ

withdrawal.

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Clinical Uses
• Generalized anxiety disorder

• Anxiety with depression.

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Adverse effects
• Dizziness, light-headedness & headache
• Increase BP in patients taking MAO inhibitors
• May increase plasma levels of haloperidol if co-
administered
• Abuse, dependence & withdrawal symptoms have not
been reported

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DrKen Kukuia 97