SEDATIVE–HYPNOTIC

AND ANXIOLYTIC DRUGS

 Introduction
2

 Up to 33.7% of the population are affected by an

anxiety disorder during their lifetime

 Etiology of anxiety disorders are based on

interactions between a combination of factors
including vulnerability (eg, genetic predisposition
and early childhood adversity) and stress (eg,
occupational and traumatic experience).

Sedative Hypnotics 2023 slu 03/29/2024

 Introduction…cont’d
3

 The distinction between a ‘pathological’ and a

‘normal’ state of anxiety is not clear-cut but
represents the point at which the symptoms
interfere with normal productive activities.
 The term ‘anxiety’ is applied to several distinct
disorders.
 Anxiety disorders recognised clinically include the
following:

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 Anxiety disorders

 Anxiety disorders as recognised clinically include:

 Generalized anxiety disorder (GAD): is characterized by
excessively worrying about numerous things on a constant basis.
 Individuals with this disorder tend to have unrealistic views and
have a difficult time controlling their worries. (an ongoing state
of excessive anxiety lacking any clear reason or focus).
 Panic disorder (attacks of overwhelming fear occurring in
association with marked somatic symptoms, such as sweating,
tachycardia, chest pains, trembling, choking, etc): appears to
have a genetic component.
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 Anxiety disorders…cont’d
5

 Social anxiety disorder(SAD) (fear of being with and

interacting with other people)
 Phobias (strong fears of specific things or situations, e.g.
snakes, open spaces, flying, swimming, social interactions
etc.) Some Bizarre Phobias decidophobia (fear of passing
decision), deipnophobia (Fear of dining with others) tec
 Post-traumatic stress disorder (PTSD) (anxiety triggered by
insistent recall of past stressful experiences).
 obsessive-compulsive disorder (OCD)compulsive
ritualistic behaviour driven by irrational anxiety
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 OCD?
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 OCD can be severely debilitating and impair functioning in

social, family, and work settings, with an overall decrease in
quality of life (QOL).
 OCD is associated with an increased risk of suicide, with 15% of
patients reporting a previous history of suicide attempt.5
 Increased understanding of symptom dimensions and treatment
response can improve QOL in patients suffering from OCD.
 The epidemiology of OCD is influenced by age and gender.
 OCD typically begins early in life, with 20% of cases occurring
in childhood, 29% in adolescence, and 49% of cases occurring by
age 20.1
 SSRIs are the drugs of choice
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 GAD
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 Psychological and Cognitive Symptoms (>6moths)

 Excessive anxiety
 Worries that are difficult to control
 Feeling keyed up or on edge
 Trouble concentrating or mind going blank
 Headaches

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 GAD…Con’d
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 Physical Symptoms
 Restlessness
 Fatigue
 Muscle tension
 Sleep disturbance
 Irritability
 Sweating
 Nausea
 Fatigue trouble sleeping

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 Pathophysiology ?
9

 Modulation of normal and pathologic anxiety states is associated

with multiple regions of the brain and abnormal function in several
NTs systems
 NAD
 GABA
 5-HT
 CRF
 CCK.
 Neuroanatomic models of and anxiety include some key brain areas.
 The amygdala, a temporal lobe structure, plays a critical role in the
assessment of fear stimuli and learned response to fear.
 LC implementing fear responses

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 Pathophysiology…cont’d
10

 Hippocampus -consolidation of traumatic memory and

contextual fear conditioning.
 The HT is the principal area for integrating neuroendocrine
and autonomic responses to a threat.
 Anterior cingulate cortex (ACC), and insula

 Low 5-HT activity may lead to a dysregulation of other NTs.

 NE and 5-HT systems are closely linked, and interactions
between the two are reciprocal and vary.
 NE may act at presynaptic 5-HT terminals to decrease 5-HT
release, and its activity at postsynaptic receptors can cause
increased 5-HT release Sedative Hypnotics 2023 slu 03/29/2024
 General Approach to Treatment
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 Therapy based on their presenting symptoms

 Eg. a nonbenzodiazepine hypnotic for difficulty sleeping.
 Short courses of exposure-based, trauma-focused cognitive
behavioral therapy -PTSD or ASD
 If symptoms (eg, hyperarousal, avoidance, dissociation,
sleep difficulties, or depressed mood) persist for 3 to 4 weeks
and the patient experiences marked social, occupational,
and/or interpersonal impairment, they can be treated with
pharmacotherapy, psychotherapy, or both.
 Treatment regimens usually combine psychoeducation,
psychosocial support and/or treatment, and pharmacotherapy
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 Sedative–hypnotic and Anxiolytic Drugs

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• Sedatives: Clam the patient and reduce anxiety without - normal sleep.
 Hypnotics: Drugs that initiate and maintain the normal sleep.
 Sedative-anxiolytic (antianxiety)
 Sedative-hypnotic
 different degree of CNS depression
 pharmacologic effects are dose related:
 small doses: sedation
 larger doses: hypnosis
 larger doses: surgical anesthesia (loss of sensation)
• Hypnotics are usually anxiolytic and hypnotic but, not all anxiolytics are
hypnotic.
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 Dose dependent effect of Sedative hypnotics

Death

Coma

Anaesthesia

Hypnosis

sedation

Amnesia

Awake
13 Sedative Hypnotics 2023 slu 03/29/2024
 Sedative–hypnotic. cont…
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 Insomnia: includes a wide variety of sleep disturbances,

such as difficulty in falling asleep, early or frequent
awakenings, and remaining unrefreshed after sleep.
 Use of sedative–hypnotic drugs is one approach to the
therapy of insomnia.
 Other measures include advice to avoid stimulants before
retiring, maintenance of a proper diet, initiation of an
exercise program, and avoidance of stressful or anxiety-
provoking situations.

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 DRUGS USED TO TREAT ANXIETY
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 Antidepressants
 Selective 5-HT reuptake inhibitors SSRIs
 Serotonin/noradrenaline reuptake inhibitors SNRIs
 Older antidepressants (tricyclic antidepressants and
monoamine oxidase inhibitors [MAOIs]) are also effective
 But a lower side-effect profile favours the use of SSRIs.
 These agents have the additional advantage of reducing
depression, which is not uncommonly associated with anxiety

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 DRUGS used to …..Anxiety
16

Benzodiazepines.
 Used to treat acute anxiety.

 Those used to treat anxiety have a long t 1/2

 They may be co-administered during stabilisation of a

patient on an SSRI.
Gabapentin and pregabalin are used to treat general
anxiety disorder,
Other antiepileptic drugs such as tiagabine, valproate
and levetiracetam may also be effective for GAD

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 DRUGS used to …..Anxiety
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 Some atypical antipsychotic agents such as

olanzapine, risperidone, quetiapine and ziprasidone
may be effective in generalised anxiety disorder
and post-traumatic stress disorder.

 BB (propranolol)-These are used to treat some

forms of anxiety, particularly where physical
symptoms such as sweating, tremor and
tachycardia are troublesome.

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 Sedative-hypnotic
Sedative-hypnoticDrugs
Drugsclasses
classes
18

Benzodiazepines Barbiturates Miscellaneous agents

Short Ultra-short
action acting
Intermediate Short
Buspirone,
Carbamates
Ethanol,
Chloral hydrate
glutethimide.
Intermediate action Zaleplon
Long Long
Zolpidem
action Sedative Hypnotics 2023acting
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 Benzodiazepines (BZDs)
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 MOA:
 BZDs act selectively act on GABAA receptors,
 enhance the response to GABA, by facilitating the opening of GABA-
activated chloride channels.
 Increase in the frequency of channel opening (Increase the entrance of
chloride into the postsynaptic cells.)
 greater Hyperpolarization.
 The most important group, used as anxiolytic and hypnotic agents.
 Chlordiazepoxide , the first BZD, synthesised by serendipity in 1961.
 The most widely prescribed drugs.
 Most possess anxiolytic, sedative–hypnotic, and anticonvulsant properties.

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 Classifications of BZDs

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According to Duration of Action: • Long acting: ( 24-72 hours)

 Short acting: (3-5 hours). – Chlorazepate
 Triazolam – Chlordiazepoxide
 Midazolam – Clonazepam
 Intermediate: (6-24 hours). – Diazepam
– Flurazepam
 Alprazolam
– Quazepam
 Lorazepam
– Prazepam
 Estazolam – Nitrazepam
 Oxazepam
 Temazepam

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21

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 Antagonist to BDZs
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 Flumazenil
 a BZD receptor antagonist.
 used in the treatment of BZD overdose and in the
reversal of BZD-induced sedation.
 Dose; IV: 0.2mg over 15 seconds (max. 1mg)

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 Pharmacokinetics

23

 Well absorbed when given orally.

 Absorption takes place from small intestine.
 Because BZDs are weak bases.
 Bind strongly to plasma protein.
 Accumulate gradually in body fat because of their high lipid
solubility.
 Distribution volumes not far from 1 L/kg body weight.
 Redistribution away from the CNS is of primary
importance in terminating their therapeutic effects.
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 Pharmacokinetics cont…

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 All metabolized, and they are eventually excreted as

glucuronide conjugates in the urine (figure below).
 Several are converted to active metabolites, such as N-
desmethyldiazepam (nordazepam), which has a half-life of
about 60 hours;
 cumulative effects and long hangovers when they are given
at regular intervals.
 The short-acting BZDs
 metabolized directly by conjugation with glucuronide.
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 Pharmacokinetics cont…

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Figure: The metabolism of benzodiazepines: Nordazepam is biologically active and has a very long
half-life. Drugs available for clinical use are shown in shaded boxes.

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 Clinical Uses BDs

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I. Anxiety
II. Insomnia
III. Epilepsy and Seizures
 Clinically Clonazepam and diazepam are used.

 Have selective anticonvulsant action.

IV. Anesthesia
 Midazolam

 Common anesthetic BZD.

V. Alcohol and Sedative–Hypnotic Withdrawal

 Chlordiazepoxide and Diazepam

 Because of low addictive potential

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 Adverse Effects of BZDs

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 Most associated with CNS depression:

 drowsiness, excessive sedation, impaired motor
coordination, confusion, and memory loss.
 Less common adverse effects:
 blurred vision, hallucinations
 BZD administration during pregnancy, delivery, or lactation
has the potential to have adverse effects on the fetus or
newborn.
 Additive effect with ethanol hence alcohol is prohibited

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 Adverse Effects cont…

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 Tolerance and dependence do occur with the use of BZDs.

 Discontinuation, particularly abrupt withdrawal
 can be associated with a variety of symptoms (rebound
insomnia, rebound anxiety).
 a gradual tapering may lessens withdrawal reaction.
 Withdrawal from a supratherapeutic dose after a drug taken
for months or years.
 muscle weakness, tremor, nausea, vomiting, weight loss,
and possibly convulsions.
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 Drug Interactions
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 When used with other sedative–hypnotics or alcohol:

 produce additive CNS depression.
 Many BZDs are metabolized by the CYP3A4.
 Coadministration with inhibitors of the enzyme such as
grapefruit juice, ketoconazole, erythromycin, ritonavir…
intensify their effect,
 whereas inducers such as rifampin, carbamazepine, and
phenytoin can reduce the therapeutic effect of the BZDs.

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 Barbiturates
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MOA:
 Share with BZDs the ability to enhance the action of GABA, but they bind a different site on the
GABA-receptor/chloride channel.
 They prolong the duration of the opening of GABA-activated chloride channels.
 Also capable of opening chloride channel in the absence of GABA.
 Are derivatives of barbituric acid
 Second choice as sedative – hypnotic.
Classification:
 Long acting (24-28 h):
 Phenobarbitone
Barbituric Acid
 Intermediate (8-24h):
 Amylobarbitone
 Short-acting (3-8h):
 Pentobarbitone
 Secobarbitone
 Amobarbital
 Ultrashort acting (25 minutes):
 Thiopental
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 Pharmacokinetics

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 Lipid soluble, weak acids.
 High lipid solubility allows rapid transport across the BBB and results in a
short onset.
 Absorbed orally.
 Distribute throughout the body.
 Redistribution to the other tissues results in short duration
of action. (Thiobarbiturates)
 Metabolized in the liver by Cyp3A4, Cyp3A5 and
Cyp3A7 to inactive metabolites.
 Well known inducer of CYP450 microsomal enzymes.
 Excreted in the urine.
 Alkalinization increases excretion (NaHCO3)
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 Cross the placenta.
 Barbiturates cont…
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 Uses :
 Anticonvulsants: (Phenobarbitone); tonic-clonic seizures, status
epilepticus.
 Induction of anesthesia (thiopental, methohexital).
 Hypnotic (pentobarbital)
 Adverse effects:
 Respiratory depression.
 Hangover: residual sedation after awakening.
 Tolerance and dependence.
 Many drug interactions.
 Allergic reaction: urticaria and skin rash.
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 Drug interactions

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 Other CNS depressants: Ethanol

 Increase metabolism of;
 Phenytoin, warfarin, and dicumarol:

Advantages of BZD over barbiturates

 Selective: minimal respiratory and cardiovascular depression.
 High therapeutic index.
 Less hangover.
 Not enzyme inducer.
 Less dependence with minimal withdrawal symptoms.
 Has specific antagonist.
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 Newer Generation Anxiolytics
Buspirone
34
 Although interact with a number of NT systems (such as DA), its
clinically relevant effects are mediated through interactions at the
5-HT1A receptor, where it acts as a partial agonist.
 Effective for GAD but not for panic disorder

Pharmacokinetics:
 Well absorbed when taken orally.
 More than 95% bound to plasma proteins.
 Extensively metabolized (Cyp3A4), with less than 1% of the
parent drug excreted into the urine unchanged.
 Parent drug elimination half-life is 4 to 6 hours.
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 Buspirone cont…

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Pharmacological Actions
 Is as effective as the BZDs in the treatment of general anxiety,
 however, it takes several weeks to develop the full anxiolytic
effect, but for BZDs only few days.
 May have complex mechanism of action.
 Little or no sedative effect.
 Does not potentiate the CNS depression caused by other drugs
or by alcohol.
 Effective in general anxiety and in anxiety with depression.
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 Buspirone cont…
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Adverse Effects
 Safe even when given in very high doses.
 The most common side effects are dizziness, light-
headedness, and headache.
 Abuse, dependence, and withdrawal have not been reported.
 No cross-tolerance to the BZDs.
 Increase blood pressure in patients taking monoamine
oxidase inhibitors.

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 PTSD treatment
37

 Antidepressants are first line agents

 In addition to their efficacy in PTSD, these agents are also
effective for concurrent depression and anxiety disorders.
 SSRIs and venlafaxine
 The TCAs amitriptyline and imipramine are also
considered second-line agents, and the MAOI phenelzine is
considered a third-line antidepressant if therapeutic trials of
SSRIs or venlafaxine have failed.
 Atypical antipsychotics, α1-adrenergic antagonists,
antidepressants, mood stabilizers, and anticonvulsants can
be used as augmenting agents for persistent symptoms
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38

Thank you

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