Chapter 9 Anxiolytics and Hypnotics Drugs

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Chapter 9Anxiolytics and Hypnotics Drugs

• Dr. Shereen Ayoub
• Faculty of Medicine
• Al-Azhar University

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Causes of Anxiety

• 1). Medical
• Respiratory
• Endocrine
• Cardiovascular
• Metabolic
• Neurologic.

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Causes of Anxiety

• 2). Drug-Induced
• Stimulants
• Amphetamines, cocaine, TCAs, caffeine.
• Sympathomimetics
• Ephedrine, epinephrine, pseudoephedrine
  phenylpropanolamine.
• Anticholinergics\Antihistaminergics
• Trihexyphenidyl, benztropine, meperidine
  diphenhydramine, oxybutinin.
• Dopaminergics
• Amantadine, bromocriptine, L-Dopa,
  carbid/levodopa.

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Causes of Anxiety

• Miscellaneous
• Baclofen, cycloserine, hallucinogens,
  indomethacin.
• 3). Drug Withdrawal
• BDZs, narcotics, BARBs, other sedatives, alcohol.

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Introduction
Hypnotics agent that induces sleep sleeping
pills, sedative medications, sedative-hypnotics

• 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 anxyolitic and hypnotic
• Not all anxiolytics are hypnotic
• situational-stress insomnia, best treated with
  hypnotics

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I. ANTIAXIETY DRUGS/SEDATIVES Various antianxiety
agents (minor tranquilizers, psychosedatives)
have been used throughout the ages to alleviate
feelings of stress, anxiety, discomfort,
etc Currently, benzodiazepines are among the most
widely prescribed antianxiety drugs because of
their higher therapeutic index (severe CNS
depressant doses/antianxiety doses) than older
agents .
Figure 22-1. Dose-response curves for two
hypothetical sedative-hypnotics
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Functional Diversity of the GABAA Receptor
Subunits Studies (largely in knockout
animalswith specific subunit deletions or
animals with variant alleles of specific
subunits) indicate (strongly suggest) functional
specificity of different GABAA subunits ? a1
subunit-containing GABAA receptors sedation ?
a2 subunit- anxiolysis. ? a3 subunit-
processing of sensory motor information related
to a schizophrenia endophenotype. ? a4 subunit-
sedative, hypnotic and anesthetic effects of some
agents in the thalamus. ? a5 subunit-
(extrasynaptic) associative temporal and spatial
memory by inhibitory modulation of activities in
the hippocampus. ? ß3 subunit- sedation,
hypnosis and anesthesia by, e.g., pentobarbital,
propofol and etomidate, but not by the
neurosteroidal anesthetic alphaxalone).
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Benzodiazepines-Anxiolytics

• chlordiazepoxide (Librium)
• diazepam (Valium)
• clonazepam (Klonopin)
• clorazepate (Tranxene)
• lorazepam (Ativan)
• oxazepam (Serax)
• alprazolam (Xanax)
• Triazolam

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BenzodiazepinesMechanism of Action

• Binds to the benzodiazepine receptors on GABA
  neuron
• GABA is the major inhibitory neurotransmitter in
  the CNS
• Benzodiazepines relieve anxiety through
  enhancement of the inhibitory activity of GABA
• No antipsycotic, No analgesic, Not affect ANS

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Benzodiazepines-Indications

• Seizure Disorders, epilepsy (clonazepam ,
  diazepam)
• Delirium
• Alcohol Withdrawal
• Conscious Sedation insomnia (flurazepam long
  acting, temazepam intermediate, triazolam short)

• Generalized Anxiety Disorder
• Panic Disorder (alprazolam)
• Insomnia
• Schizophrenia
• Muscular spasms (duiazepam)
• Depression

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BenzodiazepinesPharmacokinetic Differences
Benzodiazepine Peak Plasma Level (Hour) Speed of onset
Alprazolam 1-2 Intermediate
Chlordiazepoxide 1-4 Intermediate
Clonazepam 1-2 Intermediate
Diazepam 0.5-2 Very Fast
Lorazepam 2-4 Intermediate
Oxazepam 2-4 Slow
Facts and Comparison
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BenzodiazepinesPharmacokinetic Differences
Benzodiazepine Elimination Half Life (Hour)
Alprazolam 7-27
Chlordiazepoxide 5-30
Clonazepam 18-50
Diazepam 20-80
Lorazepam 10-20
Oxazepam 5-20
Facts and Comparison
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BenzodiazepinesParenteral Administration

• Used for acute anxiety/agitation, seizures,
  sedation
• IM lorazepam midazolam provides rapid, reliable
  and complete absorption
• Avoid IM administration of diazepam and
  chlordiazepoxide due to variability in rate and
  extent of absorption
• IV lorazepam
• onset of action 1-5 minutes
• IM lorazepam
• onset of action 15-30 minutes
• inject undiluted, deep into muscle mass

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BenzodiazepinesParenteral Administration

• Parenteral administration may produce apnea,
  hypotension, bradycardia, or cardiac arrest
  (particularly in severely ill, geriatric,
  unstable cardiovascular system, limited pulmonary
  reserve, or if drug administered to rapidly IV)
• Avoid co-administration of lorazepam IM with
  olanzapine IM due to reports of death related to
  combination
• Lipophylic, rapidly absorbed after oral
  administration
• Fate hepatic microsomal, excreted in urine as
  glucoronides or oxidized metabolites
• Cross placenta, secreted in milk

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Benzodiazepines-DDI

• Clozapine severe hypotension, respiratory or
  cardiac arrest, loss of consciousness
• Cigarette smoking may decrease the sedative
  effects of usual benzodiazepine doses
• Alcohol increases sedation
• Anti-fungals may increase plasma concentration of
  benzodiazepines

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BenzodiazepinesAdverse Reactions

• CNS depression drowsiness, sedation, psychomotor
  impairment, ataxia
• Disorientation, confusion, irritability
• Impairment in memory and recall
• Respiratory depression
• Percaution liver disease, glaucoma, alcohole,
  CNS depressant

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Benzodiazepines

• Tolerance
• Decrease in response to the medication effects
• Dependence
• Physical Dependence when medication is stopped,
  withdrawal or discontinuation symptoms occur
• Addiction complex behavioral syndrome that
  includes an obsession with obtaining and using
  the drug, excessive, prolonged and harmful use
  despite adverse consequences, denial,
  rationalization, minimization and justification

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Benzodiazepines

• Abuse
• Taking prescribed medication inappropriately
• Usually multiple substances involved
• Multiple uses for polysubstance abuse
• Enhance euphoriant effects of opioids (boost
  methadone doses)
• Alleviate withdrawal (between heroin fixes)
• Temper cocaine highs
• Augment alcohol effects and modulate withdrawal
  state

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Benzodiazepine Withdrawal

• Symptoms insomnia, anxiety, autonomic
  instability (increased heart rate and BP, tremor,
  diaphoresis) insomnia, muscle cramps, confusion,
  seizures, irritability, ataxia
• Time frame for emergence of symptoms corresponds
  to half-life of the benzodiazepine
• Example alprazolam has high risk of withdrawal-
  due to short half-life
• To Avoid Benzodiazepine Withdrawal . Convert to
  longer acting agent to taper slowly

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Benzodiazepine Overdose

• May be intentional or secondary to accumulation
  of doses
• Symptoms somnolence, impaired coordination,
  slurred speech, diminished reflexes, confusion,
  respiratory depression, hypotension

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Benzodiazepine Overdose

• Treatment Options
• Supportive and symptomatic care
• Gastric lavage
• Activated Charcoal
• IV hydration and maintain adequate airway
• IV Flumazenil (Romazicon) Benzodiazepine
  antagonist

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Flumazenil (Romazicon)

• Benzodiazepine antagonist that competitively
  binds to benzodiazepine receptors
• 0.2 mg IV over 30 seconds, then 0.5 mg at 1
  minute interval, up to 3 mg
• Rapid response 1-2 min, up to 10 min
• Duration 1-5 hours

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Flumazenil (Romazicon)

• Use with caution if patient ingest TCA and
  benzodiazepine due to risk of seizures
• Monitor patients respiratory rate and cardiac
  status
• SE Agitation, confusion, sweating,
  nausea/vomiting, blurred vision, seizure
• Re-sedation can occur due to short half-life, may
  repeat dose at 20 minutes intervals with maximum
  of 1 mg/dose and 3mg/hr

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Serotonin Agonist-Buspirone

• MOA unknown, does not interact with GABA-BZ
  receptor complex, has partial agonist of
  serotonin type 1A receptor
• Act on dopamine receptors
• No anticonvulsant or muscle relaxant
• No potential for abuse, physical dependence or
  withdrawal symptoms
• Delayed onset of action (2-3 weeks)

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Serotonin Agonist-Buspirone

• Slow onset of action, metabolized by CYP3A4
• Increase prolactin secretion and growth hormones,
  cause hypothermia
• SE nausea, dizziness, headache, insomnia,
  agitation
• Increased risk of serotonin syndrome when
  co-administered with SSRI

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Other anxiolytic hypnotic

• Zolpidem
• act on GABA, No anticonvulasant, No withdrawal
  effect
• more selective for alpha-1 subunit of
  benzodiazepine receptor complex
• orally rapid absorbed, hepatic oxidation by
  Cyt-P450
• SE nausea, dizziness, headache, insomnia,
  agitation, GI-upset
• Zaleplon
• Affect psychomotor cognitive function
• Short half life 1h
• Metabolized by Cyp 3A4

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Antihistamines

• Hydroxyzine (also antemetic)
• 50-400 mg/d
• Diphenhydramine
• 25-200 mg/d
• SE sedation, dry mouth, blurred vision,
  constipation, urinary retention, headache
• Available as injection

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Beta-Blockers

• Propranolol (Inderal)
• Atenolol (Tenormin)
• Helpful with performance anxiety by suppressing
  sympathetic nervous system activity and autonomic
  symptoms (palpitation/tremor)
• SE bradycardia, hypotension, depression,
  nightmares, insomnia

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II. HYPNOTICS Hypnotics may be indicated in
insomnia, the major symptoms of which include
inability to initiate asleep or stay asleep
once initiated (i.e., frequent/premature
awakenings). Causes of insomnia include organic
and psychological disorders, life style,
environmental factors) A. Physiology of
sleep The awake state maintained largely by the
arousal system (reticular formation) of the brain
stem. Induction and maintenance of sleep
involves (i) active inhibition of pathways
involved in wakefulness and arousal (e.g.,
serotonergic, muscarinic, adrenergic, histaminic
and dopaminergic systems), and (ii) specific
brain nuclei (e.g., median raphe nucleus of the
lower brain stem). 1. Stages of sleep
Non-rapid eye movement (NREM) sleep accounts for
70-75 total sleep duration and progresses
through 4 stages -Stage I (5-10 min duration),
Stage II (15 min duration), Stages III and IV
(Slow wave sleep 70 min) Rapid eye movement
(REM paradoxical) sleep a sleep phase during
which most dreams occur
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C. Management of sleep disorders
Nonpharmacological approaches include good
sleep hygiene
(e.g., constant bedtime, avoidance of
stimulants immediately prior to bedtime, etc)
Pharmacological approaches
The ideal hypnotic drug should have
- a rapid onset of action

- minimal effect
on normal sleep pattern/stages
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the ability to sustain sleep of normal duration

- no hangover, daytime sedative
effects, or memory impairment potential
- minimal addiction or tolerance
potential and rebound insomnia
- a high therapeutic index
Effects of most hypnotics on sleep pattern ?
onset latency, ? NREM duration, ? REM duration

• DRUGS USED IN THE MANAGEMENT OF INSOMNIA
• Benzodiazepines
• a. Mechanism of action
  
  decrease neuronal excitability
  via agonist effect at the GABAA receptor.
• b. Classification by duration of action as
  short-acting (e.g., triazolam),
  intermediate-acting (e.g., temazepam) and
  long-acting (flurazepam).

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Barbiturates

• Phenobarbital
• Pentobarbital
• Amobarbital
• Mephobarbital
• Secobarbital
• Aprobarbital

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• Barbiturates, at high concentrations, directly
  activate the GABAA receptor to enhance chloride
  permeability-- in addition to allosteric
  modulation of the GABAA receptor

- Nonspecific neuronal depression has been
reported at highly very high (toxic) doses
5. Neonatal hyperbilirubinemia and
kernicterus.
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• F. Drug Interactions
• Pharmacokinetic
• - ? metabolism of many other drugs
  (including barbiturates) with resulting
  diminution of their efficacy, due to induction of
  phase I (several CYPs) and Phase II (UGT, etc)
  enzymes.
• Pharmacodynamic
• Potentiation of CNS depressant effects of
  other CNS depressants (including benzodiazepines,
  alcohol, antihistamines, etc).
• G. Adverse effects
• - hangovers
• - hyperalgesia
• - paradoxical effects CNS excitation,
  especially in the elderly
• - hypersensitivity Allergic reactions
  occur, especially in persons with asthma,
  urticaria, angioedema, or similar conditions
• - respiratory and cardiovascular effects
• sub-lethal dose intoxication
  ganglionic blockade ? hypotension/hypothermia ?
  ? respiration.
• 10x hypnotic doses ? central
  chemoreceptor sensitivity (CO2 sensing) ?
  ?hypoxic drive of respiration ? respiratory
  failure (the major cause of barbiturate-induced
  deaths).

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Barbiturate poisoning common in suicide
attempts commonly managed by supporting
respiration and urine alkalinization (via
bicarbonate administration).
H. Contraindications

- barbiturates
and other potent inducers of cytochrome P450 are
contraindicated in acute intermittent porphyria
an inherited toxicity syndrome that results in
accumulation of porphyrrin and porphyrrin
precursors (due to abnormal regulation of
porphyrin synthesis). In affected subjects,
porphyrins and their precursors accumulate and
trigger neural and other symptoms
neural lesions widespread demyelination
of peripheral and cranial nerves ?
? paralysis and widespread CNS lesions.
skin and soft tissues
lesions - Other contraindications
concomitant CNS depressants
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Sedative Hypnotics

• Benzodiazepines
• Barbiturate
• Antihistamines
• Chloral Hydrate
• Ethanol

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Benzodiazepines- Sedative/Hypnotics

• Flurazepam (Dalmane)
• Onset of action 15-45 minutes
• Dose 15-30 mg QHS
• More effective as you take longer due to
  accumulation of active metabolite with long
  half-life
• Temazepam (Restoril)
• 10-15 hr half-life
• Dose 15-30mg QHS
• Improves sleep maintenance
• Slow absorption- so delayed onset of action

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Benzodiazepines-Sedative/Hypnotics

• Triazolam (Halcion)
• Short half-life
• Short term treatment (7-10 days)
• Dose 0.125mg-0.5mg QHS
• Benzodiazepines increase total sleep time, but
  may prevent transition from lighter stage 2 sleep
  into deep, restorative (stage 3 and 4) sleep