Download ANXIOLYTICS AND HYPNOTICS

Anxiolytics and Hypnotics
Drugs
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Causes of Anxiety
1). Medical:
a) Respiratory
b) Endocrine
c) Cardiovascular
d) Metabolic
e) Neurologic.
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Causes of Anxiety
2). Drug-Induced:
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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
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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
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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
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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 animals—with specific subunit
deletions or animals with variant alleles of specific subunits) indicate
(strongly suggest) functional specificity of different GABAA
subunits:
● α1 subunit-containing GABAA receptors: sedation
● α2 subunit-: anxiolysis.
● α3 subunit-: processing of sensory motor information related to a
schizophrenia endophenotype.
● α4 subunit-: sedative, hypnotic and anesthetic effects of some
agents in the thalamus.
● α5 subunit- (extrasynaptic): associative temporal and spatial
memory by inhibitory modulation of activities in the hippocampus.
● β3 subunit-: sedation, hypnosis and anesthesia by, e.g.,
pentobarbital, propofol and etomidate, but not by the neurosteroidal
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anesthetic alphaxalone).
Benzodiazepines-Anxiolytics
 chlordiazepoxide (Librium®)
 diazepam (Valium®)
 clonazepam (Klonopin®)
 clorazepate (Tranxene®)
 lorazepam (Ativan®)
 oxazepam (Serax®)
 alprazolam (Xanax®)
 Triazolam
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Benzodiazepines
Mechanism 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
 Generalized Anxiety Disorder
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 Seizure Disorders, epilepsy
(clonazepam , diazepam)
Panic Disorder (alprazolam)
 Delirium
Insomnia
 Alcohol Withdrawal
Schizophrenia
 Conscious Sedation insomnia
Muscular spasms (duiazepam)
(flurazepam long acting,
Depression
temazepam intermediate, triazolam
short)
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Benzodiazepines
Pharmacokinetic 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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Benzodiazepines
Pharmacokinetic Differences
Facts and Comparison
Benzodiazepine
Elimination
Half Life (Hour)
Alprazolam
7-27
Chlordiazepoxide
5-30
Clonazepam
18-50
Diazepam
20-80
Lorazepam
10-20
Oxazepam
5-20
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Benzodiazepines
Parenteral 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
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onset of action 1-5 minutes
 IM lorazepam
 onset of action 15-30 minutes
 inject undiluted, deep into muscle mass
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Benzodiazepines
Parenteral Administration
 Parenteral administration may produce apnea, hypotension,
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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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Benzodiazepines
Adverse 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
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Decrease in response to the medication effects
 Dependence
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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
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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
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Example: alprazolam has high risk of withdrawaldue 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
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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
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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
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Affect psychomotor & cognitive function
Short half life 1h
Metabolized by Cyp 3A4
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Antihistamines
 Hydroxyzine (also antemetic)
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50-400 mg/d
 Diphenhydramine
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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 which31most
dreams occur
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
- 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
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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
a. 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.
b. 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
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drive of respiration  respiratory failure (the major cause of barbiturate-induced deaths).
• 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
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 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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BenzodiazepinesSedative/Hypnotics
 Flurazepam (Dalmane®)
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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®)
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10-15 hr half-life
Dose: 15-30mg QHS
Improves sleep maintenance
Slow absorption- so delayed onset of action
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BenzodiazepinesSedative/Hypnotics
 Triazolam (Halcion®)
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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
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