ANXIOLYTICS

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ANXIOLYTICS SEDATIVE ,HYPNOTICS
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• Normal
• ?
• Relief from Anxiety
• _________ ? _________________
• SEDATION
• (Drowsiness/decrease reaction time)
• ?
• HYPNOSIS
• ?
• Confusion, Delirium, Ataxia
• ?
• Surgical Anesthesia
• ? Depression of respiratory and
  vasomotor center in the brainstem
• COMA
• ?
• DEATH

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SEDATIVE/HYPNOTICSANXIOLYTICS

• Major therapeutic use is to relief anxiety
  (anxiolytics) or induce sleep (hypnotics).
• Hypnotic effects can be achieved with most
  anxiolytic drugs just by increasing the dose.
• The distinction between a "pathological" and
  "normal" state of anxiety is hard to draw, but in
  spite of, or despite of, this diagnostic
  vagueness, anxiolytics are among the most
  prescribed substances worldwide.

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Manifestations of anxiety

• Verbal complaints. The patient says he/she is
  anxious, nervous, edgy.
• Somatic and autonomic effects. The patient is
  restless and agitated, has tachycardia, increased
  sweating, weeping and often gastrointestinal
  disorders.
• Social effects. Interference with normal
  productive activities.

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Pathological Anxiety

• Generalized anxiety disorder (GAD) People
  suffering from GAD have general symptoms of motor
  tension, autonomic hyperactivity, etc. for at
  least one month.
• Phobic anxiety
• Simple phobias. Agoraphobia, fear of animals,
  etc.
• Social phobias.
• Panic disorders Characterized by acute attacks
  of fear as compared to the chronic presentation
  of GAD.
• Obsessive-compulsive behaviors These patients
  show repetitive ideas (obsessions) and behaviors
  (compulsions).

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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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Anxiolytics

• Strategy for treatment
• Reducing anxiety without causing sedation.

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Anxiolytics

• Benzodiazepines (BZDs).
• Barbiturates (BARBs).
• 5-HT1A receptor agonists.
• 5-HT2A, 5-HT2C 5-HT3 receptor
• antagonists.
• If ANS symptoms are prominent
• ß-Adrenoreceptor antagonists (propranolol).
• ?2-AR agonists (clonidine).

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Anxiolytics

• Other Drugs with anxiolytic activity.
• TCAs (Fluvoxamine). Used for Obsessive compulsive
  Disorder.
• MAOIs. Used in panic attacks.
• Antihistaminic agents. Present in over the
  counter medications.
• Antipsychotics (Ziprasidone).

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Sedative/Hypnotics

• A hypnotic should produce, as much as possible, a
  state of sleep that resembles normal sleep.

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Sedative/Hypnosis

• By definition all sedative/hypnotics will induce
  sleep at high doses.
• Normal sleep consists of distinct stages, based
  on three physiologic measures
• electroencephalogram
• electromyogram
• electronystagmogram.
• Two distinct phases are distinguished which
  occur cyclically over 90 min
• 1) Non-rapid eye movement (NREM). 70-75 of total
  sleep. 4 stages. Most sleep ? stage 2.
• 2) Rapid eye movement (REM). Recalled dreams.

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Properties of Sedative/Hypnotics in Sleep

• 1) The latency of sleep onset is decreased (time
  to fall asleep).
• 2) The duration of stage 2 NREM sleep is
  increased.
• 3) The duration of REM sleep is decreased.
• 4) The duration of slow-wave sleep (when
  somnambulism and nightmares occur) is decreased.
• Tolerance occurs after 1-2 weeks.

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Other Properties of Sedative/Hypnotics

• Some sedative/hypnotics will depress the CNS to
  stage III of anesthesia.
• Due to their fast onset of action and short
  duration, barbiturates such as thiopental and
  methohexital are used as adjuncts in general
  anesthesia.

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Sedative/Hypnotics

• Benzodiazepines (BZDs)
• Alprazolam, diazepam, oxazepam, triazolam
• 2) Barbiturates
• Pentobarbital, phenobarbital
• 3) Alcohols
• Ethanol, chloral hydrate, paraldehyde,
  trichloroethanol,
• 4) Imidazopyridine Derivatives
• Zolpidem
• 5) Pyrazolopyrimidine
• Zaleplon

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Sedative/Hypnotics

• 6) Propanediol carbamates
• Meprobamate
• 7) Piperidinediones
• Glutethimide
• Azaspirodecanedione
• Buspirone
• 9) ?-Blockers
• Propranolol
• 10) ?2-AR partial agonist
• Clonidine

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Sedative/Hypnotics

• Others
• 11) Antyipsychotics
• Ziprasidone
• 12) Antidepressants
• TCAs, SSRIs
• 13) Antihistaminic drugs
• Dephenhydramine, Hydroxyzine

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Sedative/Hypnotics

• All of the anxiolytics/sedative/hypnotics should
  be used only for symptomatic relief.
• All the drugs used alter the normal sleep cycle
  and should be administered only for days or
  weeks, never for months.
• USE FOR
• SHORT-TERM TREATMENT
• ONLY!!

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SEDATIVE/HYPNOTICSANXYOLITICS
GABAergic SYSTEM
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Sedative/Hypnotics

• The benzodiazepines are the most important
  sedative hypnotics.
• Developed to avoid undesirable effects of
  barbiturates (abuse liability).

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Benzodiazepines

• Diazepam
• Chlordiazepoxide
• Triazolam
• Lorazepam
• Alprazolam
• Clorazepate gt nordiazepam
• Halazepam
• Clonazepam
• Oxazepam
• Prazepam

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Barbiturates

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

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• NORMAL
• ?
• ANXIETY
• _________ ? _________________
• SEDATION
• ?
• HYPNOSIS
• ?
• Confusion, Delirium, Ataxia
• ?
• Surgical Anesthesia
• ? COMA
• ?
• DEATH

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Respiratory Depression
BARBS
BDZs
Coma/ Anesthesia
Ataxia
RESPONSE
Sedation
Anticonvulsant
Anxiolytic
DOSE
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Respiratory Depression
BARBS
Coma/ Anesthesia
BDZs
Ataxia
RESPONSE
Sedation
Anticonvulsant
Anxiolytic
DOSE
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GABAergic SYNAPSE
glucose
glutamate
GAD
GABA
Cl-
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GABA-A Receptor

• Oligomeric (abdgepr) glycoprotein.
• Major player in Inhibitory Synapses.
• It is a Cl- Channel.
• Binding of GABA causes the channel to open and
  Cl- to flow into the cell with the resultant
  membrane hyperpolarization.

BDZs
BARBs
GABA AGONISTS
?
?
d
?
e
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Mechanisms of Action

• 1) Enhance GABAergic Transmission
• ? frequency of openings of GABAergic channels.
  Benzodiazepines
• ? opening time of GABAergic channels.
  Barbiturates
• ? receptor affinity for GABA. BDZs and BARBS

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Patch-Clamp Recording of Single Channel GABA
Evoked Currents
From Katzung et al., 1996
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Benzodiazepines

• PHARMACOLOGY
• BDZs potentiate GABAergic inhibition at all
  levels of the neuraxis.
• BDZs cause more frequent openings of the GABA-Cl-
  channel via membrane hyperpolarization, and
  increased receptor affinity for GABA.
• BDZs act on BZ1 ?1 (?1 and ?2
  subunit-containing) and BZ2?2 (?5
  subunit-containing) receptors.
• May cause euphoria, impaired judgement, loss of
  self control and anterograde amnesic effects.

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Pharmacokinetics of Benzodiazepines

• Although BDZs are highly protein bound (60-95),
  few clinically significant interactions.
• High lipid solubility ? high rate of entry into
  CNS ? rapid onset.
• The only exception is chloral hydrate and
  warfarin

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CNS Effects (Rate of Onset)
Lipid solubility
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Pharmacokinetics of Benzodiazepines

• Hepatic metabolism. Almost all BDZs undergo
  microsomal oxidation (N-dealkylation and
  aliphatic hydroxylation) and conjugation (to
  glucoronides).
• Rapid tissue redistribution ? long acting ? long
  half lives and elimination half lives (from 10 to
  gt 100 hrs).
• All BDZs cross the placenta
• detectable in breast milk ? may exert depressant
  effects on the CNS of the lactating infant.

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Pharmacokinetics of Benzodiazepines

• Many have active metabolites with half-lives
  greater than the parent drug.
• Prototype drug is diazepam (Valium), which has
  active metabolites (desmethyl-diazepam and
  oxazepam) and is long acting (t½ 20-80 hr).
• Differing times of onset and elimination
  half-lives (long half-life gt daytime sedation).

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Biotransformation of Benzodiazepines
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Biotransformation of Benzodiazepines

1. the kinetics of the parent drug may not reflect
   the time course of the pharmacological effect.
2. Estazolam, oxazepam, and lorazepam, which are
   directly metabolized to glucoronides have the
   least residual (drowsiness) effects.
3. All of these drugs and their metabolites are
   excreted in urine.

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Properties of Benzodiazepines

• BDZs have a wide margin of safety if used for
  short periods. Prolonged use may cause
  dependence.
• BDZs have little effect on respiratory or
  cardiovascular function compared to BARBS and
  other sedative-hypnotics.

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Side Effects of Benzodiazepines

• Related primarily to the CNS depression and
  include drowsiness, excess sedation, impaired
  coordination, nausea, vomiting, confusion and
  memory loss. Tolerance develops to most of these
  effects.
• Dependence with these drugs may develop.
• Serious withdrawal syndrome can include
  convulsions and death.

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Sedative/Hypnotics

• They produce a pronounce, graded, dose-dependent
  depression of the central nervous system.

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Toxicity/Overdose with Benzodiazepines

• Drug overdose is treated with flumazenil (a BDZ
  receptor antagonist, short half-life), but
  respiratory function should be adequately
  supported and carefully monitored.
• Seizures and cardiac arrhythmias may occur
  following flumazenil administration when BDZ are
  taken with TCAs.
• Flumazenil is not effective against BARBs
  overdose.

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Drug-Drug Interactions with BDZs

• BDZ's have additive effects with other CNS
  depressants (narcotics), alcohol gt have a
  greatly reduced margin of safety.
• BDZs reduce the effect of antiepileptic drugs.
• Combination of anxiolytic drugs should be
  avoided.
• Concurrent use with OTC antihistaminic and
  anticholinergic drugs as well as the consumption
  of alcohol should be avoided.
• SSRIs and oral contraceptives decrease
  metabolism of BDZs.

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Pharmacokinetics of Barbiturates

• Rapid absorption following oral administration.
• Rapid onset of central effects.
• Extensively metabolized in liver (except
  phenobarbital), however, there are no active
  metabolites.
• Phenobarbital is excreted unchanged. Its
  excretion can be increased by alkalinization of
  the urine.

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Pharmacokinetics of Barbiturates

• In the elderly and in those with limited hepatic
  function, dosages should be reduced.
• Phenobarbital and meprobamate cause autoinduction
  of liver enzymes.

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Properties of Barbiturates

• Mechanism of Action.
• They increase the duration of GABA-gated channel
  openings.
• At high concentrations may be GABA-mimetic.
• Less selective than BDZs, they also
• Depress actions of excitatory neurotransmitters.
• Exert nonsynaptic membrane effects.

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Toxicity/Overdose

• Strong physiological dependence may develop upon
  long-term use.
• Depression of the medullary respiratory centers
  is the usual cause of death of sedative/hypnotic
  overdose. Also loss of brainstem vasomotor
  control and myocardial depression.

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Toxicity/Overdose

• Withdrawal is characterized by increase anxiety,
  insomnia, CNS excitability and convulsions.
• Drugs with long-half lives have mildest
  withdrawal.
• Drugs with quick onset of action are most abused.
  
• No medication against overdose with BARBs.
• Contraindicated in patients with porphyria.

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Sedative/Hypnotics

• Tolerance and excessive rebound occur in response
  to barbiturate hypnotics.

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Miscellaneous Drugs

• Buspirone
• Chloral hydrate
• Hydroxyzine
• Meprobamate (Similar to BARBS)
• Zolpidem (BZ1 selective)
• Zaleplon (BZ1 selective)

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BUSPIRONE

• Most selective anxiolytic currently available.
• The anxiolytic effect of this drug takes several
  weeks to develop gt used for GAD.
• Buspirone does not have sedative effects and does
  not potentiate CNS depressants.
• Has a relatively high margin of safety, few side
  effects and does not appear to be associated with
  drug dependence.
• No rebound anxiety or signs of withdrawal when
  discontinued.

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BUSPIRONE

• Mechanism of Action
• Acts as a partial agonist at the 5-HT1A receptor
  presynaptically inhibiting serotonin release.
• The metabolite 1-PP has ?2 -AR blocking action.

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BUSPIRONE

• Side effects
• Tachycardia, palpitations, nervousness, GI
  distress and paresthesias may occur.
• Causes a dose-dependent pupillary constriction.

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Pharmacokinetics of BUSPIRONE

• Not effective in panic disorders.
• Rapidly absorbed orally.
• Undergoes extensive hepatic metabolism
  (hydroxylation and dealkylation) to form several
  active metabolites (e.g. 1-(2-pyrimidyl-piperazine
  , 1-PP)
• Well tolerated by elderly, but may have slow
  clearance.
• Analogs Ipsapirone, gepirone, tandospirone.

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Zolpidem

• Structurally unrelated but as effective as BDZs.
• Minimal muscle relaxing and anticonvulsant
  effect.
• Rapidly metabolized by liver enzymes into
  inactive metabolites.
• Dosage should be reduced in patients with hepatic
  dysfunction, the elderly and patients taking
  Cimetidine.

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Properties of Zolpidem

• Mechanism of Action
• Binds selectively to BZ1 receptors.
• Facilitates GABA-mediated neuronal inhibition.
• Actions are antagonized by flumazenil

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Properties of Other drugs.

• Chloral hydrate
• Is used in institutionalized patients. It
  displaces warfarin (anti-coagulant) from plasma
  proteins.
• Extensive biotransformation.

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Properties of Other Drugs

• ?2-Adrenoreceptor Agonists (eg. Clonidine)
• Antihypertensive.
• Has been used for the treatment of panic attacks.
• Has been useful in suppressing anxiety during the
  management of withdrawal from nicotine and opioid
  analgesics.
• Withdrawal from clonidine, after protracted use,
  may lead to a life-threatening hypertensive
  crisis.

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Properties of Other Drugs

• ?-Adrenoreceptor Antagonists
• (eg. Propranolol)
• Use to treat some forms of anxiety, particularly
  when physical (autonomic) symptoms (sweating,
  tremor, tachycardia) are severe.
• Adverse effects of propranolol may include
  lethargy, vivid dreams, hallucinations.

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OTHER USES

• 1. Generalized Anxiety Disorder
• Diazepam, lorazepam, alprazolam, buspirone
• 2. Phobic Anxiety
• a. Simple phobia. BDZs
• b. Social phobia. BDZs
• 3. Panic Disorders
• TCAs and MAOIs, alprazolam
• 4. Obsessive-Compulsive Behavior
• Clomipramine (TCA), SSRIs
• 5. Posttraumatic Stress Disorder (?)
• Antidepressants, buspirone

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• ANXYOLITICS
• Alprazolam
• Chlordiazepoxide
• Buspirone
• Diazepam
• Lorazepam
• Oxazepam
• Triazolam
• Phenobarbital
• Halazepam
• Prazepam

• HYPNOTICS
• Chloral hydrate
• Estazolam
• Flurazepam
• Pentobarbital
• Lorazepam
• Quazepam
• Triazolam
• Secobarbital
• Temazepam
• Zolpidem