SEDATIVEHYPNOTICS ANXIOLYTICS

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SEDATIVE/HYPNOTICSANXIOLYTICS

• Martha I. Dávila-García, Ph.D.
• Howard University
• Department of Pharmacology

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• Optimal
• Performance

Nervous Breakdown
Sedated
Performance
Anxiety
GOAL
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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
• Reduce 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.
• ?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).
• Novel drugs. (Most of these are still on clinical
  trials).
• CCKB (e.g. CCK4).
• EAA's/NMDA (e.g. HA966).

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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 electroencephalogra
  m, 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, oxacepam, 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

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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/Hypnotics

• Relationship between
• Older vs Newer Drugs
• Barbiturates Benzodiazepines
• Glutethimide Zolpidem
• Meprobamate Zaleplon
• All others differ in their effects and
  therapeutic uses. They do not produce general
  anesthesia and do not have abuse liability.

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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
ETOH
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
• 2) Stimulation of 5-HT1A receptors.
• 3) Inhibit 5-HT2A, 5-HT2C, and 5-HT3 receptors.

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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 and ?2 subunit-containing)
  and BZ2 (?5 subunit-containing) receptors.
• May cause euphoria, impaired judgement, loss of
  cell 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
From Katzung, 1998
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Biotransformation of Benzodiazepines

• Keep in mind that with formation of active
  metabolites, the kinetics of the parent drug may
  not reflect the time course of the
  pharmacological effect.
• Estazolam, oxazepam, and lorazepam, which are
  directly metabolized to glucoronides have the
  least residual (drowsiness) effects.
• 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.
• BDZs depress the turnover rates of norepinephrine
  (NE), dopamine (DA) and serotonin (5-HT) in
  various brain nuclei.

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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 ODC 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
  autometabolism by induction 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.

REM
NREM III and IV
1
2
3
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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

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

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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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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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GABA
(-)
(-)
(-)
(-)
ACh
?
(-)
NE
5-HT
DA
ANXIOLYTIC ?
ANTICONVULSANT/ MUSCLE RELAXANT ?
SEDATION ?
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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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Other Properties of Sedative/Hypnotics

• BDZs on the other hand, with their long
  half-lives and formation of active metabolites,
  may contribute to persistent postanesthetic
  respiratory depression.
• Most sedative/hypnotics may inhibit the
  development and spread of epileptiform activity
  in the CNS.
• Inhibitory effects on multisynaptic reflexes,
  internuncial transmission and at the NMJ.

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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

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References

• Katzung, B.G. (2001) Basic and Clinical
  Pharmacology. 7th ed. Appleton and Lange.
  Stamford, CT.
• Brody, T.M., Larner,J., and Minneman, K.P. (1998)
  Human Pharmacology Molecular to Clinical. 2nd
  ed. Mosby-Year Book Inc. St. Louis, Missouri.
• Rang, H.P. et al. (1995) Pharmacology . Churchill
  Livingston. NY., N.Y.
• Harman, J.G. et al. (1996) Goodman and Gilman's
  The Pharmacological Basis of Therapeutics. 9th
  ed. McGraw Hill.