Anxiolytics, sedativehypnotic drugs: Use and abuse

1
Anxiolytics, sedative-hypnotic drugs Use and
abuse

• Istvan Bitter
• Department of Psychiatry and Psychotherapy
• 10 March 2008

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Anxiety

• Natural human experience
• Subjective qualities of fear or related emotions
• Ensures survival and adaptation
• In excess, can cripple and destroy

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Indications for Antianxiety/Sedative-Hypnotics

• Anxiety Disorders
• Generalized anxiety disorder (GAD)
• Phobic disorders
• Panic disorder
• Obsessive-compulsive disorder
• Posttraumatic stress disorder
• Sleep disorders (most frequently insomnia)
• Anxiety due to other (non anxiety) psychiatric
  disorders e.g. depression, schizophrenia,
  substance abuse
• Anxiety due to general medical conditions

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Prevalence of Anxiety Disorders
Kessler et al. Arch Gen Psychiatry.
1995521048. Kessler et al. Arch Gen Psychiatry.
1994518.
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Course of Illness
Worry
Analyse This, Robert DiNero
anxiety level
time
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Phobic Disorders

• Disabling anxiety (at times associated with panic
  attacks) and avoidance
• Agoraphobia
• Social phobia (Social Anxiety Disorder)
• Specific phobia

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Obsessive-Compulsive Disorder (OCD)
Jack Nicholson - 'As Good As It Gets'

• Recurrent obsessions and/or compulsions
• Cause marked distress, are time-consuming, or
  interfere with functioning
• Are recognized as excessive or unreasonable
• Are not due to the effect of a substance or
  general medical condition

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Posttraumatic Stress Disorder (PTSD)
E.g. Vietnam veterans Holocaust survivors Rape
victims

• Due to an unusual experience that would be very
  stressful for almost anyone Symptoms include
• Intrusive recollections frightening dreams
  sense of event recurring
• Intensive physiological stress hyperarousal
• Persistent avoidance of stimuli associated with
  the trauma
• High comorbidity with other psychiatric disorders
• Increase suicide attempt risk
• Female-to-male lifetime prevalence ratio of 21

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Sleep Disorders

• Dyssomnias (difficulty initiating or maintaining
  sleep or not feeling rested)
• Primary Insomnia
• Primary Hypersomnia
• Circadian Rhythm Disorder
• Parasomnias (abnormal event)
• Nightmare Disorder
• Sleep Terror Disorder
• Sleepwalking Disorder

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What to prescribe for anxiety disorders?

• Benzodiazepines
• 5 HT1A ligands buspiron
• Antidepressants
• SSRI-s
• citalopram
• escitalopram
• fluoxetin
• fluvoxamine
• paroxetin
• sertralin
• SNRI
• reboxetin
• venlafaxine

• MAO-I (Mono Amino Oxidase Inhibitors
• RIMA (Reversible Inhibitor of MAO-A)
• moclobemid
• Dual action AD-s
• e.g. venlaflaxin
• Tri- and tetracyclic (old) agents
• e.g. imipramin, maprotilin
• ?antihystamines
• hydroxyzin

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Pharmacodynamics

• Benzodiazepines
• Specific binding site associated with
  g-amino-butyric acid (GABA) A receptor-chloride
  ion channel
• Potentiate GABA
• Serotonergic effects (e.g., clonazepam)
• 5-HT1 agonist buspirone
• Acutely ? firing, in dorsal raphe nuclei
  chronically, receptor desensitization ? ?
  activity
• Antidepressants

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GABA Function and Distribution

• Inhibitory neurotransmitter
• Widely distributed throughout CNS
• Local inhibitory action, therefore rapidly alters
  neuronal output
• Desensitization to inhibitory effects with
  chronic stimulation of GABA

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GABAA-BZD Supramolecular Complex
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(No Transcript)
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GABAA Receptor Structure
S.M. Paul, 1995
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Normal release and reuptake of GABA
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MECHANISM OF ACTION OF BENZODIAZEPINES

• KEY CONCEPT Benzodiazepines enhance the actions
  of the inhibitory neurotransmitter GABA
• BZDs facilitate the opening (frequency) of the
  Cl- ion channel in response to GABA enhance
  neuronal hyperpolarization.

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AGONISTS and ANTAGONISTS

• AGONIST - Has affinity for receptor and efficacy.
• ANTAGONIST - Has affinity but no efficacy.
• Competitive Antagonist
• Noncompetitive Antagonist
• Partial Agonist or Partial Antagonist - Has
  affinity and low efficacy.

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BZD Receptor Activity
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Benzodiazepines

• Anxiolysis (20 receptor occupancy)
• anticonvulsant
• muscle relaxant
• amnestic
• sedation (30 - 50 receptor occupancy)
• hypnosis (gt 60 receptor occupancy)

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Adverse Effects Benzodiazepines

• Sedation and impairment of performance
• Psychomotor skills driving engaging in
  dangerous physical activities using hazardous
  machinery, especially during initial phase of
  treatment
• Memory impairment
• Anterograde amnesia (desired before surgery,
  other procedures).
• Dose-related, and tolerance may not develop.
• Most likely with triazolam
• Disinhibition
• Possible risk factors history of aggression,
  impulsivity, borderline or antisocial personality

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BZD abuse Short-Term Effects

• Relaxation
• Drowsiness
• Dizziness
• Confusion
• Mood swings

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BZD abuse Common Long-term Effects

• Lethargy
• Irritability
• Nausea
• Loss of sexual interest
• Increased appetite
• Increased weight

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Non-Benzodiazepine Agents

• Imidazopyridines (e.g., zolpidem, alpidem)
• Pyrazolopyrimidine (e.g., zaleplon)
• Cyclopyrralone (e.g., zopiclone)
• Sedating antidepressants (e.g., trazodone)

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Non-Benzodiazepine Agents (cont)

• Antihistamines (e.g., hydroxyzin)
• Natural Remedies (e.g., melatonin, valerian)
• B-carbolines (e.g., abecarnil)
• BZD structural derivatives (e.g., biretazanil)

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Pharmacokinetics Benzodiazepines

• Absorption rapid absorption, except clorazepate
• Onset of action increase lipid solubility ?
  faster onset
• Duration of action single dose with increased
  lipid solubility ? faster redistribution to fat
  tissues? shorter duration of action. Chronic
  use in equilibrium with fat tissues
• Half life In part, determines duration of
  action
• Metabolism lorazepam, oxazepam, temazepam not
  metabolized by liver

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Abuse, Dependence, Withdrawal, and Rebound
Anxiety Benzodiazepines

• Abuse potential decreased when properly
  prescribed and supervised.
• Dependence may occur at usual doses taken beyond
  several weeks.
• Withdrawal may occur even when discontinuation is
  not abrupt (e.g., by 10 every 3 days). Symptoms
  include tachycardia, increased blood pressure,
  muscle cramps, anxiety, insomnia, panic attacks,
  impairment of memory and concentration,
  perceptual disturbances, derealization,
  hallucinations, hyperpyrexia, seizures. May
  continue for months.
• Rebound anxiety return of target symptoms, with
  increased intensity
• Differenciate from Recurrence of symptoms (due
  to lack of treatment).

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ANTIANXIETY AGENTS
Generic Names Trade Names Daily Dosage (mg/day)
BENZODIAZEPINES Chlordiazepoxide Diazepam O
xazepam Chlorazepate Lorazepam Prazepam Ha
lazepam Alprazolam AZAPIRONES Buspirone ANT
IDEPRESSANTS SSRIs Venlafaxine
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Example of a BZD as sedate-hypnotic CLUB DRUGS

• Rohypnol flunitrazepam
• Long acting, hypnotic BZD
• Strong anterograde amnesia, esp. w/ alcohol
• Potentially lethal respiratory depression when
  combined with alcohol

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SEDATIVE-HYPNOTICS
Generic Names Trade Names Daily Dosage (mg
/day) BENZODIAZEPINES Long-acting Flurazepam
Dalmane 15-45 Quaz
epam Doral 7.5-15 Intermediate-acting Estazol
am Prosom 0.5-2 Temazepam Restoril 15-45 Shor
t-acting Triazolam Halcion 0.125-0.25 NONBE
NZODIAZEPINE Zolpidem Ambien 5-20 Zaleplon
Sonata 5-20 SEDATING ANTIDEPRESSANTS Trazodo
ne Dyserel 25-100 BARBITURATE-LIKE Chloral
Hydrate Notec 500-1500 OTHER Melatonin 0.
3-2
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Serotonin Receptors

• 5-HT1A -Anxiety, alcoholism, sexual function
• 5-HT1C -Anxiety, migraine pain
• 5-HT1D -Migraine pain
• 5-HT2 -Anxiety, depression, schizophrenia
  negative symptoms, sexual function
• 5-HT3 -Migraine pain, emesis, schizophrenia
  (e.g., ondansetron)
• 5-HT4 -Anxiety, schizophrenia?

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Serotonin Agents Indications forAnxiety-Related
Disorders (US)

• SSRI
• Sertraline - OCD PD PTSD
• Paroxetine - OCD PD SAD GAD
• Fluoxetine - OCD BN PMDD
• Fluvoxamine - OCD
• Venlafaxine - GAD
• Buspirone - GAD

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Pharmacokinetics/Pharmacodynamics Buspirone

• Late onset of action (weeks)
• No sedation or impairment of performance
• No cross-tolerance with BZDs
• No tolerance or withdrawal
• No abuse potential

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Adverse Effects Buspirone

• Nausea
• Headache
• Insomnia, nervousness
• Restlessness
• Dizziness, lightheadedness

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Combination of Drugs

• BZD Antidepressants
• late onset of action of AD
• AD may worsen anxiety incl. panic in the first
  days/weeks of treatment
• BZD may eleviate the side effects of AD (GI)
• BZD may be indicated as sleeping pills
• (newer zopiclon, zolpidem- Non BZD structures)

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Drugs NOT Indicated in Anxiety Disorders

• Barbiturates
• Meprobamat
• Antihistamins
• Antiepileptics/mood stabilizers
• Cloral hydrate
• Neuroleptics/Antipsychotics

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FACTORS AFFECTING DRUG RESPONSE

• RESISTANCE (usually refers to antimicrobial
  drugs)
• TOLERANCE a decrease in drug response during
  repeated administration.
• TACHYPHYLAXIS - acute development of tolerance
  due to rapid repeated admin. of some drugs.

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Barbiturates

• Barbiturates are powerful depressants that slow
  down the central nervous system
• Classified as sedative/hypnotics
• Once a very commonly used tranquilizer but
  because they are highly habit-forming their usage
  decreased
• They have effects similar to alcohol
• They depress sympathetic nervous system activity
• They have been used to induce sleep and reduce
  anxiety
• In large doses, can lead to impaired memory and
  judgment
• Enzyme inductors!
• High toxicity compared to benzodiazepines

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Barbiturates

• Barbiturates and other sedative/hypnotics are
  medically prescribed to treat sleeplessness,
  anxiety, and tension, and to help prevent or
  mitigate epileptic seizures
• Certain barbiturates are also used to induce
  anesthesia for short surgical procedures or at
  the beginning of longer ones
• Because of the risks associated with barbiturate
  abuse, and because new and safer drugs such as
  the benzodiazepines are now available,
  barbiturates are less frequently prescribed than
  in the past
• Nonetheless, they are still available both on
  prescription and illegally
• Other names barbs, barbies, downers, goofballs

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Barbiturates

• In low doses, barbiturates have a tranquilizing
  effect
• Increased doses are hypnotic or sleep-inducing
• still larger doses act as anticonvulsants and
  anesthetics
• Barbiturates have been widely used as sleeping
  pillssuch use may lead to
• psychological dependency
• physiological tolerance
• death by overdose (often the drug of choice for
  those attempting suicide)
• Barbiturates do not relieve pain

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Barbiturates

• What it feels like
• Relaxation, peacefulness, sleepiness, pleasurable
  intoxication, dizziness, inactivity, withdrawal,
  interrupted thought processes, mood swing,
  excitement, increased pain, hostility,
  depression, anxiety, confusion, changed vision,
  intense emotions, hangover
• Barbituates give a quick high but the effects
  drop off and persist for a low level for a longer
  duration

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Barbiturates

• Besides having therapeutic uses, barbiturates are
  often used for their pleasurably intoxicating
  effects
• Some people take them in addition to alcohol, or
  as a substitute
• Heavy users of other drugs sometimes turn to them
  if their usual drugs are not available, or to
  counteract the effects of large doses of
  stimulants such as amphetamines or cocaine

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Barbiturates

• Non-medical users often start taking barbiturates
  at doses within a safe therapeutic range
• As tolerance develops, however, they
  progressively increase their daily dose to many
  times the original
• It is extremely important to note that in spite
  of acquiring tolerance to the intoxicating
  effects of barbiturates, the user develops no
  tolerance to the lethal action of the drug
• Therefore, high doses could produce fatal results
  even for tolerant abusers
• Taking barbiturates with other CNS depressants
• e.g. alcohol tranquillizers such opioids as
  heroin, morphine, meperidine (Demerol), codeine,
  or methadone and antihistamines (found in cold,
  cough, and allergy remedies) can be extremely
  dangerous, even lethal

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The Long-Term Effect of Barbiturates

• Often, high usage occurs which is not unlike a
  state of chronic inebriation
• Symptoms include the impairment of memory and
  judgment hostility, depression, or mood swings
  chronic fatigue and stimulation of preexisting
  emotional disorders, which may result in paranoia
  or thoughts of suicide
• Although the prescribing of barbiturates has
  declined notably since the safer benzodiazepine
  tranquillizers were introduced, this group of
  drugs remains a significant contributor to drug-
  related deaths
• They remain easily available to abusers through
  both licit and illicit sources

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In summary BARBITURATES SIDE EFFECTS AND ADVERSE
EFFECTS

• EXCESSIVE CNS DEPRESSION
• HYPERSENSITIVITY REACTIONS
• EXCITEMENT
• RESPIRATORY DEPRESSION AND HYPOTENSION
• TOLERANCE
• DEPENDENCE
• COMA AND DEATH

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Therapeutic and Toxic Effects are Dose-Related
Phenobarbital
Sleep
Death
Responding
ED50
LD50
Dose of Phenobarbital
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Barbiturate-like, non-barbiturates

• Examples
• glutethimide
• methaqualone
• ethchlorvynol
• Overdose produces sudden, prolonged apnea
• Highly addictive
• Withdrawal resembles barbiturate withdrawal
• Glutethimide still frequently used as a sleeping
  pill

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Meprobamat

• Effects similar to alcohol and barbiturates -
  abused in tx. anxiety disorders
• Calming effect without drowsiness
• Muscle-relaxant
• High potential for physical psychological
  dependency
• Enzyme inductor!

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Chloral hydrate

• Micky Finn when mixed with alcohol
• Rapidly absorbed, acts quickly
• Drowsiness, sleep
• Alcohol, chloral hydrate compete for metabolism
  by same enzyme
• Prolonged action for both when mixed
• Not an abused recreational drug, but is often
  misused by the elderly as a sleep aid

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Gamma-Hydroxybutyric Acid (GHB)

• GHB is a naturally occurring short-chain fatty
  acid metabolite of GABA.
• Unlike GABA, GHB easily crosses the blood-brain
  barrier to affect the activity and levels of
  dopamine, acetylcholine, dynorphin and serotonin.
• Illicit use of GHB continues because of its
  reputation for inducing a euphoric state.
• Adverse events Drowsiness, hypotonia, dizziness
  and vomiting developed within 15 to 60 minutes of
  ingestion. Central nervous system depression,
  depressed respirations, tremor, myoclonus (muscle
  twitching) and seizures.

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Dr. J.E. Dyer, in conjunction with the San
Francisco Poison Center

• documented 16 cases of adults ingesting between
  1/2 teaspoon
• and 1 full teaspoon of GHB in 1990. The symptoms
  recorded ranged from
• dizziness, confusion and nausea to coma and
  seizures. In six months,
• 57 cases were identified nationwide. The "doses"
  of GHB ingested varied
• from ½ teaspoon to 3 teaspoons. Drowsiness,
  hypotonia, dizziness and
• vomiting developed within 15 to 60 minutes of
  ingestion. Central nervous
• system depression, depressed respirations,
  tremor, myoclonus (muscle
• twitching) and seizures were also documented. The
  severity of the
• intoxication appeared to correlate with the dose
  ingested. All patients
• recovered fully in 2 to 96 hours. One analysis of
  a sample of GHB found
• that the form being marketed was a 97-98 pure
  sodium salt of GHB. The
• FDA banned GHB as a nutritional aid as a result
  of these incidents.

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  GBL, gamma hydroxybutyric acid (GHB) and 1,4
butanediol (BD)

• FDA has been warning the public about a group of
  products sold as dietary supplements for
  bodybuilding, weight loss and sleep inducement
  which have been determined to pose a significant
  public health hazard. These products are
  chemically related to gamma butyrolactone (GBL),
  gamma hydroxybutyric acid (GHB), and 1,4
  butanediol (BD), and can cause dangerously low
  respiratory rates (intubation may be required),
  unconsciousness/coma, vomiting, seizures,
  bradycardia and death.
• August 25, 1999 ( FDA Notification - FDA

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Abusers

• Anxiolytics/sedative-hypnotic drugs are abused by
  two groups of people
• Individuals who overuse these drugs to reduce
  daily tensions and to aid in sleep
• These people take excessively large doses on a
  regular basis
• Street drug users
• Attempt to achieve a state of relaxed euphoria
  or to aid in coming down from a high caused by
  taking a stimulant