Sedative-Hypnotic Drugs and Anxiety Disorders.

1
Sedative-Hypnotic Drugs and Anxiety Disorders.

• Patrick T. Ronaldson, PhD
• Department of
• Medical Pharmacology
• University of Arizona

2
Anxiety

• Term used to describe both symptoms and disorders
• Occurs normally as signal of impending danger or
  threat
• Very common, occurs in many disorders in addition
  to the anxiety disorders
• Differentiated from fear on basis of whether
  there is a clear source of danger
• i.e. fight or flight response
• Adaptive value
• helps to plan and prepare for threat
• moderate levels enhance learning and performance
• Maladaptive when chronic / severe

3
Anxiety

• Symptoms include
• physiological symptoms of activated sympathetic
  nervous system (increased heart rate, increased
  respiration, sweating etc.)
• cognitive component (awareness of being
  frightened)
• behavioral components (urge to escape)

4
Anxiety Disorders (DSM-IV)

• Panic disorder with or without agoraphobia
• Agoraphobia without panic disorder
• Specific phobias
• Social phobia
• Obsessive compulsive disorder
• Posttraumatic stress disorder
• Acute stress disorder
• Generalized anxiety disorder
• Anxiety disorder due to a general medical
  condition
• Substance-induced anxiety disorder
• Anxiety disorder not otherwise specified

5
Anxiety Disorders Prevalence
17
13
Lifetime Prevalence of Anxiety Disorders 25
7.8
5
3.5
2.5
Social anxiety disorder
Generalized anxiety disorder
Depression
Panic disorder
Obsessive-compulsive disorder
Posttraumatic stress disorder
Kessler RC, et al. Arch Gen Psychiatry
1994518-19 Stein MB, et al. JAMA
1998280708-713 Kessler RC, et al. Arch Gen
Psychiatry 1995521048-1060
6
Spectrum of Depression and Anxiety Disorders
Posttraumatic stress disorder
Social anxiety disorder
Depression
Panic disorder
Obsessive-compulsive disorder
Generalized anxiety disorder
7
Neurobiology of Anxiety Disorders

• CNS equilibrium is determined by a balance
  between excitatory and inhibitory
  neurotransmission
• Excitation -gt Glutamate is prototypical NT.
• Inhibition -gt GABA is prototypical NT.
• Inhibition via GABA is primarily mediated by the
  ionotropic GABA-A receptor.
• GABA binding to GABA-A results in an increase in
  neuronal Cl- conductance and subsequent neuronal
  hyperpolarization.

8
Neurobiology of Anxiety Disorders
Cl- - equilibrium potential is approximately -80
mV An increase in Cl- influx will decrease the
resting potential of a neuron. Therefore, the
post-synaptic neuron will require a greater
excitatory stimulus to fire an action potential.
9
Neurobiology of Anxiety Disorders
GABA Receptor
Benzodiazepines major class of anxiolytic
drugs. Act primarily via a selective binding
sites on the GABA-A receptor. - high-affinity
site. - low-affinity site. POTENTIATE the
effects of GABA at the GABA-A receptor.
10
Drugs useful in the treatment of anxiety
disorders.
Generic name Trade name Half-life
(hrs) Dosage (mg/day)
Long-acting benzodiazepines Diazepam Valium
20-80 2-60 Chlordiazepoxide Librium 24-48 1
5-100 Clorazepate Tranxene 100 7.5-60 Estazo
lam ProSom 10-24 0.5-2.0 Prazepam Centrax 1
00 20-60 Quazepam Doral 30-100 7.5-15 Hal
azepam Paxipam 15-100 20-160 Clonazepam Klo
nopin 34 1.5-20 Flurazepam Dalmane 100 15
-30 Short-acting benzodiazepines Oxazepam
Serax 8 30-120 Lorazepam Ativan 15 2-6
Alprazolam Xanax 12 0.5-6 Temazepam Restori
l 11 15-30 Triazolam Halcion 2 0.125-0.5
Midazolam Versed 2 2-4 Non-benzodiazepine
sedative/hypnotics Buspirone
(BuSpar) Serotonin 1a agonist Zolpidem
(Ambien) binds to benzodiazepine
receptor Meprobamate (Miltown) Chloral hydrate
(Noctec)
marketed as an anti-convulsant marketed
as a hypnotic parenteral only
11
Statement from the British Committee for the
Review of Medicines.

• All benzodiazepines are efficacious in the
  short-term treatment of anxiety and insomnia.
  There is no evidence which can justify the
  particular use of any particular benzodiazepine
  in either anxiety or insomnia. The usual division
  of benzodiazepines into rigid treatment
  categories of antianxiety agents and hypnotics
  does not appear to be based on the known
  pharmacological or clinical properties of this
  group of compounds.

Caveat different benzodiazepines have
additional actions (i.e., muscle relaxants,
anticonvulsants, anesthetics) and different
half-lives.
12
Benzodiazepines - Properties

• Prototypical Benzodiazepine Diazepam (Valium).
• Highly lipophilic well-absorbed orally and
  easily crosses the blood-brain and
  blood-placental barriers.
• Hepatic metabolism converted to hydrophilic
  metabolites for renal elimination.
• Metabolite desmethyldiazepam
• Same metabolite for diazepam, chlordiazepam,
  prazepam, and clorazepate.
• Desmethyldiazepam itself is pharmacologically
  active as an anxiolytic.
• Desmethyldiazepam is converted to oxazepam in the
  liver.
• Short-acting metabolite.
• Directly glucuronidated (as is lorazepam and
  flurazepam) and excreted by the kidney.

13
Benzodiazepines - Properties

• Pharmacological Effects
• Reduction of anxiety.
• Induction of sleep.
• Anesthesia some benzodiazepines.
• Respiratory depression not as great as observed
  with barbiturates.
• Adverse Effects primarily observed at plasma
  concentrations exceeding anxiolytic range.
• Expected side effects sedation, ataxia,
  dependence.
• Impaired cognition and motor function.
• Confusion.
• Amnesia.
• Fatal overdose is uncommon, except when taken
  with alcohol.

14
Benzodiazepines - Properties

• Benzodiazepines may induce tolerance in some
  individuals.
• Discontinuation of benzodiazepine therapy in
  tolerant patients MUST be gradual.
• Avoid hyperexcitability and possible seizures
  (more common with short-acting benzodiazepines).
• Block sedative side-effects of benzodiazepines
  with flumazenil (benzodiazepine receptor
  antagonist).
• Precipitate withdrawal symptoms in patients
  dependent on benzodiazepines (i.e., anxiety,
  insomnia, convulsions).

15
Benzodiazepines - Indications

• Anxiety and Insomnia
• Sedation
• Mania
• Drug-induced hyperexcitability PCP
  intoxication.
• Spasticity
• Cerebral Palsy
• Tetanus toxin toxicity.
• Anesthesia
• Alcohol withdrawal syndrome.
• Seizures.
• Clonazepam in myoclonic disorders.
• Diazepam, midazolam, and lorazepam in status
  epilepticus.
• Only effective early during status epilepticus.
• Evidence for seizure-induced translation change
  in GABA-A subunit expression.

16
Benzodiazepines Mechanism of Action
GABA-A receptors highly variable (i.e., consist
of different complements of alpha, beta, and
gamma subunits). different sensitivities to
benzodiazepines. a2 subunit is critical in
sedative effects. Benzodiazepines do NOT
activate the receptor directly. increase
frequency of chloride-channel opening produced by
GABA.
GABA Receptor
17
Autoradiography of GABA-A Receptors.
Data shows that a2 subunit is localized to limbic
system Sedation. Further evidence
site-directed mutagenesis against a2 subunit
eliminates sedative effects of benzodiazepines.
a2 subunit
a3 subunit
18
Pharmacological Effects of Benzodiazepines are
Concentration-Dependent.

• Nanomolar Concentrations
• Anxiolytic sedation via a2 subunit.
• Action effectively blocked by flumazenil.
• Micromolar Concentrations
• Anesthesia diazepam, midazolam, lorazepam.
• Activity due to binding of benzodiazepines to
  low-affinity site on GABA-A receptor.

19
Practical Points regarding Benzodiazepines.

• Lowest effective dose for the shortest possible
  time.
• Minimizes dependence and withdrawal.
• Discontinuance withdrawal is most common with
  short-acting benzodiazepines.
• Cessation of long-acting drugs produces a
  tapering effect due to long elimination
  half-life.
• Patients on short-acting benzodiazepines need
  weeks to months to be weaned.
• Generally, benzodiazepines are safe drugs with
  few medical complications and do not interact
  adversely with other medications.

20
Newer sedative/hypnotic drugs.

• Different mechanisms of action as compared to
  benzodiazepines.
• Do not act on GABA-A receptors.
• May interact only with specific GABA-A receptor
  subunits.
• Designed to produce anxiolytic effects without
  undesirable side effects associated with
  benzodiazepines.
• Daytime sedation and drowsiness.
• CNS depression in combination with alcohol.
• Potential for dependence.

21
Buspirone (BuSpar)

• Partial agonist at the serotonin 1a receptor.
• Relieves anxiety without producing sedation,
  impairment of motor skills, or memory loss.
• Does not induce withdrawal symptoms upon
  discontinuation.
• Does not act immediately.
• Can take up to 1 week to become effective.
• Used for chronic anxiety states.
• Pharmacokinetics
• Rapidly absorbed orally.
• Rapid first-pass effect.
• Elimination half-life 2-4 hrs.
• Metabolism is primarily hepatic.

22
Serotonin Pathways in the CNS
23
Serotonin and Anxiety

• Serotonin
• supported by efficacy of SSRIs
• major nuclei
• CRN limbic/ prefrontal cortex structures
• Mediates fear/ anticipatory anxiety
• RRN prefrontal cortex, basal ganglia,
  thalamus, limbic cortex, substantia nigra,
  periaqueductal grey
• Modulates cognitive/ behavioural components
• strong feedback relationship with limbic cortex.

24
Zolpidem (Ambien)

• Produces sedative properties by binding
  selectively to a1-subunit.
• Same site that also binds benzodiazepines.
• Evidence pharmacological effects blocked by
  flumazenil.
• Structurally unrelated to benzodiazepines.
• Used clinically for treatment of insomnia.
• Minimal muscle relaxing and anticonvulsant
  effects.
• Less potential for dependence and withdrawal.
• Pharmacokinetics
• Elimination half-life 1.5-3.5 hrs.
• Largely metabolized in the liver.