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BIOM 255 BDZ and Sedative Hypnotics 2011

VIEWS: 4 PAGES: 47

									Sedative-Hypnotics and
   Benzodiazepines



      Joan Heller Brown
         BIOM 255
       April 12, 2011



                          1
    CNS Depressants

• Ethanol
• Barbiturates
• Benzodiazepines
• Non-benzodiazepine hypnotics


                                 2
Stages of CNS Depression
  • Sedation
  • Hypnosis
  • Loss of consciousness
  • Surgical anesthesia
  • Coma
  • Respiratory and
    cardiovascular shutdown
                              3
4
Other Pharmacological Responses
      to CNS Depressants

• Varying degrees of CNS depression
  (above)
• Anti-seizure activity
• Psychomotor impairment
• Drowsiness, confusion, amnesia

                                   5
Common Properties of
  CNS Depressants
  • Tolerance
  • Cross-tolerance
  • Additivity
  • Physical dependence
  • Abuse potential
                          6
Causes of Insomnia not primarily
treated with Sedative Hypnotics

• Depression

• Abuse of stimulants or depressants

• Physical disorders



                                       7
Causes of Insomnia appropriate for
Treatment with Sedative Hypnotics

    • Body clock disturbances

    • External / environmental

    • Stress-associated


                                     8
What Makes an Ideal Hypnotic?
 • Decrease time to fall asleep
 • Increase duration of sleep

 • Not disrupt normal sleep pattern
 • Not cause daytime sedation
 • Not cause rebound insomnia

 •   Safe on overdose
 •   Minimal drug interactions
 •   Not cause physical dependence
 •   Low abuse potential

                                      9
Figure 22.   10
            Barbiturates
• Enhance inhibitory GABA-ergic
  transmission through allosteric effect on
  GABAA receptor
• Tolerance, physical dependence, abuse
  potential are high
• Pronounced induction of cytochrome P450s
  (and UDP glucuronosyltransferases)
• Therapeutic index is low
                                          11
          Heaven's Gate revisited
                                                                                   by the time he watched them, the
 By J. Harry Jones                                                                 group would have moved on.
 STAFF WRITER
                                                                                     Rio DiAngelo, whose real name was
            en years ago next week,                                                Richard Ford, drove with his boss
            one of the strangest events                                            from Los Angeles to the mansion. Af-
            in county history exploded                                             ter looking inside, he placed an anony-
            into the public's conscious-                                           mous phone call to 911 that dispatch-
            ness. For several days,                                                ers initially found inconceivable.
it was the biggest news story in the                                                 “I don't think anybody really be-
world.                                                                             lieved what the person was saying,”
  It began unfolding the afternoon of                                              said Robert Brunk, a sheriff's deputy
Wednesday, March 26, 1997, during a                                                who had just started his shift at the En-
period when the Hale-Bopp comet             Heaven's Gate leader Marshall          cinitas station. “It was an anonymous
could be seen in the night sky.             Applewhite, shown in this video call to the communications center stat-
                                                                                   ing that 40 people had committed sui-
  Inside a mansion in Rancho Santa          image, was known as "Do.“ APTV cide and they were cult members. It
Fe, 39 members of the Heaven's Gate                                                came out as a 'welfare check,' and they
cult lay dead. Convinced that a space-     and other drugs – the largest mass had held the call for a while because it
ship was traveling behind the comet        suicide on U.S. soil.                   was busy.”
and that they would be transported to        All went willingly under the guid- Brunk went to the address, 18241
the vessel to begin a new life “be-        ance of their leader, Marshall Apple- Colina Norte, which turned out to be a
yond human,” they had poisoned             white, also known as “Do.”
themselves. Twenty-one women and                                                   9,000-square-foot, two-story home up
18 men died by eating pudding and            Their bodies were discovered by a
applesauce laced with phenobarbital        former cult member who had received
                                           videotapes in the mail telling him that            SEE Heaven’s Gate, A16



                                                                                                                      12
Other Drugs Used as
 Sedative Hypnotics
• Chloral hydrate
• Meprobamate
• Diphenhydramine
• Trazodone
• Nutriceuticals – melatonin,
  kava, valerian
                                13
Benzodiazepines (Selected)
    • Diazepam (Valium®)
    • Flurazepam (Dalmane®)
    • Oxazepam (Serax®)
    • Alprazolam (Xanax®)
    • Temazepam (Restoril®)
    • Midazolam (Versed®)
    • Triazolam (Halcion®)    14
       Benzodiazepines vs.
          Barbiturates
• Tolerance, physical dependence, abuse
  potential are diminished

• No induction of drug metabolizing
  enzymes

• Safety on overdose (therapeutic index)
  greatly improved
                                          15
16
Table 1. General Comparison of Barbiturates and Benzodiazepines

       Characteristic             Barbiturates                   Benzodiazepines
Induction of sleep                    Rapid                            Rapid
Daytime sedation                       Yes                        Not necessarily
Effect on sleep cycle                  Yes                 Yes, but less than barbiturates
Additivity with other                  Yes                              Yes
sedative-hypnotics
Tolerance                   Yes (pharmacokinetic and         Yes (pharmacodynamic)
                               pharmacodynamic)
Physical dependence                    Yes                              Yes
Abuse potential                       High                           Moderate
Drug interactions       Many (induce cytochrome P450 and                Few
                          UDP glucuronosyltransferase)
Safety on overdose          No (low therapeutic index)        Yes (when used alone)




                                                                                     17
          Benzodiazepines
• Structural similarities (see Table 2)
• Mechanistic similarities: enhance GABA-
  ergic inhibitory transmission through
  allosteric effects on GABAA receptor
• Mechanistic distinctions: not all GABAA
  receptors are the same; potential for
  selectivity for pharmacological effects

                                            18
Table 2. Structures of Benzodiazepines




                                         19
          Benzodiazepines
• Structural similarities (see Table 2)
• Mechanistic similarities: enhance GABA-
  ergic inhibitory transmission through
  allosteric effects on GABAA receptor
• Mechanistic distinctions: not all GABAA
  receptors are the same; potential for
  selectivity for pharmacological effects

                                            20
Table 14-2
Pharmacological Effects of
     Benzodiazepines

    • Anxiolytic

    • Sedative hypnotic

    • Anticonvulsant

    • Muscle relaxant
                             22
Side Effects of Benzodiazepines

     • Drowsiness

     • Confusion

     • Amnesia (anterograde)

     • Psychomotor impairment

                                23
  Principles of BDZ treatment
• Insomnia, anxiety ( even seizures) could be
  treated with the same drug
• Action is immediate, use can be intermittent
• Withdraw gradually if used for extended
  times
• Inform patients about additivity with other
  CNS depressants
• Choice of drug is based on pharmacokinetic
  properties
                                               24
Pharmacokinetic Properties Determine
     Choice of Benzodiazepines

      • Rates of absorption

      • Routes of metabolism

      • Biological half lives


                                  25
     Rate of Absorption

• All are well absorbed orally
• Most are poorly absorbed IM
• Rapid absorption desirable for rapid
  sleep induction
• Rapid absorption desirable for
  euphoria
                                     26
      Routes of Metabolism
• Microsomal oxidation to biologically active
  N-desalkyl and a-hydroxylated metabolites
• Glucuronidation to inactive conjugated
  metabolites excreted in urine
• Some benzodiazepines are only metabolized
  by glucuronidation
• Glucuronidation is less affected by age,
  liver function, other drugs than is
  microsomal oxidation
                                             27
Figure 2. Major Routes of Metabolism for Selected Benzodiazepines (from Goodman and Gilman ).




                                                                                                28
Figure 3. Metabolism and Elimination of Selected Benzodiazepines. Compounds in bold represent
drugs available for clinical use; asterisks designate active metabolites (from Katzung).




                                                                                       29
                                                                                            7
Routes of Metabolism: So What?
• In patients with impaired hepatic function,
  BDZ half life is prolonged

• In patients taking other drugs that inhibit
  microsomal metabolism, BDZ half life is
  prolonged

• In elderly, impaired metabolism, other
  drugs and increased sensitivity contribute
  to exaggerated BDZ response
                                            30
Biological half-life varies
    widely and is not
 necessarily related to
  route of metabolism


                              31
Table 3. Pharmacokinetic Properties of Benzodiazepines in Humans


    Drug     Biological t1/2           Metabolites                     Comments
                (hours)
Alprazolam        8-15         Active: α-hydroxyalprazolam   Rapid oral absorption
Diazepam         20-70         Active: desmethyldiazepam     Poor intramuscular
                               (aka nordazepam), oxazepam    bioavailability
Flurazepam      48-120         Active: desalkyl derivative   Long elimination half-lives of
                               and others                    active metabolites
Oxazepam          5-15         Inactive: glucuronides        Slow oral absorption
Temazepam         8-20         Inactive: glucuronides        Slow oral absorption
Triazolam         2-6          Active: α-hydroxytriazolam    Rapid oral absorption
Midazolam         2-4          Active: α-hydroxymidazolam    IV in anesthesia




                                                                                        32
Biological half-life is used
       in marketing




                               33
        Table 4. Duration of Action of Common Benzodiazepines

FDA-Approved              Short               Intermediate                 Long
  Indication        Duration of Action      Duration of Action       Duration of Action

    Anxiolytic    Midazolama [Versed®]   Oxazepam [Serax®]        Diazepam [Valium®]
                                         Alprazolam [Xanax®]

    Hypnotic      Triazolam [Halcion®]   Temazepam [Restoril®]    Flurazepam [Dalmane®]



a
 Typically used for the acute anxiety associated with surgical or diagnostic procedures.




                                                                                     34
   Biological Half-lives and
       Hypnotic Choices

• Psychomotor impairment, daytime
  sedation
  – Long biological half-life contributes
    to this (drug A)
  – Short biological half-lives do not
    (drug B)


                                            35
Drug A



Drug B




         36
   Biological Half-lives and
        Hypnotic Choices

• Rebound insomnia
  – Short biological half-life allows this
    (drug B)
  – Long biological half-life limits this
    problem (drug A)



                                             37
38
39
40
The Halcion Controversy




                          41
Non Benzodiazepine Hypnotics


 • Zaleplon (Sonata®)-ultrashort
 • Zolpidem (Ambien®)-short
 • Eszopiclone (Lunesta®)-intermed



                                     42
Figure 22.   43
                   Table 5. Important FDA-Approved Hypnotics
    Class            Medication          Onset    Biological t1/2                  Comments
                                         (min)        (hr)a
    BDZsb      Triazolam [Halcion®]      15-30          2-6         Mainly for sleep-onset insomnia

               Temazepam [Restoril®]     45-60         8-20         Mainly for sleep-maintenance insomnia

               Flurazepam [Dalmane®]     60-120       48-120        Not generally recommended as a hypnotic
                                                                    because of its long t1/2
 Non-BDZs      Zolpidem [Ambien®]          30            3          Effective for sleep-onset and sleep-
that bind to                                                        maintenance insomnia
 the BDZ                                                            Ambien CR® approved for long-term use
binding site
   on the      Zaleplon [Sonata®]          20            1          Mainly for sleep-onset insomnia, but
  GABAA                                                             because of ultrashort t1/2, can be taken
  receptor                                                          during the night to improve sleep
                                                                    maintenance

               Eszopiclone [Lunesta®]      30            6          Mainly for sleep-maintenance insomnia
                                                                    Approved for long-term use
Melatonin      Ramelteon [Rozerem®]        30           1-2         Mainly for sleep-onset insomnia
 agonist                                                            Approved for long-term use
                                                                    Not a controlled (scheduled) drug


a                                                                                                        44
 Includes drug and active metabolites.
b
 Other FDA-approved BDZ hypnotics are quazepam [Doral®] and estazolam [ProSom®].
     Non BDZ vs BDZ hypnotics
• Although both classes of drugs bind to and
  enhance inhibitory transmission through GABAA
  receptors, the non BDZ hypnotics cause:
  – Less changes in sleep cycle, psychomotor impairment
  – Purportedly less physical dependence, tolerance, and
    rebound insomnia
  – Limited anxiolytic, muscle relaxant or anticonvulsant
    response at hypnotic doses
  – Zolpidem and eszopiclone tested and approved for long
    term use
                                                       45
Non Benzodiazepine Hypnotics
• Ramelteon (Rozerem®)
  – An agonist at melatonin receptors
  – Rapid onset, short half life, so particularly
    useful for treating sleep onset insomnia
  – Only approved hypnotic that is not a scheduled
    (controlled) substance



                                                    46
              Anxiolytics
• Benzodiazepines- all can be used but in
  practice
  – diazepam, oxazepam, alprazolam
  – midazolam- acute, surgery
  – clonazepam- although not approved
• Buspirone (Buspar®)
• SSRIs
• β-adrenergic antagonists

                                            47

								
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