Document Sample
                                              May 4, 2011

1. Overview clinical use of anxiolytic, sedative and muscle relaxant drugs and drug classes involved.
2. Discuss clinically useful drugs interacting with GABAA receptors.
3. Describe features of the GABAA receptor as a clinically important ligand-gated ion channel.
4. Consider unique interactions of benzodiazepines (BZs) / barbiturates (Barbs) with GABAA receptors.
5. Define agonist actions of baclofen, buspirone and ramelteon with G protein-coupled receptors.
6. Compare dose-dependent CNS actions of BZs, Barbs, zolpidem, buspirone and ramelteon.
7. Identify risk for side effect and drug tolerance / dependence with benzodiazepines / barbiturates.
8. Show how metabolism influences duration of some benzodiazepine CNS actions.

Anxiolytics /Antianxiety Drugs
These agents are intended to reduce “anxiety" without drowsiness. Anxiety (mild to psychotic)
 accompanies physical or psychological disorders like acute or generalized anxiety, panic attacks,
 anticipatory anxiety, etc. Symptoms of anxiety disorders include: tension, nervousness, irritability,
 irrational fear, apprehension, restlessness, palpitations, sweating, nausea, muscle tension and insomnia.
Therapeutic success is difficult to measure as anxiety fluctuates rapidly with a large placebo effect. For
 acute or situational anxiety, chronic dosing is unnecessary and patients may be instructed to self-
 administer as needed within limited daily dose ranges and frequencies.

Anxiety secondary to psychiatric disorders (e.g., social phobia, post-traumatic stress,
 stimulant drug abuse, depression or schizophrenia) often resolves when the primary disorder is treated.
 Antidepressants or antipsychotic drugs should be used here instead of benzodiazepines! Some
 anxiety disorders overlap major depressive disorders, (e.g., panic disorder, severe generalized anxiety
 disorder) and are increasingly found to be effectively treated with either antidepressants and/or
 anxiolytics [see NIH-NIMH “What medications are used to treat anxiety disorders” ].

Currently available drugs include:

Benzodiazepines like alprazolam (Xanax®), chlorazepate (Tranxene®), diazepam (Valium®),
 lorazepam (Ativan®) and oxazepam (Serax®). These drugs work on GABAA receptors.

Buspirone (Buspar®) a unique, non-depressant anxiolytic drug works on serotonin (5-HT1A) receptors.
Antidepressants such as paroxetine (Paxil®), approved for use in panic disorder is a selective
 serotonin reuptake inhibitor (SSRI), or venlafaxine (Effexor®), approved for generalized anxiety
 disorder, inhibits serotonin and norepinephrine reuptake. They increase transmitter in the synaptic
 cleft activating 5-HT1A receptors, with an action similar to buspirone. [Antidepressants used in
 anxiety disorders are discussed by Dr. Griffith, Antidepressants 11 am 4/27/11.] Anxiolytic and
 antidepressant drugs work in the 'amygdala / limbic system / frontal cortical' brain structures to
 dampen anxiety.

   Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB -             1
Sedative Drugs              These agents are intended to relax, induce drowsiness and sleep with little
 depression of normal brain function. Insomnia is often secondary to stress, altered diurnal cycles,
 pain, depression or drug abuse. [see NIH Natl. Sleep Disorders Ctr . . . select Patient and Public Information
 - - take the “Sleep Quiz” and Sleep Disorders Overview ] Addressing these problems first reduces the
 need for drugs. Insomnia is associated with loss of REM sleep cycles (see figure), the stage when
 refreshing sleep occurs.

                                                                                - - - REM cycles - -
Current drugs include:

Barbiturates like:
 amobarbital (Amytal®) ,
 phenobarbital (Luminol®),
 pentobarbital (Nembutal®)
 secobarbital (Seconal®).

Benzodiazepines (BZ) such as:
 flurazepam (Dalmane®),
 quazepam (Doral®),
 temazepam (Restoril®),
 triazolam (Halcion®),                     (LEFT) Stages of natural sleep (0 - 4); cortical EEG traces
 estazolam (ProSom®).                       (MIDDLE) and (RIGHT) relative sleep depth during the
                                           progression of a subjective night starting from left to right.

Non-Benzodiazepines (BZ receptor agonists) include: zolpidem, (Ambien®), zaleplon (Sonata®)
 and eszopiclone (Lunesta®).

These drugs work as allosteric positive modulators on GABAA receptors. Induce sleep by dampening
 “the ascending arousal system” and alerting mechanisms in brainstem, hypothalamus, thalamus, basal
 forebrain and cerebral cortex.

NEWER DRUG CLASS for treating insomnia recently FDA approved

Ramelteon (Rozerem®) approved in 2005 for insomnia - speeds falling asleep. Mimics melatonin and
 may improve circadian rhythm / normal sleep-wake cycle. Remelteon is a melatonin receptor agonist.

Muscle Relaxants are used to reduce muscle spasm from sprains or neck / back injury or to
 reduce painful muscle hypertonicity in chronic disorders such as cervical dystonia, stroke, spinal cord
 injury, multiple sclerosis (MS), cerebral palsy, amyotrophic lateral sclerosis (ALS) and the like. Act
 peripherally directly on skeletal muscle / neuromuscular junction or centrally on synaptic function in
 spinal cord motor neurons / reflex circuits or higher in CNS motor centers. CAN NOT USE
 neuromuscular nicotinic blockers [see Zimmer, Cholinergic Neuromuscular Blockers 1 pm, 4/6/11]
 succinylcholine, d-tubocurarine, pancuronium, etc. although some of these agents are

   Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB -                  2
 important in balanced general anesthesia to relax muscle for surgical manipulation [see Frye, General
 Anesthesia 10am 5/6/11].

Peripherally Acting Muscle Relaxants

Dantrolene (Dantrium®) which acts directly on skeletal muscle. Decreases sarcoplasmic reticulum
 Ca2+ release blunting force development during muscle contraction causing relaxation / weakness.

Botulinum toxins TYPE A - NOW CALLED OnabotulinumtoxinA (Botox®) or AbobotulinumtoxinA
 (Dysport®) and TYPE B - NOW CALLED RimabotulinumtoxinB (Myobloc®) derived from the
 anaerobic bacterium, Clostridium botulinum, are enzymes that block acetylcholine release at
 neuromuscular junctions by cleaving SNARE proteins essential for synaptic vesicle docking and
 fusion during action potential-induced exocytosis.
 Toxin is injected at the site where muscle tone is to be reduced and causes local weakness.
 Denervation lasts from weeks to months, but development of neutralizing antibodies can limit future
 use, although hypersensitivity reactions are rare. FDA issued a Block Box warning in 2009 for life-
 threatening risk of toxin spread from injection sites (see BOTOX black box warning 6-10-09.pdf)!

Centrally Acting Muscle Relaxants

Baclofen (Lioresal®), a GABAB agonist acting in
 spinal cord which can be given orally or
 intrathecally by an implanted pump in severe
 spasticity. NOTE: Pump failure can trigger a
 severe withdrawal syndrome (increased
 rigidity/spasticity, confusion, tachycardia,
 hypo- / hypertension, hyperthermia. Oral
 baclofen suppresses withdrawal.

Benzodiazepines such as diazepam (Valium®),
 work on GABAA receptors in spinal cord and
 higher motor centers in the brain.

Tizanidine (Zanaflex®) and clonidine                 GABA inputs to higher brain stem motor center
 (Catapres®), 2 adrenergic agonists;                   circuits and spinal motor neurons / reflex
 cyclobenzaprine (Flexeril®) a serotonin 5-HT2           circuits regulating skeletal muscle tone
 receptor antagonist, all increase presynaptic
 inhibition on motor neurons in the spinal cord by reducing descending excitatory noradrenergic or
 serotoninergic inputs.

   Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB -         3
Drugs Working On GABAA Receptors
GABAA Receptor Enhancement
  Benzodiazepines (BZs), zolpidem, zaleplon and
  barbiturates (related general anesthetics) increase
  GABAergic postsynaptic inhibition throughout CNS by
  potentiating Cl- mediated inhibitory postsynaptic currents
  (IPSCs) when GABAA receptors are activated by GABA
  (see figure of a GABA synapse).
  This further decreases excitability of those neurons with
  prominent GABA inputs and is the basis for CNS
  depressant actions of these drugs.                                                             IPSCs
  Also, direct activation of GABAA receptors by
  barbiturates (high doses) explains their greater lethality
  relative to BZs which require GABA activation of the
  receptor to work (see below).

Barbiturates are derived from barbituric acid where the 4 "R" groups (see structure below)
 determine pharmacological properties of various drugs. All these drugs increase GABAA receptor
 function (more on specific mechanisms below).

 Oxy-barbiturates have an oxygen atom at
 position *R1. This increases water solubility,
 prolongs drug action and slows CNS entry
 and redistribution. Only oxybarbiturates,
 like phenobarbital, (Luminol®) are
 prescribed as sedative-hypnotics and as an
                                                      barbituric                   Phenobarbital
                                                      acid                         l
 Thio-barbiturates have sulfur at position R1. Increases lipid solubility, greatly speeds, but shortens
 drug action by rapid CNS entry and redistribution. Prevents use of thio-barbiturates as sedatives.
 Thiopental (Pentothal®) is a prototype thio-barbiturate used to induce anesthesia, intravenously [see
 Frye, Inhalation / Intravenous Anesthetic Agents 11am 5/6/11].

Benzodiazepines (BZ) from the 1,4-benzodiazepine nucleus has
 6 "R" positions that contribute to subtle differences in pharmacological


   Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB -            4
 Diazepam (Valium®) is the prototype. These drugs have a wide range of uses and are prescribed as
  anxiolytics, sedatives, intravenous anesthetics, anticonvulsants and muscle relaxants. More than
  20 agents are currently available clinically, but the main differences are
  in duration of action based on rate of metabolism and active metabolites
  (see below).

 All BZs increase GABAA receptor function by an allosteric action
  (more on this follows).

Non-benzodiazepine, BZ agonists are drugs that act at the same
 GABAA receptor binding site as diazepam (e.g., a benzodiazepine that is also a benzodiazepine

 Zolpidem (Ambien®) an imidazopyridine, zaleplon (Sonata®)
  and eszopiclone (Lunesta®) also non-benzodiazepines.
  They are prescribed as sedatives due to more selective
  action in sleep-related brain areas (see GABAAR 1 subunit
  story below). These have very short durations of action
  with rapid clearance, causing less next day drowsiness!                       zolpidem

GABAARs are Clinically Important Ligand-Gated Chloride Ion Channels
GABA is an amino acid neurotransmitter that binds to a receptor site on the Cl- channel causing it to
open (gating). Once open, the channel pore allows a passive inward flow of Cl- across the cell
membrane increasing intracellular negative charge to hyperpolarize the cell (e.g., inhibitory postsynaptic
currents - IPSCs) reducing probability of firing (see figure top pg 4 and below).

Plant toxins that act on GABAA receptors (GABAARs)
 Muscimol mimics GABA (GABAAR agonist) at the GABAA receptor and can cause severe CNS
 Bicuculline inhibits GABA (competitive GABAAR antagonist) that blocks GABAergic transmission
  causing CNS excitation.
 Picrotoxin inhibits GABA chloride channels (non-competitive GABAAR antagonist). Blocks
   GABAAR activity by binding inside the Cl- channel to close it, but does not prevent GABA binding
   to the receptor. Causes CNS excitation by blocking GABAergic transmission. Both bicuculline
   and picrotoxin prevent Cl- ion inflow by different mechanisms and cause grand mal seizures by
   blocking normal GABAergic inhibition.

GABAAR-chloride channels - composed of 5 protein subunits, each has 4 membrane crossing
 domains (M1-M4). The 5 subunits come together to form two GABA binding sites and a chloride
 channel for each receptor. GABAAR subunits include 16 distinct types (different gene products)
 grouped in 5 families [alpha (), beta (), gamma (), delta (), epsilon () and pi ()].

   Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB -             5
Common GABAAR subunit complements: 2- / 2- / 1-. . . . orsubunits.Drug
 sensitivity of any GABAAR can depend on individual subunits it contains. For example: GABAARs
 must have  subunit for diazepam to work.

                                                                                           
                                                                                              
                                                                                           

           (LEFT) Schematic GABAAR & Cl- channel. (CENTER) side view of a receptor
         subunit. (RIGHT) top down view of pentameric (5 subunit) structure of a GABAAR.

 Zolpidem has higher selectivity than diazepam for GABAARs containing 1 subunits, which are
 common in sleep-related brain areas. This focused interaction with only a subset of receptors likely
 explains zolpidem's proposed greater sedative specificity (has less anxiolytic efficacy than diazepam).

 Receptors are binding sites
 on  /  subunits where BZ
 interactions allosterically
 modulate GABAAR-chloride
 channels (see fig bottom pg 6).

  Important BZ Receptor Issues
  (TOP) Drugs showing a range of
  efficacy at the BZ binding site
  (receptor). LEFT midazolam is a
  full agonist. MIDDLE flumazenil
  is a competitive antagonist.
  RIGHT DMCM is a full inverse
  BZ agonist = actions opposite
  midazolam. (BOTTOM) BZ
  receptor mediated changes in
  chloride flow through GABA-
  activated GABAARs.

   Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB -                    6
Diazepam (Valium®) and midazolam (Versed®) are full agonists that bind at the benzodiazepine
 receptor (a site distinct from the GABA binding site) and increase affinity of GABA binding site for
 GABA (e.g., positive allosteric modulation), shifting the GABA response-curve to the left.
 Translates into more channel openings (e.g., higher open frequency (f) - see figure below), which lets
 in more Cl- per unit time. Benzodiazepines only work when GABA activates the channel!

 Important Chloride Channel Function issues: (TOP) GABAA receptor Cl- channel openings are
  all-or-none events characterized by the size of the Cl- current (conductance  ), how long it flows
   (open time, ) and how often (frequency f ). (BOTTOM) BZs increase frequency ( f ), while
                Barbs increase open time (). Both actions increase total Cl- current.

Zolpidem (Ambien®) is a full agonist at the BZ receptor on 1 type GABAARs like diazepam.

Flumazenil (Romazicon®) is a competitive BZ receptor antagonist (no intrinsic activity, see vertical
  middle of figure, on bottom pg 6). It reverses overdose-related CNS depression by all BZ agonists.

    Barb effects on GABAARs
  Between arrows, GABA alone
        causes concentration
      dependent increase in Cl-
      current into neurons with
  GABAAR activation. GABA
    + BZ inverse agonist shifts
   receptor function to the right
    (lower GABA affinity). Bz
    agonists or Barbs + GABA
      shift curve to left (higher
   GABA affinity). High dose
    Barbs also increase current
  over GABA alone (= toxicity).

   Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB -            7
Inverse benzodiazepine agonists - cause allosteric antagonism - - include some benzodiazepines
 and other compounds like DMCM, a -carboline. These agents decrease GABA-activated GABAAR
 activity (e.g.., opposite of diazepam = negative intrinsic activity – see figure pg 6 above).

This negative allosteric action reduces GABA inhibition and increases anxiety (e.g., is anxiogenic) and
 experimentally have been shown to trigger panic attack.

Barbiturate (Barb) receptors are binding sites (not well characterized yet) on subunits
 where moderate doses of Barbs allosterically modulate while higher doses directly active the
 GABAAR-chloride channel.
Pentobarbital (Nembutal®) is a full Barb receptor agonist (at a site distinct from GABA or
 benzodiazepine sites on GABAA receptor-chloride channels).

Low doses of barbiturates that are sedative-hypnotic increase affinity of GABA binding site for
 GABA (ie., positive allosteric modulation). Translates into longer channel openings (see above),
 which lets in more Cl- per unit time while GABA activates the channel!

Very high doses of barbiturates induce anesthesia / lethal respiratory depression by directly activating
 GABAAR-chloride channels, independent of GABA activation (shift GABA curve to left and increase
 maximum response). No competitive antagonists for barbiturate binding sites are available.
 RECENT RESEARCH SHOWS: Anesthetic / lethal respiratory depressant actions of
  barbiturates and other intravenous anesthetics (propofol, etomidate), inhalation anesthetics
  (isoflurane, desflurane) and ethanol also could include a significant action on GABAARs outside
  the synapse. These so called 'extrasynaptic" (tonic) receptors may carry as much as 50% of total
  inhibitory chloride current during severe CNS depression by these drugs, while these agents also
  exert the expected actions to increase postsynaptic inhibition on 'synaptic' (phasic) receptors.

Drugs Working on Serotonin (5-HT1A) / GABAB / Melatonin
 (MT1/2) G Protein-Coupled (Metabotropic) Receptors
Buspirone (Buspar®) is an azapirone derivative, prescribed as an anxiolytic drug. Structurally
 distinct from benzodiazepines. It acts on serotonin rather than GABA systems. Buspirone is an
 agonist (some evidence suggests a partial agonist) at 5-
 HT1A receptors. Mimics serotonin both on pre- and
 postsynaptic 5-HT1A receptors. Presynaptic 5-HT1A
 receptors reduce serotonin release (act as autoreceptors) or
 reduce the release of other transmitters via presynaptic
 inhibition (inhibit voltage-gated Ca2+ channels important in                  buspirone
 transmitter release). Postsynaptic 5-HT1A receptors activate
 K+ channels via G proteins (K+ outflow hyperpolarizes cells to reduce excitability).

   Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB -            8
Baclofen (Lioresal®) is used as a muscle relaxant. It decreases flexor and extensor spasms associated
 with spinal cord injury and multiple sclerosis and is more selective than diazepam with less sedation
 and does not cause muscle weakness like dantrolene. Baclofen is a GABAB receptor agonist.
 Receptors are located pre-synaptically, reduce excitatory transmitter release (presynaptic inhibition)
 and post-synaptically to directly hyperpolarize spinal cord neurons by activating G protein-coupled K+
 channels (like pre- and postsynaptic 5-HT1A receptors). Unlike GABAA receptors, GABAB are not
 blocked by bicuculline (are distinct gene products / proteins from GABAARs).


Ramelteon (Rozerem®) is a sleep aid. It increases onset
 of persistent sleep, presumably through agonist actions at
 melatonin MT1 and MT2 receptors on neurons in the
 superchiasmatic nucleus. These G protein-coupled
 receptors inhibit adenylyl cyclase / reduce cyclic AMP
 formation. Not clear how this enhances sleep induction.             ramelteon

Overview of CNS Effects of Anxiolytics, Sedatives and
Dose-dependent CNS depression occurs with benzodiazepines, barbiturates, baclofen and
 zolpidem (see figure below) - - buspirone and ramelteon do not depress CNS!

Clinically useful anxiolytic actions (see "A" below) limited to benzodiazepines and buspirone.
 Benzodiazepines reduce anxiety at doses below those causing significant sedation and are active
 within minutes of dosing. Buspirone is not sedative which makes it useful for elderly who may fall or
 suffer memory lapse (amnesia) with benzodiazepines. However, anxiolytic actions only appear after
 several weeks of continued use!

Clinically useful muscle relaxation is achieved with baclofen or benzodiazepines, but at
  doses causing some sedation. Tolerance develops to the sedation.

   Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB -          9
Clinically useful sedative-hypnotic actions (see "S" or "H" see below) are
 achieved with barbiturates, benzodiazepines and zolpidem. Barbiturates less used today due to life-
 threatening overdose potential and poorer quality sleep enhancement. Benzodiazepines and zolpidem
 ALONE have little overdose lethality risk and produce higher quality sleep. Ramelteon increases rate
 of falling asleep without typical sedative-hypnotic actions.

 Increased total REM sleep time highly correlates with refreshing effects of sleep
 and is increased by benzodiazepines and zolpidem but reduced by barbiturates.

 Single REM sleep cycles are shortened by benzodiazepines but this is offset by more REM cycles.
 Barbiturates only shorten REM cycles.

     Dose-response relationships for BZ agonists (LEFT) or Barbs (RIGHT) to exert anxiolytic (A),
    sedative (S), hypnotic (H) or respiratory depressant (RD) actions. BZs are more clinically useful
    because of a the greater spread of between the dose-response curves. Also lethal RD is much less
     likely with BZs than Barbs, but is still a concern when additive effects of other CNS depressants
                                         (e.g., ethanol) are present.

Zolpidem (Ambien®) - no change in REM cycle length but more total REM cycles over ~ 6 - 8 hr.

Zaleplon (Sonata®) mainly improves falling asleep. Its duration of action (~ 2 hr) is too short to alter
 REM cycles. Can be used to offset nocturnal awakening with less morning side effect risk.

Eszopiclone (Lumnesta®) is very similar to zolpidem in duration and sleep cycle effects.

Ramelteon (Rozerem®) mainly improves falling asleep. Short duration of action (~ 2-4 hr) is too short
 to alter REM cycles.

Rebound insomnia and anxiety (a form of withdrawal syndrome) occurs with benzodiazepines
 and barbiturates when the drugs are stopped (much worse with barbiturates). Less likely with
 zolpidem, eszopiclone and zaleplon or ramelteon provided used at prescribed levels.

   Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB -             10
Some CNS "side-effects"
Benzodiazepines and zolpidem / eszopiclone can cause motor impairment, paradoxical excitation
 (behavior disinhibition) and sublethal respiratory depression (see "RD" in fig. above) which is
 rarely life-threatening unless combined with other CNS depressants (e.g., alcohol, barbiturates, etc.).

Amnesia (memory block) is a significant concern; FDA has added Black Box warnings concerning
 'sleep walking / driving / eating / sex' - behavior for which one has no memory. This applies for all
 BZs and barbiturates used as anxiolytics / sedatives.


                                             IV infusion of midazolam (M) induces amnesia (word list
Flumazenil (Romazicon ) a competitive           recall / 6 is no recall) is reversed by flumazenil (F).
  antagonist of the benzodiazepine                              Saline (S) has no effect.
  receptor will rapidly reverse all actions
  of benzodiazepine agonists and inverse agonists including sub-lethal respiratory depression and
  amnesia (see fig). However, it must be given IV due to rapid 1st pass hepatic metabolism. There is
  a risk that reversal of benzodiazepine depression may unmask other serious complications such as
  withdrawal seizures or cardiac arrhythmias due to other drugs (such as cocaine, tricyclic
  antidepressants, etc.) present in overdose emergency cases.

Barbiturates also cause motor impairment but can cause lethal respiratory depression (narrow
  safety margin) alone - there are no antagonists! Respiratory depression occurs when an overdose
  blunts medullary CO2 sensitivity, reducing respiratory drive.

Contraindications for benzodiazepine use include rare but life threatening anaphylactic
  reactions and FDA has black box warning against use during pregnancy due to earlier evidence of
  increased risk for malformations in animal studies, although BZs are not yet classified as teratogenic.

   Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB -             11
Chronic Use Leads To Adaptive Changes

Psychological Dependence occurs in susceptible individuals with benzodiazepines, zolpidem &
 barbiturates (not buspirone, baclofen or ramelteon).

Acquired Tolerance (both behavioral and functional) develops with benzodiazepines, zolpidem,
 barbiturates and baclofen (not buspirone or ramelteon).

 Benzodiazepine tolerance is difficult to detect if active metabolites accumulate increasing CNS
 depression (see below). Sedative-hypnotic actions are lost within 2 weeks which can lead patients to
 increase the dose and the chance of an overdose. No tolerance for anxiolytic effects of BZ agonists
 or buspirone!

 Metabolic tolerance only with barbiturates which can induce hepatic microsomal drug metabolism
 to accelerate clearance and lower drug levels reaching the brain.

Physical Dependence and a "withdrawal syndrome" including rebound anxiety and insomnia
 occurs with benzodiazepines, zolpidem like
 non-benzodiazepines and barbiturates (not
 buspirone, ramelteon). Continuous
 intrathecal infusion with high dose baclofen
 can cause severe withdrawal with pump
 failure! Barbiturate withdrawal is severe
 and life-threatening with grand mal
 seizures, hallucinations and hyper-autonomic
 activity like alcohol withdrawal.

 Benzodiazepine withdrawal is less severe
 especially when slow elimination of drugs /
 metabolites masks withdrawal. Flumazenil,
 a competitive benzodiazepine antagonist can
 precipitate benzodiazepine withdrawal.

Cross Tolerance & Dependence occurs
 between benzodiazepines, zolpidem,                        Signs and symptoms of BZ agonist
 barbiturates, alcohol and certain general              withdrawal. Slow clearance can mask or
 anesthetics (e.g., propofol, etomidate,                  flumazenil can precipitate reactions.
 halothane), but not opiates or CNS

   Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB -         12
Clearance of Barbs, BZ Agonists, Baclofen, Buspirone, Ramelton

Most are largely metabolized,
 which increases polarity and water
 solubility, speeding excretion.
 Metabolites are pharmacologically
 inactive except for some
 benzodiazepines and ramelteon.
 Active ramelteon metabolites have short
 1/2 life ~1-3 hr and not a problem.

Active BZ metabolites for
 flurazepam (five) and diazepam (two)
 have clinically significant CNS
 depressant actions which extend the
 apparent 1/2 life from hours to days.            Examples of active metabolites of clinically used
 Metabolites accumulate and add to                 BZ agonists. Conjugated products are inactive.
 CNS effects.

Nordazepam (N-desmethyl-diazepam) is an active metabolite of many long-acting BZs (see figure
 above) with a long half-life. Accumulates with chronic use and may be the major active BZ present.

Oxazepam (Serax®), lorazepam (Ativan®), zaleplon (Sonata®), baclofen (Lioresal®) and buspirone
 (Buspar®) have no active metabolites, short half-lives and may undergo conjugation before excretion.
 These drugs are useful in liver disease (hepatitis) and for elderly and neonates with limited drug
 metabolizing ability.

Miscellaneous "Anxiolytics / Sedatives"
Propanolol for anxiety-related symptoms. Performance anxiety (ie., stage fright) is worsened by
 peripheral acute autonomic reactions - can be offset with a -blocker like propranolol (Inderal®).

Older Barbiturate-Like Sedatives are still available but should be little used today. However,
 they are cheap! These include: Paraldehyde, chloral hydrate, meprobamate, glutethemide,
 ethchlorvynol, methprylon. These agents are capable of CNS depression, lethality, tolerance and
 dependence equivalent to that of barbiturates!

Classic H1 Blockers with sedative side-effects are prescribed as generics or available Over
 The Counter (OTC). Older antihistamines like diphenhydramine (Benadryl®) or hydroxyzine
 (Atarax®) are still used for allergic reactions because they block peripheral histamine H1 receptors also
 find use as sleep aids due to side-effects of CNS H1 and muscarinic mAChR blocking actions.
 Consider CNS H1 blocking actions similar to low dose barbiturate effects including tolerance and
 rebound insomnia.

   Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB -             13
Older antidepressants with sedative side-effects are prescribed "OFF-LABEL" for insomnia.
 For example, trazadone (Desyrel®) is frequently used in those suffering insomnia while on SSRIs.
 These agents have significant CNS antihistamine H1 antagonist activity (see above).

       FYI >>>>> Dietary Supplements that are proposed to reduce anxiety / improve
     sleep (these do not have FDA approval)! [see Frye, New Drug Development, Placebo &
                               Dietary Supplements, 9am 4/8/11]
    St. John's wort contains hypercin / hyperforin which have SSRI like antidepressant
    activity, but relative potency of preparations varies widely and side effects can be serious
    including impaired drug metabolism.
    5-OH-tryptophan thought to act as a serotonin precursor or melatonin, a pineal hormone,
    may modify diurnal sleep patterns, but neither is approved by the FDA for medical use
    and product purity and safety is a concern!
    Valerian root may have mild sleep enhancing actions with few adverse effects (Med.
    Letter 42:71, 2000), but optimal dosing and product purity issues are unclear.
    Kava root has sedative actions, was the subject of an FDA warning (3/26/02) concerning
    reports associating use with rare, but severe liver damage / failure.

  Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB -               14
                                     SELF-STUDY QUESTIONS

Which might explain resistance to sleep-inducing actions of the first dose of zolpidem taken by an
epileptic patient who has taken phenobarbital chronically:

a.   psychological dependence on phenobarbital
b.   accumulation of nordiazepam
c.   functional cross-tolerance to phenobarbital
d.   reverse tolerance to zolpidem
e.   an increase in the daily phenobarbital dose

Which is TRUE?

a. Oxy-barbiturates are more water soluble than thio-barbiturates, which prolongs drug action.
b. Acute tolerance to sedative actions does not occur with benzodiazepine receptor agonists.
c. Midazolam can induce amnesia, blocking short-term memory, but this does not occur with
d. Only the most powerful reinforcing drugs are associated with risk of psychological dependence.
e. Flumazenil blocks non-benzodiazepine agonists but not benzodiazepine inverse agonists.

An agonist at melatonin receptors:

a.   cyclobenzaprine
b.   ramelteon
c.   baclofen
d.   buspirone
e.   thiopental


a.   depletes dopamine from vesicles in motor neurons
b.   partial agonist at serotonin 5-HT1A receptors
c.   blocks chloride channel of GABAA receptors
d.   inhibits SNARE protein cleavage in nerve terminals
e.   blunts calcium release from sarcoplasmic reticulum

     Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB -          15
Answers: c, a, b, e

   Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB -   16


RELAXANTS                               Feldman, Meyer and
                                          Quenzer, 1997

       Gerry Frye, 371 Reynolds Bldg.

• Overview clinical use of anxiolytics, sedatives and
  muscle relaxants and drug classes involved.

• Discuss clinically useful drug interacting with GABAA

• Describe features of the GABAA receptor as a clinically
  important ligand-gated ion channel

• Consider unique interactions of benzodiazepines (BZs)
  and barbiturates (Barbs) with GABAA receptors.
                 OBJECTIVES (cont.)

• Define agonist actions of baclofen, buspirone and
  ramelteon with G protein-coupled receptors

• Compare dose-dependent CNS actions of BZs, Barbs,
  zolpidem, buspirone and ramelteon

• Identify risk for side effects and drug tolerance /
  dependence with BZs / Barbs

• Show how metabolism influences duration of some BZ
  CNS actions
      Anxiolytic / Antianxiety Drugs

• Intended to reduce anxiety without sedation

• Anxiety includes a range of symptoms - expressed

• Anxiety often secondary to psychiatric illness
   Anxiolytic / Antianxiety Drugs (cont.)

• Anxiety includes a range of symptoms - expressed

                                 Animal models of conditional anxiety (ie.,
                                  light avoidance in mice – is reversed by
                                diazepam / Valium) are providing powerful
                                tools to identify select molecular targets of
Limbic system structures like     anxiolytic drugs such as the a2 GABAA
  the amygdala play a role          receptor to improve drug specificity.
  Anxiolytic / Antianxiety Drugs (cont.)

• Intended to reduce anxiety without sedation

• Anxiety includes a range of symptoms - expressed

• Anxiety often secondary to psychiatric illness
•   alprazolam (Xanax®)
•   chlorazepate (Tranxene®)
•   diazepam (Valium®)              GABAA Receptors
•   lorazepam (Ativan®)
•   oxazepam (Serax®)

• buspirone (Buspar®)      OR        5HT1A Receptors

• paroxetine (Paxil®)           All act on limbic system
• venlafaxine (Effexor®)            and frontal cortex
                Loss of REM the most
                    refreshing sleep!

• Insomnia - - often secondary to other problems
         Sedative-Hypnotic Drugs

Intended to relax / induce drowiness / sleep

Ideally without depressing brain function
Sleep deprivation is a serious problem which can
            increase risk of accidents!
       Benzodiazepines                        Barbiturates
        flurazepam (Dalmane®)            amobarbital (Amytal)
        quazepam (Doral®)
                                         phenobarbital (Luminol)
        temazepam (Restoril)
        triazolam (Halcion®)             pentobarbital (Nembutal)
        estazolam (ProSom)               secobarbital (Seconal)
                             BZ agonists

                          zolpidem (Ambien)
** FDA approved 2005 **
ramelteon (Razerem)
   melatonin MT1/2
                          eszopiclone (Lunesta)
                          zaleplon (Sonata)            Aids
GABAAR activators


          Ramelteon activates SCN
           MT1/2 receptors - resets
             circadian rhythm?
Muscle Relaxants
dantrolene (Dantrium) decreases sarcoplasmic           diazepam
            reticulum Ca2+ release
botulinum toxins Type A / B blocks ACh release
       - cleaves vesicle docking proteins

 baclofen (Lioresal) GABABR
  agonist acting in spinal cord                        baclofen

 tizanidine (Zanflex) / clonidine (Catapres)
 a2 adrenergic agonists acting in spinal cord                 cyclobenzaprine

cyclobenzaprine (Flexeril) 5-HT2     botulinum toxin
 antagonist acting in spinal cord                          tizanidine / clonidine

diazepam (Valium) GABAAR
  allosteric agonist acting in CNS   dantrolene
  motor centers
enzymes cleave     Botulinum Toxin Mechanism
SNARE proteins
   - blocking
vesicle docking
 and release of
     ACh at
neuromuscular                       ACh
   junctions.                   synaptic vesicle

              terminal                 brevin
                                                 Type B

                           Type A                Docking

        Striated muscle        Presynaptic membrane
Anxiolysis            Diverges from        Sedation

 1850's Inorganic bromide salts
 1900's Sodium barbital
 1950's Meprobamate
 1960's Benzodiazepines . . . Concept of “ANXIOLYSIS”
 1970's The "Valium Decade”
 1980's Benzodiazepine antagonists - flumazenil
        Non-sedating anxiolytics - buspirone
 1990's Non-benzodiazepine-receptor agonists - zolpidem
         Anxiolytic / Antidepressant SSRIs
 2005   Non-sedative sleep induction? - ramelteon


barbituric acid
                      Drugs working on GABAA Receptors

              Oxy     1,4-benzodiazepine      diazepam
phenobarbital Thio

                           non-benzodiazepine BZ agonists

  GABAA Receptors are Ligand-
    Gated Chloride Channels
Have multiple
sites for drug


          bicuculline           picrotoxin
Pentameric = 5 Subunits in each receptor


                           1 subunit
                                              g                   a
               6 subunit families - - alpha (a1-6) beta (b1-4)
                  gamma (g1-3) delta (d) epsilon (e) pi (p)

              Subunits influence drug sensitivity! g is required for
               diazepam binding.       Zolpidem is a1 selective, a
              subunit abundant in sleep-related brain areas. a2 is
                         important of anti-anxiety activity.

   sites on
GABAA Receptors

  Antagonists         modulators
Actions at              Diazepam
                       Full Agonist
   BZ                   anxiolytic     Increase
Receptor                                Affinity

              Flumazenil                more
              Competitive             openings
                neutral           Zolpidem
                                 Full Agonist
  b-Carboline      channel        sedative
      Full          fewer

Inverse Agonist    Affinity
  anxiogenic      Decrease
Barbiturate Receptor
                          channel   Increase
    Pentobarbital         opening    Affinity
sedative - - anesthetic               more
                          without   channel
                                      Cl- current
GABA Receptor Allosteric
Modulation vs Direct Action
                         inverse agonists
                             shift right
   Barb shift left
   + act directly

  BZ full agonists
     shift left
 Severe CNS depressant drug actions on GABAARs
   may not be limited to postsynaptic receptors

    Semyanov et al., Trends in Neurosci. 27:262-269,2004.   Jacob et al., Nature Rev. Neurosci. 9:331-343,2008.

   It is now clear that as much as 50% of GABAAR-mediated Cl- current in a CNS
neuron may originate from 'extrasynaptic' receptors that provide a 'tonic' (continuous)
   hyperpolarizing inhibition. Drugs that broadly act non-selectively across many
    populations of GABAARs such as some intravenous anesthetics like propofol,
 etomidate, thio-barbiturates; inhalation anesthetics like isoflurane or desflurane and
     ethanol may exert greater relative CNS depression through a combination of
     increasing both synaptic (phasic) and extrasynaptic (tonic) GABA signaling.
                        Buspirone - agonist at
                       serotonin 5HT1A receptors

              pre-                                                           Ca2+
            synaptic                                                       channels
           Inhibition                                                      Inhibited
                                                 GTP Binding Proteins
  Postsynaptic                                                          K+ channels
   inhibition                                                            activated

                                                                        Baclofen - agonist at
                                                                          GABAB receptors
                                                                          muscle relaxant

Bowery and Smart Brit J. Pharmacol. 147:S109-S119, 2006
      Ramelteon - agonist at melatonin MT1/2
          receptors aids falling asleep

GTP Binding Proteins

                  Inhibits adenyl
                cyclase – reduces
                 cAMP formation      + SCN
Dose-Dependent CNS Depression

 Anxiolysis        Sedation        Hypnosis
              Respiratory Depression
  Clinically Useful Actions

  Anxiolytic actions - BZs low doses -sedation?
              Buspirone - no sedation - several
                   weeks to act

Muscle relaxation - BZs low-moderate doses with
        sedation (tolerance) - Baclofen - less
       Clinically Useful Actions

Sedative-Hypnotic actions - BZ agonists or Barbs moderate
            doses with sedation (tolerance)

Zolpidem and eszopiclone - - non-BZ agonists with 6-8 hr
          activity - low side effects on waking

Zaleplon - - non-BZ agonist - short action ~ 2hr - improves
      falling asleep or to offset nocturnal awakening

Ramelteon - - MT1/2 agonist - short action ~ 2hr - improves
    falling asleep - no CNS depression / tolerance
 Sedative-Hypnotic Actions
Increased REM correlates with refreshing effects
REM cycles shortened - BZs agonists and Barbs
More REM cycles with BZ agonists - not Barbs

       More REM with BZ agonists
              Less with Barbs
BZ agonists / Barbs induce tolerance - rebound
            insomnia and anxiety!
   CNS / Other Side-Effects of BZ Agonists
  Amnesia - now recognized as
  possible with all BZs, Barbs and
alcohol. Can be useful for traumatic
        medical procedures
 Black Box warning for amnesia-related 'sleep
 driving / eating / sex', etc! Has been extended to
      all BZs, barbs, related sedative-hypnotics.

   Paradoxical Excitation

Motor Impairment - increases risk of falls,
                accidents, etc.
Overdose Risk - Sub-lethal Respiratory Depression for BZs alone, BUT Life-
   threatening if combined with CNS Depressants - Alcohol, Barbs, etc.

BZ Contraindications - rare life threatening anaphylactic reactions - Black
   Box warning against use during pregnancy, not yet established as a
                          teratogen in humans.
     Antagonizing CNS Effects of BZ Agonists
Flumazenil (Romazicon)
    - competitive BZ site /
receptor antagonist - IV use
  - reverses BZ agonists /
  inverse agonists rapidly.

                                                                Flumazenil blocks


                            Can reverse BZs CNS depression including potentially
                            lethal respiratory depression, BUT action is brief due to
                                rapid redistribution out of brain. Can unmask BZ
                            withdrawal or other drug withdrawal / toxicity previously
                                              suppressed by the BZs.
BZs & Barbs




Clearance of Barbiturates, BZ Agonists,
  Baclofen, Buspirone and Ramelteon

 Metabolism increases polarity and water
      solubility, speeding excretion

    Most are largely metabolized to
 pharmacologically inactive compounds

Some benzodiazepines (older drugs) and
  ramelteon are metabolized to active
    Benzodiazepine Metabolism


       Multiple active BZ metabolites possible!

Some metabolites are as active as the parent compound!
Active BZ Metabolites Can Accumulate!



     Active metabolites of ramelteon do not
      accumulate and are not a problem.
  Miscellaneous anxiolytic and sedative drugs

b-blockers like propanolol (Inderal) blunt acute anxiety-related autonomic
reactions (ie., stage fright).

Older-barbiturate-like drugs - little used / cheap! paraldehyde, chloral hydrate,
meprobamate, glutethemide, ethchlorvynol, methprylon

Classic H1 Blockers & OTC sleeping aids - older histamine H1
antihistamines like diphenhydramine (Benadryl) or hydroxyzine (Atarax).

Older Antidepressants – with H1 blocker sedative side-effects such as trazadone
(Desyrel) used in those suffering insomnia while on SSRIs.

Dietary supplements (not FDA approved) - St. Johns Wort has SSRI-like
activity but impairs drug metabolism. 5-OH-tryptophan, serotonin precursor or
melatonin, a pineal hormone, diurnal sleep patterns (?), but neither is approved
by the FDA for medical use! Valerian root enhance sleep (few side-effects) but
at what dose? (Med. Letter). Kava root has sedative effects / liver toxicity
New Drugs     Rash
often have

St. John’s Wort


              Muller et al., Pharmacopsychiatry 31(suppl. 1:16-21), 1998
FYI - - FDA APPROVAL – sleep aid?
Dopamine D2 / D3 Agonist

                 Ropinirole (Requip;
                     ReQuip CR -
                controlled-release) is
                 largely metabolized
                  with ½ life ~ 6 hrs

Parkinson's drug now FDA approved for
  use in moderate to severe "Restless
 Legs Syndrome" is characterized by an
urge to move the legs to relieve discomfort
 or pain. Disturbs sleep and occurs more
frequently in women, increasing with age.

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