Antianxiety Drugs

Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB - gdfrye@medicine.tamhsc.
edu 1
ANXI OLYTI CS / SEDATI VES / MUSCLE
RELAXANTS

May 4, 2011

OBJECTIVES
1. Overview clinical use of anxiolytic, sedative and muscle relaxant drugs and drug classes involved.
2. Discuss clinically useful drugs interacting with GABA
A
receptors.
3. Describe features of the GABA
A
receptor as a clinically important ligand-gated ion channel.
4. Consider unique interactions of benzodiazepines (BZs) / barbiturates (Barbs) with GABA
A
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 GABA

A
receptors.

Buspirone (Buspar
) a unique, non-depressant anxiolytic drug works on serotonin (5-HT

1A
) 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-HT
1A
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 - gdfrye@medicine.tamhsc.edu 2
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.

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
),
estazolam (ProSom
).

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

These drugs work as allosteric positive modulators on GABA
A
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
(LEFT) Stages of natural sleep (0 - 4); cortical EEG traces
(MIDDLE) and (RIGHT) relative sleep depth during the
progression of a subjective night starting from left to right.
- - - REM cycles - -
-
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

Ca
2+
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 GABA
B
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 GABA
A
receptors in spinal cord and
higher motor centers in the brain.

Tizanidine (Zanaflex
) and clonidine
(Catapres
), o
2
adrenergic agonists;
cyclobenzaprine (Flexeril
) a serotonin 5-HT
2

receptor antagonist, all increase presynaptic
inhibition on motor neurons in the spinal cord by reducing descending excitatory noradrenergic or
serotoninergic inputs.

GABA inputs to higher brain stem motor center
circuits and spinal motor neurons / reflex
circuits regulating skeletal muscle tone

Drugs Working On GABA
A
Receptors

GABA
A
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 GABA
A
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.

Also, direct activation of GABA
A
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 GABA
A
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
anticonvulsant.

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
properties.

Phenobarbital
l
barbituric
acid
1,4-benzodiazepine
IPSCs
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 GABA
A
receptor function by an allosteric action
(more on this follows).

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

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 GABA
A
R o1 subunit
story below). These have very short durations of action
with rapid clearance, causing less next day drowsiness!

GABA
A
Rs are Clinically I mportant Ligand-Gated Chloride I on 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 GABA
A
receptors (GABA
A
Rs)

Muscimol mimics GABA (GABA
A
R agonist) at the GABA
A
receptor and can cause severe CNS
depression.

Bicuculline inhibits GABA (competitive GABA
A
R antagonist) that blocks GABAergic transmission
causing CNS excitation.

Picrotoxin inhibits GABA chloride channels (non-competitive GABA
A
R antagonist). Blocks
GABA
A
R 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.

GABA
A
R-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. GABA
A
R subunits include 16 distinct types (different gene products)
grouped in 5 families [alpha (o16), beta (|14), gamma (13), delta (o), epsilon (c) and pi (t)].

diazepam
zolpidem

Common GABA
A
R subunit complements: 2-o / 2-| / 1-, . . . . or o, c, t subunits. Drug
sensitivity of any GABA
A
R can depend on individual subunits it contains. For example: GABA
A
Rs
must have subunit for diazepam to work.

Zolpidemhas higher selectivity than diazepam for GABA
A
Rs containing o1 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).

Benzodiazepine
Receptors are binding sites
on o / subunits where BZ
interactions allosterically
modulate GABA
A
R-chloride
channels (see fig bottom pg 6).

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

|
|

o
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 GABA
A
Rs.
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!

Zolpidem (Ambien
) is a full agonist at the BZ receptor on o1 type GABA

A
Rs 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.

Important Chloride Channel Function issues: (TOP) GABA
A
receptor Cl
-
channel openings are
all-or-none events characterized by the size of the Cl
-
current (conductance ), how long it flows
(open time, t ) and how often (frequency f ). (BOTTOM) BZs increase frequency ( f ), while
Barbs increase open time (t). Both actions increase total Cl
-
current.
BOTTOM LINE on BZ &
Barb effects on GABA
A
Rs
Between arrows, GABA alone
causes concentration
dependent increase in Cl
-

current into neurons with
GABA
A
R 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).
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 GABA
A
Rs 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.

Inverse benzodiazepine agonists - cause allosteric antagonism - - include some benzodiazepines
and other compounds like DMCM, a |-carboline. These agents decrease GABA-activated GABA
A
R
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
GABA
A
R-chloride channel.

Pentobarbital (Nembutal
) is a full Barb receptor agonist (at a site distinct from GABA or

benzodiazepine sites on GABA
A
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
GABA
A
R-chloride channels, independent of GABA activation (shift GABA curve to left and increase
maximum response). No competitive antagonists for barbiturate binding sites are available.

Drugs Working on Serotonin (5-HT
1A
) / GABA
B
/ Melatonin
(MT
1/2
) 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-
HT
1A
receptors. Mimics serotonin both on pre- and
postsynaptic 5-HT
1A
receptors. Presynaptic 5-HT
1A

receptors reduce serotonin release (act as autoreceptors) or
reduce the release of other transmitters via presynaptic
inhibition (inhibit voltage-gated Ca
2+
channels important in
transmitter release). Postsynaptic 5-HT
1A
receptors activate
K
+
channels via G proteins (K
+
outflow hyperpolarizes cells to reduce excitability).

buspirone

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 GABA
B
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-HT
1A
receptors). Unlike GABA
A
receptors, GABA
B
are not
blocked by bicuculline (are distinct gene products / proteins from GABA
A
Rs).

Ramelteon (Rozerem
) is a sleep aid. It increases onset

of persistent sleep, presumably through agonist actions at
melatonin MT
1
and MT
2
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.

Overview of CNS Effects of Anxiolytics, Sedatives and
Hypnotics

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.

ramelteon
baclofen

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.

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.

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.

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.

Flumazenil (Romazicon
) a competitive
antagonist of the benzodiazepine
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 CO
2
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.

IV infusion of midazolam (M) induces amnesia (word list
recall / 6 is no recall) is reversed by flumazenil (F).
Saline (S) has no effect.
flumazenil

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,
barbiturates, alcohol and certain general
anesthetics (e.g., propofol, etomidate,
halothane), but not opiates or CNS
stimulants!

Signs and symptoms of BZ agonist
withdrawal. Slow clearance can mask or
flumazenil can precipitate reactions.

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.
Metabolites accumulate and add to
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 H
1
receptors also
find use as sleep aids due to side-effects of CNS H
1
and muscarinic mAChR blocking actions.
Consider CNS H
1
blocking actions similar to low dose barbiturate effects including tolerance and
rebound insomnia.

Examples of active metabolites of clinically used
BZ agonists. Conjugated products are inactive.

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 H
1
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.

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
diazepam.
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

Dantrolene:

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


Answers: c, a, b, e

SEDATIVES
Gerry Frye, 371 Reynolds Bldg.
gdfrye@medicine.tamhsc.edu
MUSCLE
RELAXANTS
ANXIOLYTICS
Feldman, Meyer and
Quenzer, 1997
OBJECTIVES
Overview clinical use of anxiolytics, sedatives and
muscle relaxants and drug classes involved.
Describe features of the GABA
A
receptor as a clinically
important ligand-gated ion channel

Consider unique interactions of benzodiazepines (BZs)
and barbiturates (Barbs) with GABA
A
receptors.

Discuss clinically useful drug interacting with GABA
A

receptors
OBJECTIVES (cont.)
Show how metabolism influences duration of some BZ
CNS actions
Identify risk for side effects and drug tolerance /
dependence with BZs / Barbs

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

Define agonist actions of baclofen, buspirone and
ramelteon with G protein-coupled receptors
Anxiolytic / Antianxiety Drugs
Anxiety often secondary to psychiatric illness
Intended to reduce anxiety without sedation
Anxiety includes a range of symptoms - expressed
intermittently
Anxiolytic / Antianxiety Drugs (cont.)
intermittently
Limbic system structures like
the amygdala play a role
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
anxiolytic drugs such as the a2 GABA
A

receptor to improve drug specificity.
Anxiolytic / Antianxiety Drugs (cont.)
Anxiety often secondary to psychiatric illness
Intended to reduce anxiety without sedation
intermittently
Benzodiazepines!
buspirone (Buspar
)
alprazolam (Xanax
)
chlorazepate (Tranxene
)
diazepam (Valium
)
lorazepam (Ativan
)
oxazepam (Serax
)
GABA
A
Receptors
5HT
1A
Receptors OR
All act on limbic system
and frontal cortex
paroxetine (Paxil
)
venlafaxine (Effexor
)

Antidepressants
Insomnia - - often secondary to other problems
Insomnia!
Loss of REM the most
refreshing sleep!
Intended to relax / induce drowiness / sleep
Sedative-Hypnotic Drugs
Ideally without depressing brain function
Sleep deprivation is a serious problem which can
increase risk of accidents!
Benzodiazepines
amobarbital (Amytal)
phenobarbital (Luminol)
pentobarbital (Nembutal)
secobarbital (Seconal)
flurazepam (Dalmane
)
quazepam (Doral
)
temazepam (Restoril)
triazolam (Halcion
)
estazolam (ProSom)
Non-benzodiazepine
BZ agonists
Barbiturates
zolpidem (Ambien)
eszopiclone (Lunesta)
zaleplon (Sonata)
Sleep
Aids
GABA
A

Receptors
ramelteon (Razerem)
melatonin MT
1/2

receptors
** FDA approved 2005 **
dampen
ascending
arousal
system
GABA
A
R activators
Ramelteon activates SCN
MT
1/2
receptors - resets
circadian rhythm?
Muscle Relaxants
dantrolene (Dantrium) decreases sarcoplasmic
reticulum Ca
2+
release
baclofen (Lioresal) GABA
B
R
agonist acting in spinal cord
diazepam (Valium) GABA
A
R
allosteric agonist acting in CNS
motor centers
dantrolene
diazepam
botulinum toxins Type A / B blocks ACh release
- cleaves vesicle docking proteins
botulinum toxin
cyclobenzaprine (Flexeril) 5-HT
2
antagonist acting in spinal cord
tizanidine / clonidine
tizanidine (Zanflex) / clonidine (Catapres)
a
2
adrenergic agonists acting in spinal cord
cyclobenzaprine
baclofen
Botulinum Toxin Mechanism
Striated muscle
ACh
terminal
Presynaptic membrane
ACh
synaptic vesicle
Synapto-
brevin
BOTOX
enzymes cleave
SNARE proteins
- blocking
vesicle docking
and release of
ACh at
neuromuscular
junctions.
Docking
Type A
Type B
SNAP-25
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
Anxiolysis
Sedation Diverges from
IPSCs
GABA
A

Receptor
Enhancement

=

Increased
Postsynaptic
Inhibition!
barbituric acid
phenobarbital
diazepam
Drugs working on GABA
A
Receptors
non-benzodiazepine BZ agonists

Oxy
vs
Thio

1,4-benzodiazepine
zolpidem
buspirone
ramelteon
Have multiple
sites for drug
interaction
GABA
A
Receptors are Ligand-
Gated Chloride Channels
Barbs
picrotoxin
bicuculline
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.
Pentameric = 5 Subunits in each receptor
1 subunit
a
b
g
a
b
Benzodiazepine
Receptors

Unique
sites on
GABA
A
Receptors

Agonists,

Antagonists
&
Inverse
Agonists
Allosteric
modulators
+
-
Actions at
BZ
Receptor
Zolpidem
Full Agonist
sedative
b-Carboline
Full
Inverse Agonist
anxiogenic
Diazepam
Full Agonist
anxiolytic
Flumazenil
Competitive
Antagonist
neutral
Increase
Affinity

more
channel
openings
D e c r e a s e
A f f i n i t y

f e w e r
c h a n n e l
o p e n i n g s
Barbiturate Receptor
Pentobarbital
sedative - - anesthetic
Direct
channel
opening

without
GABA
Increase
Affinity

more
channel
openings
Cl
-
current
GABA Receptor Allosteric
Modulation vs Direct Action
BZ full agonists
shift left
BZ
inverse agonists
shift right
Barb shift left
+ act directly
Severe CNS depressant drug actions on GABA
A
Rs
may not be limited to postsynaptic receptors
It is now clear that as much as 50% of GABA
A
R-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 GABA
A
Rs 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.
Jacob et al., Nature Rev. Neurosci. 9:331-343,2008. Semyanov et al., Trends in Neurosci. 27:262-269,2004.
K
+
channels
activated
Postsynaptic
inhibition
Baclofen - agonist at
GABA
B
receptors
muscle relaxant

pre-
synaptic
Inhibition

Ca
2+
channels
Inhibited

Buspirone - agonist at
serotonin 5HT
1A
receptors
anxiolytic
GTP Binding Proteins
Bowery and Smart Brit J. Pharmacol. 147:S109-S119, 2006
Ramelteon - agonist at melatonin MT
1/2

receptors aids falling asleep
GTP Binding Proteins
Inhibits adenyl
cyclase reduces
cAMP formation
+ SCN
neurons?
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
sedation
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 - - MT
1/2
agonist - short action ~ 2hr - improves
falling asleep - no CNS depression / tolerance
Sedative-Hypnotic Actions
Increased REM correlates with refreshing effects
TAKE HOME MESSAGE!
More REM with BZ agonists
Less with Barbs
BZ agonists / Barbs induce tolerance - rebound
insomnia and anxiety!
REM cycles shortened - BZs agonists and Barbs
More REM cycles with BZ agonists - not Barbs
Amnesia - now recognized as
possible with all BZs, Barbs and
alcohol. Can be useful for traumatic
medical procedures
Paradoxical Excitation
Overdose Risk - Sub-lethal Respiratory Depression for BZs alone, BUT Life-
threatening if combined with CNS Depressants - Alcohol, Barbs, etc.
Motor Impairment - increases risk of falls,
accidents, etc.
CNS / Other Side-Effects of BZ Agonists
Black Box warning for amnesia-related 'sleep
driving / eating / sex', etc! Has been extended to
all BZs, barbs, related sedative-hypnotics.
BZ Contraindications - rare life threatening anaphylactic reactions - Black
Box warning against use during pregnancy, not yet established as a
teratogen in humans.
Flumazenil (Romazicon)
- competitive BZ site /
receptor antagonist - IV use
- reverses BZ agonists /
inverse agonists rapidly.
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.
Flumazenil blocks
Antagonizing CNS Effects of BZ Agonists
flumazenil
Chronic
Use
Psychological
Dependence
Acquired
Tolerance
BZs & Barbs
Physical
Dependence
Cross
Tolerance
Dependence
Clearance of Barbiturates, BZ Agonists,
Baclofen, Buspirone and Ramelteon
Most are largely metabolized to
pharmacologically inactive compounds
Metabolism increases polarity and water
solubility, speeding excretion
Some benzodiazepines (older drugs) and
ramelteon are metabolized to active
compounds!
Benzodiazepine Metabolism
Some metabolites are as active as the parent compound!
Multiple active BZ metabolites possible!
5
2
0
Active BZ Metabolites Can Accumulate!
nordiazepam
diazepam
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 H
1

antihistamines like diphenhydramine (Benadryl) or hydroxyzine (Atarax).
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
concerns.
Older Antidepressants with H
1
blocker sedative side-effects such as trazadone
(Desyrel) used in those suffering insomnia while on SSRIs.
But
often
at
greater
cost!
New Drugs
often have
Benefits
Bromide
Rash
St. Johns Wort
Hyperforin
Muller et al., Pharmacopsychiatry 31(suppl. 1:16-21), 1998
FYI - - FDA APPROVAL sleep aid?
Dopamine D
2
/ D
3
Agonist
Ropinirole (Requip;
ReQuip CR -
controlled-release) is
largely metabolized
with 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.

Antianxiety Drugs

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Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB - gdfrye@medicine.tamhsc.

) and oxazepam (Serax

). These drugs work on GABA

) a unique, non-depressant anxiolytic drug works on serotonin (5-HT

), approved for use in panic disorder is a selective

), approved for generalized anxiety

) which acts directly on skeletal muscle. Decreases sarcoplasmic reticulum

) and TYPE B - NOW CALLED RimabotulinumtoxinB (Myobloc

) derived from the

) is a prototype thio-barbiturate used to induce anesthesia, intravenously [see

) an imidazopyridine, zaleplon (Sonata

) and midazolam (Versed

) are full agonists that bind at the benzodiazepine

) is a full agonist at the BZ receptor on o1 type GABA

) is a competitive BZ receptor antagonist (no intrinsic activity, see vertical

) is a full Barb receptor agonist (at a site distinct from GABA or

) is used as a muscle relaxant. It decreases flexor and extensor spasms associated

) is a sleep aid. It increases onset

) is very similar to zolpidem in duration and sleep cycle effects.

) is frequently used in those suffering insomnia while on SSRIs.

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