Download Chapter 11 outline

Chapter 11:
Antianxiety Agents
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
DHY 1330 - Therapeutics
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
Chapter 11 Outline
Antianxiety Agents

Definitions
 Benzodiazepines
 Barbiturates
 Nonbenzodiazepine-nonbarbiturate sedativehypnotics
 Nonbenzodiazepine benzodiazepine receptor
agonists
 Melatonin receptor agonist
 Centrally acting muscle relaxants
 Miscellaneous agents
 General comments about antianxiety agents
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2
Antianxiety Agents


Objectively assessing the patient’s anxiety is
necessary on both the first and subsequent
visits



Haveles (pp. 136-137) (Fig. 11-1)
The dental team will most commonly use orally
administered drugs to provide relaxation for an
anxious patient
Intravenous (IV) administration is used
infrequently; most states require a separate
certificate to administer IV agents or provide
conscious sedation
The dosing of a particular antianxiety agent is
vastly variable, involving intrapatient and
interpatient variation
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3
Definitions


Haveles (p. 137) (Fig. 11-2)
Sedative-hypnotic agents can produce
varying degrees of central nervous system
(CNS) depression, depending on the dose
administered



A small dose will produce mild CNS depression
described as sedation—reduction of activity and
simple anxiety
• This level has some anxiolytic effects
A larger dose of the same drug, the hypnotic dose,
will produce greater CNS depression
In even larger doses, sedative-hypnotics may
produce anesthesia and finally death
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4
Benzodiazepines
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

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


Haveles (pp. 137-142)
Chemistry
Pharmacokinetics
Mechanism of action
Pharmacologic effects
Adverse reactions
Abuse and tolerance
Drug interactions
Medical uses
Management of the dental patient taking
benzodiazepines
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5
Chemistry


Named according to their structure—a 1, 4—
benzodiazepine nucleus



Haveles (pp. 137-138) (Table 11-1)
chlordiazepoxide (Librium) was synthesized in 1955
diazepam (Valium) was synthesized in 1959 and
marketed in 1963
When an additional ring was added, triazolam
was synthesized

Next, midazolam and flumazenil were synthesized
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6
Pharmacokinetics
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
Benzodiazepines are well absorbed when
administered by the oral route
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
The onset of action is related to their lipid solubility
Benzodiazepines are available as tablets,
capsules, oral solution, rectal gel, and injectable
form


Haveles (pp. 138-139)
For benzodiazepines available in parenteral form the
IV route produces a rapid, predictable response; ideal
for conscious sedation
Benzodiazepines cross the blood-brain and
placental barriers to produce an effect on the
CNS and the fetus
cont’d…
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7
Pharmacokinetics


Haveles (pp. 138-139)
Benzodiazepines are metabolized by phase II
metabolism alone or by phase I metabolism
followed by phase II metabolism

Phase I metabolism involves oxidation, reduction,
hydrolysis, dealkylation, and hydroxylation
• It is hard metabolism; it is affected by external factors
such as other drugs and hepatic disease

Phase II involves glucuronidation
• It is easy metabolism; unaffected by external factors
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8
Mechanism of Action


Haveles (p. 139)
Benzodiazepines enhance or facilitate the
action of the neurotransmitter by exerting
their effects in the CNS mediated by γaminobutyric acid (GABA), a major inhibitory
neurotransmitter

The inhibitor effect of GABA is enhanced
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9
Pharmacologic Effects


Behavioral effects
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Clinical effects in humans are anxiety and panic
reduction at low doses and drowsiness and even
sleep at higher doses
Antiseizure effects


Haveles (p. 139)
Increase the seizure threshold
Muscle relaxation

Can produce relaxation of skeletal muscles
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10
Adverse Reactions of
Benzodiazepines


Haveles (p. 139)
In general, benzodiazepines, used alone,
have a wide margin of safety

They all have similar adverse effects but differ in
their frequency
cont’d…
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11
Adverse Reactions of
Benzodiazepines

CNS effects

The most common side effect is depression
manifested as fatigue, drowsiness, muscle
weakness, and ataxia
• The use of parenteral benzodiazepines during a dental
appointment reduces anxiety and alters perception of
time


Diazepam’s long half-life and metabolism to an active
metabolite prolongs its duration of action
Midazolam is metabolized primarily to inactive metabolites
• flunitrazepam (Rohypnol) is available in Europe
cont’d…
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12
Adverse Reactions of
Benzodiazepines

Anterograde amnesia
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Respiratory effects
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
Produced beginning when the drug is taken
Doses of diazepam have occasionally been reported
to produce respiratory depression
Cardiovascular effects

Relief of anxiety may result in a fall in blood pressure
and pulse rate
cont’d…
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13
Adverse Reactions of
Benzodiazepines

Visual effects
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Dental effects


Contraindicated in angle-closure (narrow-angle)
glaucoma and can produce diplopia (single object
viewed as two), nystagmus (rhythmic oscillation of the
eyeballs), and blurred vision
Have been reported to produce xerostomia, increased
salivation, swollen tongue, and a bitter or metallic
taste
Thrombophlebitis

Parenteral diazepam may cause thrombophlebitis
because propylene glycol is used to solubilize it
cont’d…
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14
Adverse Reactions of
Benzodiazepines

Other effects


Can produce cramps or pain, difficulty in urination,
allergic reactions
Pregnancy and lactation considerations

Increased risk of congenital malformations if taken
in the first trimester of pregnancy has been
reported
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15
Abuse and Tolerance


Haveles (p. 140)
Overview

Benzodiazepines can be abused; physical
dependence and tolerance have been documented
• Their abuse and addiction potential is less than that of the
other sedative-hypnotic agents such as barbiturates
• Benzodiazepines have a wider TI than barbiturates
• Combining with other CNS depressants can reduce the
safety
cont’d…
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16
Abuse and Tolerance


Haveles (p. 140)
Treatment of overdose


With recent ingestion, emesis may be induced
• Activated charcoal and a saline cathartic
To reduce some of the effects of a
benzodiazepine, flumazenil (Romazicon), a
benzodiazepine antagonist for IV administration
may be used
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17
Drug Interactions
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
Benzodiazepines will interact in an additive
fashion with other CNS depressants
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


Haveles (pp. 140-141)
Drugs that inhibit oxidative metabolism (phase I
metabolism) may increase the effect of
benzodiazepines that undergo phase I metabolism
Selective serotonin uptake inhibitors alter
clearance of diazepam
May reduce the effectiveness of levodopa
May increase the effect of digoxin, phenytoin,
and probenecid
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18
Medical Uses


Haveles (p. 141)
Useful in short-term treatment of anxiety,
panic attacks, insomnia, and alcohol
withdrawal


Used for acute treatment of seizures
Used for conscious sedation, general anesthesia,
or during surgery
cont’d…
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19
Medical Uses

Anxiety control


Insomnia management


Generalized anxiety disorders and panic disorder;
manifestations of anxiety include restlessness,
tension, tachycardia, and dyspnea
If a manifestation of anxiety
Treatment of epilepsy (seizures)

Diazepam or lorazepam is the drug of choice
cont’d…
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20
Medical Uses

Treatment of alcoholism


Used in treatment of alcohol withdrawal syndrome
Control of muscle spasms

Used to control muscle spasticity that
accompanies diseases such as multiple sclerosis
and cerebral palsy
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21
Management of the Dental
Patient Taking Benzodiazepines


Dental procedures


Orally administered diazepam to allay apprehension
Premedication


Haveles (pp. 141-142) (Box 11-2)
Used before surgical procedures to allay anxiety
Conscious sedation

Usually accompanied by IV administration
• Muscle relaxation and anterograde amnesia (events after
the injection)
cont’d…
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22
Management of the Dental
Patient Taking Benzodiazepines

Conscious sedation

Parenteral benzodiazepines have been associated
with respiratory depression and arrest when used
for conscious sedation
• Require continuous monitoring of respiratory and cardiac
function
• Dentists without additional training cannot use conscious
sedation
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23
Benzodiazepines








Haveles (p. 138) (Table 11-1)
alprazolam
chlordiazepoxide (Librium)
clonazepam (Klonopin)
chlorazepate (Tranxene)
diazepam (Valium)
estazolam (ProSom)
flurazepam (Dalmane)
cont’d…
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24
Benzodiazepines
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






Haveles (p. 138) (Table 11-1)
halazepam (Paxipam)
lorazepam (Ativan)
midazolam (Versed)
oxazepam (Serax)
quazepam (Doral)
temazepam (Restoril)
triazolam (Halcion)
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25
Barbiturates
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
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




Haveles (pp. 142-144)
Chemistry
Pharmacokinetics
Mechanism of action
Pharmacologic effects
Adverse reactions
Chronic long-term use
Contraindications
Drug interactions
Uses
cont’d…
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26
Barbiturates
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
The original sedative-hypnotic agents




Haveles (p. 142)
Problems with their use are well documented
Associated with a high rate of abuse and complete
cardiovascular and respiratory depression with
overdose
Benzodiazepines have almost completely
replaced barbiturates for treating anxiety and
insomnia
Barbiturates are still used as anticonvulsants
and to induce general anesthesia
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27
Chemistry of Barbiturates


Haveles (p. 142)
Formed by substitution of R groups on the
barbiturate nucleus sites A and B


The oxygen atom may be replaced with a sulfur
atom site C
Compounds with S substitution are effective as IV
agents such as thiopental
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28
Pharmacokinetics of Barbiturates





Haveles (p. 142)
Absorption: barbiturates are well absorbed
orally and rectally; used intravenously but not
intramuscularly
Distribution: IV agents are inactivated by
redistribution from site of action in the CNS,
to muscles, and adipose tissue
Metabolism: short- and intermediate-acting
barbiturates are rapidly and almost
completely metabolized by the liver
Excretion: long-acting barbiturates are largely
excreted through the kidneys as a free drug
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29
Mechanism of Action


Barbiturates produce their effect by
enhancing GABA receptor binding and
prolong the opening of chloride channels


Haveles (p. 142)
In higher dose may also act directly on chloride
channels
Mechanism is less specific than
benzodiazepines; may account for ability to
induce surgical anesthesia and pronounced
generalized CNS depression effects
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30
Pharmacologic Effects


Haveles (pp. 142-143)
CNS depression

With normal doses, relaxation occurs
• With larger doses, inhibitory fibers of the CNS are
depressed, resulting in disinhibition and euphoria
• When higher doses are administered, hypnosis can be
produced
• Even higher doses, can result in anesthesia, with
respiratory and cardiovascular depression and finally
arrest
cont’d…
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31
Pharmacologic Effects


Analgesia


Haveles (p. 143)
Barbiturates have no significant analgesic effect
Anticonvulsant effect

Barbiturates have anticonvulsant action
• Long-acting agents are used to treat epilepsy
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32
Adverse Reactions


Haveles (p. 143)
Sedative or hypnotic doses

In usual doses, barbiturates are relatively safe
• CNS depression may be exaggerated in elderly and
debilitated patients or those with liver or kidney impairment

Anesthetic doses


With higher doses, concentrations in the blood can
be lethal
Acute poisoning

Although a lethal dose can only be approximated,
severe poisoning will follow ingestion of 10 times the
hypnotic dose; life may be threatened when more
than 15 times the hypnotic dose is consumed
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33
Chronic Long-Term Use


Chronic use of barbiturates can lead to
physical and psychologic dependence


Haveles (p. 143)
The addict becomes progressively depressed and
is unable to function
Tolerance develops to most effects but not to
the lethal dose

A larger and larger dose must be used to produce
an effect, and this dose can approximate the lethal
dose
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34
Contraindications


Barbiturates are absolutely contraindicated in
patients with intermittent porphyria or a
positive family history of porphyria


Haveles (p. 143)
Porphyria: a group of disorders involving heme
biosynthesis
Barbiturates can stimulate and increase the
synthesis of porphyrins which are already at
an excessive level in this disease
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35
Drug Interactions


Haveles (pp. 143-144) (Box 11-3)
Barbiturates are stimulators of liver
microsomal enzyme production


These enzymes are responsible for the metabolism
of many drugs
An increase in these enzymes could increase the
rate of drug destruction and decrease the duration
of action
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36
Uses of Barbiturates


Haveles (pp. 143-144) (Table 11-2)
Therapeutic uses are determined by duration
of action



Ultrashort-acting barbiturates are used
intravenously for induction of general anesthesia
Short- and intermediate-acting barbiturates: little
medical use; replaced by benzodiazepines
Long-acting barbiturates: used for treatment of
epilepsy
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37
Nonbenzodiazepine-Nonbarbiturate
Sedative-Hypnotics



Haveles (p. 144)
chloral hydrate (Noctec)
buspirone (BuSpar)
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38
chloral hydrate
(Noctec)


An inexpensive, orally effective sedativehypnotic drug with a rapid onset and short
duration of action



Haveles (p. 144)
Therapeutic doses do not produce pronounced
respiratory or cardiovascular depression
Gastric irritation can be minimized by taking
with milk or food
Used in dentistry for preoperative sedation of
children

The dose is 50 mg/kg, up to a maximum of 1 g
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39
buspirone
(BuSpar)


Unique in structure and action


Haveles (p. 144)
Mechanism of action is unknown; believed to be
related to interactions with neurotransmitters in the
CNS
Anxioselective because of its selective
anxiolytic action without hypnotic,
anticonvulsant, or muscle-relaxant properties

Most patients prefer the benzodiazepines
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40
Nonbenzodiazepine-Benzodiazepine
Receptor Agonists


Haveles (p. 144)
Zolpidem, zaleplon, and eszopiclone
comprise a new class of drugs that are not
benzodiazepines but appear to bind to
benzodiazepine receptors and decrease
sleep latency with little effect on sleep stages


All are thought to have agonist effects on GABA
These drugs are used to treat insomnia only
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41
zolpidem
(Ambien)


Recently developed hypnotic indicated for
short-term management of insomnia


Haveles (pp. 144-145)
Has hypnotic and anxiolytic effects, but receptor
specificity produces less muscle-relaxant and
anticonvulsant effects
Likely to be useful in dentistry when an oral
anxiolytic agent is desired for relaxing an
anxious dental patient
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42
zaleplon
(Sonata)


Haveles (p. 145)
A rapid-acting hypnotic that is less potent and
has a shorter duration of action than zolpidem

Appears to have a lower risk of next-day residual
effects, even with use in the middle of the night
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43
eszopiclone
(Lunesta)


Haveles (p. 145)
The newest agent of this class available in
the United States



Anterograde amnesia has been reported
Some patients report an unpleasant taste
Eszopiclone could impair driving the morning after
nighttime administration
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44
Melatonin Receptor Agonist


Haveles (p. 145)
ramelteon (Rozeram) has been approved for
treatment of insomnia characterized by
difficulty falling asleep


An indenofuran derivative highly selective for
melatonin type 1 (MT1) and melatonin type 2 (MT2)
receptors
Animal studies indicate that the MT1 receptor
regulates sleep, and the MT2 receptor may
mediate the phase-shifting effects of melatonin on
a 24-hour biologic clock
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45
Centrally Acting Muscle
Relaxants


Haveles (p. 145)
Exert their effects on the CNS to produce
skeletal muscle relaxation
cont’d…
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46
Centrally Acting Muscle
Relaxants


Haveles (p. 145)
Pharmacologic effects

All CNS muscle relaxants produce some degree of
sedative effect because their action is on the CNS
• The sedative effects dominate over the “selective”
muscle-relaxant activity
• Useful in treating muscle spasms and back and neck
pain
cont’d…
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47
Centrally Acting Muscle Relaxants


Haveles (pp. 145-146)
Individual centrally acting muscle relaxants

Overview
• Exert their muscle-relaxing properties indirectly by producing
CNS depression


Have no direct effect on striated muscle; do not directly relax
tense skeletal muscles
Use
• An adjunct to rest and physical therapy for relief of muscle
spasm associated with acute painful musculoskeletal
conditions

May be used for symptomatic relief of temporomandibular joint
disorder
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48
Examples of Centrally Acting
Skeletal Muscle Relaxants







Haveles (p. 145) (Table 11-3)
carisoprodol (Soma)
chlorzoxazone (Parafon Forte DSC)
methocarbanol (Robaxin)
orphenadrine (Norflex)
cyclobenzapine (Flexeril)
diazepam (Valium)
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49
Miscellaneous Agents


Haveles (p. 146)
baclofen (Lioresal)

Inhibits both monosynaptic and polysynaptic reflexes at
the spinal level
• Indicated for spasticity from multiple sclerosis or spinal cord
injuries or diseases

tizanidine (Zanaflex)


A short-acting muscle relaxant
• Centrally acting α-adrenergic receptor agonist
dantrolene (Dantrium)

Affects contractile response of skeletal muscle by acting
on the muscle itself
• Indicated for treatment of spasticity from upper motor neuron
disorders
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50
General Comments About
Antianxiety Agents




Haveles (pp. 146-147)
Analgesic-sedative combinations
Special considerations
Precautions
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51
Analgesic-Sedative
Combinations


Haveles (p. 146) (Box 11-4)
Both sedation and analgesia can be obtained
from opioid analgesics alone


Prescribing an opioid to add sedation to analgesia
is undesirable unless the analgesic potency is
required
In cases in which anxiety is an important
component in pain relief, either a nonopioid or an
opioid can be used concomitantly with a sedative
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52
Special Considerations




Haveles (p. 146)
Patients who are to use antianxiety agents
should be driven to and from the dental
appointment
Drugs are not a substitute for patient
management
Drugs should not be substituted for patient
education or for the proper psychologic
approach to patient care
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53
Precautions








Haveles (p. 147)
Patients with impaired elimination may experience
exaggerated effects of these medications
Depression caused by all sedative-hypnotics will add to
depression caused by other CNS depressants
The patient should be accompanied by a responsible
adult who can drive the patient home
Psychic and physical dependence has been observed
with almost all drugs used to allay anxiety
Suicide may be attempted by taking sedative-hypnotic
drugs
These drugs should never be administered to pregnant
women or to those who may be pregnant unless the
potential benefit to the mother outweighs the risk to the
fetus
Sedatives do not provide analgesia
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54