Chapter 11 - Pharm

Chapter 11:
Antianxiety Agents
Copyright 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
DHY 1330 - Therapeutics
Chapter 11 Outline
Antianxiety Agents
Definitions
Benzodiazepines
Barbiturates
Nonbenzodiazepine-nonbarbiturate sedative-hypnotics
Nonbenzodiazepine benzodiazepine receptor agonists
Melatonin receptor agonist
Centrally acting muscle relaxants
Miscellaneous agents
General comments about antianxiety agents
Antianxiety Agents
Objectively assessing the patients 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
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 sedationreduction 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
Benzodiazepines
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
Chemistry
Named according to their structurea 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
Pharmacokinetics
Benzodiazepines are well absorbed when

administered by the oral route
The onset of action is related to their lipid solubility
Benzodiazepines are available as tablets, capsules,

oral solution, rectal gel, and injectable form
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
contd
Pharmacokinetics
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
Mechanism of Action
Haveles (p. 139)
Benzodiazepines enhance or facilitate the

action of the neurotransmitter by exerting
their effects in the CNS mediated by aminobutyric acid (GABA), a major inhibitory
neurotransmitter
The inhibitor effect of GABA is enhanced
Pharmacologic Effects
Behavioral effects
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
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
contd
11
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
Diazepams 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

contd
12
Benzodiazepines
Anterograde amnesia
Respiratory effects
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
contd
13
Benzodiazepines
Visual effects
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
contd
14
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
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
contd
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
17
Drug Interactions
Benzodiazepines will interact in an additive

fashion with other CNS depressants
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
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
contd
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

contd
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
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)
contd
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
23
Benzodiazepines
Haveles (p. 138) (Table 11-1)
alprazolam
chlordiazepoxide (Librium)
clonazepam (Klonopin)
chlorazepate (Tranxene)
diazepam (Valium)
estazolam (ProSom)
flurazepam (Dalmane)
contd
24
Benzodiazepines
halazepam (Paxipam)
lorazepam (Ativan)
midazolam (Versed)
oxazepam (Serax)
quazepam (Doral)
temazepam (Restoril)
triazolam (Halcion)
25
Barbiturates
Chemistry
Pharmacokinetics
Mechanism of action
Adverse reactions
Chronic long-term use
Contraindications
Drug interactions
Uses
contd
26
Barbiturates
Haveles (p. 142)
The original sedative-hypnotic agents

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
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
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
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
30
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
contd
31
Analgesia
Haveles (p. 143)

Barbiturates have no significant analgesic effect
Anticonvulsant effect
Barbiturates have anticonvulsant action

Long-acting agents are used to treat epilepsy
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
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
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
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
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
37
Nonbenzodiazepine-Nonbarbiturate
Sedative-Hypnotics
Haveles (p. 144)
chloral hydrate (Noctec)

buspirone (BuSpar)
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

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
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
41
zolpidem
(Ambien)
Recently developed hypnotic indicated for

short-term management of insomnia
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
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
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
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 MT 1 receptor
regulates sleep, and the MT2 receptor may mediate
the phase-shifting effects of melatonin on a 24-hour
biologic clock
45
Centrally Acting Muscle

Relaxants
Haveles (p. 145)
Exert their effects on the CNS to produce

skeletal muscle relaxation
contd
46
Centrally Acting Muscle

Relaxants
Haveles (p. 145)
All CNS muscle relaxants produce some degree of

sedative effect because their action is on the CNS
The sedative effects dominate over the selective musclerelaxant activity
Useful in treating muscle spasms and back and neck pain
contd
47
Centrally Acting Muscle Relaxants
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
48
Examples of Centrally Acting

Skeletal Muscle Relaxants
carisoprodol (Soma)
chlorzoxazone (Parafon Forte DSC)
methocarbanol (Robaxin)
orphenadrine (Norflex)
cyclobenzapine (Flexeril)
diazepam (Valium)
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 -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
50
General Comments About

Antianxiety Agents
Analgesic-sedative combinations
Special considerations
Precautions
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
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
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
54

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Chapter 11:

DHY 1330 - Therapeutics

Objectively assessing the patients anxiety is

Haveles (pp. 136-137) (Fig. 11-1)

The dental team will most commonly use orally

The dosing of a particular antianxiety agent is

Haveles (p. 137) (Fig. 11-2)

Sedative-hypnotic agents can produce varying

A small dose will produce mild CNS depression

A larger dose of the same drug, the hypnotic dose,

Haveles (pp. 137-142)

Named according to their structurea 1, 4

Haveles (pp. 137-138) (Table 11-1)

chlordiazepoxide (Librium) was synthesized in 1955

When an additional ring was added, triazolam

Next, midazolam and flumazenil were synthesized

Benzodiazepines are well absorbed when

The onset of action is related to their lipid solubility

Benzodiazepines are available as tablets, capsules,

Haveles (pp. 138-139)

For benzodiazepines available in parenteral form the IV

Benzodiazepines cross the blood-brain and

Haveles (pp. 138-139)

Benzodiazepines are metabolized by phase II

Phase I metabolism involves oxidation, reduction,

Phase II involves glucuronidation

Haveles (p. 139)

Benzodiazepines enhance or facilitate the

The inhibitor effect of GABA is enhanced

Clinical effects in humans are anxiety and panic

Haveles (p. 139)

Increase the seizure threshold

Can produce relaxation of skeletal muscles

Haveles (p. 139)

In general, benzodiazepines, used alone,

They all have similar adverse effects but differ in

The most common side effect is depression

Diazepams long half-life and metabolism to an active

flunitrazepam (Rohypnol) is available in Europe

Produced beginning when the drug is taken

Relief of anxiety may result in a fall in blood pressure

Contraindicated in angle-closure (narrow-angle)

Parenteral diazepam may cause thrombophlebitis

Can produce cramps or pain, difficulty in urination,

Pregnancy and lactation considerations

Increased risk of congenital malformations if taken

Abuse and Tolerance

Haveles (p. 140)

Benzodiazepines can be abused; physical

Abuse and Tolerance

Haveles (p. 140)

With recent ingestion, emesis may be induced

Benzodiazepines will interact in an additive

Haveles (pp. 140-141)

Drugs that inhibit oxidative metabolism (phase I

Selective serotonin uptake inhibitors alter

Haveles (p. 141)

Useful in short-term treatment of anxiety,

Used for acute treatment of seizures

Generalized anxiety disorders and panic disorder;

Treatment of epilepsy (seizures)

Diazepam or lorazepam is the drug of choice

Used in treatment of alcohol withdrawal syndrome

Control of muscle spasms