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Chapter 11: Chapter 11: Antianxiety Agents Antianxiety Agents Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

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Chapter 11 outline*
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Chapter 11:
Antianxiety Agents
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Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
DHY 1330 - Therapeutics
Chapter 11 Outline
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Antianxiety Agents
Haveles (pp. 136-137) (Fig. 11-1)
Objectively assessing the patient’s anxiety is necessary on both the first and subsequent visits
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
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Definitions
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
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Benzodiazepines
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Chemistry
Named according to their structure—a 1, 4—benzodiazepine nucleus
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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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
cont’d…
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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
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Mechanism of Action
Haveles (p. 139)
Benzodiazepines enhance or facilitate the action of the neurotransmitter by exerting their effects in the CNS mediated by γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter
The inhibitor effect of GABA is enhanced
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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
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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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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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Adverse Reactions of Benzodiazepines
Respiratory effects
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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Adverse Reactions of Benzodiazepines
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
Dental effects
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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Adverse Reactions of Benzodiazepines
Can produce cramps or pain, difficulty in urination, allergic reactions
Pregnancy and lactation considerations
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Abuse and Tolerance
Haveles (p. 140)
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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Abuse and Tolerance
Haveles (p. 140)
Treatment of overdose
Activated charcoal and a saline cathartic
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Drug Interactions
Haveles (pp. 140-141)
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
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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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Medical Uses
Anxiety control
Insomnia management
Treatment of epilepsy (seizures)
cont’d…
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Medical Uses
Control of muscle spasms
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Management of the Dental Patient Taking Benzodiazepines
Haveles (pp. 141-142) (Box 11-2)
Dental procedures
Premedication
Conscious sedation
Muscle relaxation and anterograde amnesia (events after the injection)
cont’d…
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Management of the Dental Patient Taking Benzodiazepines
Conscious sedation
Require continuous monitoring of respiratory and cardiac function
Dentists without additional training cannot use conscious sedation
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Benzodiazepines
alprazolam
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Benzodiazepines
halazepam (Paxipam)
lorazepam (Ativan)
midazolam (Versed)
oxazepam (Serax)
quazepam (Doral)
temazepam (Restoril)
triazolam (Halcion)
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Barbiturates
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Barbiturates
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
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Chemistry of Barbiturates
Haveles (p. 142)
Formed by substitution of R groups on the barbiturate nucleus sites A and B
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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
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Mechanism of Action
Haveles (p. 142)
Barbiturates produce their effect by enhancing GABA receptor binding and prolong the opening of chloride channels
In higher dose may also act directly on chloride channels
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Pharmacologic Effects
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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Pharmacologic Effects
Anticonvulsant effect
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Adverse Reactions
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
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Chronic Long-Term Use
Haveles (p. 143)
Chronic use of barbiturates can lead to physical and psychologic dependence
The addict becomes progressively depressed and is unable to function
Tolerance develops to most effects but not to the lethal dose
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Contraindications
Barbiturates are absolutely contraindicated in patients with intermittent porphyria or a positive family history of porphyria
Porphyria: a group of disorders involving heme biosynthesis
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Drug Interactions
Barbiturates are stimulators of liver microsomal enzyme production
These enzymes are responsible for the metabolism of many drugs
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Uses of Barbiturates
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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Nonbenzodiazepine-Nonbarbiturate Sedative-Hypnotics
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chloral hydrate
Haveles (p. 144)
An inexpensive, orally effective sedative-hypnotic drug with a rapid onset and short duration of action
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
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buspirone
(BuSpar)
Unique in structure and action
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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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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zolpidem
(Ambien)
Has hypnotic and anxiolytic effects, but receptor specificity produces less muscle-relaxant and anticonvulsant effects
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zaleplon
(Sonata)
Haveles (p. 145)
A rapid-acting hypnotic that is less potent and has a shorter duration of action than zolpidem
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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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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
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Centrally Acting Muscle Relaxants
Haveles (p. 145)
Exert their effects on the CNS to produce skeletal muscle relaxation
cont’d…
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Centrally Acting Muscle Relaxants
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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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
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Examples of Centrally Acting Skeletal Muscle Relaxants
Haveles (p. 145) (Table 11-3)
carisoprodol (Soma)
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Miscellaneous Agents
Inhibits both monosynaptic and polysynaptic reflexes at the spinal level
Indicated for spasticity from multiple sclerosis or spinal cord injuries or diseases
tizanidine (Zanaflex)
dantrolene (Dantrium)
Affects contractile response of skeletal muscle by acting on the muscle itself
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General Comments About Antianxiety Agents
Haveles (pp. 146-147)
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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
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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
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Precautions
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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