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Transcript of Chapter 11: Antianxiety Agents Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All...
Chapter 11:Chapter 11:
Antianxiety AgentsAntianxiety Agents
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
22Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
DHY 1330 - TherapeuticsDHY 1330 - Therapeutics Chapter 11 OutlineChapter 11 Outline Antianxiety AgentsAntianxiety Agents
DefinitionsDefinitions BenzodiazepinesBenzodiazepines BarbituratesBarbiturates Nonbenzodiazepine-nonbarbiturate sedative-Nonbenzodiazepine-nonbarbiturate sedative-
hypnoticshypnotics Nonbenzodiazepine benzodiazepine receptor Nonbenzodiazepine benzodiazepine receptor
agonistsagonists Melatonin receptor agonistMelatonin receptor agonist Centrally acting muscle relaxantsCentrally acting muscle relaxants Miscellaneous agentsMiscellaneous agents General comments about antianxiety agentsGeneral comments about antianxiety agents
33Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Antianxiety AgentsAntianxiety Agents Haveles (pp. 136-137) (Fig. 11-1)Haveles (pp. 136-137) (Fig. 11-1)
Objectively assessing the patient’s anxiety is Objectively assessing the patient’s anxiety is necessary on both the first and subsequent necessary on both the first and subsequent visitsvisits The dental team will most commonly use orally The dental team will most commonly use orally
administered drugs to provide relaxation for an administered drugs to provide relaxation for an anxious patientanxious patient
Intravenous (IV) administration is used Intravenous (IV) administration is used infrequently; most states require a separate infrequently; most states require a separate certificate to administer IV agents or provide certificate to administer IV agents or provide conscious sedationconscious sedation
The dosing of a particular antianxiety agent is The dosing of a particular antianxiety agent is vastly variable, involving intrapatient and vastly variable, involving intrapatient and interpatient variationinterpatient variation
44Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
DefinitionsDefinitions
Haveles (p. 137) (Fig. 11-2)Haveles (p. 137) (Fig. 11-2) Sedative-hypnotic agents can produce Sedative-hypnotic agents can produce
varying degrees of central nervous system varying degrees of central nervous system (CNS) depression, depending on the dose (CNS) depression, depending on the dose administeredadministered A small dose will produce mild CNS depression A small dose will produce mild CNS depression
described as described as sedationsedation—reduction of activity and —reduction of activity and simple anxietysimple anxiety• This level has some anxiolytic effectsThis level has some anxiolytic effects
A larger dose of the same drug, the A larger dose of the same drug, the hypnotic hypnotic dose, dose, will produce greater CNS depressionwill produce greater CNS depression
In even larger doses, sedative-hypnotics may In even larger doses, sedative-hypnotics may produce anesthesia and finally deathproduce anesthesia and finally death
55Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
BenzodiazepinesBenzodiazepines
Haveles (pp. 137-142)Haveles (pp. 137-142) ChemistryChemistry PharmacokineticsPharmacokinetics Mechanism of actionMechanism of action Pharmacologic effectsPharmacologic effects Adverse reactionsAdverse reactions Abuse and toleranceAbuse and tolerance Drug interactionsDrug interactions Medical usesMedical uses Management of the dental patient taking Management of the dental patient taking
benzodiazepinesbenzodiazepines
66Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
ChemistryChemistry
Haveles (pp. 137-138) (Table 11-1)Haveles (pp. 137-138) (Table 11-1) Named according to their structure—a 1, 4—Named according to their structure—a 1, 4—
benzodiazepine nucleusbenzodiazepine nucleus chlordiazepoxide (Librium) was synthesized in 1955chlordiazepoxide (Librium) was synthesized in 1955 diazepam (Valium) was synthesized in 1959 and diazepam (Valium) was synthesized in 1959 and
marketed in 1963marketed in 1963 When an additional ring was added, triazolam When an additional ring was added, triazolam
was synthesizedwas synthesized Next, midazolam and flumazenil were synthesizedNext, midazolam and flumazenil were synthesized
77Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
PharmacokineticsPharmacokinetics Haveles (pp. 138-139)Haveles (pp. 138-139)
Benzodiazepines are well absorbed when Benzodiazepines are well absorbed when administered by the oral routeadministered by the oral route The onset of action is related to their lipid solubilityThe onset of action is related to their lipid solubility
Benzodiazepines are available as tablets, capsules, Benzodiazepines are available as tablets, capsules, oral solution, rectal gel, and injectable formoral solution, rectal gel, and injectable form For benzodiazepines available in parenteral form the IV For benzodiazepines available in parenteral form the IV
route produces a rapid, predictable response; ideal for route produces a rapid, predictable response; ideal for conscious sedationconscious sedation
Benzodiazepines cross the blood-brain and Benzodiazepines cross the blood-brain and placental barriers to produce an effect on the CNS placental barriers to produce an effect on the CNS and the fetusand the fetus
cont’d…cont’d…
88Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
PharmacokineticsPharmacokinetics
Haveles (pp. 138-139)Haveles (pp. 138-139) Benzodiazepines are metabolized by phase II Benzodiazepines are metabolized by phase II
metabolism alone or by phase I metabolism metabolism alone or by phase I metabolism followed by phase II metabolismfollowed by phase II metabolism Phase I metabolism involves oxidation, reduction, Phase I metabolism involves oxidation, reduction,
hydrolysis, dealkylation, and hydroxylationhydrolysis, dealkylation, and hydroxylation• It is It is hard hard metabolism; it is affected by external factors metabolism; it is affected by external factors
such as other drugs and hepatic diseasesuch as other drugs and hepatic disease
Phase II involves glucuronidationPhase II involves glucuronidation• It is It is easy easy metabolism; unaffected by external factorsmetabolism; unaffected by external factors
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Mechanism of ActionMechanism of Action
Haveles (p. 139)Haveles (p. 139) Benzodiazepines enhance or facilitate the Benzodiazepines enhance or facilitate the
action of the neurotransmitter by exerting action of the neurotransmitter by exerting their effects in the CNS mediated by their effects in the CNS mediated by γγ--aminobutyric acid (GABA), a major inhibitory aminobutyric acid (GABA), a major inhibitory neurotransmitterneurotransmitter The inhibitor effect of GABA is enhancedThe inhibitor effect of GABA is enhanced
1010Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Pharmacologic EffectsPharmacologic Effects
Haveles (p. 139)Haveles (p. 139) Behavioral effectsBehavioral effects
Clinical effects in humans are anxiety and panic Clinical effects in humans are anxiety and panic reduction at low doses and drowsiness and even reduction at low doses and drowsiness and even sleep at higher dosessleep at higher doses
Antiseizure effectsAntiseizure effects Increase the seizure thresholdIncrease the seizure threshold
Muscle relaxationMuscle relaxation Can produce relaxation of skeletal musclesCan produce relaxation of skeletal muscles
1111Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Adverse Reactions of Adverse Reactions of BenzodiazepinesBenzodiazepines
Haveles (p. 139)Haveles (p. 139) In general, benzodiazepines, used alone, In general, benzodiazepines, used alone,
have a wide margin of safetyhave a wide margin of safety They all have similar adverse effects but differ in They all have similar adverse effects but differ in
their frequencytheir frequency
cont’d…cont’d…
1212Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Adverse Reactions of Adverse Reactions of BenzodiazepinesBenzodiazepines
CNS effectsCNS effects The most common side effect is depression The most common side effect is depression
manifested as fatigue, drowsiness, muscle manifested as fatigue, drowsiness, muscle weakness, and ataxiaweakness, and ataxia• The use of parenteral benzodiazepines during a dental The use of parenteral benzodiazepines during a dental
appointment reduces anxiety and alters perception of appointment reduces anxiety and alters perception of timetime
Diazepam’s long half-life and metabolism to an active Diazepam’s long half-life and metabolism to an active metabolite prolongs its duration of actionmetabolite prolongs its duration of action
Midazolam is metabolized primarily to inactive metabolitesMidazolam is metabolized primarily to inactive metabolites
• flunitrazepam (Rohypnol) is available in Europeflunitrazepam (Rohypnol) is available in Europecont’d…cont’d…
1313Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Adverse Reactions of Adverse Reactions of BenzodiazepinesBenzodiazepines
Anterograde amnesiaAnterograde amnesia Produced beginning when the drug is takenProduced beginning when the drug is taken
Respiratory effectsRespiratory effects Doses of diazepam have occasionally been reported Doses of diazepam have occasionally been reported
to produce respiratory depressionto produce respiratory depression Cardiovascular effectsCardiovascular effects
Relief of anxiety may result in a fall in blood pressure Relief of anxiety may result in a fall in blood pressure and pulse rateand pulse rate
cont’d…cont’d…
1414Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Adverse Reactions of Adverse Reactions of BenzodiazepinesBenzodiazepines
Visual effectsVisual effects Contraindicated in angle-closure (narrow-angle) Contraindicated in angle-closure (narrow-angle)
glaucoma and can produce diplopia (single object glaucoma and can produce diplopia (single object viewed as two), nystagmus (rhythmic oscillation of the viewed as two), nystagmus (rhythmic oscillation of the eyeballs), and blurred visioneyeballs), and blurred vision
Dental effectsDental effects Have been reported to produce xerostomia, increased Have been reported to produce xerostomia, increased
salivation, swollen tongue, and a bitter or metallic tastesalivation, swollen tongue, and a bitter or metallic taste ThrombophlebitisThrombophlebitis
Parenteral diazepam may cause thrombophlebitis Parenteral diazepam may cause thrombophlebitis because propylene glycol is used to solubilize itbecause propylene glycol is used to solubilize it
cont’d…cont’d…
1515Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Adverse Reactions of Adverse Reactions of BenzodiazepinesBenzodiazepines
Other effectsOther effects Can produce cramps or pain, difficulty in urination, Can produce cramps or pain, difficulty in urination,
allergic reactionsallergic reactions Pregnancy and lactation considerationsPregnancy and lactation considerations
Increased risk of congenital malformations if taken Increased risk of congenital malformations if taken in the first trimester of pregnancy has been in the first trimester of pregnancy has been reportedreported
1616Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Abuse and ToleranceAbuse and Tolerance
Haveles (p. 140)Haveles (p. 140) OverviewOverview
Benzodiazepines can be abused; physical Benzodiazepines can be abused; physical dependence and tolerance have been documenteddependence and tolerance have been documented• Their abuse and addiction potential is less than that of the Their abuse and addiction potential is less than that of the
other sedative-hypnotic agents such as barbituratesother sedative-hypnotic agents such as barbiturates
• Benzodiazepines have a wider TI than barbituratesBenzodiazepines have a wider TI than barbiturates
• Combining with other CNS depressants can reduce the Combining with other CNS depressants can reduce the safetysafety
cont’d…cont’d…
1717Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Abuse and ToleranceAbuse and Tolerance
Haveles (p. 140)Haveles (p. 140) Treatment of overdoseTreatment of overdose
With recent ingestion, emesis may be inducedWith recent ingestion, emesis may be induced• Activated charcoal and a saline catharticActivated charcoal and a saline cathartic
To reduce some of the effects of a To reduce some of the effects of a benzodiazepine, flumazenil (Romazicon), a benzodiazepine, flumazenil (Romazicon), a benzodiazepine antagonist for IV administration benzodiazepine antagonist for IV administration may be usedmay be used
1818Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Drug InteractionsDrug Interactions
Haveles (pp. 140-141)Haveles (pp. 140-141) Benzodiazepines will interact in an additive Benzodiazepines will interact in an additive
fashion with other CNS depressantsfashion with other CNS depressants Drugs that inhibit oxidative metabolism (phase I Drugs that inhibit oxidative metabolism (phase I
metabolism) may increase the effect of metabolism) may increase the effect of benzodiazepines that undergo phase I metabolismbenzodiazepines that undergo phase I metabolism
Selective serotonin uptake inhibitors alter Selective serotonin uptake inhibitors alter clearance of diazepamclearance of diazepam
May reduce the effectiveness of levodopaMay reduce the effectiveness of levodopa May increase the effect of digoxin, phenytoin, May increase the effect of digoxin, phenytoin,
and probenecidand probenecid
1919Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Medical Uses Medical Uses
Haveles (p. 141)Haveles (p. 141) Useful in short-term treatment of anxiety, Useful in short-term treatment of anxiety,
panic attacks, insomnia, and alcohol panic attacks, insomnia, and alcohol withdrawalwithdrawal Used for acute treatment of seizuresUsed for acute treatment of seizures Used for conscious sedation, general anesthesia, Used for conscious sedation, general anesthesia,
or during surgeryor during surgery
cont’d…cont’d…
2020Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Medical UsesMedical Uses
Anxiety controlAnxiety control Generalized anxiety disorders and panic disorder;Generalized anxiety disorders and panic disorder;
manifestations of anxiety include restlessness, manifestations of anxiety include restlessness, tension, tachycardia, and dyspneatension, tachycardia, and dyspnea
Insomnia managementInsomnia management If a manifestation of anxietyIf a manifestation of anxiety
Treatment of epilepsy (seizures)Treatment of epilepsy (seizures) Diazepam or lorazepam is the drug of choice Diazepam or lorazepam is the drug of choice
cont’d…cont’d…
2121Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Medical UsesMedical Uses
Treatment of alcoholismTreatment of alcoholism Used in treatment of alcohol withdrawal syndromeUsed in treatment of alcohol withdrawal syndrome
Control of muscle spasmsControl of muscle spasms Used to control muscle spasticity that Used to control muscle spasticity that
accompanies diseases such as multiple sclerosis accompanies diseases such as multiple sclerosis and cerebral palsyand cerebral palsy
2222Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Management of the Dental Management of the Dental Patient Taking BenzodiazepinesPatient Taking Benzodiazepines
Haveles (pp. 141-142) (Box 11-2)Haveles (pp. 141-142) (Box 11-2) Dental proceduresDental procedures
Orally administered diazepam to allay apprehensionOrally administered diazepam to allay apprehension PremedicationPremedication
Used before surgical procedures to allay anxietyUsed before surgical procedures to allay anxiety Conscious sedationConscious sedation
Usually accompanied by IV administrationUsually accompanied by IV administration• Muscle relaxation and anterograde amnesia (events after Muscle relaxation and anterograde amnesia (events after
the injection)the injection)
cont’d…cont’d…
2323Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Management of the Dental Management of the Dental Patient Taking BenzodiazepinesPatient Taking Benzodiazepines
Conscious sedationConscious sedation Parenteral benzodiazepines have been associated Parenteral benzodiazepines have been associated
with respiratory depression and arrest when used with respiratory depression and arrest when used for conscious sedationfor conscious sedation• Require continuous monitoring of respiratory and cardiac Require continuous monitoring of respiratory and cardiac
functionfunction
• Dentists without additional training cannot use conscious Dentists without additional training cannot use conscious sedationsedation
2424Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Benzodiazepines Benzodiazepines
Haveles (p. 138) (Table 11-1)Haveles (p. 138) (Table 11-1) alprazolam alprazolam chlordiazepoxide (Librium) chlordiazepoxide (Librium) clonazepam (Klonopin)clonazepam (Klonopin) chlorazepate (Tranxene)chlorazepate (Tranxene) diazepam (Valium) diazepam (Valium) estazolam (ProSom)estazolam (ProSom) flurazepam (Dalmane)flurazepam (Dalmane)
cont’d…cont’d…
2525Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Benzodiazepines Benzodiazepines
Haveles (p. 138) (Table 11-1)Haveles (p. 138) (Table 11-1) halazepam (Paxipam)halazepam (Paxipam) lorazepam (Ativan)lorazepam (Ativan) midazolam (Versed) midazolam (Versed) oxazepam (Serax) oxazepam (Serax) quazepam (Doral)quazepam (Doral) temazepam (Restoril)temazepam (Restoril) triazolam (Halcion)triazolam (Halcion)
2626Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Barbiturates Barbiturates
Haveles (pp. 142-144)Haveles (pp. 142-144) ChemistryChemistry PharmacokineticsPharmacokinetics Mechanism of actionMechanism of action Pharmacologic effectsPharmacologic effects Adverse reactionsAdverse reactions Chronic long-term useChronic long-term use ContraindicationsContraindications Drug interactionsDrug interactions UsesUses
cont’d…cont’d…
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BarbituratesBarbiturates Haveles (p. 142)Haveles (p. 142)
The original sedative-hypnotic agentsThe original sedative-hypnotic agents Problems with their use are well documentedProblems with their use are well documented Associated with a high rate of abuse and complete Associated with a high rate of abuse and complete
cardiovascular and respiratory depression with overdosecardiovascular and respiratory depression with overdose Benzodiazepines have almost completely replaced Benzodiazepines have almost completely replaced
barbiturates for treating anxiety and insomniabarbiturates for treating anxiety and insomnia Barbiturates are still used as anticonvulsants and Barbiturates are still used as anticonvulsants and
to induce general anesthesiato induce general anesthesia
2828Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Chemistry of BarbituratesChemistry of Barbiturates
Haveles (p. 142)Haveles (p. 142) Formed by substitution of R groups on the Formed by substitution of R groups on the
barbiturate nucleus sites A and Bbarbiturate nucleus sites A and B The oxygen atom may be replaced with a sulfur The oxygen atom may be replaced with a sulfur
atom site Catom site C Compounds with S substitution are effective as IV Compounds with S substitution are effective as IV
agents such as thiopentalagents such as thiopental
2929Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Pharmacokinetics of BarbituratesPharmacokinetics of Barbiturates
Haveles (p. 142)Haveles (p. 142) Absorption: barbiturates are well absorbed Absorption: barbiturates are well absorbed
orally and rectally; used intravenously but not orally and rectally; used intravenously but not intramuscularlyintramuscularly
Distribution: IV agents are inactivated by Distribution: IV agents are inactivated by redistribution from site of action in the CNS, redistribution from site of action in the CNS, to muscles, and adipose tissueto muscles, and adipose tissue
Metabolism: short- and intermediate-acting Metabolism: short- and intermediate-acting barbiturates are rapidly and almost barbiturates are rapidly and almost completely metabolized by the livercompletely metabolized by the liver
Excretion: long-acting barbiturates are largely Excretion: long-acting barbiturates are largely excreted through the kidneys as a free drugexcreted through the kidneys as a free drug
3030Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Mechanism of Action Mechanism of Action
Haveles (p. 142)Haveles (p. 142) Barbiturates produce their effect by Barbiturates produce their effect by
enhancing GABA receptor binding and enhancing GABA receptor binding and prolong the opening of chloride channelsprolong the opening of chloride channels In higher dose may also act directly on chloride In higher dose may also act directly on chloride
channelschannels Mechanism is less specific than Mechanism is less specific than
benzodiazepines; may account for ability to benzodiazepines; may account for ability to induce surgical anesthesia and pronounced induce surgical anesthesia and pronounced generalized CNS depression effectsgeneralized CNS depression effects
3131Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Pharmacologic EffectsPharmacologic Effects
Haveles (pp. 142-143)Haveles (pp. 142-143) CNS depressionCNS depression
With normal doses, relaxation occursWith normal doses, relaxation occurs• With larger doses, inhibitory fibers of the CNS are With larger doses, inhibitory fibers of the CNS are
depressed, resulting in disinhibition and euphoriadepressed, resulting in disinhibition and euphoria
• When higher doses are administered, hypnosis can be When higher doses are administered, hypnosis can be producedproduced
• Even higher doses, can result in anesthesia, with Even higher doses, can result in anesthesia, with respiratory and cardiovascular depression and finally arrestrespiratory and cardiovascular depression and finally arrest
cont’d…cont’d…
3232Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Pharmacologic EffectsPharmacologic Effects
Haveles (p. 143)Haveles (p. 143) AnalgesiaAnalgesia
Barbiturates have no significant analgesic effectBarbiturates have no significant analgesic effect Anticonvulsant effectAnticonvulsant effect
Barbiturates have anticonvulsant actionBarbiturates have anticonvulsant action• Long-acting agents are used to treat epilepsyLong-acting agents are used to treat epilepsy
3333Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Adverse ReactionsAdverse Reactions Haveles (p. 143)Haveles (p. 143)
Sedative or hypnotic dosesSedative or hypnotic doses In usual doses, barbiturates are relatively safeIn usual doses, barbiturates are relatively safe
• CNS depression may be exaggerated in elderly and CNS depression may be exaggerated in elderly and debilitated patients or those with liver or kidney impairmentdebilitated patients or those with liver or kidney impairment
Anesthetic dosesAnesthetic doses With higher doses, concentrations in the blood can With higher doses, concentrations in the blood can
be lethalbe lethal Acute poisoningAcute poisoning
Although a lethal dose can only be approximated, Although a lethal dose can only be approximated, severe poisoning will follow ingestion of 10 times the severe poisoning will follow ingestion of 10 times the hypnotic dose; life may be threatened when more hypnotic dose; life may be threatened when more than 15 times the hypnotic dose is consumedthan 15 times the hypnotic dose is consumed
3434Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Chronic Long-Term UseChronic Long-Term Use
Haveles (p. 143)Haveles (p. 143) Chronic use of barbiturates can lead to Chronic use of barbiturates can lead to
physical and psychologic dependencephysical and psychologic dependence The addict becomes progressively depressed and The addict becomes progressively depressed and
is unable to functionis unable to function Tolerance develops to most effects but not to Tolerance develops to most effects but not to
the lethal dosethe lethal dose A larger and larger dose must be used to produce A larger and larger dose must be used to produce
an effect, and this dose can approximate the lethal an effect, and this dose can approximate the lethal dosedose
3535Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
ContraindicationsContraindications
Haveles (p. 143)Haveles (p. 143) Barbiturates are absolutely contraindicated in Barbiturates are absolutely contraindicated in
patients with intermittent porphyria or a patients with intermittent porphyria or a positive family history of porphyriapositive family history of porphyria Porphyria: a group of disorders involving heme Porphyria: a group of disorders involving heme
biosynthesisbiosynthesis Barbiturates can stimulate and increase the Barbiturates can stimulate and increase the
synthesis of porphyrins which are already at synthesis of porphyrins which are already at an excessive level in this diseasean excessive level in this disease
3636Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Drug InteractionsDrug Interactions
Haveles (pp. 143-144) (Box 11-3)Haveles (pp. 143-144) (Box 11-3) Barbiturates are stimulators of liver Barbiturates are stimulators of liver
microsomal enzyme productionmicrosomal enzyme production These enzymes are responsible for the metabolism These enzymes are responsible for the metabolism
of many drugsof many drugs An increase in these enzymes could increase the An increase in these enzymes could increase the
rate of drug destruction and decrease the duration rate of drug destruction and decrease the duration of actionof action
3737Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Uses of BarbituratesUses of Barbiturates
Haveles (pp. 143-144) (Table 11-2)Haveles (pp. 143-144) (Table 11-2) Therapeutic uses are determined by duration Therapeutic uses are determined by duration
of actionof action Ultrashort-acting barbiturates are used Ultrashort-acting barbiturates are used
intravenously for induction of general anesthesiaintravenously for induction of general anesthesia Short- and intermediate-acting barbiturates: little Short- and intermediate-acting barbiturates: little
medical use; replaced by benzodiazepinesmedical use; replaced by benzodiazepines Long-acting barbiturates: used for treatment of Long-acting barbiturates: used for treatment of
epilepsyepilepsy
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Nonbenzodiazepine-Nonbarbiturate Nonbenzodiazepine-Nonbarbiturate Sedative-HypnoticsSedative-Hypnotics
Haveles (p. 144)Haveles (p. 144) chloral hydrate (Noctec)chloral hydrate (Noctec) buspirone (BuSpar)buspirone (BuSpar)
3939Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
chloral hydratechloral hydrate(Noctec)(Noctec)
Haveles (p. 144)Haveles (p. 144) An inexpensive, orally effective sedative-An inexpensive, orally effective sedative-
hypnotic drug with a rapid onset and short hypnotic drug with a rapid onset and short duration of actionduration of action Therapeutic doses do not produce pronounced Therapeutic doses do not produce pronounced
respiratory or cardiovascular depressionrespiratory or cardiovascular depression Gastric irritation can be minimized by taking Gastric irritation can be minimized by taking
with milk or foodwith milk or food Used in dentistry for preoperative sedation of Used in dentistry for preoperative sedation of
childrenchildren The dose is 50 mg/kg, up to a maximum of 1 gThe dose is 50 mg/kg, up to a maximum of 1 g
4040Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
buspironebuspirone(BuSpar)(BuSpar)
Haveles (p. 144)Haveles (p. 144) Unique in structure and actionUnique in structure and action
Mechanism of action is unknown; believed to be Mechanism of action is unknown; believed to be related to interactions with neurotransmitters in the related to interactions with neurotransmitters in the CNSCNS
Anxioselective Anxioselective because of its selective because of its selective anxiolytic action without hypnotic, anxiolytic action without hypnotic, anticonvulsant, or muscle-relaxant propertiesanticonvulsant, or muscle-relaxant properties Most patients prefer the benzodiazepinesMost patients prefer the benzodiazepines
4141Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Nonbenzodiazepine-Benzodiazepine Nonbenzodiazepine-Benzodiazepine Receptor AgonistsReceptor Agonists
Haveles (p. 144)Haveles (p. 144) Zolpidem, zaleplon, and eszopiclone Zolpidem, zaleplon, and eszopiclone
comprise a new class of drugs that are not comprise a new class of drugs that are not benzodiazepines but appear to bind to benzodiazepines but appear to bind to benzodiazepine receptors and decrease benzodiazepine receptors and decrease sleep latency with little effect on sleep stages sleep latency with little effect on sleep stages All are thought to have agonist effects on GABAAll are thought to have agonist effects on GABA These drugs are used to treat insomnia onlyThese drugs are used to treat insomnia only
4242Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
zolpidemzolpidem(Ambien)(Ambien)
Haveles (pp. 144-145)Haveles (pp. 144-145) Recently developed hypnotic indicated for Recently developed hypnotic indicated for
short-term management of insomniashort-term management of insomnia Has hypnotic and anxiolytic effects, but receptor Has hypnotic and anxiolytic effects, but receptor
specificity produces less muscle-relaxant and specificity produces less muscle-relaxant and anticonvulsant effectsanticonvulsant effects
Likely to be useful in dentistry when an oral Likely to be useful in dentistry when an oral anxiolytic agent is desired for relaxing an anxiolytic agent is desired for relaxing an anxious dental patientanxious dental patient
4343Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
zaleplonzaleplon(Sonata)(Sonata)
Haveles (p. 145)Haveles (p. 145) A rapid-acting hypnotic that is less potent and A rapid-acting hypnotic that is less potent and
has a shorter duration of action than zolpidemhas a shorter duration of action than zolpidem Appears to have a lower risk of next-day residual Appears to have a lower risk of next-day residual
effects, even with use in the middle of the nighteffects, even with use in the middle of the night
4444Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
eszopicloneeszopiclone(Lunesta)(Lunesta)
Haveles (p. 145)Haveles (p. 145) The newest agent of this class available in The newest agent of this class available in
the United Statesthe United States Anterograde amnesia has been reportedAnterograde amnesia has been reported Some patients report an unpleasant tasteSome patients report an unpleasant taste Eszopiclone could impair driving the morning after Eszopiclone could impair driving the morning after
nighttime administrationnighttime administration
4545Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Melatonin Receptor AgonistMelatonin Receptor Agonist
Haveles (p. 145)Haveles (p. 145) ramelteon (Rozeram) has been approved for ramelteon (Rozeram) has been approved for
treatment of insomnia characterized by treatment of insomnia characterized by difficulty falling asleepdifficulty falling asleep An indenofuran derivative highly selective for An indenofuran derivative highly selective for
melatonin type 1 (MTmelatonin type 1 (MT11) and melatonin type 2 (MT) and melatonin type 2 (MT22) )
receptorsreceptors Animal studies indicate that the MTAnimal studies indicate that the MT1 1 receptor receptor
regulates sleep, and the MTregulates sleep, and the MT22 receptor may mediate receptor may mediate
the phase-shifting effects of melatonin on a 24-hour the phase-shifting effects of melatonin on a 24-hour biologic clockbiologic clock
4646Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Centrally Acting Muscle Centrally Acting Muscle RelaxantsRelaxants
Haveles (p. 145)Haveles (p. 145) Exert their effects on the CNS to produce Exert their effects on the CNS to produce
skeletal muscle relaxationskeletal muscle relaxation
cont’d…cont’d…
4747Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Centrally Acting Muscle Centrally Acting Muscle RelaxantsRelaxants
Haveles (p. 145)Haveles (p. 145) Pharmacologic effectsPharmacologic effects
All CNS muscle relaxants produce some degree of All CNS muscle relaxants produce some degree of sedative effect because their action is on the CNSsedative effect because their action is on the CNS• The sedative effects dominate over the “selective” The sedative effects dominate over the “selective”
muscle-relaxant activitymuscle-relaxant activity
• Useful in treating muscle spasms and back and neck Useful in treating muscle spasms and back and neck painpain
cont’d…cont’d…
4848Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Centrally Acting Muscle RelaxantsCentrally Acting Muscle Relaxants
Haveles (pp. 145-146)Haveles (pp. 145-146) Individual centrally acting muscle relaxantsIndividual centrally acting muscle relaxants
OverviewOverview• Exert their muscle-relaxing properties indirectly by producing Exert their muscle-relaxing properties indirectly by producing
CNS depressionCNS depression Have no direct effect on striated muscle; do not directly relax Have no direct effect on striated muscle; do not directly relax
tense skeletal musclestense skeletal muscles
UseUse• An adjunct to rest and physical therapy for relief of muscle An adjunct to rest and physical therapy for relief of muscle
spasm associated with acute painful musculoskeletal spasm associated with acute painful musculoskeletal conditionsconditions
May be used for symptomatic relief of temporomandibular joint May be used for symptomatic relief of temporomandibular joint disorderdisorder
4949Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Examples of Centrally Acting Examples of Centrally Acting Skeletal Muscle RelaxantsSkeletal Muscle Relaxants
Haveles (p. 145) (Table 11-3)Haveles (p. 145) (Table 11-3) carisoprodol (Soma)carisoprodol (Soma) chlorzoxazone (Parafon Forte DSC)chlorzoxazone (Parafon Forte DSC) methocarbanol (Robaxin)methocarbanol (Robaxin) orphenadrine (Norflex)orphenadrine (Norflex) cyclobenzapine (Flexeril)cyclobenzapine (Flexeril) diazepam (Valium)diazepam (Valium)
5050Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Miscellaneous AgentsMiscellaneous Agents Haveles (p. 146)Haveles (p. 146)
baclofen (Lioresal)baclofen (Lioresal) Inhibits both monosynaptic and polysynaptic reflexes at the Inhibits both monosynaptic and polysynaptic reflexes at the
spinal levelspinal level• Indicated for spasticity from multiple sclerosis or spinal cord injuries or Indicated for spasticity from multiple sclerosis or spinal cord injuries or
diseases diseases
tizanidine (Zanaflex)tizanidine (Zanaflex) A short-acting muscle relaxantA short-acting muscle relaxant
• Centrally acting Centrally acting αα-adrenergic receptor agonist-adrenergic receptor agonist
dantrolene (Dantrium)dantrolene (Dantrium) Affects contractile response of skeletal muscle by acting on Affects contractile response of skeletal muscle by acting on
the muscle itselfthe muscle itself• Indicated for treatment of spasticity from upper motor neuron disordersIndicated for treatment of spasticity from upper motor neuron disorders
5151Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
General Comments About General Comments About Antianxiety AgentsAntianxiety Agents
Haveles (pp. 146-147)Haveles (pp. 146-147) Analgesic-sedative combinationsAnalgesic-sedative combinations Special considerationsSpecial considerations PrecautionsPrecautions
5252Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Analgesic-Sedative CombinationsAnalgesic-Sedative Combinations
Haveles (p. 146) (Box 11-4)Haveles (p. 146) (Box 11-4) Both sedation and analgesia can be obtained Both sedation and analgesia can be obtained
from opioid analgesics alonefrom opioid analgesics alone Prescribing an opioid to add sedation to analgesia Prescribing an opioid to add sedation to analgesia
is undesirable unless the analgesic potency is is undesirable unless the analgesic potency is requiredrequired
In cases in which anxiety is an important In cases in which anxiety is an important component in pain relief, either a nonopioid or an component in pain relief, either a nonopioid or an opioid can be used concomitantly with a sedativeopioid can be used concomitantly with a sedative
5353Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Special ConsiderationsSpecial Considerations
Haveles (p. 146)Haveles (p. 146) Patients who are to use antianxiety agents Patients who are to use antianxiety agents
should be driven to and from the dental should be driven to and from the dental appointmentappointment
Drugs are not a substitute for patient Drugs are not a substitute for patient management management
Drugs should not be substituted for patient Drugs should not be substituted for patient education or for the proper psychologic education or for the proper psychologic approach to patient careapproach to patient care
5454Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
PrecautionsPrecautions Haveles (p. 147)Haveles (p. 147)
Patients with impaired elimination may experience Patients with impaired elimination may experience exaggerated effects of these medications exaggerated effects of these medications
Depression caused by all sedative-hypnotics will add to Depression caused by all sedative-hypnotics will add to depression caused by other CNS depressantsdepression caused by other CNS depressants
The patient should be accompanied by a responsible The patient should be accompanied by a responsible adult who can drive the patient homeadult who can drive the patient home
Psychic and physical dependence has been observed Psychic and physical dependence has been observed with almost all drugs used to allay anxietywith almost all drugs used to allay anxiety
Suicide may be attempted by taking sedative-hypnotic Suicide may be attempted by taking sedative-hypnotic drugsdrugs
These drugs should never be administered to pregnant These drugs should never be administered to pregnant women or to those who may be pregnant unless the women or to those who may be pregnant unless the potential benefit to the mother outweighs the risk to the potential benefit to the mother outweighs the risk to the fetusfetus
Sedatives do Sedatives do not not provide analgesiaprovide analgesia