1 Chapter 22: Sedative-hypnotic Drugs. 2 Introduction A sedative drug (anxiolytic) reduce anxiety and exert a calming effectA sedative drug (anxiolytic)

1

ChapterChapter 22: 22:Sedative-hypnotic DrugsSedative-hypnotic Drugs

2

IntroductionIntroduction • A sedative drug (anxiolytic) A sedative drug (anxiolytic) reduce anxiety reduce anxiety

and exert a calming effectand exert a calming effect

• A hypnotic drug produces drowsiness and A hypnotic drug produces drowsiness and facilitates the onset and maintenance of a facilitates the onset and maintenance of a state of sleep that resembles natural sleepstate of sleep that resembles natural sleep

• Most anxiolytic and sedative–hypnotic drugs Most anxiolytic and sedative–hypnotic drugs produce dose-dependent depression of CNS produce dose-dependent depression of CNS functionfunction

3

CNS depression: dose-response curveCNS depression: dose-response curve

DRUG A

DRUG B

Increasing dose

CN

S e

ffec

ts

Sedation

Hypnosis

Anesthesia

Coma

4

Sedative-hypnotics

Benzodiazepines Barbiturates Miscellaneous agents

Short

action

Intermediate Buspirone

action Ramelteon

Long Zaleplon

action Zolpidem

5

Other drugs with sedative-hypnotic Other drugs with sedative-hypnotic effectseffects

1)1) β-blockers β-blockers (e.g. Propranolol)(e.g. Propranolol)

2)2) AntipsychoticsAntipsychotics

3)3) Antidepressants (e.g. SSRIs, TCAs, Antidepressants (e.g. SSRIs, TCAs, venlafaxine, duloxetine & MAOIs)venlafaxine, duloxetine & MAOIs)

4)4) Antihistamines (e.g. Antihistamines (e.g. Hydroxyzine, Hydroxyzine, diphenhydramine, & doxylamine)diphenhydramine, & doxylamine)

6

BenzodiazepinesBenzodiazepines

• Benzodiazepines are the most widely used Benzodiazepines are the most widely used anxiolytic drugsanxiolytic drugs

• They have largely replaced barbiturates and They have largely replaced barbiturates and meprobamate in the treatment of anxiety, b/c meprobamate in the treatment of anxiety, b/c they are safer and more effective they are safer and more effective

• The most prominent of these effects are The most prominent of these effects are sedation, hypnosis, decreased anxiety, sedation, hypnosis, decreased anxiety, muscle relaxation, anterograde amnesia, and muscle relaxation, anterograde amnesia, and anticonvulsant activityanticonvulsant activity

7

Benzodiazepines- Mechanism of actionBenzodiazepines- Mechanism of action

• The targets for The targets for bzdsbzds actions are the actions are the γ-γ-aminobutyric acid (GABAaminobutyric acid (GABAAA) receptors) receptors

• BzdsBzds enhance the response to GABA by enhance the response to GABA by facilitating the opening of GABA-activated facilitating the opening of GABA-activated chloride channelschloride channels

• They bind specifically to a regulatory site of They bind specifically to a regulatory site of the receptor, distinct from the GABA-binding the receptor, distinct from the GABA-binding site, and act allosterically to increase the site, and act allosterically to increase the affinity of GABA for the receptoraffinity of GABA for the receptor

8

GABA receptorsGABA receptors

• GABA receptors are membrane-bound proteins GABA receptors are membrane-bound proteins that can be divided into two major subtypes: that can be divided into two major subtypes: GABAGABAAA and GABA and GABABB receptors receptors

• The ionotropic GABAThe ionotropic GABAAA receptors are composed of receptors are composed of

five subunits that assembled from five subunits five subunits that assembled from five subunits selected from multiple polypeptide classes (selected from multiple polypeptide classes (αα, , ββ, , γγ, , δδ, , εε, , ρρ etc) to form an integral chloride channel etc) to form an integral chloride channel

• The GABAThe GABAAA-receptor (or recognition site), when -receptor (or recognition site), when

coupled with GABA, induces a shift in membrane coupled with GABA, induces a shift in membrane permeability, primarily to chloride ions, causing permeability, primarily to chloride ions, causing hyperpolarization of the neuronhyperpolarization of the neuron

10

GABA receptorsGABA receptors

• GABA receptor appears to be part of a GABA receptor appears to be part of a macromolecule that contains, in addition to the macromolecule that contains, in addition to the GABAGABAAA-receptor, bzds and barbiturate binding -receptor, bzds and barbiturate binding

sites and the chloride ionophore (chloride sites and the chloride ionophore (chloride channel)channel)

• The The bzdbzds, barbiturates, alcohols, and general s, barbiturates, alcohols, and general anesthetics appear to facilitate GABA anesthetics appear to facilitate GABA transmissiontransmission

• Vigabatrin, an anticonvulsant, elevates brain Vigabatrin, an anticonvulsant, elevates brain GABA by inhibiting the breakdown enzyme GABA by inhibiting the breakdown enzyme GABA-TGABA-T

11

Benzodiazepines- Mechanism of actionBenzodiazepines- Mechanism of action

• BBzdszds increase the efficiency of GABAergic increase the efficiency of GABAergic synaptic inhibitionsynaptic inhibition

• The enhancement in chloride ion conductance The enhancement in chloride ion conductance induced by the interaction of benzodiazepines induced by the interaction of benzodiazepines with GABA takes the form of an increase in with GABA takes the form of an increase in the frequency of channel-opening eventsthe frequency of channel-opening events

12

BenzodiazepinesBenzodiazepines - -Mechanism of actionMechanism of action

• Two benzodiazepine receptor subtypes Two benzodiazepine receptor subtypes commonly found in the CNS have been commonly found in the CNS have been designated as BZdesignated as BZ11 and BZ and BZ22 receptor receptor

depending on whether their composition depending on whether their composition includes the αincludes the α11 subunit or the α subunit or the α22 subunit, subunit,

respectivelyrespectively

13

Benzodiazepine Binding Site LigandsBenzodiazepine Binding Site Ligands

1.1. Agonists: Agonists: • Benzodiazepines: multiple BZ binding Benzodiazepines: multiple BZ binding

sitessites• Zolpidem, zaleplon, and eszopiclone: Zolpidem, zaleplon, and eszopiclone:

selective agonists at the BZ1selective agonists at the BZ1

2.2. Antagonists: Antagonists: FlumazenilFlumazenil

3.3. Inverse agonists:Inverse agonists: ββ-carbolines, eg, -carbolines, eg, n-n-butyl-butyl- β β -carboline-3-carboxylate (-carboline-3-carboxylate (β β -CCB)-CCB)

14


• The The PK PK properties of the properties of the bzdbzds affect their s affect their clinical utilityclinical utility

• Bzds Bzds vary greatly in duration of action and vary greatly in duration of action and can be roughly divided intocan be roughly divided into::

a.a. SShort-hort-actingactingb.b. MMedium-edium-actingactingc.c. LLong-actingong-acting

IntermediateIntermediate (6-24 hours)(6-24 hours)::AlprazolamAlprazolam, , LorazepamLorazepam, , EstazolamEstazolam,,TemazepamTemazepam

Short acting (3-8 hours)Short acting (3-8 hours): : OxazepamOxazepam, , TriazolamTriazolam

Long actingLong acting ( 24-72 hours)( 24-72 hours)::ChlorazepateChlorazepate, , DiazepamDiazepamChlordiazepoxideChlordiazepoxide,,FlurazepamFlurazepam, , QuazepamQuazepam

16


• Bzds are all metabolised both by dealkylation Bzds are all metabolised both by dealkylation (phase 1) & conjugation (phase 2) reactions(phase 1) & conjugation (phase 2) reactions

• The longer acting agents are converted in the liver The longer acting agents are converted in the liver to one or active metabolite, some with long half-to one or active metabolite, some with long half-lives than the parant druglives than the parant drug

• The tThe t1/21/2 of flurazepam in plasma is 2 hours, but ∼ of flurazepam in plasma is 2 hours, but ∼that of a major active metabolite that of a major active metabolite N-desalkyl-N-desalkyl-flurazepam is 50 hours∼flurazepam is 50 hours∼

• The short-acting compounds are metabolised The short-acting compounds are metabolised directly by conjugation with glucuronide (e.g. directly by conjugation with glucuronide (e.g. oxazepam)oxazepam)

17

• Diazepam

desmathyldiazepam active

oxazepam metabolites

conjugation

18

• Estazolam immediately converted to • Oxazepam inactive metabolites

19


• In very old patients and in patients with severe In very old patients and in patients with severe liver disease, the elimination half-lives of these liver disease, the elimination half-lives of these drugs are often increased significantlydrugs are often increased significantly

• In such cases, multiple normal doses of these In such cases, multiple normal doses of these sedative-hypnotics can result in excessive CNS sedative-hypnotics can result in excessive CNS effectseffects

20


• The distribution of the bzds from blood to tissues The distribution of the bzds from blood to tissues and back again is a dynamic process with and back again is a dynamic process with considerable influence on the onset and duration considerable influence on the onset and duration of the actionof the action

• Bzds having greater lipid solubility tend to enter Bzds having greater lipid solubility tend to enter the CNS more rapidly and thus tend to produce the CNS more rapidly and thus tend to produce their effect quicklytheir effect quickly

• Tissue redistribution (e.g., muscle and fat) is more Tissue redistribution (e.g., muscle and fat) is more rapid for drugs with the highest lipid solubilityrapid for drugs with the highest lipid solubility

• These drugs cross the placental barrier and are These drugs cross the placental barrier and are secreted into breast milksecreted into breast milk

21

Organ Level EffectsOrgan Level Effects

• The main effects of benzodiazepines are:The main effects of benzodiazepines are:

1)1) Reduction of anxiety (BZReduction of anxiety (BZ22))

2)2) Sedation and induction of sleep (BZSedation and induction of sleep (BZ11))

3)3) Reduction of muscle tone and Reduction of muscle tone and coordination (BZcoordination (BZ22 in the spinal cord) in the spinal cord)

4)4) Anticonvulsant effect (BZAnticonvulsant effect (BZ11))

5)5) Anterograde amnesia (BZAnterograde amnesia (BZ11))

22

Clinical uses of benzodiazepinesClinical uses of benzodiazepines

a.a. Treatment of anxiety stateTreatment of anxiety state• The bzds are the most widely used drugs for The bzds are the most widely used drugs for

the management of acute and chronic the management of acute and chronic anxiety b/c of their:anxiety b/c of their:

1)1) Rapid onset of actionRapid onset of action2)2) Relatively high therapeutic Relatively high therapeutic 3)3) Availability of flumazenil for treatment of Availability of flumazenil for treatment of

overdoseoverdose4)4) Low risk of drug interactionsLow risk of drug interactions5)5) Minimal effects on CV or ANSMinimal effects on CV or ANS

23


a.a. Treatment of anxiety stateTreatment of anxiety state• For most types of anxiety, none of the bzds is For most types of anxiety, none of the bzds is

therapeutically superior to any othertherapeutically superior to any other

• They should be reserved for continued severe They should be reserved for continued severe anxiety, and then should only be used for short anxiety, and then should only be used for short periods of time because of their addiction periods of time because of their addiction potentialpotential

• The antianxiety effects of the bzds are less The antianxiety effects of the bzds are less subject to tolerance than the sedative and subject to tolerance than the sedative and hypnotic effectshypnotic effects

24


a.a. Treatment of anxiety stateTreatment of anxiety state• Choice of a particular agent is usually made on Choice of a particular agent is usually made on

the basis of pharmacokinetic:the basis of pharmacokinetic:

The longer-acting agents: The longer-acting agents: preferred when preferred when anxiety is intense and sustained/ prolongedanxiety is intense and sustained/ prolonged

The short-acting agents: The short-acting agents: advantageous when advantageous when the anxiety is provoked by clearly defined the anxiety is provoked by clearly defined circumstances and is likely to be of short circumstances and is likely to be of short durationduration

25


A.A. Treatment of anxiety stateTreatment of anxiety state• Alprazolam is particularly effective in Alprazolam is particularly effective in

treatment of panic disorders & agoraphobia treatment of panic disorders & agoraphobia & is more selective in than other BDZs& is more selective in than other BDZs

26


B. Treatment of sleep disordersB. Treatment of sleep disorders• An ideal hypnotic agent would have:An ideal hypnotic agent would have:

1)1) A rapid onset of action when taken at A rapid onset of action when taken at bedtimebedtime

2)2) A sufficient duration of action to facilitate A sufficient duration of action to facilitate sleep throughout the nightsleep throughout the night

3)3) A minimal "hangover" effects the following A minimal "hangover" effects the following dayday

• Commonly prescribed bzds for sleep disorders Commonly prescribed bzds for sleep disorders include long-acting flurazepam, intermediate-include long-acting flurazepam, intermediate-acting temazepam, and short-acting triazolamacting temazepam, and short-acting triazolam

27


B. Treatment of sleep disordersB. Treatment of sleep disorders• The choice of a particular bzd to treat a sleep The choice of a particular bzd to treat a sleep

disturbance is generally based on PK criteria:disturbance is generally based on PK criteria:Long-acting compounds (e.g. flurazepam) may Long-acting compounds (e.g. flurazepam) may

ensure that a patient will sleep through the ensure that a patient will sleep through the night, they also may cause cumulative effects night, they also may cause cumulative effects resulting in daytime sluggishness or drug resulting in daytime sluggishness or drug hangoverhangover

Short-acting compounds (e.g. triazolam) avoid Short-acting compounds (e.g. triazolam) avoid the hangover problem, but their use may be the hangover problem, but their use may be associated with early awakening and an associated with early awakening and an increase in daytime anxietyincrease in daytime anxiety

28


C.C. Other Therapeutic Uses Other Therapeutic Uses 1.1. SeizuresSeizures2.2. Anesthesia & Amnesia (Midazolam)Anesthesia & Amnesia (Midazolam)• Bzds have the capacity to cause Bzds have the capacity to cause anterograde anterograde

amnesiaamnesia and often used and often used as premedication for as premedication for anxiety-provoking and unpleasant procedures, anxiety-provoking and unpleasant procedures, such as endoscopic, bronchoscopic, and certain such as endoscopic, bronchoscopic, and certain dental procedures as well as angioplastydental procedures as well as angioplasty

• They also cause a form of conscious sedation, They also cause a form of conscious sedation, allowing the person to be receptive to allowing the person to be receptive to instructions during these proceduresinstructions during these procedures

29


C. C. Other Therapeutic UsesOther Therapeutic Uses3.3. Alcohol and Sedative–Hypnotic WithdrawalAlcohol and Sedative–Hypnotic Withdrawal• Cross-dependence, defined as the ability of one Cross-dependence, defined as the ability of one

drug to suppress abstinence symptoms from drug to suppress abstinence symptoms from discontinuance of another drug, is quite marked discontinuance of another drug, is quite marked among sedative-hypnoticsamong sedative-hypnotics

• Longer-acting drugs such as chlordiazepoxide, Longer-acting drugs such as chlordiazepoxide, diazepam, and phenobarbital can be used to diazepam, and phenobarbital can be used to alleviate withdrawal symptoms of shorter-acting alleviate withdrawal symptoms of shorter-acting drugs, including ethanoldrugs, including ethanol

30

Clinical uses of sedative-hypnoticsClinical uses of sedative-hypnotics

C. C. Other Therapeutic UsesOther Therapeutic Uses4.4. Muscle RelaxationMuscle Relaxation• Diazepam is useful in the treatment of skeletal Diazepam is useful in the treatment of skeletal

muscle spasms, such as occur in muscle strain, muscle spasms, such as occur in muscle strain, and in treating spasticity from degenerative and in treating spasticity from degenerative disorders, such as multiple sclerosis and cerebral disorders, such as multiple sclerosis and cerebral palsy (CP)palsy (CP)

32

Tolerance and DependenceTolerance and Dependence

• Tolerance: Tolerance: decrease responsiveness to drug decrease responsiveness to drug following repeated exposurefollowing repeated exposure

• It may result in the need for an increase in the It may result in the need for an increase in the dose required to maintain symptomatic dose required to maintain symptomatic improvement or to promote sleepimprovement or to promote sleep

• Tolerance is less marked than it is with Tolerance is less marked than it is with barbituratesbarbiturates

• The development of tolerance has been The development of tolerance has been associated with down-regulation of brain associated with down-regulation of brain benzodiazepine receptors (benzodiazepine receptors (PD tolerancePD tolerance))

33


• Dependence Dependence on bzds can develop if high doses on bzds can develop if high doses of the drugs are given over prolonged periodof the drugs are given over prolonged period

• Abrupt withdrawal is associated with withdrawal Abrupt withdrawal is associated with withdrawal symptoms, including rebound insomnia & rebound symptoms, including rebound insomnia & rebound anxiety, which may even exceed that which anxiety, which may even exceed that which preceded the treatmentpreceded the treatment

• A gradual tapering of the dose until it is eventually A gradual tapering of the dose until it is eventually discontinued lessens the likelihood of a discontinued lessens the likelihood of a withdrawal reactionswithdrawal reactions

34


• Differences in the severity of withdrawal Differences in the severity of withdrawal symptoms resulting from individual bzds relate symptoms resulting from individual bzds relate in part to half-life:in part to half-life:

Bzds with long half-lives (e.g. Flurazepam): Bzds with long half-lives (e.g. Flurazepam): withdrawal symptoms occur slowely with few withdrawal symptoms occur slowely with few physical symptoms and last a number of days physical symptoms and last a number of days after discontinuationafter discontinuation

Bzds with short half-lives (e.g. Triazolam): Bzds with short half-lives (e.g. Triazolam): induce more abrupt and severe withdrawal induce more abrupt and severe withdrawal reactionsreactions

35

Adverse effectsAdverse effects

• Dose-dependents CNS depression: Dose-dependents CNS depression: • Most common adverse effects associated Most common adverse effects associated

with use of bzdswith use of bzds

• Include: drowsiness, excessive sedation, Include: drowsiness, excessive sedation, impaired motor coordination, ataxia, impaired motor coordination, ataxia, confusion, and memory loss, and cognitive confusion, and memory loss, and cognitive impairmentimpairment

36

Adverse EffectAdverse Effect

• Overdoses with the bzds occur commonly, Overdoses with the bzds occur commonly, but fatal toxic occurrences are rarebut fatal toxic occurrences are rare

• Fatal intoxications are more likely in children, Fatal intoxications are more likely in children, in individuals with respiratory difficulties, and in individuals with respiratory difficulties, and in individuals who have consumed another in individuals who have consumed another CNS depressant (e.g. Alcohol)CNS depressant (e.g. Alcohol)

37

Drug interactionsDrug interactions

1.1. Pharmacodynamic interactions: Pharmacodynamic interactions: • Additive effect with other CNS depressants Additive effect with other CNS depressants

which can lead to serious consequences, which can lead to serious consequences, including enhanced depressionincluding enhanced depression

38


2.2. Pharmacokinetic interactions: Pharmacokinetic interactions: • Many bzds are metabolized by the CYP3A4Many bzds are metabolized by the CYP3A4

• Coadministration of CYP3A4 inhibitors (e.g. Coadministration of CYP3A4 inhibitors (e.g. grapefruit juice, ketoconazole, itraconazole, grapefruit juice, ketoconazole, itraconazole, erythromycin) result in intensification and erythromycin) result in intensification and prolongation of the bzdprolongation of the bzd

• Coadministration of CYP3A4 inducers (e.g. Coadministration of CYP3A4 inducers (e.g. rifampin, carbamazepine, and phenytoin) rifampin, carbamazepine, and phenytoin) can reduce the therapeutic effect of bzdscan reduce the therapeutic effect of bzds

39

Flumazenil: Benzodiazepine antagonistFlumazenil: Benzodiazepine antagonist

• Flumazenil is a competitive antagonists of Flumazenil is a competitive antagonists of bzds that can rapidly reverse the effects of bzds that can rapidly reverse the effects of benzodiazepinesbenzodiazepines

• The drug is available for IV administration onlyThe drug is available for IV administration only

• Onset is rapid but duration is short, with a Onset is rapid but duration is short, with a half-life of about 1 hourhalf-life of about 1 hour

• Frequent administration may be necessary to Frequent administration may be necessary to maintain reversal of a long-acting bzdmaintain reversal of a long-acting bzd

40

Flumazenil: Benzodiazepine antagonistFlumazenil: Benzodiazepine antagonist

• Adverse effects: Adverse effects: oAgitation, confusion, dizziness, and nauseaAgitation, confusion, dizziness, and nausea

oSevere precipitated abstinence syndrome in Severe precipitated abstinence syndrome in patients who have developed physiologic patients who have developed physiologic benzodiazepine dependencebenzodiazepine dependence

o In patients who have ingested bzds with TCA, In patients who have ingested bzds with TCA, seizures and cardiac arrhythmias may follow seizures and cardiac arrhythmias may follow flumazenil administrationflumazenil administration

41

BarbituratesBarbiturates

• The barbiturates were formerly the mainstay The barbiturates were formerly the mainstay of treatment to sedate the patient or to induce of treatment to sedate the patient or to induce and maintain sleepand maintain sleep

• Today, they have been largely replaced by the Today, they have been largely replaced by the bzdbzds, primarily becauses, primarily because they: they:

a)a) IInduce tolerancenduce toleranceb)b) Induce Induce drug-metabolizing enzymesdrug-metabolizing enzymesc)c) PPhysical dependencehysical dependenced)d) AAssociated with very severe withdrawal ssociated with very severe withdrawal

symptomssymptomse)e) AAbility to cause coma in toxic dosesbility to cause coma in toxic doses

42

Barbiturates- Mechanism of actionBarbiturates- Mechanism of action

• Barbiturates—in contrast to bzds— appear to Barbiturates—in contrast to bzds— appear to increase the duration of the GABA-gated chloride increase the duration of the GABA-gated chloride channel openingschannel openings

• At high concentrations, the barbiturates may also At high concentrations, the barbiturates may also be GABA-mimetic, directly activating chloride be GABA-mimetic, directly activating chloride channelschannels

• These effects involve a binding site or sites These effects involve a binding site or sites distinct from the bzd binding sitesdistinct from the bzd binding sites

43

Barbiturates- Mechanism of actionBarbiturates- Mechanism of action

• Barbiturates are less selective in their actions than Barbiturates are less selective in their actions than bzdbzds, because they also depress the actions of s, because they also depress the actions of the excitatory neurotransmitter glutamic acid via the excitatory neurotransmitter glutamic acid via binding to the AMPA receptorbinding to the AMPA receptor

• The The multiplicity of sites of action of barbiturates multiplicity of sites of action of barbiturates may be the basis for their ability to induce full may be the basis for their ability to induce full surgical anesthesia and for their more pronounced surgical anesthesia and for their more pronounced central depressant effects compared with bcentral depressant effects compared with bzdzds s and the newer hypnoticsand the newer hypnotics

44

Organ Level EffectsOrgan Level Effects

• The main effects of The main effects of barbituratesbarbiturates are: are:

1)1) Reduction of anxietyReduction of anxiety2)2) Sedation and induction of sleepSedation and induction of sleep3)3) Anticonvulsant effectAnticonvulsant effect4)4) Dose Dose -dependent -dependent respiratory depressionrespiratory depression

espically espically in patients with pulmonary disease in patients with pulmonary disease 5)5) CVCV depression depression11,which is most evident in patients ,which is most evident in patients

hypovolemic states, HF, and other diseases that hypovolemic states, HF, and other diseases that impair CV functionimpair CV function

• Respiratory and CV effects are more marked when are Respiratory and CV effects are more marked when are given IVgiven IV

45

CCllinical usesinical uses

1)1) Anesthesia: Anesthesia: Selection is strongly influenced by Selection is strongly influenced by the desired duration of action. The ultrashort-the desired duration of action. The ultrashort-acting barbiturate, thiopental, acting barbiturate, thiopental, isis used used IVIV to induce to induce anesthesiaanesthesia

2)2) Anticonvulsant:Anticonvulsant: Phenobarbital has specific Phenobarbital has specific anticonvulsant activity that is distinguished from anticonvulsant activity that is distinguished from the nonspecific CNS depressionthe nonspecific CNS depression

3)3) Antxiety and hypnosisAntxiety and hypnosis (secobarbital) (secobarbital) : : most have been replaced by the bzdsmost have been replaced by the bzds

46

ToleranceTolerance and and DependenceDependence

• Metabolic toleranceMetabolic tolerance:: aan increase in the rate of n increase in the rate of drug metabolism in the case of chronic drug metabolism in the case of chronic administration of barbiturates contributesadministration of barbiturates contributes to the to the decreased effectdecreased effect

• Abrupt withdrawal from barbiturates may cause Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness, restlessness, nausea tremors, anxiety, weakness, restlessness, nausea and vomiting, seizures, delirium, and cardiac and vomiting, seizures, delirium, and cardiac arrestarrest

• Withdrawal is much more severe than that Withdrawal is much more severe than that associated with opiates and can result in deathassociated with opiates and can result in death

47

Adverse effectsAdverse effects

1)1) CNS:CNS: Barbiturates cause drowsiness, impaired Barbiturates cause drowsiness, impaired concentration, and mental and physical concentration, and mental and physical sluggishness sluggishness

2)2) Poisoning: Poisoning: associated with severe depression of associated with severe depression of respiration is coupled with central CV depression, respiration is coupled with central CV depression, and results in a shock-like condition with shallow, and results in a shock-like condition with shallow, infrequent breathinginfrequent breathing

• Barbiturates increase porphyrin synthesis, and Barbiturates increase porphyrin synthesis, and are contraindicated in patients with acute are contraindicated in patients with acute intermittent porphyriaintermittent porphyria

48


1)1) PD interactions: PD interactions: barbiturates combine with barbiturates combine with other CNS depressants cause severe CNS other CNS depressants cause severe CNS depression, especially ethanoldepression, especially ethanol

2)2) PK interactions:PK interactions:• BBarbiturates induce hepatic CYP450:arbiturates induce hepatic CYP450: chronic chronic

administration diminishes the action of many administration diminishes the action of many drugs that are dependent on CYP450 drugs that are dependent on CYP450 metabolism to reduce their concentration metabolism to reduce their concentration (e.g. dicumarol, phenytoin, digitalis (e.g. dicumarol, phenytoin, digitalis compounds, & griseofulvin)compounds, & griseofulvin)

49

Other Other Sedative-Sedative-Hypnotic Agents Hypnotic Agents

1.1. Benzodiazepine-Receptor AgonistsBenzodiazepine-Receptor Agonists• Agents: Zolpidem, Agents: Zolpidem, zzaleplon, & eszopiclonealeplon, & eszopiclone

• Are structurally unrelated to Are structurally unrelated to bzdbzds but share a s but share a similar mechanism of actionsimilar mechanism of action

• They act on a subset of the benzodiazepine They act on a subset of the benzodiazepine receptor family, BZreceptor family, BZ11

• Compared with the Compared with the bzdbzds,s, they have they have relatively relatively weak anxiolytic, anticonvulsant,weak anxiolytic, anticonvulsant, and skeletal and skeletal muscle relaxant properties atmuscle relaxant properties at therapeutic therapeutic dosesdoses

50


1.1. Benzodiazepine-Receptor AgonistsBenzodiazepine-Receptor Agonists• They They have efficacies similar to those of the have efficacies similar to those of the

hypnotic bzds in the management of sleep hypnotic bzds in the management of sleep disorders, with few withdrawal effects and disorders, with few withdrawal effects and minimal rebound insomniaminimal rebound insomnia

• Little or no tolerance and dependence with Little or no tolerance and dependence with prolonged useprolonged use

51


1.1. Benzodiazepine-Receptor AgonistsBenzodiazepine-Receptor Agonists• ADEs: GIT upset and CNS (dizziness, ADEs: GIT upset and CNS (dizziness,

drowsiness, nightmares, headache, drowsiness, nightmares, headache, agitation)agitation)

• Eszopiclone ADEs: dry mouth, peripheral Eszopiclone ADEs: dry mouth, peripheral edema, and unpleasant tasteedema, and unpleasant taste

52

Other Sedative-Hypnotic AgentsOther Sedative-Hypnotic Agents

2.2. Buspirone Buspirone • Buspirone exert its anxiolytic effects by Buspirone exert its anxiolytic effects by

acting as a partial agonist at brain 5-HTacting as a partial agonist at brain 5-HT1A1A

• In therapeuticIn therapeutic doses, buspironedoses, buspirone relieves relieves anxiety anxiety with little or no sedative effect with little or no sedative effect and and lacks lacks anticonvulsant or muscle relaxant anticonvulsant or muscle relaxant propertiesproperties of bzds of bzds

53


2.2. Buspirone Buspirone • Buspirone-treated patients show no Buspirone-treated patients show no

withdrawal signs on abrupt discontinuancewithdrawal signs on abrupt discontinuance

• BuspironeBuspirone causes less psychomotor causes less psychomotor impairment than bimpairment than bzdzds, and does not affect s, and does not affect driving skillsdriving skills

• Buspirone has the disadvantage of a slow Buspirone has the disadvantage of a slow onset of action, making the drug unsuitable onset of action, making the drug unsuitable for management of acute anxiety statesfor management of acute anxiety states

54


2.2. BuspironeBuspirone• It does not potentiate effects of conventional It does not potentiate effects of conventional

sedative-hypnotic drugs, ethanol, or sedative-hypnotic drugs, ethanol, or TCATCA, and , and elderly patients do not appear to be more elderly patients do not appear to be more sensitive to its actionssensitive to its actions

• The frequency of ADEs is low, with the most The frequency of ADEs is low, with the most common effects being headaches, dizziness, common effects being headaches, dizziness, nervousness, and light-headednessnervousness, and light-headedness

• BPBP may be significantly elevated in patients may be significantly elevated in patients receiving MAO inhibitorsreceiving MAO inhibitors

55


3.3. RamelteonRamelteon• It It is a selective agonist at the MTis a selective agonist at the MT11 and MT and MT22

subtypes of melatonin receptorssubtypes of melatonin receptors

• It It is indicated for the treatment of insomnia in is indicated for the treatment of insomnia in which falling asleep is the primary complaintwhich falling asleep is the primary complaint

• ADRs:ADRs: dizziness, somnolence, fatigue, dizziness, somnolence, fatigue, decreases in testosterone and increases in decreases in testosterone and increases in prolactinprolactin

Documents

1 Chapter 22: Sedative-hypnotic Drugs. 2 Introduction A sedative drug (anxiolytic) reduce anxiety and exert a calming effectA sedative drug (anxiolytic)