Sedative-HypnoticSedative-Hypnotic Drugs Drugs

A A sedativesedative drug decreases activity, drug decreases activity, moderates excitement and calms the moderates excitement and calms the recipientrecipient

A A hypnotichypnotic drug produces drowsiness drug produces drowsiness and facilitates the onset and maintenance and facilitates the onset and maintenance of a state of sleepof a state of sleep

Sedative (Anxiolytic)Sedative (Anxiolytic)

Exert a calming effect,Exert a calming effect,

Reduce tension, nervousness,Reduce tension, nervousness, fear, and apprehension,fear, and apprehension,

little or no effect on motor or little or no effect on motor or mental function.mental function.

HypnoticsHypnotics

Produce state of drowsiness,Produce state of drowsiness,

promote onset and maintenance of sleep,promote onset and maintenance of sleep,

Patient can be awakened readily.Patient can be awakened readily.

Drug ClassificationDrug Classification

BarbituratesBarbiturates

BenzodiazepinesBenzodiazepines

Miscellaneous agentsMiscellaneous agents

BarbituratesBarbiturates(duration of action)(duration of action)

Ultra Ultra Short action Short action (8-10 h)(8-10 h) ThiopentalThiopental

Short action Short action (10-40 h)(10-40 h) Amobarbital, Secobarbital, pentobarbital Amobarbital, Secobarbital, pentobarbital

Intermediate action Intermediate action (35-50 h)(35-50 h) ButabarbitalButabarbital

Long action Long action (80-120 h)(80-120 h) Phenobarbital, Phenobarbital,

BenzodiazepinesBenzodiazepines(duration of action)(duration of action)

Ultra Short action Ultra Short action (4-6 h)(4-6 h) Triazolam, MidazolamTriazolam, Midazolam

Short action Short action (12-18 h)(12-18 h) Lorazepam, Oxazepam, Temazepam, LormetazepamLorazepam, Oxazepam, Temazepam, Lormetazepam

Intermediate action Intermediate action (24h)(24h) Alperazolam, NitrazepamAlperazolam, Nitrazepam

Long action Long action (24-48 h)(24-48 h) Diazepam, Chlordiazepoxide, Florazepam, ClonazepamDiazepam, Chlordiazepoxide, Florazepam, Clonazepam

PharmacodynamicsPharmacodynamics

Both enhance action of GABA by binding to Both enhance action of GABA by binding to different site ofdifferent site of GABA GABAA A receptor/chloride channelreceptor/chloride channel Barbiturates are less specific than Benzodiazepines.Barbiturates are less specific than Benzodiazepines.

Barbiturates increase the Barbiturates increase the durationduration but but Benzodiazepines increase the Benzodiazepines increase the frequencyfrequency of GABA- of GABA- mediated chloride ion channel opening.mediated chloride ion channel opening.

PharmacodynamicsPharmacodynamics

Barbiturates Block the excitatory transmitter Barbiturates Block the excitatory transmitter glutamic acid.glutamic acid.

Barbiturates At high concentration block the Barbiturates At high concentration block the sodium channels.sodium channels.

GABAGABAAA receptorsreceptors

PharmacokineticsPharmacokinetics

AbsorptionAbsorption Oral absorption of Benzodiazepines depend on lipophilicity Oral absorption of Benzodiazepines depend on lipophilicity (Triazolam extremely rapid and Diazepam more rapid than others) (Triazolam extremely rapid and Diazepam more rapid than others)

Barbiturates are usually absorbed very rapidly Barbiturates are usually absorbed very rapidly

DistributionDistribution The more lipid solubility the more entrance the CNS The more lipid solubility the more entrance the CNS (Benzodiazepines: Diazepam & Teriazolam) (Barbiturates: (Benzodiazepines: Diazepam & Teriazolam) (Barbiturates: Thiopental)Thiopental)

RedistributionRedistribution (Barbiturates: Thiopental)(Barbiturates: Thiopental)

Protein binding Protein binding (Benzodiazepines: 60-95%) (Benzodiazepines: 60-95%)

PharmacokineticsPharmacokinetics

Biotransformation Biotransformation --Benzodiazepines:Benzodiazepines: Next slide Next slide

--Barbiturates:Barbiturates: Oxidation & Glucuronide conjugation Oxidation & Glucuronide conjugation ExcretionExcretion - - Both of them are excreted via the kidney,Both of them are excreted via the kidney,

- - 20-30%20-30% of Phenobarbital and of Phenobarbital and tracetrace amount of benzodiazepines amount of benzodiazepines is excreted unchanged,is excreted unchanged, - - Elimination of barbiturates can be increased by alkalinization of Elimination of barbiturates can be increased by alkalinization of urine urine

Pharmacokinetic of BZDPharmacokinetic of BZD

Pharmacokinetic of BZDPharmacokinetic of BZD

Barbiturates:Barbiturates: Potent inducer (cytochrome Potent inducer (cytochrome

p450), cause drug interactions & acute p450), cause drug interactions & acute

porphyriaporphyria

PharmacokineticsPharmacokinetics

Pharmacological effects and usesPharmacological effects and uses

SedationSedation

Hypnosis Hypnosis (decrease in REM duration)(decrease in REM duration) Anesthesia Anesthesia ((BenzodiazepinesBenzodiazepines: midazolam, : midazolam, BarbituratesBarbiturates: thiopental): thiopental) Anticonvulsant action Anticonvulsant action ((Benzodiazepines:Benzodiazepines: clonazepam, diazepam, clonazepam, diazepam, Barbiturates:Barbiturates:

phenobarbital)phenobarbital)

Muscle relaxation Muscle relaxation (Diazepam)(Diazepam)

Tolerance & dependenceTolerance & dependence

CNS depressionCNS depression

Hepatic metabolic uses Hepatic metabolic uses (Phenobarbital in (Phenobarbital in hyperbilirubinemia & kernicterus in neonates)hyperbilirubinemia & kernicterus in neonates)

Pharmacological effects and usesPharmacological effects and uses

Tolerance to sleep facilitationTolerance to sleep facilitation Barbiturates 2 weeksBarbiturates 2 weeks Benzodiazepines 4-6 weeksBenzodiazepines 4-6 weeks

Discontinuation Discontinuation rebound REM Sleep, Psychological rebound REM Sleep, Psychological DependenceDependence

BenzodiazepinesBenzodiazepines

Replaced BarbituratesReplaced Barbiturates

Benzodiazepine AdvantagesBenzodiazepine Advantages --Safer- higher therapeutic indexSafer- higher therapeutic index -Tolerance- lower-Tolerance- lower -Addictive liability- lower-Addictive liability- lower -Less drug interactions-Less drug interactions

Adverse EffectsAdverse Effects

Unwanted daytime sedationUnwanted daytime sedation (especially with (especially with Diazepam, flurazepam)Diazepam, flurazepam) Daytime anxiety and amnesiaDaytime anxiety and amnesia

(especially with(especially with triazolam) triazolam)

Respiratory and cardiovascular depressionRespiratory and cardiovascular depression

(especially with(especially with Barbiturates overdosage) Barbiturates overdosage)

Miscellaneous agentsMiscellaneous agents

5-HT5-HT1A1A partial agonists partial agonists

(Buspirone, Ipsapirone, gepirone)(Buspirone, Ipsapirone, gepirone) AlcoholsAlcohols

(Chloral hydrate, glutetimide)(Chloral hydrate, glutetimide) Other BZ receptor agonistsOther BZ receptor agonists

(Zaleplon, Zolpidem)(Zaleplon, Zolpidem) OthersOthers

Atypical AnxiolyticAtypical Anxiolytic

No hypnotic,anticonvulsant or muscle relaxant No hypnotic,anticonvulsant or muscle relaxant

Acts at 5-HTActs at 5-HT1A1A ((partial agonistpartial agonist)) and Dopamine and Dopamine

receptorsreceptors

Does not produce tolerance and physical dependenceDoes not produce tolerance and physical dependence

Side effect:Side effect: nausea, dizziness, headache, tachicardianausea, dizziness, headache, tachicardia,… ,…

5-HT5-HT1A1A partial agonists partial agonists

Chloral Hydrate: Chloral Hydrate: Metabolized to trichloroethanolMetabolized to trichloroethanol

Short durationShort duration

No enzyme inductionNo enzyme induction

Tolerance/Dependence Withdrawal can Tolerance/Dependence Withdrawal can be severebe severe

AlcoholsAlcohols

BZ receptor agonistsBZ receptor agonists (Zolpidem…)Zolpidem…)

Not a benzodiazepine but binds to BZ receptorNot a benzodiazepine but binds to BZ receptor

Minimal muscle relaxing & anticonvulsant effectMinimal muscle relaxing & anticonvulsant effect

Good hypnotic, with less effects on stages of sleepGood hypnotic, with less effects on stages of sleep

Can suppress REM in higher dosesCan suppress REM in higher doses

Low incidence of rebound insomnia, daytime Low incidence of rebound insomnia, daytime sedationsedation

Side effects:Side effects:

--Respiratory depressionRespiratory depression

-Tolerance less than Benzodiazepines-Tolerance less than Benzodiazepines

BZ receptor agonistsBZ receptor agonists

OthersOthers

MeprobamateMeprobamate RARELY RARELY if ever used, Similar to Barbs.if ever used, Similar to Barbs.

Beta- BlockersBeta- Blockers useful in alleviating performance anxiety.useful in alleviating performance anxiety.

FlumazenilFlumazenil

Benzodiazepine competitive Antagonist, Benzodiazepine competitive Antagonist, no activity in its own rightno activity in its own right

It reverse CNS depressant effect of It reverse CNS depressant effect of Benzodiazepines, Zolpidem and ZaleploneBenzodiazepines, Zolpidem and Zaleplone

Ineffective for most other sedativesIneffective for most other sedatives

Side effects of FlumazenilSide effects of Flumazenil

AgitationAgitation ConfusionConfusion DizzinessDizziness NauseaNausea Seizure & cardiac arrhytmia (patient treated with Seizure & cardiac arrhytmia (patient treated with

TCA)TCA) Transient improvement in mental status has been Transient improvement in mental status has been

reported in patient with hepatic encephalopathyreported in patient with hepatic encephalopathy