1. Sedative-Hypnotic Drugs
sedative-Hypnotic Drugs 1

2.  Slide producers:
 Emad yazdanpanah
 Mohammad moeini
sedative-Hypnotic Drugs 2

3.  Sedation (with concomitant relif of anxiety)
 Encourage sleep
sedative-Hypnotic Drugs 3

4.  This drug classification based
on clinical uses rather than on
similarities in chemical
structure.
sedative-Hypnotic Drugs 4

5.  Sedative:
 These agents should reduce anxiety
 Exert a calming effect
 CNS depression should be the minimum
consistant
sedative-Hypnotic Drugs 5

6.  Hypnotic:
 These should produce drowsiness
 Maintance sleep
 CNS depression is more(by increasing
the dose)
sedative-Hypnotic Drugs 6

7. Comparison
(figure22-1)
A:
barbiturates &
alcohols
B:
benzodiazopines
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8.  Benzodiazepines
 Barbiturates
 Glutethmide & Meprobamat
 Alcohole
 zolpidem,zaleplon,eszopiclone(s-enantiomer of
zopiclone)
 Ramelteon
 Buspirone
sedative-Hypnotic Drugs 8

9. sedative-Hypnotic Drugs 9

10. sedative-Hypnotic Drugs 10

11. sedative-Hypnotic Drugs 11

12.  Benzodiazepines:
 1,4-benzodiazepines
 Carboxamide group in 7-membered ring
 Halogen or a Nitro group in the 7 position
(triazolam & alprazolam have triazole ring at
the 1,2 position)
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13. It dependes on lipophilicity
All sedative-hypnotics absorbtion is good.
Examples:
 Triazolam absorbtion is rapid
 Diazepam & clorazepate is rapid than other BZ
 Barbiturates,older sedative-hypnotic & newer
hypnotics are absorbed rapidly into the blood
sedative-Hypnotic Drugs 13

14.  Cross placental barrier
 Depression of neonatal vital function
 Detectable in breast milk
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15.  They should metabolize to more water soluble
 Microsomal enzyme is important
 (few are excreted from the body in unchanged
form)
sedative-Hypnotic Drugs 15

16.  The rate of metabolism depend on the
indivdual drugs
 Most of theme undergo microsomal
oxidation(phase 1),including N-dealkylation &
aliphatic hydroxylation
 Metabolites are conjugated(phase 2) to form
glucronides
 Most of metabolites are active(e.g
desmethyldiazepam)
sedative-Hypnotic Drugs 16

17. Chlordiazpoxide Diazepam Prazepam Clorazepate
Desmethyl chlordiazpoxide
Demoxapam Desmethyldiazepam Alprazolam & Triazolam
Oxazepam alpha-hydroxy metabolites
Hydroxymethyl-
flurazepam
Lorazepam
Flurazepam CONJUGATION
CONJUGATION
desmethyl-
flurazepam
URINARY EXCRETION
URINARY
EXCRETION
sedative-Hypnotic Drugs 17

18.  Elimination of the paren drug may have little
relation to the time course of pharmacologic
effect
 Metabolism of benzodiazepines are effected by
inducers & inhabitors
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19.  Insignificant quantities are excreted
unchanged(exception:phenobarbital)
 Oxidation is involved to form
alcohols,ketones,acids which appear in the
urine as glucronide conjugates
 Elimination rate is usually slow
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20. I. Zolpidem:
 Metabolized to inactive metabolites
 CYP3A4 isozyme is involved
 Half-life: 1.5 - 3.5 hr
II. Zaleplon:
 Metabolized to inactive metabolites
 Aldehyde oxidase & partly CYP3A4 is
involved
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21.  Cimetidine,inhabits aldehyde dehydrogenase &
CYP3A4 plasma level
III. Eszopiclone :
 Metabolized by especially CYP3A4
 Half-life: 6hr
 Rifampin hepatic metabolism
 Ketokenazol hepatic metabolism
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22. Drug peak blood Elimination Comment
level(hr) half-life(hr)
Alprazolam 1-2 12-15 rapid oral absorbtion
Chlordiazpoxide 2-4 15-40 active metabolites;erratic
bioavailibility from IM injection
Clorazepate 1-2 50-100 prodrug;hydrolyzed to active from
in stomach
Diazepam 1-2 20-80 active metabolites;erratic
bioavailibility from IM injection
Eszopiclone 1 6 minor active metabolites
Flurazepam 1-2 40-100 active metabolites with long half-life
Lorazepam 1-6 10-20 no active metabolites
Oxazepam 2-4 10-20 no active metabolites
Temazepam 2-3 10-20 slow oral absorbtion
Triazolam 1 2-3 rapid onset;short duration of actoin
Zaleplon <1 1-2 metabolized via aldehyde dehydrogenase
Zolpidem 1-3 1.5-3.5 no active metabolites
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23.  They are excreted via the kidney
 Changes in renal function do not have marked
effects on the elimination
 Phenobarbital (20-30%) is excreted unchanged
in the urine
 excretion of phenobarbital by alkalinization
of the urine
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24.  Benzodiazepines:
Increase in the frequency of channel-opening
events
 barbiturates:
increase the duration of the GABAA-gated
channel opening(facilitate the action of
GABA & GABA mimetic)
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25. Figure 22-6
A model of the GABAA receptor-
chloride ion channel
macromolecular complex (others
could be proposed). A
heterooligomeric glycoprotein, the
complex consists of five or more
membrane-spanning subunits.
Multiple forms of a, b, and g
subunits are arranged in different
pentameric combinations so that
GABAA receptors exhibit molecular
heterogeneity. GABA appears to
interact with a or b subunits
triggering chloride channel
opening with resulting membrane
hyperpolarization. Binding of
benzodiazepines to g subunits or to
an area of the a unit influenced by
the g unit facilitates the process of
channel opening but does not
directly initiate chloride current.
(Modified and reproduced, with
permission, from Zorumski
CF, Isenberg KE: Insights into the
structure and function of GABA
receptors: Ion channels and
psychiatry. Am J Psychiatry
1991;148:162.)
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26.  Benzodiazepines binding site:GABAa receptor
 Three types of ligand-benzodiazepines receptor
interaction have been reported:
1) Agonist
2) Antagonist
3) Inverse agonist
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27.  Sedation
 Hypnosis
 Anesthesia
 Anticonvulsant effect
 Muscle relaxation
 Effects on respiratory & cardiovascular
function
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28. Table 22-2. clinical uses of sedative-hypnotics
For relief of anxiety
For insomnia
For sedation and insomnia before and during medical and surgical procedure
For treatment of epilepsy and seizure states
As a component of balanced anesthesia (IV)
For control of ethanol or other sedative0hypnotic withdrawal states
For muscle relaxation in spesific neuromuscular disorders
As diagnostic aids or for treatment in psychiatry
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29.  Common feature of sedative-hypnotic drug
 Result from increasing the dose to promote
sleep
 Partial cross-tolerance occures between them
 The mechanisms are not well understood
 Withdrawal symptoms occures according to
the individual drug
 Treatment:using long half-life drugs(diazepam)
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30.  Act as competetive antagonist
 Can not block ethanol,opioids,or general
anesthetics` action
 Short half-life: 0.7- 1.3 hr
 Repeated administration of the antagonis is
needed(???)
 Adverse effect:
agitation,confusion,dizzines,and nausa
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31.  For patiens who have difficulty in falling
asleep
 Agonist of MT
 Oral administration
 Has active metabolite
 CYP1A2 is responsible for metabolism
 Adverse effect:
dizziness,somnolence,fatigue,endocrine changes
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32.  Selective anxiety effect
 Differs from other sedative-hypnotic(?)
 Is not effective for withdrawal syndrome
 Uses for general anxiety
 Oral administration
 Less psychomotor imairment
 PB may be elevated in patients receiving
MAOinhabitors
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33.  Short-term use of sedative-hypnotics for
treating anxiety
 Premedication prior to surgery or some
unpleasant medical procedure
 Panic & Agoraphobia(alprazolam Is the best)
 Treatment of sleep problems(zolpidem &
zaleplon are common)
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34. Sedation Hypnosis
Drug Dosage Drug Dosage(at bedtime)
Alprazolam(xanax) 0.25-0.5 mg 2-3 times daily Chloral hydrate 500-1000 mg
Buspirone(buspar) 5-10 mg 2-3 times daily Estazolam(prosom) 0.5-2 mg
Chlordiazpoxide(librium) 10-20 mg 2-3 times daily Eszopiclone(lunesta) 1-3 mg
Clorazepate(tranxene) 5-7.5 mg twice daily Lorazepam(ativan) 2-4 mg
Diazepam(valium) 5 mg twice daily Quazepam(doral) 7.5-15 mg
Halazepam(paxipam) 20-40 mg 3-4 times daily Secobarbital 100-200 mg
Lorazepam(ativan) 1-2 mg once or twice daily Temazepam(restoril) 7.5 -30 mg
Oxazepam 15-30 mg 3-4 times daily Triazolam(halcion) 0.125-0.5 mg
Phenobabital 15-30 mg 2-3 times daily Zaleplon 5-20 mg
Zolpidem(ambiem) 5-10 mg
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35.  Result from dose-related depression of CNS
 Low doses:
drowsiness,impaired judgment,diminished motor skills
 Benzodiazopines :
 Antrograde amnesia,
 impair ability to learn new information
 Criminal use: Date rape
 Alprazolam is more toxic in overdose than other
benzodiazepines
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36.  Severe toxicity:
 Respiratory depression
 Aspiration of gastric content(more with ethanol)
 Cardiovascular depression
 In such cases the treatment is:
I. Patent airway with mechanical ventilation
II. Maintance of plasma volume
III. Renal out put
IV. Cardiac funcion
V. Dopamine preserves renal blood flow
VI. Hemodialysis or Hemoperfusion
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37.  With other CNS depressant drugs(additive
effect)
 With inhabitors & inducers of microsomal
enzymes
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38. Preparation available
Benzodiazepines Midazolam(Versed)
Alprazolam(Xanax) oral:2mg/ml syrup
oral:0.25,0.5,1,2 mg tablet,extended- parentral:1,5 mg/ml in 1,2,5,10 ml
release tablet,and orally disintegrating vial for injection
tablets;1.0 mg/ml solution
Chlordiazpoxide(Librium) Oxazepam
oral:5,10,25 mg capsules oral:10,15,30 mg capsules
parentral:100 mg powder for injection
Chorazepat(Tranxene) Quazepam(Doral)
oral:3.75,7.5,15 mg tablets & capsules oral:7.5,15 mg tablets
oral sustained-release:11.25,22.5 mg tablets
Clonazepam(Clonopin) Temazepam(Restroil)
oral:0.2,1,2 mg tablets;0.125,0.25,0.5,1,2 oral:7.5,15,22.5,30 mg capsules
mg orally disintegrating tablets
Diazepam(Valium) Traizolam(Halicion)
oral:2,5,10 mgtablets;1.5 mg/ml solution oral:0.125,0.25 mg tablets
parentral:5 mg/ml for injection
Estaolam(Prosom) Benzodiazepines antagonist
oral:1,2 mg tablets
Flurazepam(Dalmane) Flumazenil(Ramazicon)
oral:15,30 mg capsules parentral:0.1 mg/ml for iv injection
Lorazepam(Ativam)
oral:o.5,1,2 mg tablets;2 mg/ml solution
parentral:2,4 mg/ml for injection
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39. Preparation available
Barbiturates Chloral hydrate(Aqachloral supprettes)
Amobarbital(Amytal) oral:500 mg capsules;250,500 mg/5ml
parentral:powder in 250,500 mg vials to syrup
reconstitute for injection rectal:324,648 mg suppositories
Mephobarbital(Mebaral) Eszopiclone(Lunetsa)
oral:32,50,100 mg tablets oral:1,2,3 mg tablets
Pentobarbital(Nembutal sodium) Hydrazine(Atarax,Vistaril)
oral:50,100 mg capsules;4 mg/ml elixir oral:10,25,50,100 mg tablets;25,50,100
rectal:30,60,120,200 mg suppositories mg capsules;10 mg/5ml suspention
parentral:50 mg/ml for injection parentral:25,50 mg/ml for injection
Phenobarbital(Luminal sodium) Meprobamate(Eqanil,Miltown)
oral:15,16,30,60,90,100 mg tablets;16 mg oral:200,400 mg tablets
capsules;15,20 mg/5ml elixir
parentral:30,60,65,130 mg/ml for injection
Secobarbital(Secotal) Paraldehyde
oral:100 mg capsules oral,recta liquids:1g/ml
Ramelteon(Rozeram)
oral:8 mg tablets
Miscellaneous Drugs Zaleplon(sonata)
Buspiron(BuSpar) oral:5,10 mg capsules
oral:5,7.5,10,15,30 mg tablets Zolpidem(Ambien,Ambien-CR)
oral:5,10 mg tablets;6.25,12.5 mg
extended-release tablets
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40. sedative-Hypnotic Drugs 40