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
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)
sedative-Hypnotic Drugs 12
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
sedative-Hypnotic Drugs 14
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
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
sedative-Hypnotic Drugs 18
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
sedative-Hypnotic Drugs 19
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
sedative-Hypnotic Drugs 20
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
sedative-Hypnotic Drugs 22
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
sedative-Hypnotic Drugs 23
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)
sedative-Hypnotic Drugs 24
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.)
sedative-Hypnotic Drugs 25
26. Benzodiazepines binding site:GABAa receptor
Three types of ligand-benzodiazepines receptor
interaction have been reported:
1) Agonist
2) Antagonist
3) Inverse agonist
sedative-Hypnotic Drugs 26
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
sedative-Hypnotic Drugs 28
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)
sedative-Hypnotic Drugs 29
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
sedative-Hypnotic Drugs 30
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
sedative-Hypnotic Drugs 31
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
sedative-Hypnotic Drugs 32
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)
sedative-Hypnotic Drugs 33
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
sedative-Hypnotic Drugs 34
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
sedative-Hypnotic Drugs 35
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
sedative-Hypnotic Drugs 36
37. With other CNS depressant drugs(additive
effect)
With inhabitors & inducers of microsomal
enzymes
sedative-Hypnotic Drugs 37