1

Sedatives and Hypnotics

Ming-Kuan HU

School of Pharmacy

2

Drugs covered in this chapter

BZDs sedative-hypnotics

Estazolam

Flurazepam

Quazepam

Temazepam

Triazolam

Non-BZD sedative-hypnotics (3Z!)

Zolpidem

Zaleplon

Eszopiclone

Barbiturates

Amobarbital

Aprobarbital

Butabarbital

Pentobarbital

Phenobarbital

Secobarbital

Melatonin receptor agonist

Ramelteon Chloral hydrate

Histamine H1 receptor antagonists

Diphenhydramine

Doxylamine

Doxepin

3

Sedatives and hypnotics

Sedatives: Anxiolytic agents

Reduce anxiety to give calming effects with

little or no effect on motor or mental functions

Hypnotics (Sleeping pills)

Encourage the onset and maintenance of a

state of sleep

4

Dose-related pharmacological effects of

sedatives and hypnotics

Drug A: Some older sedative-hypnotics, higher dose may depress

respiratory and vasomotor center, leading to coma and death.

Drug B: e.g. Benzodiazepines, great safe.

Sedation

(Anxiolytics)

Hypnosis

Anesthesia

Coma

CNS

Effects

Increasing dose

Drug A

Drug B

5

Physiology of sleep

Sleeping states

Wakefulness

Slow-wave sleep (SWS, nonrapid eye movement (NREM), deeper stage of sleep

Paradoxical sleep (PS, rapid eye movement (REM) sleep)

Sleeping cycle of a normal young adult

75-80% NREM

20-25% REM

NREM REM NREM 90 min 20 min 90 min

6

The sleep stages

Rapid eye movement (REM): paradoxical

sleep, related to dream

Non-rapid eye movement (NREM)

Stage 1: relaxed wakefulness, ~ 5%

Stage 2: rapid-eye (a) or lighter sleep, 50%

Stage 3 (5%) & stage 4 (10-15%): rapid wave

(d) or deep sleep

Age > 65: only 10%; > 75 yr age: no exixtent

7

Insomnia

Defined as difficulty with the initiation,

maintenance, duration, or quality of sleep that

results in the impairment of daytime

functioning, despite adequate opportunity and

circumstances for sleep

Transient insomnia

Short-term insomnia (or acute insomnia)

Chronic insomnia

8

Classification of adult insomnia

Primary (15-25% patients)

Idiopathic insomnia

Psychophysiological insomnia

Paradoxical insomnia

Secondary insomnia

Adjustment insomnia — e.g. psychosocial stressors

Inadequate sleep hygiene — change of lifestyle habits

Insomnia due to a psychiatric disorder

Insomnia due to a medical condition — e.g. chronic pain, nocturnal cough or dyspnea, or hot flashes

Insomnia due to a drug or substance — e.g. due to consumption or discontinuation of medication, drugs of abuse, alcohol, or caffeine

9

Non-pharmacological therapy

Cognitive behavioral therapies —

Sleep hygiene: correct extrinsic factors affecting sleep,

such as environmental disruption

Relaxation therapy:

Physical component: e.g. progressive muscle

relaxation

Mental component: e.g. imagery training

Stimulus control: e.g. go to bed when you feel sleepy;

Do not watch TV, read, eat, or worry in bed

Sleep restriction: e.g. restricting your time in bed only

to sleep

10

Pharmacologic therapies

Benzodiazepines (BZDs) - act through the BZD–g-aminobutyric acid (GABA) receptor complex by affecting

Cl- flux

Drugs of Long, intermediate, and short half-life

Benzodiazepine receptor agonists - bind to the same receptor complex but have different affinities for various

receptor subclasses.

Drugs of intermediate, short, and ultrashort half-life

Certain sedating agents

H1 receptor antagonists

Melatonin

GABA receptors

GABA is a major inhibitory NT in CNS

GABA receptor

Ionotropic GABAA receptor: ligand-gated ion channel, modulating

conductance of Cl ion thru cell membrane

Metabotropic GABAB receptor: a 2nd messenger-linked GPCR

superfamily

Baclofen is a GABAB receptor agonist for spasticity or for hiccups

Drugs increase GABAA-mediate Cl influx (GABAA agonists)

Anxiolytic, anesthetic, anticonvulant, sedative-hypnotic activity

Drugs block Cl channel (e.g. picrotoxin)

Convulsion, state of arousal

11

Baclofen

//upload.wikimedia.org/wikipedia/commons/f/fc/Baclofen.svg

12

Benzodiazepines (BZDs)

Agonistic action of BZDs at the GABAA receptor (see

figure) subtype

O

Cl

N

N

R1

1

4

7

9

56

8

3

2

13

Efficacy of BZDs and BZD-receptor agonists

- Meta-analysis studies -

Good for relieving short-term insomnia

Improve sleep latency, total sleep time, quality

Short-acting agents

Greater effects on sleep latency

Intermediate or long-acting agents

Greater effects on total sleep time

14

Mechanism of actions of BZDs

BZDs increase the frequency of channel opening

by enhancing binding affinity btw GABA and the

GABAA receptor without extending the length of

the channel open period

Note: Barbiturates increase the duration of Cl-

channel opening

At the GABAA receptor, barbiturates increase the

efficacy of GABA; whereas, BZDs increase the

potency of GABA.

BZDs have no intrinsic agonist activity; this greatly

reduces the potential of fatalities associated with

overdose of BZDs.

15

Pharmacodynamics of BZDs

Benzodiazepines (BZDs) are agonists at the GABAA

receptor site (allosteric modulation) – When they bind,

and GABA has bound, they facilitate influx of Cl- ions,

resulting in inhibition

Do not cause the more generalized suppressive

effects on neurons that the barbiturates or alcohol do

Flumazenil (Romazicon) is an antagonist and serve

as an antidote for overdose, or to reverse BZD after

surgery

N

N

NOCH

3

CH3

F

O

O

Flumazenil

16

Agonistic action of BZDs at the GABAA

receptor subtype

In the amygdala, orbitofrontal cortex (眼眶皮質), and insula (腦島)

reduction in behavioral responses to fearful stimuli

reduction in anxiety and panic and agitation

In the cerebral cortex and hippocampus

resulting in mental confusion and amnesia

In the spinal cord, cerebellum, and brain stem

resulting in mild muscle-relaxant effects, sedation

In the cerebellum and hippocampus

Producing anticonvulsive (antiepileptic) action

17

Clinic use of BZDs

– Sedatives

– Hypnotics

– Muscle relaxants

– Intravenous anesthetics

– Anticonvulsants

Currently licensed BZDs tend to induce dependence, impair memory and psychomotor performance, dull consciousness and cloud the intellect

18

BZDs as hypnotics (I) - Long-acting agents

Flurazepam (Dalmane® ): T1/2 2.4 hr

N-desethylflurazepam: T1/2 47~100 hr Quazepam (Doral® ): T1/2 39 hr

Prazepam

Actions

Having active metabolites; slow elimination; slow development of tolerance

Reduce sleep latency, increasing stage 1 & 2 of SWS; reducing its stage 3 & 4 of SWS and REM

Side effects

Daytime sleepiness, dizziness, in-coordination; ―hangover‖ in the elderly

Rare withdrawal effects (rebound insomnia)

Deficits in memory

Long term use: drug dependence

19

Structures of long-acting BZDs

Active metabolites of long-acting BZDs:

Flurazepam N-desethylflurazepam

Quazepam N-desethyl & oxidized metabolites

Prazepam nordazepam

Oxidation:

Loss of S to O

N-Desalkylation

N

NCl

F

N(Et)2

N

NCl

F

CF3

S

Flurazepam Quazepam

N-Desalkylation

Prazepam

o

http://en.wikipedia.org/wiki/File:Prazepam_structure.svg

20

BZDs as hypnotics (II) – intermediate- and

short-acting agents

Intermediate-acting BZDs

Temazepam (Restoril® ): T1/2 8~15 hr

Estazolam (Prosom® ): T1/2 10~24 hr; metabolism: 3-hydroxylation

Short-acting BZD

Triazolam (Halcion® ): T1/2 2~5 hr

metabolism (hydroxylation) similar to alprazolam: -Me -CH2OH

Hydroxylation Conjugation

(N-Methyloxazepam)

NN

N

NCl

NN

N

NCl

CH3

CH3

N

NCl

O

OH

NN

N

NCl

CH3

Cl

Estazolam AlprazolamTemazepam Triazolam

Hydroxylation

21

BZDs as hypnotics (II) – Intermediate and

short-acting agents

Actions

Side effects

Mild withdrawal effects for intermediate-acting

drugs, but marked rebound insomnia for short-

acting triazolam

Deficits in memory

22

SAR of BZDs

7-position: e--attracting gp: stronger, more active.

6, 8, 9-positions: 無取代基.

5-position: phenyl gp,活性增加

2‘ and/or 6‘-positions: e--attracting gp, 活性增加.

4,5-double bond: if saturated, 活性降低.

3-position: if substituent exists,活性降低 (except -OH).

O

Cl

N

N

R1

1

4

7

9

56

8

3

2

2’ or 6’ position

23

BZDs as anticonvulsants

Clonazepam

Diazepam (Valium® )

Clorazepate.2K+ (Tranxene® )

Active form: Desmethyldiazepam & convert to oxazepam in liver

Lorazepam (Ativan® )

Midazolam H

N

N

O

OH

ClO

2N

Clonazepam

CH3

N

NCl

O

Diazepam

N

NCl

OH

CO2K

Clorazepate dipotassium

.KOH

N

N

NCl

CH3

F

Midazolam

H

N

NCl

O

OH

Cl

Lorazepam

24

BZDs as anxiolytics

Chlordiazepoxide.HCl (Librium® )

Lorazepam (Ativan® )

Alprazolam (蝴蝶片,Xanax® ): CH3 group CH2OH following conjugation.

Oxazepam (Serax® )

Helazepam (Paxipam® ): active metabolites: nordazepam & oxazepam

H

N

NCl

O

OH

Cl

Lorazepam

NN

N

NCl

CH3

Alprazolam

H

N

NCl

O

OH

Oxazepam

F3CH

2C

N

NCl

O

Helazepam

25

1,2-Fused triazole/imidazolo BZDs

Anxiolytic: Alprazolam,

Anticonvulsant: Midazolam

Hypnotic: Triazolam

Metabolites: a-hydroxylated compounds, still active & eliminated rapidly

NN

N

NCl

CH3

NN

N

NCl

CH3

Cl

Alprazolam Triazolam

N

N

NCl

CH3

F

Midazolam

Hydroxylation

26

Metabolism of BZDs (I)

N-Desalkylation: rapid

Drugs without 3-OH:

Non-polar, long T1/2, (via 3-hydroxylation, slow!)

O

Cl

N

N

H

Diazepam etcHalazepam, Librium

O

Cl

N

N

H

OH

Y

Oxazepam (Y=H)

Lorazepam (Y=Cl)

Nordazepam

O

Cl

N

N

H

OGlucuronic acid

Oxazepam glucuronide

O

Cl

N

N

CH3 O

Cl

N

N

H

CO2K

.KOH

Clorazepate

27

Metabolism of BZDs (II)

Drugs with 3-OH:

polar, direct eliminated as glucuronides

N

Cl

N

N

NH3C

Cl

Temazepam Triazolam

O

Cl

N

N

CH3

OH

O

Cl

N

N

CH2CH2NEt2

F .2HCl

Flurazepam

N1-Desalkyl flurazepamGlucuronidemetabolites N

Cl

N

N

NHOH2C

Cl

(Active)

(Quite active)

Diazepam

28

PK of BZDs

Weak acids: pKa of ~3.5 to 5.0

Lipophilicity affects speed of onset and duration

Oral absorption: Cmax occurs within ~1 hour

Some slow absorption (e.g., oxazepam, lorazepam); some rapid (e.g., triazolam)

Clorazepate changes into active form in GI

I.V. injection is appropriate if a rapid effect is needed.

I.M. is less effective than oral doses ‗cause BZDs bind to proteins

Alcohol can nearly double the blood levels of diazepam and a small drink increased the T1/2 of chlordiazepoxide by 60%

29

Drug Duration Onset Dose Cost

(mg) (U$,1 wk)

-------------------------------------------------------------------------------

Triazolam 短效 中度 0.25 4.6 (Halcion) (T1/2 < 6 h)

Oxazepam* 中效 中度 15-30 6.6 (Serax) (T1/2: 6-12 h)

Estazolam 中效 短-中度 1-2 6.2 (Prosom)

Lorazepam* 中效 中度 1-2 5.8 (Ativan)

Temazepam 中效 中/長度 15-30 4.0 (Restoril)

*Not approved used as hypnotics by FDA

Common BZDs as hypnotics (I)

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Drug Duration Onset Dose Cost

(mg) (U$,1 wk)

------------------------------------------------------------------------------

Clonazepam*長效 中度 0.5 4.9 (Klonopin) (T1/2 > 12 h)

Diazepam* 長效 短 5-10 0.9 (Valium)

Flurazepam 長效 短/中度 30 2.0 (Dalmane)

Quazepam 長效 短 15 16.9 (Doral)

Common BZDs as hypnotics (II)

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Non-benzodiazepine GABAA agonists

MOA: bind to GABAA 1-receptor Pharmacological action: increase sleep time, not affect sleep

cycle, no rebound effect, no muscle-dilating or anti-epileptic effects

Three-Z Hypnotics Drug Duration T1/2 Onset Dose (mg) Cost (U$,1 wk)

---------------------------------------------------------------------------- - Imidazopyridines - Zolpidem short 3 hr short 10 14.9

(Ambien)

- Pyrazolopyrimidine -

Zaleplon Ultrashort 1 hr short 10 14.8

(Sonata)

- Cyclopyrrolone - Eszopiclone Intermediate 5-7 hr short 7.5

(Lunesta)

Zolpidem (Ambien, Stilnox® )

An imidazopyridine derivative with hypnotic actions

Rapid onset: 1.4 hr; Its actions are similar to triazolam.

Metab: hydroxylation (CYP3A4, major) followed by oxidation (alcohol dehydrogenase)

Short-acting; elimination T1/2: 3 h

10 mg/tab; Dose reduction required in patients with hepatic dysfunction, in elder patients.

Side effects: Amnesia，自制不能，偶發夢遊, Sleep-eating disorder, characterized by sleepwalking and excessive nocturnal overeating (compulsive hyperphagia).

32

Alpidem is anti-anxiety,

but never approved!

33

Metabolism of zolpidem

Zolpidem and metabolites

N

NCH

3CH

3

N

O

CH3

CH3

N

NCH

3CH

2

N

O

CH3

CH3

OH

N

NCH

3

N

O

CH3

CH3

OH

O

N

NCH

2CH3

N

O

CH3

CH3

OHN

NCH

3

N

O

CH3

CH3

OH

O

N

NCH

3CH

3

N

O

CH3

CH3

OH

Alcohol

dehydrogenase

CYP3A4

CYP3A4

Alcohol

dehydrogenase

inactive

inactiveM III M I, primary metab

M II

M IV

34

Eszopiclone (Lunesta® )

originally marketed as racemic mixture; currently marketed as active S-isomer: Eszopiclone

MOA: binds broadly at GABA receptor as BZDs

Short actions; T1/2: 3~6 hr

Lower potency for desmethyl metabolite

35

Zaleplon (Sonata® )

Actions: similar to

zolpidem but more short

action (T1/2 ~ 1 hr)

Metabolism: thru CYP3A4

& inhibited by cimetidine

Use: decrease sleep

latency, but little effect on

total sleep time.

衛生署列入第四級管制藥品

36

Melatonin receptor agonists

Melatonin: poor drug due to poor absorption, low BA (10%),

rapid 1st-pass metabolism

(S)-Ramelteon (Rozerem® ): an indane isostere analogue

Binds to MT1 receptor (Ki 0.014 nM)

Shorting sleep latency but not in maintaining sleep

Dose: 8 mg taken 30 min before bedtime

NH

O

NH

CH3

CH3

O

O

NH

CH

2

H

CH3

O

Melatonin Ramelteon

Metab of (S)-ramelteon

37

38

Summary: hypnotics approved by FDA

NEJM 2005, 353, 8, 803.

39

下列鎮靜催眠藥物中，何者所產生的戒斷現象，最輕微且較慢發生？(97-1藥理)

A Prazepam

B Oxazepam

C Alprazolam

D Lorazepam

化學構造屬非benzodiazepine 但對GABAA 受體具有高度親和力者為: (98-1)

A flurazepam

B chloral hydrate

C triazolam

D zolpidem

40

Clorazepate 是diazepam 的衍生物，其在C-3 位置具有下列何官能基？(98-1)

A OH

B CH3

C Cl

D COO-

對於diazepam的構造做下列何種改變，可以使其活性增強？(98-2)

(A) N-Demethylation

(B) 在C-2‘ 加氟取代

(C) 在C-3加CO2H基

(D) 將Cl改成CH3

Clorazepate是經由何種代謝反應而產生3-hydroxy-desmethyldiazepam？(100-2)

A hydroxylation再demethylation

B decarboxylation再demethylation

C demethylation再hydroxylation

D decarboxylation再hydroxylation

與diazepam相較，oxazepam較適用於何種病人？ (100-2)

A 肝功能不佳者

B 腎功能不佳者

C 代謝率較高者

D 胃腸功能不佳者

41

下列何種藥物不具有活性代謝物（active metabolite）？ (100-2)

下列鎮靜催眠藥中，何者產生作用的速率最快且因其體內作用期間短，可以作為在長途飛行旅行時，調整時差問題時使用？(97-1藥理)

(A) Flurazepam (B) Triazolam (C) Zolpidem (D)

Buspirone

42

下列何者為下圖化合物的主要作用標的？(104-1)

A. Cannabinoid receptor

B. GABAA receptor

C. GABAB receptor

D. Melatonin receptor

43

44

Barbiturates

Discovered in 1864 by Adolf von Baeyer to search effective anxiolytic and sedative hypnotic

Malonylurea synthesized from malonic acid and urea; known as ―Barbituric acid‖

The first barbiturate: Barbital (1882)

Low lipid solubility; used to facilitate sleep; however, slow to metabolize; drowsy for over 1.5 d

Phenobarbital was synthesized (in 1912), used as anticonvulsant to treat seizures

NH

NH

O

O O

R1

R2

Barbiturates

53

1

45

Structural features of barbiturates

Strong acid type (prefers as tautomeric form) Barbituric acid:

5-H, pKa ~ 4.0 due to tautomerization to a highly acidic trihydroxypyrimidine (lactam lactim)

1-sub, or 5-sub, or 1,3-disubs, 1,5-disubs derivatives

Pharmacologically active form 5,5-disubstituted: N-H: pKa1 ~ 7.6 (7.1~8.1); pKa2 ~ 11.7-12.7

1,5,5-trisubstuted: pKa ~ 8.4.

5,5-disubstituted thiobarbiturate

pH-Dependent tautomerism of barbiturates (shown below)

NH

O

N

OH

Lactam Lactim

NH

NH

O

O O

R1

R2 N

NH

O

-O O

R1

R2 N

N

O

-O O

R1

R2

Barbiturates Monolactim(ionized)

NaOH

pKa 7.1~ 8.1

Dilactim(ionized)

pKa 11.7~ 12.7

NaOH

46

Acute effects of barbiturates

Subjective effects: Barbiturates referred to as ―Solid Alcohol‖ ; effects like those

of alcohol

Disinhibition, euphoria, sedation, loss of motor control, sleep, anesthesia, coma, death

Barbiturates cause Decrease in visual acuity

Overestimate the passage of time

Increase in body sway

Impaired eye tracking of a pendulum

Diminished performance on divided attention task

Depress respiration; impair response to hypoxia and CO2 Drop in blood pressure; precipitous with i.v. at anesthetic

doses, slight at sedative-hypnotic doses

47

SAR of 5,5-disubstituted barbiturates

Sum of carbon of the 5,5-disubstituted group: 6~10

Lipid solubility

Branched chain: greater activity/short duration

Unsaturated allyl, alkenyl, cycloalkenyl > saturated analogs (same carbon number)

Alicyclic or aromatic > aliphatic (same carbon number

N1-subs: improved lipid solubility

Thiocarbonyl analog: short onset and duration

NH

NH

O

O O

R1

R2

Barbiturates

53

1

48

Barbiturates approved for sedative-hypnotic use

(in blue marks)

NH

N

O

O* O

R1

R2

R3

Barbiturates

53

1

R1 R2 R3

- H

- H

- H

- Et - Me

- Et - H

- Et

- Et

- H- Et

- H

(or S=)

(or S=)

Amobarbital

Butabarbital

Butalbital

Mephobarbital

Phenobarbital (Luminal)

Pentobarbital

(S=): Thiopental

Secobarbital

(S=) thiamylal

Duration

S

S

I

I

L

Ultra-S

(see textbook Foye!)

49

Pharmacokinetics of barbiturates

Distribution and duration of action determined by lipid

solubility

Ultrashort : onset in seconds, duration 5-30 min; use i.v.

anesthesia (e.g., thiopental)

Short : onset within minutes, duration 3-8 hours; use

sleeping pills; preoperative sedation (e.g., secobarbital)

Intermediate : onset within an hour, duration 6-8 hours;

use sleeping pills (e.g., pentobarbital)

Long : onset over an hour, duration 10-12 hours; use

anticonvulsants, anxiolytics (e.g., phenobarbital)

50

Drug duration of barbiturates

Long duration (> 6 hr)

Barbital

Metharbital

Phenobarbital

Sedative-hypnotics,

generalized tonic-

clonic and partial

seizures.

metabolism: p-

hydroxylation & to

glucuronide

Intermediate action: (3 ~ 6 hr)

Amobarbital

Butalbarbital

Talbutal

Short duration: (< 3 hr)

Pentobarbital

Secobarbital

51

Mechanism of actions of barbiturates

Major action: To enhance the efficacy of GABAA by increasing the duration of Cl- channel opening, thus permitting a greater influx of Cl- ions for each activated channel

Affect not only GABAA and but also decrease activation of AMPA-R by glutamate

Example of different barbiturates

Increased neuronal inhibition: direct activation of GABAA receptors

e.g. Anesthetic barbiturate: pentobarbital (induces profound and fatal CNS depression)

Decreased neuronal excitation:

e.g. anticonvulsant barbiturate: phenobarbital (has greater therapeutic index than pentobarbital)

52

Other hypnotics

Clomethiazole

For alcohol withdrawal; agitated states

Shows effectiveness only after long-term and regular

use

Piperidinediones

Methyprylon

Glutethimide

Thalidomide (formerly used)

N

NH

OO

O

O

53

Methyprylon

A piperidinedione derivative

Similar to amobarbital in potency

Lack analgesic, tranquilizing or muscle relaxing or

respiratory effects.

Side effects and toxicity similar to barbiturates

Also cause dependence

A controlled substance

NH

O

O

CH3

CH3

CH3

54

Glutethimide (2-Ethyl-2-phenylglutarimide)

Used as sedative and hypnotic

Most active non-barbiturate hypnotic

500 mg dose 100 mg of pentobarbital

Not affect respiration or blood pressure

Safer than barbiturates

Exhibits anticholinergic action

NH

OCH

3O

55

Meprobamate (Miltown® )

Approved only for anxiety disorders

Effective against absence seizure, also a centrally acting

skeletal muscle relaxant with interneuronal blocking action

Overdose causes hypotension, respiratory depression

NH2

O O

O

CH3

C3H

7O

NH2

56

Antihistamines and anticholinergics

H1-receptor antagonists for sedative effects as OTC

drugs

Diphenhydramine

Doxylamine

HO N

CH3

CH3

N

CH3

O NCH

3

CH3

57

Herbal sedatives

Valerian西洋纈草: effective for insomnia

German chamomile 德國洋甘菊

Kava: no longer recommended (hepatotoxicity!)

Lavender

Hops 槐花

Lemon balm 檸檬香蜂草

Passiflora 百香果

O

CH3

CH3

CH3

OH

OO

O O

OO

O

O

Valerenic acid Valepotrioate

58

Illegal or street use of barbiturates and BZDs

Barbiturates can produce rush if injected (iv)

Secobarbital/amobarbital injected (iv) produces a rush

Injected by heroin addicts when heroin in short supply

Frequently combined with other drugs such as

amphetamine / cocaine to smooth unpleasant side

effects of the drug

BZ used in combination with alcohol

Flunitrazepam (Rohypnol, FM2) & Nimetazepam (一粒

眠、紅豆) are date rape drugs

59

Chloral hydrate (Welldorm® )

Trichloral + HOH or R-OH chloral hydrate or hemiacetal

(stable derivatives, mp 57 ℃ or 46 ℃)

Hospital use only; Onset: 1 hr; duration: 4~8 hr

Prolonged Activity: trichloroethanol (T1/2: 8~ 11 hr)

Ethanol, by increasing [NADH], enhances the reduction of chloral to

the more active trichloroethanol

Exerting barbiturate-like effects

No analgesic or tranquilizing or respiratory effects

Cl HCl

Cl O

ClH

Cl

Cl OHOH

Cl

Cl

Cl

OH Cl

Cl

Cl

OH

O

+ H2O

Chloral Chloral hydrate

AlcoholDH

AldehydeDH

60

Orexin

Orexin promotes wakefulness

Orexin receptors two GPCRs: orexin receptors, OX1 and OX2

Orexin increases the craving for food

The research on orexin/hypocretin is still in an early phase, although many scientists believe that orexin/hypocretin-based drugs could help narcoleptics and increase alertness in the brain without the side effects of amphetamines.

Orexin antagonists, new sleeping pills

under development

Orexins are released during active wakefulness but

not during the sleep period, so orexin antagonists

may not benefit most people with insomnia.

Antagonists may be very effective in shift workers or

people with jet lag trying to sleep

Suvorexant (by Merck)

In Ph III trial

Almorexant (by GSK & Actelion Pharm.)

SB-649868 (by GSK)

61

62

Orexins: looking forward to sleep, back at addiction

Figure 1 Among their many functions, the orexin neurons

promote wakefulness and modulate reward pathways.

63

Tackling alcoholism with drugs

Alcohol dependence afflicts 4% adults and the 3rd

leading cause of preventable death in USA

Science 2008, 320, 168-70.

64

Chronic tolerance

Barbiturates

Develop and dissipate at different rates for different

effects

Anticonvulsant effect shows no tolerance; impairment

of reaction time and eye-hand coordination disappear

within a week

BZDs

Anticonvulsant and drowsiness effects develop

tolerance slowly

REM suppression develops tolerance, but not sleep

inducing properties

65

Neurophysiology of barbiturates and BZDs

Barbiturates and BZDs enhance inhibition mediated by GABA

Work with a GABA receptor Cl- channel complex

GABA binds to GABA receptor; Cl- channel opens; influx of Cl-; membrane becomes more stable (clamp membrane potential at -70 mV)

BZD binds to a BZD site; this enhances the ability of GABA to open Cl- channel

Low doses of barbiturates bind to a barbiturate site and enhances the action of GABA; high doses open Cl- ion channel directly

66

Individual BZDs (I)

Diazepam (Valium® ): broad clinic use

Clorazepate.2K+ :

A prodrug, eliminate a water and a -CO2-

group to give active form.

Long duration & convert to oxazepam in liver

CH

3

N

NCl

O

DiazepamChlordiazepoxidehydrochloride

Cl

N

N

O

NHCH3

.HCl

N

NCl

OH

CO2K

Clorazepate dipotassium

.KOH

H

N

NCl

O

OH

Oxazepam

67

CNS NTs related to sleep (I)

Catecholamines from locus ceruleus

intact transmission needed for REM

Serotonin

Blocking 5-HT2 receptors: [NREM] increase; [REM] decrease

Histamine

H1 (postsynaptic) agonists

H3 (presynaptic) antagonists

Acetylcholine

a role in wakefulness and initiation of REM sleep

Adenosine

Stimulation of A1 receptor: hypnotic effect

GABA

Activation of GABAA receptor (Cl--channel): hypnotic effect

increase wakefulness

68

CNS NTs related to sleep (II)

Growth hormone and prolactin

GH pulse secretions during NREM

Melatonin

hormone of darkness

oral admin fastening sleep onset and increasing total sleeping time

CNS delta-sleep-inducing peptides (DISP)

Trp-Ala-Gly-Gly-Asp-Ser-Gly-Glu

enhancing NREM & REM sleep

69

Buspirone

anixolytic & antidepressant

No hypnotic, anticonvulsant, or muscle relaxant properties; minimal abuse liability

No rebound anxiety or withdrawal sign

Actions: partial agonist at 5-HT1A receptors.

Metabolism: hydroxylation & dealkylation

major metabolite: 1-(2-pyrimidyl)-piperazine (1-PP)

1-PP: a2-blocking actions, not known its CNS action

N N N

N

N

O

O .HCl

Busiprone

Benzodiazepine類安眠鎮靜劑，在其第七位置皆有取代基，其中不包括以下何者？(100-1)

A NO2

B Cl

C OH

D Br

下列何種化合物的酸性最強？ (100-1)

A CH3COOH

B ClCH2COOH

C Cl2CHCOOH

D Cl3CCOOH

70

下列有關zolpidem的敘述何者錯誤？ (101-1)

A 具有benzodiazepine結構

B作用於GABAA受體

C 屬短效型藥物

D作為安眠藥物

下列benzodiazepines中，何者較適用於肝功能不良的病人？ (101-1)

A diazepam

B fludiazepam

C nimetazepam

D oxazepam

71

Flumazenil可拮抗下列何者的作用？ (101-1)

A Barbiturates

B Meprobamate

C Zolpidem

D Ethanol

下列有關鎮靜-安眠（sedative-hypnotic）藥物作用之敘述，何者有誤？ (101-1)

A Benzodiazepines類藥物較Barbiturates類藥物不易引起呼吸抑制的副作用

B 長效型藥物在停藥後所產生的禁斷現象（withdrawal symptoms）通常較短效型藥物嚴重

C Barbiturates類藥物會直接打開GABAA受體氯離子管道，但Benzodiazepines類藥物則否

D 鎮靜-安眠藥物與酒精會產生交互依賴性（cross-dependence）的現象

72

下列那一種鎮靜催眠藥物所產生的戒斷現象較輕微且較慢發生？(101-2)

A. Oxazepam

B. Prazepam

C. Alprazolam

D. Lorazepam

下列何者不是鎮靜安眠藥之臨床用途？ (101-2)

A.可用治療恐慌症

B.可用手術前鎮靜作用

C.可用治療酒精之戒斷症狀

D.短效之鎮靜安眠藥可用來治療其他鎮靜安眠藥之戒斷症狀

73

下列那一種Benzodiazepines類藥物必須先在體內轉化成活性產物，才能執行其鎮靜-催眠的作用？(102-1)

A. Alprazolam

B. Triazolam

C. Clorazepate

D. Oxazepam

下列那一種安眠藥（Hypnotics）其排除半衰期（half-life）最長？(102-1)

A. Eszopiclone

B. Estazolam

C. Flurazepam

D. Zolpidem

74

有關Zaleplon之敘述，下列何者正確？(102-1)

A.短效型鎮靜安眠藥物，易產生反彈性失眠的現象

B.較Benzodiazepine類藥物不易產生耐藥性

C.具有抗痙攣或肌肉鬆弛的特性

D.可增加睡眠之非快速動眼期（non-rapid eye movement, NREM）之stage 2

鎮靜催眠藥物benzodiazepine所作用之GABAA受體主要係為調控下列何種離子管道的通透性？(102-1)

A.鈉離子管道（Sodium channels）

B.鈣離子管道（Calcium channels）

C.鉀離子管道（Potassium channels）

D.氯離子管道（Chloride channels）

75

鎮靜-催眠（sedative-hypnotic）用藥若逐漸提高使用劑量時，其對中樞神經系統所產生之作用依序為何？(102-2)

A.鎮靜（sedation） → 麻醉（anesthesia） → 催眠（hypnosis） → 昏迷（coma）

B.鎮靜（sedation） → 催眠（hypnosis） → 麻醉（anesthesia） → 昏迷（coma）

C.催眠（hypnosis） → 鎮靜（sedation） → 麻醉（anesthesia） → 昏迷（coma）

D.催眠（hypnosis） → 麻醉（anesthesia） → 鎮靜（sedation） → 昏迷（coma）

37.關於Benzodiazepines類鎮靜-催眠（sedative-hypnotic）藥物，對於正常睡眠週期的影響，下列敘述何者錯誤？(102-2)

A.縮短眼球快動型睡眠（Rapid eye movement）的期間

B.縮短第四期非眼球快動型睡眠（Non-rapid eye movement）的期間

C.縮短第二期非眼球快動型睡眠（Non-rapid eye movement）的期間

D.縮短進入睡眠所需要的時間

76

Benzodiazepines類鎮靜-催眠（sedative-hypnotic）藥物與Barbiturates類鎮靜-催眠藥物相較而言，則下列敘述何者錯誤？(102-2)

A. Benzodiazepines類藥物較不易引起呼吸抑制的副作用

B. Benzodiazepines類藥物較會縮短眼球快動型睡眠（Rapid eye movement）的期間

C. Barbiturates類藥物較易誘導肝臟中的P450微粒體酶活性

D. Barbiturates類藥物會直接打開GABAA受體氯離子管道，但Benzodiazepines類藥物則否

下列那一種鎮靜安眠藥物為時下青少年普遍所濫用之藥物，俗稱“FM2‖ (104-2)

A. Flurazepam

B. Flunitrazepam

C. Diazepam

D. Triazolam

77

下列那一種Benzodiazepine類的鎮靜－催眠（sedative-hypnotic）用藥必需先在體內代謝成活性成分，才會產生其藥理作用？(104-2 理)

A.Diazepam

B.Oxazepam

C.Lorazepam

D.Clorazepate

美華正在服用diazepam治療睡眠問題，但需要同時治療胃潰瘍，下列何者最不適宜併用？(104-2 理)

A. Cimetidine

B. Ranitidine

C. Nizatidine

D. Famotidine

78

下列何者不是flurazepam的主要代謝產物？(103-1)

A. B. C. D.

79

下列何者是zaleplon的主要代謝產物？(103-1)

A. B. C. D.

80