Sedative hypnotics

Dr. Majdi BkhaitanDr. Majdi Bkhaitan
SEDATIVE/HYPNOTICSEDATIVE/HYPNOTIC
SS
ANXIOLYTICSANXIOLYTICS
Dr. Majdi Bkhaitan
Dr. Nashwa Ibrahim
Department Of Pharmaceutical
chemistry
mmbakhaitan@uqu.edu.sa

On successful completion of this chapter
students should be able to:
 Describe anxiety and Insomnia.Describe anxiety and Insomnia.
 Describe state of lifeDescribe state of life
 classify anxiolytic drugs.classify anxiolytic drugs.
 Explain anxiolytic drugs MOA.Explain anxiolytic drugs MOA.
 Interpret and predict anxiolytic drugs SAR.Interpret and predict anxiolytic drugs SAR.
 Recognize hypnotic non anxiolytic agents.Recognize hypnotic non anxiolytic agents.
 Differentiate between addictive and non-Differentiate between addictive and non-
addictive hypnotics.addictive hypnotics.

AnxietyAnxiety
 feeling of helplessnessfeeling of helplessness
 difficulty in concentratingdifficulty in concentrating
 irritability & insomniairritability & insomnia
 GI disturbancesGI disturbances
 muscle tensionmuscle tension
 excessive perspirationexcessive perspiration
 palpitationspalpitations
 dry mouthdry mouth
 impending doomimpending doom
 dreaddread

Clinical DisordersClinical Disorders
• Panic disorder
• Obsessive-compulsive disorder
• Post-traumatic stress disorder
• Social phobia
• Social anxiety disorder
• Generalized anxiety disorder
• Specific phobias
 Anxiolytic sedative, minor tranquilizers, antianxiety,
tensiolytics, are used to control neuroses and stress.
Strategy for treatment
– Reduce anxiety without causing sedation.

NormalNormal

Relief from AnxietyRelief from Anxiety
__________________  __________________________________
SEDATIONSEDATION
(Drowsiness/decrease reaction time)(Drowsiness/decrease reaction time)

HYPNOSISHYPNOSIS

Confusion, Delirium, AtaxiaConfusion, Delirium, Ataxia

Surgical AnesthesiaSurgical Anesthesia

Depression of respiratory and vasomotor centerDepression of respiratory and vasomotor center
in the brainstemin the brainstem
COMACOMA

DEATHDEATH

AnxiolyticsAnxiolytics
1)1) Benzodiazepines (BZDs).Benzodiazepines (BZDs).
2)2) Barbiturates (BARBs).Barbiturates (BARBs).
3)3) 5-HT5-HT1A1A receptor agonists.receptor agonists.
4)4) 5-HT5-HT2A2A, 5-HT, 5-HT2C2C & 5-HT& 5-HT33 receptorreceptor
antagonists.antagonists.
If ANS symptoms are prominentIf ANS symptoms are prominent::
• ß-Adrenoreceptor antagonists.ß-Adrenoreceptor antagonists.
∀ αα22-AR agonists (clonidine).-AR agonists (clonidine).

AnxiolyticsAnxiolytics
 Other Drugs with anxiolytic activity.Other Drugs with anxiolytic activity.
– TCAs (Fluvoxamine). Used for ObsessiveTCAs (Fluvoxamine). Used for Obsessive
compulsive Disorder.compulsive Disorder.
– MAOIs. Used in panic attacks.MAOIs. Used in panic attacks.
– Antihistaminic agents. Present in over theAntihistaminic agents. Present in over the
counter medications.counter medications.
– Antipsychotics (Ziprasidone).Antipsychotics (Ziprasidone).
 Novel drugsNovel drugs.. (Most of these are still on clinical trials).(Most of these are still on clinical trials).
– CCKCCKBB (e.g. CCK(e.g. CCK44).).
– EAA's/NMDA (e.g. HA966).EAA's/NMDA (e.g. HA966).

Drug ChoicesDrug Choices
Older:Older:
 Barbiturates (drugs ending in “barbital”)Barbiturates (drugs ending in “barbital”)
 Alcohols / Choral HydrateAlcohols / Choral Hydrate
Newer:Newer:
 Benzodiazepines (drugs name ending in “lam” orBenzodiazepines (drugs name ending in “lam” or
“pam”)**“pam”)**
 Benzodiazepine “Like” (zolpidem & zaleplon)Benzodiazepine “Like” (zolpidem & zaleplon)
 5-HT5-HT1A1A partial agonist (buspirone)partial agonist (buspirone)
** The most commonly used anxiolytics

Mechanism of ActionMechanism of Action
• “Most” sedative-hypnotics exert effects on GABAA R’s
• GABA - the major inhibitory NT in the CNS
• GABAA receptors - heteromultimeric structure
– 5 transmembrane polypeptide subunits
per receptor/channel complex
– α,β,δ,ε,γ,π polypetide subtypes
– muliple isoforms for each (e.g. α1-6)
• GABA binding stimulates Cl-
current
- hyperpolarizing effect
- inhibitory effect on neuronal
excitability

GABAergic SYNAPSEGABAergic SYNAPSE
GABA
glutamate
glucose
Cl
-
GAD

BarbituratesBarbiturates
Barbiturates
Benzodiazepin
GABA
Multiple mechanisms
1) Bind to GABAA receptors at different site
• Don’t compete for BNZ binding & are not blocked
by flumazenil
• Increases the duration of Cl-
channel openings

BarbiturateBarbiturate Multiple MOAMultiple MOA
1.1. Increase GABA effect (increased durationIncrease GABA effect (increased duration
of openings)of openings)
2.2. Directly activate GABADirectly activate GABAAA channels atchannels at highhigh
concentrationsconcentrations
3.3. Block glutamate NT* effectsBlock glutamate NT* effects
4.4. Block Na channelsBlock Na channels
* Glutamate is an excitatory NT

 Barbiturates modify the mechanism ofBarbiturates modify the mechanism of
synaptic transmission, they reduce thesynaptic transmission, they reduce the
excitability of post-synaptic cell by alteringexcitability of post-synaptic cell by altering
the permeability of the cell membrane.the permeability of the cell membrane.
They exert their action on the centralThey exert their action on the central
synaptic transmission process of thesynaptic transmission process of the
reticular activating system, and thereticular activating system, and the
cerebral cortex becomes deactivatedcerebral cortex becomes deactivated
(antidepolarizing blocking agents).(antidepolarizing blocking agents).
Barbiturates act also upon the limbic,Barbiturates act also upon the limbic,
hypothalamic, and thalamic synaptichypothalamic, and thalamic synaptic
system.system.

 Physical dependence may be induced byPhysical dependence may be induced by
various doses of the drugs.various doses of the drugs. As a rule, drugAs a rule, drug
dependence is followed by tolerance,dependence is followed by tolerance, inin
which increased doses are required towhich increased doses are required to
obtain the same pharmacological effect.obtain the same pharmacological effect.
 Barbiturates don’t induce natural sleep.

HN NH
O
OO
R1 R2
R( ) 1
2
3
4
5
6
Barbiturates: SAR
 In order to posses good hypnotic
activity, a barbiturate must be a weak
acid and must have a lipid /water
partition coefficient between certain
limits.

SAR: 5,5,-disubstituted & 1,5,5-
trisubstituted are active
1,3-disubstituted or 1,3,5,5-
tetrasubstituted are inactive or
produce convulsions
All other substitution ► inactive
* Replacement of C-2 O by S → ↑ lipid solubility. Thiopental used as IV
anesthetics due to rapid onset & quick brain levels achieved.
* Introduction of more sulfur atoms (2,4-dithio derivatives) destroys
potency, due to decreased hydrophilic character beyond required limits.
17

Barbiturates: SAR

HN N
O
O
R1 R2
OH
HN N
O
O
R1 R2
O
N N
O
R1 R2
O
-
O
-
-
K1
K2
AcidityAcidity::
pKa of unsubstituted barbituric acid equals 4.12, whilepKa of unsubstituted barbituric acid equals 4.12, while
pKa of 5,5 disubstituted barbituric acid equals 7.1-8.1.pKa of 5,5 disubstituted barbituric acid equals 7.1-8.1.
So, salts of the 5,5 disubstituted barbituric acid can beSo, salts of the 5,5 disubstituted barbituric acid can be
obtained with bases such NaH. A second ionization canobtained with bases such NaH. A second ionization can
occur with pKa values 11.7-12.7. It is possible tooccur with pKa values 11.7-12.7. It is possible to
assume that dialkali metal salts could be prepared.assume that dialkali metal salts could be prepared.

Barbiturates - Metabolism
Oxidation of
substituent at C- 5
by CYP450’s
Most Barbiturates
Aromatic Hydroxylation
Phenobarbital
Mephobarbital
Slide 6
Glucuronide and
sulfate conjugates
An ultimate (ω) or penultimate (ω -1) oxidation of C-5 substituents

Desulfuration
Thiobarbiturates
N-Methylbarbiturates
N-Dealkylation
Slide 7
mephobarbital phenobarbital
Desulfuration of 2-thiobarbiturates to yield more hydrophilic barbiturates

hepatic metabolic inactivation
N-oxidation
Hydrolysis
Most Barbiturates
Most Barbiturates
Slide 5

OC2H5
OC2H5
O
O
R
R
NH2
NH2
X
C2H5OH
N
H
N
H
O
O
X
R
R
+
Disubstituted
diethylmalonate
X=O in urea
X=S in thiourea
X=O in
X=S in thio
barbiturates
barbiturates
-2
Synthesis of Barbiturates
27
Barbiturate Abuse:
•Prolonged use leads to habituation, (tolerance to increased doses and
physical dependence).
•Monooxygenase enzyme synthesis is increased by repeated dose of
phenobarbital (enzyme induction), therefore the drug will be rapidly
metabolized leading to tolerance.

Benzodiazapines
 Many derivatives of the 1,4-benzodiazepine seriesMany derivatives of the 1,4-benzodiazepine series
display:display:
 TranquilizingTranquilizing
 Muscle relaxantMuscle relaxant
 Anticonvulsant andAnticonvulsant and
 Sedative effects.Sedative effects.
 No 1,4-benzodiazepin can be selected exclusivelyNo 1,4-benzodiazepin can be selected exclusively
as a hypnotic agent in preference to otheras a hypnotic agent in preference to other
benzodiazepins.benzodiazepins.
 Benzodiazepins that are rapidly metabolized andBenzodiazepins that are rapidly metabolized and
eliminated (e.g. temazepam) have gained popularityeliminated (e.g. temazepam) have gained popularity
as sleep inducers, because of lack of toxicity neitheras sleep inducers, because of lack of toxicity neither
through neither accumulation nor hangover.through neither accumulation nor hangover.

Benzodiazepine MOABenzodiazepine MOA
GABA
GABA +
diazepam
Pressure
5 mV
1sec
• CNS BNZ receptors: thalamus, limbic
system, cerebral cortex.
• BNZs - increase the frequency of Cl-
channel openings in presence of GABA

Barbiturates
Benzodiazepine
GABA
Benzodiazepine Mechanism of ActionBenzodiazepine Mechanism of Action
• GABAA receptor composition varies in different regions
• BNZs bind to receptors with alpha & gamma subunits.
• BNZ binding “enhances” the effect of GABA on the Cl-
current
• BNZs exert no effect in the absence of GABA

Barbiturates
Benzodiazepines
GABA
Benzodiazepine Mechanism of ActionBenzodiazepine Mechanism of Action
• BNZ effect & binding blocked by flumazenil (BNZ antagonist)
• Not all BNZs are identical (may be due to differences in
effects on different GABAA R isoforms)
• BNZs - high doses commonly produce anterograde amnesia
more common with BNZs vs. other hypnotics)

N
N
O
X
R
1 2
3
45
N
N
O
Cl
CH3
N
N
Cl
O
N
CH3
H
N
N
O
Cl
CH3
OH
N
N
Cl
NN
CH3
N
N
Cl
N
CH3
F
DIAZEPAM
CHLORDIAZEPOXIDE OXAZEPAM
ALPRAZOLAMMIDAZOLAM

 SAR:SAR:
 Presence of an electron-Presence of an electron-
withdrawing group inwithdrawing group in
positionposition 77 is required foris required for
activity. More theactivity. More the
electron-withdrawingelectron-withdrawing
more will be the activity.more will be the activity.
 Position 6,8 and 9 shouldPosition 6,8 and 9 should
not be substituted.not be substituted.
N
N
O
X
R
1 2
3
45
6
7
8
9

 A phenyl ring in position 5A phenyl ring in position 5
promotes activity, activitypromotes activity, activity
is increased when theis increased when the
phenyl is ortho or diorthophenyl is ortho or diortho
substituted with electron-substituted with electron-
withdrawing groups.withdrawing groups.
Substitution in paraSubstitution in para
position brings aboutposition brings about
decrease in activity.decrease in activity.
 Saturation of the N4-C5Saturation of the N4-C5
double bond or its shiftingdouble bond or its shifting
to other positionsto other positions
decreases activity.decreases activity.
N
N
O
X
R
1 2
3
45
6
7
8
9

 Substitution with alkyl group atSubstitution with alkyl group at
position 3 decreases activity,position 3 decreases activity,
substitution with OH groupsubstitution with OH group
doesn’t. This hydroxyl affects thedoesn’t. This hydroxyl affects the
pharmacokinetic of the drug,pharmacokinetic of the drug,
truly, compounds that doesn’ttruly, compounds that doesn’t
posses OH in 3 are non-polar,posses OH in 3 are non-polar,
and have long duration of action,and have long duration of action,
and undergo hepatic oxidation,and undergo hepatic oxidation,
whereas, compoundswhereas, compounds
possessing the 3-OH group arepossessing the 3-OH group are
more polar and are readilymore polar and are readily
conjugated and excreted.conjugated and excreted.
N
N
O
X
R
1 2
3
45
6
7
8
9

 2-carbonyl function is2-carbonyl function is
optimal for the activity, as isoptimal for the activity, as is
the nitrogen atom atthe nitrogen atom at
position 1, the N-position 1, the N-
substituent should be small.substituent should be small.
On the other hand thereOn the other hand there
were obtained compoundswere obtained compounds
with a fused triazole ringwith a fused triazole ring
represented by “triazolam”represented by “triazolam”
and alprazolam, alsoand alprazolam, also
midazolam, with a fusedmidazolam, with a fused
imidazole ring. In theseimidazole ring. In these
latter mentioned cases thelatter mentioned cases the
presence of the 7- electron-presence of the 7- electron-
withdrawing group is notwithdrawing group is not
required for the activity.required for the activity.
N
N
O
X
R
1 2
3
45
6
7
8
9

Pharmacokinetics of BenzodiazepinesPharmacokinetics of Benzodiazepines
• Hepatic metabolism. Almost all BDZsHepatic metabolism. Almost all BDZs
undergo microsomal oxidation (N-undergo microsomal oxidation (N-
dealkylation and aliphatic hydroxylation)dealkylation and aliphatic hydroxylation)
and conjugation (to glucoronides).and conjugation (to glucoronides).
• Rapid tissue redistributionRapid tissue redistribution  long actinglong acting 
long half lives and elimination half liveslong half lives and elimination half lives
(from 10 to > 100 hrs).(from 10 to > 100 hrs).
• All BDZs cross the placentaAll BDZs cross the placenta  detectabledetectable
in breast milkin breast milk  may exert depressantmay exert depressant
effects on the CNS of the lactating infant.effects on the CNS of the lactating infant.

Pharmacokinetics of Benzodiazepines
• Many have active metabolites with half-livesMany have active metabolites with half-lives
greater than the parent drug.greater than the parent drug.
• Prototype drug is diazepam (Valium), which hasPrototype drug is diazepam (Valium), which has
active metabolites (desmethyl-diazepam andactive metabolites (desmethyl-diazepam and
oxazepam) and is long acting (t½ = 20-80 hr).oxazepam) and is long acting (t½ = 20-80 hr).
• Differing times of onset and elimination half-livesDiffering times of onset and elimination half-lives
(long half-life => daytime sedation).(long half-life => daytime sedation).
 Estazolam, oxazepam, and lorazepam, which are
directly metabolized to glucoronides have the
least residual (drowsiness) effects.
 All of these drugs and their metabolites areAll of these drugs and their metabolites are
excreted in urine.excreted in urine.

Biotransformation of BenzodiazepinesBiotransformation of Benzodiazepines
From Katzung, 1998

Metabolism

 Piperidindione:
 Such as Glutethimide, which is considered the most
active non-barbiturate hypnotic. Like barbituratres it
is a rostral reticular depressant and exhibit a potent
anticholinergic activity. It is metabolized by
hydroxylation at various positions, then it is
glucuronated.
N OO
C2H5
H

Nonbenzodiazepine GABAA Agonists
 Historically, benzodiazepines have been the mainstay for treatment
of sleeping disorders, yet they have many shortcomings. A new
group of sedative-hypnotic agents similar to the benzodiazepines—
zaleplon, zolpidem, and zopiclone—have been developed with
affinity for the GABA receptor complex. This produces a more
efficacious clinical profile with fewer side effects than the
benzodiazepines.
 Zolpidem, zopiclone, and zaleplon (the “Z” drugs) are structurally
distinct, and are being used as short-acting sedative-hypnotics in
the United States and Europe. They act at the GABAA high-affinity
receptors comparable to the benzodiazepines but with different
subunit specificity. Because of variation in binding to the GABA
receptor subunits

Imidazopyridine:
Such as zolpidem (stilnox®) and alpidem., which are
non benzodiazepine hypnotic agents. Acting on the
high-affinity benzodiazepine receptor subtype in the
brain. They have no major effect on sleep stages, have
no rebound effect after withdrawal, and used mainly as
hypnotic.
Zolpidem was the first non-benzodiazepine ω1 “BDZ
1” agonist marketed. It is a hypnotic agent with
minimal anticonvulsant and anxiolytic effects
N
N
O
CH3
CH3
CH3
N CH3
Zolpidem (stilnox )

 Cyclopyrolone: such as zopiclone (Imovane) a non
benzodiazepine hypnotic agent, Acting on the high-
affinity benzodiazepine receptor subtype in the brain,
at 7.5mg dose. It decreases sleep latency, increase
total sleep duration, reduce the number of awakenings
and increase sleep efficiency, REM sleep is
substantially unaffected by zopiclone. Rebound effect
and withdrawal symptoms do not accompany
discontinuation of Zopiclone, it is also devoid of
abuse and dependence potential.
N
N
N
O
N
O C
O
N N CH3
Cl
Zopiclone (Imovane)

Pyrazolopyrimidine
Zaleplon
It displays a unique binding profile with
GABAA that is distinct from the
benzodiazepines but similar to that of
zolpidem . Because of it greater potency for
GABAA, the starting dose for zaleplon is
comparable to that of zolpidem. It is rapidly
absorbed, zaleplon. It is rapidly metabolized
by the liver, with an elimination half- life of
pproximately 1 hour. The oxidative
metabolites are inactive, conjugated with
glucuronic acid, and eliminated in the urine.
zaleplon has been shown to improve sleep
quality with minimal adverse effects and no
significant rebound insomnia on stopping
the drug. Dr. Majdi BkhaitanDr. Majdi Bkhaitan

 Buspirone “BuSparBuspirone “BuSpar®®
””

8- Melatonin Receptor Agonist
 It is effective in initiating sleep (shortening sleep latency) but not in maintaining
sleep (has short half-life).
 It is a very potent & very selective ligand for the MT1 receptor
 used in the treatment of insomnia.
 Does not bind with other receptors associated with sleep (GABAA
or dopamine).
MT receptor play important role in discovery and approval of ramelteon.
Ramelteon
52

Sedative hypnotics

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