Medicinal chemistry I- Unit 4A. sedative and hypnotics.pptx

Mr. Mote G.D.
ADCBP,ASHTA
Mr. Mote G.D, ADCBP, Ashta

Defination
• A sedative drug decreases activity and
excitement of the patient and clams anxiety
by producing mild depression of CNS without
causing drowsiness or sleep
• A hypnotic drug produces drowsiness, forcing
the patient to sleep by depressing the CNS,
particularly the reticular activity which
influences wakefulness

Dose dependent activity
• All sedative, hypnotic and GA depress the CNS
• The observed effect depends on the dose
given to patient
• Small dose cause sedation (calmness)
• Medium dose cause hypnosis (sleepy)
• Largerdose causes surgical anesthesia

Utility
Sedatives counter various types of anxiety such as
• Obsessive-compulsive disorder (OCD)
• Post-traumatic stress disorder (PTSD)
• Social anxiety disorder
• Specific phobias
Hypnotics is for insomnia. Insomnia is a condition
where person is not able to fall sleep

Ideal properties of hypnotics
1. Cause a temporary decrease in the level of
consciousness for the purpose of falling
asleep without any alteration to sleep cycle
2. Must not decrease or arrest respiration, even
at high doses
3. Cause no addiction, tolerance or dependence

Sleep cycle

Stage 1
Stage one begins when a person shifts from wakefulness to sleep. It is a
period of light non-REM sleep that slows down a person’s heart rate,
breathing, eye movements, and brain waves. The muscles also relax,
although they may twitch occasionally.
This stage is short and lasts for around 1–5 minutes.
Sleep Cycle

Stage 2
This is a period of deeper non-REM sleep, where the muscles relax further, eye
movements stop, and body temperature drops.
During the first sleep cycle of the night, this stage lasts for around 25 minutes,
lengthening with each new sleep cycle. Overall, it accounts for more than 50% of
sleep in adults.
Sleep Cycle

Stage 3
Stage 3 non-REM sleep is the deepest stage of sleep and the hardest to
awaken from. During this stage, heart rate, breathing, and brain waves
become regular.
A person will experience the most deep sleep during the first half of the
night. With each sleep cycle, the amount of deep sleep decreases.
This is the stage people typically find most difficult to wake from. If a person
wakes during deep sleep, they may feel mentally foggy for around 30–60
minutes. The overall percentage of deep sleep tends to decrease with age
Sleep Cycle

Stage 4
The last stage of the sleep cycle is REM sleep. The term “REM” refers to a
person’s eye movements. During this stage, the eyes move quickly and rapidly
from side to side.
During REM sleep, breathing quickens and becomes more erratic. Other vital
signs, such as blood pressure and heart rate, become less regular.
REM is the sleep stage most associated with dreaming,
Sleep Cycle

• sleep cycle : Sleep proceeds in cycles of light
sleep and deep sleep
• Light sleep – NREM sleep, lasts for about 90
mins
• Easy to wake in this period
• Deep sleep – REM sleep, last 5 to 10 mins
• Difficult to wake in this time

Classification of Sedative-Hypnotics
Sedative-
Hypnotics
Barbiturates
Phenobarbital
Mephobarbital
Amobarbital
Butabarbital
Pentobarbital
Secobarbital
Benzodiazepine
Chlordiazepoxide
Diazepam
Oxazepam
Chlorazepate,
Lorazepam,
Zolpidem
Amides
Glutethmide.
Alcohol
Meprobomate,
Ethchlorvynol.
Aldehyde
Triclofos
sodium
Paraldehyde

1. Barbiturates
Barbiturates
Phenobarbital Mephobarbital Amobarbital Butabarbital Pentobarbital Secobarbital

2. Benzodiazepines
Benzodiazpines
Chlordiazepoxide Diazepam Oxazepam Chlorazepate, Lorazepam, Zolpidem

3. Amides
HN
O
O
Glutethimide

4. Alcohol
Alcohol
Meprobamates Ethchlorvynol.

5. Aldehyde
Aldehyde
Triclofos
sodium
Para aldehyde.

Barbiturates
• All derivatives of Barbituric acid
• They are CNS depressants. They are effective
as anxiolytics, hypnotics, anticonvulsants and
analgesics.
• They have addiction potential, both physical
and psychological.
• Thus Benzodiazipines have largely replaced
them in term of sedative-hypnotic

Types
Barbituric Acid
Amobarbital Pentobarbital
Short acting
Intermediate acting
Long-Acting
Thiopental sodium
Ultra shortacting
Phenobarbital

Factors effecting Duration of action as by the SAR
Phenobarbital Thiopental Sodium
Branched R group
Short ethyl chain
Total carbon = 2 (not counting
aromatic)
Long chain of R group
Total C = 7
Additional improvements to
Thiopental Sodium tofurther
decrease duration of action
•N methylation (potency also inc)
•Unsaturated R group

• Mode of action of barbiturates
1. They have positive allosteric effect at GABA
receptor. They bind at a different site than GABA
or Benzodiazepines and stimulate the
pharmacologic action of GABA which is the
principal inhibitory neurotransmitter in the CNS
2. They inhibit AMPA receptor, which binds
glutamate which is principal excitatory
neurotransmitter in the CNS
3. At higher does they inhibit Ca2+ dependent
release of neurotransmitters

• Allosteric drugs bind the receptor at different site. They can both
stimulate or inhibit the receptor function.
• Agonist can only stimulate the receptor function
• Antagonist can only inhibit the receptor function

Structure-Activity Relationship
• Barbituric acid itself does not possess any hypnotic
properties.
•Activity requires a balance of acidic and lipophilic properties.
To make the drug sufficiently acidic, both or at least one of
the two nitrogen must be unsubstituted
To make drug sufficiently lipophilic, the two hydrogen
atoms at position 5 : 5 must have the appropriate substituent
(e.g., alkyl or aryl groups)
The type of substituent's control 2 aspects of the drug
Potency
Duration of Action.

N NH
O
O O
HN NH
O
O O
HN NH
O
O O
HN NH
O
O O
Inactive inactive coz not lipophilic enough
R R R
R R
R
N N
O
O O
R
R
R R
Inactive coz not acidic enough
active
active
inactive
coz not lipophilic enough
Barbituric acid

 the total number of carbon atoms present in the two groups
at carbon 5 must not be less than 4 and more than 10 and
influences onset of action and duration
Total carbon Duration of action
7-9 Rapid onset n shorter
duration
5-7 Intermediate duration
of action
4 Slowest onset and
longest duration of
action

Only one of the substituent groups at position 5 may be a
cyclic group.
C
N C
C
C
HN
C2H5
O
O
O
CH3
Methylepentobarbital

The branched chain isomer exhibits greater activity but
shorter duration. The greater the branching, the more potent
is the drug (e.g., pentobarbital > amobarbital).
This Branched, cyclic or unsaturated alkyl groups reduce
duration of action due to increased ease of metabolic
inactivation
Pentobarbital Amobarbital

(iv) Double bonds in the alkyl substituent groups produce
compounds more readily vulnerable to tissue oxidation ;
hence, they are short-acting.
Pentobarbital Sodium

 Aromatic and alicyclic moieties exert greater potency than
the corresponding aliphatic moiety having the same number
of carbon atoms.
C
HN C
C
C
HN
C2H5
O
O
O
C
N
H
C
C
C
HN C2H5
O
O
O
1 2
3
4
5
6
1
2
3
4
5
6
more potent than

Short chains at carbon 5 resist oxidation and hence are
long-acting. Long chains are readily oxidized and thus produce
short-acting barbiturates.
Pentobarbital Sodium
Barbital

Inclusion of a halogen atom in the 5-alkyl moiety enhances
activity.
Inclusion of polar groups (e.g., OH, CO, COOH, NH2, RNH, and
SO3H) in the 5-alkyl moiety reduces potency considerably.
Methylation of one of the imide hydrogens enhances onset and
reduces duration of action
Methylepentobarbital

The replacement of O-atom with an S-atom, at C- 2 position
of the barbiturates significantly enhances the lipid solubility.
The resulting modified versions of the barbiturates thus
obtained exert a rapid onset of activity by virtue of the fact
that they attain maximal thiobarbiturate-brain levels.
Therefore, such drugs as ‘thiopental sodium’ find their profuse
and abundant application as ‘intravenous anaesthetics’.
Thiopental sodium
HC
HN C
C
C
HN
SNa
O
O
C2H5
CH
(CH2)2CH3
CH3

Inclusion of more sulphur atoms (at C-2 and C-6) decreases
activity. Likewise replacement of Oxygen with Nitrogen
abolishes activity
N N
NH
O O
R
R
R R
Inactive

Phenobarbital
• Phenobarbital or phenobarbitone is
a barbiturate which is most widely
used anticonvulsant worldwide and
the oldest still commonly used.
Phenobarbital
C
C
N
H
C
NH
C
O
O O
C2H5

• It also has sedative and hypnotic
properties but, as with other
barbiturates, has been outdated by the
benzodiazepines for these indications.
• first-line for partial and generalized tonic-
clonic seizures
• first line choice for the treatment of
neonatal seizures

• Sedation and hypnosis are the principal
side effects of phenobarbital. Also
dizziness, nystagmus and ataxia are
common.
• In elderly patients, it may cause
excitement and confusion while in
children, it may result in paradoxical
hyperactivity.
• Overdose may also lead to pulmonary
edema and acute renal failure

• It is one of the longest-acting
barbiturates available – it remains
in the body for a very long time
(half-life of 2 to 7 days) and has
very low protein binding
• Phenobarbital is metabolized by
the liver, mainly through
hydroxylation and glucuronidation
• It is excreted primarily by the
kidneys

Synthesis of
Phenobarbi
tone
Benzyl cyanide
i)Acid hydrolysid
ii) EtOH
C C
O
CH2
CH2 C
O
OC2H5
Ethyl phenyl acetate
EtOH
and Na
(-OC2H5)
Diethyl
oxalate
CH C OC2H5
O
C C OC2H5
O O
Distilled at 180O
C
(-CO)
H
C
C OC2H5
O
C OC2H5
O
CN
Phenyl malonic ester Diethyl phenyl-oxyalo-
acetate
C2H5-Br(ethyl bromide)
C2H5-ONa (sodium ethoxide)
C
C OC2H5
O
C OC2H5
O
C2H5
H2N
C
O
NH2
urea
-2 EtOH
Ethylphenyl malonic
ester
Phenobarbital
OC2H5
O
C2H5O
C
C
N
H
C
NH
C
O
O O
C2H5
-HBr

Thiopental sodium
•Ultra short acting barbiturate (5-10 mins)
•Rapid action (10 -15 sec) and rapid
recovery
•Used mainly as inducing anesthetic
• has no analgesic properties
• anesthetic state maintained by inhalation
anesthetic eg N20
•it is a poor muscle relaxant
HC
HN C
C
C
HN
NaS
O
O
C2H5
CH
(CH2)2CH3
CH3

• it possesses potent anticonvulsant activity it may
be given to treat epileptic seizures that do not
respond to other therapy.
• It is stored as a solid white salt and needs to be
prepared in sterile water to inject the patient
• Rapid recovery not due to rapid metabolism
• It is due to lowered concentration caused by
redistribution of drug from brain to blood. This is
made possible becoz of the salt form of drug

• Dose: 3 to 7 mg/kg.
• It does not have any direct toxic effects on
the liver or kidney
• Although it crosses the placenta it is a safe
agent for induction in pregnancy

Synthesis of Thiopental sodium
i) Preparation of Diethyl ester of ethyl-(1-methyl butyl)
malonic acid
C2H5 O C
C
O
O
O
C2H5
Na
C2H5 O C
C
O
O
O
C2H5
C2H5-Br
Ethyl Bromide
- NaBr
C2H5 O C
C
O
O
O
C2H5
C2H5
C-CH2-CH2-CH3
2-Bromopentane
- HBr
CH3
C2H5 O C
C
O
O
O
C2H5
C2H5
H
Sodium Metal
Diethyl
malonate
Diethyl ester of
ethyl malonic acid
C-CH2-CH2-CH3
CH3
Br
Diethyl ester of ethyl-
(1-methyl butyl)
malonic acid
H
H
Na
H
-H

ii) Preparation of Thiopental sodium
C2H5 O C
C
C
O
O
O
C2H5
C2H5
C-CH2-CH2-CH3
CH3
Diethyl ester of ethyl-
(1-methyl butyl)
malonic acid
C
NH2
NH2
S
HN
C
HN C
C
C
S
O
O
C2H5
- 2 EtOH
NaOH
N
C
HN C
C
C
HS
O
O
C2H5
C-CH2-CH2-CH3
CH3
C-CH2-CH2-CH3
CH3
Thiourea
Keto form
Enol form
HN
CH
HN C
C
C
NaS
O
O
C2H5
C-CH2-CH2-CH3
CH3
Thiopental sodium

Thiamylal
• Ultra short acting barbiturate
• Rapid action but not rapid recovery due to high
lipophilicity and subsequent drug accumulation in
the fatty tissues
• Used mainly as inducing anesthetic in lab animals
• anesthetic state maintained by inhalation
anesthetic eg N20
• Use limited to Veterinary field. Only its sodium
salt is used in humans

Benzodiazepines
• Chemically they are a fusion of a benzene
ring and a diazepine ring
• Benzodiazepines enhance the effect of the
GABA at the GABAA receptor, resulting in
sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety)
anticonvulsant, and muscle relaxant properties
•useful in treating anxiety, insomnia, seizures,
muscle spasms, alcohol withdrawal and preanesthetic
• are safer than barbiturate and not additive

MOA of benzodiazepines
1. They have positive allosteric effect at GABA receptor. They
bind at a different site than GABA or Benzodiazepines and
stimulate the pharmacologic action of GABA which is the
principal inhibitory neurotransmitter in the CNS
2. They block reuptake of Adenosine which is sedating
neurotransmitter, thus promoting its sedative action.
Attach to and directly block the Acetylcholine (ACh) receptors
in the hippocampus thus causing amnesia. (Hippocampus is
where memory is stored and processed. This is how date rape
drug Flunitrazepam works)

SAR of benzodiazepine

R2= carbonyl group
( C=O)

Mostly Cl or NO2 is used at position 7

But para substitution (position 4’) decreases activity

(Note--> inclusion of OH,NH3,SO4,PO4, COOH groups increase polarity)

Types of benzodiazepines
Half life example
Long acting > 24 hrs Diazepam,Nitrazepam
chlordiazepoxide, flurazepam
Intermediate acting 12-24 hrs alprazolam, lorazepam
clonazepam, flunitrazepam,
Short acting < 1-12 hrs midazolam and triazolam.
Based on drug elimination (metabolism + kidney filtration),
3 category of benzodiazepines exist
longer-acting benzodiazepines are recommended for the
treatment of anxiety
Short- and intermediate-acting are preferred for the
treatment of insomnia;

Midazolam
• Midazolam has a rapid onset of action, high
effectiveness and low toxicity level and fast recovery
time
• Properties: It has potent anxiolytic, amnestic, hypnotic,
anticonvulsant, skeletal muscle relaxant, and sedative
properties
• Uses: Used for treatment of acute seizures, moderate
to severe insomnia and for inducing sedation and
amnesia before medical procedures
• used mostly as a premedication for sedation and less
commonly for induction or maintenance of anesthesia.
• MOA- alloteric GABAA enhancer

Diazepam
• Long acting benzodiazepine (>20 hrs)
• due to high blood protein binding of 98.5% which reduces rate of
elimination and it’s metabolic product is also active
• Properties: It has anxiolytic, anticonvulsant, hypnotic -
sedative, skeletal muscle relaxant, and amnestic properties
• Uses :anxiety, panic attacks, insomnia, seizures , muscle
spasms (such as in tetanus cases), restless legs syndrome, alcohol
withdrawal, opiate withdrawal syndrome
• Not used for long term epilepsy due to development of tolerance
• Avoid during pregnancy
• MOA – Allosteric GABAA enhancer

Lorazepam
• high-potency, intermediate acting
duration benzodiazepine drug
Properties: anxiolysis, short term
amnesia, sedation/hypnosis, anticonvulsion, muscle
relaxation
Uses:
• short-term treatment of anxiety, insomnia, acute
seizures, sedation of aggressive patients
• to decrease the likelihood of agitation and seizures in
patients who have overdosed on stimulant drugs
• lorazepam has advantage over diazepam, as in
– Better at ending seizures and
– more prolonged anticonvulsant effect

Lorazepam
• lorazepam is removed from the blood more
rapidly than many other benzodiazepines,
there is less chance that lorazepam
concentrations in blood will reach high levels
and become toxic

Alprazolam
• It belongs to intermediate acting benzodiazepine
• Properties: It has potent anxiolytic, amnestic, hypnotic,
anticonvulsant, skeletal muscle relaxant, and sedative
properties
• Main uses: Alprazolam is used for the treatment of
anxiety disorders and panic attacks
• can cause fetal abnormalities and should not be used
in pregnancy
• It is excreted in breast milk and should not be used by
women who are nursing

Nitrazepam
• A long acting benzodiazepine
• Properties: It has anxiolytic, anticonvulsant, hypnotic -
sedative, skeletal muscle relaxant,
and amnestic properties
• Uses: Nitrazepam is used to treat short-term sleeping
problems (insomnia) and short term management of
epilepsies
• Nitrazepam is not suitable for use in the elderly,
children, pregnant women, or those with chronic
obstructive pulmonary disease

Barbiturates vs Benzodiazepines
Barbiturates Benzodiazepines
They cause high physiological and
psychological dependence
They cause very less physiological and
psychological dependence
Long term use avoided due to toxicity Long term use is relatively safe
Sleep induced by it causes hangover
effect after waking up
Sleep induced by it is just like natural
sleep and is refreshing to wake up
Increase duration of GABA Cl channel
opening
Increase frequency of GABA Cl channel
opening
High Respiratory depression Manageable Respiratory depression

Different alpha units of GABAA have different effects
GABA A receptors containing
alpha 1 subunits are involved in
sleep.
GABA A receptors containing
alpha 2 or alpha 3 subunits are
involved in anxiety.

GABAA Alpha 1 Selective Hypnotics –
MOA of Zaleplon and Zolpidem
• The GABAA receptor contain 6 different alpha subunits
• Benzodiazepines bind to four of GABAA alpha
subunits: alpha 1, alpha 2, alpha 3 and alpha 5.
• Each of these subunits is associated with different
effects, and thus benzodiazepines not only cause
sedation but are also anxiolytic, cause muscle
relaxation, and have alcohol potentiating actions.
• The hypnotics zaleplon and zolpidem bind selectively
to GABA-A receptors that contain the alpha 1 subunit
(sleep).

Advantages over benzodiazepines
• A relatively short half life so one does not wake up
with a "hangover" the following day
• Having little effect on sleep staging, allowing the
individual to obtain approximately the same amount
of time in each stage of sleep as one would without
the medications
• Less likely to cause addiction, withdrawal, or
tolerance relative to older sleeping medications.

• These drugs are very lipophillic which
increases absorption into brain
• They are metabolized by liver into water
soluble metabolites which is rapidly cleared
out in urine and thus avoid accumulation
Zolpidem Zalephon

• Zalephon : hypnotic dose 6-10 mg
Used as hypnotic drug
Good at inducing sleep but not good at maintaining
it since it has short elimination half life
• Zolpidem : hypnotic dose 5-10 mg
Used as hypnotic drug
Slower acting but maintains effect overnight period
due to long elimination half life

Paraldehyde
• Paraldehyde is the cyclic trimer of acetaldehyde
molecules. It is a colorless liquid and sparingly
soluble in water and highly soluble in alcohol.
• Properties: It has an effective anticonvulsant,
hypnotic and sedative
• MOA:
Paraldehyde increases the effects of GABA, a
inhibitory neurotransmitter that depresses CNS, at
the GABAa receptor and decreases levels of
glutamate, which is stimulatory neurotransmitter
that excites CNS

Uses:
•to induce sleep, and is also used to calm psychiatric patients
•it is used to prevent hallucinations and tremors caused due to
alcohol withdrawal
•used to control seizures in infantsm not responding to
phenobarbitone and phenytoin,
• Unlike diazepam and other benzodiazepines, it does not
suppress breathing at therapeutic doses and so is safer when
the patient's breathing is already compromised.
•It is very addictive and Paraldehyde also can stress the
gastrointestinal tract so that a patient can develop ulcers
•Synthesis
•
H3C CH3
O
O O
O CH3
H3C
CH3
H2SO4
ACETALDEHYDE
PARALDEHYDE

Glutethimide
• Properties: sedative, hypnotic
• Use: was used for insomnia but rarely prescribed
today just as likely to cause addiction and caused
severe withdrawal symptoms as barbiturates.
• When taken with codeine, it stimulates metabolic
conversion of codeine into morphine, which is used
for its hallucinogenic effect
• MOA: It binds at the GABAa receptor which
increases the effects of GABA which is a inhibitory
neurotransmitter that depresses CNS

Synthesis of Glutethimide
• Glutethimide (2-ethyl-2-phenylgutarimide) is synthesized by addition of 2-phenylbutyronitrile
to the methylacrylate (Michael reaction), and the subsequent alkaline hydrolysis of the nitrile
group in the obtained compound into an amide group, and the subsequent acidic cyclization
of the product into the desired glutethimide

Chloral Hydrate
• Synthesis
4 Cl2 + C2H5OH + H2O → Cl3CCH(OH)2 + 5 HCl
Chloral hydrate is metabolized to trichloroethanol, which is
responsible for its physiological and psychological effects.
Higher doses can depress respiration and blood pressure.
Properties: seadtive, hypnotic
Use:
It has a very narrow therapeutic window making this drug difficult
to use. Instead benzodiazepines are preferred.
• short time (no more than 2 weeks) treatment of insomnia
• Used in organic synthesis as a reagent
MOA: It binds at the GABAa receptor which increases the effects
of GABA which is a inhibitory neurotransmitter that depresses
CNS
Cl C
Cl
Cl
CH
OH
OH
metabolized
Cl C
Cl
Cl
CH2
OH
Trichloroethanol
(Active compound)
Chloral Hydrate

Synthesis of Barbital
C
O
NH
HN
C
C
C
O
O
O O
H3C
CH3
H2C CH2
CH3 CH3
HN NH
O
H2C
CH2
CH3
CH3
O
O
+ CH3 CH2 OH
2
Sodium Ethoxide
H
H
Urea
2-,2 Diethyl malonate
Barbital

Synthesis of Diazepam
C
O
NH
Cl
N
H
H
C
H2
C
O
C2H5O
+
HN
C
C
CH2
N
O
H
-C2H5OH
Ethyl-2-amino acetate
2-amino ,4-chloro
benzophenone
Cl
S
OCH3
OCH3
O
O
N
C
C
CH2
N
O
Cl
H3C
Diazepam

Existing Benzodiazepines are Non-selective
• Benzodiazepines bind to GABA-A alpha subunits: alpha 1, alpha 2, alpha 3 and
alpha 5.
• Each of these subunits is associated with different effects, and thus
benzodiazepines not only cause sedation but are also anxiolytic, cause muscle
relaxation, and have alcohol potentiating actions.

Location of RAS in brain
(no. 7)
RAS is brain centre for arousal and sleep cycle

Medicinal chemistry I- Unit 4A. sedative and hypnotics.pptx

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