Barbituric Acid
Ultra shortacting
Long-Acting
Intermediate acting Short acting
Thiopental sodium
Phenobarbital
Amobarbital Pentobarbital
Factors effecting Duration of action as by the SAR
Phenobarbital Thiopental Sodium
Branched R group
Short ethyl chain Long chain of R group
Total carbon = 2 (not counting Total C = 7
aromatic)
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.
O
HN NH Barbituric acid
O O
Inactive inactive coz not lipophilic enough
O O O
R
HN NH HN NH N NH
O O O O O O
R R R R
R
inactive active active
coz not lipophilic enough
O
R R
N N
O O
R R
HN C
C2H5
O C C
N C
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.
HN C O 2
1
C2H5 6 4
O C C C
5 3 6
more potent than HN C C2H5
HN C
1 5
C C
2 4 O N O
O H
3
Short chains at carbon 5 resist oxidation and hence are
long-acting. Long chains are readily oxidized and thus produce
short-acting barbiturates.
Inclusion of polar groups (e.g., OH, CO, COOH, NH2, RNH, and
SO3H) in the 5-alkyl moiety reduces potency considerably.
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 ͚thiopeŶtal sodiuŵ͛ find their profuse
and abundant application as ͚iŶtraveŶous aŶaesthetics͛.
O
HN C
C2 H5
SNa HC C (CH2)2CH3
HN C CH
CH3
Thiopental sodium O
Inclusion of more sulphur atoms (at C-2 and C-6) decreases
activity. Likewise replacement of Oxygen with Nitrogen
abolishes activity
NH
R R
N N
Inactive
O O
R R
Phenobarbital
• Phenobarbital or phenobarbitone is
a barbiturate which is most widely
used anticonvulsant worldwide and
the oldest still commonly used.
O
C2H5
C
C NH
C C
O N O
H
Phenobarbital
• 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
O
Diethyl
EtOH oxalate
and Na C2H5O C C OC2H5
(-OC2H5)
Synthesis of H
C
O
C
O
OC2H5
Phenobarbi C
O
OC2H5
O
Diethyl phenyl-oxyalo-
C
O
OC2H5
tone -HBr
C2H5-Br(ethyl bromide)
C2H5-ONa (sodium ethoxide)
acetate
O O
C2H5
C2H5 O
C OC H C
2 5
H2N NH2 C NH
C C urea
C C
C OC2H5 N
O H O
O -2 EtOH
Ethylphenyl malonic Phenobarbital
ester
O
HN C
C2H5
HN C
C
CH
(CH2)2CH3
CH3
C2H5 O C Na
C2H5-Br
C2H5 O C H
-H Ethyl Bromide
C Na C
C2H5 O H C2H5 O H
Sodium Metal - NaBr
Diethyl O O
malonate
O O
Br C-CH2-CH2-CH3
C2H5 O C C2H5 C2H5 O C
CH3 C2H5
C 2-Bromopentane C
CH3
O O
Diethyl ester of ethyl- Diethyl ester of
(1-methyl butyl) ethyl malonic acid
malonic acid
ii) Preparation of Thiopental sodium
O
S C C
HN C C-CH2-CH2-CH3
HN C C-CH2-CH2-CH3
CH3
CH3 O
O
Enol form Keto form
NaOH
O
HN C
C2H5
Thiopental sodium
NaS CH C
HN C C-CH2-CH2-CH3
CH3
O
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
Long term use avoided due to toxicity Long term use is relatively safe
Sleep induced by it causes hangover Sleep induced by it is just like natural
effect after waking up sleep and is refreshing to wake up
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
H3C O CH3
•Synthesis O
H2SO4
• O O
H3C CH3
PARALDEHYDE
ACETALDEHYDE
CH3
Glutethimide
Chloral Hydrate
Cl C CH2
OH
Cl Cl
Chloral Hydrate Trichloroethanol
(Active compound)
• 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
Herbal sedatives
• Ashwagandha
• Valerian
• Passiflora
Ashwagandha
• Withania somnifera, also known as
Ashwagandha, is a plant in Solanaceae or
nightshade family.
Uses:
• Ashwagandha is effective for insomnia but
does not act as a good sedative
Main compounds
• Steroids :withaferin A
• Alkaloids :anaferine
NH O
N
H
anaferine
withaferin A
• MOA
• increases the effects of GABA which is a
inhibitory neurotransmitter that depresses
CNS by binding at the GABAa receptor
Valerian
Valerian (Valeriana officinalis), a member of the
Valerianaceae family.
chemical compounds responsible for sedative
effect is Valerenic acid H