CNS depressants
CNS depressants can be classified into:
I- Sedative hypnotics II- Anxiolytic drugs
III- CNS depressants with skeletal muscle relaxant properties
IV- Anticonvulsants V- Antipsychotics
I- Sedative hypnotics
- Can be used to overcome insomnia (restlessness)
- Cause drowsiness, initiation and/or maintenance of sleep
- Pharmacological effects are dose related:
Dose: ↑ Sedation ► Hypnosis ► Surgical anesthesia
- No common structural features, include:
1- Barbiturates. 2- Chloral. 3- Ureides. 4- Piperidinediones.
5- Cyclopyrrolones 6- Imidazopyridines. 7- Benzodiazepines
8- Melatonin Receptor Agonist 9- Antihistamines 1
2
1- Barbiturates
• The barbiturates are 5,5-disubstituted barbituric acids.
• For good hypnotic activity, barbituric acid derivatives must be weak
acids .
• They must have lipid/water partition coefficient between certain limit.
• The acidity of the barbiturates in aqueous solution depends on the
number of substituents attached to barbituric acid.
NH NH
OO
O
N NH
OO
OH
N N
O OH
OH
MOA:
Enhance the GABA-ergic inhibitory response (as Benzodiazepines).
S.E.
Slowly eliminated barbiturates: hangover (overshadow) & psychomotor
impairment (injury).
Now barbiturates get minimal use as sedatives & hypnotics (Why?)
1. They have higher toxicity, that cause greater CNS depression.
2. They induce many of the liver metabolizing enzymes.
3. Barbiturates cause tolerance and, often physical dependence.
N.B.:
When an individual addicted to barbiturates, sudden withdrawal should be
avoided, because it can cause grand mal seizures, which lead to a spasm
of the respiratory musculature, producing impaired respiration, cyanosis,
and possibly death. 3
SAR:
HN NH
R R
OO
O
if replaced with S give thiobarbiturates
1
3
5
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.4
Substitution on nitrogen:
Substitution on one NH by alkyl gp ↑ lipid solubility
►quicker onset & shorter duration
As the N-alkyl increases in size, the lipid solubility increases, But larger
alkyl groups (> methyl) ► convulsant properties.
Alkyl substitution on both N1 & N3 renders the drug nonacidic (inactive).
HN NH
R R
OO
O
1
3
5
5,5-Disubstitution:
1. Both substituents shoud be between 6-10 carbon.
2. Branching, unsaturation, replacement of alkyl with alicyclic or aromatic
substituents, ↑ the lipid solubility leading to high potency.
3. Introduction of a halogen atom into the 5-alkyl substituent ↑ the potency.
4. Introduction of polar groups e.g. OH, NH2, RNH, CO, COOH and SO3H into
the 5-alkyl substituent ↓ the lipid solubility (may destroy potency).
For hypnotic activity, the compound must
be a weak acid with suitable log P.
5
6
Classification
Barbiturates are classified according to their duration of action into:
• Long duration of action (> 6 hours).
• Intermediate duration of action (3-6 hours).
• Short duration of action (< 3 hours).
• Ultrashort duration of action (intravenous anesthetics).
Onset up to 1 hourlasts about 12 hoursused for ; daytime sedation seldom used. - treatment of seizure disorders
Daytime Sedatives and Typical Anticonvulsants
Long-Acting Barbiturates
7
CH2CHCH2 (CH3)2CH H
CH3CH2 (CH3)2CHCH2CH2 H
B. Intermediate duration of action
Aprobarbital
Amobarbital
CH3CH2CH3CH2CH2CH
CH3
H
CH2 CHCH2 CH3CH2CH2CH
CH3
H
C. Short duration of action
Pentobarbital
Secobarbital
used for : - insomnia. - preoperative sedation.- Anesthesia and euthanasia in animals
Sedatives and Hypnotics
used for - preoperative sedation.- insomnia (seldom used).
Typical Sedatives and Hypnotics
• thiocarbonyl and C-5 side chain with 5 carbon unit •(ethyl or allyl e.g. Thiamylal CH2CH=CH2)
D. Ultra-Short-Acting Barbiturates
NH NH
S
O OCH3CH2CH2(CH3)CH CH2CH3
1 2 34
56
ThiopentalInduction Anaesthesia
8
OC2H5
OC2H5
O
O
R
R
NH2
NH2
XC2H5OH
NH
NH
O
O
X
R
R+
Disubstituteddiethylmalonate
X=O in ureaX=S in thiourea
X=O in X=S in thio
barbituratesbarbiturates
-2
Synthesis of Barbiturates
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.
Barbiturates - Metabolism
Oxidation of substituent at C- 5by CYP450’s
Most Barbiturates
Aromatic Hydroxylation
PhenobarbitalMephobarbital
Slide 6
Glucuronide and sulfate conjugates
An ultimate (Ω) or penultimate (Ω-1) oxidation of C-5 substituents
Barbiturates - Metabolism
Desulfuration
Thiobarbiturates
N-Methylbarbiturates
N-Dealkylation
Slide 7
mephobarbital phenobarbital
Desulfuration of 2-thiobarbiturates to yield more hydrophilic barbiturates
Barbiturates - Metabolism
hepatic metabolic inactivation
N-oxidation
Hydrolysis
Most Barbiturates
Most Barbiturates
Slide 5
12
Cl
Cl
Cl H
O
H2O Cl
Cl
Cl
OH
OH
H
alcoholdehydrogenase
Cl
Cl
Cl OH
trichloroethanol
chloral
aldehyde dehydrogenase
chloral hydrate
Cl
Cl
Cl OH
O
trichloroacetic acidProlonged
effect
Inactive metabolite
Init. effect
Has no analgesic or tranquilizing effect & devoid of adverse respiratory effects
A weak acid (electron-withdrawing CCl3 group) ► irritating to stomach.
MOA: Trichloroethanol has barbiturate-like effects on the GABAA receptor.
Metabolism: 1. Quickly reduced to trichloroethanol (hypnotic activity).
2. Quickly detoxified to the inactive trichloroacetic acid.
2- Chloral (Chloral hydrate)Trichloroacetaldehyde monohydrate
13
3- Ureides Only Acetylcarbromal (1-Acetyl-3-(2-Bromo-2-ethyl-
butyryl)-urea ) is still available.
Prolonged use is not recommended due to
in vivo release of bromide ions (bromism)
4- Piperidinediones
e. g. Methyprylon 3,3-diethyl-5-methyl-2,4- piperidinedione
They are effective sedative-hypnotics, structurally related to
barbiturates (Hence, many biological respects).
NH
O
O
CH3
5- Cyclopyrrolones
e. g. Zopiclone
A new hypnotic agent with no withdrawal symptoms
(no accumulation on repeated administration).
Metabolism:
Major: less active, zopiclone N-oxide Minor: inactive, N-desmethylzopiclone
N
Cl
N
N
NN
NO
O
O
CH3
14
6- Imidazopyridines
e. g. Zolpidem
short t1/2 (rapid metabolic oxidation to inactive COOH acid metabolites.
N
N
H3C
CH3
N
O
H3C CH3
N
N
HOOC
COOH
N
O
H3C CH3ii) aldehyde dehydrogenase
i) CYP3A4Two different metabolites
or
Nonbenzodiazepine GABAA Agonists: [Z drugs] zopiclone &
zolpidem Advantages:
They are used as short-acting sedative-hypnotics.
They have high-affinity for GABAA receptors ~ to benzodiazepines.
They are highly lipophilic, so rapid absorption & distribution.
They have very little physical dependence & abuse potential.
7- Benzodiazepines
MOA: bind to specific binding sites in GABAA receptors.
Used as anxiolytics, hypnotics, anticonvulsants and muscle relaxants.
Advantages: Over Barbiturates:
Relative safety (no respiratory depression). Preferred for patients with suicidal
intentions. Fewer drug interactions.
Disadvantages:
Slowly eliminated due to active metabolites in blood and brain (hangover effect and
accumulation on repeated dose).
N
N
OH
Cl
Cl
OCH3
N
N
OH
Cl
OCH3
N
N
F
O
O2N
CH3
N
N
NBr
OH
N
N
O
O2N
H
LormetazepamTemazepamFlunitrazepamBromazepam Nitrazepam
15
N
HN
O
8- Melatonin Receptor Agonist
HN
O
NH
CH3O
NH
O
OCH3
H
CH3
RamelteonMelatonin
Constrained analogues of melatonin.
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
16
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