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

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