Drugs Acting on CNS

Dr. Amged 1

Depressant Drugs

Dr. Amged 2

Sedatives & Hypnotics

Dr. Amged 3

Sedative & Hypnotics

• A Sedative drug is a CNS depressant that

decreases excitability but does not induce

sleep.

• A hypnotic drug is a CNS depressant that

produces sleep; used to induce sleep when

natural sleep is impossible.

• Both are referred to as sleeping bills and used

to treat insomnia.

Dr. Amged 4

• Insomnia can be classified as:

- Primary (pathogenesis unknown).

- Secondary (situational stress, lifestyle habits,

drugs, and psychiatric or medical disorders).

Dr. Amged 5

Sleep Cycle

• Wakefulness.

• Nonrapid eye movement [NREM] sleep.

• Rapid eye movement [REM] sleep.

Dr. Amged 6

Sleep Factors

• Many autonomic, physiologic, and

biochemical changes are associated with

wakefulness, NREM sleep, REM sleep, and

circadian rhythmicity.

• Neurotransmitters: catecholamines, serotonin,

histamine, acetylcholine, adenosine, γ-

aminobutyric acid.

• Hormones: growth hormone, prolactin, and

melatonin.

Dr. Amged 7

Sedative-Hypnotic Drugs

• Chloral hydrate.

• Barbiturates.

• Benzodiazepines.

• Nonbenzodiazepines

• Melatonin receptor agonists.

• Antihistamines.

• Antidepressants.

Dr. Amged 8

The ideal sedative-hypnotic should:

• Cause transient decrease in the level of

consciousness for the purpose of sleep without

lingering effects (sleep induction and sleep

maintenance).

• Have no potential for decreasing or arresting

respirations (even at relatively high doses).

• Produce no abuse, addiction, tolerance or

dependence.

Dr. Amged 9

Chloral Hydrate

• It was introduced as a sedative in 1869. During

the 1950s and 1960s, chloral hydrate was

widely promoted as a hypnotic.

• Today, it still finds use as a sedative in

nonoperating room procedures for pediatric

patients.Dr. Amged 10

• Chloral hydrate is a weak acid (pKa = 10.04).

• Quite irritating to mucous membranes, such as

in the stomach.

• Readily absorbed form GIT.

Dr. Amged 11

Dr. Amged 12

Barbiturates

• Cyclic ureides are formed when a dicarboxylic

acid reacts with urea.

Dr. Amged 13

• The cyclic ureides are acidic owing to

enolization.

Dr. Amged 14

• Cyclic ureides derived from malonic acid or

malonic esters are known as barbiturates

because of their relationship of barbituric acid

(malonyl urea).Dr. Amged 15

Dr. Amged 16

• Barbituric acid itself does not possess any

hypnotic properties, but such characteristic is

conferred only when the hydrogen atoms at C-

5 are replaced by organic groups (alkyl or aryl)

Dr. Amged 17

Dr. Amged 18

Dr. Amged 19

Classification of Barbiturates

• Long acting (6-8 hours).

• Intermediate acting (2-6 hours).

• Short acting (1-2 hours).

• Ultra-Short acting ( minutes).

Dr. Amged 20

Long Acting Barbiturates

Dr. Amged 21

Intermediate Acting Barbiturates

Dr. Amged 22

Short Acting Barbiturates

Dr. Amged 23

Ultra-Short Acting Barbiturates

Dr. Amged 24

Mechanism of Action of Barbiturates

• The principal mechanism of action of

barbiturates is believed to be their affinity to

GABAA receptors.

• Barbiturates bind to the GABAA receptors at

binding sites distinct from GABAB binding

sites.

• Barbiturates potentiate the effect of GABA at

these receptors.

Dr. Amged 25

Structure Activity Relationships

Dr. Amged 26

Structure Activity Relationships: 5,5-Disubstitution

• Lipophilic groups increase the activity of

barbiturates (to certain limit).

• Polar groups decrease the activity of

barbiturates.

Dr. Amged 27

Structure Activity Relationships: Substitution on Nitrogen

• Monosubstitution increases lipophilicity.

• Disubstitution renders barbiturates inactive.

Dr. Amged 28

Structure Activity Relationships: Modification of Oxygen

• Replacement of C2 oxygen by sulfur increases

lipid solubility.

Dr. Amged 29

Benzodiazepines

Dr. Amged 30

Nonbenzodiazepines (Z compounds)

Dr. Amged 31

Melatonin Receptor Agonists

• Melatonin, at times referred to as the hormone

of darkness, is synthesized in the pineal gland

and normally is secreted during the night.

Dr. Amged 32

Design of Ramelteon

Dr. Amged 33

Design of Ramelteon

Dr. Amged 34