Sedative and Hypnotic Drugs, Slides of Pharmacology

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Sedative, Hypnotic Drugs

Contents

⚫ Sedatives, Hypnotics and Anxiolytics

⚫ Excitatory and Inhibitory Neurotransmitters

⚫ Classification of Sedative-Hypnotics

⚫ Benzodiazepines

⚫ Classification of Benzodiazepines

⚫ Mechanism of Action of Benzodiazepines

⚫ Pharmacokinetics of Benzodiazepines

⚫ Adverse Effects of Benzodiazepines

⚫ Barbiturates

⚫ Mechanism of Action and Uses of Barbiturates

⚫ NBRAs

⚫ Miscellaneous Sedative-Hypnotics

Excitatory and Inhibitory Neurotransmitters

Structure of GABA Receptors

How GABA works

Benzodiazepines

All of the benzodiazepines have the same general chemical structure,

as shown. Different benzodiazepine drugs have been developed

through the years based on chemical substitutions at major positions

on the benzodiazepine structure.

Therefore, all benzodiazepines are simply variations on the same core

chemical structure.

Used as anesthetics, sleep-inducers and anxiolytics.

Figure: Core Structure of Benzodiazepines

Classification of Benzodiazepines

The benzodiazepines are frequently classified into three groups: (1) short-acting, (2) intermediate-acting and (3) long-acting.

Benzodiazepines

Mechanism of Action:

• The molecular site of action for the benzodiazepines is at the GABA (^) A receptors in the CNS. GABA is an amino acid neurotransmitter that has an inhibitory effect on neurotransmission in the CNS. Therefore, an increase in the effect of GABA results in general suppression of the CNS.
• When GABA binds to GABA (^) A receptors, the result is an influx of chloride ions into neurons through the ion channel. It is the influx of chloride ions that causes the negative effect on neurotransmission.

Mechanism of Action Conti..

• On the GABA (^) A receptors there is also a site, separate from the GABA binding site, for benzodiazepines to bind at. When both GABA and a benzodiazepine is bound to a GABA (^) A receptor, the result is an increase in the influx of chloride by increasing the frequency of ion channel opening of the receptor. Therefore, benzodiazepines are said to increase the effect that GABA has at GABA (^) A receptors when it binds.
• Overall, this effect is said to be GABAergic, because the overall effect is one of increasing the inhibitory effect of GABA in the CNS.
• Finally, it should be pointed out that the benzodiazepines do not have a direct effect on the GABA (^) A receptor; if GABA is not bound to the GABA (^) A receptor, then benzodiazepine binding has no effect on chloride ion influx.

Pharmacokinetics:

❑ Lipid-soluble and are absorbed well from the gastrointestinal tract, with good distribution to the brain.

❑ Extensively plasma protein-bound drugs.

❑ Many benzodiazepines are converted initially to active metabolites. After several days of therapy with some drugs ( eg, diazepam ), accumulation of active metabolites can lead to excessive sedation.

❑ Most of the benzodiazepines undergo both oxidative metabolism (phase 1 metabolism) and conjugation to glucuronic acid (phase 2 metabolism).

❑ Some benzodiazepines do not undergo significant oxidative metabolism ( temazepam, oxazepam, lorazepam ); there may be some benefit to using these agents in patients with liver disease or compromised hepatic function, as the majority of oxidative metabolism occurs in the liver.

Benzodiazepines

Benzodiazepines

Adverse Effects:

1. Psychomotor dysfunction- Ataxia , i.e. impaired coordination, which can

affect the ability to operate machineries properly.

2. Amnesia may also occur with benzodiazepines, especially when used at

high dosage.

3. May cause hangover , including "sleep driving," defined as –"driving

while not fully awake after ingestion of a sedative-hypnotic product."

Problems Associated with Long Term Use:

Dependence: Physical and psychological dependence may occur after long

term use.

Withdrawal Symptoms: Anxiety, anorexia, convulsion, delirium etc.

Mechanism of Action:

Barbiturates also bind to the GABA (^) A receptor but at different

sites from those with which benzodiazepines interact.

Barbiturates act like benzodiazepines, and simply increase the

effect of GABA at the GABA (^) A receptor by prolonging the

duration of channel opening. They may also block the

receptors for excitatory neurotransmitter glutamic acid at a

high concentration.

Barbiturates

Uses:

Barbiturates are rarely used for sedation or sleep induction nowadays, because of their extreme side effects on the CNS.

However, some highly lipid soluble barbiturates such as-

thiopental is commonly used for the induction of anesthesia.

Barbiturates in high doses are used for physician-assisted

suicide (PAS) for euthanasia