Pharmacology - An Illustrated Review

9. Anxiolytic and Sedative-Hypnotic Drugs

Central nervous system (CNS) depressants are used to relieve anxiety (anxiolytic), to produce sedation (sedative), or to induce sleep (hypnotic). They are also anticonvulsants, centrally acting muscle relaxants, and drugs that produce amnesia. Physical and psychological dependence develops with prolonged use of these agents.

Benzodiazepines

There are many benzodiazepines in use, varying mainly in potency and pharmacokinetics (i.e., onset and duration of action). Depending on these properties, specific agents are used to treat insomnia, anxiety, epilepsy, and for anesthetic induction.

Diazepam, Midazolam, Temazepam, Triazolam, Flurazepam, Clonazepam, Oxazepam, Lorazepam, and Alprazolam

Mechanism of action. The benzodiazepines potentiate the actions of gamma-aminobutyric acid (GABA) by increasing the flow of Cl ions through the GABAA receptor (Fig. 9.1). Many benzodiazepines have active metabolites.

Effects. Benzodiazepines act almost exclusively in the CNS. The only peripheral effects are coronary vasodilation after certain benzodiazepines are injected intravenously (IV) and neuromuscular block after very high doses.

Note: Benzodiazepines have a higher therapeutic index than barbiturates. This is because benzodiazepines act by facilitating the effects of endogenous GABA, whereas barbiturates facilitate the effects of endogenous GABA and have direct GABA-like effects, thus producing more CNS depression.

– Diazepam has a direct muscle relaxant effect in addition to CNS actions.

– Alprazolam has an additional antidepressant effect.

– Triazolam may result in rebound anxiety following cessation of administration.

Uses. Table 9.1 lists the primary use for each of the benzodiazepine drugs, which is related to their duration of action.

  Table 9.1 image Summary of Benzodiazepine Uses

Benzodiazepine Agent

Duration of Action

Use(s)

Midazolam

Short

Anesthetic induction

Triazolam

 

Insomnia

Temazepam

Intermediate

Insomnia

Clonazepam

 

Anticonvulsant

Oxazepam

 

Anxiolysis

Lorazepam

 

Anxiolysis

Alprazolam

 

Anxiolysis

Diazepam

Long

Anxiolysis

Flurazepam

 

Insomnia

Side effects

– Incoordination, dizziness, drowsiness, and decreased cognitive function

– Fatal overdose can occur when combined with ethanol.

Flumazenil

Mechanism of action. Flumazenil is a relatively specific competitive antagonist at benzodiazepine receptors.

Uses

– Overdose or poisoning with benzodiazepines

Nonbenzodiazepine Benzodiazepine Receptor Agonists

Eszopiclone, Zaleplon, and Zolpidem

Mechanism of action. These agents are structurally unrelated to the benzodiazepines but bind to a specific subclass of benzodiazepine receptor found in the brain. They have poor muscle-relaxing or anticonvulsant activity.

Uses. They are used exclusively to treat insomnia.

Tolerance, Dependence, and Withdrawal

– Tolerance develops to the effects of these agents.

– Physical dependence can occur.

– Withdrawal symptoms are generally opposite to the effects of the drugs: anxiety, insomnia, and convulsions in severe withdrawal.

Barbiturates

Barbiturates as drugs of abuse are discussed on page 122.

Thiopental, Phenobarbital, Thiomylal, Methohexital, Amobarbital, Pentobarbital, and Secobarbital

Mechanism of action. Barbiturates increase the chloride conductance of the GABAA receptor by facilitating the action of GABA. They also have direct GABA-like effects (see Fig. 9.1).

Pharmacokinetics

– Barbiturates have a low therapeutic index, so overdose (accidental or deliberate) is a problem with these agents (see note in Benzodiazepine section on p. 82). They are also used recreationally.

– These agents induce cytochrome P-450 microsomal enzyme activity, which increases the rate of their own metabolism, as well as other drugs metabolized by this system.

– They also induce δ-aminolevulinic acid (δ-ALA) synthetase, the rate-limiting step in heme biosynthesis. Thus, barbiturates are contraindicated in patients with acute intermittent porphyria, porphyria variegata, or a positive family history of these porphyrias (see call-out box on page 27).

Fig. 9.1 image Mechanism of action of benzodiazepines and barbiturates.

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system (CNS). When GABA is released from GABAergic neurons, it binds to the β subunit of the pentameric GABA receptor, leading to opening of the chlorine channel, Cl influx, neuronal hyperpolarization, and decreased excitability. Benzodiazepines bind to the α subunits of the GABAA receptor, enhancing the binding and effects of GABA. Barbiturates also bind to the α subunits of the GABAA receptor. They increase the length of time that the chlorine channel is open when acted upon by GABA.

image

Uses

Table 9.2 summarizes the use of each of the barbiturate drugs.

  Table 9.2 image Summary of Barbiturate Uses

Barbiturate Drug

Duration of Action

Use(s)

Thiopental

Methohexital

Thiomylal

Ultra-short acting

Anesthetic induction

Amobarbital

Pentobarbital

Secobarbital

Intermediate*

Insomnia

Phenobarbital

Long

Anticonvulsant

* Intermediate-acting drugs are more prone to abuse.

Side effects

– Incoordination, dizziness, drowsiness, and decreased cognitive function occur with intensity proportional to potency and dose.

– Fatal overdose may occur by suppression of the neurogenic and hypoxic drive for respiration.

Alcohol

Alcohol is discussed in detail on pages 119122.

Ethanol

Ethanol is the most widely used sedative-hypnotic.

Mechanism of action. The mechanism of action is unknown.

Uses. Used as a solvent, germicide, and for several topical applications.

Other Sedative-Hypnotic and Anxiolytic Drugs

Buspirone

Mechanism of action. Buspirone is a 5-hydroxytryptamine type 1A (5-HT1A) receptor agonist.

Pharmacokinetics. Buspirone has a selective anxiolytic action with a slow therapeutic onset (action may be delayed up to 2 weeks).

Uses. Buspirone is used in the treatment of anxiety.

Note: Buspirone does not potentiate the effects of ethanol or other CNS depressants; thus, it is useful for treating anxiety in alcoholics.

Side effects

– Headache, dizziness, and nervousness

Doxylamine and Diphenhydramine

Mechanism of action. Doxylamine and diphenhydramine are H1 antihistamines that are able to penetrate into the CNS, causing sedation.

Uses. Doxylamine and diphenhydramine are used to treat insomnia.

Side effects

– Drowsiness, dry mouth, headache, and increased appetite

Ramelteon

Mechanism of action. Ramelteon is a melatonin receptor agonist.

Pharmacokinetics. Metabolized by CYP-1A2 in the liver.

Uses. Insomnia.

Side effects

– Dizziness, drowsiness, and decreased alertness

Contraindications. Ramelteon is contraindicated in combination with fluvoxamine, which is a strong CYP-1A2 inhibitor.