Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 22. Sedative-Hypnotic Drugs

Sedative-Hypnotic Drugs: Introduction

The sedative-hypnotics belong to a chemically heterogeneous class of drugs almost all of which produce dose-dependent CNS depressant effects. A major subgroup is the benzodiazepines, but representatives of other subgroups, including barbiturates, and miscellaneous agents (carbamates, alcohols, and cyclic ethers) are still in use. Newer drugs with distinctive characteristics include the anxiolytic buspirone, several widely used hypnotics (zolpidem, zaleplon, eszopiclone), and ramelteon, a novel drug used in sleep disorders.

High-Yield Terms to Learn

Sedation Reduction of anxiety Addiction The state of response to a drug whereby the drug taker feels compelled to use the drug and suffers anxiety when separated from it Anesthesia Loss of consciousness associated with absence of response to pain Anxiolytic A drug that reduces anxiety, a sedative Dependence The state of response to a drug whereby removal of the drug evokes unpleasant, possibly life-threatening symptoms, often the opposite of the drug's effects Hypnosis Induction of sleep REM sleep Phase of sleep associated with rapid eye movements; most dreaming takes place during REM sleep Sedation Reduction of anxiety Tolerance Reduction in drug effect requiring an increase in dosage to maintain the same response

Pharmacokinetics

Absorption and Distribution

Most sedative-hypnotic drugs are lipid-soluble and are absorbed well from the gastrointestinal tract, with good distribution to the brain. Drugs with the highest lipid solubility (eg, thiopental ) enter the CNS rapidly and can be used as induction agents in anesthesia. The CNS effects of thiopental are terminated by rapid redistribution of the drug from brain to other highly perfused tissues, including skeletal muscle. Other drugs with a rapid onset of CNS action include eszopiclone, zaleplon, and zolpidem.

Metabolism and Excretion

Sedative-hypnotics are metabolized before elimination from the body, mainly by hepatic enzymes. Metabolic rates and pathways vary among different drugs. Many benzodiazepines are converted initially to active metaboliteswith long half-lives. After several days of therapy with some drugs (eg, diazepam, flurazepam), accumulation of active metabolites can lead to excessive sedation. Lorazepam and oxazepam undergo extrahepatic conjugation and do not form active metabolites. With the exception of phenobarbital, which is excreted partly unchanged in the urine, the barbiturates are extensively metabolized. Chloral hydrate is oxidized to trichloroethanol, an active metabolite. Rapid metabolism by liver enzymes is responsible for the short duration of action of zolpidem. A biphasic release form of zolpidem extends its plasma half-life. Zaleplon undergoes even more rapid hepatic metabolism by aldehyde oxidase and cytochrome P450. Eszopiclone is also metabolized by cytochrome P450 with a half-life of 6 h. The duration of CNS actions of sedative-hypnotic drugs ranges from just a few hours (eg, zaleplon < zolpidem = triazolam = eszopiclone < chloral hydrate) to more than 30 h (eg, chlordiazepoxide, clorazepate, diazepam, phenobarbital).

Mechanisms of Action

No single mechanism of action for sedative-hypnotics has been identified, and the different chemical subgroups may have different actions. Certain drugs (eg, benzodiazepines) facilitate neuronal membrane inhibition by actions at specific receptors.

Benzodiazepines

Receptors for benzodiazepines (BZ receptors) are present in many brain regions, including the thalamus, limbic structures, and the cerebral cortex. The BZ receptors form part of a GABA A receptor-chloride ion channel macromolecular complex, a pentameric structure assembled from 5 subunits each with 4 transmembrane domains. A major isoform of the GABAA receptor consists of 2 1, 2 2, and 1 2 subunits. In this isoform, the binding site for benzodiazepines is between an 1 and the 2 subunit. However, benzodiazepines also bind to other GABAA receptor isoforms that contain 2, 3, and 5 subunits. Binding of benzodiazepines facilitates the inhibitory actions of GABA, which are exerted through increased chloride ion conductance (Figure 22-1).

FIGURE 22-1

A model of the GABA A receptor-chloride ion channel macromolecular complex. A hetero-oligomeric glycoprotein, the complex consists of 5 or more membrane-spanning subunits. Multiple forms of , and  subunits are arranged in various pentameric combinations so that GABAA receptors exhibit molecular heterogeneity. GABA appears to interact at two sites between  and  sububits, triggering chloride channel opening with resulting membrane hyperpolarization. Binding of benzodiazepines and the newer hypnotic drugs such as zolpidem occurs at a single site between  and  subunits, facilitating the process of chloride ion channel opening. The benzodiazepine antagonist flumazenil also binds at this site and can reverse the hypnotic effects of zolpidem. Note that these binding sites are distinct from those of the barbiturates.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 22-6.)

Benzodiazepines increase the frequency of GABA-mediated chloride ion channel opening. Flumazenil reverses the CNS effects of benzodiazepines and is classified as an antagonist at BZ receptors. Certain -carbolines have a high affinity for BZ receptors and can elicit anxiogenic and convulsant effects. These drugs are classified as inverse agonists.

Barbiturates

Barbiturates depress neuronal activity in the midbrain reticular formation, facilitating and prolonging the inhibitory effects of GABA and glycine. Barbiturates also bind to multiple isoforms of the GABAA receptor but at different sites from those with which benzodiazepines interact. Their actions are not antagonized by flumazenil. Barbiturates increase the duration of GABA-mediated chloride ion channel opening. They may also block the excitatory transmitter glutamic acid, and, at high concentration, sodium channels.

Other Drugs

The hypnotics zolpidem , zaleplon, and eszopiclone are not benzodiazepines but appear to exert their CNS effects via interaction with certain benzodiazepine receptors, classified as BZ 1 or 1 subtypes. In contrast to benzodiazepines, these drugs bind more selectively, interacting only with GABA A receptor isoforms that contain 1 subunits. Their CNS depressant effects can be antagonized by flumazenil.

Pharmacodynamics

The CNS effects of most sedative-hypnotics depend on dose, as shown in Figure 22-2. These effects range from sedation and relief of anxiety (anxiolysis), through hypnosis (facilitation of sleep), to anesthesia and coma. Depressant effects are additive when 2 or more drugs are given together. The steepness of the dose-response curve varies among drug groups; those with flatter curves, such as benzodiazepines and the newer hypnotics (eg, zolpidem), are safer for clinical use.

FIGURE 22-2

Relationships between dose of benzodiazepines and barbiturates and their CNS effects.

Sedation

Sedative actions, with relief of anxiety, occur with all drugs in this class. Anxiolysis is usually accompanied by some impairment of psychomotor functions, and behavioral disinhibition may also occur. In animals, most conventional sedative-hypnotics release punishment-suppressed behavior.

Hypnosis

Sedative-hypnotics can promote sleep onset and increase the duration of the sleep state. Rapid eye movement (REM) sleep duration is usually decreased at high doses; a rebound increase in REM sleep may occur on withdrawal from chronic drug use. Effects on sleep patterns occur infrequently with newer hypnotics such as zaleplon and zolpidem.

Anesthesia

At high doses of most older sedative-hypnotics, loss of consciousness may occur, with amnesia and suppression of reflexes. Anterograde amnesia is more likely with benzodiazepines than with other sedative-hypnotics. Anesthesia can be produced by most barbiturates (eg, thiopental) and certain benzodiazepines (eg, midazolam).

Anticonvulsant Actions

Suppression of seizure activity occurs with high doses of most of the barbiturates and some of the benzodiazepines, but this is usually at the cost of marked sedation. Selective anticonvulsant action (ie, suppression of convulsions at doses that do not cause severe sedation) occurs with only a few of these drugs (eg, phenobarbital, clonazepam). High doses of intravenous diazepam, lorazepam, or phenobarbital are used in status epilepticus. In this condition, heavy sedation is desirable.

Muscle Relaxation

Relaxation of skeletal muscle occurs only with high doses of most sedative-hypnotics. However, diazepam is effective at sedative dose levels for specific spasticity states, including cerebral palsy. Meprobamate also has some selectivity as a muscle relaxant.

Medullary Depression

High doses of conventional sedative-hypnotics, especially alcohols and barbiturates, can cause depression of medullary neurons, leading to respiratory arrest, hypotension, and cardiovascular collapse. These effects are the cause of death in suicidal overdose.

Tolerance and Dependence

Tolerance—a decrease in responsiveness—occurs when sedative-hypnotics are used chronically or in high dosage. Cross-tolerance may occur among different chemical subgroups. Psychological dependence occurs frequently with most sedative-hypnotics and is manifested by the compulsive use of these drugs to reduce anxiety. Physiologic dependence constitutes an altered state that leads to an abstinence syndrome (withdrawal state) when the drug is discontinued. Withdrawal signs, which may include anxiety, tremors, hyperreflexia, and seizures, occur more commonly with shorter-acting drugs. The dependence liability of zolpidem, zaleplon, and eszopiclone may be less than that of the benzodiazepines since withdrawal symptoms are minimal after their abrupt discontinuance.

Skill Keeper: Loading Dose

(See Chapter 3)

Three hours after ingestion of an unknown quantity of diazepam, a patient was hospitalized and the drug concentration in the plasma was found to be 5 mg/L. Assume that in this patient pharmacokinetic parameters for diazepam are as follows: oral bioavailability, 100%; Vd, 80 L; CL, 38 L/day; half-life, 2 days. Estimate the dose of diazepam ingested. The Skill Keeper Answer appears at the end of the chapter.

Clinical Uses

Most of these uses can be predicted from the pharmacodynamic effects outlined previously.

Anxiety States

Benzodiazepines are favored in the drug treatment of acute anxiety states and for rapid control of panic attacks. Although it is difficult to demonstrate the superiority of one drug over another, alprazolam and clonazepam have greater efficacy than other benzodiazepines in the longer term treatment of panic and phobic disorders. Note the increasing use of newer antidepressants in the treatment of chronic anxiety states (see Chapter 30).

Sleep Disorders

Benzodiazepines, including estazolam, flurazepam, and triazolam, have been widely used in primary insomnia and for the management of certain other sleep disorders. Lower doses should be used in elderly patients who are more sensitive to their CNS depressant effects. More recently there has been increasing use of zolpidem, zaleplon, and eszopiclone in insomnia, since they have rapid onset with minimal effects on sleep patterns and cause less daytime cognitive impairment than benzodiazepines. Note that sedative-hypnotic drugs are not recommended for breathing-related sleep disorders.

Other Uses

Thiopental is commonly used for the induction of anesthesia, and certain benzodiazepines (eg, diazepam, midazolam) are used as components of anesthesia protocols including those used in day surgery. Special uses include the management of seizure disorders (eg, clonazepam, phenobarbital) and bipolar disorder (eg, clonazepam) and treatment of muscle spasticity (eg, diazepam). Longer acting benzodiazepines (eg, chlordiazepoxide, diazepam) are used in the management of withdrawal states in persons physiologically dependent on ethanol and other sedative-hypnotics.

Toxicity

Psychomotor Dysfunction

This includes cognitive impairment, decreased psychomotor skills, and unwanted daytime sedation. These adverse effects are more common with benzodiazepines that have active metabolites with long half-lives (eg, diazepam, flurazepam), but can also occur after a single dose of a short-acting benzodiazepine such as triazolam. The dosage of a sedative-hypnotic should be reduced in elderly patients, who are more susceptible to drugs that cause psychomotor dysfunction. In such patients excessive daytime sedation has been shown to increase the risk of falls and fractures. Anterograde amnesia may also occur with benzodiazepines, especially when used at high dosage, an action that forms the basis for their criminal use in cases of "date rape." Zolpidem and the newer hypnotics cause modest day-after psychomotor depression with few amnestic effects. However, all prescription drugs used as sleep aids may cause functional impairment, including "sleep driving," defined as "driving while not fully awake after ingestion of a sedative-hypnotic product, with no memory of the event."

Additive CNS Depression

This occurs when sedative-hypnotics are used with other drugs in the class as well as with alcoholic beverages, antihistamines, antipsychotic drugs, opioid analgesics, and tricyclic antidepressants. This is the most common type of drug interaction involving sedative-hypnotics.

Overdosage

Overdosage of sedative-hypnotic drugs causes severe respiratory and cardiovascular depression; these potentially lethal effects are more likely to occur with alcohols, barbiturates, and carbamates than with benzodiazepines or the newer hypnotics such as zolpidem. Management of intoxication requires maintenance of a patent airway and ventilatory support. Flumazenil may reverse CNS depressant effects of benzodiazepines, eszopiclone, zolpidem, and zaleplon but has no beneficial actions in overdosage with other sedative-hypnotics.

Other Adverse Effects

Barbiturates and carbamates (but not benzodiazepines, eszopiclone, zolpidem, or zaleplon) induce the formation of the liver microsomal enzymes that metabolize drugs. This enzyme induction may lead to multiple drug interactions. Barbiturates may also precipitate acute intermittent porphyria in susceptible patients. Chloral hydrate may displace coumarins from plasma protein binding sites and increase anticoagulant effects.

Atypical Sedative-Hypnotics

Buspirone

Buspirone is a selective anxiolytic, with minimal CNS depressant effects (it does not affect driving skills) and has no anticonvulsant or muscle relaxant properties. The drug interacts with the 5-HT 1A subclass of brain serotonin receptors as a partial agonist, but the precise mechanism of its anxiolytic effect is unknown. Buspirone has a slow onset of action (>1 week) and is used in generalized anxiety disorder (s), but is less effective in panic disorders. Tolerance development is minimal with chronic use, and there is little rebound anxiety or withdrawal symptoms on discontinuance. Buspirone is metabolized by CYP3A4, and its plasma levels are markedly increased by drugs such as erythromycin and ketconazole. Side effects of buspirone include tachycardia, paresthesias, pupillary constriction, and gastrointestinal distress. Buspirone has minimal abuse liability and is not a schedule-controlled drug. The drug appears to be safe in pregnancy.

Ramelteon

This novel hypnotic drug that activates melatonin receptors in the suprachiasmatic nuclei of the CNS decreases the latency of sleep onset with minimal rebound insomnia or withdrawal symptoms. Ramelteon has no direct effects on GABA-ergic neurotransmission in the CNS. Unlike conventional hypnotics ramelteon appears to have minimal abuse liability, and it is not a controlled substance. The drug is metabolized by hepatic cytochrome P450 forming an active metabolite. The CYP inducer rifampin markedly reduces plasma levels of ramelteon and its metabolite. Conversely, inhibitors of CYP1A2 (eg, fluvoxamine) or CYP2C9 (eg, fluconazole) increase plasma levels of ramelteon. The adverse effects of the drug include dizziness, fatigue, and endocrine changes including decreased testosterone and increased prolactin.

Skill Keeper Answer: Loading Dose

(See Chapter 3)

Because the half-life of diazepam is 2 days, one may assume that the plasma concentration 3 h after drug ingestion is of an order of magnitude similar to that of the peak plasma level. If so, and assuming 100% bioavailability, then

Dose ingested = Plasma concentration x Vd

= 5 mg/L x 80 L

= 400 mg

Checklist

When you complete this chapter, you should be able to:

 Identify major drugs in each sedative-hypnotic subgroup.

Recall the significant pharmacokinetic features of the sedative-hypnotic drugs commonly used for treatment of anxiety and sleep disorders.

 Describe the proposed mechanisms of action of benzodiazepines, barbiturates, and zolpidem.

 List the pharmacodynamic actions of major sedative-hypnotics in terms of their clinical uses and their adverse effects.

 Identify the distinctive properties of buspirone, eszopiclone, ramelteon, zaleplon, and zolpidem.

 Describe the symptoms and management of overdose of sedative-hypnotics and withdrawal from physiologic dependence.

Drug Summary Table: Sedative-Hypnotics

Subclass Mechanism of Action Clinical Applications Pharmacokinetics and Drug Interactions Toxicities Benzodiazepines Alprazolam Chlordiazepoxide Clorazepate Clonazepam Diazepam Flurazepam Lorazepam Midazolam, etc Bind GABAA receptor subunits to facilitate chloride channel opening; membrane hyperpolarization

Acute anxiety states, panic attacks, generalized anxiety disorder, insomnia; skeletal muscle relaxation; seizure disorders Hepatic metabolism; active metabolites. Additive CNS depression with many drugs Half-lives: 2-4 h Extension of CNS depressant actions; tolerance; dependence liability Benzodiazepine antagonist Flumazenil Antagonist at benzodiazepine sites on GABAA receptor

Management of benzodiazepine overdose IV form Short half-life Agitation, confusion; possible withdrawal syndrome Barbiturates Amobarbital Butabarbital Pentobarbital Phenobarbital Secobarbital Thiopental Bind to GABAA receptor sites (distinct from benzodiazepines); facilitate chloride channel opening

Anesthesia (thiopental); insomnia and sedation (secobarbital); seizure disorders (phenobarbital) Oral activity; hepatic metabolism; induction of metabolism of many drugs Half-lives: 4-60 h Extension of CNS depressant actions; tolerance; dependence liability > benzodiazepines Newer hypnotics Eszopiclone Zaleplon Zolpidem Bind to GABAA receptor sites (close to benzodiazepine site); facilitate chloride channel opening

Sleep disorders, esp when sleep onset is delayed Oral activity, CYP substrates Additive CNS depression with ethanol and other depressants Short half-lives Extension of CNS depressant effects; dependence liability Melatonin receptor agonist Ramelteon Activates MT1 and MT2 receptors in suprachiasmatic nucleus Sleep disorders, esp when sleep onset is delayed Not a controlled substance Oral activity; forms active metabolite via CYP1A2; fluvoxamine inhibits metabolism Dizziness, fatigue, endocrine changes 5-HT agonist Buspirone Partial agonist at 5-HT receptors and possibly D2 receptors Generalized anxiety states Oral activity; forms active metabolite; interactions with CYP3A4 inducers and inhibitors; short half-life GI distress, tachycardia; paresthesias



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