4-11 Sedatives & Hypnotics DSA

Question 1

What is a sedative?

Answer 1

1. Reduces anxiety and exerts a calming effect.
2. Sedation is a side effect of many drugs that are not general CNS depressants (e.g., antidepressants, antihistamines, neuroleptics/antipsychotics).
3. Agents that produce sedation as a side effect can intensify the effects of CNS depressants.

Question 2

What is a hypnotic?

Answer 2

1. Produces drowsiness and facilitates the onset and maintenance of a state of sleep.
2. Hypnotic effects involve more pronounced depression of the CNS, which can be achieved with many sedative-hypnotics by increasing the dose.

Question 3

What is the MOA for benzodiazepines?

Answer 3

1. MOA: promote binding of g-aminobutyric acid (GABA), major inhibitory neurotransmitter, to the GABA_A receptor; enhance GABA-induced ion currents (increase frequency of channel opening).

Question 4

What do benzodiazepines do, functionally speaking?

Answer 4

1. Capable of causing: sedation, hypnosis, muscle relaxation, anxiolytic and anticonvulsant effects.
2. High anxiolytic potency in relation to their depression of CNS function.

Question 5

Why have benzos replaced barbituates for sedatives?

Answer 5

1. Because of their low capacity to produce fatal CNS depression, benzodiazepines have displaced barbiturates as preferred sedative-hypnotic agents.

Question 6

What is the MOA for barbituates?

Answer 6

1. : bind to GABA_A receptors and potentiate GABA-induced chloride currents (increases duration of channel opening).
2. Can activate the channel directly by acting as a GABA-mimetic at high concentrations.

Question 7

What are the effects of barbituates?

Answer 7

1. Capable of causing a wide spectrum of effects, from mild sedation to anesthesia, including anxiolytic, hypnotic and anticonvulsant effects.

Question 8

What is a drawback of the clinical use of barbituates?

Answer 8

1. Barbiturates possess a narrow therapeutic index and it is often not possible to achieve a desired effect without evidence of general depression of the CNS.

Question 9

How are sedatives and hypnotics absorbed and distributed?

Answer 9

1. Lipid solubility plays a major role in determining the rates at which a given sedative-hypnotic will enter the CNS.
2. Most barbiturates, older sedative-hypnotics, and newer agents such as eszopiclone, zaleplon, and zolpidem are rapidly absorbed into the blood following oral administration.
3. The absorption rates and rates of onset of sedative-hypnotics vary depending on their lipid solubility (e.g., triazolam, thiopental, and newer hypnotics are all fast acting and very lipid soluble).
4. All sedative-hypnotics cross the CNS, placental barrier, and breast milk.

Question 10

How are sedative/hypnotic drugs eliminated?

Answer 10

Liver drug-metabolizing enzyme systems are the most important mediators of sedative-hypnotic drug inactivation and elimination (transition from lipid-soluble to more water-soluble agents).

Question 11

How are benzodiazepines metabolized?

Answer 11

1. Hepatic metabolism accounts for the clearance of all benzodiazepines; most undergo phase I reactions, predominantly by CYP3A4, then glucuronidation (phase II).
2. Many phase I metabolites are pharmacologically active (e.g., desmethyldiazepam is an active metabolite of chlordiazepoxide, diazepam, and clorazepate with a t_1/2 > 40 hours).

Question 12

How does half life determine use as a sedative versus hypnotic?

Answer 12

1. Triazolam has a short elimination t_1/2 (2-3 hours), favors use as a hypnotic rather than sedative.

Question 13

What are some cumulative toxicity factors with benzos?

Answer 13

1. benzodiazepines (parent drug or active metabolite) with long t_1/2 are more likely to cause cumulative effects (excessive drowsiness) with multiple doses.

Question 14

What is a relative contraindication for benzos?

Does this apply to all of them?

Answer 14

Benzodiazepines that are extensively metabolized by the liver are a poor choice in the treatment of individuals with hepatic insufficiency (oxazepam and lorazepam are more appropriate)
.

Question 15

How are barbituates eliminated?

Answer 15

1. Aside from phenobarbital (20-30% excreted unchanged), most ingested barbiturates undergo hepatic metabolism and are excreted in the urine as glucuronide conjugates.
2. Elimination t_1/2’s are relatively long and multiple dosing can lead to cumulative toxic effects.

Question 16

How are newer hypnotics eliminated?

Answer 16

1. CYP3A4 enzymes play a role in the biotransformation of eszopiclone, zolpidem, and zaleplon and t_1/2 of these drugs are relatively short (< 6 hours; well suited for use as sleep aids).

Question 17

How are barbituates and benzos excreted?

Answer 17

1. Water soluble metabolites (mostly formed from phase II conjugation of phase I metabolites) primarily excreted via the kidney; changes in renal function do not have a marked effect on the elimination of parent drug.
2. 20-30% of phenobarbital is excreted unchanged in the urine; alkalinization of the urine can increase its elimination rate (pKa of phenobarbital is 7.4).

Question 18

What are the factors affecting bioavailability in sedatives and hypnotics?

Answer 18

1. Alterations in hepatic function, such as liver disease or drug-induced increases or decreases in hepatic metabolizing enzymes, can affect sedative-hypnotic bioavailability.
2. Example: phenobarbital and meprobamate can induce hepatic CYPs after long-term use, which can cause an increase in metabolism of themselves and other drugs.
3. Example: lorazepam and oxazepam are better choices for individuals with hepatic disease compared to diazepam or chlordiazepoxide.

Question 19

What is the molecular structure and fxn of the GABAa receptor?

Answer 19

The GABA_A receptor is a ligand-gated ion channel (ionotropic) made up of five subunits that, when activated by the endogenous compound GABA, allows chloride ions to enter the cell.

One major isoform of the GABA_A receptor in the brain is composed of two α1 subunits, two β2 subunits, and one g2 subunit

Under normal physiological conditions, GABA activation causes normal chloride influx and polarization; reduces the number of action potentials.

GABA_A receptors are responsible for most inhibitory transmission in the CNS.

Question 20

How do benzodiazepines affect the GABAa receptor?

Answer 20

1. MOA: increase the efficiency of GABAergic synaptic inhibition.
2. The benzodiazepines DO NOT substitute for GABA but enhance the effects of GABA allosterically (bind to the receptor at a site other than the active site) without directly activating GABA_A receptors or opening the chloride channel.
3. Ultimately, this leads to an increase in the frequency of channel-opening events, causing increased chloride influx, hyperpolarization of neurons, and reduced number of action potentials (depressed state of the CNS).

Question 21

How do barbituates affect the GABAa receptors?

Answer 21

1. MOA: increase the duration of GABA-gated chloride channel openings.
2. At high concentrations, barbiturates may also directly activate the receptor.
3. Increased channel openings or activation leads to an increase of chloride ions, hyperpolarization of neurons, and reduced number of action potentials.
4. Barbiturates are less selective in their actions (they also depress actions of excitatory neurotransmitters, such as glutamic acid) and exert nonsynaptic membrane effects in parallel with their effects on GABA neurotransmission.

Question 22

What are the 3 types of benzodiazepine binding site-receptor interactions?

Answer 22

Agonists

Antagonists

Inverse Agonists

Question 23

What do agonists at the GABAa receptor do? What are some examples?

Answer 23

1. Facilitate GABA actions
2. Examples include benzodiazepines, eszopiclone, zaleplon, and zolpidem
3. Eszopiclone, zaleplon, and zolpidem are agonists only when the α₁-subunit is included in the GABA_A receptor makeup

Question 24

What do antagonists at the GABAa receptor do?

Answer 24

1. Block the actions of benzodiazepines, eszopiclone, zaleplon, and zolpidem but do not antagonize the actions of barbiturates, meprobamate, or ethanol because these compounds bind at a different site
2. Example: flumazenil (see below)

Question 25

What do inverse agonists do at the GABAa receptor?

Answer 25

1. Act as negative allosteric modulators of GABA receptor function; produce anxiety & seizures
2. Examples include the β-carboline class of compounds.

Question 26

How do sedative/hypnotic agents affect sedation?

Answer 26

1. Sedative-hypnotics exert calming effects with concomitant reduction of anxiety.
2. Most (not all) agents produce some depressant effects on psychomotor and cognitive functions.
3. Benzodiazepines and older sedative-hypnotics disinhibit punishment-suppressed behavior in animal models, which is equated with antianxiety effects associated with agents in this specific class (antihistamines & tricyclic antidepressants produce sedation but do nothing to anxiety).
4. Benzodiazepines exert dose-dependent anterograde amnesic effects

Question 27

What are the hypnotic effects of hypnotic/sedatives?

Answer 27

1. Given in high enough doses (higher than doses utilized for sedation/anxiety) sedative-hypnotic agents induce sleep.
2. Newer sedative-hypnotics decrease the time to fall asleep while eszopiclone, specifically, increases total sleep time.

Question 28

How are barbituates and benzos used in anesthesia?

Answer 28

1. High doses of certain sedative-hypnotic agents, particularly the barbiturates and older sedative-hypnotics, depress the CNS to the point known as stage III general anesthesia.
2. Thiopental and methohexital are very lipid-soluble and penetrate the brain tissue rapidly following IV administration (favorable characteristics of agents that induce anesthesia).
3. Benzodiazepines (diazepam, lorazepam, midazolam) are used IV for anesthesia in combination with other drugs.
4. If certain benzodiazepines are given in high enough doses, they may contribute to a persistent postanesthetic respiratory depression (owing to relatively long half-lives and the formation of active metabolites).

Question 29

Which sed./hypnotics work as anticonvulsants?

Answer 29

1. Some benzodiazepines (clonazepam, nitrazepam, lorazepam, diazepam) and barbiturates (phenobarbital) are sufficiently selective to be used clinically in the management of seizures.
2. Zolpidem, zaleplon, and eszopiclone lack anticonvulsant activity.

Question 30

Which sed./hypnotics do muscle relaxation?

Answer 30

1. Benzodiazepines (diazepam) and carbamates (meprobamate) can exert inhibitory effects on polysynaptic reflexes and internuncial transmission and maHow y also depress transmission at the skeletal neuromuscular junction at high doses.
2. Zolpidem, zaleplon, and eszopiclone do not cause muscle relaxation.

Question 31

What are the effects of sedative/hypnotics on resp and CV function?

Answer 31

1. Sedative-hypnotics can produce significant dose-dependent respiratory depression in patients with pulmonary disease.
2. Depression of the medullary respiratory center is the usual cause of death due to overdose of sedative-hypnotics.
3. At normal doses, sedative-hypnotics can cause cardiovascular depression in patients with diseases that impair cardiovascular function (heart failure, hypovolemia), most likely a result of depression of the medullary vasomotor centers.
4. At toxic doses, myocardial contractility and vascular tone may both be depressed and could lead to circulatory collapse.
5. Effects on respiration and cardiovascular function are more marked when agents are given intravenously.

Question 32

Why do sed./hypnotics cause tolerance?

Answer 32

1. There are multiple mechanisms responsible for tolerance (both pharmacokinetic and pharmacodynamic), but changes in responsiveness of the CNS are a main reason for the tolerance of sedative-hypnotics.
   
   1. Pharmacodynamic example: benzodiazepine tolerance in animals has been associated with down-regulation of brain GABA_A receptors. Down-regulation of receptors leads to hyperexcitability of the CNS during periods of withdrawal, leading to the symptoms characteristic of sedative-hypnotic withdrawal.
   2. Pharmacokinetic example: barbiturates stimulate the production of higher levels of hepatic CYPs, causing more rapid removal and breakdown of barbiturates from the circulation. This results in a decrease in their efficacy.

Question 33

Why do sed./hypnotics cause psychological dependence?

Answer 33

1. Due to the relief of anxiety, euphoria, disinhibition, and promotion of sleep by sedative-hypnotic agents, most of these drugs are classified as schedule III or IV drugs (see table below for more information on the classification of controlled substances)

Question 34

What are the symptoms of physiological dependence with sed./hypnotics?

Answer 34

1. Altered physiologic state that requires continuous drug administration to prevent an abstinence of withdrawal syndrome.
2. Characterized by states of increased anxiety, insomnia, and CNS excitability that may progress to convulsions.
3. Composed of both a psychologic and physiologic component.

Question 35

Why is it important to taper sedative-hypnotics?

Answer 35

1. Abrupt withdrawal of high doses of sedative-hypnotics leads to more serious withdrawal signs.
2. To avoid withdrawal symptoms (particularly in patients taking benzodiazepines and/or barbiturates), the dose of sedative-hypnotics are tapered gradually over time.
3. Drugs with long half-lives (e.g., diazepam) are eliminated slowly enough to accomplish gradual withdrawal with few physical symptoms.
4. Drugs with very short half-lives for hypnotic effects may lead to signs of withdrawal even between doses (e.g., triazolam has a half-life of 4 hours and has been reported to cause daytime anxiety when used to treat sleep disorders).
5. Intensity of withdrawal symptoms from zolpidem, zaleplon, or eszopiclone (if any) is usually of less than those seen with benzodiazepines.
6. Flumazenil

Question 36

Why are the psychological aspects of dependence?

Answer 36

1. Dependency of the mind that can lead to psychological withdrawal symptoms (e.g., cravings, irritability, insomnia, depression, anorexia, etc.).
2. Similar to neurotic behavior patterns of the persistent coffee drinker or cigarette smoker.
3. When sedative-hypnotic use becomes compulsive, physiologic dependence and tolerance are likely to develop.

Question 37

What are the clinical uses of sedative-hypnotics?

Answer 37

Relief of anxiety

Insomnia

Sedation and amnesia before and during medical surgical procedures

Treatment of epilepsy and seizure states

Component of balanced anesthesia (IV administration)

Control of ethanol or other sedative-hypnotic withdrawal states

Muscle relaxation in specific neuromuscular disorders

Diagnostic aids or for treatment in psychiatry

Question 38

What is the MOA, therapeutic use, and ADRs of flumazenil?

Answer 38

MOA: binds benzodiazepine binding site on GABA_A receptors and acts as a competitive antagonist.

Blocks the actions of benzodiazepines, zolpidem, zaleplon, and eszopiclone

does not block the CNS effects of other sedative-hypnotics (barbiturates, meprobamate, buspirone, ramelteon), ethanol, opioids, or general anesthetics.

Uses: reversing CNS depressant effects of benzodiazepine overdose and to shorten recovery following benzodiazepine in anesthetic and diagnostic procedures

ADRs: agitation, confusion, dizziness, nausea

Flumazenil can precipitate abstinence syndrome in patients who have developed physiologic benzodiazepine dependence

Question 39

What are some examples of benzos being more effective in treatment of particular disorders?

Answer 39

Alprazolam is effective in the treatment of panic disorders and agoraphobia and appears to be more selective in these conditions than other benzodiazepines (lorazepam and clonazepam are also useful for acute panic disorders).

Question 40

When are benzos generally used to treat anxiety?

Answer 40

Concomitant treatment of anxiety on a short-term basis with benzodiazepines and SSRIs is useful until SSRIs become effective (on the order of 4-6 weeks, after which benzodiazepines would be removed from treatment).

Benzodiazepines are widely used for the management of acute anxiety states (situational anxiety) and rapid control of panic attacks as well as long-term management of generalized anxiety disorder and panic disorders

Question 41

What are some drawbacks to using benzos for treating anxiety?

Answer 41

1. Although many different benzodiazepines can relieve symptoms of anxiety, demonstration of one drug’s superiority over another is difficult to prove.
2. Currently, use of newer antidepressants [selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)] preferred in treatment of generalized anxiety disorders/certain phobias, although benzodiazepines still used for acute anxiety states.
3. Concomitant treatment of anxiety on a short-term basis with benzodiazepines and SSRIs is useful until SSRIs become effective (on the order of 4-6 weeks, after which benzodiazepines would be removed from treatment).

Question 42

What are some benzo advantages in treating anxiety?

Answer 42

1. High therapeutic index
2. Availability of flumazenil for overdose
3. Low risk of drug interactions based on liver enzyme induction
4. Minimal effects on cardiovascular or autonomic functions

Question 43

What are some disadvantages to using benzos for anxiety?

Answer 43

1. Risk of dependence
2. Depression of CNS functions
3. Amnestic effects
4. Additional CNS depression when combined with other drugs (including ethanol)

Question 44

What are some newer agents that have efficacies similar to those of the hypnotic benzodiazepines in the management of sleep disorders?

Answer 44

zolpidem, zaleplon, and eszopiclone

Question 45

What are some advantages of zolpidem for sleep?

Answer 45

Zolpidem is also available in a biphasic release formulation that provides sustained drug levels for sleep maintenance.

The t_1/2 of zaleplon and zolpidem are fairly similar (1-2 hours and 1.5-3.5 hours, respectively) and are appropriate agents for individuals who have trouble falling asleep.

Question 46

What are some advantages of zaleplon for sleep?

Answer 46

Zaleplon acts rapidly, and due to short t_1/2, has value in the management of patients who awaken early in the sleep cycle.

may cause less amnesia or day-after somnolence than zolpidem or benzodiazepines at recommended doses

appropriate agent for individuals who have trouble falling asleep

Question 47

What are some advantages of eszopliclone for sleep?

Answer 47

may cause less amnesia or day-after somnolence than zolpidem or benzodiazepines at recommended doses.

Eszopiclone has a t_1/2 of approximately 6 hours and is more effective treating individuals who awaken early and have difficulty sleeping through the night

Question 48

What are some disadvantages for using zolpidem, zaleplon, and eszopiclone for sleep?

Answer 48

Abrupt discontinuation of sedative-hypnotic drug treatment may lead to rebound insomnia.

Note: long-term use of hypnotics is an irrational and dangerous medical practice. The failure of insomnia to remit after 7-10 days of treatment may indicate the presence of a primary psychiatric or medical illness that should be evaluated. Non-pharmacologic therapies include proper diet and exercise, avoiding stimulants before retiring, ensuring a comfortable sleeping environment, and retiring at a regular time each night.

Question 49

In addition to sleep and anxiety, what are some other uses for sedative-hypnotic agents?

Answer 49

Sedative-hypnotic agents are also used in the management of seizure disorders and as intravenous agents in anesthesia.

Oral formulations of shorter-acting agents are preferred for sedative and possible amnestic effects during medical or surgical procedures (endoscopy, bronchoscopy) as well as premedication prior to anesthesia.

Long-acting benzodiazepines (chlordiazepoxide, diazepam) and phenobarbital may be used to treat patients in withdrawal from physiologic dependence of ethanol or other sedative-hypnotics.

Diazepam is approved for treatment of muscle spasticity

Question 50

What are some direct toxic actions of sedative hypnotics?

Answer 50

Many common adverse effects of sedative-hypnotics result from dose-related CNS depression.

Low doses may lead to drowsiness, impaired judgment, and diminished motor skills that can lead to impacts on driving ability, job performance, and personal relationships.

With severe toxicity, respiratory depression from central actions of the drug may be complicated by aspiration of gastric contents in the unattended patient (more pronounced if ethanol is present).

Question 51

What are some relative contraindications for sedative-hypnotics in older patients?

Answer 51

An increased sensitivity to sedative-hypnotics is more common in patients with cardiovascular disease, respiratory disease, or hepatic impairment and in older patients (doses approximately half of those used in younger adults are safer and usually as effective).

Question 52

How do barbituates affect heme synthesis?

Answer 52

Barbiturates enhance porphyrin synthesis and are contraindicated in patients with a history of acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, or symptomatic porphyria.

Question 53

How does tolerance work in sedatives hypnotics? Does it affect lethal dose or tolerance to other agents?

Answer 53

proportionately greater dosage increments are required to achieve CNS depression that is more profound than hypnosis

The lethal dose range is not altered significantly by sedative-hypnotic tolerance.

Cross-tolerance between different sedative-hypnotics (including ethanol) can lead to an unsatisfactory therapeutic response when standard doses of a drug are used.

Drugs with longer t_1/2 (chlordiazepoxide, diazepam, phenobarbital) can be used to alleviate withdrawal symptoms of shorter-acting drugs, including ethanol

Question 54

What are some common ADRs with sedative/hypnotics?

Answer 54

Most common drug interactions involving sedative-hypnotics are with other CNS depressants and lead to additive effects.

Examples of drug interactions: alcoholic beverages, opioid analgesics, anticonvulsants, phenothiazines, and some antihistamines, antihypertensive agents, and antidepressant drugs of the tricyclic class.

Question 55

Explain the sedative/hypnotic relationship with cytochrome p450.

Answer 55

1. Cytochrome P450 induction
   
   1. Phenobarbital and meprobamate can induce P450 induction with long-term use.
2. Cytochrome P450 inhibition
   
   1. Many benzodiazepines and newer hypnotics are metabolized by P450s, particularly CYP3A4.
   2. Co-administration of agents that inhibit P450s will cause a marked increase in the concentrations of these sedative-hypnotics.

Question 56

What is the MOA, clinical use, interactions/contraindications and ADRs with ramelteon?

Answer 56

Clinical Use: Approved for treatment of insomnia characterized by difficulty with sleep onset.

MOA: agonist at MT­­₁ and MT₂ melatonin receptors located in the suprachiasmic nuclei of the brain.

Contra: Avoid co-administration with fluvoxamine (SSRI) because it is an inhibitor of CYP1A2.

caution in patients with hepatic impairment

ADRs: dizziness, somnolence, fatigue, and endocrine changes (decreases in serum cortisol, decreases in testosterone, and increases in prolactin).

Question 57

What is the MOA, clinical use, interactions/contraindications and ADRs with buspirone?

Answer 57

Clinical Use: Approved for the treatment of generalized anxiety disorder (anxiolytic effects may take 3-4 weeks to become established, making buspirone less effective in acute panic disorders).

Does not cause sedation, hypnotic, euphoric, anticonvulsant, or muscle relaxant effects.

MOA: unknown; effects may be mediated by a variety of CNS receptor systems including serotonergic or dopaminergic systems.

Extensive metabolism by CYP3A4; use with caution in patients with hepatic impairment.

ADRs: tachycardia, palpitations, nervousness, gastrointestinal distress, paresthesias, and dose-dependent papillary constriction.