1. Chapter 22: Sedative-hypnotic Drugs

2. Introduction
A sedative drug (anxiolytic) reduce anxiety and exert a calming effect
A hypnotic drug produces drowsiness and facilitates the onset and maintenance of a state of sleep
Hypnosis involves more pronounced CNS depression…achieved by increasing the dose
Most anxiolytic and sedative–hypnotic drugs produce dose-dependent depression of CNS function

3. Dose-response curves for two hypothetical sedative hypnotics
The linear slope for drug A is typical of many of the older sedative-hypnotics, including the barbiturates and alcohols
for drug B, require proportionately greater dosage increments to achieve CNS depression more profound than hypnosis. This appears to be the case for benzodiazepines and for certain newer hypnotics that have a similar mechanism of action.
Graded dose-dependent depression of CNS function is a characteristic of most sedative-hypnotics. However, individual drugs differ in the relationship between the dose and the degree of CNS depression. Two examples of such dose-response relationships are shown in Figure 22–1. The linear slope for drug A is typical of many of the older sedative-hypnotics, including the barbiturates and alcohols. With such drugs, an increase in dose higher than that needed for hypnosis may lead to a state of general anesthesia. At still higher doses, these sedative-hypnotics may depress respiratory and vasomotor centers in the medulla, leading to coma and death. Deviations from a linear dose-response relationship, as shown for drug B, require proportionately greater dosage increments to achieve CNS depression more profound than hypnosis. This appears to be the case for benzodiazepines and for certain newer hypnotics that have a similar mechanism of action.

4. Sedative-Hypnotics The main group of drugs are as follows:
Benzodiazepines (anxiolytic and hypnotic)
Barbiturates (their used is now confined to anesthesia and epilepsy)
Miscellaneous agents

6. Other drugs with sedative-hypnotic effects
β-blockers (e.g. Propranolol)
Antipsychotics
Antidepressants (e.g. SSRIs, TCAs, venlafaxine, duloxetine & MAOIs)
Antihistamines (e.g. Hydroxyzine, diphenhydramine, & doxylamine)
Other classes of drugs that exert sedative effects include antipsychotics (see Chapter 29), and many antidepressant drugs (see Chapter 30). The latter are currently used widely in management of chronic anxiety disorders. Certain antihistaminic agents including hydroxyzine and promethazine (see Chapter 16) are also sedating. These agents commonly also exert marked effects on the peripheral autonomic nervous system. Other antihistaminic drugs with hypnotic effects, eg, diphenhydramine and doxylamine, are available in over-the-counter sleep aids.

7. Benzodiazepines
Benzodiazepines are the most widely used anxiolytic drugs
They have largely replaced barbiturates and meprobamate in the treatment of anxiety, b/c they are safer and more effective
The most prominent of these effects are sedation, hypnosis, decreased anxiety, muscle relaxation, anterograde amnesia, and anticonvulsant activity
Anterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories created prior to the event are lost.
Propofol may cause retrograde amnesia (general anasthetic)

8. Anterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to
retrograde amnesia, where memories created prior to the event are lost.

10. The chemical structures of some older and less commonly used sedative-hypnotics, including several barbiturates, are shown in Figure 22–3. Glutethimide and meprobamate are of distinctive chemical structure but are practically equivalent to barbiturates in their pharmacologic effects. They are rarely used. The sedative-hypnotic class also includes compounds of simpler chemical structure, including ethanol (see Chapter 23) and chloral hydrate.

11. Novel drugs with different chemical structures introduced recently for use in sleep disorders:
Zolpidem, zaleplon, and eszopiclone (similar mechanism of action to benzodiazepines)
Ramelteon, Tasimelteon: a melatonin receptor agonist….new hypnotic drug
Buspirone: slow-onset anxiolytic agent with quite different actions

12. Mechanism of action
Their targets of actions are the γ-aminobutyric acid the inhibitory neurotransmitter (GABAA) receptors (bzns, barbs, eszopiclone, zolpidem, zaleplon)
Bzds enhance the response to GABA by facilitating the opening of GABA-activated chloride channels
They bind specifically to a regulatory site of the receptor, distinct from the GABA-binding site, and act allosterically to increase the affinity of GABA for the receptor
This receptor, which functions as a chloride ion channel, is activated by the inhibitory neurotransmitter GABA

13. Benzodiazepines- Mechanism of action
Bzds increase the efficiency of GABAergic synaptic inhibition
The enhancement in chloride ion conductance induced by the interaction of benzodiazepines with GABA takes the form of an increase in the frequency of channel-opening events
No change in the conductance or mean open time
Bzds do not affect receptors for other amino acids

14. Barbiturates- Mechanism of action
Barbiturates—in contrast to bzds— appear to increase the duration of the GABA-gated chloride channel openings
At high concentrations, the barbiturates may also be GABA-mimetic, directly activating chloride channels
These effects involve a binding site or sites distinct from the bzd binding sites

15. Barbiturates- Mechanism of action
Barbiturates are less selective in their actions, they also depress the actions of the excitatory neurotransmitter glutamic acid via binding to the glutamate receptor
The multiplicity of sites of action of barbiturates may be the basis for their ability to induce full surgical anesthesia and for their more pronounced central depressant effects compared with bzds and the newer hypnotics

16. GABA receptors
GABA receptors are membrane-bound proteins divided into two major subtypes: GABAA and GABAB receptors
The ionotropic GABAA receptors has a pentameric structure assembled from five subunits selected from multiple polypeptide classes (α, β, γ, δ, ε, ρ etc) to form an integral chloride channel
Two benzodiazepine receptor subtypes commonly found in the CNS have been designated as BZ1 and BZ2 receptor depending on whether their composition includes the α1 subunit or the α2 subunit, respectively
In this isoform, the two binding sites for GABA are located between adjacent α1 and β2 subunits, and the binding pocket for benzodiazepines (the BZ site of the GABAA receptor) is between an α1 and the γ2 subunit

17. Benzodiazepines- Mechanism of action
Major isoform of the GABAA receptor found in many regions of the brain consists of two α1 subunits, two β2 subunits, and one γ2 subunit
The GABAA-receptor (or recognition site), when coupled with GABA, induces a shift in membrane permeability, primarily to chloride ions, causing hyperpolarization of the neuron

18. (α1 & β2 subunits)
(α1 & γ2 subunits)

19. GABA receptors
GABA receptor appears to be part of a macromolecule that contains, in addition to the GABAA-receptor, bzds and barbiturate binding sites and the chloride ionophore (chloride channel)
zolpidem, zaleplon, and eszopiclone bind more selectively because these drugs interact only with GABAA-receptor isoforms that contain α1 subunits
In contrast to GABA itself, sedative-hypnotics have a low affinity for GABAB receptors (spasmolytic baclofen)
Baclofen, sold under the brand name Lioresal among others, is a central nervous system depressant used as a skeletal muscle relaxant. It is primarily used to treat spasticity. It is also used in topical creams to help with pain.[1]

20. Benzodiazepine Binding Site Ligands
Agonists:
Benzodiazepines: multiple BZ binding sites
Zolpidem, zaleplon, and eszopiclone: selective agonists at the BZ1
Antagonists: Flumazenil (blocks the actions of bzd, zolpidem, zaleplon….but not that of barbiturates)
Inverse agonists:  negative allosteric modulators of GABA-receptor function can produce anxiety and seizures….β-carbolines, (eg, n-butyl- β -carboline-3- carboxylate (β -CCB))

21. Benzodiazepines….PK
The PK properties of the bzds affect their clinical utility
Bzds vary greatly in duration of action and can be roughly divided into:
Short-acting (Zolpidem, Triazolam)
Medium-acting (Alprazolam, Lorazepam, Oxazepam)
Long-acting (Chlorazepate, Diazepam, Flurazepam)
Lipid solubility plays a major role in determining the rate at which a particular sedative-hypnotic enters the CNS. This property is responsible for the rapid onset of the effects of triazolam, thiopental
Lipid solubility plays a major role in determining the rate at which a particular sedative-hypnotic enters the CNS. This property is responsible for the rapid onset of the effects of triazolam, thiopental (see Chapter 25), and the newer hypnotics.

22. Short-acting (Zolpidem, Triazolam)
Lexotan® (bromazepam); Valium® (diazepam); Xanax® (alprazolam)
Short-acting (Zolpidem, Triazolam)
Medium-acting (Alprazolam, Lorazepam, Oxazepam)
Long-acting (Chlorazepate, Diazepam, Flurazepam)

23. Benzodiazepines…..PK
Bzds with greater lipid solubility tend to enter the CNS more rapidly and thus tend to produce their effect quickly
Tissue redistribution (e.g., muscle and fat) is more rapid for drugs with the highest lipid solubility
These drugs cross the placental barrier and are secreted into breast milk…..depression of neonatal vital functions
Biotransformation to more water-soluble metabolites is necessary for clearance of sedative-hypnotics…..metabolised by dealkylation (phase 1) & conjugation (phase 2) reactions
The distribution of the bzds from blood to tissues and back again is a dynamic process with considerable influence on the onset and duration of action

24. Benzodiazepines…..PK
The longer acting agents are converted in the liver to one or active metabolite, some with long half-lives than the parent drug…..
The t1/2 of desmethyldiazepam in plasma is ∼40 hours
Alprazolam & triazolam…are short-acting compounds metabolized directly by glucuronidation
Benzodiazepines with long half-lives are more likely to cause cumulative effects with multiple doses…..less a problem with short half-lives drugs (estazolam, oxazepam, and lorazepam)
Benzodiazepines for which the parent drug or active metabolites have long half-lives are more likely to cause cumulative effects with multiple doses. Cumulative and residual effects such as excessive drowsiness appear to be less of a problem with such drugs as estazolam, oxazepam, and lorazepam, which have relatively short half-lives and are metabolized directly to inactive glucuronides

25. Short-acting (Zolpidem, Triazolam)
For example, desmethyldiazepam, which has an elimination half-life of more than 40 hours, is an active metabolite of chlordiazepoxide, diazepam, prazepam, and clorazepate. 
The formation of active metabolites has complicated studies on the pharmacokinetics of the benzodiazepines in humans because the elimination half-life of the parent drug may have little relation to the time course of pharmacologic effects
Short-acting (Zolpidem, Triazolam)
Medium-acting (Alprazolam, Lorazepam, Oxazepam)
Long-acting (Chlorazepate, Diazepam, Flurazepam)

26. Benzodiazepines…..PK
The metabolism of several commonly used benzodiazepines is affected by inhibitors and inducers of hepatic P450 isozymes
In very old patients and in patients with severe liver disease, the elimination half-lives of these drugs are often increased significantly
In such cases, multiple normal doses of these sedative-hypnotics can result in excessive CNS effects . 

27. Barbiturates…..PK
Only insignificant quantities of the barbiturates are excreted unchanged (except phenobarbital)
The major metabolic pathways involve oxidation by hepatic enzymes and glucuronidation….the conjugates appear in the urine
The overall rate of hepatic metabolism in humans depends on the individual drug but (with the exception of the thiobarbiturates) is usually slow
T1/2 of secobarbital and pentobarbital range 18-48hrs in different individuals. Phenobarbital T1/2 is 4–5 days

28. Newer hypnotic…..PK
Zolpidem and Zaleplon are rapidly metabolized to inactive metabolites by hepatic CYP3A4
Eszopiclone is metabolized by hepatic cytochromes to form the inactive derivative and weakly active desmethyleszopiclone
Dosage should be reduced in patients with hepatic impairment and in elderly
Inhibitors of CYP3A4 (eg, ketoconazole) may prolong t1/2 while inducers of CYP3A4 (eg, rifampin) increase the hepatic metabolism
The elimination T1/2 of zolpiedm is greater in women and is increased significantly in the elderly. is due to a slower clearance of zolpidem in women
Sublingual and oral spray formulations of zolpidem are also available.
The elimination T1/2 of zolpiedm is greater in women and is increased significantly in the elderly. is due to a slower clearance of zolpidem in women
A biphasic extended-release formulation extends plasma levels by approximately 2 hours.

29. Organ Level Effects…..
Sedation: exert calming effects with concomitant reduction of anxiety at relatively low doses.
Accompanied by some depressantion on psychomotor and cognitive functions
BZD also exert dose-dependent anterograde amnesia (inability to remember events occurring during the drug’s duration of action).
(decrease the latency to persistent sleep) (time to fall asleep)
However, even at therapeutic doses, sedative-hypnotics can produce significant respiratory depression in patients with pulmonary disease

30. Organ Level Effects…..
Hypnosis: by definition, all of the sedative-hypnotics induce sleep if high enough doses are given
BZD decrease the latency of sleep onset
Anesthesia: at higher doses depress the CNS causing general anesthesia.
Thiopental and methohexital very lipid-soluble, penetrate brain tissue rapidly used IV for the induction of anesthesia
Diazepam, lorazepam, midazolam (BZD)—used IV in anesthesia
Such depressant actions of benzodiazepines are usually reversible with flumazenil
(decrease the latency to persistent sleep) (time to fall asleep)
However, even at therapeutic doses, sedative-hypnotics can produce significant respiratory depression in patients with pulmonary disease

31. Organ Level Effects …..
Anticonvulsant Effects: capable to inhibit the development and spread of electrical activity in the CNS
Bzd and barbiturates are effective in tx of seizures
Zolpidem, zaleplon, eszopiclone lack anticonvulsant activity
Muscle Relaxation: exert inhibitory effects on polysynaptic reflexes and at high doses may also depress transmission at the skeletal neuromuscular junction
Observed with meprobamate, Bzd

32. Organ Level Effects …..
Effects on Respiration and Cardiovascular Function: At therapeutic doses can produce significant respiratory depression in patients with pulmonary disease….depression of the medullary respiratory center….common cause of death in overdoses
In hypovolemic states, heart failure, and other diseases that impair cardiovascular function, normal doses of sedative-hypnotics may cause cardiovascular depression
Effects on respiration are dose-related, and depression of the medullary respiratory center is the usual cause of death due to overdose of sedative hypnotics.

33. Tolerance and Dependence
Tolerance: decrease responsiveness to drug following repeated exposure – common feature of sedative-hypnotics
It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep
Tolerance is less marked than it is with barbiturates
The development of tolerance has been associated with down- regulation of brain benzodiazepine receptors (PD tolerance)
An increase in the rate of drug metabolism (PK/metabolic tolerance) may be partly responsible in the case of chronic administration of barbiturates
It is important to recognize that partial cross-tolerance occurs between the sedative-hypnotics described here and also with ethanol (see chapter 23)—a feature of some clinical importance, as explained below.

34. Tolerance and Dependence
Dependence can develop if high doses of the drugs are given over prolonged period
The consequences of abuse of these agents can be defined in both psychologic and physiologic terms
Abrupt withdrawal is associated with withdrawal symptoms: rebound insomnia & anxiety, and central nervous system excitability that may progress to convulsions……gradual tapering of the dose

35. Tolerance and Dependence
Differences in the severity of withdrawal symptoms resulting from individual bzds relate in part to half-life:
Bzds with long half-lives (e.g. Flurazepam): withdrawal symptoms occur slowly with few physical symptoms and last a number of days after discontinuation
Bzds with short half-lives (e.g. Triazolam): induce more abrupt and severe withdrawal reactions

36. Tolerance and Dependence
Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness, restlessness, nausea and vomiting, seizures, delirium, and cardiac arrest
Abrupt cessation of zolpidem, zaleplon, or eszopiclone may also result in withdrawal symptoms, though usually of less intensity than those seen with bzds
- Withdrawal is much more severe than that associated with opiates and can result in death

37. Flumazenil: Benzodiazepine antagonist
Flumazenil is a competitive antagonists of bzds that can rapidly reverse the sedative effects of benzodiazepines, zolpidem, zaleplon, and eszopiclone (overdose)……antagonism of benzodiazepine-induced respiratory depression is less predictable
The drug is available for IV administration only
Onset is rapid but duration is short, with a half-life of about 1 hour due to hepatic clearance
Frequent administration may be necessary to maintain reversal of a long-acting bzd

38. Flumazenil: Benzodiazepine antagonist
Adverse effects:
Agitation, confusion, dizziness, and nausea
Severe precipitated abstinence syndrome in patients who have developed physiologic benzodiazepine dependence
Precipitation of seizures and cardiac arrhythmias may follow flumazenil administration

39. Clinical uses Treatment of anxiety state
The bzds are the most widely used drugs for the management of acute and chronic anxiety and replaced the barbiturates because:
Rapid onset of action
Relatively high therapeutic index
Availability of flumazenil for treatment of overdose
Low risk of drug interactions
Minimal effects on CV or ANS
The psychologic, behavioral, and physiologic responses that characterize anxiety can take many forms. Typically, the psychic awareness of anxiety is accompanied by enhanced vigilance, motor tension, and autonomic hyperactivity. Anxiety is often secondary to organic disease states—acute myocardial infarction, angina pectoris, gastrointestinal ulcers, etc—which themselves require specific therapy. Another class of secondary anxiety states (situational anxiety) results from circumstances that may have to be dealt with only once or a few times, including anticipation of frightening medical or dental procedures and family illness or other stressful event. Even though situational anxiety tends to be self-limiting, the short-term use of sedative-hypnotics may be appropriate for the treatment of this and certain disease-associated anxiety states. Similarly, the use of a sedative-hypnotic as premedication prior to surgery or some unpleasant medical procedure is rational and proper (Table 22–2).
Excessive or unreasonable anxiety about life circumstances (generalized anxiety disorder, GAD), panic disorders, and agoraphobia are also amenable to drug therapy, sometimes in conjunction with psychotherapy. The benzodiazepines continue to be widely used for the management of acute anxiety states and for rapid control of panic attacks. They are also used, though less commonly, in the long-term management of GAD and panic disorders. 

40. Clinical uses Treatment of anxiety state
For most types of anxiety, none of the bzds is therapeutically superior to any other
They should be reserved for continued severe anxiety, and then should only be used for short periods of time because of their addiction potential
The antianxiety effects of the bzds are less subject to tolerance than the hypnotic effects
Typically, the psychic awareness of anxiety is accompanied by enhanced vigilance, motor tension, and autonomic hyperactivity.
The barbiturates were formerly the mainstay of treatment to sedate the patient or to induce and maintain sleep
Today, they have been largely replaced by the bzds, primarily because they:
Associated with more tolerance
Physical dependence
Associated with very severe withdrawal symptoms
Ability to cause coma in toxic doses
Induce drug-metabolizing enzymes

41. Treatment of anxiety state
Clinical uses
Treatment of anxiety state
Choice of a particular agent is usually made on the basis of pharmacokinetic:
The longer-acting agents: preferred when anxiety is intense and sustained/prolonged
The short-acting agents: advantageous when the anxiety is provoked by clearly defined circumstances and is likely to be of short duration
Anxiety is often secondary to organic disease states—acute myocardial infarction, angina pectoris, gastrointestinal ulcers, etc—which themselves require specific therapy. Another class of secondary anxiety states (situational anxiety) results from circumstances that may have to be dealt with only once or a few times, including anticipation of frightening medical or dental procedures and family illness or other stressful event. Even though situational anxiety tends to be self-limiting, the short-term use of sedative-hypnotics may be appropriate

42. Clinical uses
Sedative-hypnotics should be used with appropriate caution so as to minimize adverse effects
The patient should be warned of the possibility to avoid impairment of performance of any task requiring mental alertness and motor coordination
Some patients may tolerate the drug better if most of the daily dose is given at bedtime for the shortest period (2 months)
Combinations of antianxiety agents should be avoided. Cautious with consumption of alcohol or concurrent use of OTC antihistaminic or anticholinergic drugs

43. Clinical uses B. Treatment of sleep disorders
True primary insomnia is rare
Useful 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
Not all bzds are useful as hypnotic agents, although all have sedative or calming effects

44. Clinical uses….
In some cases, however, the patient will need and should be given a sedative-hypnotic for a limited period. An ideal hypnotic agent would have:
A rapid onset of action when taken at bedtime
A sufficient duration of action to facilitate sleep throughout the night
A minimal "hangover" effects the following day
Not all bzds are useful as hypnotic agents, although all have sedative or calming effects
Commonly prescribed bzds for sleep disorders include long-acting flurazepam, intermediate-acting temazepam, and short-acting triazolam
Drowsness, headache, problem of concentration, dry mouth, GI complains, fatigue, sweating, nausea, anxiety

45. Clinical uses
The choice of a particular bzd to treat a sleep disturbance is generally based on PK criteria:
Long-acting compounds (e.g. flurazepam) may ensure that a patient will sleep through the night, they also may cause cumulative effects resulting in daytime sluggishness or drug hangover
Short-acting compounds (e.g. triazolam) avoid the hangover problem, but their use may be associated with early awakening and an increase in daytime anxiety
Benzodiazepines can cause a dose-dependent decrease in both REM and slow-wave sleep, though to a lesser extent than the barbiturates. The newer hypnotics zolpidem, zaleplon, and eszopiclone are less likely than the benzodiazepines to change sleep patterns
Displaying little movement or activity, inactive, lacking alertness or energy; Slow to perform or respond to stimulation.

46. Clinical uses
Anticonvulsant: Phenobarbital has specific anticonvulsant activity that is distinguished from the nonspecific CNS depression
Anesthesia: Selection is strongly influenced by the desired duration of action. The ultrashort-acting barbiturate, thiopental, is used IV to induce anesthesia

47. Clinical uses Amnesia (Midazolam)
Bzds have the capacity to cause anterograde amnesia and often used as premedication for anxiety-provoking and unpleasant procedures, such as endoscopic, certain dental procedures as well as angioplasty
They also cause a form of conscious sedation, allowing the person to be receptive to instructions during these procedures
& Amnesia (Midazolam)

48. Clinical uses of benzodiazepines
C. Other Therapeutic Uses
Alcohol and Sedative–Hypnotic Withdrawal
Cross-dependence, defined as the ability of one drug to suppress abstinence symptoms from discontinuance of another drug, is quite marked among sedative-hypnotics
Longer-acting drugs such as chlordiazepoxide, diazepam, and phenobarbital can be used to alleviate withdrawal symptoms of shorter-acting drugs, including ethanol

49. Clinical uses of benzodiazepines
C. Other Therapeutic Uses
Muscle Relaxation
Diazepam is useful in the treatment of skeletal muscle spasms, such as occur in muscle strain, and in treating spasticity from degenerative disorders, such as multiple sclerosis and cerebral palsy (CP) (disorder of movement, muscle tone or posture)

50. Overdoses
Overdoses of barbitutares are associated with severe respiratory and central CV depression
Overdoses with the bzds occur commonly, but fatal toxic occurrences are rare…..
…..more likely to occur in children, in individuals with respiratory difficulties, or have consumed another CNS depressant (e.g. Alcohol)

51. Adverse effects Dose-dependents CNS depression:
This is the most common adverse effects
Include: drowsiness, impaired judgment, and diminished motor skills, sometimes with a significant impact on driving ability, job performance, and personal relationships
Barbiturates increase porphyrin synthesis, and are contraindicated in patients with acute intermittent porphyria

52. Porphyria (poor-FEAR-e-uh) refers to a group of disorders that result from a buildup of natural chemicals that produce porphyrin in your body. Porphyrins are essential for the function of hemoglobin — a protein in your red blood cells that links to porphyrin, binds iron, and carries oxygen to your organs and tissue.

53. Drug interactions
PD interactions: Additive effect with other CNS depressants which can lead to serious consequences, including enhanced CNS depression (ethanol)

54. Drug interactions PK interactions:
Many bzds are metabolized by the CYP3A4
CYP3A4 inhibitors (e.g. grapefruit juice, ketoconazole, itraconazole, erythromycin) result in intensification and prolongation of the bzd
CYP3A4 inducers (e.g. rifampin, carbamazepine, and phenytoin) can reduce the therapeutic effect of bzds
Barbiturates induce hepatic CYP450: chronic administration diminishes the action of many drugs dependent on CYP450 metabolism (e.g. dicumarol, phenytoin, digitalis compounds, & griseofulvin)

55. Other Sedative-Hypnotic Agents
Benzodiazepine-Receptor Agonists
Agents: Zolpidem, zaleplon, & eszopicolone
Are structurally unrelated to bzds but share a similar mechanism of action
They act on a subset of the benzodiazepine receptor family, BZ1
Compared with the bzds, they have relatively weak anxiolytic, anticonvulsant, and skeletal muscle relaxant properties at therapeutic doses

56. Other Sedative-Hypnotic Agents
Benzodiazepine-Receptor Agonists
They have efficacies similar to those of the hypnotic bzds in the management of sleep disorders, with few withdrawal effects and minimal rebound insomnia
Little or no tolerance and dependence with prolonged use

57. Other Sedative-Hypnotic Agents
Benzodiazepine-Receptor Agonists
ADEs: GIT upset and CNS (dizziness, drowsiness, nightmares, headache, agitation)
Eszopiclone ADEs: dry mouth, peripheral edema, and unpleasant taste

58. Other Sedative-Hypnotic Agents
Buspirone
Buspirone exert its anxiolytic effects by acting as a partial agonist at brain 5-HT1A
In therapeutic doses, buspirone relieves anxiety with little or no hypnotic effect and lacks anticonvulsant or muscle relaxant properties of bzds

59. Other Sedative-Hypnotic Agents
Buspirone
Buspirone-treated patients show no withdrawal signs on abrupt discontinuance
Buspirone causes less psychomotor impairment than bzds, and does not affect driving skills
Buspirone has the disadvantage of a slow onset of action (3–4 weeks), making the drug unsuitable for management of acute anxiety states

60. Other Sedative-Hypnotic Agents
Buspirone
It does not potentiate effects of conventional sedative-hypnotic drugs, ethanol, or TCA, and elderly patients do not appear to be more sensitive to its actions
The frequency of ADEs is low, with the most common effects being headaches, dizziness, nervousness, and light-headedness
BP may be significantly elevated in patients receiving MAO inhibitors

61. It is rapidly absorbed orally but undergoes extensive first-pass metabolism.
The elimination half-life is 2–4 hours, and liver dysfunction may slow its clearance.
Rifampin, an inducer of cytochrome P450, decreases the half-life of buspirone; inhibitors of CYP3A4 (eg, erythromycin, ketoconazole, grapefruit juice, nefazodone) can markedly increase its plasma levels.
Causes less psychomotor impairment than benzodiazepines not affect driving skills.
Does not potentiate effects of conventional sedative-hypnotic drugs, ethanol, or tricyclic antidepressants; and elderly
Buspirone is an FDA category B drug in terms of its use in pregnancy.

62. Ramelteon and Tasimelteon
Melatonin receptors are thought to be involved in maintaining circadian rhythms underlying the sleep-wake cycle
Ramelteon, a novel hypnotic drug prescribed specifically for patients who have difficulty in falling asleep.
It is an agonist at MT1 and MT2 melatonin receptors located in the suprachiasmatic nuclei of the brain and Tasimelteon is similar

63. These drugs have no direct effects on GABAergic neurotransmission in the central nervous system.
The drug is rapidly absorbed after oral administration and undergoes extensive first-pass metabolism, forming an active metabolite with longer half-life (2–5 hours) than the parent drug

64. Ramelteon should be used with caution in patients with liver dysfunction
The CYP inducer rifampin markedly reduces the plasma levels of both ramelteon and its active metabolite
ADR: dizziness, somnolence, fatigue, and endocrine changes.