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 that resembles natural sleep
Most anxiolytic and sedative–hypnotic drugs produce dose-dependent depression of CNS function

3. CNS depression: dose-response curve
Coma
DRUG A
DRUG B
Anesthesia
Hypnosis
CNS effects
Sedation
Hypnotic effects involve more pronounced depression of the CNS than sedation, and this can be achieved with many drugs in this class simply by increasing the dose
Increasing dose

4. Sedative-hypnotics Benzodiazepines Barbiturates Miscellaneous agents
Short
action
Intermediate Buspirone
action Ramelteon
Long Zaleplon
action Zolpidem

5. 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)

6. 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

7. Benzodiazepines- Mechanism of action
The targets for bzds actions are the γ-aminobutyric acid (GABAA) receptors
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

8. GABA receptors
GABA receptors are membrane-bound proteins that can be divided into two major subtypes: GABAA and GABAB receptors
The ionotropic GABAA receptors are composed of five subunits that assembled from five subunits selected from multiple polypeptide classes (α, β, γ, δ, ε, ρ etc) to form an integral chloride channel
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

9. The ionotropic GABAA receptors are composed of five subunits that assembled from five subunits selected from multiple polypeptide classes (α, β, γ, δ, ε, ρ etc) to form an integral chloride channel
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

10. 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)
The bzds, barbiturates, alcohols, and general anesthetics appear to facilitate GABA transmission
Vigabatrin, an anticonvulsant, elevates brain GABA by inhibiting the breakdown enzyme GABA-T

11. 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

12. Benzodiazepines -Mechanism of action
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

13. Benzodiazepine Binding Site Ligands
Agonists:
Benzodiazepines: multiple BZ binding sites
Zolpidem, zaleplon, and eszopiclone: selective agonists at the BZ1
Antagonists: Flumazenil
Inverse agonists: β-carbolines, eg, n-butyl- β -carboline-3-carboxylate (β -CCB)

14. Benzodiazepines Short-acting Medium-acting Long-acting
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
Medium-acting
Long-acting

15. Intermediate (6-24 hours):Alprazolam, Lorazepam, Estazolam,Temazepam
Short acting (3-8 hours): Oxazepam, Triazolam
Intermediate (6-24 hours):Alprazolam, Lorazepam,
Estazolam,Temazepam
Long acting ( hours):Chlorazepate, Diazepam
Chlordiazepoxide,Flurazepam, Quazepam

16. Benzodiazepines
Bzds are all metabolised both by dealkylation (phase 1) & conjugation (phase 2) reactions
The longer acting agents are converted in the liver to one or active metabolite, some with long half-lives than the parant drug
The t1/2 of flurazepam in plasma is ∼2 hours, but that of a major active metabolite N-desalkyl-flurazepam is ∼50 hours
The short-acting compounds are metabolised directly by conjugation with glucuronide (e.g. oxazepam)
The patterns and rates of metabolism depend on the individual drugs

17. Diazepam
desmathyldiazepam active
oxazepam metabolites
conjugation

18. Estazolam immediately converted to
Oxazepam inactive metabolites

19. Benzodiazepines
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
The patterns and rates of metabolism depend on the individual drugs

20. Benzodiazepines
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 the action
Bzds having 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

21. Organ Level Effects The main effects of benzodiazepines are:
Reduction of anxiety (BZ2)
Sedation and induction of sleep (BZ1)
Reduction of muscle tone and coordination (BZ2 in the spinal cord)
Anticonvulsant effect (BZ1)
Anterograde amnesia (BZ1)

22. Clinical uses of benzodiazepines
Treatment of anxiety state
The bzds are the most widely used drugs for the management of acute and chronic anxiety b/c of their:
Rapid onset of action
Relatively high therapeutic
Availability of flumazenil for treatment of overdose
Low risk of drug interactions
Minimal effects on CV or ANS

23. Clinical uses of benzodiazepines
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 sedative and hypnotic effects

24. Clinical uses of benzodiazepines
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

25. Clinical uses of benzodiazepines
Treatment of anxiety state
Alprazolam is particularly effective in treatment of panic disorders & agoraphobia & is more selective in than other BDZs

26. Clinical uses of benzodiazepines
B. Treatment of sleep disorders
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
Commonly prescribed bzds for sleep disorders include long-acting flurazepam, intermediate-acting temazepam, and short-acting triazolam
Not all bzds are useful as hypnotic agents, although all have sedative or calming effects

27. Clinical uses of benzodiazepines
B. Treatment of sleep disorders
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

28. Clinical uses of benzodiazepines
Other Therapeutic Uses
Seizures
Anesthesia & Amnesia (Midazolam)
Bzds have the capacity to cause anterograde amnesia and often used as premedication for anxiety-provoking and unpleasant procedures, such as endoscopic, bronchoscopic, and 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

29. 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

30. Clinical uses of sedative-hypnotics
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)

31. Tolerance and Dependence
Tolerance: decrease responsiveness to drug following repeated exposure
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)

32. Tolerance and Dependence
Dependence on bzds can develop if high doses of the drugs are given over prolonged period
Abrupt withdrawal is associated with withdrawal symptoms, including rebound insomnia & rebound anxiety, which may even exceed that which preceded the treatment
A gradual tapering of the dose until it is eventually discontinued lessens the likelihood of a withdrawal reactions

33. 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 slowely 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

34. Adverse effects Dose-dependents CNS depression:
Most common adverse effects associated with use of bzds
Include: drowsiness, excessive sedation, impaired motor coordination, ataxia, confusion, and memory loss, and cognitive impairment

35. Adverse Effect
Overdoses with the bzds occur commonly, but fatal toxic occurrences are rare
Fatal intoxications are more likely in children, in individuals with respiratory difficulties, and in individuals who have consumed another CNS depressant (e.g. Alcohol)

36. Drug interactions Pharmacodynamic interactions:
Additive effect with other CNS depressants which can lead to serious consequences, including enhanced depression

37. Drug interactions Pharmacokinetic interactions:
Many bzds are metabolized by the CYP3A4
Coadministration of CYP3A4 inhibitors (e.g. grapefruit juice, ketoconazole, itraconazole, erythromycin) result in intensification and prolongation of the bzd
Coadministration of CYP3A4 inducers (e.g. rifampin, carbamazepine, and phenytoin) can reduce the therapeutic effect of bzds

38. Flumazenil: Benzodiazepine antagonist
Flumazenil is a competitive antagonists of bzds that can rapidly reverse the effects of benzodiazepines
The drug is available for IV administration only
Onset is rapid but duration is short, with a half-life of about 1 hour
Frequent administration may be necessary to maintain reversal of a long-acting bzd

39. Flumazenil: Benzodiazepine antagonist
Adverse effects:
Agitation, confusion, dizziness, and nausea
Severe precipitated abstinence syndrome in patients who have developed physiologic benzodiazepine dependence
In patients who have ingested bzds with TCA, seizures and cardiac arrhythmias may follow flumazenil administration

40. Barbiturates
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:
Induce tolerance
Induce drug-metabolizing enzymes
Physical dependence
Associated with very severe withdrawal symptoms
Ability to cause coma in toxic doses

41. 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

42. Barbiturates- Mechanism of action
Barbiturates are less selective in their actions than bzds, because they also depress the actions of the excitatory neurotransmitter glutamic acid via binding to the AMPA 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

43. Organ Level Effects The main effects of barbiturates are:
Reduction of anxiety
Sedation and induction of sleep
Anticonvulsant effect
Dose-dependent respiratory depression espically in patients with pulmonary disease
CV depression1,which is most evident in patients hypovolemic states, HF, and other diseases that impair CV function
Respiratory and CV effects are more marked when are given IV
1 probably as a result of actions on the medullary vasomotor centers

44. Clinical uses
Anesthesia: Selection is strongly influenced by the desired duration of action. The ultrashort-acting barbiturate, thiopental, is used IV to induce anesthesia
Anticonvulsant: Phenobarbital has specific anticonvulsant activity that is distinguished from the nonspecific CNS depression
Antxiety and hypnosis (secobarbital) : most have been replaced by the bzds

45. Tolerance and Dependence
PK/metabolic tolerance: an increase in the rate of drug metabolism in the case of chronic administration of barbiturates contributes to the decreased effect
Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness, restlessness, nausea and vomiting, seizures, delirium, and cardiac arrest
Withdrawal is much more severe than that associated with opiates and can result in death

46. Adverse effects
CNS: Barbiturates cause drowsiness, impaired concentration, and mental and physical sluggishness
Poisoning: associated with severe depression of respiration is coupled with central CV depression, and results in a shock-like condition with shallow, infrequent breathing
Barbiturates increase porphyrin synthesis, and are contraindicated in patients with acute intermittent porphyria

47. Drug interactions
PD interactions: barbiturates combine with other CNS depressants cause severe CNS depression, especially ethanol
PK interactions:
Barbiturates induce hepatic CYP450: chronic administration diminishes the action of many drugs that are dependent on CYP450 metabolism to reduce their concentration (e.g. dicumarol, phenytoin, digitalis compounds, & griseofulvin)

48. 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

49. 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

50. 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

51. 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 sedative effect and lacks anticonvulsant or muscle relaxant properties of bzds

52. 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, making the drug unsuitable for management of acute anxiety states

53. 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

54. Other Sedative-Hypnotic Agents
Ramelteon
It is a selective agonist at the MT1 and MT2 subtypes of melatonin receptors1
It is indicated for the treatment of insomnia in which falling asleep is the primary complaint
ADRs: dizziness, somnolence, fatigue, decreases in testosterone and increases in prolactin
1 Normally, light stimulating the retina transmits a signal to the suprachiasmatic nucleus (SCN) of the hypothalamus, that in turn relays a signal via a lengthy nerve pathway to the pineal gland that inhibits the release of melatonin from the gland. As darkness falls and light ceases to strike the retina, melatonin release from the pineal gland is no longer inhibited, and the gland begins to secrete melatonin. Stimulation of MT1 and MT2 receptors by melatonin in the SCN is able to induce and promote sleep and is thought to maintain the circadian rhythm underlying the normal sleep-wake cycle