SEDATIVE AND HYPNOTICS

1. Sedative and Hypnotics

2. • An effective sedative (anxiolytic) agent should
reduce anxiety and exert a calming effect. The
degree of central nervous system depression
caused by a sedative should be the minimum
consistent with therapeutic efficacy.
• A sedative drug decreases activity, moderates
excitement, and calms the recipient.

3. • A hypnotic drug should produce drowsiness and
encourage the onset and maintenance of a state
of sleep. Hypnotic effects involve more
pronounced depression of the central nervous
system than sedation, and this can be achieved
with many drugs in this class simply by increasing
the dose.
• Graded dose-dependent depression of central
nervous system function is a characteristic of
most sedative-hypnotics.

4. • Hypnotic drug produces drowsiness and
facilitates the onset and maintenance of a
state of sleep that resembles natural sleep in
its electroencephalographic characteristics
and from which the recipient can be aroused
easily.

5. Anxiety disorders as recognised clinically include:
• generalised anxiety disorder (an ongoing state of
excessive anxiety lacking any clear reason or focus)
• panic disorder (sudden attacks of overwhelming fear
occur in association with marked somatic symptoms,
such as sweating, tachycardia, chest pains, trembling
and choking). Such attacks can be induced even in
normal individuals by infusion of sodium lactate, and
the condition appears to have a genetic component)

6. • phobias (strong fears of specific objects or
situations, e.g. snakes, open spaces, flying,
social interactions)
• post-traumatic stress disorder (anxiety
triggered by recall of past stressful
experiences)
• obsessive compulsive disorder (compulsive
ritualistic behaviour driven by irrational
anxiety, e.g. fear of contamination).

7. CLASSIFICATION OF ANXIOLYTIC AND
HYPNOTIC DRUGS
• Benzodiazepines. This is the most important
group, used as anxiolytic and hypnotic agents.
• Buspirone. This 5-HT1A receptor agonist is
anxiolytic but not appreciably sedative.

8. • β-Adrenoceptor antagonists (e.g. propranolol).
These are used to treat some forms of anxiety,
particularly where physical symptoms such as
sweating, tremor and tachycardia are
troublesome. Their effectiveness depends on
block of peripheral sympathetic responses rather
than on any central effects. They are sometimes
used by actors and musicians to reduce the
symptoms of stage fright, but their use by
snooker players to minimise tremor is banned as
unsportsmanlike.

9. • Zolpidem. This hypnotic acts similarly to
benzodiazepines, although chemically distinct,
but lacks appreciable anxiolytic activity.
• Barbiturates. These are now largely obsolete,
superseded by benzodiazepines. Their use is
now confined to anaesthesia and the
treatment of epilepsy.

10. • Miscellaneous other drugs (e.g. chloral
hydrate, meprobamate and methaqualone).
They are no longer recommended, but
therapeutic habits die hard and they are
occasionally used. Sedative antihistamines,
such as diphenhydramine, are sometimes
used as sleeping pills, particularly for wakeful
children. They are included in various over-
the-counter preparations intended to improve
children's sleep patterns.

11. Benzodiazepines
• The first benzodiazepine, chlordiazepoxide,
was synthesised by accident in 1961, the
unusual seven-membered ring having been
produced as a result of a reaction that went
wrong in the laboratories of Hoffman-la
Roche. Its unexpected pharmacological
activity was recognised in a routine screening
procedure, and benzodiazepines quite soon
became the most widely prescribed drugs in
the pharmacopoeia.

12. • Benzodiazepines (once thought to be acting as 'non-
specific depressants') act selectively on GABAA
receptors, which mediate fast inhibitory synaptic
transmission throughout the central nervous system
(CNS). Benzodiazepines 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. Benzodiazepines do not affect receptors for
other amino acids, such as glycine or glutamate

13. • The GABAA receptor is a ligand-gated ion
channel consisting of a pentameric assembly
of different subunits, the main ones being α,β
and γ, each of which occurs in three or more
isoforms. The potential number of
combinations is therefore huge, but three
combinations predominate in the adult brain,
namely α1β2γ2, α2β3γ2 and α3β3γ2.

14. • The various combinations occur in different
parts of the brain, and linking this diversity
with physiological function and
pharmacological specificity presents a
difficult, although familiar, problem.
Sensitivity to benzodiazepines requires the
presence of both α and β subunits, and
mutation of a single amino acid (histidine) in
the α subunit eliminates benzodiazepine
sensitivity.

15. • Some benzodiazepines include
• Diazepam
• Desmethyldiazepam
• Chlordiazepoxide
• Flurazepam
• Oxazepam
• Lorazepam
• Nitrazepam
• Triazolam
• Alprazolam

16. PHARMACOLOGICAL EFFECTS AND
USES
The main effects of benzodiazepines are:
• Reduction of anxiety and aggression
• Sedation and induction of sleep
• Reduction of muscle tone and coordination
• Anticonvulsant effect (clonazepam, nitrazepam,
lorazepam and diazepam)
• Anterograde amnesia.
• Anesthesia (diazepam, lorazepam and
midazolam)

17. • Benzodiazepine administration typically increases
total sleep time, largely by increasing the time
spent in stage 2 (which is the major fraction of
non-REM sleep). The effect is greatest in subjects
with the shortest baseline total sleep time.
• The number of shifts to lighter sleep stages (1
and 0) and the amount of body movement are
diminished. Nocturnal peaks in the secretion of
growth hormone, prolactin, and luteinizing
hormone are not affected.

18. BENZODIAZEPINE INVERSE AGONISTS
AND ANTAGONISTS
• The term inverse agonist is applied to drugs
that bind to benzodiazepine receptors and
exert the opposite effect to that of
conventional benzodiazepines, producing
signs of increased anxiety and convulsions.
Diazepam-binding inhibitor is an example, and
some benzodiazepine analogues act similarly.

19. • Benzodiazepine receptor exists in two distinct
conformations, only one of which (A) can bind
a GABA molecule and open the chloride
channel. The other conformation (B) cannot
bind GABA. Normally, with no benzodiazepine
receptor ligand present, there is an
equilibrium between these two
conformations; sensitivity to GABA is present
but submaximal.

20. • Benzodiazepine agonists (e.g. diazepam) are
postulated to bind preferentially to conformation
A, thus shifting the equilibrium in favour of A and
enhancing GABA sensitivity. Inverse agonists bind
selectively to B and have the opposite effect.
Competitive antagonists such as flumazenil bind
equally to A and B, and consequently do not
disturb the conformational equilibrium but
antagonise the effect of both agonists and inverse
agonists.

21. • Some of the molecular variants of the GABAA
receptor seem to show different relative
affinities for agonists, antagonists and inverse
agonists, and it is possible that this reflects
differences in the equilibrium between the A
and B states as a function of the subunit
composition of the receptor.

22. Pharmacological effects on other
organs
• Respiration
• At higher doses, such as those used for
preanesthetic medication or for endoscopy,
benzodiazepines slightly depress alveolar
ventilation and cause respiratory acidosis.
• These effects are exaggerated in patients with
chronic obstructive pulmonary disease
(COPD), and alveolar hypoxia and CO2 narcosis
may result.

23. • These drugs can cause apnea during
anesthesia or when given with opioids.
Patients severely intoxicated with
benzodiazepines only require respiratory
assistance when they also have ingested
another CNS-depressant drug, most
commonly ethanol.

24. • Hypnotic doses of benzodiazepines may
worsen sleep-related breathing disorders by
adversely affecting control of the upper airway
muscles or by decreasing the ventilatory
response to CO2. The latter effect may cause
hypoventilation and hypoxemia in some
patients with severe COPD, although
benzodiazepines may improve sleep and sleep
structure in some instances.

25. • Cardiovascular System
• In preanesthetic doses, all benzodiazepines
decrease blood pressure and increase heart rate.
• Diazepam increases coronary flow, possibly by an
action to increase interstitial concentrations of
adenosine, and the accumulation of this
cardiodepressant metabolite also may explain the
negative inotropic effects of the drug.

26. • GI Tract
• Benzodiazepines partially protect against
stress ulcers in rats, and diazepam markedly
decreases nocturnal gastric secretion in
humans.

27. PHARMACOKINETIC ASPECTS
Drugs active at the benzodiazepine receptor may be
divided into four categories based on their
elimination t1/2:
• Ultra-short-acting benzodiazepines, midazolam
• Short-acting agents (t1/2 <6 hours), including
triazolam, the non-benzodiazepine zolpidem (t1/2
~2 hours), and eszopiclone (t1/2 5-6 hours)
• Intermediate-acting agents (t1/2 6-24 hours),
including estazolam and temazepam
• Long-acting agents (t1/2 >24 hours), including
flurazepam, diazepam, and quazepam

28. • Benzodiazepines are well absorbed when
given orally, usually giving a peak plasma
concentration in about 1 hour. Some (e.g.
oxazepam, lorazepam) are absorbed more
slowly. They bind strongly to plasma protein,
and their high lipid solubility causes many of
them to accumulate gradually in body fat.

29. • They are normally given by mouth but can be
given intravenously (e.g. diazepam in status
epilepticus, midazolam in anaesthesia).
Intramuscular injection often results in slow
absorption. Diazepam can be used for alcohol
withdrawal

30. • Benzodiazepines are all metabolised and
eventually excreted as glucuronide conjugates in
the urine. They vary greatly in duration of action
Several are converted to active metabolites such
as N-desmethyldiazepam (nordiazepam), which
has a half-life of about 60 hours, and which
accounts for the tendency of many
benzodiazepines to produce cumulative effects
and long hangovers when they are given
repeatedly.

31. • The short-acting compounds are those that
are metabolised directly by conjugation with
glucuronide.

32. UNWANTED EFFECTS
• Toxic effects resulting from acute overdosage
• Benzodiazepines in acute overdose are
considerably less dangerous than other
anxiolytic/hypnotic drugs. Because such
agents are often used in attempted suicide,
this is an important advantage. In overdose,
benzodiazepines cause prolonged sleep,
without serious depression of respiration or
cardiovascular function.

33. • However, in the presence of other CNS
depressants, particularly alcohol,
benzodiazepines can cause severe, even life-
threatening, respiratory depression. The
availability of an effective antagonist,
flumazenil, means that the effects of an acute
overdose can be counteracted,3 which is not
possible for most CNS depressants.

34. • Unwanted effects occurring during normal
therapeutic use
• The main side effects of benzodiazepines are
drowsiness, confusion, amnesia and impaired
coordination, which considerably affects
manual skills such as driving performance.
Benzodiazepines enhance the depressant
effect of other drugs, including alcohol, in a
more than additive way.

35. • The long and unpredictable duration of action
of many benzodiazepines is important in
relation to side effects. Long-acting drugs such
as nitrazepam are no longer used as
hypnotics, and even shorter-acting
compounds such as lorazepam can produce a
substantial day-after impairment of job
performance and driving skill.

36. Ideal Hypnotic
• An ideal hypnotic agent would have a rapid
onset of action when taken at bedtime, a
sufficiently sustained action to facilitate sleep
throughout the night, and no residual action
by the following morning. Among the
benzodiazepines that are used commonly as
hypnotic agents, triazolam theoretically fits
this description most closely.

37. • Flurazepam might seem to be unsuitable for
this purpose because of the slow rate of
elimination of desalkylflurazepam. In practice,
there appear to be some disadvantages to the
use of agents that have a relatively rapid rate
of disappearance, including the early-morning
insomnia that is experienced by some patients
and a greater likelihood of rebound insomnia
on drug discontinuation

38. Tolerance and dependence
• Tolerance (i.e. a gradual escalation of dose
needed to produce the required effect) occurs
with all benzodiazepines, as does dependence,
which is their main drawback. They share these
properties with other hypnotics and sedatives.
Tolerance is less marked than it is with
barbiturates, which produce pharmacokinetic
tolerance because of induction of hepatic drug-
metabolising enzymes -this does not occur with
benzodiazepines. Such tolerance as does occur
appears to represent a change at the receptor
level, but the mechanism is not well understood

39. Abstinence syndrome
• Physiologic dependence can be described as an
altered physiologic state that requires continuous
drug administration to prevent an abstinence or
withdrawal syndrome.
• This syndrome is characterized by states of
increased anxiety, insomnia, and central nervous
system excitability that may progress to
convulsions. Most sedative-hypnotics—including
benzodiazepines—are capable of causing
physiologic dependence when used on a long-
term basis.

40. • When higher doses of sedative-hypnotics are used,
abrupt withdrawal leads to more serious withdrawal
signs. Differences in the severity of withdrawal
symptoms resulting from individual sedative-hypnotics
relate in part to half-life, since drugs with long half-
lives are eliminated slowly enough to accomplish
gradual withdrawal with few physical symptoms. The
use of drugs with very short half-lives for hypnotic
effects may lead to signs of withdrawal even between
doses. For example, triazolam, a benzodiazepine with a
half-life of about 4 hours, has been reported to cause
daytime anxiety when used to treat sleep disorders.

41. Benzodiazepine Antagonists:
Flumazenil
• Flumazenil blocks many of the actions of
benzodiazepines, zolpidem, zaleplon, and
eszopiclone, but does not antagonize the central
nervous system effects of other sedative-
hypnotics, ethanol, opioids, or general
anesthetics.
• Flumazenil is approved for use in reversing the
central nervous system depressant effects of
benzodiazepine overdose and to hasten recovery
following use of these drugs in anesthetic and
diagnostic procedures.

42. • When given intravenously, flumazenil acts
rapidly but has a short half-life (0.7–1.3 hours)
due to rapid hepatic clearance. Because all
benzodiazepines have a longer duration of
action than flumazenil, sedation commonly
recurs, requiring repeated administration of
the antagonist.

43. • Adverse effects of flumazenil include agitation,
confusion, dizziness, and nausea. Flumazenil
may cause a severe precipitated abstinence
syndrome in patients who have developed
physiologic benzodiazepine dependence.

45. BUSPIRONE
• Buspirone is a partial agonist at 5-HT1A receptors
and is used to treat various anxiety disorders. It
also binds to dopamine receptors, but it is likely
that its 5-HT-related actions are important in
relation to anxiety suppression, because related
compounds (e.g. ipsapirone and gepirone,
neither of which are approved for clinical use,
which are highly specific for 5-HT1A receptors;
show similar anxiolytic activity in experimental
animals). 5-HT1A receptors are inhibitory
autoreceptors that reduce the release of 5-HT
and other mediators.

46. • They also inhibit the activity of noradrenergic
locus coeruleus neurons and thus interfere
with arousal reactions. However, buspirone
takes days or weeks to produce its effect in
humans, suggesting a more complex indirect
mechanism of action. Buspirone is ineffective
in controlling panic attacks or severe anxiety
states.

47. • Buspirone has side effects quite different from
those of benzodiazepines. It does not cause
sedation or motor incoordination, nor have
withdrawal effects been reported. Its main
side effects are nausea, dizziness, headache
and restlessness, which generally seem to be
less troublesome than the side effects of
benzodiazepines.

49. Zolpidem
• Zolpidem is a non-benzodiazepine sedative-
hypnotic drug. It is classified as an
imidazopyridine
• The actions of zolpidem are due to agonist effects
on GABAA receptors and generally resemble
those of benzodiazepines, it produces only weak
anticonvulsant effects in experimental animals,
and its relatively strong sedative actions appear
to mask anxiolytic effects in various animal
models of anxiety

50. • Zolpidem has little effect on the stages of
sleep in normal human subjects. The drug is as
effective as benzodiazepines in shortening
sleep latency and prolonging total sleep time
in patients with insomnia. After
discontinuation of zolpidem, the beneficial
effects on sleep reportedly persist for up to 1
week .

51. • Zolpidem is approved only for the short-term
treatment of insomnia.
• Incidence of adverse effects (e.g., GI
complaints or dizziness) is low.
• Little or no unchanged zolpidem is found in
the urine, elimination of the drug is slower in
patients with chronic renal insufficiency

52. Zaleplon
• Zaleplon preferentially binds to the
benzodiazepine-binding site on GABAA
receptors containing the 1 receptor subunit.
Zaleplon is absorbed rapidly and reaches peak
plasma concentrations in 1 hour.
• Zaleplon (usually administered in 5-, 10-, or
20-mg doses) has been studied in clinical trials
of patients with chronic or transient insomnia

53. Eszopiclone
• Eszopiclone has no structural similarity to
benzodiazepines, zolpidem, or zaleplon.
• Eszopiclone is used for the long-term
treatment of insomnia and for sleep
maintenance. It is prescribed to patients who
have difficulty falling asleep as well as those
who experience difficulty staying asleep

54. • Eszopiclone is believed to exert its sleep-
promoting effects through its enhancement of
GABAA receptor function at the
benzodiazepine binding site.

55. BARBITURATES
• The sleep-inducing properties of barbiturates
were discovered early in the 20th century, and
hundreds of compounds were made and tested.
Until the 1960s, they formed the largest group of
hypnotics and sedatives in clinical use.
Barbiturates all have depressant activity on the
CNS, producing effects similar to those of
inhalation anaesthetics. They cause death from
respiratory and cardiovascular depression if given
in large doses, which is one of the main reasons
that they are now little used as anxiolytic and
hypnotic agents.

56. • Amobarbital, Uses: Insomnia, pre-op sedation,
emergency management of seizures, t1/2 : 10-
40hrs, dosage form: IM, IV
• Butabarbital Uses: Insomnia, pre-op sedation,
t1/2 :35-40 hrs, oral
• Mephobarbital, Uses: Seizure disorders,
daytime sedation, t1/2 : 10-70 hrs, oral
• Methohexital, Uses: Induction and
maintenance of anesthesia, t1/2 : 3-5 hrs, IV

57. • Pentobarbital, Uses: Insomnia, pre-op sedation,
emergency management of seizures, t1/2 : 15-50
hrs, dosage form: oral, IM, IV, rectal.
• Phenobarbital, Uses: Seizure disorders, status
epilepticus, daytime sedation, t1/2 : 80-120 hrs,
oral, IM, IV
• Secobarbital , Uses: Insomnia, preoperative
sedation, t1/2 : 15-40 hrs, oral
• Thiopental: Induction/maintenance of
anesthesia, pre-op sedation, emergency
management of seizures, t1/2 : 8-10 hrs, IV

58. • Pentobarbital and similar typical barbiturates
with durations of action of 6-12 hours are still
very occasionally used as sleeping pills and
anxiolytic drugs, but they are less safe than
benzodiazepines. Pentobarbital is often used as
an anaesthetic for laboratory animals.
• Barbiturates share with benzodiazepines the
ability to enhance the action of GABA, but they
bind to a different site on the GABAA
receptor/chloride channel, and their action is less
specific.

59. • As well as being dangerous in overdose,
barbiturates induce a high degree of tolerance
and dependence. They also strongly induce the
synthesis of hepatic cytochrome P450 and
conjugating enzymes, and thus increase the rate
of metabolic degradation of many other drugs,
giving rise to a number of potentially
troublesome drug interactions. Because of
enzyme induction, barbiturates are also
dangerous to patients suffering from the
metabolic disease porphyria.

60. Ramelteon
• It was approved in the U.S. in 2005 for the
treatment of insomnia, specifically sleep onset
difficulties.
• Two GPCRs for melatonin, MT1 and MT2, are
found in the suprachiasmatic nucleus, each
playing a different role in sleep. Binding of
agonists, such as melatonin, to MT1 receptors
promotes the onset of sleep while melatonin
binding to MT2 receptors shifts the timing of the
circadian system .

61. • Ramelteon binds to both MT1 and MT2
receptors with high affinity .
• Ramelteon is efficacious in combating both
transient and chronic insomnia. Subjects given
16 or 64 mg of ramelteon in a clinical trial
showed a significantly shorter latency to sleep
onset, as well as increased total sleep time,
compared to placebo controls

62. • The drug was generally well tolerated by
patients and did not impair next-day cognitive
function. Ramelteon is also useful in the
treatment of chronic insomnia, with no
tolerance occurring in its reduction of sleep
onset latency even after 6 months of drug
administration.