Sedatives and hypnotics (1)

1. Presented By:
Maryam Manzoor
Lecturer Pharmacology
Rashid Latif College of Pharmacy

2.  What is anxiety
 Study and explain sedatives and hypnotics
 Differentiate between sedatives and hypnotics
 Actions of sedatives-hypnotics
 Classifications of sedatives/hypnotics with mechanism
of actions, clinical uses and side effects.

3.  Anxiety is an unpleasant state of tension or uneasiness,
a fear that seems to arise from a sometimes unknown
source.
 The physical symptoms of severe anxiety are similar to
those of fear (such as tachycardia, sweating, trembling,
and palpitations) and involve sympathetic activation.
 The term anxiolytic is sometimes applied to a sedative-
hypnotic.

4.  Sedative refers to a substance that moderates
hyperactivity and excitement while inducing a calming
effect
 Hypnotic refers to a substance that causes drowsiness
and facilitates the onset and maintenance of natural
sleep.

5.  An effective sedative (anxiolytic) agent should reduce
anxiety and exert a calming effect.
 Graded dose-dependent depression of central nervous
system function is a characteristic of sedative-
hypnotics

6. SEDATIVES HYPNOTICS
A drug that reduces excitement and
calms the patient without inducing
sleep.
A drug which produces sleep
resembling natural sleep.
Sedatives in therapeutic doses are
anxiolytic agents.
They are used for initiation or
maintenance of sleep.
Most sedatives in larger doses produce
hypnosis.
Hypnotics in larger doses produce
anesthesia.
Site of action is limbic system which
regulates thought and mental
functions.
Site of action is on mid brain and
ascending RAS which maintains awake
fullness.

7. At still higher doses, these sedative-hypnotics may depress respiratory and
vasomotor centers in the medulla, leading to coma and death

10. NORMAL

ANXIETY
_________  _________________
SEDATION

HYPNOSIS

Confusion, Delirium, Ataxia

Surgical Anesthesia

COMA

DEATH

11. Major therapeutic use is to
 cause sedation (with concomitant relief of anxiety)
or to encourage sleep.

12. Sedation
 Benzodiazepines, barbiturates, and most older
sedative-hypnotic drugs exert sedative or calming
effects with concomitant reduction of anxiety at
relatively low doses.
Hypnosis
 By definition, all of the sedative-hypnotics will induce
sleep if high enough doses are given.

13. Anesthesia
 certain sedative-hypnotics in high doses will depress
the central nervous system to the point known as stage
III of general anesthesia e.g
 Benzodiazepines—including diazepam, lorazepam,
and midazolam—are used intravenously in anesthesia.
 Barbiturates like thiopental and methohexital are also
used in III stage anesthesia

14. Anticonvulsant Effects
 Most of the sedative-hypnotics are capable of
inhibiting the development and spread of epileptiform
activity in the central nervous system. This effect is
partially, although not completely,mediated by GABAA
receptors.

15. Muscle Relaxation
 Some sedative-hypnotics, at high doses may also
depress transmission at the skeletal neuromuscular
junction that lead to muscle relaxation

16. Effect on Respiratory Functions
 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.

17. Effect on cardiovascular Functions
 At doses up to those causing hypnosis, no
significant on CVS.
 At toxic doses, myocardial contractility and
vascular tone may both be depressed by central
and peripheral effects, leading to circulatory
collapse.
 Respiratory and cardiovascular effects are more
marked when sedative-hypnotics are given
intravenously.

18.  Benzodiazepines
 Barbiturates
 Antihistamines
 Other sedative- hypnotics

20. 3-8 hours 10-12 hours 1-3 days

22. Pharmacokinetics
 Absorption and Distribution
 The rates of oral absorption of benzodiazepines differ
depending on a number of factors, including
lipophilicity. Oral absorption of triazolam is extremely
rapid, and that of diazepam.
 The more the lipid solubility, the more enterance to
CNS

23. Biotransformation
 Metabolic transformation to more water-soluble
metabolites is necessary for clearance of sedative-
hypnotics from the body. The microsomal drug-
metabolizing enzyme systems of the liver are most
important.

24. Excretion
 The water-soluble metabolites of benzodiazepines and
other sedative-hypnotics are excreted mainly via the
kidney.

26.  Gamma-aminobutyric acid (GABA) is the major
inhibitory neurotransmitter in the central nervous
system.

27.  The GABAA receptor (in which the receptor is part of a
ligand-gated ion channel complex ), which functions
as a chloride ion channel, is activated by the inhibitory
neurotransmitter GABA

28.  First choice as sedative - hypnotic

29.  Bzs facilitate GABA-induced chloride channels
hyperpolarization = GABA-mediated inhibitory
neurotansmission, by binding to BZ receptors.

32.  Drowsiness and confusion: These effects are the two
most common side effects of the benzodiazepines.
 Ataxia occurs at high doses and precludes activities
that require fine motor coordination, such as driving
an automobile.
 Cognitive impairment (decreased long-term recall and
acquisition of new knowledge) can occur with use of
benzodiazepines.

33.  Triazolam, one of the most potent oral benzodiazepines
with the most rapid elimination, often shows a rapid
development of tolerance, early morning insomnia,
and daytime anxiety, along with amnesia and
confusion.

34.  Alcohol and other CNS depressants enhance the
sedative-hypnotic effects of the benzodiazepines.

35.  a selective competitive antagonist of BZD receptors
(Bz1).
 Blocks action of benzodiazepines but not other
sedative /hypnotics.

36.  Second choice as sedative - hypnotic
Mechanism of Action
Facilitation of GABA action on the brain.
increase the duration of the GABA gated
channel opening.

37. 1) Enhance GABAergic Transmission
 frequency of openings of GABAergic channels.
Benzodiazepines
 opening time of GABAergic channels.
Barbiturates
 receptor affinity for GABA. BDZs and BARBS

38.  Barbiturates are less selective in their actions than
benzodiazepines,
 They also depress the actions of excitatory
neurotransmitters (eg, glutamic acid) and exert
nonsynaptic membrane effects in parallel with their
effects on GABA neurotransmission.
 This multiplicity of sites of action of barbiturates may
be the basis for their ability to induce full surgical
anesthesia----------------- less safety margin.

39.  1. Selective: minimal respiratory and
cardiovascular depression.
 2. High therapeutic index.
 3. Less dependence with minimal withdrawal
symptoms
 4. Has specific antagonist

40.  Anesthesia:
The ultrashort-acting barbiturates, such as
thiopental, are used intravenously to induce anesthesia.
 Anticonvulsant:
Phenobarbital is used in long-term management of
tonic-clonic seizures, status epilepticus, and eclampsia.
 Anxiety:
Barbiturates have been used as mild sedatives to relieve
anxiety, nervous tension, and insomnia.

42.  Diphenhydramine
 Dimenhydrinate
 Hydroxyzine
 Promethazine

43.  Act on H1 receptors by blocking them.
 Histamine depolarizes human cortical neurons via
action at an H1 receptor---- generates action potential
and increase excitatory post synaptic potential.
 Treat mild insomnia and anxiety disorder
 Tolerance ----long term use

44.  Zolpidem
 Zaleplon
 Chloral hydrate
 Ethanol
 Buspirone
 Ramelteon
 Eszopiclone

45.  Acts on benzodiazepine receptors (BZ 1) &
facilitate GABA mediated neuronal inhibition.
 Its action is antagonized by flumazenil.
 Rapidly absorbed from GIT and metabolized
to inactive metabolites via liver CYT P450.
 Short duration of action ( 2- 4 h).

46.  Respiratory depression occur at high doses in
combination with other CNS depressant as
ethanol.
Uses
 A hypnotic drug for short term treatment of
insomnia

47.  Action same to that of Zolpidem.
 Interacts with the GABA receptor complex and
shares some of the pharmacological properties of
the benzodiazepines.
 Rapid absorption
 Short onset of action
 Short duration of action (1 hr)
 Metabolized by liver microsomal enzymes.

48.  Little effect on sleep pattern
 Potentiates action of other CNS depressants
(alcohol).
 Used as hypnotic drug.

49.  It is a prodrug
 Metabolized to active
metabolite(trichloroethanol).
 Short onset of action
 Short duration of action T 1/2 = 6- 8 hours
 It synergizes with alcohol.

50. Chloral hydrate exerts its pharmacological
properties via enhancing the GABA receptor
complex
Disadvantages
 1. GIT irritation
 2. Bad taste
 3. Tolerance
Use
 - Short term treatment of insomnia

51.  Buspirone is useful in the treatment of
generalized anxiety disorder.
 Acts via serotonin (5-HT1A) receptors.
 Causes only mild sedation

52.  Buspirone undergoes metabolism by CYP3A4.
 The most common effects being headaches, dizziness,
and nervousness.
 Dependence is unlikely.
 Slow onset of action.

53.  Used in patients with concerns for addiction or
dependence or a history of addiction or dependence to
other substances.
 The SSRIs, TCAs, venlafaxine, duloxetine and MAOIs
all have potential usefulness in treating anxiety

54.  Ramelteon is a selective agonist at the MT1 and MT2
subtypes of melatonin receptors.
 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.

55.  For the treatment of insomnia in which falling asleep
(increased sleep latency).
 Low addiction
 Common adverse effects of ramelteon include
dizziness, fatigue, and somnolence.

56.  The precise mechanism of action of eszopiclone as a
hypnotic is unknown, but its effect is believed to result
from its interaction with GABA receptor complexes at
binding domains located close to benzodiazepine
receptors.
 Eszopiclone is an oral non benzodiazepine hypnotic and is
also used for treating insomnia.
 Rapid absorption (peak time= 1 hour)

57.  Metabolism by oxidation.
 Excretion in urine.
 Elimination half-life is approximately 6 hours.
 Adverse events include anxiety, dry mouth,
headache, peripheral edema, somnolence, and
unpleasant taste

58.  Ethanol (ethyl alcohol) has anxiolytic and sedative and
hypnotic effects, but its toxic potential outweighs its
benefits.
 It is readily absorbed orally.
 Ethanol is metabolized primarily in the liver, first to
acetaldehyde by alcohol dehydrogenase and then to
acetate by aldehyde dehydrogenase.

59.  Elimination is mostly through the kidney, but a
fraction is excreted through the lungs.
 Inhibits the NMDA glutamate receptor (inhibits an
excitatory effect)