Download 7-Sedative Hypnotic

Sedative Hypnotics and
anxiolytics
Terminology
Tranquilizers (anxiolytics): Treat
excitment and anxiety
Sedative-Hypnotics (sleeping pills):
Sedation and sleep

Sedative
hypnotics
are
drugs
used
for
the
treatment of anxiety and
sleep disorders.
A sedative
A hypnotic drug
Sometimes calledproduces
drowsiness and
anxiolytic, or
minor tranquilizer, encourage the
reduces anxiety onset and
maintenance of
and exerts a
sleep
calming effect
Anxiety disorders
•Generalized anxiety disorder (GAD)= excessive
anxiety
lacking any clear reason
•Panic disorder (sudden attacks of severe fear
accompanied by sweating, tachycardia, chest
pains,….)
•Phobias (strong fears of snakes, open spaces,
flying)
•Post-traumatic stress disorder (anxiety
triggered by recall of past stressful
experiences)
•Obsessive compulsive disorder (OCD) e.g. fear
Examples
drugs:
of
Sedative-Hypnotic
1- Benzodiazepines
2- Buspirone
3- Zolpidem
4- Barbiturates
5- Ethyl alcohol
NB: BZs and barbiturates
share very similar
properties but BZs have
a much safer
pharmacological profile

All have the same
Mechanism of action
(acting on GABA)
except Buspirone
 Graded dose-dependent depression of
the CNS function
is a characteristic of sedative-hypnotics.
 Individual drugs differ in the
relationship between the dose and the
degree of CNS depression
BENZODIAZEPINES


Benzodiazepines (BZs) are the
most widely
used
sedativehypnotic drugs
They have replaced barbiturates
for most uses, particularly for
treatment of anxiety and sleep
disorders
How Do BZ Work?
A model of the GABAA receptor-chloride ion channel
The receptor consists of five or more membrane-spanning
subunits. GABA interact with alpha or beta subunits
triggering chloride channel opening with resultant
membrane hyperpolarization.
Binding of BZs to gamma subunits potentiates effects of
GABA, facilitates the process of channel opening.
 BZs increases the
frequency of channel
opening by a given
concentration of GABA,
but no change in the
mean open time
Pharmacokinetics:
absorption: well absorbed if given
orally , Cmax reached in about 1
h
 strongly bound to plasma
proteins
 distribution: high lipid solubility
 metabolism: hydroxylation
&conjugation with glucuronic acid

Pharmacological
Actions
The main effects of BZs
are:
1- Reduction of anxiety and
aggression
2Sedation
&
induction of sleep
3- Reduction of skeletal muscle
tone and coordination
4- Anticonvulsant (antiepileptic)
effect 5- Anterograde amnesia
., they obliterate memory of events
experienced while under their influence
Therapeutic uses
1) as anxiolytic

Short-term treatment of acute anxiety
states
2) for insomnia


BZs decrease rapid eye movement (REM) sleep, which
is associated with dreaming
For short-term courses, as tolerance , dependence,
hangover may occur
3) Reduction of muscle tone and
coordination


Increased muscle tone is a common
feature of anxiety states in humans
and may contribute to the aches and
pains, headache
The relaxant effect of BZs may
therefore be clinically useful
4) As anticonvulsants
Clonazepam has selective anticonvulsant
action ( epilepsy)
Diazepam i.v. in status epilepticus
5) Muscular disorders
strong muscle-relaxing properties
 In cases of :
- muscle spasm
- spastic disorders (MS, cerebral palsy)

6) Ttreatment of alcohol
withdrawal symptoms
By ameliorating the
alcohol withdrawal
syndrome
 The commonly used drug
is Diazepam

7) as a pre-ansthetic
medication
for :
i) Anxiolytic effects
ii) Amnesia
(impair short-term memory)
7) To control extreme
mania
Pharmacokinetics
 BZS are well absorbed orally, giving a peak
plasma concentration in about 1 hour
 They bind strongly to plasma protein, and
their high lipid solubility causes many to
accumulate in body fat
 given by mouth or i.v. (e.g. diazepam in
status epilepticus, midazolam in anaesthesia)
 BZs are all metabolized and excreted in the
urine
Classificaion
of
BZs
According to duration of action:
•Very short (< 6 h): Triazolam ,
midazolam
• Short
(12-18):
Lorazepam
(Ativan)
• Medium
(24
h):
Alprazolam
(Xanax),
• Long
(24-48
h):
Diazepam
(Valium)
 The longer acting agents form active
metabolites with long half-lives
Classificaion of BZs
• According to therapeutic uses:
HypnoticTemazepam,
Nitrazepam
Anti-anxiety- Diazepam, Oxazepam
For
panic
attacks;
Alprazolam
Anticonvulsant- Diazepam, Lorazepam,
Advantages
Why BZ have replaced barbiturates ??
1- Less tolerance & physical dependence
2- They cause less disturbance in sleep patterns
3- Barbiturates causes drug interaction because they
are enzyme inducers
e.g. They increase metabolism of warfarin
due to induction of cytochrome P450
thus making it less effective
4- BZ are Safe in overdose while
Barbiturates have lower therapeutic index
(easily overdosed)
They don’t produce marked and fatal CNS
depression
 Symptoms of overdose of BZ are less than of
barbiturates
5- BZs produce minimal sedation and motor
impairment

6- A Benzodiazepine antagonist is available
(Flumazenil)
Advanges as Hypnotics
 REM sleep ( rapid eye movement)
is less affected if compared with
the same effect of other
hypnotics
 artificial interruption of REM sleep
causes irritability and anxiety
even if the total amount of sleep
is not reduced
BZ antagonist “Flumazenil”
Mechanism of action
Flumazenil acts as a competitive
antagonist to the binding of BZs to
their receptors
Flumazenil is a short-acting drug
while, most BZs have longer halflives, therefore, repeated i.v.
administration
of
flumazenil
is
required to avoid relapse into the
sedative state
Side Effects
•Drowsiness and confusion, amnesia
• BZ may paradoxically produce an
increase
in
irritability
and
aggression
in
some
individuals
(particularly if short- acting drugs
are given (triazolam)
•Hypotension in old patients
•Ataxia occurs at high doses and
interfere with motor coordination
(e.g. driving a car)
•BZs enhance the depressant effect
Tolerance and dependence
•If high doses of BZs are given over
a prolonged period, weight gain as
well as physical dependence may
develop
• Abrupt discontinuation of BZs
causes
withdrawal
symptoms,
including
confusion,
anxiety,
restlessness ,tremor and dizziness
• Short-acting BZs (triazolam) cause
more withdrawal effects
Contraindications
1.Pregnancy, labour and lactation:



During pregnancy
Late in pregnancy or around the time of
labor and delivery
During the period of breast feeding
2. In patients with myasthenia gravis:
due to the muscle relaxing effect of
BZs
3.Pre-existing CNS depression
II.
BUSPIRONE
Mechanism of action:
 Buspirone is a 5HT1A receptor agonist
with anxiolytic activity but little
sedation
 5-HT1A receptors are inhibitory
receptors that reduce the release of
5-HT and other mediators
Advantages of buspirone:
1.Unlike
BZs,
buspirone
has
no
sedative hypnotic, anticonvulsant, or
muscle relaxant properties (anxiolytic
only)
3.Buspirone
causes
less
psychomotor
impairment than BZs and does not affect
driving skills
4. The drug does not potentiate the CNS
depressant effects of other sedativehypnotics e.g. ethyl alcohol
Disadvantages of buspirone:
Its anxiolytic effect takes days or weeks
to develop . (useful in chronic anxiety
states)
 Buspirone is ineffective in controlling panic
attacks or severe anxiety states

Side effects
Buspirone has side effects quite
different from those of BZs. It does
not cause sedation or motor
incoordination, nor have withdrawal
effects been reported.
 Main side effects are nausea,
dizziness, headache and restlessness
 Less troublesome than the side
effects of BZs

IV. BARBITURATES
 Barbiturates are non-selective
CNS
depressants.
They
can
produce varying degrees of CNS
depression
ranging
from
mild
sedation to general anesthesia
Barbiturates have been largely
replaced
by BZs, because of the following:
High incidence of tolerance and physical
dependence following chronic use
Barbiturates have a low therapeutic index
(they are dangerous in overdose)
Barbiturates are enzyme inducers especially
cytochrome P450 system, they increase the
rate of metabolic degradation of many other
drugs, so liable to cause drug interactions
They don’t have an antagonist
Mechanism of Action:
Barbiturates like BZs, cause
activation of GABAA receptor and
opening
of
the
Clchannel
associated with the receptor
The
neuronal
membrane
is
hyperpolarized and less likely to
fire
Actions :
At
low
doses,
produce sedation
barbiturates
At higher doses, they cause
hypnosis followed by anesthesia
Overdosage may cause respiratory
depression and death
CNS depression
death ★
medullary depression★
Barbiturates
anesthesia ★
hypnosis ★
BZDs
sedation ★
antianxiety★
Relative concentration
Classification
•Ultra-short acting: Thiopental Na
is
an i.v. anesthetic that acts
within seconds with short duration
of action
•Short-acting: Pentobarbital and
secobarbital act for 3-8 hours
•Long-acting:
Phenobarbital
(>
than 24 h)
Therapeutic Uses:
1- Anesthesia: Thiopental Na is
used iv to induce anesthesia
2- As sedative-hypnotic agents:
Barbiturates have been replaced by
BZs
3-Anticonvulsants:
Emergency
treatment
of convulsions in status epilepticus
by thiopental as the last approach
4-Phenobarbital is used in long-term
management of tonic-clonic seizures and
eclampsia
5- To lower serum bilirubin in Neonatal
jaundice (kernicterus)
Barbiturates such as phenobarbital can
increase the conjugation of bilirubin and
reduces this risk by inducing the activity
of glucuronyl transferase enzyme
Side effects
1-CNS effects: drowsiness can interfere with
motor & mental performance; hangover. In
large doses, barbiturates cause marked
depression of CNS (may be fatal)
2- Induction of P450 thus the rate at which they
are metabolized increases over the first few
days of administration. Also, it leads to
increased metabolism of other drugs e.g.
estrogen and warfarin ( oral contraceptives and
oral anticoagulants)
3-Tolerance and physical dependence with
prolonged use
III. ZOLPIDEM, Z drugs
Mechanism of action:
Zolpidem is a non-benzodiazepine hypnotic
that binds selectively to a subset of the
BZs receptor family and facilitates GABAmediated neuronal inhibition
Zolpidem has a rapid onset and a short
duration of action (about 4 hours)
 Its action is antagonized by flumazenil
 Zopiclone is similar to zolpidem
Advantages
Disadvantages






Rapid onset
less daytime
sleepiness
Less tolerance or
dependence with
prolonged use
It has no effect on
psychomotor skills
Antagonized by
flumazenil
Least effect on




Short duration of
action
Nightmares
GIT upset
Respiratory depression
occurs only if large
doses of zolpidem are
ingested together with
other central
depressants
Hypnotic drugs
Benzodiazepines (e.g. Temazepam ,
nitrazepam)
 Related drugs working on the BZ
receptor (e.g. zolpidem, zopiclone)
 Sedating antihistamines (e.g.
promethazine), which cause drowsiness
and are used for occasional insomnia.
They can impair performance the day
after

V. ETHYL ALCOHOL (Ethanol)

Ethyl alcohol (ethanol) is the
most
abused drug in the world. Ethyl
alcohol in low to moderate amounts
relieves
anxiety
and
causes
euphoria

Large dose causes hypnosis
and respiratory depression which
may be fatal
Mechanism of action
Ethanol
enhances GABAmediated synaptic inhibition
Ethanol inhibits excitatory
NMDA glutamate receptors
Treatment of Chronic Alcoholism
•Hospitalization, psychotherapy and
nutritional therapy may be needed.
 Drug therapy includes:
•BZs (e.g. diazepam) are used to
prevent
alcohol
withdrawal
symptoms. They are preferred over
barbiturates because of their wide
margin of safety. The dose must
be tapered slowly over several
weeks
Disulfiram
The drug given by itself to
nondrinkers has little effects
however,
it
causes
extreme
discomfort to patients who drink
alcohol
(Flushing,
throbbing
headache,
nausea,
vomiting,
sweating,
hypotension
and
confusion)
Mechanism of action
Disulfiram
acts
by
inhibiting
aldehyde
dehydrogenase
thus,
alcohol is metabolized as usual but
acetaldehyde
accumulates.
Acetaldehyde will form the toxic
intermediates;
methanol
and
formaldehyde
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