Download Sedative-Hypnotic Drugs

Chapter 22:
Sedative-hypnotic Drugs
1
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
2
CNS depression: dose-response curve
Coma
DRUG A
CNS effects
Anesthesia
DRUG B
Hypnosis
Sedation
Increasing dose
3
Sedative-hypnotics
Benzodiazepines
Short
action
Intermediate
action
Long
action
Barbiturates
Miscellaneous agents
Buspirone
Ramelteon
Zaleplon
Zolpidem
4
Other drugs with sedative-hypnotic
effects
1) β-blockers (e.g. Propranolol)
2) Antipsychotics
3) Antidepressants (e.g. SSRIs,
venlafaxine, duloxetine & MAOIs)
TCAs,
4) Antihistamines
(e.g.
Hydroxyzine,
diphenhydramine, & doxylamine)
5
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
6
Benzodiazepines- Mechanism of action
• The targets for bzds actions are the γaminobutyric 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
7
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
8
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
10
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
11
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
12
Benzodiazepine Binding Site Ligands
1. Agonists:
• Benzodiazepines: multiple BZ binding
sites
• Zolpidem, zaleplon, and eszopiclone:
selective agonists at the BZ1
2. Antagonists: Flumazenil
3. Inverse agonists: β-carbolines, eg, nbutyl- β -carboline-3-carboxylate (β -CCB)
13
Benzodiazepines
• The PK properties of the bzds affect their
clinical utility
• Bzds vary greatly in duration of action and
can be roughly divided into:
a. Short-acting
b. Medium-acting
c. Long-acting
14
Short acting (3-8 hours) :Oxazepam ,Triazolam
Intermediate (6-24 hours):Alprazolam ,Lorazepam ,
Estazolam,Temazepam
Long acting ( 24-72 hours):Chlorazepate ,Diazepam
Chlordiazepoxide,Flurazepam ,Quazepam
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 halflives than the parant drug
• The t1/2 of flurazepam in plasma is ∼2 hours, but
that of a major active metabolite N-desalkylflurazepam is ∼50 hours
• The short-acting compounds are metabolised
directly by conjugation with glucuronide (e.g.
oxazepam)
16
• Diazepam
desmathyldiazepam
oxazepam
conjugation
active
metabolites
17
• Estazolam
• Oxazepam
immediately converted to
inactive metabolites
18
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
19
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
20
Organ Level Effects
•
The main effects of benzodiazepines are:
1) Reduction of anxiety (BZ2)
2) Sedation and induction of sleep (BZ1)
3) Reduction of muscle tone and
coordination (BZ2 in the spinal cord)
4) Anticonvulsant effect (BZ1)
5) Anterograde amnesia (BZ1)
21
Clinical uses of benzodiazepines
a. Treatment of anxiety state
•
The bzds are the most widely used drugs for
the management of acute and chronic
anxiety b/c of their:
1) Rapid onset of action
2) Relatively high therapeutic
3) Availability of flumazenil for treatment of
overdose
4) Low risk of drug interactions
5) Minimal effects on CV or ANS
22
Clinical uses of benzodiazepines
a. 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
23
Clinical uses of benzodiazepines
a. 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
24
Clinical uses of benzodiazepines
A. Treatment of anxiety state
•
Alprazolam is particularly effective in
treatment of panic disorders & agoraphobia
& is more selective in than other BDZs
25
Clinical uses of benzodiazepines
B. Treatment of sleep disorders
• An ideal hypnotic agent would have:
1) A rapid onset of action when taken at
bedtime
2) A sufficient duration of action to facilitate
sleep throughout the night
3) A minimal "hangover" effects the following
day
• Commonly prescribed bzds for sleep disorders
include long-acting flurazepam, intermediateacting temazepam, and short-acting triazolam
26
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
27
Clinical uses of benzodiazepines
C. Other Therapeutic Uses
1. Seizures
2. 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
28
Clinical uses of benzodiazepines
C. Other Therapeutic Uses
3. 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
29
Clinical uses of sedative-hypnotics
C. Other Therapeutic Uses
4. 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)
30
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
barbiturates
less
marked
than
it
is
• The development of tolerance has
associated with down-regulation of
benzodiazepine receptors (PD tolerance)
with
been
brain
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
1. Pharmacodynamic interactions:
• Additive effect with other CNS depressants
which can lead to serious consequences,
including enhanced depression
37
Drug interactions
2. 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:
oAgitation, confusion, dizziness, and nausea
oSevere precipitated abstinence syndrome in
patients who have developed physiologic
benzodiazepine dependence
oIn 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:
a)
b)
c)
d)
Induce tolerance
Induce drug-metabolizing enzymes
Physical dependence
Associated with very severe withdrawal
symptoms
e) 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:
1)
2)
3)
4)
Reduction of anxiety
Sedation and induction of sleep
Anticonvulsant effect
Dose -dependent respiratory depression
espically in patients with pulmonary disease
5) 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
44
Clinical uses
1) Anesthesia: Selection is strongly influenced by
the desired duration of action. The ultrashortacting barbiturate, thiopental, is used IV to induce
anesthesia
2) Anticonvulsant: Phenobarbital has specific
anticonvulsant activity that is distinguished from
the nonspecific CNS depression
3) Antxiety and
hypnosis (secobarbital):
most have been replaced by the bzds
45
Tolerance and Dependence
• 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
1) CNS: Barbiturates cause drowsiness, impaired
concentration, and mental and physical
sluggishness
2) 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
1) PD interactions: barbiturates combine with
other CNS depressants cause severe CNS
depression, especially ethanol
2) 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
1. Benzodiazepine-Receptor Agonists
•
Agents: Zolpidem, zaleplon, & eszopiclone
•
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
1. 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
1. 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
2. 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
2. 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
2. 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
3. Ramelteon
•
It is a selective agonist at the MT1 and MT2
subtypes of melatonin receptors
•
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
55