BDZ
Mechanism of action
Pharmacological effects
Adverse effects
Therapeutic Uses
-Benzodiazepines (BDZ)
bind to receptors located
at the interface between
alpha and gamma subunits
of the GABA-A receptorchloride ion channel
macromolecular complex.
-The binding increases the
affinity of the GABA-A
receptor for GABA, which
in turn causes an
increased frequency of
chloride channel opening
(since BDZ need GABA for
their activity, a ceiling
effect occurs with high
doses).
-In this way BDZ potentiate
GABAergic inhibition at all
levels of CNS.
-Their sedative, hypnotic
and amnestic effects seem
mediated at the alpha-1
subunit.
-Their anxiolytic effect
seems mediated at the
alpha-2 subunit
-Their muscle relaxant
effect seems mediated at
the alpha-3 subunit.
-All BDZ produce a dose
dependent but limited
depression of the CNS.
-This leads to the
following four actions:
1-Anxiolytic: reduction
of anxiety, fear, and
apprehension.
2-Sedative-hypnotic:
reduction of
restlessness, induction
of sleep, impairment of
formation of new
memory (which can
lead to anterograde
amnesia).[ high doses
can cause general
anesthesia , but BDZ are
not fully effective when
are given alone because
of the ceiling effect].
3-Anticonvulsant:
inhibition of the
development and
spread of epileptic
activity in the CNS.
4-Muscle relaxant:
inhibitory effects on
polysynaptic reflexes in
the spinal cord (a
central action)
CNS
Drowsiness, dizziness, sedation
(common, dose related)
Impaired motor skills (can be
insidious because
underestimated)
Impaired concentration and
judgment
Paradoxical effects, i.e. symptoms
of CNS stimulation (2-5%)
Confusional states, anterograde
amnesia (with high doses)
Lethargy, medullary depression
(with very high doses)
Rebound effects (insomnia,
restlessness, etc.) after abrupt
discontinuation of 2-3 weeks of
treatment.
Increased risk of falls and
fractures in the elderly (mainly
with long half-life drugs)
(All the above mentioned effects
are more common in the elderly)
Tolerance and dependence
develop after long-term use of
high doses. (These effects are
discussed in detail under ‘Drugs of
Abuse’)
Respiratory system
No effect on respiration at
low/intermediate doses in
healthy subjects. .
Respiration can be depressed by
high doses, or when BDZ are used
together with other CNS
depressants, or in persons with
pulmonary diseases.
Cardiovascular system
Hypotension (mainly in the
elderly).
Overdosage
rarely fatal when used alone (the
therapeutic index is more than
200).
Pregnancy
category D by FDA because
exposure has been associated
with malformations (mainly cleft
lip/palate).
1-Situational
stress (short term
use)
2-Anxiety
disorders (second
choice drugs)
3-Sleep disorders
4-Seizure
disorders
5-Muscle spasms
and spasticity
6-Induction of
‘conscious
sedation” and
amnesia
7-Induction of
general
anesthesia
8-Ethanol (or
barbiturate)
detoxification
Benzodiazepines
Contraindications and Precautions
Contraindications / Precautions
Explanations
When the CNS is already depressed
CNS depression can worsen
(e.g. due to drugs, coma, shock, etc.)
Major depressive illness
Depression can worsen if these drugs are used
Bipolar disorder
Mania and hypomania can ensue
Parkinson’s disease
Impaired cognition and psychosis can worsen
Myasthenia Gravis, muscular dystrophies
These condition can be exacerbated
States of respiratory depression
Ventilatory failure can ensue
(COPD, asthma, sleep apnea, etc.)
History of substance abuse
Benzodiazepine can cause dependence
An acute attack of glaucoma can start
Closed-angle glaucoma
(mechanism unknown)
Elderly
CNS effects are more pronounced
Pregnancy
Benzodiazepines are classified as FDA category D
BDZ Inverse agonists
BDZ Antagonists
Beta-carboline derivatives act as inverse agonists at
BDZ receptors (an inverse agonist is a drug that
decreases the response of an effector system below
its basal level).
Therefore they decrease the affinity of GABA for its
receptor, so decreasing chloride influx by the GABA-A
ionophore.
Their effects are opposite to those of BDZ.
Flumazenil is a competitive BDZ receptor
antagonist that can block both the effects of BDZ
and those of beta-carboline derivatives.
It also blocks the effects of zolpidem but does not
antagonize those of other CNS depressants
(barbiturates, buspirone, ethanol etc.).
It is used clinically to counteract excessive effects
of BDZ.
Since it can cause several (and sometimes serious)
unwanted effects is not used in case of BDZ
poisoning
Other Anxiolytic Drugs
Buspirone
Mechanism of action
Pharmacological
effects
Adverse effects
The precise
mechanism is still
unknown. The drug
acts as a partial
agonist at 5-HT1A
receptors in the
limbic system, where
they are mainly
postsynaptic and
facilitate serotonin
transmission.
-Selective
anxiolytic actions
-Negligible
sedative,
hypnotic and
amnesic effects
-Negligible
anticonvulsant
and muscle
relaxant effects.
-Negligible abuse
liability.
-No cross
tolerance with
benzodiazepines.
-Delayed onset
of action (initial
effects are
observed within
the first 7-10
days, but 3-4
weeks may be
needed for
optimal results).
Most common
(up to 10%):
dizziness,
drowsiness.
Therapeutic uses
To treat anxiety
disorders that have not
responded to
SSRis/SNRIs. (The drug
is ineffective in severe
anxiety, panic disorders
and acute anxiety
attack)
BRB
Mechanism of action
Pharmacological
effects
Adverse Effects
Contraindications
and Precautions
Therapeutic Uses
-Barbiturates(BRB) bind
to receptors located on
the alpha and beta
subunits of the GABAA
receptor-chloride ion
channel
macromolecular
complex.
-The binding increases
the affinity of the
GABAA receptor for
GABA, which in turn
causes an increased
duration of chloride
channel opening
-All BRB produce a
dose-dependent
depression of the
CNS, but the doseeffect curve is much
steeper than that of
BDZ. Therefore:
1-After low doses:
reduction of anxiety
with pronounced
sedation and sleep
induction (the
duration of REM
sleep during the
night is decreased).
2-After intermediate
doses: euphoria
disinhibition,
impaired judgment,
emotional instability,
loss of self-control.
3-After high doses:
induction of general
anesthesia.
-Inhibition of the
development and
spread of epileptic
activity in the
CNS
-Dose-dependent CNS
depression
-Euphoria and behavioral
disinhibition
-Hangover effects
-Confusional states
-Paradoxical effects
-Increased pain
perception
-Lethargy, medullary
depression (with high
doses)
-Tolerance and
dependence (not with
phenobarbital)
Respiratory system
-Dose-dependent
depression of respiration.
-Coughing, sneezing,
laryngospasm
(respiratory reflexes are
only slightly affected).
Cardiovascular system
-Hypotension.
-Cardiovascular collapse
(when given IV).
Hypersensitivity
reactions
-Minor allergic reactions
are common
-Serious allergic reactions
can occur (exfoliative
dermatitis, lupoid
syndrome, StevensJohnson syndrome).
Idiosyncratic reactions
Exacerbation of acute
intermittent porphyria
(due to increase
porphyrin biosynthesis).
Overdosage
Poisoning (TI: 10-15).
Pregnancy
category D by FDA ( risk
of malformations )
1-Absence,
myoclonic and
atonic seizures
2-Porphyria
(acute
intermittent,
variegata)
3-Previous history
of serious allergic
reactions to BRB.
4-Major
depression.
5-Serious
respiratory, liver
or kidney
diseases
6-Patients with
severe pain (BRB
may cause
excitement and
even delirium in
patients with
pain).
7-Elderly
8-Pregnancy
-Induction of
general anesthesia
(thiopental).
-Seizure disorders
(phenobarbital).
-Sleep disorders
(very rarely used).
-Psychiatric
procedures
-Neonatal jaundice
(phenobarbital,
rarely used today).
-High doses of BRB may
also:
A-can directly increase
chloride channel
opening in the absence
of GABA (it is mainly for
this reason that they do
not exhibit a ceiling
effect).
B-can block AMPA
glutamate receptors.
CNS (anticonvulsant
action).
-Dose-dependent
depressant effects
on respiration
(neurogenic drive is
affected first,
followed by the
chemoreceptor
drive, and finally by
the hypoxic drive).
-Induce cytochrome
P450 in the liver.
Therefore BRB can
hasten their own
metabolism as well
as that of other
drugs
Newer Hypnotic Drugs
Z-hypnotics
Zolpidem,
zaleplon,
eszopiclone
*They are
pyridine
derivatives
Ramelteon
Mechanism of action
Pharmacological effects
Adverse effects
Therapeutic uses
They bind selectively to
alpha1 subunit of the
GABA receptor chloride
channel complex. The
selective binding may
account for their
relative lack of effect
on sleep architecture
and stages.
-Selective hypnotic actions
-Decreased sleep latency
-Negligible effects on sleep
architecture and stages.
-Short duration of action
(zolpidem, zaleplon: see t1/2)
-No effect on next day
psychomotor performance.
-Negligible anxiolytic,
anticonvulsant and muscle
relaxant properties.
-Abuse liability seems low but
abuse does occur (the fast acting
nature and the short half-life of
these compounds encourages the
recreational use).
-Most common
(>5%): dizziness,
drowsiness.
-Sleep-eating
disorder, brief
psychotic reactions
(rare)
-Sleep-onset
insomnia (zolpidem,
zaleplon)
-Nocturnal insomnia
(eszopiclone)
-Melatonin receptors
seem to be involved in
maintaining circadian
rhythms underlying the
sleep-wake cycle
-The drug activates
melatonin receptors
located in the
suprachiasmatic nuclei
of CNS. It has no direct
effects on GABAergic
transmission.
-Decreased latency to sleep onset.
-Negligible rebound insomnia and
withdrawal symptoms.
-Abuse liability is absent.
Dizziness, fatigue,
endocrine changes
(decrease
testosterone,
increased prolactin).
Approved by FDA for
sleep onset
insomnia.
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