Anxiolytic Sedative-Hypnotic Drugs

ANXIOLYTIC
and
SEDATIVE-
HYPNOTIC DRUGS
Anxiolytic and sedative-hypnotic drugs
A sedative-hypnotic drug (terminology)

Sedation
can be defined as
a supression of responsiveness to a constant level of
stimulation,
with decreased spontaneous activity and ideation.
Anxiolytic and hypnotic drugs
A h y p n o t i c drug should produce drowsiness

and encourage the onset and maintenance of a state
of „sleep“ that as far as possible resembles
the natural state of sleep.
H y p n o t i c effects involve more pronounced

depression of the CNS than s e d a t i o n,
and this can be achieved with most sedative drugs simply
by increasing the dose.
An x i e t y
In anxiety states the fear response to threatening stimuli
occur in an anticipatory manner independently of external
events.
Among other the fear response includes defensive
behaviours, autonomic reflexes, arousal and alertness,
corticoid secretion and negative emotions.
An effective anxiolytic agent should reduce anxiety
and exert a calming effect - sedation - with

little or no effect on motor and menthal function.
Anxiolytic and hypnotic drugs (Fig 1)
Graded dose-dependent depression of the CNS function

is a characteristic of sedative-hypnotics. However,
individual drugs differ in the relationship between the dose
and the degree of CNS depression (see Fig 1). The linear
slope for drug A is typical of many of the older sedative-
hypnotics. With such drugs, an increarse in dose above that
needed for hypnosis may lead to a state of general
anesthesia. At still high doses, sedative-hypnotics may
depress respiratory and vasomotor centres in the
medulla, leading to coma and death.
Anxiolytic and hypnotic drugs (Fig 1)
Deviation from a linear dose-response relationship, as

shown for drug B, will require proportionately greater
dosage increments in order to achive CNS depression more
profound than hypnosis.
This appears to be the case for most drugs of
the benzodiazepine class, and the greater margin of
safety is an important reason for their clinical use to treat
anxiety states and sleep disorders.
Anxiety disorders include:

- generalised anxiety disorder (an ongoing state
of excessive anxiety lacking any clear reason )
- panic disorder (attacks of overwhelming fear
occuring in association with somatic symptoms
(sweating, tachycardia, chest pain)
- phobias (strong fears of specific things or situation
(snakes, flying)
- postraumatic stress disorder (anxiety triggered
by insistent recall of past stressful experiences
In most developed countries anxiolytic drugs are
among the most frequently prescribed drugs
Classes:
• benzodiazepines
• newer drugs:
5 -HT1A -receptor agonists (buspiron)
zolpidem, zaleplon
• miscellaneous other drugs
older sedative-hypnotics
• barbiturates (obsolete)
• benzodiazepines
Pharmacodynamics:
(BZ) act selectively
on gamma-aminobutyric acid A (GABAA) receptors,
which mediate fast inhibitory synaptic transmission
through the CNS. 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 receptors.
By facilitating the opening of GABA activated
chloride-channels BZ enhance the response to GABA.
The antagonist – f l u m a z e n i l
Fig 2:
A model of the GABAA receptor-chloride ion channel
macromolecular complex.
The complex consists of five or more membrane-spanning
subunits. GABA appears to interact with alpha or beta
subunits triggering chloride channel opening with resultant
membrane hyperpolarization.
Binding of BZs to gamma subunits facilitates the process of
channel opening.
Anxiolytic and hypnotic drugs - benzodiazepines
(BZ)
Pharmacokinetics:
- absorption: well absorbed if given orally , Cmax
reached in about 1 h
- binding: strongly bound to plasma proteins
- distribution: large Vd: accumulation in body fat (high
lipid solubility)
- metabolism: (Fig 2):
hydroxylation
conjugation with glucuronic acid
short-, medium- and long-acting BZ
the role of N-desmethyldiazepam
(BZ)
Fig. 3
Anxiolytic and hypnotic drugs – benzodiazepines
(BZ)
Fig. 3 : demonstrates
• the short-acting drugs are those that are
metabolised directly by conjugation with
glucuronide.
• gradual bild-up and slow disappearance of
nordazepam from the plasma gives long-acting
drugs.
Remember AGE: advancing age affects the rate of
oxidative reactions more than that of conjugation.
the effect of long-acting BZs tends to increase
with age (drowsiness and confusion)
(BZ)
Pharmacological effects and uses:
The main effects:

• reduction of anxiety and agression
• sedation and induction of sleep
• reduction of muscle tone and coordination
• anticonvulsant effects
• anterograde amnesia
Anxiolytic and hypnotic drugs – benzodiazepine
(BZ)
• reduction of anxiety and agression
Note: BZ may paradoxically produce an increase

in irritability and aggression in some individuals
(particularly if short- acting drugs are given (triazolam)
• sedation and induction of sleep

BZs decrease the time taken to get to sleep
increase the total duration of sleep (only in
subjects who normally sleep for less than about 6 hours
each night)
(BZ)
REM sleep ( rapid eye movement) is less affected if

compared with the same effect of other hypnotics.
Is that important? Yes, artificial interruption of REM
sleep causes irritability and anxiety even if the total
amount of sleep is not reduced).
(BZ)
• reduction of muscle tone and coordination
may be clinically useful: increased muscle tone is a common
feature of anxiety states and may contribute to pains
(headache). Influence of manual skills (!)
• anticonvulsant effects (GABAA receptors)

clonazepam to treat epilepsy
diazepam (i.v.) status epilepticus to control life-
threatening seizures
• anterograde amnesia
BZs obliterate memory of events experienced while under
their influence
(BZ)
Unwanted effects
• acute overdosage
• effects occuring during normal therapeutic use
• tolerance and dependence
• acute overdosage (BZs are relatively safe in overdose)

BZs produce prolonged sleep, without serious depression of
respiration or cardiovascular function
Severe even life-threatening respiratory depression may
appear in BZ combination with other CNS depressants,
particularly alcohol.
Acute overdosage can be counteracted with flumazenil
(BZ)
• unwanted effects occuring during therapeutic use

---Influence of manual skills (such as driving performance)
due to drowsiness, confusion, amnesia and impaired
coordination
--- enhance of depressant action of other drugs (in a more than
additive way)
• tolerance , dependence
Tolerance (gradual escalation of dose needed to produce the
required effect) occurs with all BZs. T.appears to represent a
change at the receptor level.
Dependence –In human subjects and patients, stopping BZ
treatment after weeks and months causes an increase in
symptoms of anxiety, together with tremor and dizziness.
(BZ)
The withdrawal syndrome: short acting BZs

cause more abrupt withdrawal effects
Addiction (-craving -severe psychological dependence) is
not a major problem.
Anxiolytic and hypnotic drugs - 5 -HT1A -receptor
agonists
• newer drugs
5 -HT1A -receptor agonists
Buspiron-anxiolytic effects take days or weeks to
develop.That is the most distinctive drug in terms of
antianxiety actions, since these are achieved with minimal
effects on psychomotor functions.
Unwanted effects
appear to be less troublesome: dizziness, nauzea, headache,
not sedation or loss of coordination
Anxiolytic and hypnotic drugs –
zoplidem, zaleplon
Zolpidem pharmacodynamics
• binds selectively to the BZ1 subtype of BZ receptors and
facilitates GABA-mediated neuronal inhibition
• like the BZs, the actions of zolpidem are antagonised by
flumazenil
• minimal muscle relaxing and anticonvulsant effects
• the risk of development of tolerance and dependence
with extended use is less than with the use of
hypnotic BZs
pharmacokinetics
rapidly metabolized to inactive metabolites by the liver,
T1/2 1.5-3.5 h. Dosage reduction in hepatic dysfuction,
elderly.
Anxiolytic and hypnotic drugs –
zoplidem, zaleplon
Ind- short-term treatment of insomnia
Zaleplon
resembles zolpidem, t1/2 = 1h
Rapid onset and short duration of action are favorable
properties for those patients who have difficulty falling
asleep.
Anxiolytic and hypnoptic drugs – miscellaneous other
drugs
miscellaneous other drugs-

older sedative-hypnotics:
meprobamate, glutethimide
rarely used
Anxiolytic and hypnotic drugs – barbiturates (BA)
• barbiturates (obsolete)
BA: the sleep-inducing properties were discovered early
in the 20th century . Until the 1960s, they formed the largest
group of hypnotics and sedatives in clinical use.
Pharmacodynamics:
BA share with BZs the ability to enhance the action of GABA,
but they bind to a different site of the GABAA-receptor/chloride
channel- their action is less specific.
Disadvantage of use:
• if given in a large dose—death from respiratory and
cardiovascular depression (flumazenil not effective)
• a high degree of tolerance: BA strongly induce the synthesis
and activity of hepatic CYP450 and conjugating enzymes
thus increasing the rate of metabolic degradation of many other drugs
--- drug-drug interactions
•. dependence
BA are now little used
as anxiolytic and hypnotic drugs
BA in practical use
• use as sedative and hypnotic agents is no longer

recommended
BAs are mainly used:
• in anaesthesia - thiopental (i.v.)
• treatment of epilepsy - phenobarbital
(BZ)
Fig.1.

Anxiolytic Sedative-Hypnotic Drugs

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What are some common anxiety disorders discussed?

What are some common anxiety disorders discussed?

What properties make zolpidem and zaleplon favorable for insomnia?

What properties make zolpidem and zaleplon favorable for insomnia?

ANXIOLYTIC

A sedative-hypnotic drug (terminology)

A h y p n o t i c drug should produce drowsiness

H y p n o t i c effects involve more pronounced

An effective anxiolytic agent should reduce anxiety

and exert a calming effect - sedation - with

Graded dose-dependent depression of the CNS function

Deviation from a linear dose-response relationship, as

Anxiety disorders include:

Pharmacological effects and uses:

The main effects:

• reduction of anxiety and agression

Note: BZ may paradoxically produce an increase

• sedation and induction of sleep

REM sleep ( rapid eye movement) is less affected if

• anticonvulsant effects (GABAA receptors)

• acute overdosage (BZs are relatively safe in overdose)

• unwanted effects occuring during therapeutic use

The withdrawal syndrome: short acting BZs

Ind- short-term treatment of insomnia

miscellaneous other drugs-

• use as sedative and hypnotic agents is no longer

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