ANXIOLYTIC

and
SEDATIVEHYPNOTIC DRUGS
Prof. Martnkov 2006

Anxiolytic and sedative-hypnotic drugs

A sedative-hypnotic drug (terminology)
Sedation
can be definedas
a supression of responsiveness to a constant level of stimulation,
with decreased spontaneous activity and ideation.

Anxiolytic and hypnotic drugs

Ah 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 ceffects 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.

Anxiolytic and hypnotic drugs

Anxiet 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.

Anxiolytic and hypnotic drugs

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

Anxiolytic and hypnotic drugs

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)

Anxiolytic and hypnotic drugs

benzodiazepines

Pharmacodynamics:(BZ) act selectively

on gamma-aminobutyric acid A (GABAA)

receptors,

o
o

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

BZenhancethe response to GABA.

The antagonist f l u m a z e n i l

Anxiolytic and hypnotic drugs

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

Anxiolytic and hypnotic drugs - benzodiazepines

(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.

RememberAGE: 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)

Anxiolytic and hypnotic drugs benzodiazepines

(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 decreasethe timetaken to get to sleep

increase the total durationof sleep (only in subjects who normally sleep for less than
about 6 hours each night)

Anxiolytic and hypnotic drugs benzodiazepines

(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).

Anxiolytic and hypnotic drugs benzodiazepines

(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 epilepticusto control life-threatening seizures

anterograde amnesia

BZs obliterate memoryof events experienced while under their influence

Anxiolytic and hypnotic drugs benzodiazepines

(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 withflumazenil

Anxiolytic and hypnotic drugs benzodiazepines

(BZ)

unwanted effects occuring duringtherapeuticuse

---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.

Anxiolytic and hypnotic drugs benzodiazepines

(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

Zolpidempharmacodynamics

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 drugsolder 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.

Anxiolytic and hypnotic drugs barbiturates (BA)

Disadvantage of use:

if given in a large dosedeath 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

Anxiolytic and hypnotic drugs barbiturates (BA)

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

Anxiolytic and hypnotic drugs - benzodiazepines (BZ)

Fig.1.