1. ANXIOLYTIC
and
SEDATIVE-
HYPNOTIC DRUGS

2. 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.

3. 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.

4. Anxiolytic and hypnotic drugs
A n 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.

5. 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.

6. 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.

8. 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

9. 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)

10. Anxiolytic and hypnotic drugs
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

11. 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.

13. 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

14. Anxiolytic and hypnotic drugs - benzodiazepines (BZ)
Fig. 3

15. 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)

17. 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

18. 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)

19. 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).

20. 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 epilepticus to control life-threatening seizures
anterograde amnesia
BZs obliterate memory of events experienced while under their influence

21. 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 with flumazenil

22. Anxiolytic and hypnotic drugs – benzodiazepines (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.

23. 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.

24. 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

25. 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
f l u m a z e n i l
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/ h. Dosage reduction in hepatic dysfuction, elderly.

26. 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.

27. Anxiolytic and hypnoptic drugs – miscellaneous other drugs
older sedative-hypnotics:
meprobamate, glutethimide
rarely used

28. 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.

29. Anxiolytic and hypnotic drugs – barbiturates (BA)
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

30. 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

31. Anxiolytic and hypnotic drugs - benzodiazepines (BZ)
Fig.1.