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ANXIOLYTIC
and SEDATIVE- HYPNOTIC DRUGS
Prof. Martínková 2006
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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.
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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.
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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.
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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.
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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.
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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
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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)

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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

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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.
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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

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

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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

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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)

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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).
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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

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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

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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.

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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.
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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

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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, T1/2 1.5-3.5 h. Dosage reduction in
  hepatic dysfuction, elderly.

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

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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

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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

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