Clinical pharmacology of sedative-hypnotic drugs: pharmacodynamics

1. Pharmacodynamics of
benzodiazepines, barbiturates
and newer hypnotics
Domina Petric, MD

2. Molecular pharmacology of
GABAA receptors
The benzodiazepines,
barbiturates, zolpidem, zaleplon,
eszopiclone and other drugs bind
to molecular components of the
GABAA receptor in neuronal
membranes in the CNS.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

3. Molecular pharmacology of
GABAA receptors
• GABAA receptor functions as a chloride ion
channel.
• It is activated by the inhibitory
neurotransmitter GABA.
• This receptor has a pentameric structure.
• The major isoform of the GABAA receptor,
found in many regions in the brain, consists
of two α1, two β2 and one γ2 subunits.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

4. Molecular pharmacology of
GABAA receptors
• The binding sites for GABA are located
between adjecent α1 and β2 subunits.
• The binding pocket for benzodiazepines
(the BZ site) is between an α1 and γ2
subunit.
• Barbiturates bind to multiple isoforms of
the GABAA receptor, but at different
sites than benzodiazepines.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

5. Molecular pharmacology of
GABAA receptors
• Zolpidem, zaleplon and eszopiclone
bind more selectively: these drugs
interact only with GABAA-receptor
isoforms that contain α1 subunit.
• Benzodiazepines and other sedative-
hypnotics have a low affinity for
GABAB receptors.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

6. Neuropharmacology
• GABA (γ-aminobutyric acid) is a major
inhibitory neurotransmitter in the CNS.
Benzodiazepines potentiate GABAergic
inhibition at all levels of the neuraxis:
• the spinal cord, hypothalamus
• hippocampus, substantia nigra
• cerebellar cortex, cerebral cortex
Katzung, Masters, Trevor. Basic and clinical pharmacology.

7. Neuropharmacology
• Benzodiazepines increase the efficiency
of GABAergic synaptic inhibition.
• They enhance GABA´s effects
allosterically without directly
activating GABAA receptors or
opening the associated chloride
channels: there is increase in the
frequency of channel-opening events.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

8. Neuropharmacology
• Barbiturates facilitate the actions of
GABA at multiple sites in the CNS.
• They incrase the duration of the GABA-
gated chloride channel openings.
• At high concentrations, the barbiturates
may also be GABA-mimetic, directly
activating chloride channels.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

9. Neuropharmacology
Barbiturates are less selective in their actions
than benzodiazepines.
They also depress the actions of the excitatory
neurotransmitter glutamic acid via binding to
the AMPA receptor.
Barbiturates also exert nonsynaptic membrane
effects in parallel with their effects on GABA
and glutamate neurotransmittion.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

10. Benzodiazepine binding site
ligands
• Agonists facilitate GABA actions.
• This occurs at multiple BZ binding
sites in the case of the benzodiazepines.
• The nonbenzodiazepines zolpidem,
zaleplon and eszopiclone are selective
agonists at the BZ sites that contain an
α1 subunit.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

11. Benzodiazepine binding site
ligands
• Antagonist FLUMAZENIL blocks
the actions of benzodiazepines,
eszopiclone, zaleplon and
zolpidem.
• Flumazenil does not antagonize the
actions of barbiturates,
meprobamate or ethanol.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

12. Benzodiazepine binding site
ligands
• Inverse agonists act as negative allosteric
modulators of GABA-receptor function.
• Their interaction with BZ sites on the
GABAA receptor can produce anxiety and
siezures.
• These molecules, like n-butyl-β-carboline-3-
carboxylate, can block the binding and the
effects of benzodiazepines.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

13. ORGAN LEVEL EFFECTS
Katzung, Masters, Trevor. Basic and clinical pharmacology.

14. Sedation
• Benzodiazepines, barbiturates and most
older sedative-hypnotic drugs exert
calming effects with concomitant reduction
of anxiety at relatively low doses.
• The anxiolytic actions of sedative-
hypnotics are accompanied by some
depressant effects on psychomotor and
cognitive functions.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

15. Sedation
• Euphoria, impaired judgment and loss of
self-control may occur at dosages in the
range of those used for the management
of anxiety.
• The benzodiazepines also exert dose-
dependent anterograde amnesic effects:
inability to remember events occurring
during the drug´s duration of action.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

16. Hypnosis
• All of the sedative-hypnotics induce
sleep if high enough doses are given.
• The effects of sedative-hypnotics on
the stages of sleep depend on
specific drug, the dose and the
frequency of its administration.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

17. The general effects of benzodiazepines and older sedative-
hypnotics on patterns of normal sleep are:
• The latency of sleep onset is decreased
(time to fall asleep).
• The duration of stage 2 NREM (nonrapid
eye movement) sleep is increased.
• The duration of REM sleep is decreased.
• The duration of stage 4 NREM slow-
wave sleep is decreased.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

18. Hypnosis
• The newer hypnotics all decrease the
latency to persistent sleep.
• Zolpidem decreases REM sleep, but has
minimal effect on slow-wave sleep.
• Zaleplon decreases the latency of sleep
onset with little effect on total sleep
time, NREM and REM sleep.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

19. Hypnosis
• Eszopiclone increases total sleep time,
mainly via increases in stage 2 NREM
sleep.
• Al low doses has little effect on sleep
patterns.
• At the highest recommended dose,
eszopiclone decreases REM sleep.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

20. Hypnosis
• More rapid onset of sleep and
prolongation of stage 2 are clinically
useful effects.
• Deliberate interruption of REM sleep
causes anxiety and irritability followed
by a rebound increase in REM sleep at
the end of the experiment.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

21. Hypnosis
REM rebound effect can be detected
following abrupt cessation of drug
treatment with older sedative-
hypnotics, especially when drugs
with short durations of action
(triazolam) are used at high doses.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

22. Hypnosis
Rebound insomnia occurs with both
zolpidem and zaleplon if used at
higher doses.
The use of sedative-hypnotics for
more than 1-2 weeks leads to some
tolerance to their effects on sleep
patterns.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

23. Anesthesia
• High doses of certain sedative-hypnotics
depress the CNS to the stage III or
general anesthesia.
• Barbiturates thiopental and methohexital
are very lipid-soluble.
• These agents penetrate brain tissue
rapidly following intravenous
administration: induction of anesthesia.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

24. Anesthesia
• Rapid tissue redistribution accounts for
the short duration of action of thiopental
and methohexital.
• This is useful in recovery from anesthesia.
• Benzodiazepines diazepam, lorazepam and
midazolam are used intravenously in
anesthesia, often in combination with
other agents.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

25. Anesthesia
• Benzodiazepines given in large doses as
adjuncts to general anesthetics may
contribute to a persistent postanesthetic
respiratory depression.
• This is related to their relatively long
half-lives and the formation of active
metabolites, which can be reversed with
flumazenil.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

26. Anticonvulsant effects
Benzodiazepines clonazepam, nitrazepam,
lorazepam and diazepam are sufficiently
selective to be clinically useful in the
management of seizures.
Phenobarbital and metharbital are
effective in the treatment of
generalized tonic-clonic seizures.
Zolpidem, zaleplon and eszopiclone
lack anticonvulsant activity.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

27. Muscle relaxation
Carbamates and benzodiazepines exert
inhibitory effect on polysynaptic reflexes
and internuncial transmission.
At high doses these drugs may also
depress transmission at the skeletal
neuromuscular junction.
Muscle relaxation is not a characteristic
action of zolpidem, zaleplon and
eszopiclone.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

28. Effects on respiration and
cardiovascular function
• At therapeutic doses, sedative-hypnotics
can produce significant respiratory
depression in patients with pulmonary
disease.
• Effects on respiration are dose-related.
• Depression of the medullary respiratory
center is the usual cause of death due to
overdose of sedative-hypnotics.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

29. Effects on respiration and
cardiovascular function
• In hypovolemic states, heart failure
and other diseases that impair
cardiovascular function, normal
doses of sedative-hypnotics may
cause cardiovascular depression.
• This is probably due to actions on
the medullary vasomotor center.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

30. Effects on respiration and
cardiovascular function
• At toxic doses, myocardial contractility
and vascular tone may both be
depressed by central and peripheral
effects, leading to circulatory collapse.
• Respiratory and cardiovascular effects
are more marked when sedative-
hypnotics are given intravenously.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

31. Tolerance
• Tolerance is decreased responsiviness to
a drug following repeated exposure.
• This is common feature of sedative-
hypnotics use.
• Tolerance my result in the need for an
increase in the dose required to maintain
symptomatic improvement or to promote
sleep.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

32. Tolerance
• Partial cross-tolerance occurs between
the sedative-hypnotics and also with
ethanol.
• An increase in the rate of drug
metabolism (metabolic tolerance) may be
partly responsible for the development of
tolerance in the case of chronic
administration of barbiturates.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

33. Tolerance
Changes in responsiveness of
the central nervous system,
which is called
pharmacodynamic tolerance,
is important mechanism of
tolerance development.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

34. Abuse
• Compulsive misuse of sedative-hypnotic
drugs occurs very often.
• The consequences of abuse of these
agents have psychological and
physiologic component.
• The most serious complication is
development of dependence.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

35. Dependence
• Dependence is altered physiologic state
that requires continuous drug
administration to prevent an abstinence
or withdrawal syndrome.
• Sedative-hypnotics withdrawal syndrome
is characterized by states of increased
anxiety, insomnia and CNS excitability,
that may progress to convulsions.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

36. Dependence
• Most sedative-hypnotics can cause
dependence when used on a long-
term basis.
• When higher dose of sedative-
hypnotics are used, abrupt
withdrawal leads to more serious
withdrawal signs.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

37. Dependence
• The use of drugs with very short half-
lives for hypnotic effects may lead to
signs of withdrawal even between doses.
• Triazolam, which has a half-life 4 hours,
has been reported to cause daytime
anxiety when used to treat sleep
disorders.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

38. Dependence
The abrupt cessation of use of
zolpidem, zaleplon and eszopiclone
may result in withdrawal
symptoms, but usually of less
intensity than symptoms seen with
benzodiazepines.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

39. Benzodiazepine antagonists
• Flumazenil is competitive antagonist.
• It has high affinity for the BZ binding site on
the GABAA receptors.
• It blocks many of the actions of
benzodiazepines, zolpidem, zaleplon and
eszopiclone.
• It does not antagonize the CNS effects of other
sedative-hypnotics, ethanol, opioids and
general anesthetics.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

40. Benzodiazepine antagonists
• Flumazenil is approved for use in
reversing the CNS depressant effects of
benzodiazepine overdose and to hasten
recovery following use of these drugs in
anesthetic and diagnostic procedures.
• When given iv., it acts rapidly, but has a
short half-life (0,7-1,3 hours) due to rapid
hepatic clearance.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

41. Benzodiazepine antagonists
• All benzodiazepines have a longer
duration of action than flumazenil.
• Sedation commonly recurs, requiring
repeated administration of flumazenil.
• Adverse effects of flumazenil include
agitation, confusion, diziness and
nausea.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

42. Benzodiazepine antagonists
• Flumazenil may cause a severe precipitated
abstinence syndrome in patients who have
developed marked benzodiazepine
dependence.
• In patients who have ingested
benzodiazepines with tricyclic
antidepressants, seizures and cardiac
arrhythmias may follow flumazenil
administration.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

43. Literature
• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.