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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Organ level effects
Katzung, Masters, Trevor. Basic and clinical pharmacology.

14. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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.
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23. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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.
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24. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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.
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27. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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.
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36. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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.