1. Sedative-hypnotic drugs part I
Domina Petric, MD

2. I.
introduction

3. Sedatives vs. hypnotics
An effective sedative (anxiolytic) agent should reduce anxiety and exert a calming effect.
The degree of central nervous system depression should be the minimum consistent with therapeutic efficacy.
A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep.
Hypnotic effects involve more pronounced depression of the CNS than sedation.

4. Chemical classification
II.
Chemical classification

5. The benzodiazepines These are widely used sedative-hypnotics.
Most of them contain a carboxamide group in the 7-membered heterocyclic ring structure.
An electronegative substituent in the 7 position, such as a halogen or a nitro group, is required for sedative-hypnotic activity.
The structures of triazolam and alprazolam include the addition of a triazole ring at the 1,2-position.

6. Other drugs Barbiturates Zolpidem (imidazopyridine)
Zaleplon (pyrazolopyrimidine)
Eszopiclone (cyclopyrrolone)
Ramelteon (a melatonin receptor agonist)
Buspirone (slow-onset hypnotic drug)

7. III.
pharmacokinetics

8. Absorption, distribution
The absorption of traizolam is extremely rapid. Diazepam and the active metabolite clorazepate have also very rapid absorption. Most of the barbiturates, older sedative hypnotics and newer hypnotics (eszopiclone, zaleplon, zolpidem) are absorbed rapidly into the blood following oral administration. Lipid solubility is responsible for the rapid onset of central nervous system effects of triazolam, thiopental and newer hypnotics eszopiclone, zaleplon and zolpidem. All sedative-hypnotics cross the placental barrier during pregnancy. They are also detectable in breast milk and may exert depressant effects in the nursing infant.

9. Biotransformation
Metabolic transformation to more water-soluble metabolites is necessary for clearance of sedative-hypnotics from the body.
The microsomal drug-metabolizing enzyme systems of the liver are most important.
Elimination half-life of these drugs depends mainly on the rate of their metabolic transformation.

10. Benzodiazepines
Hepatic metabolism accounts for the clearance of all benzodiazepines. Most benzodiazepines undergo microsomal oxidation (phase I reactions), including N-dealkylation and aliphatic hydroxylation, catalyzed by cytochrome P450 isozymes, especially CYP3A4. The metabolites are subsequently conjugated (phase II reactions) to form glucuronides that are excreted in the urine. Many phase I metabolites of benzodiazepines are pharmacologically active, some with long half-lives. Desmethyldiazepam is an active metabolite of chlordiazepoxide, diazepam, prazepam and clorazepate. Desmethyldiazepam has half-life more than 40 hours.

11. Benzodiazepines
Alprazolam and triazolam undergo α-hydroxylation. Resulting metabolites have short-lived pharmacologic effects because they are rapidly conjugated to form inactive glucuronides. The short elimination half-life of triazolam (2-3 hours) favors its use as a hypnotic rather than as a sedative drug. Benzodiazepines for which the parent drug or active metabolites have long half-lives are predictably more likely to cause cumulative effects with multiple doses. Estazolam, oxazepam and lorazepam have relatively short half-lives and are metabolized directly to inactive glucuronides. Cumulative and residual effects such as excessive drowsiness are less of a problem with these drugs.

12. Barbiturates
Only insignificant quantities of the barbiturates are excreted unchanged, except phenobarbital. The major metabolic pathways involve oxidation by hepatic enzymes to form alcohols, acids and ketones, which appear in the urine as glucuronide conjugates. The overall rate of hepatic metabolism in humans depends on the individual drug, but it is usually slow. The elimination half-lives of secobarbital and pentobarbital range from 18 to 48 hours in different individuals. The elimination half-life of phenobarbital in humans is 4-5 days. Multiple dosing with these agents can lead to cumulative effects.

13. Newer hypnotics
After oral administration of the standard formulation, zolpidem reaches peak plasma levels in 1,6 hours. Zolpidem is rapidly metabolized to inactive metabolites via oxidation and hydroxylation by hepatic cytochromes P450 including the CYP3A4 isozyme. The elimination half-life of the drug is 1,5-3,5 hours. Clearance is decreased in elderly patients.

14. Newer hypnotics
Zaleplon is metabolized to inactive metabolites, mainly by hepatic aldehyde oxidase and partly by the cytochrome P450 isoform CYP3A4.
The half-life of the drug is about 1 hour.
Dosage should be reduced in patients with hepatic impairment and in the elderly.

15. Newer hypnotics
Cimetidine, which inhibits both aldehyde dehydrogenase and CYP3A4, increases the peak plasma level of zaleplon. Eszopiclone is metabolized by hepatic cytochromes P450, especially CYP3A4, to form the inactive N-oxide derivative and weakly active desmethyleszopiclone. The elimination half-life of eszopiclone is 6 hours. It is prolonged in elderly and in the presence of inhibitors of CYP3A4 (ketoconazole). Inducers of CYP3A4 (rifampin) increase the hepatic metabolism of eszopiclone.

16. Drug
Peak blood level (hours)
Elimination half-life (hours)
Comments
Alprazolam
1-2
12-15
Rapid oral absorption
Chlordiazepoxide
2-4
15-40
Active metabolites, erratic bioavailability from im. injection
Clorazepate
50-100
Prodrug, hydrolyzed to active form in stomach
Diazepam
20-80
Active metabolites, erratic bioavailability from im. inj.
Eszopiclone 1 6
Minor active metabolites
Flurazepam
40-100
Active metabolites with long half-lives
Lorazepam
1-6
10-20
No active metabolites
Oxazepam
Temazepam
2-3
10-40
Slow oral absorption
Triazolam
Rapid onset, short duration of action
Zaleplon
<1
Metabolized via aldehyde dehydrogenase
Zolpidem
1-3
1,5-3,5

17. Excretion
The water-soluble metabolites of sedative-hypnotics, mostly formed via the conjugation of phase I metabolites, are excreted mainly via the kidney. Changes in renal function do not have a marked effect on the elimination of parent drug. Phenobarbital is excreted unchanged in the urine to a certain extent (20-30% in humans) and its elimination rate can be increased significantly by alkalinization of the urine. This is partly due to increased ionization at alkaline pH, since phenobarbital is a weak acid with a pKa of 7,4.

18. Factors affecting biodisposition
In very old patients and in patients with severe liver disease, the elimination half-lives of sedative-hypnotics are often increased singificantly. Multiple normal doses of these drugs can result in excessive central nervous system effects. The activity of hepatic microsomal drug-metabolizing enzymes may be increased in patients exposed to certain older sedative-hypnotics on a long-term basis. Barbiturates, especially phenobarbital and meprobamate are most likely to cause this effect. Benzodiazepines and the newer hypnotics do not change hepatic drug-metabolizing enzyme activity with continuous use.

19. Ramelteon
Melatonin receptors are involved in maintaining circadian rhythms underlying the sleep-wake cycle. Ramelteon (Rozerem) is an agonist at MT1 and MT2 melatonin receptors located in the suprachiasmatic nuclei of the brain. The drug has no direct effects on GABAergic neurotransmission in the CNS. Ramelteon reduces the latency of persistent sleep with no effects on sleep architecture: no rebound insomnia or significant withdrawal symptoms. This drug has minimal potential for abuse. It is rapidly absorbed after oral administration and undergoes extensive first-pass metabolism, forming an active metabolite with longer half-life (2-5 hours) than the parent drug.

20. Ramelteon
The CYP1A2 isoform of cytochrome P450 is mainly responsible for the metabolism of ramelteon. CYP2C9 isoform is also involved. The drug should not be used in combination with inhibitors of CYP1A2 (cirpofloxacin, fluvoxamine, tacrine, zileuton) or CYP2C9 (fluconazole). Ramelteon should be used cautiously in patients with liver disease. Rifampin reduces the plasma levels of both ramelteon and its active metabolite. Adverse effects of ramelteon are dizziness, somnolence, fatigue and endocrine changes (decreases testosterone, increases prolactin). Category C drug for pregnancy.

21. Buspirone
Buspirone has selective anxiolytic effects. It relieves anxiety without causing marked sedative, hypnotic or euphoric effects. Buspirone has no anticonvulsant or muscle relaxant properties. It does not interact directly with GABAergic systems. It may exert its anxiolytic effects by acting as a partial agonist at brain 5-HT1A receptors. It has also affinity for brain dopamine D2 receptors. Buspirone shows no rebound anxiety or withdrawal signs on abrupt discontinuance. The drug is not effective in blocking the acute withdrawal syndrome resulting from abrupt cessation of use of benzodiazepines or other sedative-hypnotics.

22. Buspirone
It has minimal abuse liability. The anxiolytic effects of buspirone may take more than a week to become established: no use in acute anxiety. The drug is used in generalized anxiety states, but it is less effective in panic disorders. Buspirone is rapidly absorbed orally, but undergoes extensive first-pass metabolism via hydroxylation and dealkylation reactions. The major metabolite is 1-2-pyrimidyl-piperazine (1-PP), which has α2-adrenoreceptor-blocking actions and enters the CNS to reach higher levels than the parent drug. The elimination half-life of buspirone is 2-4 hours. Liver dysfunction may slow clearance of buspirone.

23. Buspirone
Rifampin decreases the half-life of buspirone. Inhibitors of CYP3A4 (erythromycin, ketoconazole, grapefruit juice, nefazodone) can increase its plasma levels. Buspirone causes less psychomotor impairment than benzodiazepines. It does not affect driving skills. Side effects are nonspecific chest pain, tachycardia, palpitations, dizziness, nervousness, tinnitus, gastrointestinal distress, paresthesias and dose-dependent pupillary constriction. Blood pressure may be significantly elevated in patients receiving MAO inhibitors. Pregnancy category B drug.

24. Katzung, Masters, Trevor. Basic and clinical pharmacology.