Sedative Hypnotic Agents

1. Sedative Hypnotic Agents

2. Sedative Hypnotic Agents • Cause drowsiness and facilitates the initiation and maintenance of sleep • Grouped with anti-anxiety agents • Effects of these drugs are dose related • Ideal hypnotic should meet the following criteria • Transient decrease in the level of consciousness for the purpose of sleep without lingering effects • Have no potential for decreasing or arresting respirations even at high doses • Produce no abuse, addiction, tolerance or dependence

3. Classification of Hypnotics • An arbitrary classification is as follows • Benzodiazepines • Barbiturates • Others

4. Sedative Hypnotics • Benzodiazepines • Used as daytime anxiolytics, sleep inducers, anesthetics, anticonvulsants and muscle relaxants • Depending on the dose any benzodiazepine may be used as a hypnotic • The benzodiazepines were shown to bind to the GABAA receptors involved in the regulation of the chloride channel. • Studies suggest two subclasses of receptors BZ1 and BZ2 • It has been proposed that compounds specific for the BZ1 subclass would be “nonsedative” and the BZ2 subclass is responsible for the sedative-hypnotic character of the benzodiazepines.

5. Sedative Hypnotics - Benzodiazepines • Major advantage in that they are relatively safe • Fatalities from overdose is rare • Their tendency to interact with other drugs is less than that seen with other hypnotics

6. Benzodiazepine N at position 1 optimal for activity R2 – various alkyl substitutions R3 – O, S, N (2-carbonyl is optimal) Fuzed triazoloring at positions 1 &2 or an imidazolo ring may be present. In these compounds position 7 electron withdrawing groups are not required. Sedative Hypnotics

7. Benzodiazepine Alkyl group at 3 decreases activity, -OH retains activity Saturation of the 4,5 double bond or bond shift to 3,4 decreases activity Phenyl group at 5 enhances activity Electron withdrawing groups are required at position 7 (R1) Positions 6,8 & 9 should not be substituted Sedative Hypnotics

8. Benzodiazepine Substitution at 2’ or 6’ or both with electron withdrawing groups increase activity. Para substitution decreases activity tremendously Sedative Hypnotics

9. Estazolam (Prosom) Used as a sedative and hypnotic in the treatment of insomnia Increase total sleep Decrease nocturnal wakefullness, body movements, number of awakenings and sleep latency No active metabolite Sedative Hypnotics - Benzodiazepines

10. Triazolam (Halcion) Used as a sedative and hypnotic in the treatment of insomnia No active metabolite Oral benzodiazepine and has an intermediate rate of absorption High receptor binding affinity Ultra-short half life Hydroxylation of triazole methyl group makes an inactive metabolite Sedative Hypnotics - Benzodiazepines

11. Temazepam (Restoril) Has an inactive metabolite Absorbed slowly Rapidly metabolized Sedative Hypnotics - Benzodiazepines

12. Flurazepam (Dalmane) Induces impairment of motor function and has hypnotic properties Used to treat insomnia Has active metabolites Metabolized by N-dealkylation and hydroxylation a to the imine Oral benzodiazepine and is absorbed most rapidly Sedative Hypnotics - Benzodiazepines

13. Quazepam (Doral) Induces impairment of motor function and has hypnotic properties Used to treat insomnia Has active metabolites Metabolized by oxidation to the 2-oxo compound and then N-dealkylation Sedative Hypnotics - Benzodiazepines

14. Oxazepam(Serax) Prototype for the 3-hydroxy compounds Short duration of action Sedative Hypnotics - Benzodiazepines

15. Alprazolam (Xanax) Oxidative metabolism of the methyl group to the methyl alcohol followed by conjugation is rapid Short duration of action Highly potent on milligram basis Sedative Hypnotics - Benzodiazepines

16. Chlordiazepoxide (Librium) N-demethylation and hydrolysis of the condensed amidino group produces demoxepam an active metabolite with anticonvulsant properties. It is converted to nordazepam which is converted to oxepam which undergoes conjugation and then is excreted. Sedative Hypnotics - Benzodiazepines Demoxepam

17. Nordiazepam It is converted to norda1zepam which is converted to oxazepam which undergoes conjugation and then is excreted. Sedative Hypnotics - Benzodiazepines Oxazepam

18. Clorazepate (Tranxene) Prodrug Undergoes rapid loss of water then carboxylation to nordiazepam which is converted to oxazepam Sedative Hypnotics - Benzodiazepines

19. Diazepam (Valium) Metabolized by N-demethylation to nordazepam which is then metabolized ot oxazepam Sedative Hypnotics - Benzodiazepines

20. Lorazepam (Ativan) Recognized as the 2’ chloro substituted analog of oxazepam This substitution increases activity Sedative Hypnotics - Benzodiazepines

21. Midazolam Also an anesthetic Sedative Hypnotics - Benzodiazepines

22. Clonazepam (Klonopin) Also used in some seizures Treatment of panic disorder extensively metabolised by reduction to 7-amino-clonazepam and by N-acetylation to 7-acetamino-clonazepam. Hydroxylation at the C-3 position also occurs. Sedative Hypnotics - Benzodiazepines

23. Minimal use as sedative hypnotics due to toxicity Cause greater CNS depression Induces liver drug metabolizing enzymes Cause tolerance and dependence Some use as sedative hypnotics Primarily used as anesthetics and antiseizure drugs Sedative Hypnotics - Barbiturates 2 1 3 6 4 5

24. Sedative Hypnotics - Barbiturates • Act postsynaptically to promote GABA binding and prolong the mean open time of Cl ion channels by binding to a site other than the BD binding site or the GABA binding site 2 1 3 6 4 5

25. Sedative Hypnotics - Barbiturates • A good hypnotic must be a weak acid • 5,5-disubstituted barbituric acids, 5,5-disubstituted thiobarbituric acids and 1,5,5-trisubstituted barbituric acids possess acceptable hypnotic activity • Other substitutiona are inactive or produce convulsions 2 1 3 6 4 5

26. What would be the product of barbituric acid (structure shown) reacting with NaOH twice? Show the intermediate product as well. Sedative Hypnotics - Barbiturates 2 1 3 6 4 5

27. Sedative Hypnotics – Barbiturates 5,5-Disubstitution • As you increase the # of carbons, lipophilicity increases • Branching, unsaturation, replacement of alicyclic or aromatic substituents for alkyl substituents, halogens onn the alkyl substituents all increase lipid solubility • As lipophilicity increases, hydrophilicity decreases • Polar groups decreases lipid solubility

28. Sedative Hypnotics – Barbiturates Substitution on Nitrogen • Substitution on one imide hydrogen by an alkyl group increases lipid solubility • Quicker onset and shorter duration of action • As the size of the N-alkyl substituent increases the lipid solubility increases and hydrophilic character decreases • Attachment of large alkyl groups imparts convulsant properties • Alkyl substituents to both nigrogens makes the drug nonacidic and inactive

29. Sedative Hypnotics – Barbiturates Modification of Oxygen • Replacement of C-2 oxygen by sulfur increases lipid solubility • Onset of activity is rapid • Used as iv anesthetics

30. Phenobarbital (Luminal) 5-ethyl, 5-phenyl subst. Also anticonvulsant Mephobarbital (Metharbital) 3-methyl, 5-phenyl and 5-ethyl substituents N-dealklyated to phenobarbital Also anticonvulsant Barbiturates – Long Duration of Action (6+ hours)

31. Amobarbital (Amytal) 5-ethyl and 5-isopentyl substituents Sedative-hypnotic Has a water-soluble sodium salt Amobarbital Sodium (Alurate) Butabarbital Sodium (Butisol Sodium) Water-soluble salt of 5-sec-butyl-5-ethylbarbituric acid Sedative-hypnotic Barbiturates – Intermediate Duration of Action (3-6 hours)

32. Pentobarbital Sodium (Nembutal) 5-ethyl, 5-(1methylbutyl) substituents More rapid metabolism Secobarbital (Seconal) 5-allyl, 5-(1-methylbutyl) substituents More rapid metabolism Barbiturates – Short Duration of Action (less than 3 hours)

33. MiscellaneousSedative Hypnotic Agents

34. Zolpidem (Ambien) Short acting hypnotic Acts at the GABAA receptor Imidazolpyridine Binds with higher affinity at the BZR1 receptor Drug dependence Rapid onset and short elimination half life Metabolized to inactive metabolites Sedative Hypnotics - Nonbenzodiazepines

35. Zaleplon (Sonata) Oyrazolopyrimidine derivative Short half-life Interacts with the GABAA receptor at the BZR1 receptor Inactive metabolites Sedative Hypnotics - Pyrazolopyrimidine

36. Eszopiclone (Lunesta) Used for insomnia single chiral center with an (S)-configuration very slightly soluble in water, slightly soluble in ethanol, and soluble in phosphate buffer pyrrolopyrazine extensively metabolized by oxidation and demethylation Sedative Hypnotics Cyclopyrrolone

37. Ramelteon (Roxerem) Melatonin Receptor Agonist • Activates MT1 and MT2 receptors • Rapid onset of sleep with minimal rebound insomnia or withdrawal symptoms • (S)-enantiomer • freely soluble in organic solvents, slightly soluble in water • oxidation to hydroxyl and carbonyl derivatives, with secondary metabolism producing glucuronide conjugates

38. Flumazenil Antagonist at benzodiazepine binding sites on the GABAA receptor Blocks actions of benzodiazepines and zolpidem but not other sedative hypnotics Management of benzodiazepine overdose Sedative Hypnotics Benzodiazepine Antagonist

39. Buspirone (Buspar) 5-HT Receptor Agonist • Partial agonist at 5-HT receptors • Slow onset (1-2 weeks) • Minimal psychomotor impairment • No additive CNS depression with sedative-hypnotic drugs

40. Chloral Hydrate (Noctec) A diol Metabolized to an active metabolite (trichloroethanol) Metabolite responsible for prolonged hypnotic effect Sedative in non operating room procedures for pediatrics