1. sedative hypnotics

5. Introduction Sedatives • Drugs that have an inhibitory effect on the CNS to the degree that they reduce: • Nervousness • Excitability • Irritability without causing sleep Hypnotics • Calm or soothe the CNS to the point that they cause sleep • A sedative can become a hypnotic if it is given in large enough doses

6. Classification • Barbiturates: • Ultra-short acting: Thiopental • Short-acting: Pentobarbital • Intermediate- acting: Amobarbital • Long-acting: Phenobarbital

7. Benzodiazepines • Chlordiazepoxide • Miscellaneous Sedative- Hypnotics • Amides and Imides: Glutethimide • Alcohols and Their carbamate derivatives Ethinamate • Aldehydes and Their derivatives Chloral hydrate

8. Benzodiazepine • Indication • Sedation • Sleep induction • Skeletal muscle relaxation • Anxiety relief • Treatment of alcohol withdrawal • Agitation • Depression • Epilepsy • Balanced anesthesia • Drug effect • Calming effect on the CNS • Useful in controlling agitation and anxiety • Reduce excessive sensory stimulation, inducing sleep • Induce skeletal muscle relaxation

9. Mechanism of action: BZD • Low concentration- combine with GABA and GABA receptor, exerts postsynaptic inhibitory effect ( Antianxiety effect) • High concentration- block calcium ion entry into presynaptic neurons and alter neurotransmitter release. ( sedation)

12. Crucial difference

13. Benzodiazepines: SAR • Genaral Structure • Position 7- Electron attracting group • Position 6,8 & 9- Unsubstituted • Position 5- Phenyl group promotes activity • ortho (2’) or di-ortho (2’,6’) - Electron attracting group, activity is increased • para substitution – greatly decreased activity. • Saturation of 4,5 double bond or shift to 3-4 : decreased activity. • 2-carbonyl function- Optimal for activity • Alkyl substitution at position 3- decreased activity • 3- hydroxyl substitution – very important pharmacokinetically. • N – substituent should be small.

14. Position 7- Electron attracting group chlordiazepoxide • Position 6,8 & 9- Unsubstituted Diazepam

15. Position 5- Phenyl group promotes activity • ortho (2’) or di-ortho (2’,6’) - Electron attracting group, activity is increased • para substitution – greatly decreased activity. Lorazepam • Saturation of 4,5 double bond or shift to 3-4 : decreased activity. • 2-carbonyl function- Optimal for activity • Alkyl substitution at position 3- decreased activity • 3- hydroxyl substitution – very important pharmacokinetically. • N – substituent should be small.

16. Metabolism • Diazepam • Prazepam • Halazepam • Clorazepate nordiazepam oxazepam • Chlordiazepoxide demoxepam oxazepam glucuronide

17. Temazepam 7-Chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one Hypnotic Duration of action: Short • Bromazepam 7-Bromo-1,3-dihydro-5-(2-pyridinyl)-2H-1,4-benzodiazepin-2-one Hypnotic and antianxiety Duration of action: long

18. Nitrazepam 7-Nitro-1,3-dihyro-5-phenyl-2H-1,4-benzodiazepin-2-one Sedative hypnotic Duration of action: long • Midazolam 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]-benzodiazepine Oral sedative and anticonvulsant. Rapid onset and short duration of action

19. Barbiturates • Indication • Hypnotic • Sedative • Anticonvulsant • Anesthesia for surgical procedures • Drug effect • Low doses: sedative effects • High doses: hypnotic effects (also lowers respiratory rate) • Notorious enzyme inducers • Stimulate liver enzymes that cause the metabolism or breakdown of many drugs

20. Barbiturates: Mechanism of action • Act postsynaptically to promote GABA binding and prolong the mean open time of chloride channel (sedative and antianxiety) • Chloride conductance in absence of GABA (sedative-hypnotic and anesthetic) • Reduce calcium-dependent action potentials and thereby inhibit neurotransmitter release (sedative-hypnotic and anesthetic) • The GABA effect in the absence of GABA and effects on calcium may be involved in sedation, hypnosis and anesthesia

21. Barbiturates

22. Barbiturates: side effects Body SystemEffects CNS Drowsiness, lethargy, vertigo, mental depression, coma Respiratory Respiratory depression, apnea,bronchospasms, cough GI Nausea, vomiting, diarrhea constipation Other Agranulocytosis, vasodilation, hypotension, Stevens-Johnson syndrome

23. Barbiturates: Toxicity and Overdose • Overdose frequently leads to respiratory depression, and subsequently, respiratory arrest • Overdose produces CNS depression (sleep to coma and death) • Can be therapeutic • Anesthesia induction • Uncontrollable seizures: “phenobarbital coma”

24. Barbiturates: SAR • General structure • Both hydrogen atoms at the 5-position of barbituric acid must be replaced • 7-9 total carbon atoms substituted on 5-position: Increase in onset and a decrease in duration of action. • There is inverse correlation between the total number of carbon atoms substituted on the 5-position and the duration of action • Phenyl substituent • Branching of alkyls • Presence of double or triple bond • Alkyl groups in the 1- or 3-position shorten onset and duration of action • Replacement of oxygen by sulfur on carbon-2 shortens the onset and duration of action

25. Both hydrogen atoms at the 5-position of barbituric acid must be replaced Trihydroxypyrimidine (pKa ≈ 4)

26. 7-9 total carbon atoms substituted on 5-position: Increase in onset and a decrease in duration of action. Barbital Phenobarbital Butalbital Talbutal Long acting Intermediate acting Pentobarbital Secobarbital Short acting • There is inverse correlation between the total number of carbon atoms substituted on the 5-position and the duration of action • Phenyl substituent • Branching of alkyls • Presence of double or triple bond

27. Alkyl groups in the 1- or 3-position shorten onset and duration of action Metharbital Hexobarbital • Replacement of oxygen by sulfur on carbon-2 shortens the onset and duration of action Ultra short acting Thiopental

28. Barbiturates: Metabolism • Oxidation of olefins Secobarbital Secodiol • Oxidation at allylic carbon atom O- glucouronide conjugate Hexobarbital 3’- hydroxyhexobarbital 3’- oxohexobarbital

29. Oxidation at Aliphatic and Alicyclic carbon atoms Amobarbital 3’-hydroxyamobarbital • Oxidations involving carbon-sulphur system Thiopental Pentobarbital 3’-hydroxypentobarbital

30. Phenobarbital 5-Ethyl-5-phenylbarbituric acid Long-acting sedative and hypnotic Metabolism : p-hydroxylation • Talbutal 5-Allyl-5-sec-butylbarbituric acid Intermediate duration of action Metabolism : oxidation at olefins

31. Pentobarbital 5-Ethyl-5-(1-methylbutyl)barbituric acid Short acting • Secobarbital 5-Allyl-5-(1-methylbutyl)barbituric acid Short acting

32. Hexobarbital • 5-cyclohexyl-5-methyl

33. Miscellaneous sedative hypnotics • Glutethimide 3-ethyl-3-phenylpiperidine-2,6-dione Imide: Structural resemblance with barbiturates Sedative hypnotic Absorption: GIT Metabolism is extensive • Ethinamate 1-Ethynyl-cyclohexanol carbamate Sedative hypnotic Rapid onset of action and short duration of action Metabolism: hydroxylation of cyclohexane ring

34. Chloral hydrate • Trichloroacetaldehyde monohydrate • Hypnotic • Metabolism: Trichloroethanol

35. Nonbenzodiazepine GABAA agonist Zolpidem (imidazopyridine) Zolpiclone (pyrrolopyrazine)

36. Synthesis of Nitrazepam 2-amino-5-nitrobenzophenone  2-(bromoacetamido)-5-nitro benzophenone