Med chem hypnotics and sedatives

It contains classification, SAR, MOA, metabolism and usd of hypnotics and sedatives. Barbiturates and benzodiazepines were discussed as per PCI syllabus. This helps B.Pharm students to learn with focus

1. MEDICINAL CHEMISTRY I B. Pharmacy II/IV (Second sem.) Dr. K. Purna Nagasree M.Pharm . (BITS, Pilani ), Ph.D., PDF (DST, WOSA) Associate Professor VIGNAN INSTITUTE OF PHARMACEUTICAL TECHNOLOGY (Approved by PCI, AICTE New Delhi and affiliated to JNTUK) ANISO 9001:2015, ISO 14001:2015, OHSAS 18001:2007 Certified institution, beside VSEZ, Duvvada , Vishakapatnam-530049, Andhra Pradesh, India 2021

2. Drugs acting on the CNS –Unit IV Sedatives and Hypnotics Anti Psychotics Anti convulsants

3. Sedatives and Hypnotics Benzodiazepines – SAR, Chlordiazepoxide , Diazepam* , Oxazepam , Chlorazepate , Lorazepam , Alprazolam , Zolpidem Barbiturates – SAR, Barbital* , Phenobarbital, Mephobarbital , Amobarbital , Butabarbital , Pentobarbital, Secobarbital Miscellaneous – Amides & Imides – Glutethemide Alchohol and their carbamate derivatives – Meprobamate , Ethchlorvynol Aldehyde and their derivatives – Triclofos sodium, Paraldehyde

4. Sedatives and Hypnotics Sedatives are central nervous system (CNS) depressant drugs that reduce excitement, tension, and produce relaxation. Hypnotics are drugs that depress the CNS and produce sleep similar to that of natural sleep. Both sedative and hypnotic action may reside in the same drug. At lower dose - sedative, higher dose – hypnotic (Same drug)

5. Sedatives and Hypnotics Uses Antianxiety agents Anticonvulsants Muscle relaxants General anaesthetics Preanaesthetic medication Antipsychiatrics To potentiate analgesic drugs Adjuvant to anaesthesia Co-drug in the treatment of hypertension

6. Sedatives and Hypnotics Classification based on their chemical structure Benzodiazepines: Chlordiazepoxide , Diazepam* , Oxazepam , Chlorazepate , Lorazepam , Alprazolam , Zolpidem Barbiturates: Barbital* , Phenobarbital, Mephobarbital , Amobarbital , Butabarbital , Pentobarbital, Secobarbital Acyclic hypnotics containing nitrogen – Meprobamate Cyclic hypnotics containing nitrogen Alcohols and aldehydes – Ethchlorvynol , Paraldehyde Glutethamide , Triclofos sodium Acetylene derivatives

7. Sedatives and Hypnotics Miscellaneous a. Inorganic salts b. Acids and esters c. Antihistaminic and anticholinergic agents d. Sulphones e. Plant extracts f. Endogenous substances g. Other opioids : morphine, pethidine h. Neuroleptics: chlorpromazine, triflupromazine Newer agents - Zolpidem

8. Sedatives and Hypnotics Mode of action: Benzodiazepine receptors are present in the brain and they form a part of GABA A receptor’s chloride ion channel macromolecular complex. Binding of benzodiazepines to these receptors produces activation of GABA A receptor and increases chloride conductance by increasing the frequency of opening chloride ion channel . Hyper-polarization–block depolarization- decrease neural excitment

9. Mode of action Sedatives and Hypnotics

10. Sedatives and Hypnotics – Benzodiazepines and Triazolo benzodiazepines Chlorazepate Zolpidem

11. Uses of benzodiazepines the symptomatic relief of tension and anxiety, acute alcohol withdrawal adjunct therapy in skeletal muscle spasm, and management of status epilepticus The long-term use - physical dependence – small dose

12. Sedatives and Hypnotics Metabolism of Benzodiazepines: Compounds without the hydroxyl group are nonpolar , and undergoes hepatic oxidation Compounds with hydroxyl groups have more polarity and are readily converted into the glucuronide conjugates and excreted easily These compounds are also metabolized by 3-hydroxylation of benzodiazepine ring

13. Sedatives and Hypnotics Metabolism of Benzodiazepines

14. Benzodiazepines Chlordiazepoxide Adverse reactions include drowsiness, ataxia, confusion Used for the relief of anxiety and tension, withdrawal symptoms of acute alcoholism, and also used as sedative as well as muscle relaxant .

15. Chlorazepate 7-Chloro-2-oxo-5-phenyl-1, 4-benzodiazepin-3-carboxylic acid It is used as a sedative and hypnotic Benzodiazepines A water-soluble benzodiazepine derivative effective in the treatment of anxiety. It has also muscle relaxant and anticonvulsant actions.

16. Diazepam* 7-Chloro-1-methyl-5-phenyl-1,4-benzodiazepin-2-one ( Calmpose , Valium ) It is used as a skeletal muscle relaxant, anticonvulsant and antianxiety agent. Patients on the drug should be cautioned not to drive an automobile or to operate dangerous machinery until a few days after the drug has been discontinued. Benzodiazepines

17. Oxazepam 7-Chloro-3-hydroxy-5-phenyl-1,4-benzodiazepin-2-one It is useful for the control of acute tremulousness, anxiety associated with alcohol withdrawal. Side effects that have been observed include rashes, nausea, lethargy, oedema etc. More severe reactions include leucopenia and jaundice. Benzodiazepines

18. Lorazepam 7-Chloro-5-(2-chlorophenyl)-3-hydroxy-1,4-benzodiazepin-2-one It is used as sedative and hypnotic It has much more polarity than diazepam duration of action is short Benzodiazepines

19. Alprazolam R = H, R1 = CH3 Metabolism of Alprazolam : The methyl group of this drug is metabolized by oxidation reaction to methyl alcohol and conjugation reaction takes place. It is useful in the short-term management of insomnia The duration of action is short and the drug is a highly potent anxiolytic Benzodiazepines 8-chloro-1-methyl-6-phenyl-4H-triazolo benzodiazepine

20. Zolpidem (Newer drug) It is an imidazopyridine agent and is an agonist at the benzodiazepine α1 receptor subunit of the GABA A receptor, used for the management of insomnia. Non Benzodiazepines N,N-dimethyl-2-[6-methyl-2-(4-methylphenyl) imidazo pyridin -3-yl] acetamide

21. SAR of Benzodiazepines •The presence of electron attracting substituents ( Cl , F, Br, NO 2 ) at position C-7 is required for the activity, •Position 6, 8, and 9 should be un substituted for the activity. •Phenyl (or) pyridyl at the C-5 promotes activity. If the phenyl ring substituted with electron attracting groups at 2’ or 2’, 6’ position, then the activity is increased. substituents at 3’, 4’, and 5’ decreases activity • Saturation of 4, 5 double bond or shift of it to the 3, 4 position decreases the activity. •Alkyl substitution at position 3 decreases the activity, but the presence or absence of hydroxyl group is essential.

22. Benzodiazepines

23. SAR of Benzodiazepines Compounds without 3-hydroxyl group are nonpolar and usually have long half-life. Compounds with the 3-hydroxyl group have short half-life because of rapid conjugation with glucuronic acid. Substitution at N1 by alkyl, halo alkyl, and amino alkyl group increases the activity. Reduction of carbonyl function at C-2 position to CH 2 yields less potent compound. Triazolo benzodiazepine ( Alprazolam ) is found to be more potent .

24. Diazepam Synthesis Lewis acid e Benzophenone derivative Chloro acetyl chloride

25. BARBITURATES Mode of action: Barbiturates primarily act on GABA: benzodiazepin receptor Cl – channel complex and potentiate GABA ergic inhibitory action by increasing the lifetime of Cl – channel opening induced by GABA. Barbiturates do not bind to benzodiazepine receptor, but it binds on to α and ß subunit

26. BARBITURATES Barbiturates are derivatives of barbituric acid . Their hypnotic activity is conferred by the replacement of H-atom attached to the C-5 position by aryl or alkyl radicals.

27. Barbiturates Classification Barbiturates classified on the basis of duration of their action. a. Long-acting barbiturates (6 h or more than 6 h) b. Intermediate-acting barbiturates (3–6 h) c. Short-acting barbiturates (less than 3 h) d. Ultra short-acting barbiturates (15 min) Thiopental sodium

28. Barbiturates - Barbital* Barbitone sodium (Barbital sodium ) Barbitone sodium forms water-soluble salts with sodium hydroxide. It is a powerful hypnotic drug and used in the treatment of epileptic seizures. Pyrimidine 2,4,6 trione

29. Synthesis of Barbital sodium Condensation and cyclisation

30. Phenobarbital/ Phenobarbitone Phenobarbital sodium is a hygroscopic substance. It is used as sedative, hypnotic and antiepileptic (drug of choice in the treatment of grandmal and petitmal epilepsy ) An overdose of it can result in coma, severe respiratory depression, hypotension leading to cardiovascular collapse, and renal failure.

31. Methyl phenobarbitone / Mephobarbital Mephobarbitone is a strong sedative with anticonvulsant action, mild hypnotic. used for the relief of anxiety, tension and apprehension, and is an antiepileptic in the management of generalized tonic- clonic and absence seizures.

32. Amylobarbitone / Amobarbital A barbiturate with hypnotic and sedative properties (but not antianxiety ). Adverse effects are mainly a consequence of dose-related CNS depression and the risk of dependence with continued use is high. 5-ethyl-5-(3-methylbutyl)- barbituric acid

33. / Butabarbital Butabarbital is a fast onset barbiturate with short duration of action   Treats severe insomnia and pre-operative anxiety Butabarbital has been detected in multiple biofluids , such as urine and blood. It is a potentially toxic compound . Butabarbital  is less commonly used ------ benzodiazepines are preferred 5-butan-2-yl-5-ethyl-barbituric acid Butisol or secbutobarbitone

34. Pentobarbital It is used as a sedative or hypnotic for the short-term management of insomnia and is a preanaesthetic medication, used in the treatment of strychnine poisoning . Administered intravenously, for the control of certain convulsive syndromes. This barbiturate reduces cerebral blood flow and, thereby, decrease oedema and intracranial pressure.

35. Quinobarbitone sodium / Secobarbital It is used in status epilepticus and in toxic reactions to strychnine and as local anaesthetic .

36. Barbiturates

37. Metabolism of Barbiturates These drugs are metabolized in the liver and forms less lipophilic compounds. These are mediated through glucuronide or sulphate conjugation . Oxidation of a substituent at C-5 forms alcohols or phenols – glucuronide 2 . It undergoes oxidative N- dealkylation at nitrogen. 3 . Oxidative desulphation of 2-thio barbiturates yields more hydrophilic barbiturates, which is excreted through urine.

38. Metabolism of Barbiturates

39. SAR of Barbiturates 1. Acidity On the basis of acidity values, barbiturates are divided into two classes: Active class

40. SAR of Barbiturates Inactive class They are inactive since they are not acidic Attachment of alkyl substituent to both N1 and N3 renders the drug non acidic, making them inactive

41. SAR of Barbiturates 2. Lipid water solubility lipid-water solubility or partition co-efficient is calculated to find out whether the compound is active or not. 3. The sum of the carbon atoms of both the substituents at c-5 should be between 6 and 10, to attain optimal hypnotic activity eg . Barbital is ineffective than phenobarbital This sum is also an index of the duration of action. 4. The greater the branching, more potent will be the drug. Example: pentobarbital

42. SAR of Barbiturates 5. Introduction of a halogen atom into the C-5 substituents increase potency. Introduction of a polar substituents (OH, NH 2 , COOH, etc ) into the aromatic group at C-5 results in decreased lipid solubility and potency. Replacement of oxygen by sulphur atoms at C-4 and C-6 position reduces the hypnotic activity. sulphur atoms at C-2 rapid onset and short duration of action

43. Acyclic hypnotics containing nitrogen – Miscellaneous- Meprobamate It is used in the treatment of anxiety disorders. It is also a centrally acting skeletal muscle relaxant. The agents in this group find use in a number of conditions, such as strains and sprains that may produce acute muscle spasm.

44. Glutethamide It is used as a hypnotic drug to induce sleep without depressing respiration . Over dosage is less likely to depress respiration Adverse reactions include a generalized rash, rarely nausea Some of these side effects may be due to the anticholinergic activity of this drug.

45. Alcohols and Aldehydes - Miscellaneous- Ethchlorvynol It also possesses muscle relaxant and anticonvulsant properties Adverse effects include suppression of REM sleep, ataxia, and hypotension. Hypnogram

46. Alcohols and Aldehydes - Miscellaneous- Paraldehyde 2, 4, 6-Trimethyl-1,3,5-trioxane It is exclusively used in the management of hospitalized patients undergoing alcohol withdrawal.

47. Aldehyde and their derivatives – Miscellaneous - Triclofos sodium Used as hypnotic

48. Miscellaneous