SEDATIVES AND HYPNOTICS.pptx EDATIVES pp

SEDATIVES AND HYPNOTICS.pptx SEDATIVES AND HYPNOTICS.pptx

1. SEDATIVES AND HYPNOTICS Drug acting on central nervous system

2. The drugs that act on the central nervous system (CNS) influence the lives of everyone at all times. These drugs can selectively relieve pain, reduce fever, suppress disordered movement, induce sleep or arousal , and reduce the desire to eat or ally the tendency to vomit . Selectively, acting drugs can be used to treat anxiety, mania, depression, or schizophrenia and do so without altering consciousness. The electrophysiological signs of action in the CNS falls into two categories ( i ) excitatory (produce depolarization) and (ii) inhibitory (produces hyperpolarization) in the neurons Sedative     Sedatives are central nervous system (CNS) depressant drugs that reduce excitement, tension, and produce relaxation. A drug that subdues excitement and calms the subject without inducing sleep, though drowsiness may be produced. Sedation refers to decreased responsiveness to any level of stimulation; is associated with some decrease in motor activity and ideation.

3. Hypnotic   Hypnotics are drugs that depress the CNS and produce sleep like that of natural sleep.   Difference b/w Sedatives and hypnotics   Sedatives are drugs that decreases activity and have a calming, relaxing effect. Peoples use these drugs mainly to reduce anxiety. At higher doses, sedatives usually cause sleep. Drugs used mainly to cause sleep are called Hypnotics. The difference between sedative and hypnotic is usually the amount of the dose- At lower dose have a calming effect and higher doses cause sleep. At lower dose, the drug may act as sedative, while at a higher dose the same drug may act as hypnotic   Sedatives and hypnotics are also used as the following:   Antianxiety Agents Anticonvulsants Muscle Relaxants General Anesthetics Preanesthetic Medication Ant psychiatrics To Potentiate Analgesic Drugs Adjuvant to Anesthesia

4. Long-acting barbiturates Barbital Phenobarbital Mephobarbital Metharbital Short-acting barbiturates Butobarbital Pentobarbital Secobarbital Amobarbital Cyclobarbital Heptabarbital Ultra short- acting barbiturates (15 min) Thiopentone methohexitone Hypnotics Diazepam Flurazepam Nitrazepam Alprazolam Triazolam Anti-anxiety Diazepam Chlordiazepoxide Oxazepam Lorazepam Alprazolam Anti-convulsant Diazepam Lorazepam Clonazepam clobazam Also known as Z-Drugs Zopiclone Zolpidem Zaleplon Amide & imides  Glutethmide Alcohol & their carbamate derivatives  Meprobamate  Ethchlorvynol Aldehyde & their derivatives  Triclofos sodium  Paraldehyde

5. Benzodiazepines (BZD) Chemistry of BZD   All the BZD’s have a benzene ring (Blue color) attached to a diazepine ring (red color). BZD have a cyclic structure that includes one benzene ring with a heterocycle ring where 2 atoms are “Nitrogen” (Diazepine), Normally in 1 & 4 th position, but which can also be in 1,5 th and 2, 3 rd position. Normally BZD used in clinically that are 1,4-dinitrogenated system.

6. SAR of Benzodiazepines

7. Possibilities of Modification at Ring A, Ring B and Ring C RING- A The minimum requirement for 5-phenyl-1,4-benzodiaipin-2-one derivatives to BZD include an aromatic or hetero aromatic ring. An electronegative group (halo or nitro) substituted at R1 position markedly increase activity and binding affinity Substitution on 6,8 and 9 decrease the activity. Replacement of ring A with heterocyclic ring have weak activity and affinity as compared to phenyl derivatives.

8. RING- B   Alkyl substitution at R2 position will increases the activity. A proton accepting group C=O ( carbonyl oxygen ) at 2 nd position of ring B is necessary to interact with receptor binding site. Substitution at 3 rd position methylene or imine nitrogen is sterically unstable. Substitution at 3 rd position with hydroxy moiety have comparable potency to CH analogue but are excreted faster. Phenyl substitution at 5 th position increases the activity.   RING- C   Replacement of Ring C with aromatic heterocyclic ring increases the anxietolytic activity. Substitution at R3 position with Halogen, increases the activity. Substitution at 4’ position is unfavorable for activity.

9. Benzodiazepine receptors are present in the brain and they form a part of GABAA receptor’s chloride ion channel macromolecular complex. Binding of benzodiazepines to these receptors produces activation of GABAA receptor and increases chloride conductance by increasing the frequency of opening chloride ion channel. These in turn inhibit neuronal activity by hyper-polarization and de-polarization block.

10. Diazepam Uses: skeletal muscle relaxant, anticonvulsant and antianxiety agent.   Side effect: drowsiness, sedation, muscle weakness.

11. Zolpidem: (all non-BZD’s drugs having same action as zolpidem) (“Z”- drugs) Less hangover effect than BZD’s Can given orally and well observed metabolized in liver & excreted by urine Having short duration of action mostly used for short-term insomnia Less tolerance and dependence MOA: Zolpidem Binds to selectively to BZD receptors GABA mediated neuronal inhibition CNS depression

12. 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. The barbiturates were used extensively as sedative–hypnotic drugs. SAR of Barbiturates

13. Substitution at C-5 (R2, R3) position should be alkyl chain length is 6-10 carbon to attain optimal activity Substitution at R2, R3 position with branched chain shows greater lipid solubility and hypnotic activity but has shorter duration of action. The greater branching shows more potent will be the drug. eg. : - pentobarbitone Alicyclic or aromatic substituted analogue are more potent than aliphatic substituted analogue with the same number of carbon atom. Substitution at C-5 position shows the higher potency. Replacement of Oxygen atom by Sulphur atom at C-4 and C-6 position, reduce the hypnotic activity Replacement of Oxygen atom by Sulphur atom at C-2 position leads to rapid onset of action and shorter duration of action.

14. Barbiturates do not bind to benzodiazepine receptor promptly, but it binds to another site on the same macromolecular complex to exert the GABAergic facilitator actions. The barbiturate site appears to be located on α and β subunit. At high concentrations, barbiturates directly increase Cl– conductance and cause CNS depression. Synthesis of Barbital

15. Side effects

16. Glutethamide It is used as a hypnotic drug to induce sleep without depressing respiration. Meprobomate It is used in the anxiety disorder and centrally action skeletal muscle relaxant Ethchlorvyno Used for short-term hypnotic therapy in the management of insomnia   the exact mechanism of action is unknown, ethchlorvynol appears to depress the central nervous system in a manner similar to that of barbiturates

17. 1.Currently,barbiturates,are,primarily,used,as:, a. Hypnotic-- b. Sedative- c. Antiepileptic- d. Preanesthetic-medication 2 .The primary mechanism of action of benzodiazepines is: a. A.-Dopamine-antagonism- b. Adenosine-antagonism- c. Opening-of-neuronal-chloride-channels d. Facilitation-of-GABA-mediated-chloride-influx- 3.Select,the,correct,statement,about,benzodiazepines,(BZDs):, a. All-BZDs-facilitate-GABA-mediated-Cl-influx-into-neurones b. Different-BZDs-exert-the-same-degrees-of-hypnotic,-anxiolytic-and-anticonvulsant- actions c. The-BZD-receptor-is-homogeneous-at-all-neuronal-sites- d. The-muscle-relaxant-action-of-BZDs-is-not-blocked-by- flumazen

18. 4.The key structural feature that differentiates Z-drugs like Zolpidem from benzodiazepines is: a) Presence of a diazepine ring b) Modulation of the 𝐺𝐴𝐵𝐴𝐴 receptor at a different binding site c) Substitution of a sulfur atom for oxygen d) An imidazole or pyrrolopyrazine ring structure 5.Which of the following drugs is a benzodiazepine that is primarily metabolized by glucuronide conjugation, making it a preferred choice in patients with hepatic impairment? a) Diazepam b) Flurazepam c) Lorazepam d) Alprazolam 6.Which of these is a long-acting sedative-hypnotic? a) Alprazolam b) Diazepam c) Temazepam d) Secobarbital 

19. 7.Barbiturates primarily act on the receptor by: a) Increasing the frequency of chloride channel opening b) Increasing the duration of chloride channel opening c) Functioning as a competitive antagonist at the GABA site d) Directly blocking the chloride channel  8 .The mechanism of action of benzodiazepines involves binding to a specific site on the 𝐺𝐴𝐵𝐴𝐴 receptor, leading to: a) Reduced chloride influx into the neuron b) Hyperpolarization and CNS depression c) Increased sodium influx, causing CNS stimulation d) Binding at the GABA binding site itself