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Sedative and hypnotics
- 1. SEDATIVE AND HYPNOTICS BENZODIAZEPINES AND BARBITURATES
- 2. SEDATIVE • A drug which reduce excitement and calms the patient(without inducing sleep) • Sedative as therapeutc dose are anxiolytics agent. • Most sedative in large dose produces hypnosis. • Site of action on limbic part of brain which controls thoughts and mental health HYPNOTIC • A drug which produces the resembling sleep as natural sleep. • They are initiation and/or maintenance of sleep. • Hypnosis in higher dose produces general anesthesia. • Site of action on mid brain and ascending RAS which controls weakfulness.
- 3. There are main two types of sleep 1 (rapid eye movement) 2(non rapid eye movement)
- 4. Sedative and hypnotics Miscellaneous Anxiolytics Antidepresent Buspirone Hypnotics Z drugs Antihistaminics doxepins Benzodiazepines +short acting +intermediate +long acting Barbiturates +ultra short action +short action +long action
- 5. BARBITURATES Ultra short acting -thiopentone -methohexitone Short acting - pentobarbitone -butobarbitone Long acting - phenobarbitone (also use in epilepsy and neonatal juandice)
- 8. 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 Category 1 Category 2 Category 3 alcohol and barbiturat es benzodiaz epines Anesthesia Hypnosis Sedative Coma Death
- 10. Benzodiazepines: frequently opens and close Cl channel Barbiturates :increases duration of GABA gated Cl ion channel
- 11. SAR OF BARBITURATES (STRUCTURAL ACTIVITY RELATIONSHIP) • In order to posses good hypnotic activity a barbiturate must weak acid and should have high lipid water partition co-efficient. • 5,5-disubstituted barbituric acid derivative (ACTIVE). • 1,5,5-trisubstituted barbituric acid derivatives(ACTIVE). • 1,3,5,5-tetrasubstituted barbituric acid derivative (INACTIVE)(PRODUCE SIDE EFFECT CONVULSANT)(NOT ACIDIC). • If we replace O by S on 2nd position then we get derivative which have high lipid solubility. • And given via I.V due to fast onset of action and quick brain achived. • But if we do more substitution of S the structure will be less hydrophilic and decreases potency and get destroy. Chemical structure
- 12. SAR OF BARBITURATES To introduce hypnotic activity into barbituricacid we have to do addition of side chain at least one should be branched on 5th position. 5th position has to contain two substitution. ACID unsubstituted>disubstituted and do not compress CNS. Unionized drug can penetrate the membrane. If we attach aryl or alkyl group on 5th position of carbon it will effect acidity(decreases) of structure and do effect on lipophilicity. If we do introduce polar groups like carbonyl,hydroxyl,amino,keto,ether as side chain It usually destroy the CNS depressant effect. The length of side chain on 5th position also effect the potency and duration of action of derivatives. EX/secobarbital and tiamylal more potent than pentobarbital and thiopental. If we replace sulfur atom with oxygen atom on 2nd it will give fast onset of action and shorter duration of action. If we do methylation on 1 position the methohexital get produced and it not only get rapid onset of action but also increases side effects because modification therefore modification of drug increases lipophilicity of a hypnotic barbiturate generally increases potency and onset of action which is short duration of action.
- 13. Long duration of action phenobarbital more than 6 hours Intermediate amobarbital 3 to 6 hours Short action thiopental and pentobarbital less than 3 hours METABOLISM Occurs primarily in the liver where through metabolism the lipophilic nature decreases through Oxidation of substituents at 5th C Hydrolytic cleavage of barbitalring with formation of acetamide Desulferation of 2-thiobarbital
- 15. Adverse effect 1.CNS:BARBITURATES cause drowsiness,impaired concentration 2.DRUG HANGOVAR: hypnotic dose of barbiturates produce a feeling of tiredness well after the patient wakes 3.Barbiturates induce P450 system monooxygenase clearance 4 by inducing aminolevulinic acid (ALA) synthase barbiturates increases prophyrin synthesis and are contraindication in patients with acute intermittent prophyria(ABNORMAL METABOLISM OF BLOOD PIGMENTS HEAMOGLOBIN).
- 16. SAR OF BENZAZEPIN (STRUCTURAL ACTIVITY RELATIONSHIP) DIAZEPAM • Presence of an electron attracting substituent at position 7 is required for activity • Position 6,8and 9 should not be substituted • A phenyl group at 5th position promotes activity if this is ortho or di orhto substituted with electron attracting groups activity is increased • On the other hand para substitution decreases activity of agent • The 2 carbonyl function is optimal for activity as in the nitrogen atom at 1st position • The n-substitution should be small. Chemical structure
- 17. Substitution with alkyl group on 3rd position decreases the activity but substitution with OH group doesn’t. This hydroxyl affects the pharmacokinetics of the drug. Truly compound that doesn’t contains OH group on 3rd position are Non polar and have long duration of action and under go hepatic oxidation whereas compounds possesing the 3-OH group are more polar and are rapidly conjugated are excreted . 2 carbonyl function is optimal for the activity as is the nitrogen atom at position 1,the n-substituent should be small. On the other hand there were obtained compound with fused triazole ring represent by triazole and alprazolam with the fused imidazole in this ring in these the prescence of the 7-electron withdrawing group is not require for activity.
- 19. Clinical uses of benzodiazepines sedative-hypnotics Seizure control anxiety Alcohol withdrawal Insomia Muscle relaxant Anesthesia Combination with others for sedation