Sedative and hypnotics

Drugs action on CNS

1. Sedatives and hypnotics K. Neha Research Scholar

2. Introduction Sedative drugs Hypnotics drugs -reduces excitement, calms the patient -produces sleep -used as anxiolytic agents -used for initiation/maintenance of sleep -at higher doses, produces hypnosis -at higher doses, act as general anaesthesia -act on limbic system (regulation of thoughts and mental function) -act on mid brain and ascending RAS -slow acting drug -quicker onset Sedatives are drugs that decrease activity and have a calming, relaxing effect. People use these drugs mainly to reduce anxiety. At higher doses, sedatives usually cause sleep. Drugs used mainly to cause sleep are called hypnotics . Sedative and hypnotic drugs are used in the treatment of insomnia and anxiety . Barbiturates & Benzodiazepines are widely used as sedative & hypnotic.

3. Classification of sedative and hypnotics Pharmacological effects Depresses all functions of the brain. Selectively depresses the motor cortex. Depresses the respiratory center in medulla. Produce good muscle relaxation. Decreases blood pressure and heart rate. Induce microsomal enzymes and increase the metabolic rate of the animal.

4. Benzodiazepines Benzodiazepines are useful for treating insomnia and anxiety. They are the class of medications that work in the central nervous system and are used for a variety of medical conditions . It increase the action of GABA neurotransmitter on its receptor which causes influx of chloride ion into the neuronal cells leading to depression of the CNS . Classification of Benzodiazepines: Based on duration of action: A long duration of action: ( 1-3 days) e.g : Diazepam, Nitrazepam An intermediate of action: ( 10-20 hours) e.g : Alprazolam, Lorazepam . A short duration of action: ( 3-8 hours) e.g : Oxazepam , Triazolam .

5. Structure Activity Relationship (SAR) of benzodiazepines Ring A The presence of an electron attracting substituent at position 7 is required for activity Position 6,8 and 9 should not be substituted Replacement of ring A with heterocyclic ring reveals weak activity and affinity. Ring B The 2 carbonyl function is optimal for activity as in the nitrogen atom at 1 position. Substitution 3-position methylene or imine nitrogen is sterically unfavorable The N-substituent should be small . Ring C A phenyl group at the 5 position promotes activity if this group is ortho or di ortho substituted with electron attracting groups , activity is increased. On the other hand , para substitution decreases activity greatly. A B C

6. Chlordiazepoxide Trade name: Librium White crystalline powder S oluble in ethanol and very slightly soluble in water S hows polymorphism U sed as sedative and hypnotic. Synthesis:

7. Diazepam Brand name: Z ycalm White crystalline powder S oluble in ethanol and very slightly soluble in water U sed as a skeletal muscle relaxant, anticonvulsant and antianxiety agent Drug given once or twice a day as it take long time to achieve sedative and antianxiety effects. Synthesis:

8. Oxazepam Trade name: Serax White crystalline powder S lightly soluble in ethanol and insoluble in water Useful for acute tremulousness, inebriation, or anxiety associated with alcohol withdrawal Side effects include rashes, nausea, lethargy, oedema , slurred speech, tremor, and altered libido. More severe reactions include leucopenia and jaundice. Synthesis:

9. Clorazepate Brand name:  Tranxene Used as a sedative and hypnotic. Common adverse effects are cognitive impairment, confusion, anterograde amnesia, falls in the elderly, ataxia, hangover effects, and drowsiness . Synthesis: used in the form of di-potassium salt.

10. Lorazepam Brand name: Ativan White crystalline powder Shows polymorphism I nsoluble in water, sparingly soluble in ethanol and methylene chloride Used as sedative and hypnotic M ore polar than diazepam ( uncomplicated metabolism, short acting). Synthesis:

11. Alprazolam Brand name: Xanax White crystalline powder Shows polymorphism Management of insomnia P ractically insoluble in water, freely soluble in methylenechloride and sparingly soluble in acetone and in alcohol. Short acting and highly potent anxiolytic in milligram doses. Synthesis:

12. Zolpidem Brand name: Ambien White crystalline powder H ygroscopic in nature Slightly soluble in water, sparingly soluble in methanol, and insoluble in methylene chloride. I midazopyridine agent and agonist of benzodiazepine α1 receptor (subunit of GABA-A receptor) Used for insomnia . Synthesis:

13. Adverse effects of benzodiazepines Light-headedness Fatigue Increased reaction time Motor incoordination Impairment of mental and motor functions Confusion Antero -grade amnesia Cognition appears to be affected less than motor performance. All of these effects can greatly impair driving and other psychomotor skills, especially if combined with ethanol.

14. Barbiturates Barbiturates are an old class of drugs used to relax the body and help people sleep . Potentiate the effect of GABA neurotransmitter leading to depression of the brain and inhibits excessive motor discharge. Classification of Barbiturates: Based on duration of action: A long duration of action: (6 hours or more) e.g : Barbital, Phenobarbital. An intermediate duration of action: (3 to 6 hours ) e.g : Amobarbital , Talbutal . A short duration of action: (less than 3 hours) e.g : Pentobarbital, Secobarbital .

15. Structure Activity Relationship (SAR) of Barbiturates Both hydrogen atoms in position 5 of barbituric acid must be replaced for maximal activity. Increasing the length of an alkyl chain in the 5 position enhances potency up to 5 or 6 carbon atoms. Branched , cyclic or unsaturated in the 5 position generally produce a briefer duration of action than do normal saturated chains containing the same number of carbon atoms. Compounds with alkyl groups in the 1 or 3 position may have a shorter onset & duration of action. Replacement of oxygen by sulfur on the 2 carbon shortens onset & duration of action. 1 3 2 4 5 6

16. Barbital/ barbitone Brand name: Veronal White crystalline powder or colorless crystals S oluble in boiling water and in alcohol F orms water-soluble salts with sodium hydroxide Powerful hypnotic drug and generally used of epileptic seizures . Synthesis:

17. Phenobarbital T rade name: Luminal White crystalline powder Hygroscopic substance Freely soluble in water and alcohol Used as sedative, hypnotic, antiepileptic, nervous and related tension states O verdose can result in coma, severe respiratory depression, hypotension leading to cardiovascular collapse and renal failure. Synthesis:

18. Mephobarbital Brand name: M ebaral White crystalline powder Odorless with a bitter taste, and a saturated is solution acid to litmus Soluble in water, alcohol, chloroform and in solutions of alkali hydroxides or carbonates Strong sedative with anticonvulsant action, mild hypnotic. Synthesis:

19. Amobarbital Trade name: Amytal White crystalline powder N o odor and a slightly bitter taste. Used as sedative and hypnotic at different dose intervals. S ide effects of overdose include confusion, decrease in or loss of reflexes, drowsiness, fever , irritability, low body temperature, slurred speech, staggering, poor judgment, shortness of breath, slow heartbeat, trouble in sleeping, unusual movements of the eyes. Synthesis:

20. Butabarbital B rand name: Butisol Highly potent Fast onset of effects and short duration of action. Used as a sedative and hypnotic, especially for insomnia. Adverse effect include a pnea, night terrors and sleep disturbances, headache, dizziness, agitation or nervousness, confusion, nausea, vomiting, constipation, hallucinations, ataxia, bradycardia , hepatotoxicity, hypoventilation, fainting, rash, psychiatric disturbance Synthesis:

21. Pentobarbital B rand name:  Nembutal White crystalline powder Hygroscopic in nature Very soluble in water Used as a sedative or hypnotic Pre- anaesthetic medication, used in the management of strychnine poisoning Reduces cerebral blood flow and thereby, decrease oedema and intracranial pressure. Synthesis:

22. Secobarbital Brand name: Seconal White , hygroscopic powder Bitter in taste pH found between 9.7 and 10.5 Soluble in water and alcohol Used in status epilepticus and as local anaesthetic . Synthesis:

23. Adverse effects of barbiturates CNS: Barbiturates cause drowsiness, impaired concentration. Drug hangover: Hypnotic doses of barbiturates produce a feeling of tiredness well after the patient wakes. Barbiturates induce the P450 system. By inducing Aminolevulinic acid (ALA) synthetase , barbiturates increase porphyrin synthesis, and are contraindicated in patients with acute intermittent porphyria . Serious allergic reactions Paradoxical excitement Respiration depression Hypotension Cardiovascular collapse

24. Miscellaneous Amides and imides Gluthmide Alcohol and their carbamate derivatives Meprobomate Ethchlorvynol Aldehyde and their derivatives Triclofos sodium paraldehyde

25. Glutethimide  B rand name: Doriden    Hypnotic drug to induce sleep without depressing respiration. CYP2D6 enzyme inducer. Over dosage is less likely to depress respiration, but more likely to cause hypertension than most other barbiturates. Adverse reactions includes rashes, rarely nausea, hangover, paradoxical excitation and blurred vision. Extended use can cause delirium , hallucinations, convulsions and fever . Synthesis:

26. Meprobamate Trade name: Miltown White amorphous or crystalline powder S lightly soluble in water and freely soluble in alcohol. Used in the management of anxiety disorders. It is also a centrally acting skeletal muscle relaxant. Its overdose can cause drowsiness , headache, sluggishness, unresponsiveness, or coma; loss of muscle control; severe impairment or cessation of breathing; or shock . Synthesis:

27. Ethchlorvynol   Trade name:   Placidyl Also possesses muscle relaxant and anticonvulsant properties Adverse effects includes suppression of rapid eye movement sleep, ataxia, and hypotension. Overdose can cause confusion , fever, peripheral numbness and weakness, reduced coordination, slurred speech, reduced heartbeat, respiratory depression, and in extreme overdoses, coma and death. Synthesis:

28. Triclofos sodium Brand name: F oskid White powder Hygroscopic in nature . Freely soluble in water, slightly soluble in ethanol, practically insoluble in ether. Used as hypnotic . Triclofos is a  prodrug ,  which is metabolised in the liver into the active drug  trichloroethanol .  It decreases the time taken to fall asleep and increases sleep duration. Side effects may include: headache, rash, dizziness, flatulence, confusion, nightmares, dependence, diarrhoea, constipation, nausea, vomiting, abdominal pain, and ataxia.

29. Paraldehyde Brand name: Paral Colorless or slightly yellow transparent liquid. Solidifies on cooling to form a crystalline mass. Miscible with alcohol, essential oils and soluble in water, Used for patients undergoing alcohol withdrawal. CNS depressant activity look like that of alcohol and chloral hydrates. Synthesis:

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