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CNS depressants CNS depressants can be classified into: I- Sedative hypnotics II- Anxiolytic drugs III- CNS depressants with skeletal muscle relaxant properties.

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Presentation on theme: "CNS depressants CNS depressants can be classified into: I- Sedative hypnotics II- Anxiolytic drugs III- CNS depressants with skeletal muscle relaxant properties."— Presentation transcript:

1 CNS depressants CNS depressants can be classified into: I- Sedative hypnotics II- Anxiolytic drugs III- CNS depressants with skeletal muscle relaxant properties IV- Anticonvulsants V- Antipsychotics I- Sedative hypnotics - Can be used to overcome insomnia (restlessness) - Cause drowsiness, initiation and/or maintenance of sleep - Pharmacological effects are dose related: Dose: ↑ Sedation ► Hypnosis ► Surgical anesthesia - No common structural features, include: 1- Barbiturates. 2- Chloral. 3- Ureides. 4- Piperidinediones. 5- Cyclopyrrolones 6- Imidazopyridines. 7- Benzodiazepines 8- Melatonin Receptor Agonist 9- Antihistamines 1

2 1- Barbiturates The barbiturates are 5,5-disubstituted barbituric acids. For good hypnotic activity, barbituric acid derivatives must be weak acids. They must have lipid/water partition coefficient between certain limit. The acidity of the barbiturates in aqueous solution depends on the number of substituents attached to barbituric acid. 2

3  MOA: Enhance the GABA-ergic inhibitory response (as Benzodiazepines).  S.E. Slowly eliminated barbiturates: hangover (overshadow) & psychomotor impairment (injury).  Now barbiturates get minimal use as sedatives & hypnotics (Why?) 1.They have higher toxicity, that cause greater CNS depression. 2.They induce many of the liver metabolizing enzymes. 3.Barbiturates cause tolerance and, often physical dependence. N.B.: When an individual addicted to barbiturates, sudden withdrawal should be avoided, because it can cause grand mal seizures, which lead to a spasm of the respiratory musculature, producing impaired respiration, cyanosis, and possibly death. 3

4 SAR: 5,5,-disubstituted & 1,5,5- trisubstituted are active 1,3-disubstituted or 1,3,5,5- tetrasubstituted are inactive or produce convulsions All other substitution ► inactive * Replacement of C-2 O by S → ↑ lipid solubility. Thiopental used as IV anesthetics due to rapid onset & quick brain levels achieved. * Introduction of more sulfur atoms (2,4-dithio derivatives) destroys potency, due to decreased hydrophilic character beyond required limits. 4

5 Substitution on nitrogen:  Substitution on one NH by alkyl gp ↑ lipid solubility ►quicker onset & shorter duration  As the N-alkyl increases in size, the lipid solubility increases, But larger alkyl groups ( > methyl) ► convulsant properties.  Alkyl substitution on both N 1 & N 3 renders the drug nonacidic (inactive). 5,5-Disubstitution: 1.Both substituents shoud be between 6-10 carbon. 2.Branching, unsaturation, replacement of alkyl with alicyclic or aromatic substituents, ↑ the lipid solubility leading to high potency. 3.Introduction of a halogen atom into the 5-alkyl substituent ↑ the potency. 4.Introduction of polar groups e.g. OH, NH 2, RNH, CO, COOH and SO 3 H into the 5-alkyl substituent ↓ the lipid solubility (may destroy potency). For hypnotic activity, the compound must be a weak acid with suitable log P. 5

6 6 Classification Barbiturates are classified according to their duration of action into: Long duration of action (> 6 hours). Intermediate duration of action (3-6 hours). Short duration of action (< 3 hours). Ultrashort duration of action (intravenous anesthetics). Onset up to 1 hour lasts about 12 hours used for ; daytime sedation seldom used. - treatment of seizure disorders Daytime Sedatives and Typical Anticonvulsants Long-Acting Barbiturates

7 7 used for : - insomnia. - preoperative sedation. - Anesthesia and euthanasia in animals Sedatives and Hypnotics used for - preoperative sedation. - insomnia (seldom used). Typical Sedatives and Hypnotics thiocarbonyl and C-5 side chain with 5 carbon unit (ethyl or allyl e.g. Thiamylal CH 2 CH=CH 2 ) D. Ultra-Short-Acting Barbiturates Thiopental Induction Anaesthesia

8 Synthesis of Barbiturates 8 Barbiturate Abuse: Prolonged use leads to habituation, (tolerance to increased doses and physical dependence). Monooxygenase enzyme synthesis is increased by repeated dose of phenobarbital (enzyme induction), therefore the drug will be rapidly metabolized leading to tolerance.

9 Barbiturates - Metabolism Oxidation of substituent at C- 5 by CYP450’s Most Barbiturates Aromatic Hydroxylation Phenobarbital Mephobarbital Slide 6 Glucuronide and sulfate conjugates An ultimate (Ω) or penultimate (Ω-1) oxidation of C-5 substituents

10 Barbiturates - Metabolism Desulfuration Thiobarbiturates N-Methylbarbiturates N-Dealkylation Slide 7 mephobarbital phenobarbital Desulfuration of 2-thiobarbiturates to yield more hydrophilic barbiturates

11 Barbiturates - Metabolism hepatic metabolic inactivation N-oxidation Hydrolysis Most Barbiturates Slide 5

12 12 Prolonged effect Inactive metabolite Init. effect  Has no analgesic or tranquilizing effect & devoid of adverse respiratory effects  A weak acid (electron-withdrawing CCl 3 group) ► irritating to stomach.  MOA: Trichloroethanol has barbiturate-like effects on the GABA A receptor.  Metabolism: 1. Quickly reduced to trichloroethanol (hypnotic activity). 2. Quickly detoxified to the inactive trichloroacetic acid. 2- Chloral (Chloral hydrate) Trichloroacetaldehyde monohydrate

13 13 3- Ureides  Only Acetylcarbromal ( 1-Acetyl-3-(2-Bromo-2-ethyl- butyryl)-urea ) is still available.  Prolonged use is not recommended due to in vivo release of bromide ions (bromism) 4- Piperidinediones e. g. Methyprylon 3,3-diethyl-5-methyl-2,4- piperidinedione  They are effective sedative-hypnotics, structurally related to barbiturates (Hence, many biological respects). 5- Cyclopyrrolones e. g. Zopiclone  A new hypnotic agent with no withdrawal symptoms (no accumulation on repeated administration). Metabolism: Major: less active, zopiclone N-oxide Minor: inactive, N-desmethylzopiclone

14 14 6- Imidazopyridines e. g. Zolpidem  short t 1/2 (rapid metabolic oxidation to inactive COOH acid metabolites. Nonbenzodiazepine GABA A Agonists: [Z drugs] zopiclone & zolpidem Advantages:  They are used as short-acting sedative-hypnotics.  They have high-affinity for GABA A receptors ~ to benzodiazepines.  They are highly lipophilic, so rapid absorption & distribution.  They have very little physical dependence & abuse potential.

15 7- Benzodiazepines MOA: bind to specific binding sites in GABA A receptors.  Used as anxiolytics, hypnotics, anticonvulsants and muscle relaxants. Advantages: Over Barbiturates:  Relative safety (no respiratory depression). Preferred for patients with suicidal intentions. Fewer drug interactions. Disadvantages:  Slowly eliminated due to active metabolites in blood and brain (hangover effect and accumulation on repeated dose). 15

16 8- Melatonin Receptor Agonist  It is effective in initiating sleep (shortening sleep latency) but not in maintaining sleep (has short half-life).  It is a very potent & very selective ligand for the MT 1 receptor  used in the treatment of insomnia.  Does not bind with other receptors associated with sleep (GABA A or dopamine). MT receptor play important role in discovery and approval of ramelteon. Ramelteon 16


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