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CNS depressants I- Sedative hypnotics

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1 CNS depressants I- Sedative hypnotics
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 Chloral Ureides Piperidinediones. 5- Cyclopyrrolones Imidazopyridines Benzodiazepines 8- Melatonin Receptor Agonist Antihistamines

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.

3 Enhance the GABA-ergic inhibitory response (as Benzodiazepines). S.E.
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?) They have higher toxicity, that cause greater CNS depression. They induce many of the liver metabolizing enzymes. 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. T

4 5,5,-disubstituted & 1,5,5-trisubstituted are active
SAR: All other substitution ► inactive 1,3-disubstituted or 1,3,5,5-tetrasubstituted are inactive or produce convulsions * 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.

5 Both substituents shoud be between 6-10 carbon.
5,5-Disubstitution: Both substituents shoud be between 6-10 carbon. Branching, unsaturation, replacement of alkyl with alicyclic or aromatic substituents, ↑ the lipid solubility leading to high potency. Introduction of a halogen atom into the 5-alkyl substituent ↑ the potency. Introduction of polar groups e.g. OH, NH2, RNH, CO, COOH and SO3H 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. 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 N1 & N3 renders the drug nonacidic (inactive).

6 Daytime Sedatives and Typical Anticonvulsants
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 Long-Acting Barbiturates Mephobarbital metabolically N-dealkylated to phenobarbital slow onset (30-60 min), relatively long duration (10-16h) relatively low lipophilicity and low plasma protein binding (<40%) Daytime Sedatives and Typical Anticonvulsants

7 Sedatives and Hypnotics Typical Sedatives and Hypnotics
used for : - insomnia. - preoperative sedation. - Anesthesia and euthanasia in animals Sedatives and Hypnotics used for - preoperative sedation. - insomnia (seldom used). Typical Sedatives and Hypnotics D. Ultra-Short-Acting Barbiturates thiocarbonyl and C-5 side chain with 5 carbon unit (ethyl or allyl e.g. Thiamylal CH2CH=CH2) Induction Anaesthesia Thiopental

8 Barbiturate Abuse: Synthesis of Barbiturates
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
An ultimate (Ω) or penultimate (Ω-1) oxidation of C-5 substituents Oxidation of substituent at C- 5 by CYP450’s Most Barbiturates Barbiturates lose their activities through metabolic transformation in the liver. In the course of metabolism the lipophilic character decreases which will diminish the concentration of the barbiturates in the cerebral tissues with loss in depressant activity. Aromatic Hydroxylation Phenobarbital Mephobarbital Glucuronide and sulfate conjugates Slide 6

10 Barbiturates - Metabolism
Desulfuration Thiobarbiturates N-Methylbarbiturates N-Dealkylation Slide 7 Desulfuration of 2-thiobarbiturates to yield more hydrophilic barbiturates N-demethylation does not proceed rapidly and excreted slowly therefore the produced metabolite accumulates with the N-alkylated barbiturates. During the course of mephobarbital therapy a definite blood level of phenobarbital has been established mephobarbital phenobarbital

11 Barbiturates - Metabolism
N-oxidation Most Barbiturates Hydrolytic cleavage of the ring leads to the formation of acetamide or dialkylacetylurea Hydrolysis Most Barbiturates hepatic metabolic inactivation Slide 5

12 2- Chloral (Chloral hydrate)
Trichloroacetaldehyde monohydrate Has no analgesic or tranquilizing effect & devoid of adverse respiratory effects A weak acid (electron-withdrawing CCl3 group) ► irritating to stomach. MOA: Trichloroethanol has barbiturate-like effects on the GABAA receptor. Metabolism: 1. Quickly reduced to trichloroethanol (hypnotic activity). 2. Quickly detoxified to the inactive trichloroacetic acid. Init. effect Inactive metabolite Prolonged effect

13 3- Ureides 4- Piperidinediones 5- Cyclopyrrolones
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 6- Imidazopyridines e. g. Zolpidem short t1/2 (rapid metabolic oxidation to inactive COOH acid metabolites. Nonbenzodiazepine GABAA Agonists: [Z drugs] zopiclone & zolpidem Advantages: They are used as short-acting sedative-hypnotics. They have high-affinity for GABAA receptors ~ to benzodiazepines. They are highly lipophilic, so rapid absorption & distribution. They have very little physical dependence & abuse potential.

15 7- Benzodiazepines Advantages: Over Barbiturates: Disadvantages:
MOA: bind to specific binding sites in GABAA 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).

16 8- Melatonin Receptor Agonist
MT receptor play important role in discovery and approval of ramelteon. Ramelteon 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 MT1 receptor used in the treatment of insomnia. Does not bind with other receptors associated with sleep (GABAA or dopamine).

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