CNS depressants CNS depressants can be classified into :

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 maintenanceof 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

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. MOA: • Enhance the GABA-ergic inhibitory response(as Benzodiazepines). • S.E. • Slowly eliminated barbiturates: hangover (overshadow) & psychomotor impairment (injury). • Nowbarbituratesget 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, producingimpaired respiration, cyanosis, • and possibly death.

4. 5,5,-disubstituted & 1,5,5-trisubstituted areactive SAR: All other substitution► inactive 1,3-disubstituted or 1,3,5,5-tetrasubstituted are inactiveor produce convulsions * Replacement of C-2ObyS → ↑ 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. 5,5-Disubstitution: • Both substituents shoud be between6-10 carbon. • Branching, unsaturation, replacement of alkyl withalicyclic 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 the5-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 & N3renders the drug nonacidic (inactive).

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

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 D. Ultra-Short-Acting Barbiturates • thiocarbonyl and C-5 side chain with 5 carbon unit • (ethyl or allyl e.g. Thiamylal CH2CH=CH2) Thiopental Induction Anaesthesia

8. Synthesis of Barbiturates Barbiturate Abuse: • Prolonged useleads to habituation, (tolerance to increased doses and physical dependence). • Monooxygenaseenzymesynthesis is increased by repeated dose of phenobarbital (enzyme induction), therefore the drug will be rapidly metabolizedleading totolerance.

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 Aromatic Hydroxylation Phenobarbital Mephobarbital Glucuronide and sulfate conjugates Slide 6

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

11. Barbiturates - Metabolism N-oxidation Most Barbiturates 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 • OnlyAcetylcarbromal(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.Methyprylon3,3-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 • MOA:bind to specific binding sites in GABAA receptors. • Used as anxiolytics, hypnotics, anticonvulsants and muscle relaxants. • Advantages:OverBarbiturates: • Relative safety (no respiratory depression). Preferredfor 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).