lecture 3 barbiturates as sedatives and hypnotics.pptx

lecture in medicinal chemistry of Barbiturates as sedatives and hypnotics. structure activity relationship. lipophilicity and pharmacokinetic profile. non barbiturate derivatives and their categories such as glutethimide, meprobamate, chloral hydrate and mephensine as musculoskeletal relaxant

1. [iv] Barbiturates

2. [iv] Barbiturates The barbiturates were used extensively as sedative–hypnotic drugs. Except for a few specialized uses, they have been replaced largely by the much safer benzodiazepine. They exert most of their characteristic CNS effects mainly by binding to an allosteric recognition site on GABA A receptors as positive modulators. Unlike benzodiazepines, they bind at different binding sites and appear to increase the duration of the GABA-gated chloride channel openings. By binding to the barbiturate modulatory site, barbiturates can also increase chloride ion flux without GABA attaching to its receptor site on GABA A . This has been termed a GABA mimetic effect.

3. Barbiturates are derivatives of barbituric acid (2,4,6-trioxohexahydropyrimidine). Barbituric acid is a relatively strong acid (≈ 5 × AcOH ). Barbituric acid is mainly ionized at physiological pH 7.4, with little nonionic lipid-soluble compound available to cross the blood-brain barrier. The basis of the acidity is the pH-dependent tautomerization referred to as the lactam- lactim tautomerism. Lactam- lactim tautomerism in barbituric acid.

4. Why is barbituric acid acid inactive? Barbituric acid is biologically inactive due to poor physicochemical properties (hydrophile-lipophile balance). ❖ However, di-alkylation at position 5 confers pharmacological activity. ➢ All pharmacologically active barbiturates are disubstituted at position 5. ❖ Disubstitution at position 5 decreases acidity since the ability to resonate is decreased. ➢ The 5,5-disubstituted barbiturates are weak acids. ➢ They also exhibit lactam- lactim tautomerism.

5. Barbiturates and salt formation • Tautomerism enables formation of soluble salts with alkali and alkali-earth metals. • They are usually formulated as sodium salts.

6. How do they work? They enhance GABAergic inhibitory response, in a mechanism similar to benzodiazepines (i.e., by increasing the duration of opening the chloride channel). Barbiturates have the ability to induce liver microsomal enzymes that lead to increased rate of biotransformation of many commonly used drugs, including barbiturates themselves

7. ☼ SAR: Hypnotic activity. Side chains at position 5 (especially if one of them is branched) is essential for activity.

8. ☼ SAR: Both the hydrogen atoms at 5th position should be replaced because if one hydrogen is available at position 5, tautomerization to a highly acidic trihydroxypyrimidine ( pKa ~ 4) can occur.

9. ☼ SAR: In general, increasing lipophilicity increases hypnotic potency with rapid onset and short duration of action due to redistribution and ease of metabolism. Beginning with lower alkyls, there is a rapid onset and a decrease in duration of action with increasing hydrocarbon content up to about seven to nine total carbon atoms substituted on the 5-position.

10. ☼ SAR: The inclusion of polar functional groups at the 5-position resulted in compounds that were fully devoid of sedative hypnotic or anticonvulsant activity

11. ☼ SAR: N- methylation increases lipophilicity leading to quicker onset and shorter duration of action

12. ☼ SAR: Replacement of Sulfur instead of oxygen atom at position 2 has more rapid onset of action but shorter duration due to increasing lipophilicity.

13. Metabolism Barbiturates are mainly metabolized in liver by the following routes:-  -oxidation of the alkyl groups at C-5. N- dealkylation of the N-alkyl barbiturates e.g., Mephobarbital and Methabarbital

14. Metabolism Desulfuration of the 2-thione group of thiobarbiturates e.g., thiopental Hydroxylation at the para position of the phenyl ring of 5-phenyl barbiturates e.g., phenobarbital The resulting metabolites are mainly inactive and polar compounds that can readily be excreted

15. Metabolism

16. Side effects of Barbiturates The abuse of barbiturates leads to: Tolerance, Psychic and physical dependence. Drowsiness Overdose can produce hypotension, tachycardia, respiratory depression, coma and death. Accordingly, barbiturates have been largely replaced by the much safer benzodiazepines

17. [v] Selective serotonin receptor agonist Serotonin receptors have been the focus of intensive research in recent years, because preclinical and clinical evidence supports the involvement of serotonin in anxiety. Serotonin 5-HT 1A receptors are found in relatively high density in the midbrain region, which is involved in the modulation of anxiety. Buspirone The pyrimidinylbutylpiperazine derivative, buspirone is a partial agonists on 5-HT 1A receptors in the midbrain. It is a selective anxiolytic with no sedative or hypnotic effect. The anxiolytic effects appear after 10 -14 days. The anxiolytic drug of choice for elderly patient. No physical dependance. Never taken with SSRI due to risk of serotonin syndrome.

18. [vi] Miscellaneous

19. A) Amides and Imides: Glutethimide: ( Doriden ) It is one of the most active non barbiturate hypnotics that is structurally similar to the barbiturates, especially phenobarbital. Glutethimide is a hypnotic sedative that was introduced in 1954 as a safe alternative to barbiturates to treat insomnia. Before long, however, it had become clear that glutethimide causes addiction and similar withdrawal symptoms. Manufacturing of the drug was discontinued in the US in 1993. Glutethimide is a CYP2D6 enzyme inducer. When taken with codeine, it enables the body to convert higher amounts of the codeine to morphine. The general sedative effect of the glutethimide also adds to the effect of the combination. It produces an intense, long-lasting euphoria similar to IV heroin use.

20. B) Alcohols and their Carbamate derivatives: 1- Mephenesin 2- Mephenesin carbamate 3- Chlorphenesin carbamate t he prototype . Weak activity &short duration  due to rapid metabolism of OH. m ore active > Mephenesin (OH is protected  Carbamoylation  activity). P-Chlorination   lipophilicity & block P-position hydroxylation.

21. Meprobamate Launched in 1955, it rapidly became the first blockbuster psychotropic drug in American history. It was revealed that the sale of meprobamate earned $40,000,000 by 1970, meprobamate was listed as a controlled substance after it was discovered to cause physical and psychological dependence.

22. Ethchlorvynol Ethchlorvynol is a GABA receptor agonist and central nervous system depressant with anxiolytic, sedative, and hypnotic developed by Pfizer in the 1950s. In the United States it was sold by Abbott Laboratories under the trade name Placidyl Abbott discontinued production in 1999 due to problems of the widespread abuse of the substance, and substances within benzodiazepine family (with drugs such as Librium and Valium)

23. ☼ MOA: Act on GABA receptors  [bind to another site than barbiturates & BZP]. All enhance GABA inhibitory effect centrally. ☼ Advantage: NOT cause respiratory center depression. ☼ Disadvantage: Unpleasant odour & taste. GIT irritant  nausea & vomiting.

24. Thank You