General Anaesthesia (Medicinal Chemistry)

General anaesthetics are group of drugs that produces loss of consciousness, and therefore, loss of all sensations.
The absolute loss of sensation is termed as anaesthesia.

1. 4/29/2020 1 GENERAL ANAESTHETICS Yogesh Tiwari M Pharma (Pharmaceutics) Assistant Professor VIPER, Sagar (MP)

2. CONTENT INTRODUCTION STAGES OF ANAESTHESIA TYPES OF GENERAL ANAESTHETICS MODE OF ACTION SYNTHESIS , PROPERTY AND USES 4/29/2020 2

3. education school college “Poisons and medicine are often the same substance given with different intents.” Astrology Religious Literature 4/29/2020 3

4. INTRODUCTION General anaesthetics are group of drugs that produces loss of consciousness, and therefore, loss of all sensations. The absolute loss of sensation is termed as anaesthesia. These drugs are used in surgical operations to induce unconsciousness and, therefore, abolish the sensation of pain. 4/29/2020 4

5. Cont….. In 1844, Horace Wills (dentist) successfully used N2O as an anaesthetic for tooth extraction In 1847, chloroform was used. The first intravenous anaesthetic , thiopentone , was introduced in 1935. The ligand -gated ion channels are the major target of anaesthetic action. 4/29/2020 5

6. STAGES OF ANAESTHESIA 4/29/2020 6

7. Cont….. 1. Stage I ( analgesia):- The patient is conscious and experience sensations of warmth, remoteness, drifting, falling, and giddiness. This stage is often used in minor surgery. 2. Stage II ( delirium):- This stage begins with the loss of consciousness. Depression of higher centres produces variety of effects including excitement, involuntary activity 4/29/2020 7

8. Cont….. 3. Stage III ( surgical anaesthesia):- This is the stage of unconsciousness and paralysis of reflexes, respiration is regular and blood pressure is maintained All surgical procedures are carried out in this stage. 4. Stage IV ( Medullary paralysis): Respiratory and circulatory failures take place as a result of the depression of the vital centres of the medulla, and brain stem occurs. 4/29/2020 8

9. TYPES OF GENERAL ANAESTHETICS 4/29/2020 9

10. Volatile/Inhalation anaesthetics 4/29/2020 10 S NO. NAME STRUCTURE 1 Halothane* CF 3 CHClBr 2 Enflurane CHFClCF 2 OCHF 2 3 Methoxy Flurane CHCl 2 CF 2 OCH 3 4 Isoflurane CF 3 CHClOCHF 2 5 Sevoflurane CF 3 CHCF 3 OCH 2 F

11. Non Volatile/Intravenous anaesthetics 1 Ultra short acting barbitutrates Methohexital sodium* (C 14 H 18 N 2 O 3 ) Thiamylal sodium (C 12 H 17 N 2 NaO 2 S) Thiopental sodium (C 11 H 17 N 2 NaO 2 S) 2 Dissociative anesthetics: Ketamine hydrochloride* (C 13 H 17 Cl 2 NO) 4/29/2020 11

12. Mode of Action General anaesthetics target the ligand gated ion channels and produce the anaesthetic action. The GABA receptor gated chloride channels are the most important sites and opens to perform the inhibitory action. N2O and ketamine do not affect the GABA or glycine gated Cl –channel. 4/29/2020 12

13. Volatile/Inhalation anaesthetics 1 Halothane (CF 3 CHClBr) Synthesis:- Halothane, 2-bromo-2-chloro-1,1,1-trifluorethane is made by the addition of hydrogen  fluoride  to tricholoroethylene and simultaneous substitution of  chlorine  atoms in the presence of antimony(III)  chloride  at 130 °C. The resulting 2-chloro-1,1,1-trifluorethane undergoes further  bromination  at 450 °C to form  halothane  . 4/29/2020 13

14. Volatile/Inhalation anaesthetics 1 Halothane (CF 3 CHClBr) Synthesis:- Properties:- It is a clear, colourless , heavy, nonflammable liquid, Slightly soluble in water, miscible with ethanol, and with trichloroethylene. 4/29/2020 14

15. Volatile/Inhalation anaesthetics 1 Halothane (CF 3 CHClBr) Uses:- Halothane is a modern and widely used inhalation anaesthetic. It is a potent, relatively safe general inhalation anaesthetic. It is used with succinyl choline for skeletal muscle relaxation 4/29/2020 15

16. Volatile/Inhalation anaesthetics 2 Enflurane ( CHFClCF 2 OCHF 2 ) Synthesis:- Enflurane   (2-chloro-1-( difluoromethoxy )-1,1,2-trifluoroethane, Ethrane ) a regioisomer of  isoflurane , is synthesized on industrial scale by free radical chlorination of methoxy-1,1,2-trifluoro-2-chloroethane followed by halogen(chloride to fluoride) exchange in the presence of HF/SbCl 5 4/29/2020 16

17. Volatile/Inhalation anaesthetics 2 Enflurane ( CHFClCF 2 OCHF 2 ) Synthesis:- Properties:- It is a clear, colourless , volatile liquid with pleasant hydrocarbon-like odour . Soluble in water, miscible with organic solvents. 4/29/2020 17

18. Volatile/Inhalation anaesthetics 2 Enflurane ( CHFClCF 2 OCHF 2 ) Uses:- may be  used for  induction and maintenance of general anesthesia. may be  used to  provide analgesia for vaginal delivery. may also be  used to  supplement other general anesthetic agents. 4/29/2020 18

19. Volatile/Inhalation anaesthetics 3 Methoxy Flurane ( CHCl 2 CF 2 OCH 3 ) Synthesis:- Methoxyflurane , (2,2-dichloro-1,1-difluoroethylmethyl ether) is synthesized from 1,1-difluoro-2,2,2-trichloroethane , which undergoes  dehydrochlorination by potassium hydroxide to give 1,1-dichloro-2,2-difluoroethylene to which methanol is added in the presence of potassium hydroxide . 4/29/2020 19

20. Volatile/Inhalation anaesthetics 3 Methoxy Flurane ( CHCl 2 CF 2 OCH 3 ) Synthesis:- Properties:- It is a clear, colourless liquid, noninflammable. It is the most potent of the inhalational agents. It is employed to cause light anaesthesia with deep analgesic and muscle relaxation feature, 4/29/2020 20

21. Non Volatile/Intravenous anaesthetics 1 Ultra short acting barbitutrates Methohexital sodium* (C 14 H 18 N 2 O 3 ) Synthesis:- The reaction of malonic ester derivatives with derivatives of urea. The resulting allyl -(1-methyl-2-pentynyl) malonic ester is synthesized by subsequent alkylation of the malonic ester itself, Beginning with 2-bromo-3-hexyne, which gives (1-methyl-2-pentynyl) malonic ester, and then by allylbromide . In the final step, reaction of the disubstituted malonic ester with  N - methylurea gives methohexital . 4/29/2020 21

22. Methohexital sodium* (C 14 H 18 N 2 O 3 ) Synthesis:- 4/29/2020 22

23. Non Volatile/Intravenous anaesthetics Properties and uses:- White to off-white hygroscopic powder, essentially odourless, and The solution is alkaline to litmus, soluble in water. It is more potent and has shorter duration of action. It is used for the induction of anaesthesia through the intravenous administration. It is specifically useful for short surgical operations, such as oral surgery, gynaecological investigation. 4/29/2020 23

24. Non Volatile/Intravenous anaesthetics Thiopental sodium (C 11 H 17 N 2 NaO 2 S) Synthesis:- Thiopental, [5-ethyl-5-(1-methylbutyl)2-thiobarbituric acid] is synthesized by the alkylation of ethylmalonic  ester with 2-bromopentane in the presence of sodium ethoxide . The product ethyl-(1-methylbutyl) malonic ester undergoes  heterocyclization with thioura using sodium ethoxide as a base. 4/29/2020 24

25. Non Volatile/Intravenous anaesthetics Thiopental sodium (C 11 H 17 N 2 NaO 2 S) Synthesis:- Properties and uses:- A yellowish-white powder, hygroscopic, freely soluble in water, and partly soluble in ethanol. Onset is rapid (about 30 sec) and duration is brief (10–30 min) . It is also used as a sedative, hypnotic, and anticonvulsant. 4/29/2020 25

26. Non Volatile/Intravenous anaesthetics Dissociative anesthetics: Ketamine hydrochloride* (C 13 H 17 Cl 2 NO) Synthesis:- The syntheis starts with the reaction of cyclopentyl Grignard and o- chlorobenzonitrile to give o- chlorophenyl - cyclopentyl ketone , followed by alpha bromination of the ketone . Then reaction with methylamine to form an alpha- hydroxy imine (1-Hydroxycyclopentyl-(o- chlorophenyl )- ketone -N- methylimine ). Heating this imine results in Ketamine . 4/29/2020 26

27. Dissociative anesthetics: Ketamine hydrochloride* (C 13 H 17 Cl 2 NO) 4/29/2020 27

28. Non Volatile/Intravenous anaesthetics Ketamine hydrochloride* (C13H17Cl2NO) Properties and uses:- It is a white or almost white crystalline powder, freely soluble in water, methanol, and ethanol. It produces unpleasant hallucinations and strong feelings of dissociation from the environment. It is a rapidly acting non barbiturate general anaesthetic that produces anaesthesia 4/29/2020 28

29. Some Questions ….. Describe general anaesthetic in detail. Name some inhalation anaesthetics and ultra short acting barbiturate. Discuss how general anaesthetics work. 4/29/2020 29

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