General Anesthetics

1. General Anesthetics • Agents are used to produce unconsciousness and loss of perception to painful surgical procedures. • Physiologic state induced by general anesthetics include: analgesia, amnesia, loss of consciousness, inhibition of sensory and autonomic reflexes, skeletal muscle relaxation. • An ideal anesthetic would induce a smooth and rapid loss of consciousness while allowing for prompt recovery after discontinuation of administration.

2. General Anesthetics • An ideal anesthetic would • induce a smooth and rapid loss of consciousness while allowing for prompt recovery after discontinuation of administration. • Possess a wide margin of safety and be free of adverse effects

3. General Anesthetics • No agent alone has the ideal properties • Most commonly the drugs are used in combination of i.v. and inhalation

4. General Anesthetics Intravenous Anesthetics used alone or in combination with other anesthetic and analgesics

5. General Anesthetics • I.V. anesthetics • Barbiturates • The sodium salts of the ultra-short-acting barbiturates may be administered in aqueous solutions to induce anesthesia • Unconsciousness is produced within seconds of injection • Duration of action is about 30 minutes

6. General Anesthetics • I.V. anesthetics • Barbiturates

7. ….Intravenous Anesthetics • This intravenous group include the Na salts of ultra-short acting barbiturates (~30 min duration); administered IV in aqueous solution • Administered with maintaining inhalation anesthesia • Methohexital Sodium (Brevital Sodium) • N-methyl barbiturate: 1-Methyl-5-allyl-5-(1-methyl-2-pentynyl) barbiturate • pKa of 8.4 compared to pKa of ~7.6 for non-N-methylated cpds. • Therefore higher amounts of lipid-soluble free acid form that easily penetrates the BBB. It has an accessible site for metabolic inactivation: hydroxylation at the CH2a to the triple bond. • Thiopental Sodium (Pentothal Sodium): 5-Ethyl-5-(1-methylbutyl)-2-thiobarbiturate • Most widely used ultra-short acting anesthetic barbiturate. • A prototype for ultra-short acting barbiturates; a standard for studying effects of structure on duration of action. Fast onset of action, the time it takes to reach the CNS. Consciousness is gained in about 30 minutes.

8. …General Anesthetics (Benzodiazepines) • Benzodiazepines: Tend to bind to benzodiazepine recognition site that modulate the GABA binding to GABAA (a receptor which is a ligand- gated chloride ion channel) • SAR: An electroneg. atom at position 7 is required for activity. No sub. in positions 6, 8 and 9. A phenyl at position 5 promotes activity. If the phenyl has ortho (2’) or diortho (2’,6’) electron attracting sub., activity is increased, parasub. decreases activity. Saturation of the 4,5 double bond or a shift of it to the 3,4 position decreases actvity. Alkyl subs. At the 3-position decrease actiity. The 3-OH are much more polar and are converted to the excreted glucoronide. Those without 3-OH, have longer half lives and undergo hepatic oxidation. Diazepam: Non polar and is rapidly absorbed (has high lipid/water partition coefficient; therefore very long acting). Known metabolism to oxazepam as shown below. Used for anxiety states, anticonvulsant and pre-medication in anesthesia.

9. …General Anesthetics (Benzodiazepines) Midazolam (Versed) a benzodiazepine that is CNS depressant; used IV to induce anesthesia. Midazolam has lower lipid/water partition coefficient and an improved pharmacokinetic properties. Lorazepam (generic, Ativan) – almost insoluble in water. Is also a CNS depressant, highly addictive Lorazepam

10. …General Anesthetics (Phenols, Ketones) • Ketamine. HCl, USP (Ketalar): It is a 2-(o-chlorophenyl)-2-methylaminocyclohexanone, a structural relative ofphencylidine (PCP); different mechanism than other anesthetics; blocks glutamic acid N-methyl-D-aspartate (NMDA) receptors. Causes dissociation from events being experienced followed by anesthesia, analgesia and sometimes amnesia. Incidence of hallucinations is lower than PCP.

11. …General Anesthetics (Phenols) • Fosprofofol (Lusedra) – sedative/analgesic. Metabolized to Propofol in the liver by phosphatases. Water soluble. • Propofol (Diprivan): Phenols are generally toxic (tissue destruction) but the 2,6-isopropyl groups of propofol mitigate the effect. • Insoluble in water. Thus, given IV as an emulsion. • Rapid BBB penetration and distribution as a product with high lipid-water partition coefficient. Used for induction and maintenance of anesthesia. • Binds allosterically to GABAA receptors at non-benzodiazepine sites. Fospropofol (Lusedra)

12. …General Anesthetics • Etomidate (Amidate)Etomidate is a base. Thus, water-soluble salts are used for IV administration. A 4-carboxylic acid ester-substituted imidazole moiety and is related to the imidazolo benzodiazepines. It is a positive allosteric modulator of GABAA receptors. Has a depression of steroidogenesis as a side effect. • Dexmedetomidine - is the S-enantiomer of medetomidine. It isfreely soluble in water and has a pKa of 7.1 • Both drugs are also sedative-hypnotics Dexmedetomidine (Precedex)

13. General Anesthetics • Droperidol (Inapsine) • Reducing nausea and vomiting during surgeries and diagnostic procedures. • Inapsine is a tranquilizer. It is unknown exactly how Inapsine works. • Infrequent but possibly fatal heart problems have occurred with Inapsine when used at or even below recommended doses

14. Inhaled Anesthetics • Volatile liquids • Nitrous oxide is an important adjuvant • Most commonly used agents are: isoflurane, desflurane and sevoflurane • Other agents are also used

15. …Inhalation Anesthetics • Nitrous oxide: N2O, Nitrogen Monoxide, • Is a gas at room temperature, but a liquid under pressure when supplied. Good analgesic at lower conc. from depressant effect on synaptic transmission of pain messages (possible effect on opioid receptors). Required to be 80% in inspired air to achieve anesthesia; (care for dangers of possible hypoxia). • Given with other anesthetics. • It is a positive modulator of GABA on GABAA receptors for its anesthetic action.

16. General Anesthetic Agents • Inhalation Anesthetics: • Halothane:CH(Br)Cl-CF3 • Volatile (B.P. of 500 C), Nonflammable, Highly potent with low blood/gas partitioning, Mostly is excreted unmetabolized • High electronegativity of F makes –CF3 group stable. • Methoxyflurane (Penthrane):CHCl2CF2-O-CH3 • Volatile liquid (B.P. 1050 C), it does not have a high vapor pressure, so conc. Of the inspired air is low. The compound is very soluble in lipids; thus, recovery is slow. Large blood/gas partition coefficient (slow induction of anesthesia). Produces excellent anesthesia and good muscle relaxation. • 70% metabolized to form: Dichloroacetic acid, Difluoromethoxyacetic acid, Oxalic acid and Fluoride • Fluoride and oxalic acid cause renal damage due to prolonged use.

17. …Inhalation Anesthetics • Enflurane (Ethrane):HF2COCF2CHFCl, Volatile liquid; • Depresses respiration, therefore mechanical ventilation and O2 supplementation.Tonic-clonic convulsive side effect (not recommended for patients with epileptic foci). • 5% of drug metabolized to F- & difluoromethoxydifluoroacetic acid. • Isoflurane (Forane): F3CC(H)ClOCF3 • Structurally and functionally related to enflurane except: • Lack of electroencephalogram and tonic-clonic activity. • Only 0.2% is metabolized to F- and trifluoroacetic acid. • Desflurane (Suprane): FC(H2)-O-C(H)F-C(H)F2 • Sevoflurane: FC(H2)-O-CH(CH3)2: Rapidly taken up and rapidly eliminated