General Anesthetic Drugs

1. General Anesthetic Drugs Deepak Bose Department of Pharmacology |& Therapeutics, Anesthesia & Internal Medicine University of Manitoba

2. General Anesthesia • General anesthesia is a state of reversible loss of consciousness for the purpose of carrying out surgery. • This is achieved by: • Analgesia • Amnesia • Immobility • Loss of consciousness • Skeletal muscle relaxation • many other effects accompany • Some desirable • Others undesirable

3. General Anesthesia History • In preanesthetic days, surgery was limited and surgeons functioned with blinding speed, a dash of alcohol and/or opium or the silver hammer • 1800 - Sir Humphrey Davy – discovered N2O.Nown as ‘laughing gas, it caused euphoria, analgesia & unconsciousness - tried it on the prime minister of England. • Horace Wells, an American, used it to pull his tooth, while he himself squeezed the bag

4. General Anesthesia History • Ether introduced first in a disreputable sort of way for facilitating ‘ether frolics’ • Henry Morton, a dentist, used it to extract teeth in 1846. • He then became a medical student at Harvard and implored the chief of surgery, Warren, to use it for surgery. Warren grudgingly accepted. • The demonstration, after some fumbling, worked well. Warren told the large audience, “Gentleman, this is no humbug”

5. General Anesthesia History • Oliver Wendell Holmes, a neurologist and author, coined the word Anesthesia and wrote in appreciation of Morton’s success:“The knife is searching for disease, the pulleys are dragging the dislocated limb - Nature herself is working out the primal curse which doomed the tenderest of her creatures to the sharpest of her trials, but the fierce extremity of suffering has been steeped in the water of forgetfulness, and the deepest furrow in the knotted brow of agony has been smoothed forever”

6. General Anesthesia History • Morton spent the rest of his life fighting with a collaborator over some patent dispute • 1847 - Glasgow - James Simpson used chloroform for labor. Denounced by the clergy.“Chloroform is the decoy of Satan, offering itself to bless women; but in the end it will harden society and rob God of the deep, earnest cries which arise in times of trouble, for help” • 1853 - Opposition silenced when Queen Victoria gave birth to her 7th child under general anesthesia

7. Theories of Anesthesia • Many simple unreactive compounds produce sleep • Anesthetic potency is closely correlated with lipid solubility (Overton-Meyer rule) and not with chemical structure, suggesting that interaction is involved with a hydrophobic domain of the cell • Two main theories postulate interaction with either: • the lipid membrane bilayer or • with hydrophobic binding sites on protein molecules

8. Theories of Anesthesia • Action on specific receptors • Barbiturates and benzodiazepines promote the actions of the inhibitory neurotransmitter GABA • Opioids act on their own specific receptors • Ketamine activates kappa opioid receptors

9. General Anesthetics - Pharmacological Effects • Anesthesia involves three main changes: • Unconsciousness • Loss of response to pain • Loss of motor reflexes

10. General Anesthetics - Pharmacological Effects • In high doses all agents can cause death by cardiovascular and respiratory depression via the brain stem

11. General Anesthetics - Pharmacological Effects • At the cellular level, anesthetics affect synaptic transmission through decreased transmitter release, rather than decreasing axonal conduction

12. General Anesthetics - Pharmacological Effects • Though all parts of the CNS can be affected, loss of consciousness is mainly through the inhibition of the reticular formation and amnesia through the hippocampus • Most anesthetics, with the exception of ketamine, cause similar neurophysiological effects. The difference lies in their potency, duration of action, toxicity • Most anesthetics, excepting ketamine & opioids, depress the cardiovascular system directly and, indirectly, through the CNS

13. Requirements forGeneral Anesthesia • Premedication • Induction+ intubation or mask • Maintenance • Emergence • Postoperative pain control IV Inhalation

14. Premedication • Relief of anxiety (benzodiazepine, clonidine, scopolamine, morphine) • Reduction of secretions & vagal reflexes (scopolamine, atropine, glycopyrrolate) • vagal reflex prominent in children & is provoked by halothane, succinylcholine & stimulation • vagal reflex provoked in eye surgery • Preemptive analgesia • Analgesics prior to painful stimuli are more effective than when given afterwards

15. Premedication • Preemptive analgesia • Painful stimuli set up a positive feedback mechanism in the spinal cord (wind-up) which accentuates pain • General anesthetics do not prevent wind-up - so post operative pain can be troublesome • NSAIDS, opioids, local anesthetics can effectively prevent wind-up

16. Premedication • Postoperative anti-emesis • Best to give towards end of surgery rather than before • Droperidol, metoclopramide, phenergan commonly used

17. Intravenous Anesthetics • For more rapid induction in adults than inhalational anesthesia • Speed depends upon brain blood flow (so slower in shock) • Duration of anesthesia depends upon redistribution (low dose) & metabolism (large repeated doses)

18. Intravenous Anesthetics • Agents commonly used: • Thiopental • Propofol • Midazolam • Ketamine • Opioids

19. Intravenous Anesthetics Thiopental • Most commonly used induction agent, enhances GABA action • Highly alkaline. Irritant if extravasated • Duration 4-6 minutes but liver metabolism only 12-16% per hour. So redistribution is the mechanism of the brief action • Hyperalgesic • Myocardial depressant • Reduces cerebral blood flow (important for neurosurgery cases as it reduces brain volume) • Rarely, may cause anaphylaxis or laryngospasm • Precipitates porphyria (CNS & GI symptoms)

20. Thiopental Distribution

21. Intravenous Anesthetics Propofol • A newer lipid soluble agent dispensed as an emulsion in intralipid® • Very rapid onset and short duration of action. • Best given as an infusion • Unlike thiopental, no hangover • Mechanism of action not known but may be through GABA • Hypotension caused mainly by vasodilatation rather than cardiac depression (cf thiopental) • Non-analgesic • Antiemetic • Reduces cerebral blood flow • Promotes bacterial growth (hence short shelf life of open solution)

22. Intravenous Anesthetics Ketamine • Can be given IV or IM • Does not depress the CV system • Very good analgesic but does not produce all the signs of unconsciousness • Eye and body movements may persist • Acts perhaps on opioid receptor • Causes hallucination and bad dreams in adults (reduced by midazolam) • Metabolized in the liver - action lasts 15 min • Good for induction and painful burn dressings

23. Intravenous Anesthetics Midazolam • A benzodiazepine which is water soluble due to open ring structure • In the body the ring closes, making the compound lipid soluble • Action terminated by redistribution. • Metabolized in the liver • Increases effectiveness of GABA • Mild CV effects but causes respiratory depression • Very good amnestic drug - good dreams too • Used with opioids for ‘conscious sedation’

24. Intravenous Anesthetics Opioids • Commonly used: • Alfentanil • Fentanyl • Sufentanyl • More lipid soluble than morphine • More potent than morphineMorphine (1), Alfentanil (10), Fentanyl (100), Sufentanil (1000) • m receptor stimulants • Antagonized by naloxone

25. Intravenous Anesthetics Opioids • Advantages: • Excellent analgesia • Minimal hemodynamic depression • Good suppression of endotracheal tube response • Problems: • Respiratory depression • Incomplete suppression of intraoperative awareness • Used mainly for cardiac anesthesia and also in smaller doses as a part of balanced anesthesia for non-cardiac cases

26. Intravenous Anesthetics Opioids Alfentanil • More lipid soluble than morphine • Rapid onset (60 sec) • Short duration (short elimination half-time of 90 min) • Small Vd • Low pK (90% drug non-ionized) • Metabolized in the liver (99.5%) • Good for short outpatient procedures (e.g. D&C) • Good for infusion because of no accumulation

27. Intravenous Anesthetics • Opioids • Fentanyl • More lipid soluble than morphine • Rapid onset (60 sec) • Elimination half time (200 min) is longer than the duration of clinical effect • Very highly bound to lung as a function of time. So half-life of effect depends upon duration of administration because of an increase in storage. • Available as IV, transdermal patch & lollipop

28. Intravenous Anesthetics • Opioids • Sufentanil • Rapid onset (60 sec) • Medium duration (elimination half-time of 150 min) • Metabolized in the liver (99%)

29. Inhalational Agents GAS • Nitrous oxide VOLATILE AGENTS • Halothane • Isoflurane • Enflurane • Desflurane

30. Anesthesia Machine

31. Inhalational Agents Inspired gas Upper airways/face mask Alveoli Pulmonary membrane Arterial blood Pulmonary blood Venous blood CNS Other tissue Metabolized

32. Pharmacokinetics of Inhaled Agents Rapid onset desirable Rate of onset: • Directly proportional to the inspired concentration of the agent • Directly proportional to the pulmonary ventilation • Inversely proportional to the solubility of the agent in lipids

33. Pharmacokinetics of Inhalational Agents • If an agent is more soluble in blood (lipids) then a larger amount is needed to produce the same partial pressure as a less soluble agent • The rate of attaining equilibrium is slower with more soluble agent • If an agent is more soluble in blood then a larger quantity is removed from the alveoli in a given time - so alveolar partial pressure decreases and the driving force for anesthetic transfer to blood decreases

34. Relation of Solubility with Partial Pressure Fat insoluble anesthetic Stores/Solubility Brain Fat soluble anesthetic Stores/Solubility Brain

35. Inhalational Anesthesia -Potency • MAC (minimum alveolar concentration) is a rough measure of potency • It is the concentration in the alveolus (therefore in the brain at equilibrium) which makes 50% of the subjects unresponsive to a surgical stimulus • MAC of different agents are additive • Actual amount needed during surgery depends on the nature of the painful stimulus and the overall surgical objective

36. Induction - how to make it faster • Use an intravenous agent • Use a gas or volatile agent with low fat solubility (e.g. nitrous oxide or desflurane) • Use the ‘second gas effect’ of nitrous oxide to speed up uptake of the volatile agent

37. Emergence • Reverse of induction • Depends on the solubility of the agent in fat • Depends on the duration of anesthesia • Depends on the depth of anesthesia

38. Inhalational Agents Nitrous Oxide • Rapid onset & offset • Good analgesic • Entonox (50% oxygen & nitrous oxide) for labor pain • Low potency (MAC >100) • Used mostly as an adjuvant • Second gas effect • DIffusion hypoxia • Toxicity • Inhibits methionine synthetase • Leucopenia & megaloblastic anemia • Expands gas spaces in the body

39. Inhalational Agents Halothane • Very widely used in children.Not so in adults due to fear of hepatotoxicity • Hepatotoxicity (1:35000). • Caused by metabolite causing immunological effect • More common with frequent repetition • Transient, reversible hepatic depression more common • Potent (MAC 0.8), pleasant smelling, good for induction in children • Cardiac depressant, causes hypotension

40. Inhalational Agents Halothane (continued) • Sensitizes heart to adrenaline-induced cardiac arrhythmia • Relaxes skeletal & smooth muscle • Cerebral vasodilator (causes increased intracranial pressure • 30% metabolized by oxidative or reductive pathways releasing Br-, Cl-, trifluoroacetic acid • Spontaneous degradation on storage, minimized by brown bottle & thymol • May cause malignant hyperthermia

41. Malignant Hyperthermia • Rare genetic disorder, first found in pigs • Exposure to halogenated agents & succinylcholine causes abnormal Ca release from the sarcoplasmic reticulum • High Ca uncouples mitochondrial oxidative phosphorylation, resulting in increased heat production & decreased ATP synthesis • Hyperthermia, increased CO2 production and muscle rigidity occurs • Fatal if not treated with dantrolene

42. Inhalational Agents Isoflurane • Most commonly used GA in adults • MAC 1.2, more irritant smell than halothane, so not good for inhalation induction • Very little metabolized • Hypotension caused mainly by vasodilation • Less arrhythmogenic than halothane • Good for neuroanesthesia, causes much less cerebral vasodilation than halothane

43. Inhalational Agents Enflurane • An isomer of isoflurane • MAC (1.8) • Less likely to cause hepatic and renal damage than halothane • Hypotension caused by cardiac depression • May cause seizure-like activity • Strong respiratory depressant

44. Inhalational Agents Desflurane • A newer halogenated agent • MAC (4.8%); Less lipid soluble than other halogenated agents • More rapid onset and offset • Very volatile - so needs special vaporizer • Potentiates arrhythmic effect of adrenaline less than halothane • Metabolism minimal • Expensive

45. Inhalational Agents • Agents which are metabolized more (e.g. halothane) release metabolites and are more likely to be toxic than those that are excreted unchanged (e.g. isoflurane)

46. Neuromuscular Blockade • Used to facilitate induction & intubation • Rapidly acting agents, e.g. succinylcholine or mivacurium • Used to provide muscle relaxation where needed, e.g. fracture reduction, abdominal surgery • Used to reduce concentration of general anesthetic where immobility is very important, e.g. neurosurgery or vascular surgery

47. Neuromuscular Blockade • Intermediate acting agents used for shorter surgery (e.g. vecuronium, atracurium) • Long acting agents used for prolonged surgery (e.g. pancuronium, metubine) • Depth of paralysis is judged by nerve stimulation • Block reversed with a cholinesterase inhibitor at the end of surgery

48. Modern General Anesthesia • Extremely safe despite severe physiological trespasses made, due to: • Use of many drugs to tailor-make effect • Minimize individual toxicity • Improved monitoring of physiological parameters and presence of alarm systems Suffice it to say that the life of an anesthetist consists of: Hours of boredom andmoments of intense terrorthank goodness the patient is asleep