General and local Anesthetics 2024v2.pptx

General and local Anesthetics 2024v2.ppt

1. General and Local Anesthetics Pharmacology Department UCC – School of Medicine

2. General Anesthetics Drug Classes and Drugs to consider (Major or Prototype Drugs Capitalized) Inhaled Intravenous DESFLURANE, ISOFLURANE, NITROUS OXIDE (N 2 O), SEVOFLURANE ETOMIDATE, KETAMINE, PROPOFOL Methohexital, thiopental Intravenous Adjuncts FENTANYL, MIDAZOLAM, MORPHINE alfentanil, remifentanil, sufentanil , antimuscarinic agents Topics Specific Learning Objectives Physiology and pathophysiology Define the terms “general anesthesia” and “balanced anesthesia.” State the objectives of general anesthesia, characteristics of an ideal anesthetic, and the stages of general anesthesia. Mechanism of action List the current theories of the mechanisms of action of inhalation anesthetics, and of intravenous anesthetics. Pharmacokinetics Compare the available inhalation anesthetics with respect to their pharmacokinetic properties including biotransformation. Explain how the solubility of a gas in a liquid is defined. List the conditions that must be specified to determine the concentration of gas in the liquid phase. Describe how the physical properties of inhalation anesthetics influence the rate of equilibration of anesthetic in the inspired air to anesthetic in alveoli, blood, brain, muscle and fat. Explain how this information is related to onset and recovery from inhalation anesthesia. Compare and contrast commonly used intravenous induction agents their speed of onset, and duration of action. Describe the relative roles of distribution and metabolism in determining duration of action and how this may change with repeated administration of an intravenous anesthetic. Adverse effects, drug interactions and contraindications List and explain the complications that may ensue with the use of Nitrous Oxide as a direct result of the high concentrations at which it is administered and its blood solubility relative to that of nitrogen. Describe malignant hyperthermia, list some common triggering agents, and discuss its prevention and treatment. Describe the utility and adverse effects of drugs commonly used as pre-anesthetic medications or in combination with inhalation anesthetics to create a "complete or balanced anesthetic". Include opioids, benzodiazepines, neuromuscular blocking agents and antimuscarinic agents in your discussion. Indicate how the concomitant use of these drugs may affect the concentrations of inhaled anesthetics used to maintain the anesthetic state. Describe the pharmacological effects of the drugs in each class on pulmonary, cardiovascular, endocrine, renal, and CNS function (aside from anesthesia).

3. General Anesthetics Therapeutic uses Define MAC (minimal alveolar concentration), name the physical property of an inhalation anesthetic that correlates best with its MAC, and explain how the concept of MAC is used in anesthesiology. Discuss relative advantages and disadvantages of intravenous vs. inhalation anesthesia. Discuss the factors involved in choosing an anesthetic protocol, including the relative advantages and disadvantages of inhalation and intravenous anesthesia. Clinical Pharmacology One significant issue involves increased risk of cardiovascular mortality with propofol due to concurrent hypokalemia (increased arrhythmia risk) – this is the result of not controlling serum potassium when propofol was used as an anesthetic agent. Relevance USMLE topic: Central and Peripheral Nervous System Principles of Therapeutics: Mechanisms of action and use of drugs for treatment of disorders if the nervous system - anesthetics AAMC Medical School Objectives: Project Report X Patient Safety-Table 1 Topic C: Drug treatment of common conditions, and diseases using frequently prescribed drugs for the treatment and prevention of disease

4. Local Anesthetics Drug Classes and Drugs to consider (Major or Prototype Drugs Capitalized) Primary agents Secondary agents BENZOCAINE, BUPIVACAINE, LIDOCAINE, PROCAINE, ROPIVACAINE articaine , cocaine, prilocaine, tetracaine Topics Specific Learning Objectives Physiology and pathophysiology Explain how the actions of clinically used anesthetics might be influenced by the frequency of impulse transmission in peripheral nerves, size and class of the peripheral axons, pH, and by the vascularity of the injected area. Review the concept of weak bases, the Henderson-Hasselbalch equation, and drug transport across membranes. Discuss the relevance of isoforms of the voltage-gated sodium channel to the development of new local anesthetics. Describe the ionic basis of the action potential. Pharmacodynamics Discuss the mechanism of action of local anesthetics, including a description of how the action of benzocaine differs from that of other primary agents. Pharmacokinetics Explain how the actions of clinically used anesthetics might be influenced by the frequency of impulse transmission in peripheral nerves, size and class of the peripheral axons, pH, and by the vascularity of the injected area. Adverse effects, drug interactions and contraindications List the common adverse effects of local anesthetics and indicate appropriate treatments should they occur. List the significant differences between amide and ester-type local anesthetics. Therapeutic uses Describe the common routes of administration of local anesthetics. List anesthetics that cannot be used topically, that cannot be used for infiltration. Explain why these routes are not effective. Describe methods used to restrict local anesthetics to a desired site of action and indicate how these methods reduce adverse effects. Compare and contrast the advantages and potential adverse effects of epidural and intrathecal use of local anesthetics with similar use of opioids (see “opioid analgesics, agonist-antagonists, and antitussives).

5. Local Anesthetics Clinical Pharmacology There should be caution concerning increased cardiac morbidity and seizures if significant concentrations are achieved in the circulation. Relevance USMLE topic: Central and Peripheral Nervous System Principles of Therapeutics: Mechanisms of action and use of drugs for treatment of disorders if the nervous system – local anesthetics AAMC Medical School Objectives: Project Report X Patient Safety-Table 1 Topic C: Drug treatment of common conditions, and diseases using frequently prescribed drugs for the treatment and prevention of disease

6. Summary Table: General Anesthetics Drug Mechanism of action Pharmacological effects Pharmacokinetics Side effects/ Interactions Inhaled anesthetics: Desflurane, Enflurane, Halothane, Isoflurane, Sevoflurane, Nitrous oxide Facilitate GABA-mediated Inhibition. Block brain NMDA and ACh -N receptors Increase cerebral blood flow; enflurane and halothane decrease cardiac output. Others cause vasodilation; all decrease respiratory functions; lung irritation (desflurane) Rate of onset and recovery vary by blood:gas partition coefficient; recovery mainly due to redistribution from brain to other tissues Toxicity: extensions of effects on brain, heart/vasculature, lungs Drug interactions: additive CNS depression with many agents, especially opioids and sedative-hypnotics IV anesthetics: Barbiturates Thiopental, Thioamylal , Methohexital Barbiturates, benzodiazepines, etomidate, and propofol facilitate GABA mediated inhibition at GABA A receptors Circulatory and respiratory depression; decrease intracranial pressure High lipid solubility; fast onset and short duration due to redistribution Extensions of CNS depressant actions; additive CNS depression with many drugs IV anesthetics: Benzodiazepines Midazolam Less depressant than barbiturates Slower onset, but longer duration than barbiturates Postoperative respiratory depression reversed by flumazenil IV anesthetics: Imidazole Etomidate Minimal effects on CV and respiratory functions Short duration due to redistribution No analgesia, ain on injection (may need opioid), myoclonus, nausea, and vomiting IV anesthetics: Dissociative Ketamine Blocks excitation by glutamate at NMDA receptors Analgesia, amnesia and catatonia but consciousness retained; cardiovascular (CV) stimulation! Moderate duration of action; hepatic metabolism Increased intracranial pressure; emergence reactions IV anesthetics: Opioids: Fentanyl, Alfentanil, Remifentanil, Morphine Interact with μ, κ, and δ opioid receptors Marked analgesia, respiratory depression Alfentanil and remifentanil fast onset (induction) Respiratory depression; reversed by naloxone IV anesthetics: Phenols: Propofol, Fospropofol Uncertain Vasodilation and Hypotension; negative inotropy. Fospropofol water-soluble Fast onset and fast recovery due to inactivation Hypotension (during induction), cardiovascular depression

7. Summary Table: Local Anesthetics Drug Mechanism of action Pharmacokinetics Clinical Applications Side effects/ Interactions Amides: Articaine Bupivacaine Levobupivacaine Lidocaine a Mepivacaine Prilocaine Ropivacaine Blockade of Na+ channels slows, then prevents action potential propagation Hepatic metabolism via CYP450 in part; Half-lives: lidocaine, prilocaine < 2 h, others 3–4 h Analgesia via topical use, or injection (perineural, epidural, subarachnoid); rarely IV CNS: excitation, seizures; CV: vasodilation, hypotension, arrhythmias (bupivacaine) Esters: Benzocaine a Cocaine a Procaine Tetracaine a As above, plus cocaine has intrinsic sympathomimetic actions Rapid metabolism via plasma esterase's; short half-lives Analgesia, topical only for cocaine and benzocaine As above re CNS actions; Cocaine vasoconstricts. When abused cocaine has caused hypertension, seizures, and cardiac arrhythmias a Topical fomulations available.

8. 8 Case Study: General Anesthetics An anxious 5-year-old child with chronic otitis media and a history of poorly controlled asthma presents for placement of ventilating ear tubes. General anesthesia is required for this short elective ambulatory surgery procedure. What pre-anesthetic medication should be administered? Which of the three commonly used anesthetic techniques would you choose to use in this situation: (1) inhalational anesthesia with sevoflurane for induction and maintenance in combination with nitrous oxide, (2) intravenous anesthesia with propofol for induction and maintenance of anesthesia in combination with remifentanil, or (3) balanced anesthesia using propofol for induction of anesthesia followed by a combination of sevoflurane and nitrous oxide for maintenance of anesthesia? General Anesthetics.

9. 9 Case Study: Local Anesthetics A 25-year-old woman with a 2-inch superficial laceration on her face is brought by the police to the emergency department after a street brawl. Her wound is still bleeding but appears clean. After washing and application of pressure, the bleeding stops, and closure of the wound with sutures is planned. What local anesthetic would be appropriate for this relatively short procedure in an area where a good cosmetic result is desirable? Is a vasoconstrictor appropriate? Local Anesthetics.

10. History of Anesthesiology: 10 General and local Anesthetics

11. 11 Principles of Administration of General Anesthetics General Anesthetics.

12. 12 General Anesthesia: General Anesthetics. Modern practice commonly involves the use of combinations of drugs, taking advantage of favorable properties while minimizing potential harmful effects. No single anesthetic agent can achieve all these desirable effects. In addition to anesthetics, other drugs are administered preoperatively, intra-operatively, and postoperatively HOWEVER To ensure smooth induction, analgesia, sedation, muscle relaxation, and recovery.

13. 13 General Anesthesia: Protocols Anesthesia protocols vary depending on the proposed diagnostic, therapeutic, or surgical procedure type. Oral sedatives in conjunction with regional local anesthesia is usually used for minor procedures . Conscious sedation can be achieved with the use of intravenous benzodiazepines and opioid analgesics . This provides profound analgesia while retaining the ability to maintain a patent airway and respond to verbal commands. Major surgical procedures : Requires preoperative sedatives, induction of anesthesia with thiopental or other rapidly acting intravenous drugs, and provision of deeper levels with inhaled anesthetics alone or in combination with intravenous drugs . General Anesthetics.

14. Stages of Anesthesia 14 Stage I:   “Analgesia” Analgesia (depends on agent) Amnesia Euphoria Stage II: Disinhibition  “Excitement” Excitement Delirium Combative behavior Stage III:   “Surgical Anesthesia” Unconsciousness Regular respiration Decreasing eye movement Stage IV:   “Medullary Depression” Respiratory arrest Cardiac depression and arrest No eye movement Awake Awake Surgery Completed Commence surgery

15. 16 General Anesthetics. Types of General Anesthetics

16. 17 General Anesthetics. General Anesthetics: Inhaled anesthetics

17. 18 Inhaled anesthetics: Depth of anesthesia is determined by drug concentration in CNS. Loss of consciousness and amnesia likely ensue from supraspinal action (i.e., activity in the brainstem, midbrain, and cerebral cortex). At the same time, immobility in response to noxious stimuli is caused by depression of both supraspinal and spinal sensory and motor pathways. Effective brain concentration depends on pharmacokinetic factors that influence: the uptake and distribution of anesthetics (rate of transfer from lung to blood and blood to brain and other tissues). MAC: Minimal Alveolar Concentration ( P alv that abolishes movement response to a surgical incision in 50% of patients)(potency of anesthetic inversely related to its MAC). General Anesthetics.

18. Properties of General Anesthetics 19 General Anesthetics.

19. 20 General Anesthetics In this schematic diagram, solubility in blood is represented by the relative size of the blood compartment (the more soluble, the larger the compartment). Relative partial pressures of the agents in the compartments are indicated by the degree of filling of each compartment. For a given concentration or partial pressure of the two anesthetic gases in the inspired air, it will take much longer for the blood partial pressure of the more soluble gas (halothane) to rise to the same partial pressure as in the alveoli. Since the concentration of the anesthetic agent in the brain can rise no faster than the concentration in the blood, the onset of anesthesia will be slower with halothane than with nitrous oxide. Why induction of anesthesia is slower with more soluble anesthetic gases?

20. Tissue tensions of an anesthetic's gas during uptake and elimination 21

21. The Meyer-Overton Rule 22 MAC Potency The Meyer-Overton Rule. Molecules with a larger oil/gas partition coefficient (Moil/gas) are more potent general anesthetics. This log-log plot shows the very tight correlation between lipid solubility (Moil/gas)) and anesthetic potency over five orders of magnitude . Even gases like xenon and nitrogen can act as general anesthetics when breathed at high enough partial pressures. The equation describing the line is: Potency = l (oil/gas) / 1.3. Recall that Potency = 1/MAC.

22. 23 Isoflurane Dose – Response Curve for Various End-Points These curves depict the percentage of patients exhibiting endpoints of non-responsiveness to a set of stimuli and of cardiac arrest as the alveolar partial pressure of isoflurane is increased. Note that the dose-response curves are quite steep, especially for mild stimuli, and that higher partial pressures are required to achieve lack of response to stronger stimuli. In the example shown, lack of response to intubation in 50% of patients requires nearly 0.02 atm isoflurane, while lack of response to a squeeze of the trapezius muscle requires only 0.008 atm. The MAC is defined as the alveolar partial pressure at which 50% of patients do not respond to a skin incision. The therapeutic index is defined as the LDso divided by the MAC. The theoretical curve for cardiac arrest is derived from a known therapeutic index of about 4 for isoflurane. Accordingly, the anesthesiologist must carefully monitor each individual patient to achieve the desired effect and to avoid cardiac depression.

23. 24 General Anesthetics Rate of Approach of the Alveolar toward the Impaired Partial Pressure

24. 25 General Anesthetics. Effects of Changes in Ventilation and Cardiac Output on the Rate at which Alveolar Partial Pressure Rises Toward Inspired Partial Pressure. The rate of equilibration of the alveolar partial pressure with the inspired partial pressure can be affected by changes in ventilation (A) and cardiac output (B). Increasing ventilation from 2 L/min (dashed lines) to 8 L/min (solid lines) accelerates equilibration. On the other hand, increasing cardiac output from 2 L/min (dashed lines) to 18 L/min (solid lines) slows equilibration. Both effects are much larger for more blood-soluble gases, such as halothane and diethyl ether, which have rather slow induction times. For nitrous oxide, the rate of equilibration is so fast that any changes caused by hyperventilation or decreased cardiac output are small. The dashed horizontal line represents 63% equilibration of Pay with Pi: the time required for each curve to cross this line represents t¡Pal ->Pi

25. 26 Using halothane as an example, the alveolar partial pressure of anesthetic rises more quickly in children than in adults. The faster induction time in children results from a balance between children's increased respiration (favoring faster induction) and increased cardiac output (favoring slower induction) ; the time-dependent increase in the mixed venous partial pressure of anesthetic limits anesthetic uptake from the lungs, dampening the effect of increased cardiac output on induction time. Anesthesia Induction in Children

26. 27 Applying Overpressure to Speed Induction. Using halothane as an example, the anesthesiologist can use an initial P, greater than the final desired Pbrain to speed induction. If the desired partial pressure of anesthetic in the brain is about 0.01 atm, then the anesthesiologist could initially administer the inspired anesthetic at a higher partial pressure, for example, 0.04 atm. This method is effective because the time constant for Pa->P, is independent of the absolute value of P. In other words, if P, is increased, then the ratio Pa/P, will increase proportionally at the same rate, resulting in a greater absolute rise in P. in a given amount of time. The anesthesiologist must be sure to decrease the inspired partial pressure in a timely manner, however, or the desired Pbrain for anesthesia can be overshot and, instead, partial pressures capable of causing respiratory depression can be reached. On the other hand, if the inspired partial pressure is reduced too rapidly, the patient may awaken as Palv is decreased because of uptake of anesthetic from the alveoli into the bloodstream (not shown).

27. 28 Recovery from Inhaled Anesthetics. These curves show, as a function of time, the exhaled partial pressure of anesthetic (P E0 ) as a fraction of the exhaled partial pressure at the moment administration of the anesthetic is stopped (P E0 ). The rate of recovery is inversely proportional to the l ( blood/gas) of the anesthetic because aesthetics with smaller M (blood/gas) values equilibrate faster between alveolar and inspired partial pressures (the latter being zero after anesthetic administration is stopped). The recovery rate is also proportional to the duration of anesthesia because the partial pressures of anesthetic in the muscle and fat groups increase with duration. During recovery, anesthetic redistributes from these slowly equilibrating, high-capacity tissues to the vessel rich group, thus slowing the rate of fall of   P brain . 

28. 29 When a bolus of intravenous anesthetic is administered, it is initially transported through the vascular system to the heart and is then distributed to the tissues. The vessel rich group (VRG) receives the highest percentage of the cardiac output; its anesthetic concentration rises rapidly, reaching a peak within 1 minute. Redistribution of anesthetic to the muscle group (MG) then quickly decreases the anesthetic level in the VRG. Because of very low-fat group (FG) perfusion, redistribution from the MG to the FG does not occur until much later. Note that rapid redistribution from the VRG to the MG does not occur if the MG has previously approached saturation through prolonged administration of anesthetic (not shown); this can lead to significant toxicity if intravenous barbiturates are administered continuously for long periods of time. New agents, such as propofol, are designed to be eliminated by rapid metabolism and, therefore, can be used safely for longer periods of time. Distribution of a Bolus of Intravenous Anesthetic

29. 30 The extreme variability in the structures of these molecules, all of which are capable of causing general anesthesia, suggests that not all general anesthetics interact with a single receptor site. * - carbons where asymmetry results in enantiomeric structures. Structures of General Anesthetics

30. 31 Anesthetics potentiate the action of endogenous agonists at inhibitory receptors, such as GABA and glycine receptors, and inhibit the action of endogenous agonists at excitatory receptors, such as nicotinic acetylcholine, 5HTs, and NMDA glutamate receptors. At GABA receptors, anesthetics both decrease the ECso of GABA (i.e., GABA becomes more potent) and increase the maximum response (i.e., GABA becomes more efficacious. The latter effect is thought to be due to the ability of anesthetics to stabilize the open state of the receptor channel. At excitatory receptors, anesthetics decrease the maximum response while leaving the ECso unchanged; these are the pharmacologic hallmarks of non-competitive inhibition. Actions of Anesthetics on Ligand-Gated Ion Channels

31. 32 Nitrous Oxide (MAC = >100: Blood/Gas partition coefficient = 0.47) An anesthetic gas that lacks potency to produce surgical anesthesia. Good analgesic and sedative properties but not skeletal muscle relaxant properties. Used as a sole agent in brief procedures, in second stage of labor, and as a sedative with local anesthetics. Often used in combination with other inhalation anesthetics to increase their rate of uptake and to add to their analgesic activity. (second gas effect) Often supplemented with sedative-hypnotics, analgesics, and skeletal muscle relaxants. Postoperative nausea and vomiting is common. Depresses levels of methionine synthase used in vitamin B 12 synthesis. General Anesthetics. WARNING: Nitrous oxide (N 2 O) should NOT be confused with nitric oxide (NO) or nitrogen dioxide (NO 2 )

32. 33 General Anesthetics.

33. 34 Enflurane [ Ethrane ] (MAC = 1.7: Blood/Gas partition coefficient = 1.8) Relatively rapid induction and recovery with little excitation. Pungency may result in breath holding or coughing and less acceptance by children than halothane. Produces good analgesia and hypnosis. CNS stimulation at high doses and produces no sensitization of heart to catecholamines. Cardiovascular depression similar to halothane with a little more decrease in vascular resistance. No evidence of hepatotoxicity. General Anesthetics.

34. 35 General Anesthetics.

35. 36 General Anesthetics.

36. Effect of infusion duration on rate of elimination of intravenous anesthetics 37

37. 38 A. Ultra-short-acting Barbiturates: Thiopental and Methohexital Used i.v. to induce or supplement sedation and hypnosis during anesthesia Result in a smooth, pleasant, and rapid induction Have no analgesic or muscle-relaxant properties 2. Short duration (15 min) because of redistribution from highly vascular tissue, including brain, to less vascular tissues such as muscle and adipose tissue General Anesthetics. Intravenous Anesthetics and Preanesthetic Drugs:

38. 39 B . Benzodiazepines (Diazepam and Midazolam; intravenously or orally; and Barbiturates (Pentobarbital and Secobarbital) Used for sedation and to reduce anxiety. The benzodiazepines are supplanting the use of barbiturates because they are safer and because they also produce anterograde amnesia. Diazepam has a slow onset of action, unpredictable dose-response relationship, and long duration of hypnosis. It produces minimal cardiovascular depression. Used with opioids in cardiac patients. Causes phlebitis, reduces lower esophageal pressure and may increase gastric reflux. 3. Midazolam has a rapid onset of action and a more predictable dose-response relationship. Produces more cardiovascular depression and excellent amnesia. Intravenous Anesthetics and Preanesthetic Drugs: General Anesthetics.

39. 40 Opioids: Fentanyl, Morphine, Meperidine, and Pentazocine. Administered preoperatively to reduce pain and/or to produce sedation. Use for sedation is being supplanted by the benzodiazepines No amnestic effect; Increase the risk of pre- and postoperative nausea and vomiting Fentanyl plus Droperidol [ Innovar ]. An illogical combination of a short-duration opioid (longer acting at high doses) and long-acting butyrophenone. Used rarely for diagnostic and therapeutic procedures such as burn dressings and cardiac catheterization. Droperidol is useful as an antiemetic. 4. Fentanyl depresses respiration; assisted ventilation required during anesthesia. Produces minimal cardiovascular depression; has replaced morphine for cardiac patients. Rapid i.v. infusion may cause spasm of respiratory muscles (wooden rigidity) Intravenous Anesthetics and Preanesthetic Drugs: General Anesthetics.

40. 41 Fentanyl (continuation): A synthetic opioid 80-100 times stronger than morphine. FDA-approved as an analgesic and anesthetic. Illegal use: Fentanyl is combined with heroin to increase its potency, a combination that often results in overdose deaths. Street Names: Apace, China Girl, China Town, China White, Dance Fever, Goodfellas, Great Bear, He-Man, Poison and Tango & Cash It can be injected, snorted/sniffed, smoked, taken orally by pill or tablet, and spiked onto blotter paper. Fentanyl patches are abused by removing their gel contents and then injecting or ingesting these contents. Patches have also been frozen, cut into pieces, and placed under the tongue or in the cheek cavity.

41. 42 Fentanyl (continuation): Like other commonly used opioid analgesics (e.g., morphine), it produces effects such as relaxation, euphoria, pain relief, sedation, confusion, drowsiness, dizziness, nausea, vomiting, urinary retention, pupillary constriction, and respiratory depression. Overdose may result in stupor, changes in pupillary size, cold and clammy skin, cyanosis, coma, and respiratory failure leading to death. Symptoms such as coma, pinpoint pupils, and respiratory depression are strongly suggestive of opioid poisoning. Involved in almost 29 percent of all overdose deaths in 2016, making it the most-used drug involved in overdose fatalities, according to the CDC. The total number of drug overdose deaths increased by 54 percent each year between 2011 and 2016, with 63,632 drug overdose deaths reported in the United States in 2016 (with most overdoses involving more than one drug).

42. 43 D. Anticholinergic Drugs: Atropine, Scopolamine, and the Quaternary Ammonium Compound Glycopyrrolate Rarely used except in infants and small children. Used to decrease salivation and bronchial secretions, and to protect against bradycardia and hypotension caused by succinylcholine. Decrease tone of the lower esophageal sphincter, which may increase the risk of reflux. 4. May prolong postoperative drowsiness or confusion Intravenous Anesthetics and Preanesthetic Drugs: General Anesthetics.

43. 44 E. Ketamine ( Ketalar ) Ketamine produces an effect like neuroleptanalgesia in which patients feel dissociated from their surroundings (dissociative anesthesia). Analgesic effect is to superficial pain but not visceral pain. Also results in amnesia. In adults, frequently results in distortions of reality, terrifying dreams, and delirium. Used primarily for infants and children. Airway and ventilation well maintained; blood pressure, heart rate, and cardiac output increased (vagal inhibition and sympathetic stimulation). Increases intracranial pressure and contraindicated for patients with tumors and head injuries. 6. Potent bronchodilator; useful in asthmatics Intravenous Anesthetics and Preanesthetic Drugs: General Anesthetics.

44. 45 F. Etomidate (Amidate) 1. Nonbarbiturate anesthetic 2. Rapid-onset, short-duration hypnosis 3. Minimal cardiorespiratory depression 4. Pain on injection; opioids administered first 5. Unpredictable myoclonus, often severe; need neuromuscular blocking drug Intravenous Anesthetics and Preanesthetic Drugs: General Anesthetics.

45. 46 General Anesthetics.

46. 47

47. 48 Case Study: Local Anesthetics A 25-year-old woman with a 2-inch superficial laceration on her face is brought by the police to the emergency department after a street brawl. Her wound is still bleeding but appears clean. After washing and application of pressure, the bleeding stops, and closure of the wound with sutures is planned. What local anesthetic would be appropriate for this relatively short procedure in an area where a good cosmetic result is desirable? Is a vasoconstrictor appropriate? Local Anesthetics.

48. Local Anesthetics.

49. A primary afferent neuron mediating pain, its synapse with a secondary afferent in the spinal cord, and the targets for local pain control 50

50. Prototypical Local Anesthetics 51 Local Anesthetics. Procaine and lidocaine are two types of local anesthetics. Procaine is ester-linked while lidocaine is amide-linked. Local anesthetics have an aromatic group and a tertiary amine connected by an ester or amide linkage. In a high pH solution, the basic form is favored. Ester-linked local anesthetics break down more easily than amide-linked, which are more stable and have a longer duration of action.

51. 52 Local Anesthetics. Structure and properties of some ester and amide anesthetics

52. 53 Local Anesthetics. Structure and properties of some ester and amide anesthetics

53. 54 A: Cartoon of the sodium channel in an axonal membrane in the resting (m gates closed, h gate open), activated (m gates open, h gate open), and inactivated states (m gates open, h gate closed). Recovery from the inactivated, refractory state requires closure of the m gates and opening of the h gate. Local anesthetics bind to a receptor (R) within the channel and access it via the membrane phase or from the cytoplasm. B: Molecular arrangement of the six membrane-spanning peptides, four of which combine to form the channel around a central pore. The S4 segments (marked with "+" signs) are thought to constitute the voltage-sensing m gates of the channel. The linker peptide connecting the III and IV hexamers acts as the inactivation h gate. Ions travel through an open channel along a pore defined at its narrowest dimension by partial membrane penetration of the four extracellular loops of protein connecting S5 and S6 in each domain. Local anesthetic binding occurs on S6 segments and at other regions of the channel. C: Three-dimensional drawing showing the configuration of the four hexamers around the central pore in the membrane. Functional and structural features of the Na + channel that determine local anesthetic interactions. Local Anesthetics

54. 55 Pharmacokinetic Properties of Several Amide Local Anesthetics Local Anesthetics

55. Relative Size and Susceptibility of Different Types of Neve Fibers to local Anesthetics 56 Local Anesthetics

56. Peripheral Nerve Anatomy and local anesthetics 57 Epinerium >> Perinerium >> Endonerium Local Anesthetics

57. First and Secondary Pain First pain: transmitted by A d fibers, is sharp and highly localizable. can be blocked by selective blockade of A d, -fibers  Second pain transmitted by C-fibers, is slower arriving, duller, and longer lasting (A).  can be blocked by selective blockade of C-fibers (C).  Because A d -fibers are more susceptible than C-fibers to blockade by local anesthetics, the first pain often disappears at concentrations of anesthetic lower than that required to eliminate the second pain. 58 Local Anesthetics

58. 59 Either esters or amides, usually linked to a lipophilic aromatic group and to a hydrophilic, ionizable tertiary amine Most are weak bases with pK a values between 8 and 9, and at physiological pH are primarily in the charged, cationic form. Produce a transient and reversible loss of sensation (analgesia) in a circumscribed region of the body without loss of consciousness. Local Anesthetics I. Overview and Mechanism A. Properties Local Anesthetics

59. 60 Administered: Topically Infiltration into tissues to bathe local nerves Injection directly around nerves and their branches Injection into epidural or subarachnoid spaces Local Anesthetics I. Overview and Mechanism A. Properties Local Anesthetics

60. 61 The cationic form interacts with open Na + channels on the inner aspect of the axonal membrane during nerve excitation to block sodium current and increase the threshold for excitation. Cause a dose-dependent decrease in impulse conduction and in the rate of rise and amplitude of action potential. Effect is more pronounced in rapidly firing axons where Na + channels are more often in an open configuration. In general: smaller nerve fibers are more susceptible. smaller non-myelinated dorsal root type C fibers and lightly myelinated delta type A fibers carry pain and temperature sensations (and also sympathetic type C un-myelinated postganglionic fibers) and are blocked before larger heavily myelinated type A fibers, which transmit sensory proprioception and motor functions. Local Anesthetics I. Overview and Mechanism B. Mechanism of Action Local Anesthetics.

61. 62 1. Generally, directly into the nerve areas to be blocked. Except after topical application: The rate and extent of absorption into and out of nerves,(which is correlated with the relative lipid solubility of the uncharged form) it’s important in determining the: rate of onset of action rate of termination of action potential for systemic adverse effects 3. At therapeutic doses, all local anesthetics except cocaine are Local Anesthetics II. Absorption and Metabolism A. Administration Local Anesthetics.

62. 63 4. Co-administration of the vasoconstrictor epinephrine with a local anesthetic of short or intermediate duration of action (1:200,000 or less) reduces systemic absorption of the local anesthetic and prolongs its action. Epinephrine should not be co-administered for nerve block in areas supplied with end-arteries (may cause ischemia or necrosis) and should be used cautiously in patients in labor, with thyrotoxicosis, or with cardiovascular disease Local Anesthetics II. Absorption and Metabolism A. Administration Local Anesthetics.

63. 64 Local Anesthetics II. Absorption and Metabolism B. Rate of Absorption 1. Influenced by the dose and drug ’ s physical-chemical properties, as well as by tissue blood flow and drug binding. Systemic absorption is more rapid in highly vascularized tissues. C. Metabolism Some ester-typed local anesthetics are rapidly hydrolyzed by plasma cholinesterase and thus have very short plasma half-lives. Metabolism is decreased in patients with decreased or genetically atypical cholinesterase. 2. Amide-type local anesthetics are metabolized by hepatic microsomal enzymes. Metabolism is decreased in patients with liver disease or decreased hepatic blood flow. Local Anesthetics.

64. 65 Specific Drugs/Therapeutic Uses Selection: Based on the duration of drug action (short = 20 min; intermediate = 1-1.5 hr; long = 2-4 hr), effectiveness at the site of administration, and potential for toxicity A. Amides 1. Lidocaine (Prototype) [Xylocaine] Intermediate duration of action Generally preferred for infiltration block and epidural anesthesia. 2. Mepivacaine [ Carbocaine ] Intermediate duration of action, but longer than lidocaine Actions like lidocaine Not used topically Less drowsiness and sedation than lidocaine Local Anesthetics.

65. 66 A. Amides (continuation) Prilocaine [ Citanest ] Actions like lidocaine, but less toxic. Not used topically or for subarachnoid anesthesia. Toluidine metabolites may produce methemoglobin. Should not be used in patients with cardiac or respiratory disease or with idiopathic or congenital methemoglobinemia. Methemoglobinemia can be reversed by administration of methylene blue. 4. Bupivacaine [Marcaine, Sensorcaine ] Long duration of action. Generally preferred for infiltration block and epidural anesthesia. 5. Etidocaine [ Duranest ] Long acting. Rarely used for infiltration and peripheral nerve block, and epidural anesthesia. Motor block may appear before or without sensory block. Local Anesthetics.

66. 67 B. Esters 1. Procaine [Novocain] Short acting Not effective topically 2. Chloroprocaine [ Nesacaine ] Very rapidly metabolized by plasma cholinesterase-less reported toxicity than procaine. 3. Cocaine Short acting, naturally occurring alkaloid used only for topical anesthesia of mucous membranes Systemically, will block uptake of catecholamines into nerve terminals and may induce intense vasoconstriction. Adverse effects include euphoria, CNS stimulation, tachycardia, restlessness, tremors, seizures, and arrhythmias Should be used cautiously for patients with hypertension, cardiovascular disease, or thyrotoxicosis, or with other drugs that potentiate catecholamine activity Controlled substance that is subject to abuse Local Anesthetics.

67. 68 4. Tetracaine [Pontocaine] Long acting, but slow onset (> 10 min) Often preferred for spinal anesthesia Not generally used for peripheral nerve block, infiltration block, or lumbar epidural nerve block 5. Dibucaine [Nupercaine] Long acting, but slow onset (15 min) Used only for topical and spinal anesthesia 6. Benzocaine [Americaine] and Butamben Picrate [Butesin] Topical use only (sunburn, minor burns, pruritus) B. Esters (continuation) Local Anesthetics.

68. 69 Adverse Effects and Toxicity Usually, the result is an overdose or because of inadvertent injection into the vascular system. Systemic effects most likely occur with administration of amide class. A. Central Nervous System 1. Lightheadedness, dizziness, restlessness, tinnitus, visual disturbances, tremor. 2. Lidocaine and procaine may cause sedation and sleep. 3. High concentrations: nystagmus, shivering tonic- clonic convulsions, respiratory depression, coma and death. 4. Treatment includes maintenance of airway and assisted ventilation, i.v. diazepam for convulsions (or prophylactically), and succinylcholine to suppress muscular reactions. Local Anesthetics.

69. 70 B. Cardiovascular System Bradycardia from block of cardiac sodium channels and depression of pacemaker activity. 2. Hypotension from arteriolar dilation and decreased cardiac contractility. C. Allergic Reactions Rare: rash, edema, and anaphylaxis. Usually associated with ester-type drugs, which are derivates of p- aminobenzoic acid. Adverse Effects and Toxicity Local Anesthetics.

70. 71

71. Drugs to be stopped, continued, or started preoperatively 72

72. Anesthetic interaction with pre-existing drug therapy 73

73. Classification of perioperative drugs, probable mechanisms of action, and adverse effects 74

74. Airway and breathing decisions in general anesthesia 75