Pharmacology II - General Anesthetics PDF

1 PM 719 Pharmacology II Chapter 25 General Anesthetics Lecture Notes (LN) Types of General Anesthesia (a) monitored anesthesia care techniques = local anesthetic and sedatives, patient can still respond to verbal commands (b) balanced anesthesia = iv anestheti...

1 PM 719 Pharmacology II Chapter 25 General Anesthetics Lecture Notes (LN) Types of General Anesthesia (a) monitored anesthesia care techniques = local anesthetic and sedatives, patient can still respond to verbal commands (b) balanced anesthesia = iv anesthetic + inhaled anesthetic Intravenous Anesthetics (a) barbiturates (thiopental, methohexital) (b) benzodiazepams (midazolam, diazepam) (c) propofol (d) ketamine (e) opioid analgesics (morphine, fentanyl, sufentanil, alfentanil, remifentanil) (f) misc sedative hypnotics (etomidate, dexmedetomidine) Inhaled Anesthetics (a) halothane, enflurane, isoflurane, desflurane, sevoflurane = volatile anesthetics, liquids at room temp (b) nitrous oxide, xenon = gaseous anesthetics, gas at room temp Balanced Anesthesia (a) iv for induction (b) inhaled for maintenance of anesthesia Stages of Anesthesia (a) Stage I Analgesia, initially analgesia without amnesia (b) Stage II Excitement, delirious and vocalizing but amnesic (c) Stage III Surgical Anesthesia, pupil size used to determine plane of this stage (d) Stage IV Medullary Depression, CNS depression, death ensues (e) The most reliable indication of Stage III Surgical Anesthesia is loss of response to noxious stimuli (trapezius muscle squeeze) and reestablishment of regular respiratory pattern  2 Inhaled Anesthetics Pharmacokinetics (a) major factors that control rate of entry into the CNS: (b) concentration of inhaled anesthetic gas is proportional to its partial pressure (also called tension) (c) factors that control movement of gas into the CNS (time to induction) (1) Solubility (a) blood:gas partition coefficient (b) solubility of gas in inspired gas vs blood (c) nitrous oxide has low solubility in blood, has rapid onset of action (moves into the brain rapidly) (d) Table 25-1 pg 459 Katzung for list of inhaled anesthetics and blood:gas partition ratios (e) nitrous oxide 0.47 vs methoxyflurane 12 (rapid to slow induction) based on blood solubility. (2) Concentration in Inspired Air (a) enflurane, isoflurane, halothane have moderate blood solubility (b) increase the concentration in inspired air to 1.5% to increase blood levels and entry into brain, then reduce to 0.7% for maintenance (3) Pulmonary Ventilation (a) minute ventilation = rate and depth of ventilation (b) fourfold increase in ventilation rate almost doubles the arterial tension of halothane (c) hyperventilation increases the speed of induction of anesthesia (d) depression of respiration by opioid analgesics slows the onset of anesthesia (4) Pulmonary Blood Flow (a) increased blood flow through the lung exposes the anesthetic to larger volumes of blood in the alveoli which reduces (b) increased exposure to blood, increased solubility in blood, decreased transfer into the brain (5) Arteriovenous Concentration Gradient (a) arterial: venous blood gradient (b) venous blood returning to the lung has less anesthetic due to drug taken up into tissues (c) this will decrease drug entry into the brain  3 Elimination (a) most important factor is blood gas partition coefficient (b) gas has to leave the brain, enter the blood, then be exhaled (c) gas insoluble in blood (low blood:gas partition coefficient) is eliminated faster than more soluble gas anesthetics (d) halothane is twice as soluble in brain compared to nitrous oxide and takes longer to be eliminated compared to nitrous oxide (e) clearance of inhaled anesthetics via the lungs is the major route of elimination from the body (f) liver biotransformation may contribute to elimination for some inhaled anesthetics, halothane is 40% botransformed by liver, compared to < 10% for enflurane (g) liver biotranformation of fluoride containing inhaled anesthetics can lead to the production of chlorotrfluoroethyl free radicals which can produce an halothane hepatitis (h) liver biotransformation of enflurane and sevoflurane “may” produce fluoride ions which produce kidney dmage, more pronounced with methoxyflurane (rarely used for this reason) (j) sevoflurane is degraded by the carbon dioxide absorbent in anesthesia machines producing a vinyl ether which can cause kidney damage. Pharmacodynamics Mechanisms of Action (a) primary target is the GABAA chloride channel (b) inhaled anesthetics, barbiturates, benzodiazepines, etomidate, propofol all enhance GABA mediated inhibition (c) ketamine, a dissociate anesthetic is an antagonist at NMDA glutamic acid excitatory channels. (d) inhaled anesthetics may also act through hyperpolairzation of neurons through activation of potassium channels (e) inhaled anesthetics may also block the excitatory actions of Ach at nicotinic receptors and their cation channel receptors Dose-Response Characteristics: MAC (a) dose-response relationships for the inhaled anesthetics are unique and have ethical considerations. Low doses allow pain, higher dose can stop pain and even higher doses can induce death. (b) at steady state the concentration (partial pressure) of the inhaled anesthetic in brain = concentration (partial pressure) in the lung  4 (c) anesthic can not be measured in the brain but can be measured in the alvelor air (lung air) (d) concentration in the alvelor air is reported as the % of 760 mm Hg (atmospheric pressure at sea level) (e) MAC = minimum alveolar anesthetic (f) MAC = concentration that results in immobility in 50% of patients when exposed to noxius stimulus (surgical anesthesia) (g) MAC = surrogate measure of the anesthetic requirement (h) MAC = anesthetic potency among the different gases (i) MAC for nitrous oxide > 100%, the least potent (j) MAC for enflurane is 1.7 %, more potent (k) MAC dosing, a dose of 1 MAC will produce surgical anesthesia in 50% of patients (l) MAC decreased with coadministered drugs, opioids, sympatholytics, sedative-hypnotics (j) For all drugs, including gas anethetics, potency is a measure of how low a dose may be given in order to produce a the desired clinical effect. Drug A at 10 mg reduces blood pressure (BP) by 10%, drug B at 100 mg reduces BP by 10%. Drug A is more potent than drug B. But both drugs have the same efficacy, they both achieved a 10% reduction in BP. Gas Anesthetic MAC nitrous oxide > 100 very poor potency sevoflurane 2.0 isoflurane 1.4 halothane 0.75 high potency Servoflurane and isoflurane are similar, good potency but not very different from each other. Exams only wabt to know that the student knows the difference between 95 and 0.5. Factors that help control the time to induction (1) Gas solubility in blood (a) Solubility determined by the blood:gas partition ratio (b) As a general rule, highly blood soluble gases take longer to enter the brain and less blood soluble drugs will enter the brain faster. (c) A gas with a low blood:gas partition ratio will induce rapidly. For example, nitrous oxide works faster than halothane.  5 (2) The Minimal Alveolar Concentration (MAC) (a) MAC is a measure of the potency of an anesthetic gas. (b) Keep in mind that for drugs other than a gas anesthetic, the following is potency. Drug A reduces blood pressure to goal with 5 mg/day. Drug B reduces blood pressure to goal with 50 mg/day. So, Drug A is more potent than Drug B but they both work and are equal in efficacy. (c) Nitrous oxide has a low potency. It takes a high concentration to block pain from standardized surgical incision. Halothane is a potent anesthetic. Organ System Effects of Anesthetics Cardiovascular System (a) decrease arterial bp in direct proportion to their alveolar concentration (halothane, desflurane, enflurane, sevoflurane, isoflrane) (b) mechanism varies, halothane and enflurane decrease cardiac output; iso- flurane, desflurane, sevoflurane decrease peripheral vascular resitance (c) heart rate, halothane causes bradycardia through direct vagal stimulation, enflurane, sevoflurane no effect, desflurane and isoflurane increase heart rate. (d) beta blockers used to treat increased catecholamine stimulated increase in blood pressure Respiratory System (a) all (except nitrous oxide) produce a decrease in tidal volume and an increase in respiratory rate (b) all volatile anesthetics are respiratory depressants (c) all volatile anesthetics increase the pACO2 (d) all volatile anesthetics depress mucociliary function (mucous pooling, atelectasis, postoperative lung infection) (e) halothane and sevoflurane have bronchodilating actions which make them drugs of choice in patients with asthma, bronchitis, COPD.  6 Brain (a) all decrease the metabolic rate of the brain (b) all increase cerebral blood flow, not desired in patients with increased intracranial brain pressure due to tumor, or head injury (c) nitrous oxide less likely to increase cerebral blood flow Kidney (a) decrease the glomerular filtration Liver (a) from 15-45% decrease hepatic blood flow Toxicity (a) Liver (1) halothane hepatitis (prior exposure required) (2) incidence 1 in 25 000 – 35 000 (3) halothane may induce immune mediate cause (b) Kidney (1) methoxyflurane, enflurane, sevoflurane are biotransformed and release fluoride ions that can lead to toxicity (2) sevoflurane is degraded by carbon dioxide absorbents in anesthesia machines leads to a toxic compound which causes proximal tubular necrosis (3) methoxyflurane no longer used due to potential for fluoride induced renal toxicity (c) Malignant Hyperthermia (a) caused by a genetic disorder of skeletal muscle (b) condition induced by general anesthetics and succinylcholine (skeletal muscle relaxant) (c) condition presents with tachycardia, hypertension, muscle rigidity, hyperthermia, hyperkalemia, acidosis. (d) triggering agents Table 16-4 pg 297 and pg 465 Katzung have much on malignant hyperthermia. Never seen a pharmacology exam that did not have a question about malignant hyperthermia. (e) cause is uncontrolled release of calcium from SR in muscle (f) treat with dantrolene which blocks the release of Ca from SR (g) skeletal muscle biopsy and caffeine-halothane contracture test required to screen for malignant hyperthermia  7 (d) Chronic Toxicity (a) Mutagenicity (1) no effect demonstrated (b) Carcinogenicity (1) no effect demonstrated (c) Reproductive Organs (1) higher incidence of miscarriages among OR personnel Intravenous Anesthetics (a) used in addition to inhaled anesthetics and alone (b) faster induction of anesthesia compared to inhaled agents Barbiturates (a) thiopental, methohexital (b) readily cross BBB (lipid soluble) and rapidly induce anesthesia Benzodiazepines (a) diazepam, lorazepam, midazolam used for preanesthesia medication (b) sedative, anxiolytic, amnestic inducing (c) medazolam drug of choice for iv administration Opioids (a) used with benzos medazolam to induce anesthesia (b) fentanyl and sufentanil as adjuncts to general anesthetics Propofol (a) most popular iv anesthetic (think Michael Jackson) (b) reduced incidence of nausea and vomiting with rapid recovery at termination of iv infusion (c) used for both induction and maintenance of anesthesia (d) fospropofol, prodrug that reduces the incidence of injection site pain Etomidate (a) causes minimal cardiovascular and respiratory depression (b) has no analgesic properties and opioids must be used Ketamine (a) sold on the streets by drug dealers as “Special K” (b) drug produces dissociative anesthetic state, which includes catatonia, amnesia, analgesia with or without loss of consciousness (hypnosis). (c) drug blocks excitatory neurotransmitter glutamic acid at NMDA receptors  8 (d) only iv anesthetic with both analgesic and anesthetic properties (e) drug often induces emergence phenomena following use as an anesthetic (perceptual illusions, vivid dreams) (f) diazepam or midazolam reduces incidence of emergence phenomena (g) useful in low dose because of lack of respiratory depression Anesthetics Required are in Bold as listed below and in the text above. Inhaled Gas Anesthetics All act on GABAA receptors, and glycine and potassium channels The exact mechanism(s) of action are not completely understood Review the pharmacokinetics, pharmacodynamics and toxicity of each one. All may induce malignant hyperthermia, a genetic muscle disorder Volatile Anesthetics (liquids at room temperature) desflurane sevoflurane isoflurane enflurane halothane noted for causing halothane hepatitis Gaseous Anesthetic (gas at room temperature) nitrous oxide (blue cylinder) Intravenous Anesthetics Barbiturates All end in “tal” thiopental methohexital Benzodiazepines midazolam GABAA agonist drugs lorazepam  9 diazepam Hypnotic but not Analgesic etomidate hypnotic but not analgesic, GABAA agonist propofol (PROE po fole) fospropofol prodrug of propofol, converted by alkaline phosphatase, reduces injection site pain Dissociative Anesthetic ketamine inhibits NMDA receptors, dissociative effects Alpha2 Receptor Agonist dexmedetomidine (deks MED e toe mi deen) analgesic actions in the spinal cord hypnosis in locus caeruleus actions Factors that help control the time to induction (1) Gas solubility in blood (a) Solubility determined by the blood:gas partition ratio (b) As a general rule, highly blood soluble gases take longer to enter the brain and less blood soluble drugs will enter the brain faster. (c) A gas with a low blood:gas partition ratio will induce rapidly. For example, nitrous oxide works faster than halothane. The Minimal Alveolar Concentration (MAC) (a) MAC is a measure of the potency of an anesthetic gas. (b) Keep in mind that for drugs other than a gas anesthetic, the following is potency. Drug A reduces blood pressure to goal with 5 mg/day. Drug B reduces blood pressure to goal with 50 mg/day. So, Drug A is more potent than Drug B but they both work and are equal in efficacy. (c) Nitrous oxide has a low potency. It takes a high concentration to block pain from standardized surgical incision. Halothane is a potent anesthetic.  10 Table 1. Gas Anesthetics Gas Anesthetic Blood:gas Ratio MAC nitrous oxide 0.5 > 100 desflurane 0.5 6-7 sevoflurane 0.7 2.0 isoflurane 1.4 1.4 enflurane 1.8 1.7 halothane 2.3 0.75 NOTE: All these numbers are taken from the Katzung text book Tble 25-1 pg 467 15th edition. These numbers are simply guidelines and not hard fast precise numbers, 1.4 and 1.6 are not that different. Do not memorize the numbers, understand the concept. Additional Review: Inhaled Gas Anesthetics All act on GABAA receptors, and glycine and potassium channels The exact mechanism(s) of action are completely understood Review the pharmacokinetics, pharmacodynamics and toxicity of each one All may induce malignant hyperthermia a genetic muscle disorder Volatile Anesthetics (liquids at room temperature) desflurane  11 sevoflurane isoflurane enflurane may cause kidney damage due to release of fluoride ions halothane noted for causing halothane hepatitis Gaseous Anesthetic (gas at room temperature) nitrous oxide (blue cylinder) Intravenous Anesthetics Barbiturates All end in “tal” thiopental methohexital Benzodiazepines midazolam GABAA agonist drugs lorazepam diazepam Hypnotic but not Analgesic etomidate hypnotic but not analgesic, GABAA agonist propofol (PROE po fole) fospropofol prodrug of propofol, converted by alkaline phosphatase, reduces injection site pain Dissociative Anesthetic ketamine inhibits NMDA receptors, dissociative effects Alpha2 Receptor Agonist dexmedetomidine (deks MED e toe mi deen) analgesic actions in the spinal cord hypnosis in locus caeruleus actions