Inhaled Anesthetics Chap. 4 Part I PDF

University of Puerto Rico – Medical Sciences Campus School of Nursing – Nurse Anesthesia Program ENFE 7131 – Advanced Pharmacology I Jorge Hernandez, DNAP, CRNA v 1840 Nitrous oxide, diethyl ether & chloroform v1850 Fluroxene • First halogenated hydrocarbon • Replaced hydrogen atom with a fluorin...

University of Puerto Rico – Medical Sciences Campus School of Nursing – Nurse Anesthesia Program ENFE 7131 – Advanced Pharmacology I Jorge Hernandez, DNAP, CRNA v 1840 Nitrous oxide, diethyl ether & chloroform v1850 Fluroxene • First halogenated hydrocarbon • Replaced hydrogen atom with a fluorine atom to decrease flammability v1856 Halothane • Enhances arrhythmogenic effects of epinephrine v1960 Methoxyflurane • High lipid solubility resulted in prolonged induction and recovery. • Hepatic toxicity and nephrotoxicity with prolonged use (fluoride accumulation). v1973 Enflurane • Metabolism to inorganic fluoride and stimulation of central nervous system v1981 Isoflurane • Structural isomer of enflurane • Resistant to metabolism “The search for even more pharmacologically perfect inhaled anesthetics” qExclusion of halogens other than fluorine § Result in nonflammable liquids § Poor lipid solubility § Extremely resistant to metabolism q1992 Desflurane § Totally fluorinated methyl ethyl ether q1994 Sevoflurane § Totally fluorinated methyl isopropyl ether q Low solubility in blood • • • Facilitates rapid induction of anesthesia Precise control of end-tidal anesthetic Prompt recovery at the end of anesthesia regardless of time q Provider preference for Sevoflurane & Desflurane Vs. Isoflurane • Reflect preference fo rapid awakening • Despite factors such as airway irritation, SNS stimulation, carbon monoxide production, complex vaporizer, compound A production & greater expense. qFactors that Affect Cost § Price (cost per mL of liquid) § Vapor pressure § Fresh gas flow § Solubility of agent qDesflurane Vs. Isoflurane § 1/5 as potent § Amount (mL) needed to sustain an equivalent MAC only threefold qSevoflurane Vs. Isoflurane § MAC of Isoflurane is 74% greater § Amount (mL) needed to sustain equivalent MAC is 30% • Low molecular weight. • Inorganic, odorless to sweet-smelling nonflammable gas (can support combustion). • Low potency. • Low blood:gas. • Commonly administered with opioids or volatile anesthetics in general anesthesia. • Prominent analgesic effect but short lived after discontinuation • Minimal skeletal muscle relaxation • Adverse Effects • High volume absorption in gascontaining spaces. • Ability to inactivate Vitamin B12. • Post Operative Nausea and Vomiting (PONV). • MAC = 104%; VP = Gas; Blood:gas = 0.46 • Halogenated alkane derivative, clear and nonflammable liquid at room temperature. • Vapor has sweet bland odor • Intermediate solubility and high potency provides for intermediate onset and anesthesia recovery. • Stored in amber-color bottles, and thymol is added as preservative to prevent spontaneous decomposition. • Thymol can cause vaporize turnstiles or temperature compensation malfunction. • MAC = 0.75%; blood:gas = 2.54; VP = 244 mmHg. • Metabolism of 15 to 20%. • No longer in use in the US. • Halogenated methyl ethyl ether exists as a clear, nonflammable volatile liquid at room temperature. • Pungent, ethereal odor. • Intermediate solubility and high potency. • Decreases threshold for seizures. • Oxidized in the liver to produce inorganic fluoride which can be nephrotoxic. • Used to be used for electroconvulsive therapy. • MAC = 1.63%; Blood:gas = 1.9; VP = 172 mmHg • Halogenated methyl ethyl ether exists as a clear, nonflammable volatile liquid at room temperature. • Pungent ethereal odor. • Intermediate solubility and high potency. • Characterized by extreme physical stability. No detectable deterioration during 5 years of storage, CO2 exposure or sunlight. • No need for preservatives. • MAC = 1.17% ; VP = 240 mmHg • Blood:gas = 1.46; Metabolism of 0.2% Vs. qFluorinated methyl ethyl ether § § § § § Enhances molecular stability Increases vapor pressure (669 mmHg) Decreases potency MAC = 6.6% ; blood:gas = 0.42 Metabolism of <0.1% qUtilizes special vaporizer § § § § § § Heated (39 C) Pressurized (two atmospheres) Requires electrical power 1/5 of isoflurane potency Minimal metabolism Pungent (can cause coughing & laryngospasm) qCarbon Monoxide Poisoning § Results from degradation of desflurane by strong base present in desiccated CO2 absorbent. § Desflurane>Isoflurane>Enflurane. § Carboxyhemoglobin is difficult to detect. § Absorbent color change does not occur with desiccation. qHow to Detect It § § § § § Decrease pulse oximeter readings Erroneous gas analyzer reading (indicating mixed gas) CO-oximetry monitoring Intraoperative hemolysis can mimic symptoms Delayed symptoms (3-21 days after anesthesia exposure) ü Cognitive defects, personality changes, gait disturbances qFluorinated methyl isopropyl ether § § § § § § Uses conventional vaporizer (VP =170 mmHg). MAC = 1.8% ; blood:gas = 0.69 Non pungent with minimal odor. Suitable for induction as halothane. Bronchodilator as isoflurane. Patient emerges 3-4 min faster than isoflurane. qMetabolism (3-5%) § § § § § 100th fold that of desflurane. Produces inorganic fluorides. Does not produce trifluoroacetylated liver proteins. The least likely to form carbon monoxide. Can form Compound A when reacting with CO2 absorbent. Factors that Favor Compound A Formation • • • • Increase abosrbent temperature Dry barium hydroxyde absorbent Low flow anesthesia Long duration anesthesia Sevoflurane Vs. Isoflurane Minutes to Recovery qInert Gas with Ideal Characteristics MAC = 63 to 71% (lower requirement in females). MAC awake = 33%; Blood:gas – 0.115 Nonexplosive, odorless, and chemically inert (no metabolism & low toxicity). Not harmful to environment. High cost has hindered acceptance. Like N2O favors bubble expansion. Does not trigger MH in susceptible swine. 2 to 3 times faster emergence that that of nitrous oxide plus Iso or Sevo. Potent analgesic that suppresses catecholamine release with surgical stimulus. § Shown to block NMDA receptors (similar to Ketamine). § § § § § § § § § q A series of partial pressures gradients begin at q Pass through various barriers q Main objective is to achieve a constant and optimal brain partial pressure q Brain and all other tissues equilibrate partial pressures with arterial blood Pa q Arterial blood equilibrates with alveolar partial partial pressure PA q PA is used as index of depth, recovery and equipotency. The rise and fall in alveolar partial pressure precedes that of other tissues. Inhaled Partial Pressure o A high PI from the anesthesia machine is required initially to offset uptake. Concentration Effect “Impact of PI on the rate of rise of the PA” • The higher the PI, the faster PA approaches the PI. • Concentration effect results from: 1. Concentration effect 2. Augmentation of tracheal inflow. Concentration Effect Concentrating Effect v Increasing the inspired concentration not only increases the alveolar concentration, but also its rate of rise FA/FI v Examples: Ø If 50% of an anesthetic is taken up by the pulmonary circulation, an inspired concentration of 20% will result in an alveolar concentration of 11% Ø If the inspired concentration is raised to 80%, the alveolar concentration will result in 67% v Even when both examples have a pulmonary uptake of 50%, a higher concentration, disproportionately increases alveolar concentration. Concentration Effect Augmented Inflow Effect v Using the prior examples, the 10 part of absorbed gas must be replaced by an equal volume of the 20% mixture to prevent alveolar collapse. v Thus, the alveolar concentration becomes 12%. v In contrast, after absorption of 50% of the anesthetic with an inspired concentration of 80% gas mixture, 40 parts of 80% must be inspired to replace it. This further increases the alveolar concentration from 67% to 72% (40 plus 32 parts out of a 100). Second-Gas Effect “Reflects the ability of high-volume uptake of one gas (first gas) to accelerate the rate of increase of the PA of a concurrently administered companion gas (second gas).” • • • • Second gas effect pertains to nitrous oxide specifically Nitrous oxide is 35 times more soluble than nitrogen Reflects increased tracheal inflow of all the inhaled gases Reflects concentration of second gas or gases in a smaller lung volume Alveolar Ventilation • Increased alveolar ventilation, like PI promotes input of anesthetic to offset uptake. • Results in a more rapid rate of increase in the PA toward the PI and induction. • The greater the Alveolar ventilation to Functional Residual Capacity (FRC), the more rapid the rise in PA. • Ratio in neonates 5:1 Vs. 1.5:1 in adults. Induction faster in neonates. Spontaneous Vs. Mechanical Ventilation • Inhaled anesthetics influence their own uptake by virtue of dose-dependent depressant effects on alveolar ventilation. (Negative feedback protective mechanism). • Mechanical ventilation overrides this spontaneous breathing protective mechanism. Impact of Solubility • Any impact of changes in alveolar ventilation is also dependent on the solubility of anesthetic in blood. • The more blood soluble the anesthetic, the greater the impact that any increase in alveolar ventilation will have on its rate of rise. Anesthetic Breathing System Characteristics Influencing Rate of Rise of the PA • Volume of the external breathing system. • Solubility of Inhaled anesthetics (rubber or plastic components). • Gas inflow from the anesthetic machine. • Can delay both onset and emergence. Blood:Gas Partition Coefficients • Rate of increase in PA toward PI is inversely related to the solubility of anesthetic in blood. • Blood can be considered a pharmacologically inactive reservoir for which the size is determined by the blood:gas. • Overpressure technique: overshoot the PI above the required for maintenance to speed induction. • Blood:gas partition coefficient are about 20% less in blood with a hematocrit of 21% compared with blood with a hematocrit of 43% (erythrocytes provide blood dissolving sites). • Ingestion fatty meals alters composition of blood and can result in 20% increase in solubility. • Solubility also varies with age: Halothane, enflurane, methoxyflurane are isoflurane are about 18% less in neonates and elderly. Tissue:Blood Partition Coefficients • Determine uptake of anesthetic tissues and the time necessary for equilibration of tissues with Pa. • Pa to Pbrain requires 5 to 15 minutes (three-time constants) • Equilibration of fat with Isoflurane (three-time constants) at 2 – 3 mL per 100g of fat is estimated at 25 – 46 hrs. Oil:Gas Partition Coefficients • Parallels anesthetic requirements. • Estimated MAC: 150 divided by oil:gas partition coefficient. (150 = average of the product of oil:gas x MAC). Nitrous Oxide Transfer to Closed Gas Spaces • N2O has the capacity to accumulated in closed spaces. • It can cause damage by increasing pressure. • Blood:gas is 0.46 and has 34 times the solubility of nitrogen (0.014). • Compliant wall gas cavity = expansion (intestines, pneumothorax, pulmnary blebs, air bubbles). • Non-compliant gas cavity = pressure buildup (middle ear, cerebral ventricles, supratentorial space). • The magnitude of volume or pressure increase is influenced by: 1. Partial pressure of nitrous oxide 2. Blood flow to air-filled cavity 3. Duration Cardiopulmonary Bypass (CPBP) • CPBP produces changes in blood:gas solubility depending on temperature and priming solution. • Volatile anesthetics initiated during CPBP take longer to equilibrate. Cardiac Output (CO) • CO (pulmonary blood flow) influences uptake and therefore PA (carries more or less). • CO uptake = rate of increase of PA and induction are slowed. • CO uptake = rate of increase of PA and induction are faster (less uptake to oppose input). • CO changes have greater effect on the rate of rise in PA with more soluble inhaled anesthetics/ • Positive feedback response can occur with volatile anesthetics that depress cardiac output. Impact of a Shunt • In the absence of a shunt (intracardiac or intrapulmonary) it is assumed PA = Pa. • In the presence of a right-to-left shunt, there is a dilutive efffect thar results in a decreased Pa and slower induction. • The impact of a right-to-left shunt is more pronounced with less soluble inhaled anesthetics Vs. more soluble. • Left-to-rigth shunts occur with arteriovenous fistulas, septal defects or volatile anesthetic-induced increase in cutaneous flow. • Left-to-right results in blood going into the lungs with higher partial pressure than otherwise. • Left-to-right can offset dilutional effects of a right-to-left shunt. Alveolar-to-Venous Partial Pressure Differences (A-vD) • A-vD reflects tissue uptake of the inhaled anesthetics by affecting mixed venous partial pressure of anesthetic. • Factors that determine tissue uptake: tissue solubility, blood flow, and arterial-to-tissue partial pressure difference. • Vessel rich group equilibrate rapidly with the Pa. • Continued uptake after saturation of vessel rich group reflects entrance into skeletal muscle and fat (slow process). • Continued uptake from the vessel poor group result in continued A-vD difference for several hours. • Equilibration time of vessel-rich group (VRG) in neonates is more rapid for neonates and infants (even greater fraction of CO to VRG and less solubility in neonatal tissues. Recovery From Anesthesia • Depicted by the rate of decrease in the Pbrain as reflected by the PA. • There is no concentration effect such as it occurs with induction (not possible to administer less than zero). • Rate of decrease in PA during emergence is faster than the rate of increase in PA during induction. More soluble agents Less soluble agents