NC Hwang 2008

Inhalational agents
History 1844 Horace Wells introduced nitrous oxide for use in dental extraction 1846 Demonstration of ether anaesthesia by Morton 1951 Xenon first used clinically in UK 1951 by Cullen Halothane synthesised by Suckling at Imperial Chemical Industries, first used clinically by Michael Johnstone, Manchester, UK 1956 1963 Enflurane synthesised by Terrell, first used clinically 1966 1965 Isoflurane synthesised by Terrell, first used clinically 1971 Development of desflurane 1968 Sevoflurane synthesised by Regan at Travenol Laboratories, clinical practice in Japan 1990 1992 Desflurane first used clinically in USA Types of inhalational agents Inspired gas concentration, Fi agent determined by vaporizer concentration set concentration effect wash-in characteristics of the circuit FGF volume of breathing system losses from the circuit by dissolution (solubility of agent in material of circuit) effects of rebreathing partial pressure of an individual gas in inspired air: PIgas = FIgas x PAtm (Dalton's law of partial pressures) the greater the inspired pressure the greater the approach of FA to FI (concentration effect) this is only significant where FI is very high, as is the case for N2O (or cyclopropane) when another gas is used in the presence of such an agent, there is increased uptake of the second gas, the second gas effect Concentration effect the impact of PI on the rate of rise of PA of an inhaled anaesthetic is known as the concentration effect with higher FI anaes, the rate of rise in arterial tension Pa anaes is greater

Uptake and distribution

/Fi

Circuit wash-in During wash-in, PI >PA, at equilibrium PA = Pa = PB Uptake into alveoli transfer from inspired gas to alveoli the inspired gas concentration, FI characteristics of the anaesthetic circuit alveolar ventilation, VA determined by the FGF and the volume of the circuit faster rate of wash-in with higher FGF the volume of the anaesthetic breathing system acts as a buffer to slow the achievement of PA an average circle circuit with a volume of 7 litres, with a FGF = 6 L/min and no uptake from the circuit, FI/FD will be ~ 1.0 at 5-6 minutes corrugated hoses and fittings ~ 3 L, bag ~ 2 L, CO2 absorber ~ 2 L

NC Hwang 2008 Circuit losses both rubber and plastic components of the system may remove agent and slow circuit wash-in a significant problem for methoxyflurane less so for halothane or isoflurane virtually insignificant for N2O or desflurane similarly uptake may occur into soda lime this is small unless the soda lime is dry, when appreciable amounts of agent may be absorbed both dry and wet soda lime will absorb appreciable amounts of sevoflurane Use of circle breathing system on Fi agent rebreathing circuit FI is affected by fresh gas + the amount of exhaled gas an increase in either uptake or rebreathing will lower the FI of a highly soluble gas more than that for an insoluble gas this effect may be decreased by decreasing rebreathing high FGF rates allow predictability of FI but wasteful and result in drier inspired air Use of T-piece breathing system on Fi agent non-rebreathing circuit FI approaches vaporiser setting very quickly however, a minimum fresh gas flow rate (> minute ventilation) is necessary to maintain non-rebreathing of exhaled waste gases, and wasteful and result in drier inspired air Alveolar ventilation each inspiration delivers some anaesthetic to the lung and, if unopposed by uptake into the blood, normal ventilation would increase FA/FI to 95-98% in 2 minutes the rate of rise of FA/FI is dependent upon minute ventilation and FRC the greater the FRC, the slower the rise in FA by increasing minute ventilation, the tension in alveolar air and arterial blood will rise more quickly (lung washin) the effects of increasing minute ventilation on the rate of induction transient for gases such as N2O which are poorly soluble in blood, and thus equilibrate quickly a significant effect on the highly soluble agents, such as methoxyflurane or diethyl-ether hyperventilation will decrease cerebral blood flow this tends to offset the increased rise of FA/FI Second gas effect reflects the ability of high-volume uptake of one gas (first gas) to accelerate the rate of rise of the PA of a concurrently administered companion gas (second gas) during the inhalation of 70% N2O in O2, initially as much as 1 l/min may diffuse into the bloodstream across the lungs this effectively draws more gas into the lungs from the anaesthetic circuit, thereby increasing the effective minute ventilation Effect of minute ventilation

the second gas effect results from a concentrating effect (A) and an augmentation of tracheal inflow (B) Spontaneous inhalation of anaesthetic agent the tension in the inspired gas is limited by agent-induced airway irritability when a constant tension is inhaled, the tension in arterial blood progressively approaches the tension in alveolar air the rate at which this occurs is determined by the solubility of the agent during maintenance, PI may be considerably greater than PA, depending on the solubility of the agent during spontaneous breathing, inhaled anaesthetics influence their own uptake by dose-dependent depressant effects on alveolar ventilation this protective mechanism is lost when mechanical ventilation of the lungs replaces spontaneous breathing

NC Hwang 2008 Uptake into blood Uptake = B:G . CO. (PA/PAtm) transfer from alveoli to arterial blood alveoli to venous pressure difference, dP(A-v)Gas blood : gas partition coefficient, B:G cardiac output, CO Effects of shunt induction of anaesthesia is slow a larger P(A-a)Gas gradient develops for insoluble agents compared with soluble agents examples of shunt: endobronchial intubation, congenital heart disease Alveoli to venous pressure difference Pa cannot approach equilibrium with PA until the distribution of anaesthetic from the blood to the tissues is nearly complete with equilibration, the PA/Pv difference progressively falls as tissue tensions rise since diffusion is directly proportional to the tension difference, the rate of diffusion into the blood progressively slows Blood:gas solubility Ostwald solubility coefficient, B:G the solubility of a gas in liquid is given by the volume of gas which dissolves in one unit volume of the liquid at the temperature concerned this is independent of pressure partition coefficient represents the ratio of the concentration in blood to the concentration in the gas phase partial pressures equal in both phases serum proteins and red blood cells are the major determinants of solubility based on the blood:gas partition coefficients, inhaled anaesthetics are categorized as soluble: methoxyflurane intermediate solubility: halothane, enflurane, isoflurane poorly soluble: nitrous oxide, desflurane, sevoflurane blood:gas partition coefficient principal determinant of the approach of FA to FI the reservoir for insoluble agents is small and fills more quickly minimal amounts of the inhaled anaesthetic agents with low blood:gas partition coefficient need to be dissolved before equilibrium is reached soluble agents have a larger blood reservoir larger amount of the anaesthetic agents with high blood:gas partition coefficient must be dissolved in the blood before the Pa equilibrates with the PA lower blood:gas coefficients with haemodilution (anaemia) 20% less with Hct of 21% as compared with Hct of 43% obesity hypoalbuminaemia (starvation) higher blood:gas coefficients with adults (versus children) hypothermia hyperlipidaemia FA/FI Curves
A B

Blood gas partition coefficient

NC Hwang 2008 Effects of cardiac output right ventricular cardiac output or pulmonary blood flow determines the rate at which agents pass from gas to blood high cardiac output state: slow rate of rise of FA/FI low cardiac output state: rapid rate of rise of FA/FI effects are greater for highly soluble agents anaesthetic induced cardiovascular depression may cause a more rapid rise in arterial tension use of volatile anaesthetics, beta blockers Equilibration with tissues Brain: Pa = PB in about 15 minutes adipose tissues solubility in lipid tissues for volatile anaesthetics is far greater than that for blood at equilibrium the concentration in lipid tissues will be far greater than that in blood the tissue concentration will rise above that of blood well before pressure equilibrium, even though the tissue tension is lower lean tissues rate of tension rise in these regions is proportional to the arterial-tissue tension difference the time for equilibration is determined by the tissue time constant and tissue blood flow the amount of inhaled anaesthetic that can be dissolved in the tissue (tissue capacity, T:B) one time constant on an exponential curve represents 63% equilibration Distribution to tissues transfer from arterial blood to tissues arterial to tissue pressure difference dP(a-t)Gas tissue : blood partition coefficient, T:B tissue blood flow Tissue blood flow body tissues can be divided into groups according to their perfusion/blood flow: vessel rich group (VRG): brain, heart, kidney & liver muscle group (MG): muscle & skin fat group (FG): large capacity/minimal flow vessel poor group (VPG): bone, cartilage 63% of a process is completed in one time constant 3 time constants to about 95% equilibration at 37oC

equilibration time VRG receives 75% of the CO, after 3 time constants, 75% of the returning venous blood will be in equilibrium with PAGas

NC Hwang 2008 Induction of general anaesthesia general anaesthesia results from attaining the required tension of anaesthetic in the brain the tension in the brain relates to the tension in the blood which in turn relates to the tension in the alveolar the alveolar/brain cascade the rate of increase in tension with time is an exponential function the time constant is shortest for the agents with low blood:gas and brain:blood solubilities Minimum alveolar concentration the minimum alveolar concentration of anaesthetic, at equilibrium, at one atmosphere pressure, which produces immobility in 50% of subjects exposed to a standard noxious stimulus, which for humans is surgical incision of the skin motor response if neuromuscular blocker is administered, the feedback mechanism is lost a measure of potency, enables comparison at equilibrium, PA mirrors the PB the depth of anaesthesia varies directly with the tension of the agent in the brain FET or FA can be measured easily, therefore, PA is used as an index of depth of anaesthesia, recovery from anaesthesia, and anaesthetic potency (MAC) MAC is uniform with a variety of noxious stimuli individual variability is small MAC is not altered by sex, height, weight and anaesthetic duration doses of anaesthetics in MACs are additive Additivity parallels anaesthetic requirements an estimated MAC can be calculated as 150 divided by the oil:gas partition coefficient the constant, 150, is the average value of the product of oil:gas solubility and MAC for numerous inhalational anaesthetics Log-dose response curve of MAC the slope of the dose/response curve is steep 50% of subjects unresponsive at 1 MAC at least 95% are unresponsive at 1.3 MAC

Factors increasing MAC value age: MAC is highest at 6 months chronic alcohol abuse: enzyme induction drug induced elevation of CNS catecholamine stores ephedrine, amphetamine, cocaine hypermetabolic states thyrotoxicosis hyperthermia (Steffey EP, Eger EI 2nd. Anesthesiology 1974;41:392-6 (decrease solubility of volatile anaesthetic in blood)) hypernatraemia (Tanifuji Y, Eger EI 2nd. Anesth Analg 1978;57:404-10) hypernatremia proportionately increased cerebrospinal fluid sodium and osmolality; MAC concomitantly increased 43%, with dilution of cerebrospinal fluid, MAC was reduced by 24% Effect of body temperature on MAC value hyperthermia decreases the solubility of anaesthetic agent in blood, higher MAC value required hypothermia increases the solubility of anaesthetics in blood, lower MAC value required the more soluble the agent the greater is the change of solubility with temperature

Oil gas partition coefficient and MAC

NC Hwang 2008 Factors decreasing MAC value nitrous oxide: additivity of MAC premedication: amnesiac effects of drugs are additive age: MAC decreases with age acute alcohol intoxication hypothermia: MACHal @27C 50% of MACHal @37C, decrease is nearly linear hypotension: presumed to be due to the more rapid rise in alveolar concentration per unit time hypercarbia: carbon dioxide >120mmHg has been used as an anaesthetic - Hickman hypoxaemia: PaO2<40 mmHg anaemia pregnancy: progesterone effect sympathetic decrease: centrally acting drugs - clonidine, reserpine, methyldopa, narcotics, benzodiazepines, tranquilizers, TCA other drugs: lithium, lignocaine, magnesium Factors with no effect on MAC gender weight, body surface area duration of anaesthesia hypo/hyperkalaemia hypothyroidism PaCO2 ~ 15-95 mmHg PaO2 > 40 mmHg MAP > 40 mmHg MAC awake the concentration at which appropriate responses to commands are lost in 50% of patients and correlates also with amnesia and loss of awareness without surgical stimulation equals or exceeds the concentration to suppress awareness and capacity to learn new information Factors affecting recovery from anaesthesia (wash-out) solubility, different tensions of anaesthetic in different tissues, cardiac output, organ blood flow, dPv-A(gas) slow recovery with highly soluble agent, rapid recovery with poorly soluble agent different compartments have different own time constants depending on its capacity (solubility. mass) and blood flow the elimination time constants will determine the decrease in mixed venous tension inter-tissue redistribution anaesthetics diffuse from well perfused tissues to adjacent poorly perfused tissues which have a high capacity for the agent from heart to pericardial fat, kidneys to perinephric fat, which may account for as much as 1/3 of the agent taken up MG, FG continue to take up agent due to the longer time constants for the tissue groups, and equilibrium of partial pressures may not have been achieved between blood and MG or FG at the end of an anaesthetic consequently these groups, especially the FG, continue to take up agent and actually contribute to the decline of Pa during the first few hours
MAC

Elimination of inhaled anaesthetics Elimination curves

asleep awake

metabolism Effect of inhibition or saturation of metabolising enzymes

NC Hwang 2008 Tissue agent concentrations during wash-in and washout phases Molecular stability halogenation, especially fluorination enhances molecular stability halogens on three sides of an ether bond is very stable weakest bond strength: C-H C-Br C-Cl C-F strongest fluorination decreases vulnerability to biodegradation 0.02-0.04% desflurane versus 0.2% isoflurane CF3 resists oxidative metabolism Fluorination The ideal inhalational anaesthetic agent stable inflammable, non explosive technically easy to administer potent not an airway irritant for inhalational induction low blood:gas partition coefficient rapid induction and rapid and easily identified changes in the depth of anaesthesia high degree of specificity of action adequate relaxation of skeletal muscles analgesic the absence of toxic or other adverse effects at normal doses, including metabolites a wide margin of safety non-arrhythmogenic no CNS stimulation or uncontrolled change in CBF non-carcinogenic, non-teratogenic safe for all age groups low cost Stability of volatile agent Structural activity CF3 toxicity is probably inversely related to chemical stability, and is thought to be caused by active products of biotransformation Degradation of halothane in soda lime broken down in soda lime to vinyl compound, F-C=C-Cl 2-bromo,2-chloro,1,1-difluoroethane F Br LD50 in rats of 250 ppm during high flow anaesthesia, BCDFE is produced in concentrations of 4-6 ppm Degradation of sevoflurane in soda lime degraded by soda lime and the more reactive and exothermic Baralyme (calcium and barium hydroxide CO2 absorber) in a temperature dependent manner higher temperatures and higher concentrations of sevoflurane have been shown to increase the production of a breakdown product Compound A, a vinyl ether FH H F-C-C-O-C-H F CF3 F
sevoflurane

increasing fluorination leads to resistance to oxidative metabolism and molecular stability less potency less soluble in blood Stability of halogenated alkanes halothane chemically unstable, decomposing to HBr, HCl, and phosgene on exposure to light therefore supplied in amber coloured bottles requiring the addition of thymol 0.01% as a stabilising agent

pentafluoroisopropenyl fluoromethylether (PIFE)

H F-C=C-O-C-F + F CF3 H

HF

nephrotoxic threshold for rats is 50-114 ppm, LD50 rats is 1000 ppm

NC Hwang 2008 PIFE prolonged anaesthesia with sevoflurane, even with flows as low as 1 l/min, result in Compound A concentrations < 25 ppm with no obvious clinical side effects flow rates of less than 1 l/min have been used with resultant Compound A concentrations in the range of 50-60 ppm estimates of the concentrations required to cause cell necrosis of proximal tubules in humans range from 150-240 ppm-h (based on studies of biochemical markers of renal failure post-operatively) to as high as 800 ppm-h (based on studies in primates) no material difference between Baralyme and soda lime in the concentrations of Compound A produced at a particular inflow rate presence of strong base sodium hydroxide and/or potassium hydroxide is fundamental to this reaction FGF rate, ventilation, and carbon dioxide production are major determinants of the concentration of Compound A Carbon monoxide production a difluoromethoxy group in the volatile agent is a structural requirement for haloether degradation to carbon monoxide F -O-C-H F volatile agents that are not degraded to carbon monoxide include isoflurane, enflurane, desflurane monofluoromethyl ether (sevoflurane) methyl-ethyl ether (methoxyflurane) alkane (halothane) amount of CO formed at equimole concentration: enflurane > desflurane > isoflurane but due to lower potency of desflurane, at equiMAC: desflurane > enflurane > isoflurane a significant problem only if the soda lime is desiccated, which should not occur during low flow anaesthesia low flow anaesthesia should, therefore, help to prevent the production of carbon monoxide as compared to high flow techniques. CO production is greater with dry barium hydroxide lime than with soda lime base-catalysed difluoromethoxy proton abstraction is greater with potassium hydroxide than sodium hydroxide barium hydroxide lime contains 4.6% potassium hydroxide, whereas soda lime contains only 2.5% potassium hydroxide and 1.5% sodium hydroxide barium hydroxide per se does not catalyse difluoromethoxy proton abstraction by reducing percentage of potassium hydroxide composition of carbon dioxide absorbent can be changed to reduce production of carbon monoxide the chemical reaction of exhaustion dehydrates the absorbent to approximately 4-5% water Formaldehyde generation when desiccated CO2 absorbents are used with sevoflurane under extreme experimental conditions, flammable degradation products, including formaldehyde and methanol, may be present Structural activity CHOF2 (difluoromethoxy group) carbon monoxide production granules at or below this hydrated state are sufficiently dessicated to commence the production of carbon monoxide initial base-catalysed difluoromethoxy proton abstraction forms carbanion (which can be reprotonated by water to regenerate the anaesthetic agent)

carbanion decomposes to difluorocarbene and trifluoroacetaldehyde

difluorocarbene reaction forming CO and formate

NC Hwang 2008 Flammability fluorination decreases flammability ethers in clinical concentrations are non-flammable and non-explosive Administration variable-bypass, flow-over, temperature-compensated, agent-specific, out-of-circuit vaporisers are used to deliver halothane, enflurane, isoflurane, and sevoflurane but not desflurane. variable-bypass refers to the method for regulating output concentration as gas flow enters the vaporizer's inlet, the setting of the concentration control dial determines the ratio of flow that goes through the bypass chamber and through the vaporizing chamber. flow-over refers to the method of vaporisation the gas that is channelled to the vaporising chamber flows over the liquid anaesthetic and becomes saturated with vapour a vaporiser is classified as temperature-compensated if equipped with an automatic temperature-compensating device that helps maintain a constant vaporiser output over a wide range of temperatures vaporisers are agent-specific designed to accommodate a single agent out-of-circuit because they are to be located outside the breathing circuit Boiling points and vapour pressures

two independent gas circuits, the fresh gas circuit and the vapour circuit the fresh gas from the flowmeters enters at the fresh gas inlet, passes through a fixed restrictor, and exits at the vaporiser gas outlet the vapour circuit originates at the desflurane sump, which is electrically heated and thermostatically controlled to 39oC, a temperature well above desflurane's boiling point the heated sump assembly serves as a reservoir of desflurane vapour; at 39oC, the vapour pressure in the sump is 1500 mmHg absolute, or approximately 2 atmospheres absolute; just downstream from the sump is the shut-off valve. after the vaporiser warms up, the shut-off valve fully opens when the concentration control valve is turned to the on position; a pressure-regulating valve downstream from the shut-off valve downregulates the pressure to approximately 1.1 atmospheres absolute at a fresh gas flowrate of 10 L/min the operator controls desflurane output by adjusting the concentration control valve which is a variable restrictor the vapour flows through the concentration control valve, joins the fresh gas flow through the vaporiser gas outlet at a point downstream from the restrictors; until this point, the two circuits are physically separated and are interfaced pneumatically and electronically, through differential pressure transducers, a control electronics system, and a pressure-regulating valve when a constant fresh gas flowrate encounters the fixed restrictor, a specific back pressure, proportional to the fresh gas flowrate, pushes against the diaphragm of the control differential pressure transducer; the differential pressure transducer conveys the pressure difference between the fresh gas circuit and the vapour circuit to the control electronics system the control electronics system regulates the pressureregulating valve so that the pressure in the vapour circuit equals the pressure in the fresh gas circuit; this equalised pressure detected at the fixed restrictor and the vaporiser gas outlet is the working pressure, and the working pressure is constant at a fixed fresh gas flowrate if the fresh gas flowrate increases, more back pressure is exerted upon the diaphragm of the control pressure transducer, and the working pressure of the vaporiser increases at a specific dial setting at different fresh gas flowrates, vaporiser output is constant because the amount of flow through each circuit is proportional

Administration of Desflurane desflurane's vapour pressure of 664 mmHg is 3-4x that of contemporary inhaled anaesthetics, it boils at 23.5oC, it is moderately potent, with MAC values of 6% to 7%, makes delivering desflurane with a conventional variable bypass vaporizer unsuitable controlled vaporisation of desflurane requires an electrically heated, pressurised vaporiser, otherwise any volume of gas introduced to the vaporising chamber would result in an uncontrolled efflux of gas from the chamber because of its low potency, large amounts of liquid will need to be vaporised, resulting in excessive cooling of the chamber if there is no external heat source to achieve controlled vaporisation of desflurane, the Tec 6 vaporiser is electrically heated and pressurized

NC Hwang 2008 Tec 6 Desflurane vaporiser electrically heated, agent specific dual circuit (carrier gas is not split) constant temperature (thermostatically controlled at 39oC) gas-vapour blender (heat produces vapour, which is injected into fresh gas flow) an electrically controlled pressure regulating valve enables precisely controlled output unaffected by fresh gas flow controlled by a concentration control dial and a transducer, it is accurate at low flows can be filled during use 390 ml capacity for out of circuit use Potency compared with chlorination, fluorination produces less potent compounds Anaesthetic Methoxyflurane Halothane Enflurane Isoflurane Sevoflurane Desflurane Airway irritation all have aromatic odours although isoflurane has lower blood:gas solubility as compared to halothane, being pungent makes inhalational induction with isoflurane difficult airway reflex stimulation: increased secretions, coughing and laryngospasm, especially isoflurane and desflurane Rate of induction fluorination lowers the solubility of the agent in blood inhalational induction of anaesthesia is rapid with agents of low blood/gas and brain/blood partition coefficients with sevoflurane and desflurane, excellent control of anaesthetic depth and rapid recovery after discontinuing administration Target organ specificity depression of reticular formation neuronal activity the greater the oil/gas partition coefficient, the greater the capacity for fatty tissue to absorb the agent, similarly, the greater the brain/blood partition coefficient, the greater the capacity for the brain to absorb the agent however, a longer period of elimination follows prolonged administration MAC in % atmosphere 0.16 0.75 1.68 1.15 2 6 Relaxation of skeletal muscles mechanisms central depression (all inhalational anaesthetics) increased sensitivity of the end-plate to the action of nondepolarising muscle relaxant (halothane) action at the post-junctional membrane of the neuromuscular junction (enflurane, isoflurane) increased muscle blood flow accelerates delivery of neuromuscular drugs (isoflurane) Analgesic property methoxyflurane provides profound analgesia but not used now because of renal toxicity Adverse pharmacodynamic effects malignant hyperthermia arrhythmias increasing halogenation of the alkanes increases the propensity for the agent to cause arrhythmias ethers are less prone to disturbances of cardiac rhythm uterine smooth muscle relaxation, except methoxyflurane cardiovascular effects all volatile agents possess a narrow safety margin, resulting in severe cardiovascular depression dose-dependent hypotension results from multiple factors, direct myocardial depression (halothane) decrease baroreceptor response - no reflex tachycardia (halothane) vasodilatation (isoflurane, sevoflurane) effect on cardiac output

effect on blood pressure

NC Hwang 2008 causes of hypotension vary with the agent with isoflurane and desflurane, cardiac output is well preserved myocardial depression the order of potency for direct myocardial depression: Enflurane Halothane Methoxyflurane Isoflurane / Desflurane Sevoflurane respiratory effects inhibition of chemoreceptor responses all agents depress spontaneous ventilation in a dose-dependent manner FECO2 increases at 1 MAC, respiratory depression is greater with enflurane compared to halothane, sevoflurane or isoflurane, desflurane airway reflex stimulation increased secretions coughing and laryngospasm, especially isoflurane and desflurane Metabolism fluorination decreases vulnerability to biodegradation CF3 resists oxidative metabolism toxicity is probably inversely related to chemical stability, and is thought to be caused by active products of biotransformation Anaesthetic Methoxyflurane Halothane Enflurane Isoflurane Sevoflurane Desflurane Organ toxicity hepatotoxic chloroform trichloroethylene divinyl ether tribromoethanol methoxyflurane halothane isoflurane enflurane desflurane % Metabolised 50-70 15-20 2.4 0.2 3 0.02 Oil/gas partition coefficient (37oC) 970 224 98 99 53 19 least most Mechanisms of organ toxicity effect of metabolites produced by cytochrome P450mediated biotransformations generation of cytotoxic metabolites in the target organ (chloroform-induced hepatic and renal dysfunction) release of inorganic fluoride (methoxyfluraneinduced nephrotoxicity) immune responses to metabolite-modified hepatic protein antigens (halothane-induced hepatitis) via the cysteine conjugate -lyase pathway (trichloroethylene-induced nephrotoxicity) Chloroform toxicity bioactivation of chloroform in the liver and kidney catalysed by cytochrome P450 isoenzymes producing a highly reactive metabolite, phosgene phosgene binds covalently to cellular macromolecules (protein and lipids) clinical features prompt onset after anaesthetic administration (4872 hours) centrizonal hepatic necrosis renal proximal tubular necrosis renal and hepatic fatty infiltration Metabolism of halothane predominantly in the liver halothane catalysed by 2 cytochrome P450 isoenzymes CYP2B and CYP2EI (animal model) oxidative and reductive pathways oxidative pathway favoured at normal oxygen tensions, predominant pathway in humans during anaesthesia reductive pathway favoured at reduced oxygen tension both pathways proceed via reactive metabolites and both have been implicated in animal models of halothane toxicity immune-mediated halothane hepatitis history of exposure to halothane on many occasions patients exhibit cellular and humoral immune response to halothane-induced hepatic antigens IgG antibodies in patients sera

nephrotoxicity chloroform methoxyflurane

NC Hwang 2008 halothane-induced antigens are expressed predominantly in hepatocytes (liver specific), intracellular, in endoplasmic reticulum; and on hepatocyte surface membrane 2 groups of antigens peripheral membrane proteins (detected by immunoblotting method) generated by cytochrome P450 isoenzyme 2E1 (CYP2E1, rat model) and involves protein trifluoroacetylation normally reside inside the lumen of the endoplasmic reticulum CF3COmodification of the proteins occur intracellularly in the endoplasmic reticulum antigen generation is a slow process that occurs with a half-life of approximately 6 hours once formed the antigens have a half-life of several days integral membrane proteins (detected by enzymelinked immunosorbent assay, ELIZA) Metabolism of enflurane & isoflurane catalysed by hepatic CYP2E1 proceeds via reactive species which bind covalently to hepatic proteins metabolite hapten derived from isoflurane is believed to be CF3COgroup (trifluroacetylated-group) enflurane is CHF2OCF2COgroup (appears to be different but structurally similar) metabolite modified proteins immunochemically indistinguishable from CF3CO-modified proteins derived from halothane are recognized by the antibodies in sera from patients with halothane hepatitis Metabolism of sevoflurane about 5% of sevoflurane is metabolised by hepatic CYP2E1 to hexafluoro isopropanol and Falthough hexafluoro isopropanol is potentially hepatotoxic, its rapid excretion following conjugation with glucuronide makes toxicity less likely does not result in formation of trifluoroacetylated liver proteins, hence cannot stimulate the formation of antitrifluoroacetylated protein antibodies F- concentrations above 50 mol/l are seen with higher concentration and longer duration of usage, however the amount is limited by its relatively low solubility which promotes elimination before it can be metabolised Issue of nitrogen during low flow anaesthesia in the average adult patient, there is 1.5 L of nitrogen contained in the functional residual capacity of the lungs when breathing room air; there is about 2 L of nitrogen dissolved in body tissues pre-oxygenation with 100% oxygen prior to induction of anaesthesia is designed to eliminate the nitrogen content in the functional residual capacity once the anaesthetic begins, nitrogen from the body begins to move out of the patient and into the circuit; as this occurs, the concentration of nitrogen in the circuit can reach levels as high as 5 to 10%, reaching their peak in approximately 30 to 45 min theoretically, this additional amount of nitrogen can reduce the concentration of oxygen and result in a hypoxic mixture in practice, the initial high flow phase that is utilized to deepen the patient to adequate anaesthetic levels will also result in sufficient de-nitrogenation to avoid any problems with proper monitoring, the risk of delivering a hypoxic mixture to the patient is largely avoided and the issue of a small amount of nitrogen in the circuit becomes a minor one Metabolism of methoxyflurane renal cytochrome P450 generates F- locally from methoxyflurane increasing intrarenal F- concentrations, thus increasing its renal toxicity the duration of exposure is as important as the peak serum fluoride concentration exposure of more than 2 MAC.hrs often have plasma concentrations above the renal threshold for toxicity (40-50 mol/l) resulting in direct distal tubular damage polyuric nephropathy developed at Fconcentrations above 90 mol/l after more than 7 MAC.hours Fluoride production

NC Hwang 2008 Pharmacodynamics Cardiovascular effects Myocardial contractility volatile anaesthetics exert their negative chronotropic and inotropic effects, in part by depressing the L- and T-type calcium channels and inhibition of Ca2+ influx at 1.5 MAC (BAR MAC), halothane inhibits Ca2+ channels more than Na+/Ca2+ exchange, enflurane inhibits Na+/Ca2+ exchange more than Ca2+ channels isoflurane inhibited both systems equally Cardiac output well maintained with desflurane, sevoflurane and isoflurane even with dose-dependent decrease in systemic vascular resistance rapid increase of desflurane results in increased sympathetic activity which is probably centrally mediated (reduced by clonidine) with halothane and enflurane, there is less compensatory increase in heart rate resultant heart rate from slowest to fastest: halothane < enflurane < sevoflurane < isoflurane Heart rate the bradycardia seen with halothane is partially reversible with atropine, and is due to, decreased sympathetic activity vagal dominance, leading to sinus bradycardia, wandering pacemaker, or junctional rhythms direct slowing of the SA node: decreased phase 4 depolarization and increased threshold for depolarization halothane sensitizes the heart to catecholamines increased automaticity of the myocardium transient outward potassium channels (Ito) are involved in the mechanism of halothaneepinephrine arrhythmias (HEA) Ito blocker, 4-aminopyridine, significantly increases the arrhythmogenic dose of epinephrine (ADE) halothane also predisposes to reentrant tachyarrhythmias conduction velocity (AV node and His-Purkinje) refractory period in conducting tissue predisposition to reentry - unidirectional block and slow retrograde conduction in vivo isoflurane-induced coronary artery vasodilation is predominantly mediated by adenosine triphosphatesensitive potassium channels (KATP channels) in the vascular smooth muscle of the coronary circulation Hypotension dose-dependent halothane hypotension results from direct myocardial depression - decreasing CO by 20-50% obtundation of baroreceptor response - no reflex tachycardia hepatic blood flow markedly depressed with halothane Inhibition of endothelium dependent relaxation mechanisms responsible for the inhibition of endotheliumdependent relaxation differ among anaesthetics isoflurane inhibits formation of NO in the endothelium halothane and sevoflurane inhibit action of NO on vascular smooth muscle Myocardial depression direct myocardial depression: enflurane > halothane > methoxyflurane > isoflurane > desflurane > sevoflurane decreased LV function increases LVEDP cardiovascular depressive effects are exaggerated by betaantagonists no increased sympatho-adrenal activity in response to cardiovascular depression but, at clinical depths of anaesthesia, the normal sympathetic nervous system response to surgical stimulation remains

NC Hwang 2008 Comparing cardiovascular effects of halothane and isoflurane cerebral activity isoflurane and desflurane: similar EEG burst suppression at 1.24 MAC, isoelectric at 1.6 MAC ( BAR MAC) volatile agents inhibit descending inhibitory pain pathways activated by the opioids, therefore may decrease the effectiveness of the opioids response to carbon dioxide is maintained Effects on renal function volatile agents cause dose dependent, reversible reductions in: glomerular filtration rate, renal blood flow, urine production Refer to section on Fluoride production Calcium homeostasis Respiratory effects summary endothelial, neuronal, and cardiac calcium homeostasis altered calcium influx associated with nicotinic receptor is depressed halothane and enflurane cause Ca2+ release from the caffeine-sensitive SR and stimulating action on Ca2+ uptake airway irritation with increased secretions reduced mocuciliary flow coughing and laryngospasm, especially isoflurane and desflurane change in respiratory pattern with initial tachypnoea reduction in airway reflexes and upper airway tone reduced hypoxic pulmonary vasoconstriction increase shunt flows from 2-3% to 10-15% reduced gas exchange efficiency bronchodilatation and reversal of bronchospasm through inhibitory effect on delayed rectifier K+ channel, T-type and L-type Ca2+ channels, Clcurrents through Ca2+-activated Cl- (ClCa) channel dose-dependent inhibition of chemoreceptor responses, depression of spontaneous ventilation and altered response to hypercarbia and hypoxia enflurane > halothane > sevoflurane or isoflurane > desflurane Central nervous system effects Nitrous Oxide discovered by Joseph Priestly 1793 Physicochemical properties a colourless, non-flammable gas with a sweet taste and odour, commonly used as an anaesthetic molecular weight: 44.013 freezing point @ 1 atm.: -91. C boiling point @ 1 atm.: -88.5 C density of gas @ b.p.: 1.997 g/l (3.16kg/m3) vapour pressure @ 21C: 58.5 bar specific gravity, gas @ 21 C, 1 atm. (air=1): 1.53 critical temperature & pressure: 36.5oC, 72.45bar strongly supports combustion Production produced by thermally decomposing ammonium nitrate (NH4NO3), a common ingredient used in fertilizers and explosives a low-pressure, low-temperature (260C) reaction decomposes the ammonium nitrate to form steam (H2O) and N2O the steam is condensed out, and "crude" N2O is then further purified, compressed, dried, and liquefied for storage and distribution isoflurane and sevoflurane do not stimulate Ca2+ release or influence Ca2+ uptake desflurane induces minimal Ca2+ release from SR - a weaker trigger of malignant hyperthermia

NC Hwang 2008 Storage stored in liquid tanks shipped in blue cylinders as a gas over liquid (58.5 bar @ 20 C) can be stored in both phases as the critical temperature is not reached filling ratio of 0.65: 65% of the N20 cylinder is filled with liquid, and vapour fills the rest this allows for liquid expansion if the ambient temperature rises: if there is too much liquid in the cylinder, expansion could cause explosion the pressure gauge on a cylinder of N2O measures only the vapour pressure as the liquid in the cylinder evaporates, it constantly replenishes the gas that is used up, and the vapour pressure remains the same until there is only a small amount of liquid left by looking at the gauge you have absolutely no idea how much N2O is in the cylinder estimating the volume of N2O in a cylinder the weight of the liquid inside the cylinder = weight of cylinder (full minus empty) the molecular weight of N20 is 44 1 mole of N20 occupies 22.4 litres at standard temperature and pressure if the cylinder contains 2.5 kg (2500 g) of N20, the volume of N2O = divide the weight by the molecular weight and multiplying it by 22.4 2500/44 x 22.4 = 1272 litres cylinders should only be used in the vertical position with the valve uppermost; if not, liquid may be discharged when the valve is opened. will decompose at temperatures above 400oC, and the speed of decomposition increases with increasing temperature, with explosive decomposition occurring at 650oC at atmospheric pressure Adiabatic cooling whenever matter changes phase, an increase or decrease in the surrounding temperature occurs depending on whether it is becoming more solid or more gaseous. if a nitrous oxide cylinder is suddenly turned on "full blast", frost can actually form on the outlet due to adiabatic cooling rapid opening of the valve can cause the discharged gas to sublime as a liquefied gas and this can cause cold burns when in contact with the skin Critical temperature, critical pressure critical temperature (36.5 C): the temperature of the liquidvapour critical point, the temperature above which a gas cannot be liquefied by an increase of pressure critical pressure (72.45 bar): the vapour pressure at critical temperature Pseudocritical temperature gases in a mixture have a critical temperature at which the mixture will separate into its constituent individual gases: the Pseudo-critical temperature for entonox (50% N2O : 50%O2), this is -5.5oC below this the N20 liquefies, and the 02 remains as a gas; if one were to breath this in, one would inspire virtual 100% O2 until this is used up, and then 100% N2O a homogenous mixture is again obtained when the temperature is raised to above 10oC and the cylinder rotated 50% nitrous oxide: 50% oxygen before use, to ensure that the contents are properly mixed cylinders should be stored horizontally for 24 hours at a temperature above 10oC, or the cylinders must be maintained at a temperature above 10oC for at least 2 hours and then completely inverted 3 times Benefits analgesia Adverse effects myocardial depression by inhibition of calcium release from sarcoplasmic reticulum expansion of closed gas spaces diffusion hypoxia inhibition of methionine synthase activity, affecting conversion of noradrenaline to adrenaline; synthesis of arachidonic acid; and myelination of nerves altered folate metabolism and decreased conversion of deoxyuridine to thymidine interference with DNA synthesis, and megaloblastic change in the bone marrow, agranulocytosis N2O and closed gas spaces blood:gas partition coefficient of N2O (0.46) greater than nitrogen (0.14), and N2O can leave the blood more rapidly than nitrogen can leave the cavity to enter blood as a result of this preferential transfer of nitrous oxide, the volume or pressure of an air-filled cavity increases passage of nitrous oxide into an air-filled cavity surrounded by a: compliant wall (intestinal gas, pneumothorax) causes the gas space to expand non-compliant wall (middle ear) causes an increase in intracavitary pressure the magnitude of volume or pressure increase is influenced by the partial pressure of N2O, blood flow to the air-filled cavity, and duration of N2O administration

NC Hwang 2008 N2O and vitamin B12 B12 is a bound coenzyme of methionine synthase consists of a tetrapyrrole ring and a central monovalent cobalt atom methionine synthase is required for conversion of homocysteine to methionine and demethylation of methyl tetrahydrofolate to tetrahydrofolate, which is essential for DNA synthesis inhibition of methionine synthase activity oxidizing cobalt from Co+ to Co++ of B12 (enzyme no longer functions as a methyl carrier, resulting in the reduction of methionine and tetrahydrofolate) N2O 0.5h no measurable effect cumulative if interval < 3 days N2O 2h decrease in hepatic methionine synthase effects on DNA synthesis unpredictable N2O ~ 24h bone marrow will be megaloblastic abnormal deoxyuridine-suppression test N2O > 24h absolute contraindication treatment with folinic acid (5-formyl-THF), can restore deoxythymidine synthesis, but cannot restore methionine or SAM levels the use of N2O in pregnancy during the period of organogenesis is inadvisable irrefutable evidence that N2O is a mild teratogen, due to its effects on DNA synthesis cover with folinic acid may offer some protection Diffusion hypoxia first described by Fink in 1955 effectively the reverse of the concentration effect elimination of a poorly soluble gas (N2O) from the alveoli may proceed at as greater rate as its uptake adding as much as 1 l/min to alveolar air effectively dilutes alveolar air, and available oxygen, so that when room air is inspired hypoxia may result usually mild rarely clinically significant may occur with any anaesthetic agent, its magnitude is insignificant unless nitrous oxide has been inhaled for some time after prolonged anaesthesia up to 30 litres may be dissolved in the blood and tissues

altered folate metabolism and decreased conversion of deoxyuridine to thymidine interference with DNA synthesis megaloblastic change in the bone marrow

decreased conversion of homocysteine to methionine methionine is a precursor to S-adenosylmethionine (SAM) SAM is a methyl donor in important reactions: noradrenaline to adrenaline synthesis of arachidonic acid myelination of nerves

oxidation is irreversible effects last up to 3 days new enzyme has to be synthesized only after prolonged administration of N2O the first detectable changes are a reduction in methionine synthase activity, followed by impaired DNA synthesis manifest by an abnormal deoxyuridine suppression test following prolonged administration, ( 4 days) agranulocytosis is an almost universal result interference with thymidine synthesis is to be expected in man after 12 hrs of exposure to N2O, but may appear within 2h or even less

NC Hwang 2008 Xenon Physicochemical properties atomic Number: 54 atomic Weight: 131.293 melting Point: 161.36 K (-111.79C) boiling Point: 165.03 K (-108.12C) density: 0.005887 g/ml gas at room temperature and pressure discovered by Sir William Ramsay, a Scottish chemist, and Morris M. Travers, an English chemist, on July 12, 1898, through the study of liquefied air the earth's atmosphere is about 0.0000087% xenon, an average room containing only 4ml 9 stable isotopes, 20 unstable isotopes 4 times more dense than air manufactured by fractional distillation of air costs 2000 times more than N2O commercial uses include lasers, high intensity lamps, flash bulbs, aerospace, X-ray tubes and medicine found to be the only noble gas to be anaesthetic under normobaric conditions first used in 1951 by Cullen on an 81yr old man having an orchidectomy colourless, odourless and tasteless with no irritation to the respiratory tract; well tolerated with inhalational induction low blood/gas (0.115) and oil/water (20) partition coefficients allowing rapid induction and emergence, diffusion hypoxia is very mild xenon inhibits the plasma membrane Ca++ pump altering excitability and inhibits the nociceptive responsiveness of spinal dorsal horn neurons produces unconsciousness with analgesia equivalent analgesia compared with equipotent doses of N2O; the analgesia produced by both gases is not reversible by naloxone xenon inhibits the plasma membrane Ca++ pump altering excitability and inhibits the nociceptive responsiveness of spinal dorsal horn neurons produces unconsciousness with analgesia equivalent analgesia compared with equipotent doses of N2O; the analgesia produced by both gases is not reversible by naloxone produces a small degree of muscle relaxation MAC of 60-70% allows a reasonable inspired oxygen concentration it does cause respiratory depression, to the point of apnoea it is cardiac stable and does not sensitize myocardium to adrenaline not metabolised in the body and is eliminated rapidly and completely via the lungs it is non toxic and is not associated with allergic reactions does not trigger malignant hyperthermia stable in storage, no interaction with anaesthesia circuits or soda lime. should not be used with rubber anaesthesia circuits as there is a high loss through the rubber no occupational/ environmental disadvantages non flammable and will not support combustion expensive - routine usage will only be possible with a closed circuit delivery system that recycles xenon increases cerebral blood flow, increases intracranial pressure and decreases cerebral perfusion pressure in acute head injury patients the increase in cerebral blood flow is reversed by mild hyperventilation