Programmed Problem Set on General Anesthetics

Edward W. Pelikan, M.D.
Professor Emeritus and Former Chairman of Pharmacology
Boston University School of Medicine

Questions or comments should be mailed to Carol Walsh

This is a program about anesthetic agents and their properties. It is also concerned with a class of agents capable of producing central nervous system depression, but not used clinically as anesthetics (See Arch. Ind. Hyg., 2: 335 and 345, 1950). You will be asked to predict the biologic properties of these agents and compare them with the properties of recognized anesthetic agents. You will also have the opportunity to compare the properties of the anesthetic agents.

“Freon” is the trademark, or proprietary name, for a class of fluorocarbons that are chemically stable under conditions that occur in the body. Central nervous system depression is a prominent acute effect of those Freons that have biologic effects. Freons are used as heat exchange fluids in refrigeration and air-conditioning systems; some, the more volatile ones, have been used as aerosol propellants. Medical interest in Freons arises from their effects as odorless atmospheric pollutants in industry, homes, etc.; their lack of odor makes it difficult to detect them easily in the ambient air. Scientific interest in freons relates to their contributing to ozone depletion in the stratosphere.

In the table below, selected properties of three Freons are compared with those of three inhalation anesthetics.

You may wish to bear in mind that for materials with chemical and biologic properties like those of diethyl ether, the ratio of the atmospheric partial pressure of the material required for production of anesthesia to the vapor pressure of the pure material is constant: Pa/Ps=K. For anesthetic materials, in general, an average value of K of 0.05 can be assumed, when Ps is measured at 20°C. At 20°C, the corresponding proportionality constant for lethal effect is 0.12.

Agent Formula Molecular Weight Boiling Point (°C) Vapor Pressure (mmHg @ 20°C) Vapor Density (Air=1) Relative Water/Gas Solubility Coefficient*
MF CCl3F 137 24 674 4.8 0.02
TF CCl2F€CClF2 187 48 268 6.2 0.003
BF CCl2F€CClF 204 93 1 5.8 0.002
Ether (C2H5)2O 74 35 440 2.6 1.000
Nitrous Oxide N2O 44 -89 38,800 1.5 0.04
Cyclopropane C3H6 42 -33 4,800 1.5 0.02

*Ether = 1.0; values are proportional to the blood/gas solubility coefficient

I. Concerning the conditions for storage and administration of MF, TF and BF as experimental anesthetic agents, we would expect that:

a. BF would be stored under pressure in steel tanks, as is true for cyclopropane

Incorrect: The high boiling point of BF shows that it would not be a gas at standard temperature and pressure; hence, unlike cyclopropane, which is, BF would not be stored under pressure in steel tanks. As a matter of fact, BF has a melting point of 25°C. Needless to say, the same reasoning would apply to consideration of BF in comparison to nitrous oxide, the other anesthetic gas.

Go back to Item I and select another choice.

b. MF and TF could probably be stored under conditions appropriate for diethyl ether

Very good; MF and TF have boiling points a little higher than room temperature as diethyl ether does and, therefore, all three could be stored under similar conditions: in tightly closed containers but at ambient atmospheric pressure.

Go on to Item II.

c. MF, like ether, could not be given by the 'open-drop' method, with the patient supine, a gauze and wire mask over his/her mouth and nose, and drug poured, dropwise, onto the mask

Sorry, MF would volatilize nicely – possibly too nicely – under conditions of the “open-drop” method, since its boiling point is just a bit above room temperature ; MF also has a vapor density greater than that of air and MF vapors would “fall” nicely through the mask used in the open-drop technique. And, of course, ether was administered by this technique with good success clinically, for many years.

Go back and select another choice from Item I.

II. One can envision a model of central nervous system function which states that the probability that information is transmitted through a chain of neurones is a function of the probability with which any and every neurone in the chain will respond to a stimulus. Such a “probabilistic model” of CNS function can be used to explain any selectivity of action these agents may manifest:

a. Only if the agents act by forming ionic bonds with constituents of cell membranes

Incorrect: The probabilistic model explains selectivity in terms of the “multiplication” of effects in neurone chains of various lengths, regardless of the mechanism by which the function of the individual neurone is impaired. Sorry, go back to Item II and make another choice.

b. Only if the agents act by dissolving into cell membrane lipids

Sorry, the probabilistic model explains selectivity of action in terms of the probability that information will get through a neurone chain, regardless of the cellular mechanism by which the function of individual neurones might be altered.

Go back to Item II and try again.

c. Regardless of whether the agents act by forming ionic bonds, or by dissolving into cell lipids

Of course, the probabilistic model explains selectivity of action on the CNS of such agents as these in terms of a “multiplication” of effects on information transmission in chains of differing numbers of serially arranged neurones. Selectivity of such agents for the central nervous system is explained in terms of a lesser sensitivity to the drug of such tissues as have their functional cells not arranged in serial order; in such tissues the effect of drugs on the function of the tissue represents the sum of the effects on individual cells. In any event, the probabilistic model explains selectivity of action in terms of what happens to the function of a group of cells after the function of individual cells has been altered, and, hence, without regard to the cellular mechanism of action of the drug. (See Intern. Anesth. Clinics 2:3, 1963).

Go on to Item III.

d. If the agents act by combining preferentially with receptors in neurones found predominantly in short neurone chains, and diminish the functional capacity of the neurones

Stop! There are several things wrong about this choice. Non-polar compounds such as these give no evidence of acting on receptors as they’re usually defined. The probabilistic model suggests that the general effect of such agents as these is greatest on the longest neurone chains. The probabilistic model describes what happens to transmission of information through neurone chains after the function of individual cells has been altered, and, hence, is not concerned with the cellular mechanism by which the change was brought about.

Go back to Item II and select another choice.

III. This question has been omitted. Go on to Question IV.

IV. If concentration of agent required to provide anesthesia were expressed as volumes percent, one would expect that:

a. MF would be more potent than ether

Sorry. Pa=PsK; the partial pressure for anesthesia is proportional to the vapor pressure of the material. Concentration in volumes percent is directly proportional to the partial pressure (Pa) of gas required to produce anesthesia; VOL% = Pa/760 mmHg. Potency, therefore, is inversely related to partial pressure for anesthesia as potency is always inversely related to dose. Therefore MF should be less potent than ether. Go back to Item IV and make another choice.

b. MF would be more potent than cyclopropane

Very good; not many students make this their first choice, by the way. You’ve recognized that at equilibrium Pa=PsK, and that potency, by definition, is inversely related to dose, or Pa, in this case. You need not have known the Pa for cyclopropane exactly; you may have known only that it’s a gas at standard temperature and pressure and hence has a higher vapor pressure than 760 mmHg at 20°C. Hence it’s more volatile and less potent than MF.

You know already, I’m sure, that concentration, expressed as volumes percent, is directly proportional to the partial pressure (P) of the gas in the gas-mixture. In fact, VOL% = P/760mmHg, or torr, at standard pressure.

The relationship Pa=PsK is, of course, a way of writing Raoult’s Law – or Henry’s Law, for that matter – in which K represents the mole fraction of anesthetic agent in solution. It can be read in this way, remembering that K is essentially the same for all anesthetic gases and vapors: at equilibrium, when the concentration of anesthetic material to which an organism is exposed is sufficient to produce anesthesia, the concentration relative to the vapor pressure of the material has a constant value, regardless of the agent. According to the ideas of Ferguson, when a certain fraction of, e.g., a cell is occupied by anesthetic agent, anesthesia is produced; this fraction (mole fraction) is the same for all inert, volatile materials used as anesthetics, expressed as a fraction of the vapor pressure of the pure agent.

Now go to Item V.

c. BF would be less potent than MF or ether

Sorry, wrong choice. If the partial pressure of material in the inspired air required to produce anesthesia is proportional to the vapor pressure of the material (and it is; generally, Pa = PsK) and potency is inversely related to partial pressure for anesthesia or dose (as by definition it is), then BF should be more potent than either MF or ether. In Item I, by the way, it came out that BF might require some special treatment to volatilize it, but that’s another question.

Go back to Item IV and choose again.

d. None of the above

Sorry, one of the other choices is correct. I assume you’re using the known relation between vapor pressure and partial pressure to produce anesthesia in analyzing this item and that you aren’t confusing “potency” and “dose“.

Go back to Item IV and try to analyze the data again, and make another choice.

V. If TF were used to induce anesthesia in a subject who had a fever, for whatever cause, and a body temperature of 40°, how would the subject’s hyperpyrexia influence the apparent potency of the agent (in comparison to its potency in a subject with a normal body temperature)?

a. TF would appear to be less potent in the hyperpyrexic subject

You’re right. Pa=PsK. At the higher temperature the vapor pressure of TF would be higher than at normal body temperature (37°), the partial pressure for anesthesia would be higher, and the potency would be lower in the hyperpyrexic patient. And it works out that way; See Anesthesiol 26: 764, 1965 and papers since then such as Fed. Proc. 33: 495 (#1605) 1974. You can now probably predict correctly the effect of hypothermia on anesthetic dose. Another thing that works out all right, as you may have noticed, is the fact of Pa=PsK, even though Ps may be given at 20°C instead of at 37°C, the temperature at which the pharmacologic action of general anesthetics and similar materials occurs. Needless to say the results turn out “better” when the vapor pressure and partial pressure are determined at the same temperature.

Go on Item VI.

b. TF would appear to be more potent in the hyperpyrexic subject

Sorry. Will it help if I suggest that vapor pressure of a material like TF changes with temperature, specifically increases with temperature?

Go back to Item V and make another choice.

c. TF would appear to be equally potent in the hyperpyrexic and normal subjects

Wrong choice, I fear. May I suggest that you consider again that Pa=PsK and that Ps changes with temperature and reaches a maximum of 760 mmHg at the boiling point of the material?

Go back to Item V and choose again.

d. Known properties of general anesthetic agents don't permit predicting their effects under these conditions

Sorry; this is just another way of considering the relationship between vapor pressure for materials like TF, and the concentration of the material required to be inhaled to produce anesthesia. This one is rather like Item IV.

Go back to Item V and try again.

VI. With identical partial pressures in the inspired air, and identical alveolar-blood partial pressure differences, one would expect that diffusion of gas (or vapor) through the alveolar membrane would be more rapid for:

a. BF than MF

Sorry; diffusion constant is inversely related to the square root of molecular weight – and the square root of vapor density, too, according to Graham’s Law. If the driving force of partial pressure differences and the area through which diffusion occurs are the same for BF and MF, then…

Go back to Item VI and select another choice.

b. MF than ether

I’m afraid not. Diffusion constant is inversely proportional to the square root of molecular weight – over a wide range of weights – and inversely related to the square root of vapor density. ( You can almost see heavy molecules moving sluggishly). Therefore, with equal concentration differences and equal areas for diffusion, the diffusion rates of MF and ether should be in the proportion of…

Go back to item VI and try again.

c. BF than ether

Too bad; you may have forgotten that the square roots of both molecular weight and vapor density are inversely related to the diffusion constant, and that diffusion rate will vary with diffusion constant, concentration difference, and area through which diffusion occurs. If the last two are viewed as the same for BF and ether (one lung’s worth of area!) then it follows that….

Go back to Item VI and try again.

d. Oxygen (O2) than ether

Good. The diffusion constant for a molecule is inversely related to the square root of its molecular weight – over a wide range of weights – and O2 certainly has a lower molecular weight (32) than does ether. Given equal partial pressure differences and equal areas for diffusion (one lung’s worth) diffusion of molecular oxygen will be more rapid than diffusion of ether.

You’ll remember, of course, that for normal subjects with normal lungs, diffusion of drug across the alveolar membrane is not the rate limiting factor in induction of anesthesia. What is?

TF wasn’t included in any of the choices for this item. You’ll observe that the implied direct proportionality between molecular weight and vapor density – seen nicely in the case of MF, BF and ether – doesn’t hold true if TF is included in the series. Maybe the differences in vapor density of TF and BF couldn’t be discriminated well with the method used to get the data reported here; certainly their molecular weights indicate that their densities should be close together. Maybe our generalization is too general for the case of agents with such similar weights. Go on to Item VII.

VII. At equally effective concentrations, one would expect anesthesia to be induced more rapidly with:

a. BF than with ether

Very good; you’ve remembered that the rate limiting factor in induction of anesthesia with volatile and gaseous agents is the blood/gas solubilities of the agents. Other things – such as concentration – being equal, rate of onset of anesthesia is inversely related to the relative solubility of drug in blood. The greater the solubility of the anesthetic agent, the longer it takes to saturate this reservoir, and the longer it takes for drug to “spill-over” from blood in to the tissues where the agent has its desired – and, perhaps, some undesired – effect. BF has a lower solubility in water (blood) than does ether; hence the onset of anesthesia would be more rapid with BF than with ether.

Go on to Item VIII

b. Ether than with MF

Sorry; you may well have remembered that rate onset of anesthesia is determined by the blood/gas solubility coefficient, but you’ve misremembered the relationship.

Go back to Item VII and try again.

c. Ether than with TF

I’m afraid not; other things being equal, rate of onset of anesthesia is related inversely to the solubility of the anesthetic agent in the blood. The blood acts as a “buffer” between the concentration of agent in the alveolus and its concentration in the tissues. Therefore, in the case of ether and TF…

Go back to Item VII and make another choice.

d. MF than with TF

Too bad; you’ll have to try again. The rate limiting factor in onset of anesthesia with materials that act as general anesthetics do is the solubility of the agent in the blood. You’ll probably remember now that rate of onset of anesthesia and relative solubility in the blood are related inversely to each other.

Go back to Item VII and make a different choice.

VIII. After anesthesia sufficiently prolonged to saturate all tissues, recovery would be expected to be slower with:

a. BF than with ether

Sorry; under the conditions described, recovery from anesthesia proceeds rapidly to the extent that agent readily passes out of the tissues, through the blood (as it were), and into the pulmonary alveoli, preparatory to exhalation. If the agent is relatively soluble in the blood, the blood “reservoir” is not readily emptied, the concentration difference between tissues and blood remains small, and agent leaves the tissues slowly, i.e., the anesthetic state is prolonged. Therefore, after comparing the solubilities of BF and ether, we’d conclude that…

Go back to Item VIII and make another choice.

b. Ether than with nitrous oxide or cyclopropane

Very good, this is the correct answer. Back to reality or at least to real, clinically useful anesthetic agents. The rate at which recovery would occur depends on the rate that drug will pass from tissues to blood to the pulmonary alveoli, and to the exterior of the body, in that order. To the extent that an agent is soluble in blood (or, roughly speaking, water) the reservoir of the blood is not readily emptied, the concentration difference between tissues and blood is small, agent leaves the tissues slowly, and anesthesia is prolonged. Since ether is more soluble in water or blood than are either nitrous oxide or cyclopropane, under the conditions given, recovery would be slower with ether than with either of the other two.

The most important point, perhaps, is that you don’t have to remember isolated facts such as the solubilities of nitrous oxide and cyclopropane. You know that cyclopropane and nitrous oxide are gases at standard temperature and pressure, i.e., they have high vapor pressures at room temperature. According to Raoult’s Law, the solubility of an inert gas, in dilute solutions, is inversely proportional to the vapor pressure of the liquid solute at the given temperature. Raoult’s Law applies perfectly only to ideal dilute solutions, but it applies well enough to anesthetic materials under conditions of use to permit the generalization that the clinically useful anesthetic gases are less soluble in blood and water than the clinically useful anesthetic vapors and rates of induction and recovery from anesthesia for these two groups vary accordingly. Among the vapors and among the gases, respectively, Raoult’s Law, as given, is not a sure predictor of solubility.

Raoult’s Law has come up before in Item IV, when we were concerned with anesthetic potency. This law or relationship among partial pressure, vapor pressure, and solubility (mole fraction of solute in solution) applies to questions of potency when we’re concerned with solution of agent in a target cell, and applies to questions of rate on onset and waning of anesthesia when we’re concerned with solution of agent in blood, the medium which transports agent to the target cell. Disregard all other factors for the moment, including the fact that anesthetic agents can’t act as perfect gases under conditions of use; still, it’s no coincidence that the three agents once used clinically which are gases at STP (cyclopropane, ethylene and nitrous oxide) were of low potency, more rapid onset, and shorter duration of action than the volatile agents were.

Now, of course, only nitrous oxide is used clinically.

That was a long one. Why don’t you go on now to Item IX?

c. TF than with ether

Sorry, you’ll have to make another choice. Under the conditions described, rate of recovery, like rate of induction, is related to the water/gas or blood/gas solubility coefficients of the agent. TF is less soluble in water than ether, and recovery from anesthesia with TF would be more rapid than recovery from ether anesthesia.

Go back to Item VIII and choose again.

IX. During the induction and maintenance of experimental anesthesia with the several agents, “moment-to-moment control” of the depth of anesthesia would be greatest with:

a. MF

Sorry, wrong choice. “Moment-to-moment control” is just another way of talking about rapidity with which the depth of anesthesia can be changed.

I think you’d best go all the way back to Item VII.

b. TF

Too bad. Since “moment-to-moment” control is a reflection of the rate at which depth of anesthesia can be increased or decreased, I suggest that you’d do well to go back to Item VII.

c. BF

Very good. You’re aware that “moment-to moment” control is simply a reflection of the rate at which depth of anesthesia can be increased or decreased by changing the concentration of anesthetic agent in the inspired air. Moment-to-moment control is a miniature of induction and recovery from anesthesia. The old rules apply and since, of all the agent in the table, BF has the lowest water/gas solubility coefficient, moment-to-moment control would be greatest with BF.

Go on to Item X.

d. Ether

Sorry, moment-to-moment control would be least with ether. Since moment-to-moment control is so much related to problems of rate in induction and recovery from anesthesia, I suggest you go back to Item IX.

X. One can determine experimentally the duration of the exposure to a given concentration of gas or vapor that is required to produce a specified biological effect: anesthesia, for example, in the case of MF, BF, TF or ether. One can repeat the experiment using different concentrations of the agent under investigation. If one plots concentration (on the ordinate) against duration of exposure or latent period (on the abscissa), one obtains a curve convex with respect to the origin, and approximating an hyperbola. For each of such series of points on a true hyperbola, the product of concentration and time would be constant: CT=K. K, for a given agent, computed from experimental data, is called the “CT Index” of the agent and is a measure of its potency. CT indices have wide application in toxicology, industrial hygiene, air pollution studies, experimental pharmacology, etc., as a means of comparing biologically active materials.

The plot of concentration against time frequently departs from the theoretical hyperbolic form unless one corrects for: 1) The fact that with even the highest concentrations of an agent, a finite time is required for effects to be produced and observed, and 2) the fact that, at concentrations at or below a certain minimum – the “threshold concentration”, by definition – no biological effects will be observed after an exposure of even theoretically infinite duration. In much practical work, such niceties can be disregarded and the CT index can be computed – and used – without actually making such corrections.

For the agents in the table, assuming their concentration-latency curves are parallel, the CT index would probably be:

a. Larger for ether than for MF

Sorry, you’ve made an incorrect choice. The less potent an agent is, the greater the concentration required to produce a given effect, i.e., the greater the partial pressure required to produce anesthesia (Pa). Pa is proportional to vapor pressure. Therefore, the greater the vapor pressure, the larger the CT Index, when concentrations are determined for equal times of exposure and the concentration-latency curves are parallel. Maybe it would help to sketch the curves involved here.

Go back to Item X and choose again.

b. Larger for MF than for ether

Very good, you’ve made the correct choice. The dose of agent required to produce anesthesia, for these agents, is proportional to the vapor pressure, of course; you’ve undoubtedly referred, in your thinking, to the relationship Pa=PsK discussed in Item IV. Since the concentration-latency curves of MF and ether are parallel, by the terms of our problem, at any and all durations of exposure, the Pa, or C, for MF is greater than that for ether, and the CT for MF is greater than the CT for ether for any exposure time, T.

Go on to Item XI, now.

c. Larger for BF than for MF or TF

Sorry, wrong choice. Perhaps you’d better review Question IV to refresh your memory about the relationships among Pa, Ps and measured potency. In analyzing the data for Item X, remember that we’ve established that the concentration-latency curves for BF, TF, and MF are parallel. Maybe it would help to draw sketch-graphs of the curves for the agents.

Go back and make another choice in Item X.

XI. In analogy with known anesthetic agents, contact of MF, TF, and BF with hot metal surfaces – as might occur during an industrial or hospital accident – might be expected to result in:

a. Flame and possible explosion, as would occur with halothane or chloroform

Sorry, saturated hydrocarbons that are extensively halogenated, such as halothane, chloroform, and Freons, are generally not flammable.

Go back to Item XI and choose again.

b. Flame and possible explosion, as would occur with ether or cyclopropane

Sorry, saturated hydrocarbons that are extensively halogenated – as the Freons are, and as halothane and chloroform are – are generally not flammable. Of course, ether and cyclopropane are highly flammable. Go back and make another choice from Item XI.

c. Oxidation of the surface without explosion hazard, as would occur with cyclopropane

Too bad, wrong choice. Perhaps you’re confusing the properties of cyclopropane, which is not an oxidizing agent but is eminently flammable, with those of nitrous oxide, which is not flammable but is an oxidizing agent. Freons, by the way, aren’t oxidizing agents.

Make another choice in Item XI.

d. Production of toxic products such as phosgene, as would occur with chloroform or trichloroethylene

Good, this is the correct choice, reasoning by analogy. One of the hazards in the use of chloroform and trichloroethylene – particularly in industry, where they are used as solvents and degreasing agents – is the formation of phosgene from the agents in the presence of heat. Carbon tetrachloride is guilty of having the same property; it may no longer be used in fire-extinguishers; too many victims avoided injury or death from fire, but succumbed later to the effects of phosgene, which produces pulmonary edema – and a succession of consequent effects – by virtue of its properties as a pulmonary irritant.

Go on to Item XII and remember phosgene; anesthesiology and industrial hygiene have more in common than the CT Index!

XII. In analogy with known anesthetic agents, adverse effects of MF, TF, and BF that might be anticipated during experimental anesthesia would include:

a. Abrupt, severe hypertension during surgical anesthesia, as is characteristic of halothane

Stop! Whatever the Freons might do, occurrence of hypertension during surgical anesthesia is not characteristic of halothane. Review the cardiovascular effects of anesthetics with the aid of your text, go back to Item XII, and make another choice.

b. Cardiac arrhythmias, as is more characteristic of enflurane and isoflurane than of halothane

Sorry. Whatever the Freons might do, enflurane and isoflurane don’t characteristically induce cardiac arrhythmias more frequently than does halothane. You’d do well to review the cardiac effect of anesthetic agents as given in the textbook before going back to Item XII and making another choice.

c. 'Sensitization' of the myocardium to arrhythmias produced by epinephrine, as is characteristic of halothane and chloroform

Very good, you’ve chosen correctly. Not only do halothane and chloroform “sensitize” the heart to epinephrine-induced arrhythmias, the Freons do it too. One of the hazards of inhaling aerosol propellants to achieve euphoria (probably more appropriately called self-induced Stage I anesthesia, when we discuss it) is sudden death not unlikely caused by cardiac arrhythmia, which itself might be caused by the halogenated hydrocarbon propellant, such as a Freon. See, for example, JAMA 214: 81, 1970; JAMA 219: 33, 1972, and Arch. Environ. Health 22: 265, 1971. By the way, what drug(s) should prevent occurrence of the arrhythmias we’re talking about?

Early in the history of chloroform anesthesia, sudden death occurring during induction was not just a tragic technical, professional problem; the knowledge that such deaths occurred worked against public acceptance of general anesthesia as a desirable medical procedure.

Now go on to Item XIII.

d. 'Sensitization' of the myocardium to arrhythmias produced by epinephrine, as is characteristic of nitrous oxide

Too bad. Whatever the effects of the Freons on the heart, cardiac arryhythmias and sensitization of the heart to epinephrine are not characteristic of anesthesia with nitrous oxide. Why don’t you refresh your memory concerning the cardiac effects of anesthetic agents by referring to your text. Then go back to Item XII and make another choice.

XIII. Conditions which might predispose a patient to the occurrence of ventricular arrhythmias during clinical general anesthesia include:

a. Facilitated AV conduction, caused by a direct action of the anesthetic agent

Sorry, wrong choice. It is hard to see why facilitated AV conduction could predispose to occurrence of ventricular arrhythmias, and, in any case, the direct effect of general anesthetic agents is to slow or impair AV conduction. One might have expected that, perhaps, knowing the effect of anesthetic agents on cell functions generally. You might review this matter as it is presented in your text, even in your textbook of physiology!

Now go back to Item XIII and try again.

b. Shortened atrial refractory period, caused by a direct action of the agent

Incorrect: The direct effect of the agent would be, I think, to prolong the atrial refractory period and (or while) increasing the threshold of the atrial muscle to stimuli.

Please go back to Item XIII and choose again.

c. Increase of SA nodal rates to ca. 100 to 110 beats/min

Quite the contrary. The ventricle beating at such a rate, under the impetus of regular stimuli from the SA node, spends so much of its time in either controlled contraction or in a refractory state, so to speak, that there is little opportunity for the slow inherent rhythmicity of the ventricle to be manifest.

I’d suggest that a look into your textbook of physiology might help clear up points such as those.

Try another choice among those in Item XIII.

d. Hypercarbia

Right. And any of a number of mechanisms, direct and indirect, have been suggested as accounting for the association of hypercarbia and ventricular arrhythmias. The association was apparent particularly in deep cyclopropane anesthesia: respiratory depression produced by the drug led to hypercarbia that was not accompanied by – or signalled by – the signs of hypoxia, since the concentration of oxygen in the inspired gas mixture (70-80%, or more) was more than adequate even though tidal exchange was reduced.

As for mechanism, try this one: Hypercarbia is associated with acidosis, and this leads to an increased concentration, locally at least, of ionized calcium. Calcium ions themselves decrease the SA rate; calcium ions (acting synergistically, additively, with the anesthetic agent in this case) also lead to slowed AV conduction. Under this combination of circumstance, the inherent rhythmicity of the ventricle can be manifest and ventricular arrhythmias are observed.

During hypercarbia, both epinephrine and cellular potassium are released into the blood stream by mechanisms which are not entirely clear; these agents may play a role in inducing ventricular arrhythmias during hypercarbia as they do under other circumstance.

Maybe your textbooks of pharmacology and physiology have more light to shed on this subject. By the way, regardless of their clinical usefulness, what drugs might facilitate production of ventricular arryhthmias during hypercarbia? Might militate against their occurrence?

After a moment’s thought on that, why don’t you go on to Item XIV?

XIV. Agents which appear to undergo substantial biotransformation under clinical conditions of use include:

a. Isoflurane and nitrous oxide, but not halothane

Sorry, it’s really the other way around: halothane, but neither isoflurane nor nitrous oxide undergoes substantial biotransformation in the body. Might it be useful to review the relevant parts of your textbook?

Back to Item XIV, I’m afraid, and another choice.

b. Halothane, but not nitrous oxide

Perfectly correct. Halothane is one of the clinically useful general anesthetic agent – let’s not debate the clinical role, if any, of ethanol – to undergo substantial biotransformation in the body. What are the names of the others?

Some things, I fear, are facts to be learned: either there’s no figuring them out from first principles, or reasoning them out is more trouble than just remembering!

Now try Item XV.

c. Nitrous oxide, but not isoflurane

Too bad. Neither of these materials undergoes substantial biotransformation in the body. I suspect your memory on these points needs refreshing, by referring to your text.

Back to Item XIV and another choice.

d. Halothane, methoxyflurane and nitrous oxide

I’m afraid you’ve made a wrong choice. Not all of these undergo biotransformation to any degree in the body. I think you should refresh your memory on this topic by reference to your text, then,

Back to Item XIV and make another choice.

XV. Diethyl ether has a prominent effect under conditions of clinical use, to stabilize the post- synaptic membrane at the skeletal neuromuscular junction. When used with adjuvants to clinical anesthesia, one would expect ether to act:

a. Synergistically with tubocurarine and antagonistically to at least some effects of succinylcholine

Of course, you’re perfectly correct. Tubocurarine, too, acts to stabilize the post-junctional membrane, but specifically to the stimulant effects of acetylcholine released from the pre-synaptic nerve terminal and competing with tubocurarine for the same receptors. Succinylcholine – true to its chemical nature – acts like acetylcholine at the neuromuscular junction and causes depolarization of the cell subsequent to the drug’s combination with receptors in the post-junctional membrane. Hence, ether acts additively, synergistically, with tubocurarine, and antagonistically to succinylcholine.

Under what circumstances might tubocurarine act synergistically with succinylcholine? Antagonistically?

It’s time to go on to Item XVI.

b. Antagonistically to tubocurarine

Incorrect: Ether and tubocurarine act synergistically with each other ar the neuromuscular junction. Sorry, you’ll have to go back to Item XV and try again.

c. Antagonistically to tubocurarine and gallamine

Stop! Ether acts synergistically with tubocurarine at the skeletal neuromuscular junction. Since gallamine has the same mode of action at that site as does tubocurarine, it follows that ether should act synergistically with gallamine. Indeed, it does. Back to Item XV, and try a different choice.

d. Antagonistically to gallamine, and synergistically with succinylcholine

Sorry; gallamine acts synergistically with ether at the neuromuscular junction. Since gallamine acts antagonistically to succinylcholine, at least when administration of gallamine precedes administration of succinylcholine, it seems reasonable to suspect that ether acts antagonistically to succinylcholine – at least to the manifestation of succinylcholine’s intrinsic activity. And that’s actually what happens!

Back to Item XV and try again.

XVI. Respiratory arrest, as an effect of the anesthetic agent alone on the respiratory center, can be produced without anoxia (when a gas – or vapor-oxygen mixture is used) by:

a. Nitrous oxide, and cyclopropane

Stop! Disregarding cyclopropane for the moment, nitrous oxide can’t be used under these conditions to produce Stage IV anesthesia.

Go back to Item XVI and please, try again.

b. Cyclopropane, but not nitrous oxide

You are perfectly right. This problem has a solution that’s a variation on our old theme of Pa = PsK, that the partial pressure of the gas or vapor required to produce anesthesia is proportional to the vapor pressure of the material (see Question IV). A similar relationship applies when effects other than anesthesia are under consideration. For production of anesthesia, the proportionality constant is about 0.05, for all agents; for production of Stage IV anesthesia – respiratory arrest from the agent alone – the proportionality constant is about 0.12. The vapor pressures of nitrous oxide is so great that the partial pressure predicted (from the product of vapor pressure and 0.12) to cause respiratory arrest is greater than 760 mmHg: at atmospheric pressure, there’s no room in the inspired gas mixture for both the requisite amount of drug and sufficient oxygen to prevent anoxia. Of course, one could always give anesthesia with this agent under hyperbaric conditions… if one wanted to produce Stage IV anesthesia! The “safety” of nitrous oxide, under the usual conditions of drug administration, is at least in part an inevitable consequence of its low boiling point and high vapor pressure. Cyclopropane doesn’t qualify, physicochemically speaking; its vapor pressure – although it is a gas at standard temperature and pressure – is low, as gases go, and cyclopropane, in the presence of a concentration of oxygen adequate to prevent anoxia, can readily produce Stage IV anesthesia.

Remember that many inert gases, such as xenon, for example, can produce anesthesia from Stage I through Stage IV when given under hyperbaric conditions. SCUBA divers recognized this, too, after unfortunate accidents resulted from breathing the inert gas nitrogen under conditions of high partial pressures.

Observe, that if P1 is the partial pressure of gas required to produce Stage IV anesthesia, a lethal effect, P1/Pa is a sort of “therapeutic index“. Then P1/Pa = .12 Ps/.05 Ps for any agent; Ps “cancels out”, and we see that every anesthetic agent (i.e. regardless of its vapor pressure, fugacity, thermodynamic activity, or whatever) has a “therapeutic index” of about 2.4. It happens to be true, experimentally, and seems likely to remain true for agents of this type.

O.K., now on to Item XVII.

c. Halothane and ether, but not cyclopropane

Sorry, all of these agents can produce respiratory arrest – i.e. Stage IV anesthesia – under the conditions given.

Back to Item XVI and make another choice.

d. Halothane and nitrous oxide

Sorry, halothane will, but nitrous oxide cannot, produce respiratory arrest, – i.e. Stage IV anesthesia – under the conditions given.

You’ll have to go back to Item XVI and try again.

XVII. Other things being equal, post-operative nausea and vomiting would be more likely to occur following use of :

a. Ether, than of nitrous oxide

Right you are! Generally speaking post-operative nausea and vomiting occur when there is a relatively slow recovery from anesthesia, a relatively slow recovery of willful or involuntary control over vomiting mechanisms. I think we’ve agreed recovery from ether tends to be slower than recovery from the equivalent degree of anesthesia produced by nitrous oxide; if we’re not agreed to this, I suggest you review Item VIII. In addition, of course, ether is by far the more irritating to the mucous membranes of the oro-pharynx and the tracheo-bronchial tree and the gastrointestinal tract (all the anesthetic gases pass into the gas bubbles that always exist inside the gastrointestinal tract); these factors – in addition to its sometimes unpleasant smell – would contribute to vomiting following ether, but not nitrous oxide, anesthesia.

Good, go on to Item XIII.

b. Nitrous oxide, than of ether

Sorry, wrong choice; but before you go back to Item XVII to choose again, I suggest you review Item VIII.

c. Cyclopropane, than of ether

Too bad, wrong choice. Before going back to Item XVII to make another choice, why don’t you review Item VIII; I think it might help.

XVIII. In analogy with known anesthetic agents, adverse effects of MF, TF, and BF that might be anticipated during experimental anesthesia would include:

a. Lowered diastolic blood pressure consequent to ganglionic blockade

True enough; why don’t you make an additional choice or two from Item XVIII?

b. Lowered systolic blood pressure consequent to a negative inotropic effect

Absolutely true; now would you like to make an additional choice or two from Item XVIII?

c. Lowered systolic blood pressure consequent to central respiratory depression and both central and peripheral skeletal muscle relaxation

Very good and very true. Wouldn’t you like to go back to Item XVIII and see if there are any more true answers?

d. Only two of the above

No. Are you really satisfied that only two of these effects would be produced by the mechanisms suggested? Go back to Item XVIII and be adventurous and daring: Try choice e.

e. a, b, and c above

Very good; all these effects would be produced by the mechanisms suggested and would be observed during the course of deep clinical anesthesia.

Carry on, and try Item XIX

XIX. Preanesthetic medication with conventional doses of atropine (ca. 0.5-1.0mg, s.c. or i.m.):

a. Markedly reduces the amount of thiopental sodium required to induce anesthesia

Sorry, unlike scopolamine, atropine has negligible central nervous system depressant effects in doses such as those described. Certainly, any such effects are of a kind and severity that do not permit or require reduction in the “induction dose” of thiopental. Should you review the pharmacology of atropine?

Go back to Item XIX and make another choice.

b. Interferes with detection of very deep anesthesia by preventing pupillodilation

Wrong choice, I fear. Atropine might produce pupillodilation by blocking the effects of the parasympathetic nervous system on the circular muscles of the iris, but probably not in this low dose. The pupillodilation seen in deep anesthesia is the result of both a “neurogenic” effect and the effect of the agent on the muscles of the iris themselves; it’s like the pupillodilation of a completely denervated eye. It’s not prevented by atropine, and is, ultimately, more intense than that produced by even maximally effective doses of atropine. Hence, atropine won’t interfere with detecting the ocular signs of deep anesthesia. Obviously other signs of deep anesthesia – and its consequences – are of more clinical importance than eye signs such as pupillodilation.

Go back to Item XIX and choose again.

c. Provides effective protection against vagal reflexes evoked by, e.g., sudden severe traction on viscera

Sorry, atropine provides protection against some of the vagal reflexes that occur during anesthesia, but doesn’t protect much against such severe and biologically significant stimuli as traction on the viscera.

Might it be useful to review the pharmacology of atropine?

Go back to Item XIX and try another choice.

d. Decreases salivary and respiratory tract secretions that might otherwise interfere with ventilation

Very true; the perfect choice

Go on to Item XX

XX. Just for fun, which of the sets of associations below is correct:

a. Linus Pauling - the hydrate microcrystal theory of general anesthesia

Correct; Pauling is responsible for originating the theory. See Science 134: 15, 1961 and Anesth. and Analges. 43: 1, 1964.

Might not another choice or two be correct as well? Go back to Item XX and try again.

b. John Snow - cholera-chloroform

Correct, when he wasn’t studying the epidemiology of cholera or taking the handle from the Broad Street pump, Snow was busy being, probably, the first professional anesthesiologist; Queen Victoria used his services during several of her obstetrical deliveries.

Incidentally, Benjamin Ward Richardson (Richardson’s Law: anesthetic potencies of aliphatic alcohols are inversely related to their water solubilities) also combined an interest in anesthesiology with an interest in epidemiology! Do you think this is anything more than coincidence?

You might be interested in Keys, T. E., The History of Surgical Anesthesia, Dover Publications, 1963.

But might one or another choice also be correct?

Go back to Item XX and have another try.

c. W.T.G. Morton - ether - Boston

Of course, the first successful public demonstration of surgical anesthesia is summarized by the triad of Morton-Ether-Boston. But might another choice be equally correct?

d. Cyclopropane - Madison, Wisconsin; Ethylene - Chicago; Trichloroethylene - Cincinnati

Perfectly correct; not every “first” in anesthesiology happened in Boston. Might another choice be equally correct?

Go back to Item XX and choose again.

e. All of the above

Completely correct at last! (Do read the comments for the other choices to Item XX… if you have not done so already)… and this is the end of the program.