Department of Pharmacology

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 at ctwalsh@bu.edu

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: P a /P s =K. For anesthetic materials, in general, an average value of K of 0.05 can be assumed, when P s 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 CCl 3 F 137 24 674 4.8 0.02
TF CCl 2 F€CClF 2 187 48 268 6.2 0.003
BF CCl 2 F€CClF 204 93 1 5.8 0.002
Ether (C 2 H 5 ) 2 O 74 35 440 2.6 1.000
Nitrous Oxide N 2 O 44 -89 38,800 1.5 0.04
Cyclopropane C 3 H 6 42 -33 4,800 1.5 0.02
*Ether = 1.0; values are proportional to the blood/gas solubility coefficient

You will undoubtedly wish to refer to the data in the table as you proceed through the program, therefore, if you would like to print out this table, click here .

I. Concerning the conditions for storage and administration of MF, TF and BF as experimental anesthetic agents, we would expect that:
  1. BF would be stored under pressure in steel tanks, as is true for cyclopropane
  2. MF and TF could probably be stored under conditions appropriate for diethyl ether
  3. 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
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:
  1. Only if the agents act by forming ionic bonds with constituents of cell membranes
  2. Only if the agents act by dissolving into cell membrane lipids
  3. Regardless of whether the agents act by forming ionic bonds, or by dissolving into cell lipids
  4. 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
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: [ Click for Table ]

  1. MF would be more potent than ether
  2. MF would be more potent than cyclopropane
  3. BF would be less potent than MF or ether
  4. None of the above
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)? [ Click for Table ]
  1. TF would appear to be less potent in the hyperpyrexic subject
  2. TF would appear to be more potent in the hyperpyrexic subject
  3. TF would appear to be equally potent in the hyperpyrexic and normal subjects
  4. Known properties of general anesthetic agents don't permit predicting their effects under these conditions
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: [ Click for Table ]
  1. BF than MF
  2. MF than ether
  3. BF than ether
  4. Oxygen (O 2 ) than ether
VII. At equally effective concentrations, one would expect anesthesia to be induced more rapidly with: [ Click for Table ]
  1. BF than with ether
  2. Ether than with MF
  3. Ether than with TF
  4. MF than with TF
VIII. After anesthesia sufficiently prolonged to saturate all tissues, recovery would be expected to be slower with: [ Click for Table ]
  1. BF than with ether
  2. Ether than with nitrous oxide or cyclopropane
  3. TF than with ether
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: [ Click for Table ]
  1. MF
  2. TF
  3. BF
  4. Ether
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:

  1. Larger for ether than for MF
  2. Larger for MF than for ether
  3. Larger for BF than for MF or TF
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: [ Click for Table ]
  1. Flame and possible explosion, as would occur with halothane or chloroform
  2. Flame and possible explosion, as would occur with ether or cyclopropane
  3. Oxidation of the surface without explosion hazard, as would occur with cyclopropane
  4. Production of toxic products such as phosgene, as would occur with chloroform or trichloroethylene
XII. In analogy with known anesthetic agents, adverse effects of MF, TF, and BF that might be anticipated during experimental anesthesia would include:
  1. Abrupt, severe hypertension during surgical anesthesia, as is characteristic of halothane
  2. Cardiac arrhythmias, as is more characteristic of enflurane and isoflurane than of halothane
  3. "Sensitization" of the myocardium to arrhythmias produced by epinephrine, as is characteristic of halothane and chloroform
  4. "Sensitization" of the myocardium to arrhythmias produced by epinephrine, as is characteristic of nitrous oxide
XIII. Conditions which might predispose a patient to the occurrence of ventricular arrhythmias during clinical general anesthesia include:
  1. Facilitated AV conduction, caused by a direct action of the anesthetic agent
  2. Shortened atrial refractory period, caused by a direct action of the agent
  3. Increase of SA nodal rates to ca. 100 to 110 beats/min
  4. Hypercarbia
XIV. Agents which appear to undergo substantial biotransformation under clinical conditions of use include:
  1. Isoflurane and nitrous oxide, but not halothane
  2. Halothane, but not nitrous oxide
  3. Nitrous oxide, but not isoflurane
  4. Halothane, methoxyflurane and nitrous oxide
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:
  1. Synergistically with tubocurarine and antagonistically to at least some effects of succinylcholine
  2. Antagonistically to tubocurarine
  3. Antagonistically to tubocurarine and gallamine
  4. Antagonistically to gallamine, and synergistically with succinylcholine
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:
  1. Nitrous oxide, and cyclopropane
  2. Cyclopropane, but not nitrous oxide
  3. Halothane and ether, but not cyclopropane
  4. Halothane and nitrous oxide
XVII. Other things being equal, post-operative nausea and vomiting would be more likely to occur following use of :
  1. Ether, than of nitrous oxide
  2. Nitrous oxide, than of ether
  3. Cyclopropane, than of ether
XVIII. In analogy with known anesthetic agents, adverse effects of MF, TF, and BF that might be anticipated during experimental anesthesia would include:
  1. Lowered diastolic blood pressure consequent to ganglionic blockade
  2. Lowered systolic blood pressure consequent to a negative inotropic effect
  3. Lowered systolic blood pressure consequent to central respiratory depression and both central and peripheral skeletal muscle relaxation
  4. Only two of the above
  5. a, b, and c above
XIX. Preanesthetic medication with conventional doses of atropine (ca. 0.5-1.0mg, s.c. or i.m.):
  1. Markedly reduces the amount of thiopental sodium required to induce anesthesia
  2. Interferes with detection of very deep anesthesia by preventing pupillodilation
  3. Provides effective protection against vagal reflexes evoked by, e.g., sudden severe traction on viscera
  4. Decreases salivary and respiratory tract secretions that might otherwise interfere with ventilation
XX. Just for fun, which of the sets of associations below is correct:
  1. Linus Pauling - the hydrate microcrystal theory of general anesthesia
  2. John Snow - cholera-chloroform
  3. W.T.G. Morton - ether - Boston
  4. Cyclopropane - Madison, Wisconsin; Ethylene - Chicago; Trichloroethylene - Cincinnati.
  5. All of the above