Programmed Problem Set on Agents Affecting the Autonomic Nervous System

Ladislav Volicer, M.D.,Ph.D
Professor of Pharmacology
Boston University School of Medicine

Questions or comments should be mailed to Carol Walsh

This set of questions should help you to familiarize yourself with drugs acting on the autonomic nervous system, their effects and mechanisms of action. The package is composed of two parts which are independent; each of them consists of ten items.

PART A

The dose-effect curves labeled A, B, C, D, and E below represent curves for drugs administered alone or in combination. Use these curves to help you choose the most appropriate answer for the following items.

I. Before we can consider specific agents, you have to know the basic principles governing receptor-drug interactions. Which of the following statements is true?

a. Drug A is more potent than drug C in producing effect Y.

Right. The dose of drug A which is required to produce effect Y is lower than an equipotent dose of drug C. Since potency varies inversely with the magnitude of the dose required to produce a given effect, drug A is more potent than drug C. There is, however, one other true statement in this item. Go back to Item I and try to find it.

b. Drug B is more potent than drug A in producing effect Y.

Wrong. The maximal effect produced by drug B is larger than the maximal effect of drug A, which indicates that drug B might have higher intrinsic activity. However, the dose of drug B which is required to produce effect Y is higher than an equipotent dose of drug A. Since potency varies inversely with the magnitude of the dose required to produce a given effect, drug A is more potent than drug B. Go back to Item I and try again.

c. Drug B has a higher intrinsic activity than Drug A.

Right. The intrinsic activity depends on the amount of biological effect produced per unit of drug-receptor complex formed. An agent producing greater maximum effect (in our case drug B) has the greater intrinsic activity. There is, however, one other true statement in this item. Go back to Item I and try to find it.

d. Two of the above statements are true

Very good. I hope you considered statement a and c to be true. If you did, you have a good understanding of the concepts of potency and intrinsic activity. If you thought that statement b is true, you should review the comment to Item Ib. Now you can go to Item II.

e. None of the above statements is true

Wrong. You do not understand the concept of potency and intrinsic activity. Review these terms in the Glossary of Terms and Symbols Used in Pharmacology (Course Manual, Chapter 3), and then go back to Item I.

II. Many drugs act by affecting the activity of endogenous substances, such as neurotransmitters, autacoids, and hormones. Some of them potentiate an effect, some of them inhibit or antagonize it. There are three types of antagonists: chemical, physiological and pharmacological. Which of the following statements about an agent and its antagonist is true?

a. Atropine is a physiological antagonist of acetylcholine

Wrong. Physiological antagonism is caused by agonist and antagonist acting at two independent sites and inducing independent, but opposite, effects. Atropine acts at the same site as acetylcholine. Go back to Item II.

b. Phenoxybenzamine is a chemical antagonist of norephinephrine

Wrong. Chemical antagonism is caused by a combination of agonist with antagonist, resulting in inactivation of the agonist. Phenoxybenzamine antagonizes norepinephrine by decreasing the number of alpha-receptors available for norepinephrine. Go back to Item II.

c. Norepinephrine is a pharmacological antagonist of acetylcholine

Wrong. Prazosin is a pharmacological antagonist of norepinephrine, not of acetylcholine. Go back to Item II.

d. Ipratropium is a pharmacological antagonist of acetylcholine

Right. Ipratropium is a pharmacological antagonist of acetylcholine because it acts at the same site (receptor) as acetylcholine. Go to Item III.

e. Phentolamine is a physiological antagonist of norephinephrine

Wrong. Physiological antagonism is caused by agonist and antagonist acting at two independent sites and inducing independent, but opposite effects. Phentolamine and norepinephrine act at the same site (alpha-receptor). Go back to Item II.

III. There are two types of pharmacological antagonists: competitive and non-competitive. A competitive antagonist interacts with the ligand-binding site on a receptor and produces a reversible or irreversible antagonism depending on the kinetics of its binding and dissociation. A non-competitive antagonist interacts with a site on the receptor other than the ligand-binding site or within the receptor signal transduction mechanism.

If you assume that some of the dose-effect curves shown above were obtained with a combination of an agonist and an antagonist, which of the following statements is true?

a. If curve A represents the effect of drug A given alone, curve C represents the effect of drug A after treatment with an irreversible competitive antagonist

Wrong. An irreversible competitive antagonist acts by decreasing the number of receptors available for binding an agonist. Therefore even high agonist concentration cannot overcome an irreversible blockade, and the maximal effect of an agonist is smaller in the presence than in the absence of an irreversible antagonist. Go back to Item III.

b. If curve C represents the effect of drug C given alone, curve D represents the effect of drug C after treatment with an irreversible competitive antagonist

Right. An irreversible competitive antagonist acts by decreasing the number of receptors available for binding an agonist. Therefore, even a high agonist concentration cannot overcome a irreversible blockade, and the maximal effect of an agonist is smaller in the presence than in the absence of an irreversible antagonist. There is, however, one other true statement in this item. Go back to Item III and try to find it.

c. If curve C represents the effect of drug C given alone, curve D represents the effect of drug C in the presence of a reversible competitive antagonist

Wrong. A reversible competitive antagonist acts by competing with the agonist for receptor binding. Therefore it is possible to overcome a competitive blockade by increasing the concentration of agonist. The presence of a competitive antagonist usually shifts the dose-effect curve to the right, but it does not change the maximal effect. Go back to Item III.

d. If curve C represents the effect of drug C given alone, curve D represents the effect of drug C given in the presence of a non-competitive antagonist

Right. A non-competitive antagonist reduces the maximal effect, but does not change the ED50. There is, however, one other true statement in this item. Go back to Item III and try to find it.

e. Two of the above statements are true

Right. Statements b and d are both correct. A decrease in the Emax with no shift in the EC50 is seen either in the presence of a non-competitive antagonist or after treatment with an irreversible competitive antagonist.

IV. If curve C represents the increase of motility of isolated stomach after acetylcholine was administered alone, which curve represents the effect of acetylcholine in a preparation pretreated with physostigmine?

a. Curve A

Right. Physostigmine potentiates the effects of acetylcholine by inhibiting acetylcholinesterase, an enzyme which hydrolyzes acetylcholine. Potentiation of an agonist effect shifts the dose-effect curve to the left. Go to Item V.

b. Curve B

Wrong. Physostigmine does not have an effect by itself and, therefore, it cannot increase the maximal effect of acetylcholine. Go back to Item IV.

c. Curve C

Wrong. Physostigmine modifies acetylcholine effects. Before you go back to Item IV, review the pharmacologic effects and mechanism of action of physostigmine.

d. Curve D

Wrong. Physostigmine potentiates the effects of acetylcholine, which means that the same dose of acetylcholine will produce a greater effect in the presence of physostigmine. Curve D indicates smaller effects of the same doses than Curve C. Go back to Item IV.

e. None of the above

Wrong. There is a curve representing the effect of acetylcholine in a preparation pretreated with physostigmine. Go back to Item IV and think about it again.

V. If curve C represents the increased heart rate of an isolated heart after treatment with norepinephrine, which curve might represent the effect of isoproterenol in the same preparation?

a. Curve A

Right. Isoproterenol is more potent than norepinephrine at cardiac B1 receptors. Go to Item VI.

b. Curve C

Wrong. Isoproterenol and norepinephrine have different potencies at cardiac adrenergic receptors. Go back to Item V.

c. Curve D

Wrong. Isoproterenol and norepinephrine are both full agonists at cardiac receptors, so they should have similar maximal effects.

d. Curve E

Wrong. Isoproterenol is not less potent than norepinephrine at cardiac receptors. Go back to Item V.

e. None of the above

Wrong. Chlorpheniramine modifies the effect of histamine on blood vessels. Before you go back to Item V, review the pharmacology of chlorpheniramine and other antihistamines.

VI. If curve C represents the vasoconstriction after norepinephrine was given alone, which curve represents the effect of norepinephrine in a preparation pretreated with cocaine?

a. Curve A

Right. Cocaine potentiates norepinephrine by inhibiting the reuptake of norepinephrine into the sympathetic nerve endings. Since this uptake is the major mechanism for terminating norepinephrine effect, inhibition of the uptake shifts the dose-effect curve of norepinephrine to the left. Go to Item VII.

b. Curve B

Wrong. Cocaine itself does not produce vasoconstriction and, therefore, it cannot increase the maximal effect of norepinephrine. Go back to Item VI.

c. Curve C

Wrong. Cocaine modifies norepinephrine effects. Before you go back to Item VI, review the pharmacological effects and mechanism of action of cocaine.

d. Curve D

Wrong. Cocaine potentiates the effects of norepinephrine. That means that the same dose of norepinephrine will produce a greater effect in the presence of cocaine. Curve D indicates a smaller effect of the same dose than Curve C. Go back to Item VI.

e. None of the above

Wrong. There is a curve for norepinephrine in the presence of cocaine. Go back to Item VI and think about it again.

VII. If curve C represents the increased heart rate of an isolated heart after norepinephrine was given alone, which curve represents the effect of norepinephrine in a preparation pretreated with phentolamine?

a. Curve A

Wrong. The effect of norepinephrine in a preparation pretreated with phentolamine is represented by a different curve. Go back to Item VII.

b. Curve E

Wrong. The effect of norepinephrine in a preparation pretreated with phentolamine is represented by a different curve. Go back to Item VII.

c. Curve C

Right. Phentolamine does not affect the increase of heart rate of an isolated heart because this effect is mediated through beta receptors and phentolamine is an alpha receptor blocking agent. Go to Item VIII.

d. Curve D

Wrong. The effect of norepinephrine in a preparation pretreated with phentolamine is represented by a different curve. Go back to Item VII.

e. None of the above

Wrong. There is a curve which represents the curve for norepinephrine in the presence of phentolamine. Go back to Item VII and think about it again.

VIII. If curve C represents contraction of an isolated skeletal muscle after acetylcholine was administered alone, which curve represents the effect of acetylcholine in a preparation pretreated with succinylcholine?

a. Curve A

Wrong. Pretreatment with succinylcholine blocks the effect of acetylcholine at the neuromuscular junction. Therefore, acetylcholine cannot have greater effect in a preparation pretreated with succinylcholine than when it is given alone. Go back to Item VIII.

b. Curve C

Wrong. Succinylcholine modifies the effect of acetylcholine on skeletal muscle. Before you go back to Item VIII, review the pharmacological effects and mechanisms of action of succinylcholine and other neuromuscular blocking agents.

c. Curve D

Right. Succinylcholine is a depolarizing neuromuscular blocking agent which prevents the effect of acetylcholine by initially depolarizing the membrane (phase I) and then desensitizing the receptors (phase II). Therefore, its blockade cannot be abolished by increasing the dose of acetylcholine.

d. Curve E

Wrong. Succinylcholine is a depolarizing blocking agent at the neuromuscular junction. You have to keep in mind that the effect of succinylcholine cannot be abolished by increasing the dose of acetylcholine. Go back to Item VIII.

e. None of the above

Wrong. There is a curve which represents the curve for acetylcholine in a preparation pretreated with succinylcholine. Go back to Item VIII and think about it again.

IX. If curve C represents contraction of an isolated blood vessel after phenylephrine was administered alone, which curve represents the effect of phenylephrine in a preparation pretreated with phenoxybenzamine?

a. Curve E

Wrong. Phenoxybenzamine is not a reversible competitive antagonist of phenylephrine. Therefore, in a preparation treated with phenoxybenzamine, even high doses of phenylephrine will not produce a substantial increase of the blood pressure. Go back to Item IX.

b. Curve B

Wrong. Pretreatment with phenoxybenzamine blocks the alpha adrenergic receptors. Therefore, phenylephrine cannot have a greater effect in a preparation pretreated with phenoxybenzamine than when it is given alone. Go back to Item IX.

c. Curve C

Wrong. Pretreatment with phenoxybenzamine modifies the effect of phenylephrine on blood vessels. Before you go back to Item IX, review the pharmacological effects and mechanisms of action of phenoxybenzamine and other sympathetic blocking agents.

d. Curve D

Right. Phenoxybenzamine binds irreversibly to alpha adrenergic receptors. and therefore produces a non-competitive block of these receptors. The effect of phenylephrine, which stimulates vascular alpha receptors, is inhibited in a preparation pretreated with phenoxybenzamine. Go on to Item X.

e. None of the above

Wrong. There is a curve which represents the effect of phenylephrine in a preparation pretreated with phenoxybenzamine. Go back to Item IX and try to find it.

X. If curve C represents contraction of an isolated skeletal muscle after acetylcholine administration, which curve represents the effect of acetylcholine in a preparation pretreated with d-tubocurarine?

a. Curve A

Wrong. Pretreatment with d-tubocurarine blocks the effect of acetylcholine. Therefore, acetylcholine cannot have a greater effect in a preparation pretreated with d-tubocurarine, than when it is given alone. Go back to Item X.

b. Curve B

Wrong. Pretreatment with d-tubocurarine blocks the effects of acetylcholine. Therefore, acetylcholine cannot have greater effect in a preparation pretreated with d-tubocurarine than when it is given alone. Go back to Item X.

c. Curve C

Wrong. D-tubocurarine modifies the pharmacological effect of acetylcholine on skeletal muscles. Before you go back to Item X, review the pharmacological effects and mechanisms of action of d-tubocurarine and other neuromuscular blocking agents.

d. Curve D

Wrong. D-tubocurarine is a reversible competitive antagonist of acetylcholine. By increasing the dose of acetylcholine, it is possible to obtain the same maximal effect in the presence of d-tubocurarine as with acetylcholine alone. Go back to Item X.

e. Curve E

Right. D-tubocurarine is a reversible competitive antagonist of acetylcholine at the neuromuscular junction. The blocking effect of d-tubocurarine can be overcome by anticholinesterase drugs, which increase the concentration of acetylcholine at the neuromuscular junction.

PART B

An experiment was set up to record the blood pressure and heart rate of a cat, anesthetized with pentobarbital and maintained at plane III surgical anesthesia. The right vagus nerve was isolated and separated from its central connections. A pair of stimulating electrodes was placed around the distal vagus for stimulation when desired. Both carotids were isolated in the neck (below the carotid sinus) and were readily available for occlusion when desired. Doses of different drugs were administered intravenously or the nerves were stimulated for a period of two to three seconds. Blood pressure was measured with a pressure transducer, and heart rate was recorded as increased (+) or decreased (-) with respect to the base line represented as 0.

Use the information above to answer the following questions:

XI. Which procedure or drug would induce the changes of the blood pressure and heart rate observed 3 min after the beginning of the experiment?

a. Vagus nerve stimulation

Right. Stimulation of the distal vagus would decrease both the heart rate, due to direct parasympathetic inhibition of the sinus node, and the blood pressure, due to decreased cardiac output. Go on to Item XII.

b. Acetylcholine administration

Wrong. Acetylcholine administration would produce a decrease of the blood pressure but the heart rate would not decrease. Actually the heart rate after acetylcholine is usually slightly elevated because decrease of the blood pressure induces sympathetic activation through baroreceptors. Go back to Item XI.

c. Histamine administration

Wrong. Histamine administration would decrease the blood pressure not the heart rate. The heart rate after histamine is usually slightly elevated because decrease of the blood pressure induces sympathetic activation through baroreceptors. Go back to Item XI.

d. Two of the above

Wrong. All of the drugs listed, as well as vagus nerve stimulation, would induce a decrease in blood pressure. However, only one of these conditions would produce a decrease of the heart rate also. Go back to Item XI and try to find it.

e. None of the above

Wrong. There is one condition which would produce changes of the blood pressure and heart rate similar to those which occurred 3 minutes after the beginning of the experiment. Go back to Item XI and try to find it.

XII. Which drug or procedure would induce the changes of the blood pressure and heart rate observed 6 min after the beginning of the experiment?

a. Phenylephrine administration

Wrong. Phenylephrine would increase blood pressure by producing vasoconstriction, but this increase of blood pressure would induce bradycardia through stimulation of carotid baroreceptors. Go back to Item XII.

b. Administration of a low dose of epinephrine

Wrong. A low dose of epinephrine would increase heart rate, but at the same time it would decrease blood pressure because it would produce vasodilation through stimulation of adrenergic beta receptors. Go back to Item XII.

c. Occlusion of carotid arteries below the carotid sinus

Right. Occlusion of carotid arteries would decrease the blood pressure at the carotid sinus, and would produce an increased sympathetic outflow which would increase both heart rate and peripheral blood pressure. Go on to Item XIII.

d. Two of the above

Wrong. There is only one drug or procedure which would simultaneously increase both blood pressure and heart rate. Go back to Item XII and try to find it.

XIII. Which of the following in the same dose would diminish and/or abolish the blood pressure changes resulting from both distal vagal nerve stimulation and carotid occlusion?

a. Atropine

Wrong. Atropine would abolish the effect of vagal nerve stimulation but it would not decrease the response to carotid occlusion. Go back to Item XIII.

b. Phentolamine

Wrong. Phentolamine would abolish the effect of carotid occlusion, but not the effect of distal vagal nerve stimulation. Go back to Item XIII.

c. Propranolol

Wrong. Propranolol would abolish the effect of carotid occlusion on the heart rate but not the effect of carotid occlusion or distal vagal verve stimulation on the blood pressure. Go back to Item XIII.

d. Hexamethonium

Right. Hexamethonium would prevent both the effects of distal vagal nerve stimulation and carotid occlusion by blocking transmission at the parasympathetic and sympathetic ganglia. Go to Item XIV.

e. Two of the above

Wrong. There is only one drug which would diminish the blood pressure changes resulting from both distal vagal nerve stimulation and carotid occlusion. Go back to Item XIII and try to find it.

XIV. Which drug or drug combinations would induce the changes of the blood pressure and heart rate observed 12 min after the beginning of the experiment?

a. Administration of an average dose of epinephrine

Right. An average dose of epinephrine would increase both the heart rate, through simulation of beta adrenergic receptors, and the blood pressure, through stimulation of alpha adrenergic receptors. There is, however, one more drug or drug combination which would produce this effect. Go back to Item XIV and try to find it.

b. Administration of a large dose of norepinephrine in a preparation pretreated with phentolamine

Right. Phentolamine pretreatment would block the alpha adrenergic receptors, but since phentolamine is a competitive inhibitor, a large dose of norepinephrine would still slightly increase the blood pressure. At the same time, phentolamine would not affect the increase of heart rate produced by stimulation of beta adrenergic receptors. However, there is one more drug which would also produce this effect. Go back to Item XIV and try to find it.

c. Histamine administration

Wrong. Histamine would produce slight tachycardia, but it would markedly decrease the blood pressure by dilation of small blood vessels. Go back to Item XIV.

d. Two of the above

Very good. I hope you consider a and b as the right answers. Go to Item XV.

e. All of the above

Wrong. Review the cardiovascular effects of catecholamines and histamine before going back to Item XIV.

XV. Which drugs would induce the changes of the blood pressure and heart rate observed 15 min after the beginning of the experiment?

a. Tyramine administration

Wrong. Tyramine would increase blood pressure mainly through release of norepinephrine from the nerve endings. However, there would be a decrease of the heart rate mediated through stimulation of carotid baroreceptors. Go back to Item XV.

b. Albuterol administration

Wrong. Albuterol is a selective B2 agonist and therefore would be expected to activate vasodilator B2 receptors, decrease total peripheral resistance, and decrease blood pressure, reflex effects, and (at higher concentrations) effects on B1 receptors might cause an increased heart rate. (Recall that this drug is administered by inhalation to treat asthma, in order to increase the selectivity of its effects on pulmonary B2 receptors and decrease the risk of cardiovascular side effects such as tachycardia.) Go back to Item XV.

c. Prasozin Administration

No. An alpha1 selective antagonist like prazosin would not be expected to increase the blood pressure of an anesthetized cat. An initial effect of vascular alpha receptor blockade might be a decrease in blood pressure due to a decrease in total peripheral resistance. Go back to Item XV.

d. Two of the above

Wrong. Go back to Item XV and reconsider.

e. None of the above

Correct. None of the drugs listed would markedly increase both the blood pressure and the heart rate. Go on to Item XVI.

XVI. Which of the following could induce the changes of the blood pressure and heart rate observed 18 min after the beginning of the experiment?

a. Administration of epinephrine to a patient treated chronically with propranolol

Right. Pretreatment with propranolol would block the stimulation of beta receptors by epinephrine. Therefore, only increased blood pressure, mediated by stimulation of alpha adrenergic receptors, and reflex bradycardia, would be observed after administration of epinephrine in a patient treated chronically with propranolol. There is, however, another drug or drug combination which would induce similar changes. Go back to Item XVI and try to find it.

b. Administration of methoxamine

Right. Methoxamine selectively stimulates the alpha adrenergic receptors and, therefore, would produce an increase of blood pressure and reflex bradycardia. There is, however, another drug or drug combination which would induce similar changes. Go back to Item XVI and try to find it.

c. Ingestion of cheese in a patient treated chronically with phenelzine (an MAO inhibitor)

Right. Phenelzine inhibits monamine oxidase, the enzyme which metabolizes many biogenic amines. Some kinds of heavy cheese have a high content of substances, mainly tyramine, which can produce an increase in blood pressure. Normally, after ingestion of such cheese, these substances are broken down rapidly by monamine oxidase. In a patient treated with phenelzine, metabolism of these amines is inhibited, and, therefore, they can produce a dangerous rise of blood pressure accompanied by a reflex bradycardia. There is, however, another drug or drug combination which would induce similar changes. Go back to Item XVI and try to find it.

d. Two of the above

Wrong. You forgot one other treatment which would also increase the blood pressure and decrease the heart rate. Read a comment corresponding to this agent before proceeding to Item XVII.

e. All of the above

Very good. All of the listed treatments would simultaneously increase the blood pressure and decrease the heart rate. Go on to Item XVII.

XVII. Which treatment would induce the changes of the blood pressure and heart rate observed 21 min after the beginning of the experiment?

a. Isoproterenol administration

Right. Isoproterenol stimulates chiefly beta adrenergic receptors and would, therefore, produce tachycardia and decrease the blood pressure, due to peripheral vasodilation. There is, however, another treatment which would produce similar changes. Go back to Item XVII and try to find it.

b. Carotid occlusion

Wrong. You either skipped or forgot the answer to Item XII. Go back and answer Item XII before you try to answer Item XVII again.

c. Administration of epinephrine in a preparation pretreated with phentolamine

Right. Phentolamine blocks alpha adrenergic receptors; therefore epinephrine, in a preparation pretreated with phentolamine, stimulates only beta receptors and produces tachycardia and vasodilation. There is, however, another treatment which would produce similar changes. Go back to Item XVII and try to find it.

d. Two of the above

Very good. I hope you chose a and c as the right answers. Go to Item XVIII.

e. All of the above

Wrong. There is one treatment listed which does not simultaneously decrease the blood pressure and increase the heart rate. Go back to Item XVII and try to find it.

XVIII. If phenoxybenzamine were administered to the animal and the test procedures were repeated, you might expect which of the following?

a. The change in blood pressure resulting from carotid occlusion would be greater than that seen in the control period

Wrong. Carotid occlusion produces an increase in the blood pressure and this increase would be antagonized by the alpha blocking agent phenoxybenzamine. Go back to Item XVIII.

b. The change in blood pressure resulting from the administration of isoproterenol would be less than that seen in the control period

Wrong. Isoproterenol decreased blood pressure by stimulating beta receptors; this effect would be unaffected or enhanced by phenoxybenzamine pretreatment. Go back to Item XVIII.

c. The change in blood pressure resulting from the administration of a low dose of epinephrine would be greater than that seen in the control period

Right. A low dose of epinephrine decreases blood pressure and this decrease would be enhanced by blockade of alpha adrenergic receptors. Go to Item XIX.

d. Two of the above

Wrong. There is only one true statement listed. Go back to Item XVIII and try to find it.

e. All of the above

Wrong. There is only one true statement listed. Go back to Item XVIII and try to find it.

XIX. Which treatment would induce the changes of the blood pressure and heart rate observed 24 minutes after the beginning of the experiment?

a. Vagus nerve stimulation

Wrong. You either skipped or forgot Item XI. Go back to Item XI before trying to answer Item XIX again.

b. Acetylcholine administration

Right. Acetylcholine would decrease blood pressure and induce secondary reflex tachycardia. There is, however, another treatment which would produce similar effects. Go back to Item XIX and try to find it.

c. Histamine administration

Right. Histamine would decrease blood pressure and induce secondary reflex tachycardia. There is, however, another treatment which would produce similar effects. Go back to Item XIX and try to find it.

d. Two of the above

Very good. I hope you consider histamine and acetylcholine to be the right answer. You are now at the end of the program and I hope that you learned something in answering it.

e. All of the above

Wrong. There is one treatment listed which does not simultaneously decrease the blood pressure and increase the heart rate. Go back to Item XIX and try to find it.