experimental pharmacology

168 Pages·2013·2.61 MB·English

A Laboratory Manual of
EXPERIMENTAL PHARMACOLOGY

for Veterinary Students

BERNARD V. ALFREDSON, D.V.M., M.S.
Professor of PhysIology and Pharmacology
MIChIgan State College

BURGESS PUBLISHING COMPANY
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Received. 2S~-'J-~ 71 Book No.

l\!GIPC-S2~Ul-6-42-9-5-39-20(J,

Copynght 1943. 1947
by
Bernard V Alfredson

Second Prmhng 1948

PRINTED IN THE UNITED S1 A TES OF AMERICA

PREFACE

The selection of the eXperlments presented in this Manual is
based upon several years of laboratory trial in an effort to apply
standard. experimental proced.ures to the special needs of veterinary
students.
The primary objective has been to provide the minimum of
training necessary far the more important disciplines in therapeutics
and clinical pharmacology.
For this reason, the material presented
is not to be construed as representing a complete coverage of the
field of experimental :pharmacodynamics in which there are already
available several excellent treatises.

The arrangement of the various exercises conforms to a general
outline based upon the pharmacology of particular organs or systems
rather than individual drugs.
This is for the convenience of the
student who wishes to review the normal physiology in conjunction
with its application in interpreting results seen with drugs in the
laboratory •

It will be noted that each exercise usually calls for repeti-
tion on a wide variety of animals.
Due to the difficulty occasion-
ally encountered in obtaining suitable mammalian material, this
affords same latitude in planning the laboratory work.
Only such
drugs as are necessary to demonstrate the characteristic effects of
a drug group upon an organ or system have been included far study.
The time-consuming nature of any laboratory course makes it neces-
sary to reserve details concerning the action of many drugs far mare
adequate discussion in the dldatic phase of this and subsequent
courses.

The illustrations contained in this manual are for the most part
reproductions of actual posed photographs.
The -writer is deeply in-
debted to Mr. C. Albert Alfredson far his painstaking care in execut-
ing these drawings.

East Lansing, Michigan
June 30, 1947

B. V. Alfredson

TABLE OF CONTENTS

Introduction

General Instructions

Pharmacology of the Central Nervous System.

A.
Drugs Depressing the Central Nervous System.

l. Action of Soporifics and HYPnotics on the Frog
2.
Morphine, Barbiturates, Magnesium, and Other
Central Depressants
3. _ Effect of Ether, Chloroform, and Alcohol on the
Frog
4.
The Action of Alcohol, Chloroform and Ether on
Mammals

B.
Drugs Stimulating the Central Nervous System.

5.
Strychnine POisoning, Acute Barbiturate Depression,
and Their Physiological Antagonism
6.
Pharmacodynamic s of Certain Medullary Stimulant
Drugs

Pharmacology of the Circulatory and Respiratory Systems.

7.
The Effect of Certain Drugs on the Cardiac
Mechanism of the Turtle and the Systemic
Action of Nicotine on the Frog
8.
The Effect of Drugs on the Cardiac Mechan~sm
9.
The Effect of Drugs on Blood Pressure and
Respiration
lO.
The Effect of Drugs on Perfusion Rate and
Organ Volume

Pharmacology of the Blood.

ll.
The Systemic Action of Cyanide

Pharmacology of the Vrinary System.

12 .
Diuretic s

Pharmacology of the Peripheral Nervous System.

l3.
Cocaine, Procaine, Mydriatics, and Myotics
l4.
The Action of Drugs on the Cervical Sympathetic
Nerves and Other Effects of Autonomic Drugs
in the Rabbit

11

Page

l

II

25

33

4l

57

65

_ 7l
77

85

93

99

l03

l09

ll7

Pharmacology of the Gastro-intestinal Tract.

15.
Druga Producing Emesis __
l6.
Saline Cathar~lcs and Irritant Purgatives
17.
The Action of Various Drugs on Intestinal Motility

Pharmacology of the Female Reproductive System.

18.
Effect of Druga on the Isolated Guinea Pig and
Rabbit Uterus

Pharmacology o£ Astrirsents; Irritants; and Corrosives.

19.
The Action of Drugs on Various Tissues and
Other Organic Material

Appendix.
Functions of the Autonomic Nervous System

iii

Page

123
l29
133

145

151

155

INTRODUCTION

The purpose of this introQuction is large~ to acquaint the stUQent with certain
terms and related basic material as it applies to the work outlineQ in this manual. The
various Qefini tions presenteQ thus serve merely as a sample of the terms encountered in
the field of pharmacology. It is necessary, therefore, to supplement this outline by
perusal of the more Qetailed treatments in such stanQarQ pharmacology texts as So~*
or Goodman and Gilman**.

I. General terms.

The term l?harmacology is defined as the SUlD. of the knowledge regarQing drugs. A Illore
accurate conception of the breaQth of this science can be obtained by consiQerinB
its various subQ1visions:

1. Pharmacognosy
2. Materia MeQfca
3. Pharmacy
4. Pharmacodynamics
5. Therapeutics
6. Toxicology

These will be defined and commented upon in the above order.

1. Pharmacognosy is a subdivision of pharmacology which treats of the characteristics
of crude drugs.
Since most crude drugs are of botanical origin, this science is
concerned mainly with the botanical characteristics of the plants from which crude
drugs are obtained as well as of the characteristics of the drugs themselveS, such
as gross and microscopic appearance, the nature of common contaminating material,
. etc.

2. Materia Medica is a subdivision of pharmacology which deals with the sourceS,
preparations, uses, and sometimes actions of drugs.
Freely interllreted thiS
science must then encroach upon pharmacognosy as well as include certain addi-
tional features such as the study of the various pharmaceutical preparations
made !ram crude drugs and a consideration of their uses.
Furthermore it mEJY
conceivably treat of many drugs which are neither crude nor of botanical origin.
The science is confusing in its scope and, as a consequence, the term ~
medica is vague.

3. Pharmacy is classically defined as the art of preparing, compounding, and diS-
pensing drugs.
While, for economic reasons, the art is still of considerable
service to veterinarians, modern trends in the preparation and merchandisinB of
drugs may be operating to alter this older conception of pharmacy.

4. Pharmacodynamics is the study of the actions of drugs on the living organism.
This also includes their absorption, fate, and excretion. Within :r:ecent yearS
the term l?harmacology has been used loosely as synonyIllous with pharmaco~cs.
A thorough understanding of the function of the normal organism is fundamental
to an explanation of all pharmacodynamic phenomena.
Physiology must then be the
primary basis upon which pharmacodynamics rests.
Furthermore the treatment of
disease is complicateQ by the influence of pathological states on the actions of
many drugs.
Thus it becomes necessary to add the field of pathology to our list.
For obvious reasons, chemistry is another indispensible basic area of knowledge.
Pharmacodynamics thus becomes, in a certain sense, a borderline science in which

*Sollmann, Torald, .! Manual of Pharmacology, W. B. Saunders Co., Philadelphia.
**GoodJ:n.an., Louis and Alfred Gilman, The PharmacologicaJ. ~
of Therapeutics, The
MacMillan Co., New York.
1

2
MANUAL OF EXPERJMENTAL VETERINARY PHARMACOLOGY

a knowledge of chemistry, pathology, and physiology is necessary.
In another
sense it could occupy a position analagous to pathology since both sciences are
essentially the study of organisms whose physiology has been subjected to abnor-
mal influences:
by drugs (pharmacodynamics); by disease (pathology).

5. Therapeutics is a general term referring to the treatment of disease and borders
upon many fields other than pharmacology.
The subject has various subdi visions
depending upon whether it is classified according to the objectives attainable or
according to the means by which these objectives are attained.
According' to the
farmer, therapeutics ~
be specific or ~-specific (symptomatic, palliative,
etc.) while the latter classification would include subdivisions such as chemo-
therapy, physical therapy, biological therapy, etc.
The term chemotherapy or
pharmacotherapeutics has reference to the use of drugs in the treatment of dis-
ease.

6. TOXicology is the study of pOisons:
their effects, identification, and the treat-
ment of conditions produced by them.
This borderline science which embraces phar-
macology, chemistry, phySiology, and pathology is best handled either separately
or integrated with the study uf therapeutics.

II. Terms associated with dosage (posology) and related phenomena.

A. Definitions of dosages

1. Toxic dose.
The amount of a drug which causes untoward symptoms in the aver-
age indi vidual wi thin a species.

2. Fatal dose.
The amount that causes death.

3. Minimal Lethal Dose (M. L. D.).
The amount that kills a certain proportion
(usually 50 per cent) of a series of animals under carefully controlled ex-
perimental conditions.

4. Minimal dose.
The smallest amount that has a therapeutic effect.

5. Maximal dose.
The largest amount that can be tolerated without producing
toxic symptoms.

6. Therapeutic dose.
The optimal dose that lies somewhere between the minimal
and maximal dose.

7. Therapeutic ratio
MLD
Therapeutic dose

With the possible exception of the few drugs recognized by the National Form-
ulary, veterinary dosages have never represented the sum of the considered
opinions of qualified individuals to the extent that this has been achieved
in the field of human medicine.

B. Tolerance, Idiosyncrasy, etc.

1. Tolerance, as the name implies, means lack of sensitivity to a drug.
There-
fore comparatively large doses are necessary to elicit a response.

Tolerance may be divided into:

a. Species tolerance; as rabbits toward belladonna.

b. Acguired tolerance; as toward morphine, alcohol, arsenic, etc.

c. Individual tolerance; tolerance not explained by a and b above.

INTRODUCTION

d. Cross tolerance.
The acquisition of tolerance to alcohol by human<
may result in increased tolerance to ether.

i

2. Addiction to a drug is characterized, upon withdrawal, by varied organic di"-
turbances known as abstinence Symptoms.

3. Hypersensitivity to drugs is present when a full effect characteristic of the
drug occurs with relatively small doses.

4. Idiosyncrasy is said to occur when an animal shows an abnormal response to a
drug not shown by other animals after very large ,doses.
This is comparative-
ly rare in animals.

The veterinarian is primarily concerned with species tolerance and species
hypersensitivity.
Some examples illustrating these are found in certain of
the exercises in this manual.

C. Miscellaneous factors influencing dosage.

1. Rate of excretion or destruction.
The continued administration of drugs at
a rate which exceeds their normal excretion or d.estruction will result in
accumulation of the drug in the body.
This condition is called cumulative
effect and is prone to occur with such agents as digitalis and arsenic.
The
cumulative effect of drugs may be aggravated if the organs essential for
their excretion or destruction be rendered functionally inefficient by dis-
ease. Mercurials in certain types of nephritis and some barbiturates in
impaired liver function are typical examples.

2. Influence 9! other drugs given simultaneously.
Other agents administered
simultaneously with a given drug may in certain cases, either act to antago-
nize or assist its action.
In the case of drugs which assist the action of
another drug, the effect may be simply additive; or it may obey the law of
diminishing returns; in other cases the drugs may potentiate each other.-These
phenomena are described by the general term synergism.and the adjectives ~­
plementary, complementary, and potentiated have been used in this order to
describe the effects enumerated above.
When the term synergism is used with-
out a modifYing adjective, it is generally taken to mean the potentiated
effect.
This is the most common use of the term.

3. ~
Weight.
While the total dose of a drug in a given species increases with
an increase in body weight, it is not necessarily proportional and, generally
speaking, the dose of many drugs per unit of body weight is smaller in large
animals than in small animals.
For example, where the anesthetic dose of
sodium pentobarbital in a 7 kilogram dog may be approximately 35 mg. /Kg.,
comparable level of anesthesia may be produced in dogs weighing 30 kilograms
by as little as 25 mg/Kg. of the drug.
However, this is' not true of all
drugs and generalizations are, therefore, dangerous.

4. Relative Size Qf Dose for Different Species.
While earlier writers such as
Winslow* were disposed to generalize on this subject, no speci~ic rule has
yet been evolved which will apply to a majority of veterinary drugs.

5. Relative Size Q_f Dose !!y Different Routes of Administration.
While, in gen-
eral, the oral dose is greater than the subcutaneous and the subcutaneous
greater than the intravenous, the influencing factors are too great to war-
rant further generalization.

*Winslow, Kenelm, Veterinary Materia Medica and Therapeutics, William R. Jenkins Co.,
New York (1916)

4
MANUAL OF EXPERIMENTAL VETERINARY PHARMACOLOGY

III. Terms Associated 'With the Absorption and Fate of Drugs in the Body.

A. Absorption of Drugs.
A drug is considered to be absorbed only when it has en-
tered the general circulation. This involves processes such as solution, fil-
tration, osmOSis, diffusion, diaLysis, and other phenomena associated with---
living cells. The rate of absorption determines largely the time of onset of
drug action.

1. Factors modifying absorption of drugs.

a. Route of administration.
The rate of absorption, with the more common
a;ern:;:es of administration, occurs in the following general order be-
ginning with the most rapid:

( 1)
(2)
(3)
(4)

Intravenous
By inhalation
Intraperitoneal
Intramuscular
\

(5)
(6)
(7)
( 8)

Subcutaneous
Stomach
Rectum
Skin

The following comments concerning these routes of administration may be of in-
terest to beginning stUdents:

(1) Intravenous Injection. This is absorp;tion since drugs are injected
directly into the blood stream.
Due to the diluting action of the
blood, many !rri tating drugs (e. g. chloral hydrate) can be injected
in this manner. Phlebitis may occur if the rate of injection be
too rapid or if the solution be too concentrated.
Response to a
drug can be quickly evaluated (barbiturate anesthesia) although
there is an unexplained delay with some agents (picrotoxin). All
intravenous injections must be made slowly.
So called speed or
injection shock from temporary flocculation of plasma colloids or
from transient precipitation of the drug (barbiturates) may occur.
There is also some danger from thrombosis and embolism although
this appears to be overestimated.
In the case of air embolisms
one should be especially careful in the case of rabbits and young
animals, especially calves.
The danger is not so great in older
animals.

(2) Itt inhalation. Absorption is extremely rapid due to the tremen-
dous size of the absorptive area given by the lining of the pul-
monaryalveoli. Certain volatile drugs such as ether, chloroform,
and amyl nitrite are given this way.

(3) Intraperitoneal injection. Absorption is rapid due to the compar-
atively large size of the absorptive area offered by the peritoneum.
Chloral hydrate is occasionally given to large animals and barbit-
urates to dogs by this route.
In the case of !rr! tant drugs, there
may be some danger from peritonitis with resultant adhesion forma-
tion.

(4) Intramuscular injections.
These are made deep into muscle tissue
preferably in the heavily muscled areas of the body.
Aqueous
solutions are absorbed rapidly while drugs in solvents such as oil
are more slowly and uniformly absorbed.
Certain irritating sub-
stances (e.g. camphor in oil) may be given by this route since they
are diluted or spread out over wide areas from, travelling along
fascial planes.

(5) Subcutaneous (hypodermic) injection. Irritating drugs should never
be given by this route; they are very painful and there is danger
of sloughing.
The better sites for the subcutaneous administration
of drugs in animals are in areas where the skin is relatively loose
such as the ventral region of the neck, behind the front legs, etc.

INTBODUCTION
5

One should always make certain that the tip of the needle is not
accidentalJ..y lodged in the lumen of a blood vessel. This is most
easiJ..y accomplished by putting gentle traction on the plunger of
the syringe; if no blood is withdrawn one may proceed with the
injection.

(6) Drugs !!l way ~ mouth (~ os; per orem).
The fact that absorp-
tion of almost all orally administered drugs occurs from the
intestine (especially the small intestine) is of special interest
to veterinarians since it is obvious that one of the influencing
factors would be the time interval required for the drug to reach
this site. Ruminants constitute a special class in this respect.
Cattle for example are very tolerant to digitalis when the drug is
administered orally but are susceptible to the injectable gluco-
sides of digitalis when given parenterally*. Birds exhibit a
similar tolerance to strychnine, nicotine, and other alkaloids.

In addition to species differences it is obvious that factors af-
fecting emptying time of the stomach would also influence absorp-
tion of drugs.
The selective impermeability of the intestinal
mucosa to various substances is another important consideration.
The cations Mg++ and Ba++, and anions such as 804-- and COOCH3-
are typical examples.
Also many drugs (e.g. epinephrine) cannot
be given orally for systemic effect because they are destroyed too
rapidly to be absorbed efficiently.

(7) Rectal administration of drugs.
For obvious reasons
is rather impractical in the medication of animals.
enema is necessary first, the vehicle must be bland,
mixtures are retained with difficulty.

this method
A cleansing
and irritant

(8) Administration of ~
~ ~
of the skin. While the skin is
generally a poor medium for the absorption of drugs, certain sub-
stances such as mercury, methyl salicylate, nicotine, some hormones,
etc. can be absorbed in sufficient amounts to produce systemic ef-
fects.

b. Vehicle, diluent, etc. In general, aqueous or alcoholic solvents
facilitate while adsorbant substances such as certain colloids and
Fuller I s earth retard absorption.
Concentrated solutions are usually
more quickJ..y absorbed than dilute solutions.
This is especialJ..y true
in carnivora and omnivora; the re'sults in herbivora, especially rumi-
nant, are less predictable.

c. Local conditions in the alimentary canal, anatomic differences, etc.
Mild irritation may facilitate absorption probabJ..y from a combination
of factors such as increased blood to the part, increased activity of
the gut, and decreased emptying time of the stomach. If, however, the
irritation is sufficiently great to severely injure or cause death of
mucosal cells, absorption may be increased enormously 'and many sub-
stances normally barred from the general circulation may be absorbed.
The administration of certain toxic ions such as barium, to which the
gut mucosa is normally inpermeable, may result in sufficient absorp-
tion to produce poisoning.

Astringents, on the other hand, which set up a barrier by precipitat-
ing the superficial elements of the exposed surfaces of mucosal cells,
may retard absorption.
A relatively full digestive tract will also
decrease rate of absorption of drugs.
This is of especial importance

*Parenteral drug administration has reference to avenues other "than the intestinal canal
(e.g. subcutaneous, intravenous, etc.)

6
MANUAL OF EXPERIMENTAL VE~ERINARY PHARMACOLOGY

in the oral medication of herbivora who possess anatomic areas which
are normally always relatively full and it is necessary for the clini-
cian to have in mind that certain species (ruminants) have this area
located above the site of maximum drug absorption (small intestine)
while in other species (horse) the area (colon) is located below the
small intestine.
This fact may serve to explain in part the larger
oral dose of many drugs in cattle, for example, than in horses.
In
recent years attempts have been made to by-pass the rumen by producing
closure of the oesophageal groove through the use of agents such as

copp~r sulfate prior to the oral administration of drugs to ruminants.

B. Fate of Drugs in the Body.

After absorption, drugs are subject to the following possible dispositions:

1. Complete break down leaving no trace.

2. Complete inactivation o~ breakdown with excretion of end products.

3. Excretion partly as inactivated or breakdown products and partly as pure
drug.

4. Excretion as the pure drug.

The first three possibilities are doubtless influenced by many factors not
the least of which may be the relative size of the dose and the functional
state of the organs of excretion or inactivation.
Drugs are inactivated in
the body largely by OXidation, hydrolySiS, or conjugation.
Elimination from
the body may take place through many channelsj principally by way of the kid-
ney and intestine.
The lungs j salivary, mammary, and sweat glands are avenues
of lesser importance.
Certain agents (e.g. lead) may be stored for variable
periOds of time in the body.

IV.
Terms associated with Drug Action (Mechanism.s, Influencing Factors, etc.)

It is often difficult to interpret the term mechanism when applied to the action of
drugs.
For example, in explaining 'the mechanism of action of digitalis in cardiac
decompensation, the following general statements could be made:

1. Digitalis increases the strength of the heart beat especially in certain ab-
normalities, etc.

2. This effect is accomplished by the direct action of the drug on cardiac
muscle cells.

3. The basic mechanism by which the cardiac muscle effect is accomplished is
obscure.

A similar treatment of epinephrine in a normal animal could be developed somewhat
as follows:

1. Epinephrine raises blood pressure by constricting blood vessels in certain
areas, and increasing the rate and irritability of the heart.

2. This effect is accomplished by stimulation of possibly the receptor substance
of effector cells largely innervated by sympathetic nerves, stimulation of
the vasomoter center, and direct action on the heart muscle cells.

3. Explanation of the basic mechanisms concerned are theoretical and usually
inv'olve comparisons with the action of the sympathetiC neurohormone (sympa-
thin) •

INTRODUCTION
7
It will be observed that the statements proceed from a more superficial to a more
basic treatment according to.the following steps:

1. What the drug does.

2. Where it acts and the nature of the action (e.g. augmentation or inhibition,
etc.).

3. Mechanism of action (general pharmacology).

The two examples cited are typical of the limited extent of our established knowledge
ca..'1..:"erning the action of all too :rna:ny drugs.
Furthermore the theories concerning the
basic mechanisms of action are often subject to controversy. It is also apparent
that v:le term mechanism may have several gradations of interpretation depending upon
the particular drug, and upon the nature of the information required.
To meet the
minimum. clinical reqUirements, a knowledge of what the drug does is of primary im-
portance; in order to make progress in the field of clinical medicine, a knowledge
of how the action is accomplished is also necessary; while the more theoretical as-
pects of general pharmacology may be of major interest only to those who wish to
specialize in that field.

A. The Nature of the Response of Cells to Drugs.

Pharmacologic agents £§!l ~
augment 2!' diminish the normal functions of ~ cell.
For example, no drug can impart a secretary function to muscle tissue.
The follow-
ing terms are used to describe these quantitative effects of drugs on living cells:

1. Stimulation:
an increase in function.

2. Irritation: an increase in function accompanied by inflammatory phenamena*.

;. Fatigue or exhaustion:
a decrease or absence of function as the result of
prolonged or excessive stimulation.

4. Depression:
a decrease in function which is the result of causes other than
fatigue.

5. Paralysis:
an abolition of function which is the result of causes other than
fatigue.

The degree of augmentation or diminution of function may be inflUenced by the size
of the dose, the functional state o~ the tissue affected, or both.

Size of the dose.
Many drugs may produce stimulation with small doses or early with
large doses -anddepression as the terminal effect with large doses.
The ratio of the stim-
ulant to the depressant phases may vary widely with different durgs.
Thus it is possible
for certain drugs to produce depression preceded by little or no stimulation while, on the
other extreme, same drugs may produce stimulation followed by 11 ttle or no. depression. The
early and late effects seen with large doses, are not to be confused with primary and
secondary drug action to be considered later.

Functional state of the tissue affected. If the normal functional reserve of a
tissue be lowered by disease, the augmentary response to stimulant drugs is decreased.
A
classic example often cited is the failure of response of exhausted myocardium to the
stimulant action of digitalis in cardiac decompensation.
While experimental evidence is
lacking, it may be conjectured that a carrolary of more practical veterinary importance
could be the decreased response to purgative drugs in certain atonic states of the rumen
in cattle and of the colon in horses.

*Note that this use of the term is different from that employed by physiologists.

8
MANUAL OF EXPERIMENTAL VETERINARY PHARMACOLOGY

Many other factors may operate to affect responses to drugs.
Diuretics work ~oarly
in dehydrated animals although the functional state of the kidney may be perfect. Anti-
pyretics will lower body temperature in fever from most causes but will have little effect
on normal body temperature.
The non-gr-avid uterus does not respond as well to posterior
pituitary as does the gr-avid uterus.
The influence of physiologically antagonistic drugs
must be reckoned with in certain situations.

B. Selective Action of Drugs.

The action of same drugs is thought to arise fram the chemical affinity of their
active principles for the tissues acted upon so that small doses will affect cer-
tain structures, yet have no influence upon other tissues.
The number of structures
affected varies with the particular drug.
Same typical examples are:

1. Bacterial Stains.

2. Strychnine on the proto~asm of cells of the spinal card.

3. Digitalis on heart muscle.

4. Nitrites and posterior pituitary on smooth muscle.

5. Atropine on the receptor mechanism of the parasympathetic system.

6. General anesthetics on neurons of the central nervous system.

The affinity of drugs for certain tissues is usually quantitative, i.e. small doses
of atropine will have no effect other than paralysis of parasympathetic myoneural
junctions, whereas large doses will also stimulant, then depress, the CNS. Further-
more, although drugs may have an affinity far certain structures, the mechanism by
which they produce their effect may vary widely.
Far example, the action of physo-
stigmine is analogous to stimulation of cholinergic (parasympathetic) nerves. It
produces its effect however, not by direct stimulation of the effector tissue but
indirectly by inhibiting the en~ (cholinesterase) which normally destroys acetyl
choline. Atropine, on the other hand, has an opposite effect which is accomplished
by an entirely different mechanism.
Instead of hastening the destruction of acetyl-
choline, it produces its inhibition by preventing the access of acetylcholine to the
effector cells.

C. Local and Systemic Drug Action.

The terms used to describe local and systemic drug actions are often confused in the
pharmacologic literature and the outline presented below is not intended to clarifY
the situation but is, rather, an attempt to generalize the usages of certain of
these terms.

1. Local Drug Action.

a. Acting at the site of application (skin and mucous membranes including
mucosa of the alimentary tract).
I
b. Acting at the site of absorption or elimination.

c. When injected into tissues for action at the site of injection (local
anesthetics; epinephrine*).

2. Systemic Drug Action.

As the term is ordinarily employed, systemic drug action is taken to mean the
effect of a drug on the body as a whole after absorption. In this sense it
includes both the primary and secondary effects of a drug in the body.

*Selective drug action has also been called local action.