Pulmonary Pharmacology (1996) 9, 357–364
Mechanisms of Action of Central and Peripheral Antitussive
Donald C. Bolser
Department of Physiological Sciences, Box 100144, University of Florida, Gainesville, FL 32610, U.S.A.
INTRODUCTION an important caveat that is usually assumed but rarely
emphasized. Antitussive drugs are classiﬁed as peri-
pheral or central based on their site(s) of actionCough is the most common reason why sick patients
visit physicians in the United States.
Antitussive drugs following systemic administration. Many techniques
used to determine the site of action of antitussivesuch as codeine and dextromethorphan are among
the most commonly used prescription and over-the drugs involve non-systemic routes of administration.
These methods are best combined with other tech-counter drugs in the world.
These drugs suppress the
responsiveness of one or more components of the niques involving systemic administration to provide
convincing evidence regarding the site of action of anreﬂex pathway for cough and are intended to be useful
against cough of diverse aetiologies.
While most of antitussive drug.
the currently available antitussive drugs are relatively
old, there are several new compounds currently under
development or being marketed by pharmaceutical PERIPHERAL ANTITUSSIVE DRUGS
Ironically, relatively little is known about
how most antitussive drugs act to inhibit cough. It is A variety of methods have been used to investigate
possible peripheral actions of antitussive drugs. Mosttherefore important to consider the mechanism of
action of this large class of drugs. The purpose of of these methods are based on the idea that the drug
in question inhibits the response of one or morethis report is to review the mechanisms of action
of antitussive drugs and the methods by which this types of airway sensory aﬀerent to mechanical and/
or chemical stimuli that produce cough. Theseinformation has been generated. Other informative
reviews exist on the subject.
methods fall into several broad categories: direct re-
cording of sensory aﬀerent responses, evaluation of
the activity and/or relative potency of the drug after
administration by diﬀerent routes (inhalation, intra-CLASSIFICATION OF ANTITUSSIVE DRUGS
venous, intra-arterial, and/or intracerebroventricular),
and blockade of the activity of the putative peripheralAntitussive drugs are broadly classiﬁed into two
groups based on their site of action: peripheral or drugs by quaternary antagonists that penetrate the
CNS only to a limited extent. Each method hascentral. Peripheral antitussive drugs act outside the
central nervous system (CNS) to inhibit cough, pre- speciﬁc advantages and limitations and, as such, a
combination of two or more methods usually is thesumably by suppressing the responsiveness of one or
more vagal sensory receptors that produce cough.
Central antitussive drugs act inside the central nervous
system to suppress the responsiveness of one or more Sensory afferent responses
components of the central reﬂex pathway for cough.
These deﬁnitions are also largely based on the concept The inhibitory eﬀect of an antitussive drug on the
responsiveness of one or more types of sensory aﬀer-that peripheral drugs penetrate the CNS to a limited
extent and central drugs penetrate the CNS relatively ents responsible for cough provides evidence con-
sistent with, but not suﬃcient for, concluding that theeasily to reach their site of action. While this concept
may be true for most drugs that have been classiﬁed compound has solely a peripheral action. A sys-
temically administeredcompound may have both peri-as central or peripheral, it does not imply that central
drugs have no peripheral component to their activity pheral and central sites of action. Furthermore, there
are many diﬀerent types of sensory aﬀerents that canor that drugs classiﬁed as peripheral cannot act cent-
rally to inhibit cough. This point also brings to light contribute to the production of cough and no studies
0952–0600/96/5/60357+08 $25.00/0 1996 Academic Press Limited357
358 D. C. Bolser
have investigated the inﬂuence of peripheral anti- stimuli.
This eﬀect is usually considered to be due
to inhibition of pulmonary vagal aﬀerent discharge.tussive drugs on them all.
The most common sites known to produce cough Indeed, tracheal RAR responses are inhibited by local
However, local anaesthetics canare the larynx and lower airways, although sensory
aﬀerents from other sites can elicit cough.
In ad- penetrate the blood brain barrier and these com-
pounds may also have a central eﬀect to inhibit coughdition, within the lower airways, regional diﬀerences
in cough sensitivity to chemical stimuli exist.
even when they are administered by inhalation.
The peripheral action of antitussive drugs may alsoIn the larynx, Sant’Ambrogio et al.
that a single type of sensory aﬀerent mediates cough be due to activation of reﬂexes that inhibit cough.
Nedocromil sodium has been shown to inhibit citricproduced by low chloride aerosols or mechanical
stimuli. These laryngeal aﬀerents had rapidly adapting acid-induced cough in the dog
and cough in asth-
This drug has no eﬀect on pulmonarydischarge patterns.
Whether or not other types of
laryngeal aﬀerents have a modulatory eﬀect on the RARs, slowly adapting receptors, or pulmonary C-
However, bronchial C-ﬁbres increased theircough reﬂex is unknown.
In the lower airways, slowly adapting receptors, discharge rate after intra-arterial or aerosol ad-
ministration of nedocromil sodium
suggesting thatrapidly adapting receptors (RARs), and pulmonary
C-ﬁbres all can inﬂuence the production of cough.
the antitussive eﬀect of this compound was due to a
The role of bronchial C-ﬁbres in the production of reﬂex inhibition of cough by this population of aﬀer-
cough is unknown. There is little doubt that RARs ents. It should be noted that currently there is no
can elicit cough.
Slowly adapting receptors have a published information documenting the eﬀect of
permissive role in the production of cough,
but stimulation of bronchial C-ﬁbres on the cough reﬂex.
their importance in the generation of cough is often However, injection of bradykinin into the broncho-
overlooked. The exact role of pulmonary C-ﬁbres in oesophageal aftery of two cats inhibited mechanically-
the production of cough is more controversial, with induced cough (Bolser, unpublished observations).
some groups supporting an excitatory role
and others Bradykinin administration by this route has been
supporting an inhibitory role.
Some of this con- shown to excite bronchial C-ﬁbres in the dog.
troversy may be resolved when the role of bronchial ever, nedocromil sodium may also have stimulated
C-ﬁbres in the production of cough is addressed. aﬀerents from other organs that have reﬂex eﬀects on
Any one of these sensory aﬀerents is a potential cough. An additional caveat is that there are no studies
target for peripheral antitussive drugs. There is only ruling out a central action of this compound to inhibit
one study on the sensitivity of laryngeal aﬀerents to cough.
antitussive drugs. Low chloride solutions elicit cough There is additional evidence that antitussive drugs
that is inhibited by inhalation of the chloride transport can activate certain classes of sensory aﬀerents. Right
Interestingly, furosemide had atrial administration of codeine or dextromethorphan
no eﬀect on cough elicited by capsaicin inhalation, elicits apnoea and rapid shallow breathing similar
indicating that the action of this drug is speciﬁc to a to that produced by intravenous administration of
reﬂex pathway activated by low chloride solutions.
These eﬀects were blocked by vagotomy
The response of laryngeal RARs to low chloride or cooling the cervical vagus nerve to 1°C, but not
solutions was inhibited by furosemide.
These ﬁndings suggest that bolus administration
the most likely mechanism of action of furosemide is of these antitussive drugs activates pulmonary C-
a speciﬁc peripheral action on the responsiveness of ﬁbres in much the same way as capsaicin. Similar
laryngeal and lower airway rapidly adapting aﬀerents. observations and conclusions have been made for
However, it should be emphasized that a central action morphine.
The eﬀect of these drugs on C-ﬁbres
of furosemide cannot be ruled out on the basis of appears to be transient (less than 1 min), so the reﬂex
sensory aﬀerent responses alone. eﬀects on cough of stimulation of these aﬀerents also
In the lower airways, RARs and C-ﬁbres have been is probably transient. Other studies have shown that
the subject of most studies on the mechanism of action these drugs have central
of peripheral antitussive drugs. BW443C, a peripheral to inhibit cough. Figure 1 summarizes the potential
l-opioid agonist, inhibited the discharges of both eﬀects of peripheral antitussive drugs on diﬀerent
RARs and C-ﬁbres.
This compound was ad- classes of sensory aﬀerents, and the inﬂuence of these
ditionally shown to have solely peripheral activity by aﬀerents on cough.
As in the larynx, furosemide in-
hibits the responsivess of tracheal RARs speciﬁcally Administration of antitussive drugs by different routes
to low chloride solutions, suggesting that it is not a
generalized inhibitor of sensory aﬀerent discharge.
A common approach to obtain information regarding
putative peripheral activity of an antitussive drug isLocal anaesthetics, delivered intravenously or by
inhalation, inhibit the cough response to a variety of to administer the compound by the topical (inhalation)
Central and Peripheral Antitussives 359
pathway and cough
Fig. 1 Possible sites of action of peripherally- or centrally-active antitussive drugs. Depicted is a model of the types of peripheral
aﬀerents that contribute to, or modify, the production of cough and their inﬂuence on the central components of the cough reﬂex.
The central components of the cough reﬂex are shown as the central reﬂex pathway (including the ﬁrst central synapse and
interneurons) and a brainstem burst pattern generator that produces the cough motor pattern in brainstem and spinal motoneurons.
Available evidence indicates that this cough burst pattern generator also generates the basic respiratory rhythm.
antitussive drugs can have their eﬀects by either inhibition of sensory aﬀerents that produce cough or by excitation of sensory
aﬀerents that inhibit cough. Pulmonary slowly adapting receptors have a permissive eﬀect on cough (see text) and are shown as a
potential site of action of peripheral antitussive drugs. However, no direct evidence exists that antitussive drugs actually alter the
discharge of this group of pulmonary aﬀerents. Pulmonary C-ﬁbres are shown as two groups with diﬀering eﬀects on cough to reﬂect
the current literature (see text). Central antitussive drugs are shown as inhibiting the responsiveness of any component of the central
reﬂex pathway or cough burst pattern generator. The extent to which multiple sites of action of diﬀerent antitussive drugs exist within
the brainstem is unknown. The cerebellum also is shown as a potential site of action of centrally-active antitussive drugs.
pulmonary slowly adapting receptor, RAR: pulmonary rapidly adapting receptor. : Permissive; —: excitation; ----: inhibition.
or central (intracerebroventricular) route. A less com- an antitussive drug. In this case, a peripheral action
is inferred if the drug is active after systemic ad-mon approach is comparison of the potency of a
drug given by two routes of administration, usually ministration, but inactive after intracerebroventricular
An important considerationintravenous and intra-arterial.
It is widely assumed that antitussive activity after is that icv doses used must be much less that those
. Alternatively, if a speciﬁc ant-inhalation of a drug indicates a peripheral site of
action. However, topical administration does not re- agonist exists for the drug in question, the antagonist
can be administered by the icv route while the drugstrict a drug to the airways. For example, plasma
concentrations of local anaesthetics after inhalation is administered systemically. This approach has been
taken for 3-aminopropylphosphinic acid (3-APPi), acan be similar to those observed after intravenous
Furthermore, baclofen, a centrally- GABA-B receptor agonist with antitussive activity
after systemic administration.
Icv administration ofactive GABA-B receptor agonist, has antitussive ac-
tivity in the guinea pig when inhaled.
Baclofen is CGP 35348, a speciﬁc GABA-B receptor antagonist,
has no eﬀect on the antitussive activity of a sub-more potent by this route than 3-amino-
propylphosphinic acid, a GABA-B receptor agonist cutaneous dose of 3-APPi, indicating a peripheral
action for this drug.
with solely a peripheral action.
In fact, the anti-
tussive activity of a systemic dose of baclofen can be An eﬀective technique for determining if a drug is a
peripheral antitussive is comparison of its intravenouscompletely blocked by intracerebroventricular ad-
ministration of a GABA-B receptor antagonist, sug- potency with its intra-arterial (usually intra-vertebral
artery) potency in the form of an eﬀective dosegesting that baclofen has no peripheral site of action.
Therefore, peripheral activity of an antitussive drug ratio.
The eﬀective dose for inhibition of cough is
determined for each route of administration and acannot be concluded solely on the basis of inhalational
studies. Topical administration must be combined ratio of intravenous to intra-arterial potencies is gen-
erated. Classically, this ratio will be less than 20 forwith other tools, such as quaternary antagonists,
conclude that an antitussive drug has a peripheral a peripheral antitussive drug and greater than 20 for
an antitussive drug with a central site of action.
Central administration can be eﬀectively used to fact, more recent work has shown that for drugs with
solely a peripheral action, this ratio is usually threeobtain information regarding peripheral activity of
360 D. C. Bolser
The basis of this technique is that the of compounds that have been demonstrated to have
opioid antagonist activity.vertebral artery supplies the brainstem, the primary
central site of action of antitussive drugs.
antitussive doses for centrally-active drugs ad-
ministered via the vertebral artery will be much lower Peripheral antitussive action of bronchodilators
than those obtained after intravenous dosing because An additional issue regarding the action of peripheral
this route represents local administration of the drug antitussive drugs is the almost universal perception
to its site of action. Conversely, drugs with solely that bronchodilators, such as b-adrenoreceptor agon-
peripheral actions by must be administered to the ists, inhibit cough in asthmatics due to relaxation of
vertebral artery in suﬃciently large amounts to allow airway smooth muscle (a peripheral action). There is
recirculation to the venous system to reach their site no direct evidence that relaxation of airway smooth
of action (airway aﬀerents). The advantage of this muscle inhibits cough. Recent work in the cat indicates
technique is that it is very robust in diﬀerentiating that increases in airway tone actually inhibit cough.
drugs that have solely a peripheral site of action from Furthermore, recent work has clearly shown that
those with a central component. Conversely, utility bronchospasm does not elicit cough.
of this technique is limited by the lack of information doses of salbutamol which have signiﬁcant bron-
on diﬀerentiation of drugs that have both central and chodilating eﬀects do not inhibit cough.
It is more
peripheral components to their action from drugs that likely that the antitussive eﬀects of b-adrenoreceptor
have solely a central site of action. However, recent agonists are due to inhibition of mediator release
work on tachykinin NK
receptor ant- or a direct action on sensory aﬀerents.
There also is
agonists using this technique suggests that very high no evidence excluding the possibility that the anti-
ratios (>35) are consistent with solely a central action tussive eﬀects of b-adrenoceptor agonists are due, at
of the drug.
The extent to which this suggests that least in part, to central actions.
drugs with ratios closer to 20 have both peripheral
and central actions is unknown.
CENTRAL ANTITUSSIVE DRUGS
Blockade of peripheral antitussive activity by
quaternary antagonists The notion that antitussive drugs can have central
activity is based on the assumption that a systemic
Use of antagonists that penetrate the CNS to a limited dose of a centrally-active drug will largely leave peri-
extent after systemic administration has been limited pheral sites unaﬀected and will penetrate the CNS to
to investigations of the antitussive activity of opioid act at the level of the brainstem, where the basic
drugs, for which speciﬁc quaternary antagonists neural circuitry responsible for cough is located.
Karlsson et al.
showed that the antitussive Central antitussive drugs are thought to act solely
eﬀects of inhaled codeine in the guinea pig were within the brainstem to inhibit cough, although our
blocked by prior administration of levellorphan understanding of the exact sites at which they act
methyl iodide, a quaternary opioid receptor an- within the brainstem remains incomplete. Fur-
tagonist. Adcock et al.
showed that the antitussive thermore, a recently preliminary report indicates that
eﬀects of codeine could be antagonized by systemic the cerebellum is essential for the production of cough,
administration of a quaternary opioid receptor an- implicating this structure as a potential site of action
tagonist, N-methylnalophrine, in the guinea pig. Other
of centrally-active antitussive drugs (Figure 1).
investigators also reported similar ﬁndings in the
Many of the methods used to determine central
These ﬁndings indicated that even a
activity of antitussive drugs are the same as those
classical centrally-active antitussive drug, such as cod-
used to evaluate peripheral activity. The categories
eine, can have peripheral actions under certain con-
that these techniques fall into include: central ad-
ditions. Adcock et al.
also used N-methylnalorphine
ministration of the antitussive drug or its speciﬁc
to show that BW443C, a l-opioid receptor agonist,
antagonist, relative potency of the drug by diﬀerent
had peripheral antitussive activity in the guinea-pig.
routes (intravenous, intra-arterial), electrical stimu-
An important limitation to the use of quaternary
lation of the brainstem to elicit cough-like responses
opioid antagonists is that these compounds can have
after systemic administration of the drug, and elec-
as little as 5% or less of the receptor binding aﬃnity
of the parent compound.
Therefore, when using trical stimulation of the superior laryngeal or vagus
nerves after systemic administration of the drug. Somequaternary opioid receptor antagonists, lack of an
antagonistic eﬀect alone is not suﬃcient to indicate of these techniques have considerable limitations, even
to the extent of being unable to diﬀerentiate centralthat an antitussive drug has no peripheral site of
action. It is important to choose doses of this class from peripheral antitussive activity.
Central and Peripheral Antitussives 361
Central administration of the antitussive drug or its this situation is the compound caramiphen, a r-
receptor agonist with antitussive activity. Chou and
showed that this drug had an eﬀective dose
Studies using this approach usually employ ad- ratio of 19, but used propylene glyucol as a vehicle.
ministration of the drug itself by the icv route to However, Domino et al.
found a much lower eﬀective
investigate central antitussive activity. GABA-B re- dose ratio (7) for inhibition of cough when physio-
N-methyl-D-asparate (NMDA) re- logical saline was used as vehicle. Although Domino
opioid receptor agonists,
and et al.
concluded that caramiphen was a centrally-
adenosine receptor agonists all have been shown to active drug, the eﬀective dose ratio that they found
have antitussive activity by this method.
While res- was clearly indicative of a peripheral action. Bolser
ults of icv studies clearly document that a central et al.
found that another r-receptor agonist, car-
action of an antitussive drug is possible, they do not betapentane, had a low eﬀective dose ratio (3) using
prove that a systemically-administered dose acts at a this technique.
central site to inhibit cough. However, if systemic
administration of the drug is combined with icv ad- Electrical stimulation of the brainstem to elicit
ministration of a speciﬁc antagonist, stronger evidence cough-like responses
can be obtained supporting a central site of action of
the drug. For example, the antitussive activity of a Several groups have used electrical stimulation of
systemic dose of baclofen is completely blocked by icv various regions of the brainstem and in some cases,
CGP 35348, a speciﬁc GABA-B receptor antagonist,
the amygdala, to elicit cough-like responses.
indicating a central site of action. In fact, total block- Inhibition of these electrically-generated cough-like
ade of the antitussive action of baclofen by icv CGP responses after systemic administration of antitussive
35348 is consistent with solely a central site of action drugs has been considered to be suﬃcient evidence of
for this GABA-B receptor agonist. a central action.
The results of these studies should
The other methods of central administration that be carefully interpreted for several reasons. First, as
have been used are topical administration or micro- has been previously discussed, a systemically ad-
injection of the antitussive drug into the brainstem. ministered drug may activate sensory aﬀerents that
These methods have been used to demonstrate central have a reﬂex inhibitory eﬀect on cough. Brainstem
actions for codeine and dextromethorphan and as electrical stimulation is more appropriately combined
tools for investigation of the particular brainstem sites with other methods, such as the eﬀective dose ratio
technique, to obtain evidence for central activity of
involved in the action of these drugs.
As with icv
an antitussive drug.
Second, while a number of
administration, central microinjection is best com-
these studies have been particularly careful in com-
bined with other methods to yield deﬁnitive evidence parison of brainstem (or amygdala) evoked cough-
supporting a central site of action for an antitussive like responses with peripherally-elicited coughs,
drug. it is important to stress that cough is a complex motor
behaviour which is most appropriately evoked by
natural stimulation of airway sensory aﬀerents. Even
Administration of antitussive drugs by different routes with natural stimulation of the airways, it is diﬃcult
As described in the previous section of peripheral to diﬀerentiate the motor patterns of sneeze and cough
antitussive drugs, the ratio of eﬀective doses for in- and brainstem electrical stimulation may activate
hibition of cough by intravenous and intra-vertebral motor pathways associated with either or both. Fur-
artery administration is a reliable technique for de- thermore, brainstem electrical stimulation may ac-
tection of central activity of antitussive drugs. It tivate other central pathways that alter the sensitivity
should be emphasized that a ratio of approximately of the cough reﬂex to antitussive drugs, aﬀecting their
20 or greater provides evidence of a central action for potency.
an antitussive drug, lower ratios indicate peripheral
actions of the drug.
Furthermore, results from Electrical stimulation of the superior laryngeal or
this method are sensitive to the type of vehicle used vagus nerve to elicit cough
to administer the compound, especially by the intra-
For example, high molecular weight Electrical stimulation of the cut superior laryngeal or
carbohydrate vehicles like bcyclodextrin can enhance vagus nerves has been used to elicit cough.
the central penetration of some compounds,
pre- Because electrical nerve stimulation bypasses sensory
sumably by osmotically opening the blood-brain bar- aﬀerent terminals, antitussive activity of a systemically
rier. The ideal vehicle is physiological saline. With administered compound has been considered evidence
other vehicles, it is possible that drugs with peripheral of a central action.
However, inhibition of this type
of cough is not clear evidence of central activity.activity may appear centrally-active. An example of
362 D. C. Bolser
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