ArticlePDF AvailableLiterature Review

Mechanisms of Action of Central and Peripheral Antitussive Drugs


Abstract and Figures

No abstract
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. 53,54 Peripheral 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. 55 SAR: pulmonary slowly adapting receptor, RAR: pulmonary rapidly adapting receptor. : Permissive;-: excitation;-: inhibition.
Content may be subject to copyright.
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 aerent 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 aerent responses, evaluation of
the activity and/or relative potency of the drug after
administration by dierent 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.
strongest approach.
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 eect of an antitussive drug on the
responsiveness of one or more types of sensory aer-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 sucient 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 dierent types of sensory aerents 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 eect is usually considered to be due
to inhibition of pulmonary vagal aerent discharge.tussive drugs on them all.
The most common sites known to produce cough Indeed, tracheal RAR responses are inhibited by local
anaesthetic aerosols.
However, local anaesthetics canare the larynx and lower airways, although sensory
aerents from other sites can elicit cough.
In ad- penetrate the blood brain barrier and these com-
pounds may also have a central eect to inhibit coughdition, within the lower airways, regional dierences
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.
have suggested
that a single type of sensory aerent 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 aerents had rapidly adapting acid-induced cough in the dog
and cough in asth-
This drug has no eect on pulmonarydischarge patterns.
Whether or not other types of
laryngeal aerents have a modulatory eect 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 eect 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 aer-
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 eect 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. aerents from other organs that have reflex eects on
Any one of these sensory aerents 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 aerents 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 aerents. Right
inhibitor, furosemide.
Interestingly, furosemide had atrial administration of codeine or dextromethorphan
no eect 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 eects 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.
Therefore, 4°C.
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 aerents. observations and conclusions have been made for
However, it should be emphasized that a central action morphine.
The eect 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 aerent responses alone. eects on cough of stimulation of these aerents 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
or peripheral
of peripheral antitussive drugs. BW443C, a peripheral to inhibit cough. Figure 1 summarizes the potential
l-opioid agonist, inhibited the discharges of both eects of peripheral antitussive drugs on dierent
RARs and C-fibres.
This compound was ad- classes of sensory aerents, and the influence of these
ditionally shown to have solely peripheral activity by aerents on cough.
other methods.
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 aerent 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
drug Lower
Other ?
Cerebellum ?Central
Central reflex
pathway and cough
burst pattern
Fig. 1 Possible sites of action of peripherally- or centrally-active antitussive drugs. Depicted is a model of the types of peripheral
aerents 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 eects by either inhibition of sensory aerents that produce cough or by excitation of sensory
aerents that inhibit cough. Pulmonary slowly adapting receptors have a permissive eect 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 aerents. Pulmonary C-fibres are shown as two groups with diering eects 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 dierent 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
(icv) administration.
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
active systemically
. 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 eect 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 eective 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 eective dosegesting that baclofen has no peripheral site of action.
Therefore, peripheral activity of an antitussive drug ratio.
The eective 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 eectively 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
or less.
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 suciently 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 aerents). The advantage of this muscle inhibits cough. Recent work in the cat indicates
technique is that it is very robust in dierentiating 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.
In humans,
of this technique is limited by the lack of information doses of salbutamol which have significant bron-
on dierentiation of drugs that have both central and chodilating eects do not inhibit cough.
It is more
peripheral components to their action from drugs that likely that the antitussive eects of b-adrenoreceptor
have solely a central site of action. However, recent agonists are due to inhibition of mediator release
work on tachykinin NK
and NK
receptor ant- or a direct action on sensory aerents.
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 eects 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.
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 unaected 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
eects 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
eects 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 dierent
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 anity
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 eect alone is not sucient to indicate of these techniques have considerable limitations, even
to the extent of being unable to dierentiate 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
specific antagonist
showed that this drug had an eective 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 eective
investigate central antitussive activity. GABA-B re- dose ratio (7) for inhibition of cough when physio-
ceptor agonists,
N-methyl-D-asparate (NMDA) re- logical saline was used as vehicle. Although Domino
ceptor antagonists,
opioid receptor agonists,
and et al.
concluded that caramiphen was a centrally-
adenosine receptor agonists all have been shown to active drug, the eective 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 eective 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 sucient 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 aerents that
These methods have been used to demonstrate central have a reflex inhibitory eect 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 eective 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 aerents. Even
Administration of antitussive drugs by different routes with natural stimulation of the airways, it is dicult
As described in the previous section of peripheral to dierentiate the motor patterns of sneeze and cough
antitussive drugs, the ratio of eective 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, aecting 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-
arterial route.
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- aerent 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
publication No. (PHS) 92-1771, Public Health Service, MD.
Lavezzo et al.
showed that intravenous levo-
2. Choudry N B, Fuller R W. Sensitivity of the cough reflex in
dropropizine inhibited cough induced by electrical
patients with chronic cough. Eur Respir J 1992; 5: 296–300.
3. Irwin R S, Rosen M J, Braman S S. Cough Arch Intern Med
stimulation of the vagus nerve in the guinea-pig,
1977; 137: 1186–1191.
but this eect was not present in animals that had
4. Irwin RS, Curley FJ, Bennett FM. Appropriate use of
undergone capsaicin desensitization. Furthermore,
antitussives and protussives. Pract Ther 1993; 46: 80–91.
5. Allegra L, Bossi R. Clinical trials with the new antitussive
these investigators also showed that levodropropizine
levodropropizine in adult bronchitic patients. Arzneim-
had no eect when administered by the icv route. The
Forsch 1988; 38: 1163–1166.
findings of Lavezzo et al.
suggest that levo-
6. Aversa C, Cazzola M, Clini V, Dal Negro R, Maiorano V,
Tana F, Allegra L. Clinical trial of the ecacy and safety of
dropropizine inhibited vagally-induced cough by ac-
moguisteine in patients with cough associated with chronic
tivating a reflex mediated by capsaicin-sensitive
respiratory diseases. Drugs Exptl Clin Res 1993; 19:
aerents, and not by a central site of action.
7. Adcock JJ. Peripheral opioid receptors and the cough reflex.
Respir Med (Suppl A) 1991; 85: 43–46.
8. Braga PC. Centrally acting opioid drugs. In: Braga PC,
Allegra L, eds. Cough, New York: Raven Press, 1989; pp.
9. Fuller RW. Pharmacology of inhaled capsaicin in humans.
Virtually all of the animal studies in which antitussive
Respir Med (Suppl. A) 1991; 85: 31–34.
activity has been evaluated were performed in animals
10. Guanti EE. Drugs with direct peripheral action. In: Braga
PC, Allegra L, eds. Cough, New York: Raven Press, 1989;
with no underlying airway pathology. The extent to
pp. 197–226.
which upper and/or lower airway inflammation can
10. Kase Y. Antitussive agents and their site of action. Trends
modify the ecacy, potency, and site of action of
Pharmacol Sci 1980; 1: 237–239.
12. Bolser DC, DeGennaro FC, O’Reilly S, Chapman RW,
antitussive drugs is not well known. For example,
Kreutner W, Egan RW, Hey JA. Peripheral and central sites
inflammatory mediators, such as histamine can modify
of action of GABA-B agonists to inhibit the cough reflex in
the blood-brain-barrier.
Increases in circulating
the cat and guinea pig. Br J Pharmacol 1994; 113:
histamine in inflammatory disorders of the airways
13. Chou DT, Wang SC. Studies on the localization of the
may enhance penetration of blood-brain-barrier by
central cough mechanism: site of action of antitussive drugs.
previously peripheral drugs. Likewise, airway in-
J Pharmacol Exp Ther 1975; 223: 249–253.
14. Karlsson J-A, Sant’Ambrogio G, Widdicombe J. Aerent
flammation may ‘unmask’ perpheral sites of action for
neural pathways in cough and reflex bronchoconstriction. J
previously central drugs. We know that inflammatory
Appl Physiol 1988; 65: 1007–1023.
mediators, such as bradykinin, can sensitize the re-
15. Karlsson J-A, Hansson L, Wollmer P, Dahlback M. Regional
sensitivity of the respiratory tract to stimuli causing cough
sponsiveness of sensory aerents to stimuli.
It is
and reflex bronchoconstriction. Respir Med (Suppl. A) 1991;
possible that some antitussive drugs may only in-
85: 47–50.
fluence the response of sensitized aerents, such that
16. Hansson L, Wollmer P, Dahlback M, Karlsson J-A. Regional
sensitivity of human airways to capsaicin-induced cough. Am
there is little peripheral eect of these drugs under
Rev Respir Dis 1992; 145: 1191–1195.
normal conditions, but a more marked eect during
17. Sant’Ambrogio G, Anderson JW, Sant’Ambrogio FB,
inflammatory conditions. In this situation, a drug that
Mathew OP. Response of laryngeal receptors to water
solutions of dierent osmolality and ionic composition.
was considered to have solely a central action to
Respir Med (Suppl. A) 1991; 85: 57–60.
inhibit cough might also have a peripheral action.
18. Sant’Ambrogio FB, Sant’Ambrogio G, Anderson JW. Eect
Finally, increased baseline discharge and re-
of furosemide on the response of laryngeal receptors to low-
chloride solutions. Eur Respir J 1993; 6: 1151–1155.
sponsiveness of peripheral aerents elicited by airway
19. Tomori Z, Widdicombe JG. Muscular, bronchomotor, and
inflammation may increase central responsiveness as
cardiovascular reflexes elicited by mechanical stimulation of
well. Central hyperresponsiveness is a well known
the respiratory tract. J Physiol (Lond) 1969; 200: 25–49.
20. Hanecek J, Davies W, Widdicombe JG. Influence of lung
mechanism in the processing of other sensory systems,
stretch receptors on the cough reflex in rabbits. Respiration
such as pain.
The extent to which central hyper-
1984; 45: 161–168.
21. Sant’Ambrogio G, Sant’Ambrogio FB, Davies A. Airway
responsiveness may influence the potency and/or
receptors in cough. Bull Eur Physiopathol Respir 1984; 20:
ecacy of individual centrally-active antitussive drugs
is unknown. However, it is likely to be involved in
22. Forsberg K, Karlsson JA, Theodorsson E, Lundberg JM,
Persson CGA. Cough and bronchconstriction mediated by
generating more intense cough responses that are
capsaicin-sensitive sensory neurons in the guinea pig. Pulm
more dicult to suppress pharmacologically. Further
Pharmacol 1988; 1: 33–39.
experimental work in pathological models of cough
23. Tatar M, Webber SE, Widdicombe JG. Lung C-fibre receptor
activation and defensive reflexes in anesthetized cats. J
is clearly needed for significant advances to be made
Physiol (Lond) 1988; 402: 411–420.
in our understanding of the mechanism of action of
24. Ventresca PG, Nichol GM, Barnes PJ, Chung KF. Inhaled
antitussive drugs.
furosemide inhibits cough induced by low chloride content
solutions but not by capsaicin. Am Rev Respir Dis 1990;
142: 143–146.
25. Adcock JJ, Allan G, Richardson PJ, Schneider C, Smith TW.
Antitussive eects and inhibition of vagal sensory nerve
1. National Ambulatory Medical Care Survey: 1989 Results. activity by tyr.d.arg.gly.phe (4-NO2). pro.NH2.(443C). Br J
Pharmacol 1987; 90: 143P.Vital and Health Statistics, 1992; Series 13, No. 36, DHHS
Central and Peripheral Antitussives 363
26. Adcock JJ, Smith TW. Inhibitory eects of the opiod peptide peripheral mechanisms mediating the antitussive actions of
opioids in the guinea pig. Gen Pharmacol 1991; 22:BW443C on smaller diameter sensory nerve activity of the
vagus. Br J Pharmacol 1987; 96: 596P. 1103–1108.
48. Lara JP, Dawid-Milner MS, Gonzalez-Baron S. Eects of27. Adcock JJ, Schneider C, Smith TW. Eects of codeine,
morphine, and a novel pentapeptide BW443C, on cough, bronchoconstriction on the cough reflex in the cat. Rev Esp
Fisiol 1993; 49: 235–240.nociception and ventilation in the unanesthetized guinea pig.
Br J Pharmacol 1988; 93: 93–100. 49. Forsberg K, Karlsson JA, Zackrisson C, Persson CGA.
Selective inhibition of cough and bronchoconstriction in28. Fox AJ, Barnes PJ, Dray A. Stimulation of guinea-pig
tracheal aerent fibres by non-isomotic and low-chloride conscious guinea pigs. Respiration 1992; 59: 72–76.
50. Smith CA, Adamson DL, Choudry NB, Fuller RW. Thestimuli and the eect of frusemide. J Physiol (Lond) 1995;
482: 179–187. eects of altering airway tone on the sensitivity of the cough
reflex in normal volunteers. Eur Respir J 1991; 4: 1076–1079.29. Karlsson JA. Airway anaesthesia and the cough reflex. Bull
Eur Physiopathol Respir (Suppl 10) 1987; 23: 29s–36s. 51. Butchers PR, Skidmore IF, Vardey CJ, Wheeldon A.
Characterization of the receptor mediating the anti-30. Camporesi EM, Mortola JP, Sant’Ambrogio FB,
Sant’Ambrogio G. Topical anaesthesia of tracheal receptors. anaphylactic eects of b-adrenoreceptor agonists in human
lung tissue in vitro. Br J Pharmacol 1980; 71: 663.J Appl Physiol 1979; 47: 1123–1126.
31. Jackson DM. The eect of nedocromil sodium, sodium 52. Korpas J, Tomori Z. In: Herzog, H ed. Cough and Other
Respiratory Reflexes. New York: S. Karger 1979.cromoglycate and codeine phosphate on critic acid-induced
cough in dogs. Br J Pharmacol 1988; 93: 609–612. 53. Shannon R, Bolser DC, Lindsey BG. Neural control of
coughing and sneezing. In: Miller AD, Bianchi AL, Bishop32. Cherniack RM, Wasserman SI, Ramsdell JW. A double-blind
multicenter group comparative study of the ecacy and BP eds. Neural Control of Breathing, Boca Raton: CRC
Press, 1996; pp. 215– and nedocromil sodium in the management of asthma.
Chest 1990; 97: 1299–1306. 54. Shannon R, Baekey DM, Morris KF, Lindsey BG.
Brainstem respiratory networks and cough. Pulm Pharmacol33. Fairfax AJ, Allbeson M. A double-blind group comparative
trial of nedocromil sodium in the management of bronchial 1996; 9: 343–347.
55. Xu F, Frazier DT, Zhang Z, Shannon R. Influence of theasthma. J Int Med Res 1988; 16: 216–224.
34. Jackson DM, Norris AA, Eady RP. Nedocromil sodium and cerebellum on the cough motor pattern. Soc Neurosci Abstr
1996; 22: 1626.sensory nerves in the dog lung. Pulm Pharmacol 1989; 2:
179–184. 56. Kamei J, Tanihara H, Igarashi H, Kasuya Y. Eects of n-
methyl-d-aspartate antagonists on the cough reflex. Eur J35. Kaufman MP, Coleridge HM, Coleridge JCG, Baker DG.
Bradykinin stimulates aerent vagal C-fibers in Pharmacol 1989; 168: 153–158.
57. Kamei J, Tanihara H, Kasuya Y. Antitussive eects of twointrapulmonary airways of dogs. J Appl Physiol 1980; 48:
511–517. specific j-opioid agonists, u-50,488h and u-62,066e, in rats.
Eur J Pharmacol 1990; 187: 281–286.36. Gruhzit CC. Chemoreflex activity of dextromethorphan
(romilar), dextrorphan, codeine and morphine in the cat and 58. Kamei J, Tanihara H, Kasuya Y. Modulation of l-mediated
antitussive activity in rats by a dagonist. Eur J Pharmacolthe dog. J Pharmacol Exp Ther 1957; 120: 399–407.
37. Willette RN, Sapru HN. Peripheral versus central 1991; 203: 153–156.
59. Kamei J, Tanihara H, Kasuya Y. Modulation of j-mediatedcardiorespiratory eects of morphine. Neuropharm 1982; 21:
1019–1026. antitussive activity in rats by a d-agonist. Res Comm Chem
Pathol Pharmacol 1992; 76: 375–378.38. Bolser DC, DeGennaro FC, Chapman RW, Hey JA. Central
and peripheral sites of action of antitussive drugs in the cat. 60. Kamei J, Iwamoto Y, Misawa M, Nagase H, Kasuya Y.
Antitussive eect of b-endorphin is mediated by l-opioidIn: Trouth CO, Millis RM eds. Ventral Brainstem
Mechanisms and Control of Respiration and Blood Pressure, receptors, but not by j-ore-opioid receptors. Eur J
Pharmacol 1993; 233: 251–254.New York: Marcel Dekker, 1995; pp. 95–102.
39. Karlsson JA, Lanner AS, Persson CGA. Airway opioid 61. Kamei J, Iwamoto Y, Misawa M, Nagase H, Kasuya Y.
Involvement of adenosine a1 receptors in antitussive eect inreceptors mediate inhibition of cough and reflex
bronchoconstriction in guinea pigs. J Pharmacol Exp Ther mice. Life Sci 1994; 55: 383–388.
62. Kase Y, Wakita Y, Kito G, Miyata T, Yuizono T, Kataoka1989; 252: 863–868.
40. Cross A, Guz A, Jain SK, Archer S, Stevens J, Reynolds F. M. Centrally-induced coughs in the cat. Life Sci 1970; 9:
49–59.The eect of anaesthesia of the airway in dog and man: a
study of respiratory reflexes, sensations and lung mechanics. 63. Kito G, Kase Y, Miyata T, Takahama K. Neural mechanism
for production of spasmodic expiratory response like coughClin Sci Mol Med 1976; 50: 439–454.
41. Winning AJ, Hamilton RD, Shea SA, Knott C, Guz A. The induced by amygdala stimulation in the cat I. Pathways
from the amygdala to the lower brain stem.. Arch Inteect of airway anesthesia on the control of breathing and
the sensation of breathlessness in man. Clin Sci 1985; 68: Pharmacodyn 1977; 229: 116–128.
64. Frijlink HW, Franssen EJ, Eissens AC, Oosting R, Lerk CF,215–225.
42. Bolser DC, Aziz SM, DeGennaro FC, Kreutner W, Egan Meijer DK. The eects of cyclodextrins on the disposition of
intravenously injected drugs in the rat. Pharm Res 1991; 8:RW, Chapman RW. Antitussive eects of GABA-B agonists
in the cat and guinea pig. Br J Pharmacol 1993; 110: 380–384.
65. Domino EF, Krutak-Krol H, Lal J. Evidence for a central491–495.
43. Gallico I, Borghi A, Dalla Rosa C, Ceserani R, Tognella S. site of action for the antitussive eects of caramiphen. J
Pharmacol Exp Ther 1985; 233: 249–253.Moguisteine: a novel peripheral non-narcotic antitussive
drug. Br J Pharmacol 1994; 112: 795–800. 66. Borison HL. Electrical stimulation of neural mechanisms
regulating spasmodic respiratory acts in cats. Am J Physiol44. Lavezzo A, Melillo G, Clavenna G, Omini C. Peripheral site
of action of levodropropizine in experimentally-induced 1948; 154: 55–62.
67. Chakravarty NK, Matallana A, Jensen R, Borison HL.cough: role of sensory neuropeptides. Pulm Pharmacol 1992;
5: 143–147. Central eects of antitussive drugs on cough and respiration.
J Pharmacol Exp Ther 1956; 117: 127–135.45. Bolser DC, DeGennaro FC, O’Reilly S, McLeod RL, Hey
JA. Central antitussive activity of the tachykinin receptor 68. Kito G, Kase Y, Miyata T. A cough-like respiratory response
induced by electrical stimulation of the amygdaloid complexantagonists CP 99994 and SR 48968 in the guinea pig and
cat. Br J Pharmacol 1997; 121: 165–170. in the cat. Arch Int Pharmacodyn 1977; 227: 82–92.
69. Bolser DC. Fictive cough in the cat. J Appl Physiol 1991; 71:46. Brown DR, Goldberg LI. The use of quaternary narcotic
antagonists in opiate research. Neuropharmacology 1985; 24: 2325–2331.
70. Domenjoz R. Evaluation of cough sedatives. N S Arch181–191.
47. Callaway JK, King RG, Boura ALA. Evidence for Pharmacol 1952; 215: 19–24.
364 D. C. Bolser
71. Green AF, Ward NB. The action of analgesics and 75. Butt AM. Eect of inflammatory agents on electrical
resistance across the blood-brain barrier in pial microvesselsnalorphine on the cough reflex. Br J Pharmacol 1955; 10:
418–423. of anesthetized rats. Brain Res 1995; 696: 145–150.
76. Martin HA, Basbaum AI, Kwait GC, Gortzl EJ, Levine JD.72. Grelot L, Milano S. Diaphragmatic and abdominal muscle
activity during coughing in the decerebrate cat. Neuro Leukotriene and prostaglandin sensitization of cutaneous
high threshold C- and A-delta mechanoreceptors in the hairyReport 1991; 2: 165–168.
73. Mori M, Sakai Y. Re-examination of centrally-induced skin of rat hindlimbs. Neurosci 1987; 22: 651–659.
77. McMahon SB, Lewin GR, Wall PD. Centralcough in cats using a micro-stimulation technique. Jap J
Pharmacol 1972; 22: 635–643. hyperexcitability triggered by noxious inputs. Curr Opin
Neurobiol 1993; 3: 602–610.74. Tarayre JP, Vilain P, Lauressergues H, Cauquil J.
Pharmacological study of the antitussive and respiratory- 78. Simone DA, Sorkin LS, Oh U, Chung JM, Owens C,
LaMotte RH, Willis WD. Neurogenic hyperalgesia: centralanaleptic properties of n-(2-ethylpyrrolidino)
diphenylacetamide hydrochloride (F 1459). Arzneim-Forsch neural correlates in responses of spinothalamic tract neurons.
J Neurophysiol 1991; 66: 228–246.1983; 33: 931–935.
... In support of both Canning and Mori (2010) and Haji et al. (2012), our results indicate that the rNTS is an important area controlling the excitability and execution of coughing. We have proposed that there is a functional system that controls cough excitability in the brain stem, which has been termed a cough gate (Bolser 1996;Bolser et al. 1999;Bolser and Davenport 2002). This system is proposed to mediate the antitussive effect of centrally acting cough-suppressant drugs. ...
... This system is proposed to mediate the antitussive effect of centrally acting cough-suppressant drugs. However, in the cat the mode of action of virtually all of those drugs, whether administered systemically, centrally via the vertebral artery, or locally by microinjection into the brain stem, is to decrease CN and expiratory motor drive but not inspiratory activity during coughing (Bolser 1996;Bolser et al. 1999;Bolser and Davenport 2002). The present results do not rule out the participation of the rNTS in the proposed cough gating mechanism (Canning and Mori 2010), but the prolongation of cough phase durations and disruption of cough rhythmicity (Fig. 3) indicate a more expansive, possibly commanding role of this area in the cough generation circuit. ...
The importance of neurons in the solitary tract nucleus (NTS) in the production of coughing was tested by microinjections of the non-specific glutamate receptor antagonist kynurenic acid (kyn; 100 mM in artificial cerebrospinal fluid) in 15 adult spontaneously breathing anesthetized cats. Repetitive coughing was elicited by mechanical stimulation of the intrathoracic airway. Electromyograms (EMG) were recorded from inspiratory parasternal and expiratory transversus abdominis muscles (ABD). Bilateral microinjections of kyn into the NTS rostral to obex (55±4 nl total in two locations; n=6 or 110±4 nl total in four locations; n=5), primarily the ventrolateral subnucleus, reduced cough number and expiratory cough efforts (amplitudes of ABD EMG and maxima of esophageal pressure) compared to control. These microinjections also markedly prolonged the inspiratory phase, all cough related EMG activation, and the total cough cycle duration as well as some other cough related time intervals. In response to microinjections of kyn into the NTS rostral to the obex respiratory rate decreased, and there were increases in the durations of the inspiratory and post-inspiratory phases and mean blood pressure. However, bilateral microinjections of kyn into the NTS caudal to obex as well as control vehicle microinjections in the NTS location rostral to obex had no effect on coughing or cardiorespiratory variables. These results are consistent with the existence of a critical component of the cough rhythmogenic circuit located in the rostral ventral and lateral NTS. Neuronal structures of the rostral NTS are significantly involved specifically in the regulation of the cough magnitude and phase timing.
... Opiates. Codeine and morphine are commonly used antitussives in adult-based clinical practice and have antitussive effects via central opioid receptors 169 . Accordingly, effective antitussive doses of opiates are likely to cause sedation. ...
... Studies in laboratory animals and humans have demonstrated that opiates and other centrally acting neuromodulators (gabapentin and baclofen) can inhibit cough evoked by a broad range of chemical and mechanical stimuli [188][189][190][191] . This action is a dose-dependent generalized suppression of the nervous system (sedation), inhibition of the brainstem neurons involved in generating respiratory rhythm and/or direct suppression of cough sensory nerve activity 169,192,193 . Consequently, some nonspecific cough suppressants might cause dystussia, although the prevalence of this is not well documented. ...
Chronic cough is globally prevalent across all age groups. This disorder is challenging to treat because many pulmonary and extrapulmonary conditions can present with chronic cough, and cough can also be present without any identifiable underlying cause or be refractory to therapies that improve associated conditions. Most patients with chronic cough have cough hypersensitivity, which is characterized by increased neural responsivity to a range of stimuli that affect the airways and lungs, and other tissues innervated by common nerve supplies. Cough hypersensitivity presents as excessive coughing often in response to relatively innocuous stimuli, causing significant psychophysical morbidity and affecting patients’ quality of life. Understanding of the mechanisms that contribute to cough hypersensitivity and excessive coughing in different patient populations and across the lifespan is advancing and has contributed to the development of new therapies for chronic cough in adults. Owing to differences in the pathology, the organs involved and individual patient factors, treatment of chronic cough is progressing towards a personalized approach, and, in the future, novel ways to endotype patients with cough may prove valuable in management. This Primer by Mazzone and colleagues summarizes the epidemiology, pathophysiology, diagnosis and treatment of chronic cough and cough hypersensitivity. This Primer also discusses how cough hypersensitivity and chronic cough affect patients’ quality of life and future research directions for the field.
... Based on the site of action, antitussive medicines have been classified into two major groups. One of the major type i.e. peripheral antitussive medicine acts quickly and positively to suppress the activity of sensory nerves producing cough (Adcock 1991, Adcock, Schneider et al. 1988, Bolser 1996. Central antitussive drugs act within the CNS at the level of the brain stem, where the basic neural circuitry responsible for cough is located (Bolser, Hey et al. 1999, Shannon, Baekey et al. 1996. ...
Full-text available
Cough is the utmost common medical problem in Pakistan, affecting at least one of every tenth. Antitussive medicines are the most widely used medications after analgesics. Antitussive medicines are generally used for soothing in mild, intense, dry or sputum conditions of cough. The current study was conducted among the population of Pakistan to check awareness regarding effects of antitussive drugs and its complications. 562 participants of various demographic details were included in this study. To reduce the effects of cough, 80.78% participants were found to be using antitussive drugs whereas 19.21% were not using any. 77.94% were found to be aware of side effects of the antitussive drugs. It was established that daily routine of 46.79% participant was not found to be affected by the use of antitussive medicines. The findings of the current study indicate that the main antitussive drugs used by the citizens of Pakistan are aminophylline and Dextromethorphan. 41.63% of the participant use antitussive medicines for moderate conditions of cough, 35.02% for intense and 20.04% for sputum cough. 287 participants have taken up antitussive medicines as over-the-counter (OTC) while 151 of the participants have taken up as a prescription drug. The results of current study clearly indicate the participants of the this study have enough awaredness about using antitussive medicine for the relief of various type of cough. The participants of the current study are also found to be aware of the effects of increasing dose as well alternatives of the antitussive drugs. The participants were also found to have enough knowledge about the management of antitussive drugs alongwith other disease.
... 26. Treatment agents for cough: antitussive and mucoactive agent 1) Summary -Antitussives are classified as central and peripheral 79,80 . ㆍ Narcotic central antitussive: morphine, codeine ㆍ Nonopioid central antitussive: dextromethorphan, levopropoxyphene ㆍ Peripheral antitussive: benzonatate, benproperine, theobromine -Mucoactive agents can be classified as expectorants, mucoregulatory agents, mucolytics, and mucokinetics 81,82 . ...
Full-text available
Cough is the most common respiratory symptom that can result from various causes, and is a major clinical problem that reduces patients' quality of life. Thus, clinical guidelines for the treatment of cough were established in 2014 by the cough guideline committee under the Korean Academy of Tuberculosis and Respiratory Diseases. From October 2018 to July 2020, the cough guidelines were revised by the members of the committee based on the first guidelines. The purpose of these guidelines is to help clinicians efficiently diagnose and treat patients with cough. This article highlights the recommendations and summary of the revised Korean cough guidelines. It includes a revised algorithm for the evaluation of acute, subacute, and chronic cough. For chronic cough, upper airway cough syndrome (UACS), cough variant asthma (CVA), and gastroesophageal reflux disease (GERD) should be considered in the differential diagnoses. If UACS is suspected, first-generation antihistamines and nasal decongestants can be used empirically. In cases with CVA, inhaled corticosteroids are recommended to improve the cough. In patients with suspected chronic cough due to symptomatic GERD, proton pump inhibitors are recommended. Chronic bronchitis, bronchiectasis, bronchiolitis, lung cancer, aspiration, intake of angiotensin-converting enzyme inhibitor, intake of dipeptidyl peptidase-4 inhibitor, habitual cough, psychogenic cough, interstitial lung disease, environmental and occupational factors, tuberculosis, obstructive sleep apnea, peritoneal dialysis, and unexplained cough can also be considered as causes of chronic cough. Chronic cough due to laryngeal dysfunction syndrome has been newly added to the guidelines.
... Dextromethorphan is a central acting antitussive drug. 38 Thus it could be concluded that antitussive activity of extracts is by affecting cough center in brain. The extracts had suitable antitussive effect even better than dextromethorphan. ...
... [18] The lower airway contains specific cough-producing receptors/fibers such as slowly adapting stretch receptors, rapidly adapting receptors (irritant receptors) and pulmonary C-fibers. [23][24][25] Also, laryngeal irritant receptors and C-fibers presented in the upper airway participate in cough reflexes. [26] Among these, pulmonary and laryngeal irritant receptors are the main afferents most readily associated with the cough reflex. ...
Full-text available
Background: Nonintubated video-assisted thoracic surgery (VATS) has been widely developed during the recent years. Cough reflex is an inevitably encountered problem while approaching lung lesions, and it may induce major bleeding. Sevoflurane anesthesia may attenuate cough reflex by inhibiting the pulmonary irritant receptors. However, the incidence of postoperative nausea and vomiting (PONV) in inhalational anesthesia is higher than in the propofol-based total intravenous anesthesia (TIVA). We investigated the effect of sevoflurane combination with propofol-based TIVA on cough reflex and PONV in nonintubated VATS. Methods: Ninety patients undergoing nonintubated VATS with laryngeal mask airway (LMA) and spontaneous breathing were randomly assigned for TIVA or propofol/sevoflurane anesthesia. In the TIVA group (n = 45), anesthesia was induced and maintained with propofol and fentanyl; in the propofol/sevoflurane (P/S) group (n = 45), 1% sevoflurane anesthesia was added to propofol and fentanyl anesthesia. The primary outcome measurements were cough reflex. In addition, the incidence of PONV and extubation time were investigated. Results: Patients with cough reflex were significantly fewer in the P/S group than in the TIVA group (10/45 vs 34/45; P < .001). The cough severity (35/5/5/0 vs 11/17/17/0; P < .001) and limb movement (40/5/0/0 vs 28/17/0/0; P < .001) were lower in the P/S group than in the TIVA group. Besides, incremental fentanyl bolus for cough reflex was 5 (0 [0-1]) in the P/S group and 17 (0 [0-3]) in the TIVA group (P < .05). And there was no conversion to general anesthesia, postoperative hemorrhage, aspiration pneumonia, or PONV in the 2 groups. Besides, there was no significant difference in extubation time (TIVA: 5.04 ± 2.88 vs P/S: 4.44 ± 2.98 minutes; P = .33). Conclusion: Sevoflurane attenuated cough reflex under propofol-based TIVA and did not increase the incidence of PONV and extubation time in nonintubated VATS.
... Existing antitussives are broadly divided into two groups by their action sites: central (drugs acting on central nervous system) and peripheral (drugs acting on elements of peripheral nervous system) (Bolser, 1996). Though centrally-acting antitussive drugs, like codeine and dextromethorphan, show great efficacy towards cough, there are undesirable side effects such as sedation, nausea, addictive potential, and constipation (Reynolds et al., 2004). ...
Full-text available
Ethnopharmacological relevance: Seeds of Cardiocrinum giganteum var. yunnanense (Leichtlin ex Elwes) Stearn (Liliaceae), also known as Doulingzi, have been used as a folk substitute for conventional antitussive herb "Madouling" (Aristolochia species) to treat chronic bronchitis and pertussis. The active antitussive phytochemicals in C. giganteum seeds are not known. Aim of the study: The present work aims at isolating the active phytochemicals in C. giganteum seeds and confirming their antitussive effects. Materials and methods: Active chemicals were isolated from C. giganteum seeds ethanol extract and identified their structures. Antitussive effects were evaluated with the cough frequency of guinea pigs exposed to citric acid. Electrical stimulation of the superior laryngeal nerve in guinea pigs was performed to differentiate the acting site of potential antitussives. Results: Two racemic biflavonoids (CGY-1 and CGY-2) were isolated from C. giganteum seeds. CGY-1 was identified as (S)-2″R,3″R- and (R)-2″S,3″S-dihydro-3″-hydroxyamentoflavone-7- methyl ether, which are new compounds and firstly isolated from C. giganteum seeds. Racemic CGY-2 was identified as (S)-2″R,3″R- and (R)-2″S,3″S-dihydro-3″-hydroxyamentoflavone. Both CGY-1 and CGY-2 could significantly inhibit coughs induced by inhalation of citric acid. Further, they acted on the peripheral reflex pathway to inhibit cough after electrical stimulation of the superior laryngeal nerve in guinea pigs. Conclusions: These chemicals isolated from C. giganteum seeds showed good antitussive effects. The data provide scientific evidence to support the traditional use of C. giganteum seeds as an antitussive herbal medicine.
... These include; centrally and peripheral acting groups. [5] The centrally acting antitussive agents such as dextromethorphan hydro-bromide have been in use for decades and it is frequently a component of most over-the-counter preparations. [6] These drugs are associated with intolerable side effects such as sedation, constipation, addictive potentials, depression of the respiratory centre and nausea. ...
... Antitussive is classified as central and peripheral 51,52 . ...
Full-text available
Cough is one of the most common symptom of many respiratory diseases. The Korean Academy of Tuberculosis and Respiratory Diseases organized cough guideline committee and cough guideline was developed by this committee. The purpose of this guideline is to help clinicians to diagnose correctly and treat efficiently patients with cough. In this article, we have stated recommendation and summary of Korean cough guideline. We also provided algorithm for acute, subacute, and chronic cough. For chronic cough, upper airway cough syndrome (UACS), cough variant asthma (CVA), and gastroesophageal reflux disease (GERD) should be considered. If UACS is suspicious, first generation anti-histamine and nasal decongestant can be used empirically. In CVA, inhaled corticosteroid is recommended in order to improve cough. In GERD, proton pump inhibitor is recommended in order to improve cough. Chronic bronchitis, bronchiectasis, bronchiolitis, lung cancer, aspiration, angiotensin converting enzyme inhibitor, habit, psychogenic cough, interstitial lung disease, environmental and occupational factor, tuberculosis, obstructive sleep apnea, peritoneal dialysis, and idiopathic cough can be also considered as cause of chronic cough. Level of evidence for treatment is mostly low. Thus, in this guideline, many recommendations are based on expert opinion. Further study regarding treatment for cough is mandatory.
To determine the efficacy of nedocromil sodium in adult asthma patients using bronchodilators alone to control their disease, a consecutive sample of 127 patients with long-term asthma was studied for 16 weeks. The patients were maintained on sustained release theophylline preparations (SRT) and inhaled and oral beta-adrenergic bronchodilators (β2). One hundred sixteen patients (90 percent) completed the study; one placebo-treated patient withdrew owing to throat irradiation and wheezing. Nedocromil sodium provided an additional benefit to adult patients receiving SRT and inhaled β2-agonists. With the exception of night-time asthma, nedocromil sodium maintained this improvement for the final 12 weeks of the study despite a reduction in concomitant bronchodilator therapy.
Naproxen and flurbiprofen form complexes with hydroxypropyl--cyclodextrin; with stability constants of 2207 and 12515 M^−1 respectively. However, only small fractions of the drug remain complexed when the drug–cyclodextrin complex is added to plasma in vitro. This result can be explained by albumin effectively competing with cyclodextrin for drug binding and by the simultaneous displacement of the drug from cyclodextrins by plasma cholesterol. Naproxen and flurbiprofen were administered intravenously to rats as cyclodextrin complexes. The disposition in the body of naproxen was not significantly altered by the complexation. This indicates that immediately after administration all drug is removed from the cyclodextrin complex. However, the initial distribution of flurbiprofen was changed upon complexation. Drug concentrations in liver, brain, kidney, and spleen were increased, indicating that hydroxypropyl--cyclodextrin may improve the presentation of the flurbiprofen to biomembranes, as compared with plasma proteins. The effect was transient; 60 min after injection the differences in tissue concentration compared with controls were dissipated. Finally, the importance of protein binding in determining the mode of interaction of cyclodextrins on drug disposition is discussed.
The purpose of this study was to investigate the antitussive activity and sites of action of the NK1 and NK2 tachykinin receptor antagonists, CP-99,994, SR 48968, and the racemate of SR 48968, SR 48212A in the cat and guinea-pig. Guinea-pigs were dosed subcutaneously (s.c.) with CP-99,994, SR 48212A or SR 48968 one hour before exposure to aerosols of capsaicin (0.3 mM) to elicit coughing. Coughs were detected with a microphone and counted. Intracerebroventricular (i.c.v.) cannulae were placed in the lateral cerebral ventricles of anaesthetized guinea-pigs. Approximately one week later, the animals were dosed with CP-99,994 or SR 48212A (i.c.v.) and exposed to aerosols of capsaicin (0.3 mM) to elicit coughing. Cough was produced in anaesthetized cats by mechanical stimulation of the intrathoracic trachea and was monitored from electromyograms of respiratory muscle activity. Cannulae were placed for intravenous (i.v.) or, in separate groups of animals, intravertebral arterial (i.a.) administration of CP-99,994, SR 48212A or SR 48968. Dose-response relationships for i.v. and i.a. administration of each drug were generated to determine a ratio of i.v. ED50 to i.a. ED50, known as the effective dose ratio (EDR). The EDR will be 20 or greater for a centrally active drug and less than 20 for a peripherally active drug. In the guinea-pig, CP-99,994 (0.1–30 mg kg−1, s.c.), SR 48212A (1.0–30 mg kg−1, s.c.), and SR 48968 (0.3–3.0 mg kg−1, s.c.) inhibited capsaicin-induced cough in a dose-dependent manner. Capsaicin-induced cough was also inhibited by i.c.v. administration of CP-99,994 (10 and 100 μg) or SR 48212A (100 μg). In the cat, both CP-99,994 (0.0001–0.3 mg kg−1, i.a., n=5; 0.003–3.0 mg kg−1, i.v., n=5) and SR 48212A (0.003–1.0 mg kg−1, i.a., n=5; 0.01–3.0 mg kg−1, i.v., n=5) inhibited mechanically induced cough by either the i.v. or i.a. routes in a dose-dependent manner. SR 48968 (0.001–0.3 mg kg−1, i.a., n=5; 0.03–1.0 mg kg−1, i.v., n=5) inhibited cough when administered by the i.a. route in a dose-dependent manner, but had no effect by the i.v. route up to a dose of 1.0 mg kg−1. Intravenous antitussive potencies (ED50, 95% confidence interval (CI)) of these compounds were: CP-99,994 (0.082 mg kg−1, 95% CI 0.047–0.126), SR 48212A (2.3 mg kg−1, 95% CI 0.5–20), and SR 48968 (>1.0 mg kg−1, 95% CI not determined). The intra-arterial potencies of these compounds were: CP-99,994 (1.0 μg kg−1, 95% CI 0.4–1.8), SR 48212A (25 μg kg−1, 95% CI 13–52), and SR 48968 (8.0 μg kg−1, 95% CI 1–32). The derived EDRs for each compound were: CP-99,994, 82; SR 48212A, 92; and SR 48968, >125. We concluded that CP-99,994 and SR 48968 inhibit cough in the guinea-pig and cat by a central site of action. In the cat, the antitussive action of these compounds appears to be solely by a central site. British Journal of Pharmacology (1997) 121, 165–170; doi:10.1038/sj.bjp.0701111
Guidelines for submitting commentsPolicy: Comments that contribute to the discussion of the article will be posted within approximately three business days. We do not accept anonymous comments. Please include your email address; the address will not be displayed in the posted comment. Cell Press Editors will screen the comments to ensure that they are relevant and appropriate but comments will not be edited. The ultimate decision on publication of an online comment is at the Editors' discretion. Formatting: Please include a title for the comment and your affiliation. Note that symbols (e.g. Greek letters) may not transmit properly in this form due to potential software compatibility issues. Please spell out the words in place of the symbols (e.g. replace “α” with “alpha”). Comments should be no more than 8,000 characters (including spaces ) in length. References may be included when necessary but should be kept to a minimum. Be careful if copying and pasting from a Word document. Smart quotes can cause problems in the form. If you experience difficulties, please convert to a plain text file and then copy and paste into the form.
The present study examined the opioid receptors involved in the antitussive effect of β-endorphin in mice. β-Endorphin injected i.c.v. depresses coughs dose dependently in doses from 0.1 to 1 μg. Blockade of μ-opioid receptors by pretreatment with β-funaltrexamine significantly reduced the antitussive potency of i.c.v. β-endorphin. However, the antitussive effect of β-endorphin was not antagonized by nor-binaltorphimine, a κ-opioid receptor antagonist. Moreover, i.c.v. injection of β-endorphin-(1–27), an ϵ-opioid receptor antagonist, did not affect the antitussive effect of β-endorphin. The results indicate that the antitussive effect of β-endorphin is mediated by activation of μ-opioid receptors, but not of κ- or ϵ-opioid receptors.
Repetitive activity in unmyelinated sensory afferent neurones, arising from electrical stimuli, tissue injury or nerve damage, can induce long-lasting sensitization in dorsal horn neurones. This process can be blocked by antagonists of the NMDA receptor. In the past year it has emerged that sensory neuropeptides and nitric oxide are also essential mediators of this phenomenon.
1. Comparisons were made between the doses required of aerosol and intraperitoneally administered morphine, dextromethorphan, codeine and the specific peripherally acting μ-receptor agonist DALDA (H-Tyr-D-Arg-Phe-Lys-NH2) to suppress citric acid-induced coughing in conscious guinea pigs.2. Estimated ID50s for inhibition of numbers of coughs induced by an aerosol of 5% citric acid were 1.0 and 2.4 mg/kg for intraperitoneally administered morphine and dextromethorphan, respectively.3. The estimated ID50s after inhalation of morphine and dextromethorphan as aerosols were ≈ 2.2 and ≈ 12 μg/kg, respectively.4. Aerosilized codeine (≈ 72 μg/kg, n = 5) significantly inhibited coughing by 62 ± 23% whereas 3 mg/kg, i.p. was required to significantly reduce coughing by a similar degree (60 ± 6%, n = 7).5. Inhalation of DALDA (≈ 7.2 μg/kg, n = 7) also significantly inhibited coughing.6. The antitussive effect of inhaled morphine (≈ 7.2 μg/kg, n = 11) was inhibited after administration of 3 mg/kg of either naloxone hydrochloride or naloxone methylbromide intraperitoneally.7. The results support the hypothesis that effects at a peripheral site can make a major contribution to the antitussive actions of these drugs.
In 34 lightly pentobarbitalized cats, spasmodic expiratory response (SER) very similar to coughing or sneezing was elicited by electrical stimulation of the nucleus amygdaloideus corticalis or its adjacent structures. The production of SER was highly dependent on the frequency of stimulus, that is, low frequency stimulation was adequate for the induction of the response. SER as well as coughs induced by either electrical stimulation of the superior laryngeal nerve or by mechanical stimulation of the tracheal mucosa were depressed by common antitussives such as codeine and dextromethorphan, though effects of the drugs on SER were less effective and less prolonged than those on coughs. In contrast to this, sneeze evoked by mechanical stimulation of the nasal mucosa was not influenced by the antitussives at all. The small doses of tranquilizing agents such as chlordiazepoxide, diazepam, and chlorpromazine abolished SER, while the same dose of the drugs had suppressing effect neither on cough nor on sneeze. The results demonstrate that SER is quite different from sneeze and rather resembles cough. In 8 chronic cats, SER was always accompanied by changes in emotional behavior and the same dose of the tranquilizing agent described above could suppress such changes, while the antitussive drugs could not. The findings presented here suggest that SER may correspond to psychogenic cough in humans.
The pathways descending from the amygdala to neural structures in the lower brain stem responsible for production of spasmodic expiratory response like cough (SER), which occurred upon electrical stimulation of the cortical nucleus of amygdala (Aco), were investigated using microinjection and ablation techniques in the cat. 1) Following transection of the bilateral stria terminalis (STT), the threshold for SER production was remarkably elevated. 2) SER was suppressed by administration of procaine (20 microgram) or diazepam (5 microgram) into either side of the hypothalamic ventromedial nucleus (Hvm); furthermore, SER completely disappeared after lesion of bilateral Hvm. After lesion of the ipsilateral Hvm to the side of stimulation, the threshold for SER was obviously elevated, but SER was not affected by lesion of the contralateral Hvm. 3) After section of the substantia grisea centralis at the midcollicular level, SER disappeared. 4) Both SER and peripherally-induced coughs were depressed by codeine (10 microgram), dextromethorphan (10 microgram) or procaine (20 microgram) administered into the solitary tract nucleus (STN) or the nucleus reticularis parvocellularis. 5) SER and coughs disappeared after lesion of the bilateral STN or nucleus ambiguus (AM). These results demonstrate that most of the efferent fibers from Aco get to Hvm via STT, and further to STN and AM in the medulla.