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COUGH PHARMACOTHERAPY
 DEFINITION
i Cough is an important defense mechanism of the
body that serves to clear the airway of excessive
secretions and foreign matter

i It can be activated by
(1) Mechanical stimuli: foreign body, dust
(2) Chemical stimuli: smoke, perfumes
(3) Thermal stimuli: cold air, hot air, cold water
ingestion
 CLASSIFICATION

` Acute coughs usually begin suddenly. They are

often due to a cold, flu, or sinus infection.
They usually go away after 2 to 3weeks .
` The subacute cough lasts between3-8 weeks .

` Chronic coughs last longer than 8weeks .

 TYPES OF COUGH

Non productive cough

COUGH no sputum- antitussives

Productive
sputum - expectorants
CONSEQUENCES OF COUGH
` Persistent cough may be associated with
considerable morbidity including
i sleep loss, exhaustion, considerable social
disability
i irritability, impaired performance in daily
activities
i cough syncope,
 CONSEQUENCES

` Cough is however very common and can be

debilitating for its sufferers, leading to both
physical and psychological effects.

` Although not life threatening, cough can cause

weakness and social embarrassment, which
contribute to a deterioration in quality of life.
COMPLICATIONS OF COUGH
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COUGH PATHOPHYSIOLOGY
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 IRRITANTS

Chemical, physical COUGH Centre sends signals to

stimulus irritates respiratory muscles to contract and
sensory receptors remove irritant by forceful expiration
in lungs (Coughing)

Cough
Receptors
send signals to
cough centre
via vagus nerve
@


 
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CENTRAL COUGH REGULATION


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SECOND ORDER NEURONS

Receives inputs from peripheral
cough receptors as well as from
rhythmic inputs from respiratory
system

Glutamate NTS 6


(excitatory neurotransmitter)  

NT)
NEUROTRANSMISSION
NEUROTRANSMITTERS
 NT ACTIONS IN BODY
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NT AND EFFECT ON COUGH CENTRE
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Glutamate Excitatory Increase conc
Stimulates cough

Glycine Inhibitory Increase conc

Inhibits cough

GABA Inhibitory Increase conc

Inhibits cough

Substance P Excitatory Increase conc

Stimulates cough

Serotonin Inhibitory Increase conc

Inhibits cough
CENTRAL INTEGRATION



 
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PERIPHERAL COUGH REGULATION

` Any irritant of respiratory system is sensed

by Receptors.
` These receptors are myelinated and
unmyelinated fibers of Vagus.
` Myelinated ² Rapidly adapting receptos
- Slowly adapting fibers
- Unmyelinated ² Brhonchial C fibres
- Pulmonary C fibres
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 RECEPTORS

` Airway receptors
A Slowly adapting receptors (airway smooth muscle)
A Rapidly adapting receptors (airway epithelial cells)

A Supplied by vagus and myelinated nerve fibres

SLOWLY ADAPTING RECEPTORS

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- Exp time and resp rate with lung inflation.

Active only if TV>3l , prevents overinflation
- Prolongs insp in conditions of
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- Allowing higher TV to be achieved
RAPIDLY ADAPTING RECEPTORS

` Irritant receptors (cough )

` Carina and principal bronchi
` Noxious stimuli-dust, smoke
` Causes augumented breaths ¶



during

breathing to prevent atelectasis
` Sensation of dyspnea, chest tightness, rapid
shallow breathing in asthma
BRONCHIAL RECEPTORS
` Unmyelinated nerve endings
` Responsible for bronchospasm in asthma
` Increased tracheobronchial secretions
` Mediators- histamine, prostaglandins ,
bradykinin
PULMONARY RECEPTORS

` G

 

located near
capillary in alveolar walls
` Responds to hyperinflation & mediators in
pulmonary circulation
` Sensation of dyspnoea in heart failure due to
interstitial edema
` Mechanism: inhibition of resp motor neurons
ROLE OF RECEPTORS IN COUGH

` Only RAR and Unmyelinated C fibres

stimulation leads to sensory impulse of cough.
` Due to cough hypersensitivity syndrome
multiple sensory impulse travels to the cough
center in medulla.
` These receptors when blocked will abolish
the multiple irrelevant impulses reaching
medulla.
TREATMENT
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` SAFETY FIRST
` EFFICACY
 ANTITUSSIVE

X@
i Opioids
² Codeine
i Non Opioids ² Dextromethorphan

X 
i Levodropropizine
Y

 Y


NT AND EFFECT ON COUGH CENTER
BY CENTRAL ANTITUSSIVE
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Glutamate Excitatory Increase conc
Stimulates cough Codeine inhibits
Stimulates cough them via Î

 
 
 


Glycine
Glycine Inhibitory
Inhibitory Increase conc
Inhibits cough -
Inhibits cough

GABA Inhibitory Inhibits cough ? Dextro-

GABA Inhibitory Increase conc
methorphan
Inhibits cough

Substance P Stimulatory Stimulates cough Opioid Resistant

Substance P Excitatory Increase conc
Stimulates cough

Serotonin
Serotonin (5 HT) Inhibitory
Inhibitory Inhibits
Increasecough
conc Codeine 5HT
Inhibits cough
 OPIOID RECEPTORS
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MECHANISM OF COUGH CONTROL

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inhibitory effect on GIRK channel activated currents
i GIRK channel antagoniz the 5-HT-induced
hyperpolarization and depolarized the membrane
potential, generating action potentials in dorsal
raphe neurons
 MAJOR SIDE EFFECTS
` Respiratory depression
` Constipation
` Serotonin syndrome
` Sedation
` Dependence
RESPIRATORY DEPRESSION

` Quantified by
A Observed changes in breathing frequency
ë Severe respiratory depression considered to be
breathing rate of less than 8-10 breaths/minute
A And/or oxygen saturation
` Slowed and irregular respiration leads to
hypercapnia and hypoxia
 CONSTIPATION

` Mediated through either r or -opioid

receptors on enteric nerves, epithelial cells
and muscle.
A Reduces intestinal motility (via r-receptors)
A Reduces intestinal secretion (via -receptors)
A And increases absorption of water (via r and -
receptors)
SEROTONIN SYNDROME
` A potentially life-threatening condition caused
by excess serotonergic stimulation of the
central nervous system.
` Symptoms occur within minutes to hours
after starting a second drug
SEROTONIN SYNDROME

` Classic triad of symptoms

A Altered mental status
A Neuromuscular hyperactivity
A Autonomic hyperactivity
` All three features are not always present
together
 SEDATION
` Occurs in 20-60% patients taking opioids
` Sedation is defined as ´depression of brain
functioning by a medication, mainfested by
sleepiness, drowsiness, fatigue, slowed brain
activity, reduced wakefulness, and impaired
performance.µ
` Dose-dependent effect
` Tolerance within a few days
TOLERANCE & DEPENDENCE

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 THERAPY GAPS
` Due to little understanding of cough
physiology only central mechanism is
considered best treatment modality.

` Although dry irritating cough many times is

only a peripheral irrelevant stimulation central
antitussives are given to control them.
 THERAPY GAPS

` Associated adverse effects or disadvantages

are higher with these central antitussives than
their efficacy.

` Cough receptors are only present in lungs

and peripheral antitussives can be safely and
efficaciously used to treat dry irritating cough
 THERAPY GAPS
` Till date due to unavailability of drugs which
act by peripheral mechanism centrally acting
antitussives are taken as gold standard.

` There are resistant coughs which can be

managed only by peripheral antitussives and
not by central antitussives.
 NEED OF THE HOUR

` Approximately 20% of respiratory out-patient

referrals are for patients with chronic cough.
Failure of the cough to resolve completely is
common.
` Symptomatic cough suppressant with good
efficacy and better safety profile is required.
ë
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WHY PERIPHERAL ANTITUSSIVE

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 LEVODROPROPIZINE
` (S)-3-(4-Phenyl-1-
piperazinyl)-1,2-propanediol
` Molecular Formula
C13H20N2O2
` Molecular Weight 236.31
 LEVODROPROPIZINE
` Levodropropizine is an orally administered, non-
opioid agent with peripheral antitussive mechanism.
` In patients with pathological cough, randomized,
double-blind trials have demonstrated
levodropropizine to be efficacious compared to
dextromethorphan in non-productive cough, and
better safety profile than dihydrocodeine against
cough.
MECHANISM OF ACTION
` It acts by inhibiting the information about
irritant sent to Medulla by sensory C-fiber
afferents.
` It acts as a peripheral antitussive, with no
action in the central nervous system and so
does not cause side effects such as
constipation or respiratory depression which
are produced by opioid antitussive such as
codeine and its derivatives.
 PHARMACOKINETICS
` It is well absorbed after oral administration


 


 

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Levodropropizine 1 6

Codeine 1 6

Dextromethorphan ? 30 ?6
ß The drug is metabolized in liver and excreted
in urine.
ß I 
 ² Alcohol, CNS depressants, and
tricyclic antidepressants may cause additive
effects
RATIONAL OF PERIPHERAL AT USAGE
` As cough receptors are at peripheral site
action is limited to periphery.
` As no central NT altered safer than central
antitussives
` Efficacious in cough control.
` Cough resistant to central antitussives are
manageble by peripheral antitussives.
Ta Y