2. Contents
Introduction
Definition
Mechanism of cough production
Types of cough
Classification
Antitussives MOA
Drugs
Screening methods
2
3. Introduction
Symptom of respiratory system:
no sputum---antitussives
Cough
sputum --- expectorants
Asthma ----- antiasthmatic drugs
3
4. DEFINITION
ANTITUSSIVE:-
A drug that suppresses coughing possibly by
reducing the activity of the cough center in the brain.
EXPECTORANT:-
A drug that enhances the secretion of sputum.
4
5. Cough receptors (chemo-and-mechano receptors )
lie in mucosa of the bronchial tree from the nose
to the distal bronchi.
The impulses from these receptors are
transmitted through the vagus and
glossopharyngeal nerves to the cough center in
the medulla.
5
7. Mechanism of cough production
The cough receptors lie in the mucosa of the bronchial tree.
Afferent impulses passes to the medulla.
Then an autonomic sequence of events is triggered by
medulla
causing certain effects.
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9. Classification of cough
Acute:- less than 3 weeks.
Sub-Acute:- between 3-8 weeks.
Chronic:- longer than 8 weeks.
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10. COUGH PHYSIOLOGY
Cough Reflex:-
-Initiated by irritation of sensory receptors in the
respiratory tract.
-To remove secretion of foreign objects.
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11. Coughing
Most of the time, coughing is beneficial
Removes excessive secretions
Removes potentially harmful foreign
substances
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14. ANTITUSSIVE MOA
OPIOIDS:-
Suppress the cough reflex by acting on the
cough center in the medulla.
NON-OPIODS:-
Suppress the cough reflex by numbing the
stretch receptors in the respiratory tract and preventing
the cough reflex from being stimulated
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15. ANTITUSSIVE INDICATION
Used to stop the cough reflex when the cough is
non-productive i.e dry cough.
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17. Codeine
Selectively suppress cough center in medulla oblongata.
Pharmacokinetics:
Well absorbed from oral and injection.
10% converted to morphine through demethylation.
Clinical Uses:
Dry cough
17
19. Codeine: Possible Side Effects
Shortness of breath
Sedation
Euphoria
allergic reactions
constipation
19
20. Hydrocodone
Antitussive agent
Analgesic agent
more potent than codeine
5mg of hydrocodone is equivalent to 30 mg of
codeine when administered orally
Is combined with an anticholinergic drug
(homatropine)
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28. ANIMAL MODELS
1. Antitussive activity after irritant inhalation in guinea pig.
2. Cough induced by mechanical stimulation.
3. Cough induced by stimulation of the nervus laryngicus
superior.
4. Cough induced by ammonia in the cat
5. Cough induced by sulfuric acid in the dog
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29. Antitussive activity after irritant inhalation in
guinea pig
Purpose and rationale:-
The sensitive receptars are located in bronchial tree and
stimulated mechanically and chemically.
Requirements :
Guinea pigs (300-400g),
7.5% Citric acid in water,
Test & standard substance,
Cylindrical glass vessel.
Cylindrical glass vessel
with 2 tubes at either ends. 29
30. Procedure:-
Guinea pig of either sex 300-400gm
Animal placed in cylindrical glass vessel
Guinea pig exposed to aerosol of 7.5% citric acid in water 10 min
No of tussive response is registered
One hour later test substance is applied s.c or orally
After 30 min guinea pig is subjected to aerosol again
30
31. Evaluation:-
The number of coughs after treatment is
expressed as percentage of the control period. Using
various doses ED50 values can be calculated.
31
32. Cough induce by mechanical stimulation
Purpose and rationale :
Cough can be induced by mechanical stimulation of
the trachea in anesthetized guinea pigs.
Requirements :
Thin steel wire inserted
into trachea
Male guinea pigs (350-400g), Test drug, Standard drug-codeine(
15, 30, & 60mg/kg), Thin steel wire.
32
33. Procedure :
Male guinea pigs are lightly anesthetized.
Maintain constant body temperature of 370C by means of heated plate.
Thin steel wire is gently inserted into the trachea through a small
incision near cricoid cartilage.
Coughs are evoked by pushing the steel wire to reach bifurcation of
trachea
Animals are randomly assigned to receive the test drug at various doses
or the standard (codeine 15, 30, 60mg/kg).Ten animals per dose are
used.
33
34. Evaluation :
• Evaluation of statistical significance of the result is performed
with student’s t-test.
• ED50 values determined by logit transformation.
34
35. Cough induced by stimulation of the nervus
laryngicus superior :
Purpose and rationale :
Stimulation of Nervous laryngicus superior induces
coughing. Antitussive agents with predominately central
action suppress the coughing reflex.
Requirements :
Cats of either sex(2-3kg),
Pentobarbital (40mg/kg),
Test compound,
Standard – Codeine phosphate
Fleisch tube pneumotachograph.
Fleisch tube pneumotachograph
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36. Procedure :
Cats of either sex are anesthetized.
The fur is shaved ventrally at the neck & small incisions are made at both sides
of larynx.
The trachea is cannulated. The cannula is connected with Fleisch tube
One femoral artery and one femoral vein is cannulated
Small hook electrodes are attached to each laryngeal nerve and Wave
impulses are applied every 5min (control)
Intensity of forced expiration is measured by Fleisch pneumotachograph &
recorded with blood pressure on a polygraph. The stimuli are repeated
36
37. Evaluation :
Total or partial suppression of forced
expiration are recorded over time & expressed as
percentage of control.
37
38. Cough induced by ammonia in the cat
Purpose and rationale :
Cough is induce with the help of ammonia.
Requirements :
Cats, 6% pentobarbitone sodium, smoked paper
kymograph, Tracheal cannula, ammonia vapour, polythene
tube.
38
39. Procedure :
Cats are lightly anaesthetized.
The trachea is then cannulated; The carotid artery is connected
to a mercury nanometer.
Injections are made intravenously in the femoral vein.
Coughs are recorded on a smoked kymograph by a lightly sprung
lever
Ammonia is lead into respiratory system by means of a three way
tap.
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40. The cat is allowed to inhale ammonia vapour for one inspiration.
The cough stimuli are applied every three minutes until 3 or 4
control
cough responses of similar intensity and duration are obtained.
The test drug is then administered intravenously and cough
stimuli are
repeated at similar intervals until the cough response returns to
normal.
40
41. Evaluation :
codeine is used as the antitussive standard, since it
supresses coughing completely at a dose of 2mg/kg or less.
Pholcodeine an dihydrocodeine are approximately as potent as
codeine. The test drugs are scored accordingly.
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42. Cough induced by sulfuric acid in the dog
Rationale:
Cough is induce with the help of sulfuric acid
Requirments:
Dogs, De Vilbiss nebulizers,0.5M Sulfuric acid, Codeine,
dihydrocodeine, test antitussive drugs.
42
43. Procedure:
Dogs are placed in a special wooden box.
Through two holes a fine vapour of 0.5M sulfuric acid is
sprayed.
A count of the number of coughs is obtained by listening
through earphones to a microphone attached to the dog`s
throat.
After two test periods 1 hour apart, a drug is given before the
next test period.
43
44. Evaluation:
The percent inhibition is obtained by dividing the
number of coughs by the number of coughs during the control
period.
44
45. Referensces
Vogel, W.H., Scholkens, B.A., Sandow, J., Muller, G. and Vogel
W.F.,: Drug Discovery and Evaluation Pharmacological Assays.
2nd ed. Spinger-Verlag Berlin Heidelberg, New York, Germany,
pp. 352-376 (2002).
Turner, R.A., Hebborn, P.,: Screening Methods of
Pharmacology, Vol.-1. Academic Press, London, pp. 238
(1971).
www.wikipedia.com.
Tripathi, K.D.,: Essentials of Medical Pharmacology. 5th ed.
Jaypee Brothers Medical Publishers (P)Ltd., New Delhi, India,
pp. 195, 209 (2004).
www.googleimages.com
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