This document discusses antitussive drugs, which are used to suppress coughing. It defines antitussives and expectorants, and describes the mechanism of cough production involving cough receptors in the lungs and the cough center in the medulla. It classifies cough and antitussives, and discusses the mechanisms of action and indications of centrally- and peripherally-acting antitussives. Common antitussives discussed include codeine, hydrocodone, dextromethorphan, and benzonatate. The document also describes several animal models used to screen for antitussive effects, such as measuring coughs induced by irritants in guinea pigs and mechanical stimulation in anesthetized guinea pigs and cats.

1. ANTITUSSIVE
1

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

6. 6

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.
7

8. Two Basic Types of Cough
 Productive cough
 Congested, removes excessive secretions
 Nonproductive cough
 Dry cough
8

9. Classification of cough
 Acute:- less than 3 weeks.
 Sub-Acute:- between 3-8 weeks.
 Chronic:- longer than 8 weeks.
9

10. COUGH PHYSIOLOGY
 Cough Reflex:-
-Initiated by irritation of sensory receptors in the
respiratory tract.
-To remove secretion of foreign objects.
10

11. Coughing
Most of the time, coughing is beneficial
 Removes excessive secretions
 Removes potentially harmful foreign
substances
11

12. CLASSIFICATION
1) CENTRALLY ACTING ANTITUSSIVE:-
Narcotic antitussive:-
Codeine
Hydrocodone
Oxycodone
Non-narcotic antitussive:-
Dextromethorphan
Noscapine
Propoxyphene
12

13. CLASSIFICATION
2) PERIPHERALLY ACTING ANTITUSSIVE:-
Mucosal anaesthetics:-
Benzonatate
Chlophedianol
Hydrating agents:-
Steam
Aerosols
Miscellaneous:-
Bromhexine
13

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
14

15. ANTITUSSIVE INDICATION
 Used to stop the cough reflex when the cough is
non-productive i.e dry cough.
15

16. ANTITUSSIVE CONTRAINDICATIONS
 Asthma
 COPD
 Hypersensitivity
 Head injury
 Pregnancy
16

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

18. Codeine: Brand Names
 Codifos
 Corex
 Codokuff
 Cufex
 Tossex
18

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)
20

21. Hydrocodone:
Possible Side Effects
 Light-headedness
 Sedation
 Constipation
 allergic reactions
21

22. Dextromethorphan
 Dextrorotatory stereoisomers of a methylated
derivative of levorphanol.
 Clinical Use:
 Dry cough.
22

23. Dextromethorphan: Brand Names
 Suppressa
 Corex-DX
 Cotuss
23

24. Dextromethorphan :Possible Side Effects
 Slow breathing
 Confusion, hallucinations
 Anxiety
 Restless feeling
 Nervousness
24

25. Benzonatate
 Is a non-narcotic cough medicine
 It works by numbing the throat and lungs, making
the cough reflex less active
25

26. Benzonatate: Possible Side Effects
 Headache
 Drowsiness
 Upset stomach
 Constipation
 Mild itching or skin rash
26

27. ANIMAL MODELS
27

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
28

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 :
Male guinea pigs (350-400g), Test drug, Standard drug-
codeine(15, 30, & 60mg/kg), Thin steel wire.
Thin steel wire inserted
into trachea
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
35

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.
39

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.
41

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
45

46. THANK YOU
46

47. BACK UP SLIDES
47