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ANTITUSSIVE
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Contents
Introduction
Definition
Mechanism of cough production
Types of cough
Classification
Antitussives MOA
Drugs
Screening methods
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Introduction
Symptom of respiratory system:
no sputum---antitussives
Cough
sputum --- expectorants
Asthma ----- antiasthmatic drugs
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DEFINITION
ANTITUSSIVE:-
A drug that suppresses coughing possibly byreducing the activity of the cough center in the brain.
EXPECTORANT:-
A drug that enhances the secretion of sputum.
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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.
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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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Two Basic Types of Cough
Productive cough
Congested, removes excessive secretions
Nonproductive cough
Dry cough
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Classification of cough
Acute:- less than 3 weeks.
Sub-Acute:- between 3-8 weeks.
Chronic:- longer than 8 weeks.
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COUGH PHYSIOLOGY
Cough Reflex:-
-Initiated by irritation of sensory receptors in therespiratory tract.
-To remove secretion of foreign objects.
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Coughing
Most of the time, coughing is beneficial
Removes excessive secretions
Removes potentially harmful foreignsubstances
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CLASSIFICATION1) CENTRALLY ACTING ANTITUSSIVE:-
Narcotic antitussive:-
Codeine
Hydrocodone
Oxycodone
Non-narcotic antitussive:-
Dextromethorphan
Noscapine
Propoxyphene
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CLASSIFICATION2) PERIPHERALLY ACTING ANTITUSSIVE:-
Mucosal anaesthetics:-
Benzonatate
Chlophedianol
Hydrating agents:-
Steam
Aerosols
Miscellaneous:-
Bromhexine
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ANTITUSSIVE MOA
OPIOIDS:-
Suppress the cough reflex by acting on thecough center in the medulla.
NON-OPIODS:-
Suppress the cough reflex by numbing thestretch receptors in the respiratory tract and preventingthe cough reflex from being stimulated
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ANTITUSSIVE INDICATION
Used to stop the cough reflex when the cough isnon-productive i.e dry cough.
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ANTITUSSIVE CONTRAINDICATIONS
Asthma
COPD
Hypersensitivity
Head injury
Pregnancy
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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
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Codeine: Brand Names
Codifos
Corex
Codokuff
Cufex
Tossex
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Codeine: Possible Side Effects
Shortness of breath
Sedation
Euphoria
allergic reactions
constipation
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Hydrocodone
Antitussive agent
Analgesic agent
more potent than codeine
5mg of hydrocodone is equivalent to 30 mg ofcodeine when administered orally
Is combined with an anticholinergic drug(homatropine)
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Hydrocodone: Possible Side Effects
Light-headedness
Sedation
Constipation
allergic reactions
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Dextromethorphan
Dextrorotatory stereoisomers of a methylatedderivative of levorphanol.
Clinical Use:
Dry cough.
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Dextromethorphan: Brand Names
Suppressa
Corex-DX
Cotuss
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Dextromethorphan :Possible Side Effects
Slow breathing
Confusion, hallucinations
Anxiety
Restless feeling
Nervousness
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Benzonatate
Is a non-narcotic cough medicine
It works by numbing the throat and lungs, makingthe cough reflex less active
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Benzonatate: Possible Side Effects
Headache
Drowsiness
Upset stomach
Constipation
Mild itching or skin rash
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ANIMAL MODELS
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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 laryngicussuperior.
4. Cough induced by ammonia in the cat
5. Cough induced by sulfuric acid in the dog
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Antitussive activity after irritant inhalation in guinea pig
Purpose and rationale:-
The sensitive receptars are located in bronchial tree andstimulated 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
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
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Evaluation:-
The number of coughs after treatment isexpressed as percentage of the control period. Usingvarious doses ED50 values can be calculated.
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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
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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.
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Evaluation :
• Evaluation of statistical significance of the result is performedwith student’s t-test.
• ED50 values determined by logit transformation.
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Cough induced by stimulation of the nervuslaryngicus superior :
Purpose and rationale :
Stimulation of Nervous laryngicus superior inducescoughing. Antitussive agents with predominately centralaction 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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Procedure :
Cats of either sex are anesthetized.
The fur is shaved ventrally at the neck & small incisions are made at both sidesof 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
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Evaluation :
Total or partial suppression of forced
expiration are recorded over time & expressed aspercentage of control.
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Cough induced by ammonia in the cat
Purpose and rationale :
Cough is induce with the help of ammonia.
Requirements :
Cats, 6% pentobarbitone sodium, smoked paperkymograph, Tracheal cannula, ammonia vapour, polythenetube.
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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 sprunglever
Ammonia is lead into respiratory system by means of a three waytap.
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The cat is allowed to inhale ammonia vapour for one inspiration.
The cough stimuli are applied every three minutes until 3 or 4control
cough responses of similar intensity and duration are obtained.
The test drug is then administered intravenously and coughstimuli are
repeated at similar intervals until the cough response returns to
normal.
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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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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.
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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.
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Evaluation:
The percent inhibition is obtained by dividing thenumber of coughs by the number of coughs during the controlperiod.
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Referensces
Vogel, W.H., Scholkens, B.A., Sandow, J., Muller, G. and VogelW.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 ofPharmacology, 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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