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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