PHARMACOTHERAPY OF COUGH

WHAT IS COUGH?

A cough is a sudden and often repetitively occurring reflex which helps to clear the large breathing passages from secretions, irritants, foreign particles and microbesAlthough a beneficial reflex , if repeated and persistent,exhausts the patient, disturbs sleep, and become a social nuisance.

COUGH REFLEXComprise of three steps:

STEP 1 • AN INSPIRATION

STEP 2

• BUILDING UP OF PRESSURE IN THE LUNGS BY CONTRACTIONS OF EXPIRATORY MUSCLES AGAINST A CLOSED GLOTTIS

STEP 3

• FORCEFUL EXPIRATION THROUGH NARROWED AIRWAYS WITH HIGH VELOCITY OF AIRFLOW,WHICH SWEEPS IRRITANT UP TOWARD PHARYNX

CAUSES OF COUGH

1. Respiratory tract infection: cold, flu, pneumonia, bronchitis, sinusitis

2. Postnasal drip (from allergies or a cold) 3. Certain medications called ACE inhibitors used

to treat high blood pressure and heart disease: (Captopril (Capoten)

4. Allergies 5. Asthma 6. Chronic obstructive pulmonary disease

(COPD), which is from either emphysema or chronic bronchitis or both

7. Aspiration (foreign matter drawn into the lungs) 8. Congestive heart failure 9. Gastroesophageal reflux disease, where

stomach acid backs up into the esophagus 10.Cigarette smoking or exposure to secondhand

smoke

DRUG CLASSIFICATION

DRUGS FOR PRODUCTIVE COUGH

1.EXPECTORANTS:SEDATIVE EXPECTORANTS

ALKALINE EXPECTORANTS(pottasium citrate and acetate) NAUSEANT EXPECTORANTs(tincture ipecacuanha , ammonium chloride and carbonate)SALINE EXPECTORANTS(sodium and potassium iodide

STIMULANT EXPECTORANTS(creosate, terpene hydrate)

• 2.MUCOLYTICS(acetylcysteine , bromhexine , carbocyateine)

DRUGS FOR UNPRODUCTIVE COUGH

1.PERIPHERAL ANTITUSSIVES:A.DEMULCENTS(honey,lemon juice)B.STEAM INHALATION(with methanol)C.DRUGS WITH LOCAL ANESTHETICS

ACTIVITY(benzonatate)

2.CENTRAL ANTITUSSIVESA.OPOIDS ANTITUSSIVES

I. Non-addicting(codeine , pholcodeine)II. Addicting drugs(morphione , methadone ,

herion)

B.NONOPIOIDS ANTITUSSIVES(dextromethorphan )

PHARMACOTHERAPY OF COUGH

COUGH SUPPRESANTS

EXPECTORANTS

MUCOLYTICS

COUGH SUPPRESSANTS

Inhibit irritant and unproductive cough reflexAre of two types:CENTRALLY ACTING:

OPOIDS-codeine and pholcodeineNONOPOIDS-noscapine , dextromethorphan

PERIPHERALLY ACTING:Local anestheticsBenzoateDemulcents

CENTRALLY ACTING COUGH SUPPRESSANTS

OPIOIDS

CODEINE PHOLCODEINE

NONOPIOIDS

NOSCAPINE

DEXTROMETHORPH

AN

OPIOIDE AS COUGH SUPRESEANTS

They act centrally on the cough center in the brain to suppress dry hacking cough.

CODEINE:Codeine is a weak narcotic pain-reliever and cough suppressant similar to morphine and hydrocodone. In fact, a small amount of codeine is converted to morphine in the body. The precise mechanism of action of codeine is not known; however, like morphine, codeine binds to receptors in the brain (opioid receptors)

CONTD.Codeine was considered a prodrug,since it is metabolised in vivo to the primary active compounds morphine .But now 80% of codeine is conjugated withglucuronic acid to Codeine-6-glucuronide(C6G), which is the metabolite that is most responsible for codeine's analgesia. Only 5% of the dose is O-demethylated to morphine, which in turn is immediately glucuronidated at the and excreted renally.[9][10] A portion (~ 15%) of the codeine is N-demethylized to norcodeineCodeine is metabolized to C6G by uridine diphosphate glucuronosyl transferase UGT2B7,only about 5% of codeine is metabolized by cytochrome P450 to morphine.

SIDE EFFECTS OF CODEINE

The most frequent side effects of codeine include

lightheadedness, dizziness nausea, vomiting shortness of breath, and sedation. Other side effects include allergic reactions, constipation, abdominal pain, rash and itching. Codeine is habit forming. Mental and physical dependence can occur but are unlikely when used for short-term cough treatment.

PHOLCODINE-

Pholcodine is a drug which is an opioid cough suppressant (antitussive)Although structurally related to codeine, it has no opioid-like actions.

MECHANISM OF ACTION:

Pholcodine is readily absorbed from the gastrointestinal tract and freely crosses the blood-brain barrier. It acts primarily on the CNS causing depression of the cough reflex, partly by a direct effect on the cough centre in the medulla

Pharmakokinetics

Pholcodine is slowly biotransformed in the body via oxidation and conjugation to a series of metabolites that are eliminated primarily in the urine. average half-life ~ 2-3 daysmetabolized in the liver and its action may be prolonged in individuals with hepatic insufficiency (i.e. liver problems). Its use is therefore contraindicated in patients with liver disease.

SIDE EFFECTS OF PHOLCODEINE

RARE and may include dizziness and gastrointestinal disturbances such as nausea or vomiting

Adverse effects such as Constipation drowsiness, excitation, ataxia and respiratory depression have been reported occasionally or after large doses.

NON-OPIOIDS AS COUGH SUPRRESSANTS

1.NOSCAPINE

NOSCAPINE is naturally occuring non-addictive opium alkaloid.Noscapine is a very safe cough suppressant (antitussive)which has been in use for many decades In recent years,noscapine’s anti-cancer effect has been demonstratedwhen taken at doses higher than those used for cough suppression

FATE OF NOSCAPINEMODE OF ADMINISTERATION:

Noscapine can be given orally in tablets, lozenges, capsules, and syrup, and rectally in suppositories.

The common form of noscapine which is used in cough suppression is noscapine hydrochloride (Hcl) Noscapine Hcl has a half-life of 4.5 hours in the bodySIDE EFFECTS:

High doses may cause vomiting nd abdominal discomfort.

2.DEXTROMETHORPHAN

The primary use of dextromethorphan is as a cough suppressant, for the temporary relief of cough caused by minor throat and bronchial irritation (such as commonly accompanies the flu and common cold, as well as those resulting from inhaled irritants.

MECHANISM OF ACTION

At therapeutic doses, dextromethorphan acts centrally (brain) as opposed to locally (on the respiratory tract). It elevates the threshold for coughing, without inhibiting ciliary activity

PHARMOCOKINETICSFollowing oral administration, dextromethorphan is rapidly absorbed from the gastrointestinal tract, where it enters the bloodstream and crosses the blood-brain barrier.The first-pass through the hepatic portal vein results in some of the drug's being metabolized by O-demethylation into an active metabolite of dextromethorphan called dextrorphan.The therapeutic activity of dextromethorphan is believed to be caused by both the drug and this metabolite

SIDE EFFECTS OF DEXTROMETHORPHAN

1. dizziness 2. lightheadedness 3. drowsiness 4. nervousness 5. restlessness 6. nausea 7. vomiting 8. stomach pain

PERIPHERRALY ACTING COUGH SUPPRESSANTS

PERIPHERAALY ACTING COUGH SUPRRESSANTS

LOCAL ANESTHETIC

S

BENZONATATE

DEMULCANTS

LOCAL ANESTHETICSA local anesthetic is a drug that causes reversible local anesthesia and a loss of nociception.

MECHANISM OF ACTION:Local anesthetic drugs act mainly by inhibiting sodium influx through sodium-specific ion channels in the neuronal cell membrane, in particular the so-called voltage-gated sodium channels. When the influx of sodium is interrupted, an action potential cannot arise and signal conduction is inhibited. The receptor site is thought to be located at the cytoplasmic (inner) portion of the sodium channel.

LOCAL ANESTHETICS IN COUGH

1. Local anesthetics are specially useful for short duration interventions like brochoscopy , endoscopy etc which irritate pharyngeal wall and lead to cough.

2. Lignocaine or bupivacaine can be delivered by nebulizer for anesthetizing effect in respiratory passage.

BENZONATATEBenzonatate is chemically related to other ester local anesthetics such as procaine

MECHANISM OF ACTIONBenzonatate is thought to act as a local anesthetic, decreasing the sensitivity of stretch receptors in the lower airway and lung, thereby reducing the drive to cough after taking a deep breath.

USES OF BENZONATATE

An antitussive, benzonatate is employed to reduce coughing in various respiratory conditions such as, bronchitis, emphysema, influenza, and pneumonia. It should never be used to suppress a productive cough or in place of treatment of the actual cause of cough, such as asthma treatment.

FATE OF BENZONATATEThe drug will normally have an effect within 15 to 20 minutes of taking it. The effects will last for just about 3 to 8 hours Benzonatate is not to be confused with narcotics like codeine which is also used for cough suppression. Pregnancy

Category C

LactationUndetermined.

ChildrenSafety in children younger than 10 yr of age is not established.

SIDE EFFECTS OF BENZONATATEStuffed nose

Burning in the eyes Upset stomach Dizziness Constipation Drowsiness Headache Some side effects are possibly detrimental to your health. If you experience any of these rare yet serious symptoms contact your doctor immediately.

Hallucination: seeing and hearing things that aren’t really there. Rash or hives Itching Difficulty breathing or swallowing Confusion

DEMULCENTSA demulcent is an agent that forms a soothing film over a mucous membrane, relieving minor pain and inflammation of the membrane. Demulcents are sometimes referred to as Mucoprotective agents. Demulcents such as pectin, glycerin, honey and syrup are common ingredients in cough mixtures. They are useful in preventing the cough arising from dry pharynx.They also serve as household remedy. Eg. Lemon oil, Eucalyptus oil,

MECHANISM OF ACTION of DEMULCENTS

1. Forming a soothing film on the dry mucous membrane thus protect from irritant actions of air or other irritants

2. Increase salivation in respiratory tract

3. Reduce afferent impulses arising from the irritated mucosa

EXPECTORANTS

WHAT ARE EXPECTORANTS?

A medication that helps bring up mucus and other material from the lungs, bronchi, and tracheaExpectorants increase the bulk of the sputum by sensitizing the cells of the bronchial cavity and stimulates the bronchial reflux for the expulsion of the sputum.It helps in softening of the sputum making it less tenacious and hard and acting like a mucolytic agent.

TYPES OF EXPECTORANTS

1.DIRECTLY ACTING 2.INDIRECTLY ACTING

DIRECTLY ACTING EXPECTORANTS

These bring about a stimulation of the secretory cells of the respiratory tract directly.They act by producing demulcent effect which decreases irritation and also by decreasing the viscosity of the mucus. Since these drugs stimulate secretion, more fluid gets produced in respiratory tract and sputum is diluted, thereby helping in easy removal of sputum.EXAMPLE: potasium and sodium citrate, terpin hydrate

INDIRECTLY ACTING EXPECTORANTS

Act indirectly to relieve cough by irritating gastric mucosa which causes vomiting which increases respiratory tract fluid secretion thus decreasing viscosity of sputum.EXAMPLE:ammonium chloride , ipecacuanha

MUCOLYTICS

WHAT ARE MUCOLYTICS?Normally the respiratory mucus is watery.the glycoproteins in the mucus are linked by disulphide bonds to form polymers making it slimy.In respiratory diseases, the glycoproteins form larger polymers with plasma proteins present in the exudate and the secretions become thick and viscid.Mucolytics liquefy the sputum making it less viscid so that it can be easily expectorated.

VARIOUS MUCOLYTICS

BROMHEXINEACETYLCYSTEINECARBOCYSTEINEAMBROXOL

BROMHEXINE

Bromhexine is a mucolytic agent used in the treatment of respiratory disorders (eg. cough with phlegm) associated with viscid or excessive mucus.

MECHANISM OF ACTION OF BROMHEXINE

Bromhexine supports the body's own natural mechanisms for clearing mucus from the respiratory tract:

Bromhexine disrupts the structure of acid mucopolysaccharide fibres in mucoid sputum and produces a less viscous mucus, which is easier to expectorate.It promotes the function of cilia lining the airways thus promoting the promoting the transport of mucus outside the lungs

SIDE EFFECTS OF BROMHEXINE

Gastrointestinal side effects may occur occasionally with bromhexine and a transient rise in serum aminotransferase values has been reported. Other reported adverse effects include headache, vertigo (dizziness), sweating and allergic reactions.

AMBROXOLIt is metabolite of bromhexine and has similar uses and actionsIn addition to mucolytic effects It stimulates synthesis and release of surfactant by type II pneumocytes. Surfactants acts as an anti-glue factor by reducing the adhesion of mucus to the bronchial wall, in improving its transport and in providing protection against infection and irritating agents.,

ACETYLCYSTEINE

Acetylcysteine is a mucolytic agent given by mouth or inhalation of a nebulized solution in the treatment of respiratory disorders associated with the production of excessive or viscous mucus

MECHANISM OF ACTION

The mechanism of action behind the mucolytic properties of acetylcysteine appears to reside in the free sulfhydryl group of its molecular formula. it is believed that this group disrupts the disulfide chains typically found in mucus. The effect of this activity is a reduction in the viscosity of mucous secretions, making them less resistant to normal flow and discharge

ADVERSE EFFECT OF ACETYLCYSTEINE

These includeNausea , vomitingRhinorhheaHeadacheTinnitusUrticariaChills and fever

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