DRUGS ACTING ON RESPIRATORY SYSTEM

RESPIRATORY DISEASESAsthmaAllergic rhinitisChronic obstructive pulmonary disease

Cough

ASTHMAAsthma is characterized clinically byo Recurrent bouts of shortness of breath

o Chest tightnesso Wheezingo Reversible narrowing of bronchial airways

o Marked bronchial responsiveness to inhaled stimuli

PATHOPHSIOLOGY OF ASTHMAAsthma is a chronic inflammatory disease

of the airways that is characterized by activation of mast cells, infiltration of eosinophils, and T helper 2 (TH2) lymphocytes

Immediate cause of asthmatic bronchoconstriction is release of several mediators from the IgE sensitized mast cells

Chronic inflammation leads to marked bronchial hyperreactivity to various inhaled substances

o Lymphocytic and eosinophilic inflammation of bronchial mucosa

o Hyperplasia of secretory, vascular and smooth muscle cell

o The Th2 cytokines that are released to promote immunoglobulin (Ig)E synthesis and responsiveness in some asthmatics. IL-4 and IL-13 'switch' B cells to IgE synthesis and cause expression of IgE receptors on mast cells and eosinophils; they also enhance adhesion of eosinophils to endothelium.

ANTIBODY RESPONSE IMAGE: in the antibody (or humoral) arm of the the adaptive (acquired) immune response, the destruction of invaders is done by antibodies (immunolglobulins), shown as brick red "Y" shaped molecules at right of picture. Invading microorganisms are shown at top as golden ovoids. They are engulfed (phagocytosed) by a macrophage (green cell at top). The macrophage then presents antigens to a (purple) Helper T-Cell which in turn activates a B-Cell causing it to divide and differentiate into Plasma Cells (large bluish cells at lower left). Plasma cells have a great deal of rough endoplasmic reticulum and are devoted to protein synthesis (of antibodies). The antibodies that are released lock onto their corresponding antigens and lead to the inactivation or destruction of the invader. A dendritic cell is shown at upper left.

CLASSIFICATION OF DRUGS USED TO TREAT ASTHMA

Bronchodilators includeoBeta2 AgonistoMuscarinic antagonistoMethylxanthines

Antiinflammatory drugsSteroidsAnti IgE antibodiesLeukotriene AntagonistLipooxygenase inhibitorsLeukotirene Receptor inhibitors

STRATEGIES OF ASTHMA THERAPYAcute asthmatic bronchospasm must be treated promptly with bronchodilators. Beta 2 agonist, muscarinic antagonist, and theophylline and its derivatives are available for this indication

Long term preventive treatment requires control of inflammatory process in airways. Most important antiinflammatory drugs are corticosteroids and drugs such as cromolyn and nedocromil that inhibit release of mediators from mast cells and inflammatory cells

Long acting beta 2 agonist can improve the response to corticosteroids

Anti IgE antibodies also appear promising for chronic therapy (Omalizumab)

Leukotriene antaagonists have effects on both bronchconstriction and inflammation but are used only for prophylaxis

BRONCHODILATORSDrugs stimulating both alpha and beta receptors (adrenaline, ephedrine)

Drugs stimulating beta receptors (isoprenaline)

Selective beta 2 stimulants (salbutamol, terbutaline, salmeterol, formeterol)

EPINEPHRINE Effective, rapid acting bronchodilator Injected subcutaneously, 0.4ml of

1:1000 solution Inhaled as a microaerosol, 320 mcg

per puff Max. bronchodilation achieved in 15

min after inhalation and lasts for 60-90 min

Used in anaphylaxis Tachycardias, arrhythmias, worsening

of angina are troublesome effects

EPHEDRINEAlkaloid obtained from ephedraActs on both alpha and beta

receptorsHas long duration of actionProduces mild stimulation of CNSNow infrequently used for asthma

because of better therapies

ISOPROTERENOL (ISOPRENALINE)

Acts on beta1 and 2 receptorsPotent bronchodilator when inhaled

80-120 mcg produces max bronchodilation within 5 min

Has 60-90 min duration of action

Causes cardiac arrhythmias

BETA2 ADRENERGIC AGONISTAlbuterol, terbutaline and

metaproterenol are short acting drugsSalmeterol and formoterol are long

acting drugsMechanism of actionBeta adrenoceptor agonist stimulate

adenylyl cyclase and increases cyclic adenosine monophosphate (cAMP) in smooth muscle cells

The molecular mechanisms by which agonists induce relaxation of airway smooth muscle include: Lowering of concentration by active removal of

Ca2+ from the cytosol into intracellular stores and out of the cell

Inhibition of myosin light chain kinase activation Activation of myosin light chain phosphatase Opening of a large conductance Ca2+-activated

K+ channel, which repolarizes the smooth muscle cell and may stimulate the sequestration of Ca2+ into intracellular stores.

Other mechanisms of beta2 receptors include Prevention of mediator release from isolated

human lung mast cells (via beta2 receptors). Prevention of microvascular leakage and thus

the development of bronchial mucosal edema after exposure to mediators, such as histamine and leukotriene D4.

Increase in mucus secretion from submucosal glands and ion transport across airway epithelium; these effects may enhance mucociliary clearance, and thereby reverse the defective clearance found in asthma.

Clinical useShort-acting beta2 agonists are the

bronchodilators of choice in treating acute severe asthma.

The nebulized route of administration is easier and safer than intravenous administration and just as effective. Inhalation is preferable to the oral administration because systemic side effects are less, and inhalation may be more effective. Their effect is maximal in 15 min and lasts for 4 hrs.

Long acting drugs are used for prophylaxis. The long-acting inhaled beta2 agonists (LABA) salmeterol, formoterol, and arformoterol have proved to be a significant advance in asthma and COPD therapy. These drugs have a bronchodilator action of >12 hours and also protect against bronchoconstriction for a similar period. They improve asthma control (when given twice daily) compared with regular treatment with short-acting beta2 agonists (four to six times daily). They are used in combination with corticosteroids to improve control .

ADVERSE EFFECTS Muscle tremor due to stimulation of beta 2 receptors

in skeletal muscle is the most common side effect. It may be more troublesome with elderly patients and so is a more frequent problem in COPD patients.

Tachycardia and palpitations are due to reflex cardiac stimulation secondary to peripheral vasodilation, from direct stimulation of atrial beta 2 receptors. These side effects tend to disappear with continued use of the drug, reflecting the development of tolerance.

Hypokalemia is a potentially serious side effect. This is due to beta2 receptor stimulation of potassium entry into skeletal muscle, which may be secondary to a rise in insulin secretion.

TOLERANCE Continuous treatment with an agonist often

leads to tolerance (desensitization, subsensitivity), which may be due to down-regulation of the receptor .

Tolerance of non-airway 2 receptor–mediated responses, such as tremor and cardiovascular and metabolic responses, is readily induced in normal and asthmatic subjects.

METHYLXANTHINESMethylxanthines are purine derivativesTheophylline found in tea is the only

member used in the treatment of asthma

Mechanism of actionTheophylline inhibits phosphodiesterase

(PDE), the enzyme that degrades cAMP to AMP and thus increase cAMP

It also block adenosine receptors in CNS and inhibit sleepiness inducing adenosine

Effects on gene transcription. Theophylline prevents the translocation of the pro-inflammatory transcription factor NF-kappaB into the nucleus, potentially reducing the expression of inflammatory genes in asthma and COPD. Inhibition of NF-kappaB appears to be due to a protective effect against the degradation of the inhibitory protein. However, these effects are seen at high concentrations and may be mediated by inhibition of PDE.

Histone deacetylase activation. Recruitment of histone deacetylase-2 (HDAC2) by glucocorticoid receptors switches off inflammatory genes. Therapeutic concentrations of theophylline activate HDAC, thereby enhancing the anti-inflammatory effects of corticosteroids. This mechanism is independent of PDE inhibition or adenosine receptor antagonism and appears to be mediated by inhibition of PI3-kinase delta, which is activated by oxidative stress

Major clinical indication is asthma They are also used in prophylaxis of mild or moderate

bronchospasm Theophylline: It is poorly water soluble, hence not suitable

for injection. It is available for oral administration. The main actions of theophylline involve: relaxing bronchial smooth muscle increasing heart muscle contractility and efficiency; as a

positive inotropic increasing heart rate: positive chronotropic increasing blood pressure increasing renal blood flow some anti-inflammatory effects Central nervous system stimulatory effect mainly on the

medullary respiratory center.

Pharmacokinetics. Theophylline is distributed in the extracellular fluid,

in the placenta, in the mother's milk and in the central nervous system.

The volume of distribution is 0.5 L/kg. The protein binding is 40%. The volume of distribution may increase in neonates

and those suffering from cirrhosis or malnutrition, whereas the volume of distribution may decrease in those who are obese. Theophylline is metabolized extensively in the liver (up to 70%). It undergoes N-demethylation via cytochromeP450

Theophylline is excreted unchanged in the urine (up to 10%).

Aminophylline: It is water soluble but highly irritant. It can be administered orally. Aminophylline is less potent and shorter-acting than theophylline. Its most common use is in the treatment of bronchial asthma.

Causes bronchodilatation, diuresis, CNS and cardiac stimulation, and gastric acid secretion by blocking phosphodiesterase which increases tissue concentrations of cyclic adenine monophosphate (cAMP) which in turn promotes catecholamine stimulation of lipolysis, glycogenolysis, and gluconeogenesis and induces release of epinephrine from adrenal medulla cells

Toxicity CNS: restlessness, insomnia, headache, tremors GIT: nausea, vomiting, gastritis Heart: tachycardia, palpitation, hypotension

ANTICHOLINERGICS These drugs are now rarely used in bronchial

asthma as they often have unpleasant side effects. Some of the drugs are ipratropium bromide and tiotropium bromide. These are atropine substitutes.

They selectively block the effects of acetylcholine in bronchial smooth muscle and cause bronchodilatation. They have slow onset of action and less effective than sympathomimetic drugs in bronchial asthma.

The anticholinergics are preferred bronchodilators in COPD and often used in combination with beta2 agonists. These drugs increase air flow, alleviate symptoms and decrease exacerbation of disease. They are contraindicated in patient s with glaucoma and urinary retention.Pharmacokinetics The ipratropium is poorly absorbed after oral

administration. The drug is rapidly cleared by kidney and excreted in bile. The dose is 18 – 36 mcg (1-2 puffs) 3-4 times daily.

LEUKOTRIENE ANTAGONISTS

Leukotrienes result from action of lipooxygenase on arachidonic acid. LTC4 and LTD4 exert many effects known to occur in bronchial asthma including bronchoconstriction, increased bronchial reactivity, mucosal edema and mucus hypersecretion. Leukotriene antagonists are used to treat these diseases by inhibiting the production or activity of leukotrienes. These drugs competitively block the effects leukotrienes.

Two approaches have been pursued Inhibition of lipooxygenase, thereby

preventing leukotriene synthesis like zileuton.

Inhibition of binding of leukotriene to its receptor on target tissues, thereby preventing its action like montelukast and zafirlukast

Montelukast Montelukast is a leukotriene receptor

antagonist (LTRA) used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies. It is usually administered orally. Montelukast is a CysLT1 antagonist; that is it blocks the action of leukotrienes (and secondary ligands LTC4 and LTE4) on the cysteinyl leukotriene receptor CysLT1 in the lungs and bronchial tubes by binding to it. This reduces the bronchoconstriction otherwise caused by the leukotriene and results in less inflammation.

Clinical uses Montelukast is used for the treatment of asthma

and seasonal allergic rhinitis. Montelukast begins working after 3 to 14 days of therapy. Therefore, it should not be used for the treatment of an acute asthmatic attack.

Side effects The most common side effects with montelukast

are headache, dizziness, abdominal pain, sore throat, and rhinitis (inflammation of the inner lining of the nose). These side effects occur in 1 in 50 to 1 in 7 persons who take montelukast. Rarely, patients may experience nose bleeds.

Zafirlukast Zafirlukast is an oral leukotriene receptor

antagonist (LTD4) for the maintenance treatment of asthma, often used in conjunction with an inhaled steroid and/or long-acting bronchodilator. It is available as a tablet and is usually dosed twice daily.

Zafirlukast blocks the action of the cysteinyl leukotrienes on the CysLT1 receptors, thus reducing constriction of the airways, build-up of mucus in the lungs and inflammation of the breathing passages.

A single oral dose of 40 mg of zafirlukast attaining peak plasma concentrations of about 607 μg/L at 3.4 hours. The elimination half-life ranged from 12 to 20 hours.

ZILEUTON Zileuton is an orally active inhibitor of 5-lipoxygenase,

and thus inhibits leukotrienes (LTB4, LTC4, LTD4, and LTE4) formation. Zileuton is used for the maintenance treatment of asthma.

Pharmacokinetics Following oral administration zileuton is rapidly

absorbed with a mean time to peak serum concentration of 1.7 hours and an average half-life elimination of 2.5 hours.

The apparent volume of distribution of zileuton is approximately 1.2 L/kg. Zileuton is 93% bound to plasma proteins, primarily to albumin.

Elimination of zileuton is primarily through metabolites in the urine (~95%). The drug is metabolized by the cytochrome P450 enzymes

Clinical uses Zileuton is indicated for the prophylaxis and chronic

treatment of asthma in adults and children 12 years of age and older. Zileuton is not indicated for use in the reversal of bronchospasm in acute asthma attacks. Therapy with zileuton can be continued during acute exacerbations of asthma.

The recommended dose of 600 mg tablet, four times per day. The tablets may be split in half to make them easier to swallow. The recommended dose extended-release tablets is 2400 mg twice daily.

Research on mice suggests that Zileuton used alone or in combination with imatinib may inhibit chronic myeloid leukemia (CML).

Side effects The most common adverse reactions

reported by patients treated with zileuton were sinusitis and nausea

The most serious side effect zileuton is potential elevation of liver enzymes (in 2% of patients). Therefore, zileuton is contraindicated in patients with active liver disease or persistent hepatic function enzymes elevations

Neuropsychiatric events, including sleep disorders and behavioral changes, may occur.

Drug interactions Zileuton is a weak inhibitor of cytochrome

P450 and thus has three clinically important drug interactions, which include increasing warfarin, theophylline, and propranolol levels.

It has been shown to lower theophylline clearance significantly, doubling the AUC and prolonging half-life by nearly 25%.

Warfarin metabolism and clearance is mainly affected by zileuton. This can lead to an increase in prothrombin time.

CORTICOSTEROIDS All corticosteroids are potentially beneficial in

severe asthma; however, because of their toxicity systemic (oral) corticosteroids are used chronically only when other therapies are unsuccessful.

Local aerosol administration of corticosteroids (e.g beclomathasone, dexamethasone, fluticasone, mometasone) is relatively safe, and inhaled corticosteroids have become first line therapy for individuals with moderate to severe asthma.

Important intravenous corticosteroids for status asthamaticus include prednisolone and hydrocortisone.

Mechanism of action Corticosteroids reduce the synthesis of arachidonic acid

by phospholipase A2, and inhibit the expression of COX -2. It has been suggested that corticosteroids increase the responsiveness of beta adrenoceptors in the airway.

Effects Glucocorticoids bind to intracellular receptors and

activate glucocorticoid response elements in the nucleus, resulting in the synthesis of substances that prevent the full expression of inflammation and allergy. Reduced activity of phospholipase A2 is thought to be particularly important in asthma because the leukotrienes that result from eicosanoid synthesis are extremely potent bronchoconstrictiors and may also participate in the inflammatory response

Clinical uses Inhaled glucocorticoids are now considered appropriate

(even for children) in most cases of moderate asthma that are not fully responsive to aerosol β agonists.

In cases of severe asthma, patients are usually hospitalized and stabilized on daily systemic prednisone and then switched to inhaled or alternate- day oral therapy before discharge.

In status asthmaticus parenteral steroids are lifesaving and apparently act more promptly than in ordinary asthma

Intravenous steroids are indicated in acute asthma if lung function is <30% predicted and in patients who show no significant improvement with nebulized 2 agonist. Hydrocortisone is the steroid of choice because it has the most rapid onset (5-6 hours after administration).

Toxicity Life threatening toxicities include metabolic effects

(diabetes, osteoporosis), salt retention and psychosis. Changes in oropharyngeal flora result in candidiasis Frequent aerosol administration can cause a very

small degree of adrenal suppression. In case of oral therapy adrenal suppression can be reduced by using alternate- day therapy.

Inhaled corticosteroids may have local side effects due to the deposition of inhaled steroid in the oropharynx. The most common problem is hoarseness and weakness of the voice (dysphonia) due to atrophy of the vocal cords following laryngeal deposition of steroid

CROMOLYN AND NEDOCROMIL (MAST CELL STABILIZERS) Cromolyn (disodium cromoglycate) and

nedocromil are unusually insoluble chemicals.

They are given by aerosol for asthma. Cromolyn is the prototype of this group.

Mechanism of action It involves a decrease in the release of

mediators (such as leukotrienes and histamine) from the mast cells. The drugs donot have bronchodilator action but can prevent bronchoconstriction caused by antigen to which the patient is allergic

Effects They are not absorbed from the site of

administration, cromolyn and nedocromil have only local effects.

When administered orally, cromolyn has some efficacy in preventing food allergy.

Similar actions were noted after local application in conjunctiva and nasopharynx for allergic IgE mediated reactions in these tissues.

Clinical uses It is used in asthma especially in children Nasal and eye drop formulations are

available for hay fever Oral formulation is used for food allergy Toxicity Cromolyn and nedocromil may cause cough

and irritation of the airway when given by aerosol.

Rare instances of drug allergy have been reported.

ANTI- IGE ANTIBODY Omalizumab It is a recombinant DNA- derived monoclonal

antibody that selectively binds to human IgE. It binds to the IgE on sensitized mast cells and

prevents activation by asthma triggers and subsequent release of inflammatory mediators.

Omalizumab may be particularly useful for the treatment of moderate to severe allergic asthma in patients who are poorly controlled with conventional therapy.

It was approved in 2003 for the prophylactic management of asthma. It is very expensive and must be administered parenterally.

DRUGS USED TO TREART CHRONIC OBSTRUCTIVE PULMONARY DISEASE Chronic obstructive pulmonary disease (COPD)

is a chronic, irreversible obstruction of air flow. Smoking is the greatest risk factor for COPD and is directly linked to the progressive decline of the lung function.

In COPD, there is a predominance of neutrophils, macrophages, and cytotoxic T-lymphocytes (Tc1 cells). The inflammation predominantly affects small airways, resulting in progressive small airway narrowing and fibrosis (chronic obstructive bronchiolitis) and destruction of the lung parenchyma with destruction of the alveolar walls (emphysema)

Emphysema is a pathological condition sometimes associated with COPD, in which lung parenchyma is destroyed and replaced by air spaces that coalesce to form bullae-blister-like air-filled spaces in the lung tissue.

These pathological changes result in airway closure on expiration, leading to air trapping and hyperinflation. This accounts for shortness of breath on exertion and exercise limitation that are characteristic symptoms of COPD.

Inhaled bronchodilators, such as anticholinergic agents (ipratropium and tiotropium) and beta2 adrenergic agonists are the foundation of therapy for COPD.

Longer acting drugs such as salmeterol and tiotropium have the advantage of less frequent dosing and together provide synergistic effect. They improve the lung function and provide a better relief in COPD.

Theophylline can be given by mouth but is of uncertain benefit. Its respiratory stimulant effect may be useful for patients who tend to retain CO2. Other respiratory stimulants (e.g. doxapram; are sometimes used briefly in acute respiratory failure (e.g. postoperatively) but have largely been replaced by ventilatory support

SURFACTANTS Pulmonary surfactants act as a result of their

physicochemical properties within the airways rather than by binding to specific receptors. They are effective in the prophylaxis and management of respiratory distress syndrome in newborn babies, especially if premature. Examples include beractant and poractant alpha which are derivatives of the physiological pulmonary surfactant protein. They are administered directly into the tracheobronchial tree via an endotracheal tube

ALLERGIC RHINITIS Hay fever; Nasal allergies Rhinitis is characterized by sneezing, itchy nose/eyes,

watery rhinorrhea and nasal congestion Allergic rhinitis is a group of symptoms affecting the

nose. These symptoms occur when you breathe in something you are allergic to, such as dust, dander, insect venom, or pollen.

When a person with allergic rhinitis breathes in an allergen such as pollen or dust, the body releases chemicals, including histamine. This causes allergy symptoms.

Hay fever involves an allergic reaction to pollen. A similar reaction occurs with allergy to mold, animal dander, dust, and other allergens that you breathe in.

Symptoms that occur shortly after you come into contact with the substance you are allergic to may include:

Itchy nose, mouth, eyes, throat, skin, or any area Problems with smell Runny nose SneezingSymptoms that may develop later include: Stuffy nose (nasal congestion) Coughing Clogged ears and decreased sense of smell Sore throat Dark circles under the eyes Puffiness under the eyes Fatigue and irritability Headache

Antihistamines Over-the-counter antihistamines --

Include diphenhydramine, chlorpheniramine, clemastine. These older antihistamines can cause sleepiness. Loratadine, cetrizine, and fexofenadine do not cause as much drowsiness as older antihistamines.

Long acting drugs: These medications are longer-acting than over-the-counter antihistamines and are usually taken once a day. They include desloratadine

H1 receptor blockers have major application in allergies of the immediate type. These conditions include hay fever and urticaria. The side effects include dry mouth/ eyes, difficult urinating and defecating. These effects are transient and may resolve in 7 -10 days

Corticosteroids These prescription sprays reduce

inflammation of the nose and help relieve sneezing, itching, and runny nose. It may take a few days to a week to see improvement in symptoms.

Beclomethasone Fluticasone Mometasone Triacinolone

Cromolyn sodium This over-the-counter nasal spray prevents

the release of histamine and helps relieve swelling and runny nose. It works best when taken before symptoms start and may needed to be used several times a day.

Nasal atropine Ipratropium bromide is a prescription nasal

spray that can help relieve a very runny nose. People with glaucoma should not use this.

DECONGESTANTS Oral and nasal decongestants – Decongestants help to shrink the blood

vessels in the nasal membranes and allow the air passages to open up. Decongestants are chemically related to adrenaline, the natural decongestant, which is also a type of stimulant. Therefore, the side effect of decongestants taken as a pill or liquid is a jittery or nervous feeling, causing difficulty in going to sleep and elevating blood pressure and pulse rate.

Some decongestants may contain pseudoephedrine, which can raise blood pressure. People with high blood pressure should not take drugs containing pseudoephedrine. Using nasal decongestant sprays for more than 3 days can cause "rebound congestion," which makes congestion worse. Do not use them if emphysema or chronic bronchitis is present.

PHENYLEPHRINE Phenylephrine is an alpha 1 receptor agonist.

It causes vasoconstriction of the vessels of the nose and helps decreasing the mucus formation in the nasal cavity.

Phenylephrine is used to relieve nasal discomfort caused by colds, allergies, and hay fever. It is also used to relieve sinus congestion and pressure. Phenylephrine will relieve symptoms but will not treat the cause of the symptoms or speed recovery.

COUGH Cough is a protective reflex that removes

foreign material and secretions from the bronchi and bronchioles.

Cough can be triggered by inflammation in the respiratory tract, for example by undiagnosed asthma or chronic reflux with aspiration, or by neoplasia or by any bacterial infection.

Types of cough1. Unproductive (dry cough)2. Productive (associated with large amounts

of sputum)

DRY COUGH Stimulation of mechanoreceptors in the

tracheobronchial tree and the lung and chemoreceptors from the lung generate impulses which are carried via the glossopharyngeal and vagus nerve as afferent impulse to cough center and efferent impulses are carried via the parasympathetic and motor nerves to the diaphragm intercostal muscles and lungs. Irritation to the bronchial tract generate these impulses and trigger cough center to produce dry cough.

In these cases, cough suppressant (antitussive) drugs are sometimes useful, for example for the dry painful cough associated with bronchial carcinoma.

Antitussives should be avoided in cases of chronic pulmonary infection, as they can cause undesirable thickening and retention of sputum, and in asthma because of the risk of respiratory depression.

Dry cough is a very common adverse effect of angiotensin-converting enzyme inhibitors, in which case the treatment is usually to substitute an alternative drug, notably an angiotensin receptor antagonist which less likely cause this adverse effect.

PRODUCTIVE COUGHA classic symptom of productive cough is coughing with sputum or phlegm production. Phlegm usually contains mucus with bacteria, debris or dead tissue, and sloughed-off cells. Other symptoms include heaviness in the chest, slight to severe breathlessness. In some cases a person may even have fever, runny nose and drainage of mucus into the throat.

The airway mucosa responds to infection and inflammation in a variety of ways. This response often includes surface mucous (goblet) cell and submucosal gland hyperplasia and hypertrophy, with mucus hypersecretion.

Products of inflammation, including neutrophil-derived deoxyribonucleic acid (DNA), bacteria, and cell debris all contribute to mucus purulence. Expectorated mucus is called sputum. Mucus is usually cleared by ciliary movement, and sputum is cleared by cough.

Productive cough can be caused due to a number of factors. Some of them include viral or bacterial lung infections like in the case of a common cold. Other more serious diseases like asthma, pneumonia, chronic obstructive pulmonary disease (COPD), lung abscesses or other conditions like bronchiectasis could manifest as productive cough. 

MUCOACTIVE MEDICATIONS The general term for medications that are meant to

affect mucus properties and promote secretion clearance is “mucoactive.”

Mucoactive medications include expectorants, mucolytics, and mucokinetic drugs.

1. Expectorants are defined as medications that improve the ability to expectorate purulent secretions.

2. Mucolytics are medications that change the biophysical properties of secretions by degrading the mucin polymers, DNA and fibrin in airway secretions, generally decreasing viscosity.

3. A mucokinetic medication is a drug that increases mucociliary clearance, generally by acting on the cilia.

ANTITUSSIVES Antitussives are drugs that are used to suppress

the cough center in the medulla and are given for symptomatic relief

Antitussives are classified as Centrally acting drugs They act directly in the medulla on the cough

center. These includeNarcotics: these are controlled substances,

because they are drugs of abuse Morphine: It is an effective antitussive but is

liable to prooduce depression of respiratory center. It can relieve cough but is not used due to its addictive properties

CODEINE Codeine or 3-methylmorphine is a natural

isomer of methylated morphine. Codeine is the second mos predominant alkaloid in opium i.e upto 3%. It is a moderate agonist of mu receptors

It has antitussive and sedative action. It is analgesic but in higher doses.

Common adverse effects include euphoria, itching, nausea, vomiting, drowsiness, dry mouth, urinary retention, constipation, miosis and orthostatic hypotension.

Chronic use of codeine can cause withdrawal symptoms as it causes physical dependence. When physical dependence ha developed withdrawal symptoms may occur if a person suddenly stops the medication.

Withdrawal symptoms include drug craving, cramps, nausea, vomiting, diarrhea, muscle spasms, chills, irritability and pain.

PHOLCODINE It is a semisynthetic derivative of codeine.

The antitussive effect of 10 mg of pholcodine is comparable to 15mg of codeine. The cough of any origin can be suppressed effectively.

The onset of action is 15 minutes after parenteral dose and 30 minutes after oral dose remain for n4 hrs.

Nausea and drowsiness can occur

DEXTROMETHORPHAN HYDROBROMIDE It is a semisynthetic compound with

minimum addiction properties. It is used for dry and painful cough. It has no analgesic properties.

It s given in dose of 10-30 mg 3-4 times daily. At therapeutic doses, dextromethorphan acts

centrally and elevates the threshold of the stimulation of cough center.

It is rapidly absorbed from gastrointestinal tract and converted into active metabolite dextrophan in the liver.

It causes drowsiness, mental confusion, nausea, body rash and itching.

NOSCAPINE The opium alkaloid belonging to the

benzylisoquinoline group antitussive action equal to that of codeine.

It doesn’t produce constipation and drowsiness. The common side effect includes nausea.

Antitussive dose is 15-30 mg 3-4 times daily.LEVOPROPOXYPHENEo The levo isomer of propoxyphene has

antitussive action in a dose of 50-100 mg. It is a centrally acting agent and depresses the cough center to relieve dry cough.

NON NARCOTIC ANTITUSSIVESAntihistamines These include promethazine, chlorpheniramine,

diphenhydramine. Anithistamines suppress cough by suppressing the cough center but they dry the secretions. They are mostly given in cough associated with cold systems.

Carbetapentane (pentoxyverine)It acts peripherally on the mucous membrane of the respiratory tract and exert a local anesthetic action.It acts centrally as well by suppressing the cough center therefore also therefore also classified under non narcotic It has atropine like effects causing dry mouth, blurred vision.

Benzonatate Benzonatate acys as 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.

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 cough associated with asthma.

Side effects include drowsiness and dizziness.

EXPECTORANTS Expectorants are defined as medications that

improve the ability to expectorate purulent secretions. This term is now taken to mean medications that increase airway water or the volume of airway secretions, including

1. Secretagogues, that are meant to increase the hydration of luminal secretions (eg, hypertonic saline or mannitol)

2. Abhesives that decrease the adhesivity of secretions and thus unstick them from the airway (eg, surfactants).

The most commonly used expectorants are simple hydration, including bland aerosol oral hydration iodide-containing compounds such as super-

saturated potassium iodide or iodinated glycerol,

glyceryl guaiacolate (guaifenesin) and the more recently developed ion-channel

modifiers such as the purinergic agonists.

Dehydration might increase the tenacity of secretions by increasing adhesivity. The more secretions adhere to the epithelium, the more difficult they are to cough up. If there was an effective way to rehydrate the surface of dry secretions, this would be of benefit. Most of these medications and maneuvers are ineffective at adding water to the airway, and those that are effective are also mucus secretagogues that increase the volume of both mucus and water in the airways.

Saline Expectorants 7% hypertonic saline increases the volume of the

secretions and hydration. Ammonium salts and sodium bicarbonate have

also been used as saline expectorants. They increase the hydration.

Ammonium chloride causes gastric irritation and may cause nausea, vomiting , thirst and headache. The dose is 300mg 3-4 times daily.

Sodium bicarbonate s used for tracheal irrigation or as an aerosol.

Dry mannitol powder also increases mucus secretion.

Potassim salts of iodide and iodinated glycerol

These are directly acting exprectorants . After absorption they reach the bronchial mucus membrane and stimulate the bronchial glands to secrete mucus.

Use of potassium iodide leads to unpleasant hypersecretions in the eyes, nose and mouth. Skin rashes may appear.

The dose is 0.3g 3-4 times daily.

Surfactant can reduce sputum adhesivity and increase the efficiency of energy transfer from the cilia to the mucus layer.

Ambroxol has been thought to stimulate surfactant secretion, and has been used for many years in Europe for the management of chronic bronchitis, but it has never been approved in the United States or Canada.

VOLATILE OILS Volatile oils like oil of eucalyptus, oil of anise

and lemon oil are taken on the form of steam. All are mild respiratory antiseptic and act directly on the secretory cells of the respiratory tract and increase the secretions.

Terpenes portion of camphor, thymol and menthol also cause mild reversible anesthesia of the respiratory tract.

MUCOLYTICS Mucolytics are medications that change the

biophysical properties of secretions by degrading the mucin polymers, DNA, fibrin, or F-actin in airway secretions, generally decreasing viscosity.

Classic Mucolytics Classic mucolytics depolymerize the mucin

glycoprotein oligomers by hydrolyzing the disulfide bonds that link the mucin monomers. This is usually accomplished by free thiol (sulfhydryl) groups, which hydrolyze disulfide bonds attached to cysteine residues of the protein core.

N ACETYL CYSTEINE This is a derivative of naturally occuring

aminoacid, 1-cysteine It improves the ability to expectorate mucus.

Acetylcysteine can decrease mucus viscosity in vitro, but, because oral acetylcysteine is rapidly inactivated and does not appear in airway secretions, it is ineffective in vivo. It is given by inhalation as aerosol.

It depolymerises the mucin glycoprotein oligomers by hydrolyzing disulfide polymers that link mucin polymers.

Published evidence suggests that oral acetylcysteine may improve pulmonary function in selected patients with chronic lung disease, including chronic obstructive pulmonary disease (COPD), but the clinical benefit observed is probably due to antioxidant properties.

Daily use of acetylcysteine reduces the risk of re-hospitalization for COPD exacerbation by approximately 30%

It may cause fever, gastric irritation, nausea, urticaria and rhinorrhea

PEPTIDE MUCOLYTICS The mucin polymer network is essential for

normal mucus clearance. It may be that the classic mucolytics are generally ineffective because they depolymerize essential components of the mucus gel. With airway inflammation and inflammatory cell necrosis, a secondary polymer network of DNA and F-actin develops in purulent secretions. In contrast to the mucin network, this pathologic polymer gel serves no obvious purpose in airway protection or mucus clearance.

The peptide mucolytics are designed specifically to depolymerize the DNA polymer (dornase alfa) or the F-actin network (eg, gelsolin, thymosin 4) and are most effective when sputum is rich in DNA pus.

MUCOKINETIC AGENTS A mucokinetic medication is a drug that

increases mucociliary clearance, generally by acting on the cilia. Although a variety of medications, such as tricyclic nucleotides, beta agonist bronchodilators, and methylxanthine bronchodilators, all increase ciliary beat frequency, these agents have only a minimal effect on mucociliary clearance in patients with lung disease

BROMOHEXINE (BISOLVON) Bromohexine is a mucolytic agent used in the treatment

of respiratory disorders associated with viscid or excessive mucus. It has antioxidant properties as well.

It is a synthetic derivative of the herbal active ingriedient vasicine from the plant Adhatoda vasica.

It has been shown to increase the proportion of serous bronchial secretions, making it more easily expectorated.

Bromohexine also enhances mucus transport by reducing mucus viscosity and by activating the ciliated epithelium.

Bromohexine showed secretolytic and secretomotoric effects in bronchial tract area which facilitates expectoration and eases cough.

It is usually administered in dose of 8-16 mg 3-4 times daily.