Drugs for Cough and Bronchial Asthma

Submitted by : Navlika Dutta

Cough is a protective reflex, its purpose being expulsion of respiratory secretions or foreign particles from air passages. Occurrence: due to stimulation of mechanoor chemoreceptors in throat, respiratory passages or stretch receptors in the lungs. Useless/useful cough.

Pharyngeal demulcents : Lozenges, cough drops, linctuses containing syrup, glycerine, liquorice. Expectorants ( Mucokinetics) : Bronchial secretion enhancers: Sodium or Potassium citrate, Potassium iodide, Guaiphenesin, Balsam of Tolu, Vasaka, Ammonium chloride. Mucolytics: Bromohexine, Ambroxol,Acetyl cysteine, Carbocisteine. Antitussives ( Cough centre suppressants): Opioids: Codeine, Pholcodeine.

Non opioids: Noscapine, dextromethorphan, chlophedianol. Antihistamines : Chlorpheniramine, Diphenhydramine,Promethazine. Adjuvant antitussives: Bronchodilators : Salbutamol, Terbutalin.

Soothe inflamed/ irritated pharyngeal mucosa Decrease the afferent impulses arising from throat Provide symptomatic relief from dry cough arising from throat.
-Lozenges, cough drops, linctuses containing syrups, glycerine, liquorice

Expectorants are the drugs believed to increase bronchial secretion or reduce its viscosity, facilitating its removal by coughing. Cough is less tiring and more productive

Na and K citrate- increase bronchial secretion by salt action Guaicol obtained from wood, increases bronchial secretion and mucosal

ciliary action, guaiphenesin is less irritant derivative. Tolu balsam and vasaka also act by the same mechanism KI- irritates bronchial glands and increases secretion. Also gastric irritant and reflexly increases bronchial secretions. Less popular as
Bronchial irritant- not safe if bronchial mucosa is inflamed Some patients are sensitive to iodine Adolescents- cause acne Pregnant and lactating women- child may get goitre/ hypothyroidism Prolonged use- can cause goitre, hypothyroidism

Ammonium salts and Syrup Ipecac- gastric irritants, reflexly enhance

bronchial secretions.

Bromohexine- derivative of vasicine- an alkaloid from Adhathoda vasica. Potent mucolytic and mucokinetic. Copious secretions produced, depolymerising mucopolysaccharides directly as well as by releasing lysosomal enzymes.Network of fibres in tenacious sputum broken down.
S/E- rhinorrhoea, lacrymation.

Acetylcysteine breaks disulfide bonds of mucopolysaccharides in sputum and makes it less viscid.
Aerosol/ tracheal instillation. Carbocisteine can be given orally.

Drugs that act on CNS to raise the threshold of cough centre and/or act peripherally on the respiratory tract to reduce tussive impulses. Only used for dry, unproductive cough, or if cough is unduly tiring, disturbs sleep or is hazardous (likely to cause hernia, piles, cardiac disease).

 Codeineopium alkaloid, similar to morphine but less potent. More selective for cough centre, suppresses it for more than 6 hrs. Antitussive action blocked by naloxone (opioid antagonist), so opioid receptors may be involved. Abuse potential low but present, constipation, drowsiness. Higher doses respiratory depression. Contraindicated in asthmatics and patients with low respiratory reserve.

Pholcodeine- no analgesic or addicting property. Like

codeine, acts for 12 hrs. Ethylmorphine- same as codeine.

 Noscapine- opium alkaloid

Depresses cough, nearly potent as codeine, used in spasmodic cough. No analgesic, narcotic/ dependence inducing properties. S/E- Headache, nausea. Releases histamine, causes bronchoconstriction in asthmatics Dextromethorphanantitussive action not blocked by naloxone- so not mediated through opioid receptors No constipating or addicting action S/E- Dizziness, nausea Carbetapentane, oxeladin etc- devoid of addicting actions.

H1 antihistaminic actions provide relief by sedative

and antichoinergic actions No expectorant action, no selectivity for cough centre, may reduce secretions due to anticholinergic action Promoted for cough in respiratory allergy states. Not effective in asthma First generation antihistaminic drugs like chlorpheniramine, diphenhydramine and promethazine commonly used. Second generation antihistaminics not effective

Relieve cough in patients with bronchial hyperreactivity by relieving bronchoconstriction and clearing secretions by increasing superficial velocity of cough.

Asthma is characterised by chronic airway inflammation and increased airway hyperresponsiveness leading to symptoms of wheeze, cough, chest tightness and dyspnoea. It is characterised functionally by the presence of airflow obstruction which is variable over short periods of time, or is reversible with treatment. Characterized by hyper-responsiveness of tracheobronchial smooth muscle to stimuli Results in narrowing of air tubes, increased secretions, mucosal edema and mucus plugging

The prevalence of asthma increased steadily over the latter part of the last century in countries with a Western lifestyle and is also increasing in developing countries. Current estimates suggest that 300 million people world-wide suffer from asthma and an additional 100 million may be diagnosed with asthma by 2025. In childhood, asthma is more common in boys, but following puberty females are more frequently affected. The socio-economic impact of asthma is enormous, particularly when poor control leads to days lost from school or work, hospital admissions and, for some patients, a premature death.

Dietary intake may be important. Milk fat and antioxidants such as vitamin E and selenium may protect against the development of asthma in children; however, in other studies early exposure to cows' milk protein has been linked to the development of atopy and asthma. higher levels of Lactobacillus in the gut may protect against the development of atopic disease.

The increase in asthma may also be linked to the rise of obesity in Western society through mechanical mechanisms such as gastro-oesophageal reflux. Shared genetic traits modification of the immune system by diet, or alteration of airway responsiveness by hormones are, however, alternative explanations.

In some circumstances the appearance of asthma relates to the use of medications. Beta-adrenoceptor antagonists (-blockerseven when administered topically as eye drops) may induce bronchospasm. Aspirin and other non-steroidal antiinflammatory drugs are associated with asthma in about 10% of patients.

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extrinsic External factor identifiable Serum shows high levels of IgE &IgG

Intrinsic(cryptogenic) No such factor No raised Ab levels but increased eosinophils present ,aspirin sensitivity, & presence of nasal polyp

Atopic manifestations may be present

Dermatological and respiratory s/s show a see-saw relationship Positive family history present Affects persons of 10-15 yrs

No atopy
Not associated with skin s/s

Affects persons over 40 yrs

Causes House dust Pollen Fungi Animal hairs Insect scales Fumes and drugs food Infection with respiratory syncitial virus Exercise induced asthma Exposure to cold

Once sensitization occurs these antigens release chemical mediators from the mast cells by interacting with the IgE molecules on their surfaceType 1 hypersensitivity reactionimmediate asthmatic paroxysm Some times type 3 hypersensitivity reaction also occurs and it is mediated by IgG delayed paroxysm
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The inhalation of an allergen in a sensitised atopic asthmatic patient results in a two-phase bronchoconstrictor response . The inhaled allergen rapidly interacts with mucosal mast cells via an IgE-dependent mechanism, resulting in the release of mediators such as histamine and the cysteinyl leukotrienes with resulting bronchoconstriction. In persistent asthma a chronic and complex inflammatory response ensues, which is characterised by an influx of numerous inflammatory cells, the transformation and participation of airway structural cells, and the secretion of an array of cytokines, chemokines and growth factors

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Airflow limitation Usually reverses spontaneously or with treatment Airway hyper-reactivity Exaggerated bronchoconstriction to a wide range of non-specific stimuli, e.g. exercise, cold air Airway inflammation :Eosinophils, lymphocytes, mast cells, neutrophils; associated oedema, smooth muscle hypertrophy and hyperplasia, thickening of basement membrane, mucous plugging and epithelial damage
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With increasing severity and chronicity of the disease, remodelling of the airway occurs, leading to fibrosis of the airway wall, fixed narrowing of the airway and a reduced response to bronchodilator medication

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Typical symptoms include recurrent episodes of breathlessness wheezing, cough. chest tightness

Common precipitants include exercise, particularly in cold weather,

exposure to airborne allergens

pollutants viral upper respiratory tract infections (beware the cold that

'goes to the chest' or takes more than 10 days to clear).

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Inflammatory disease Allergic basis only 10 % in adults Infections, irritants, pollution, psychogenic, cold air etc Initial reaction release of inflammatory mediators- histamine, PGs, LTs from mast cells neutrophils, eosinophils, macrophages, Tlymphocytes recruited Results in bronchoconstriction, mucosal edema, hyperemia, viscid secretions airway obstruction. More inflammatory mediators like cytokines released more inflammatory cells recruited increased hyperreactivity. Vagal reflexes also increased

Prevention of Ag:Ab reaction- avoid antigen if known Nonspecific reduction of bronchial hyperreactivitycorticosteroids Prevention of release of inhibitors- mast cell stabilizers Antagonism of released mediators- antihistamines, leukotriene antagonists Blockade of constrictor neurotransmitter- anticholinergic drugs Mimicking dilator neurotransmitter- sympathomimetics Directly acting bronchodilators- methylxanthines

Bronchodilators
I. Sympathomimetic b-agonists

Albuterol (Ventolin) Bitolterol (Tomalate) Isoetherine (Bronkosol) Isoproterenol (Isuprel) Metaproterenol (Alupent) Pirbuterol (Maxair) Salmeterol (Serevent) Terbutaline (Brethine)

II. Methylxanthines Aminophylline Theophylline Oxtriphylline III. Antimuscarinic Agents Ipratropium (Atrovent) Anti-inflammatory agents
I. Corticosteroid (Aerosol) Beclomethasone (Banceril) Dexamethasone (Decadron) Flunisolide (AeroBid) Fluticasone (Flovent) Prednisone (Deltasone)

II. Mast cell stabilizer Cromolyn sodium(Intal) Nedocromil (Tilade) III. Lipo-oxygenase inhibitor Zileuton (Zyflo) IV. Leukotriene Antagonists Zafirlukast (Accolate) Montelukast (Singulair)

2 stimulation cAMP smooth muscle relaxation (bronchodilatation) inhibits mediator release from mast cells.
Adrenaline- rapid action (within 15 mins) lasts for 1-2hrs. Route: inhalation, action may help in mucosal decongestion and bronchoconstriction masked by 2 stimulation. Systemic effects through and 1 action can cause tachycardia, arrhythmias, palpitations, rise in BP. Can worsen angina, hypertension. Ephedrine- similar A/E profile. Less efficacious but longer duration of action (3-5 hrs). Seldom used now. Isoprenaline- nonselective agonist. Action within 5 mins, lasts for 1-2 hrs. Rise in mortality rate in asthmatics due to arrhythmias.

Less cardiac side effects. Selectivity further enhanced by inhalation. Muscle tremors, restlessness may be seen. Prolonged use can increase bronchial hyperreactivity due to down- regulation of receptors. Must be taken during acute attacks only, for symptomatic relief and supplemented by prophylactic drugs.

Salbutamol, terbutaline By inhalation- maximal bronchodilation in 30 mins, lasts

for 3-4 hrs. Available as oral tablets.Terbutaline- s.c inj severe asthma when aerosolized therapy not available.

Salmeterol, Formoterol Slow action but long duration of action (12 hrs).

Maintenance therapy with corticosteroids. Used in maintenance therapy & also for nocturnal asthma.

Theophylline, theobromine, caffeine. Aminophylline is theophyllineethylenediamine Mechanism of action High doses- inhibits phosphodiesterases cAMP

degradation inhibited cAMP bronchodilatation and decreased inflammatory mediator release from mast cells. Blocks adenosine receptors on cell surfaces at therapeutic doses bronchodilatation, mediator release.

COPD and Mild to moderately severe asthma- supplemented by 2 agonists for long term therapy. Monitoring required (520 mg/L) Apnoea in premature infants Other pharmacological uses:
CNS- stimulants increase alertness, allays fatigue (especially caffeine).

Higher doses- nervousness, restlessness, insomnia, excitement. Still higher doses tremors, convulsions (especially theophylline) CVS- positive chrono- and ino- tropic actions. At high concentrations releases Ca2+ from sarcoplasmic reticulum to further enhance stimulatory effects. High doses arrhythmias. Theophylline dilates blood vessels including coronaries PVR decreased. Caffeine constricts cranial vessels useful in migraine. Vasomotor stimulation, cardiac stimulation rise in BP

Vagal stimulation, direct vasodilatation > fall in BP Net- rise in systolic BP, fall in diastolic BP. GIT- Enhance gastric acid, pepsin secretion. Theophylline > caffeine. Both gastric irritants. Vomiting at high doses. Kidney- Mild diuretic, especially theophylline.S mooth muscle- relaxation. Especially bronchodilation. Skeletal Muscles- contraction, especially high doses due to calcium release. Improve ventilation by enhancing diaphragm contraction. Mast cells- inhibits release of inflammatory mediators.

Bronchodilatation by blocking M3 cholinergic receptors. Less efficacious than symathomimetics. More effective in asthmatic bronchitis, COPD, psychogenic asthma as vagal component more. Inhaled ipratropium bromide, tiotropium bromide slower response suited for prophylaxis than acute attack

Sodium cromoglycate/ cromolyn sod

Inhibits degranulation of mast cells release of histamine,

LTs, PGs, PAF, interleukins inhibited Inhibits mediator release from other cells Chemotaxis of inflammatory cells inhibited Reduces bronchial hyperreactivity and inflammatory response. Bronchospasm can be prevented.Ineffective during asthmatic attack as it does not interfere with Ag:Ab reaction, no bronchodilation, does not block constrictor action of histamine. Administered as aerosol through metered- dose inhaler as it is not absorbed orally

Bronchial asthma- long- term prophylactic, reduces frequency and severity of asthmatic attacks especially atopic/extrinsic asthma. Adjunct to bronchodilators in mild to moderate asthma, not severe asthma where inhaled steroids preferred. Allergic rhinitis- prophylactic. Need for nasal decongestants is reduced Allergic conjunctivitis- useful in chronic cases Adverse Effects

Bronchospasm, throat irritation, cough in some patiens with fine

powder inhalationNasal congestion, headache, dizziness, rashes

Are very useful in the control of asthma, particularly when the patient is unresponsive to theophylline and beta-adrenergic agents. In patients with serious asthmatic attacks, intravenous hydrocortisone or methylprednisolone is preferred. Hydrocortisone should be given in a dose of 3-4 mg per kilogram body weight intravenously every 6 hours. The dose is tapered as the patient improves. If required, injections should be replaced by oral prednisolone. For long-term therapy, 10 mg or less per day is a desirable goal. If total withdrawal of the drug is not possible, then alternateday therapy with short-acting steroids may be tried.

Beclomethasone dipropionate is available for inhalation. The aerosolised steroids are active locally with less systemic adverse effects. The daily dose is up to 16 puffs . It is usually started at 2 puffs 6 hourly. The best time to start beclomethasone is when oral corticosteroids are being tapered.

Montelukast, zafirlukast, zileuton

Competitively antagonize cysLT1 receptor mediated bronchoconstiction, increases vascular permeability, recruit eosinophils. Indicated for prophylactic therapy in mild to moderate asthma as alternative to inhaled glucocorticoids. Efficacy is less than steroids. Very safe- occ. headache, rashes Given orally,monte- 10 mg od, zafir- 20mg od

Achieve and maintain control of symptoms Prevent asthma exacerbations Maintain pulmonary function as close to normal as possible Avoid adverse effects from asthma medications Prevent development of irreversible airflow limitation Prevent asthma mortality Patient education Avoidance of aggravating factors

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