Submitted by : Navlika Dutta

Drugs for Cough and Bronchial Asthma

Drugs for Cough

Cough is a protective reflex, its purpose being expulsion of respiratory secretions or foreign particles from air passages.

Occurrence: due to stimulation of mechano- or chemoreceptors in throat, respiratory passages or stretch receptors in the lungs.

Useless/useful cough.

Classification

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.

Pharyngeal Demulcents

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

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.

MUCOLYTICS

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.

Anti tussives

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).

Opioids

Codeine- opium 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.

Non opioids

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 Dextromethorphan-

antitussive 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.

Anti histamines

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 asthmaFirst generation antihistaminic drugs like

chlorpheniramine, diphenhydramine and promethazine commonly used. Second generation antihistaminics not effective

Bronchodilators

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

BRONCHIAL ASTHMA

Asthma

Asthma is characterised by chronic airway inflammation and increased airway hyper-responsiveness 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 tracheo-bronchial 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.

 epidimology

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 (β-blockers-even when administered topically as eye drops) may induce bronchospasm.

Aspirin and other non-steroidal anti-inflammatory drugs are associated with asthma in about 10% of patients.

Mechanism of asthma

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extrinsic Intrinsic(cryptogenic)

External factor identifiable No such factor

Serum shows high levels of IgE &IgG

No raised Ab levels but increased eosinophils present ,aspirin sensitivity, & presence of nasal polyp

classification

Atopic manifestations may be present

No atopy

Dermatological and respiratory s/s show a see-saw relationship

Not associated with skin s/s

Positive family history present

Affects persons of 10-15 yrs 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

extrinsic asthma

Once sensitization occurs these antigens release chemical mediators from the mast cells by interacting with the IgE molecules on their surface- Type 1 hypersensitivity reaction-immediate asthmatic paroxysm

Some times type 3 hypersensitivity reaction also occurs and it is mediated by IgG –delayed paroxysmwww.similima.com 22

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

Pathophysiology

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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

CARDINAL PATHOLOGICAL FEATURES OF ASTHMA

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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).

Clinical features

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Cellular response in asthma

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Pathogenesis

Inflammatory diseaseAllergic basis only 10 % in adultsInfections, irritants, pollution, psychogenic, cold

air etcInitial reaction release of inflammatory

mediators- histamine, PGs, LTs from mast cells neutrophils, eosinophils, macrophages, T-lymphocytes 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

Treatment Strategies

Prevention of Ag:Ab reaction- avoid antigen if known

Nonspecific reduction of bronchial hyperreactivity- corticosteroids

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

Drugs used for Asthma with Brand name

Bronchodilators

I. Sympathomimetic b-agonists

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

Continued….

II. Methylxanthines Aminophylline Theophylline OxtriphyllineIII. Antimuscarinic Agents Ipratropium (Atrovent)

Anti-inflammatory agents

I. Corticosteroid (Aerosol) Beclomethasone (Banceril) Dexamethasone (Decadron) Flunisolide (AeroBid) Fluticasone (Flovent) Prednisone (Deltasone)

Continued…..

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

Sympathomimetics

β2 stimulation ↑cAMP smooth muscle relaxation (bronchodilatation) inhibits mediator release from mast cells.

Adrenaline- rapid action (within 15 mins) lasts for 1-2hrs. Route: inhalation, α action may help in mucosal decongestion and bronchoconstriction masked by β2 stimulation. Systemic effects through α and β1 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 β agonist. Action within 5 mins, lasts for 1-2 hrs. Rise in mortality rate in asthmatics due to arrhythmias.

β2 selective agonists

Less cardiac side effects. Selectivity further enhanced by inhalation.

Muscle tremors, restlessness may be seen.

Prolonged use can increase bronchial hyper-reactivity due to down- regulation of β 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.

Methyl Xanthines

Theophylline, theobromine, caffeine. Aminophylline is theophylline-

ethylenediamineMechanism 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.

Uses

COPD and Mild to moderately severe asthma- supplemented by β2 agonists for long term therapy. Monitoring required (5-20 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

Uses… 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.

Anticholinergics

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

Mast cell stabilizers

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

Uses

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

Corticosteroids

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 alternate-day 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.

Leukotriene

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

THE GOALS OF ASTHMA MANAGEMENT

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