Respiratory Pharmacology: Asthma

• Respiratory Pharmacology studies asthma, pneumonia and cough preparations

Asthma

• Asthma causes inflammation of the airway wall and hypersensitivity of the trachea and bronchi to various stimuli.
• Asthma also causes generalized narrowing of the airways, which resolves spontaneously or after therapy.
• Asthma symptoms include recurrent episodes of coughing, shortness of breath (dyspnoae), chest tightness, and wheezing.
• The severity of asthma is defined by the frequency of occurrence of its symptoms.
• Symptoms can occur in mild asthma after exposure to allergens, cold air, strong odors, pollutants, during exercise, or after a viral upper respiratory tract infection.
• Allergic and nonallergic asthma are two identified subtypes.
• Most asthmatic individuals are atopic and have allergen exposures responsible for asthmatic inflammation.
• Asthma in nonallergic individuals normally occurs later in life.
• Asthma generally results from an immune response to inhaled allergens
• It culminates in the recruitment and activation of inflammatory cells and mediators.
• Cytokine and eosinophil activation and stimulation of IgE production is the hallmark of asthma.

Drug treatment of asthma

• Pharmacotherapy of asthma employs drugs that reduce airway inflammation and drugs that decrease bronchospasm to produce symptom relief.
• Therapeutic agents for asthma include bronchodilators (ẞ receptor agonists, methylxanthines), anti-muscarinic agents, glucocorticoids, leukotriene inhibitors, chromones, and inhibitors of immunoglobulin E (IgE).

Classes of anti-asthmatic drugs

• Agents directly relax airway smooth muscle, like sympathomimetics (salbutamol, salmeterol) and methylxanthines (theophylline).
• Anti-inflammatory agents like glucocorticoids are used.
• Agents that prevent mast cell degranulation, such as cromolyn and nedocromil are used.
• Leukotriene inhibitors such as zileuton and zafirlucast can be used.
• Antimuscarinic agents inhibit the effect of Ach released from the vagal nerves (e.g., ipratropium).
• Inhibitors of IgE reduce the amount of IgE bound to mast cells (e.g., omalizumab).

Treatment of asthma

• Most antiasthmatic drugs are delivered topically to the lungs as aerosols.
• Aerosol therapy delivers a high local concentration of drug in the lungs
• The pathophysiology only involves the respiratory tract.
• Aerosols can control episodes in most individuals.
• Aerosols cause a reduction of systemic side effects due to low systemic drug delivery.
• Most antiasthmatic drugs (ẞ₂ adrenergic receptor agonists, glucocorticoids) have serious side effects when delivered systemically.
• Aerosol delivery requires specialized technique and only a small fraction (10-20%) of the aerosolized drug reaches the lungs.
• Over 50% of patients using inhalers do not use proper technique
• They deposit too small a fraction of inhaled drug into the lungs
• Patients need counselling on proper inhaler use.

Sympathomimetic drugs

• Adrenoceptor agonists cause relaxation of airway smooth muscles via stimulation of ẞ₂ adrenoceptors and inhibit release of bronchoconstricting substances from mast cells.
• Beta-agonists stimulate adenylcyclase activity, increasing intracellular cyclic AMP in airway tissue
• This leads to relaxation of airway smooth muscle and bronchodilation
• Increase cyclic AMP also results in the inhibition of inflammatory mediators and cytokines.
• Beta2-selective adrenoceptor agonists are more effective bronchodilators than non-selective beta agonists, they also have fewer cardiac effects.
• These agonists are available as inhalational and oral preparations and are classified as short-acting (2 hr) and long-acting (12 hr).
• Short-acting agonists are used only for symptomatic relief of asthma.
• Long-acting agonists are used prophylactically in treating the disease.
• Short-acting Beta2 adrenoceptor agonists include albuterol, salbutamol, metaproterenol, terbutaline, and pirbuterol.
• The oral forms of these drugs have a longer duration of action.
• Long-acting agonists include salmeterol, formoterol, indacarterol, and vilanterol.
• Chronic use of Beta2 agonists may desensitize some receptor-response pathways, reducing effectiveness in decreasing airway inflammation.
• Inhaled Beta2 receptor agonists have few side effects because they are delivered locally, but high doses may cause cardiac effects ( increased heart rate, cardiac arrhythmias).

Methylxanthines

• Examples are theophylline, theobromine, and caffeine.
• They are mainly obtained from tea, cocoa, and coffee, respectively.
• Xanthines inhibit phosphodiesterase (PDE) enzymes which degrades cyclic nucleotides (cAMP, cGMP), increasing cellular cAMP concentration.
• Increased cAMP leads to relaxation of bronchiole smooth muscles (bronchodilation).
• Theophylline also competitively antagonizes cell surface receptors of adenosine
• Adenosine causes contraction of isolated airway smooth muscle and histamine release from airway mast cells
• Inhibition of adenosine actions results in brochodilation.
• Theophylline has a narrow therapeutic index and requires regular blood concentration measurement.
• Plasma clearance is faster in children versus adults.
• Neonates and young infants have the slowest drug clearance.
• Theophylline toxicities include anorexia, nausea, vomiting, abdominal discomfort, headache, and anxiety.

Glucocorticoids (Corticosteroids)

• The mechanism of action is to inhibit the synthesis of inflammatory mediators (leukotrienes, prostaglandins, cytokines, etc.) and inhibit inflammatory cell accumulation (e.g., eosinophils, basophils, leukocytes).
• These drugs reduces bronchial reactivity and the frequency of asthma exacerbations are reduced if taken regularly.
• They are very effective in the treatment of asthma due to anti-inflammatory effects.
• Glucocorticoids can be given orally, as inhalations, or parenterally.
• Inhalational preparations are particularly useful because of local anti-inflammatory action in the lungs, reducing systemic side effects.
• They control asthma and are used over a long period
• Examples include: beclomethasone dipropionate, triamcinolone acetonide, flunisolide, budesonide and fluticasone propionate.
• Oral glucocorticoids (prednisone) and parenteral glucocorticoids (hydrocortisone) are absorbed into systemic circulation, causing more systemic side effects.
• They are used for acute asthma exacerbations and chronic severe asthma.
• Inhaled glucocorticoids can cause oropharyngeal candidiasis and dysphonia, while systemic use can cause impaired glucose control, mood disturbances, increased appetite, candidiasis, and poor wound healing.

Leukotriene inhibitors

• Leukotrienes are inflammatory mediators that are released from arachidonic acid by inflammatory cells in the airways like eosinophils, mast cells, macrophages, and basophils.
• They are potent chemo-attractants and bronchoconstrictors, capable of causing mucus hypersecretion and hyperreactivity.
• Leukotriene inhibitors modify leukotriene action by either inhibiting leukotriene synthesis or by competitive antagonism of leukotriene receptors.

Leukotriene receptor antagonists

• Examples are zafirlukast and montelukast
• They inhibit the leukotriene receptor- CysLT₁
• CysLT₁ is the receptor for the cysteinyl leukotrienes- CysLTs (LTC4, LTD4 and LTE4) responsible for the bronchoconstrictor effect of leukotrienes.
• Zafirlukast and montelukast are highly selective competitive antagonists of the CysLT₁ receptor
• They inhibit LT-mediated bronchoconstriction.

Leukotriene synthesis inhibitors-

• Zileuton inhibits 5-lipoxygenase activity, blocking the formation of all 5-lipoxygenase products.
• It inhibits the synthesis of the CysLTs, as well as LTB4 (a potent chemotactic autacoid).

Leukotriene inhibitors - Pharmacokinetics

• They are administered orally and are absorbed rapidly from the GIT with high bioavailability (> 70 %).
• They undergo extensive metabolism by cP450 (CYP2C9) enzyme with different half-lives: zafirlukast (10 h), montelukast (3–6 h), and zileuton (2.5 h).
• Montelukast and zafirlukast are long-acting.
• Zileuton has a short duration of action and may be taken 4 times a day.
• Montelukast is 99% bound to plasma protein.
• Zileuton increases plasma concentrations of theophylline and warfarin by decreasing their plasma clearance.

Mast cell degranulation inhibitors

• Cromolyn and Nedocromil inhibit mast cell degranulation, thereby inhibiting the release of histamine, they cause bronchodilation.
• These agents inhibit cellular activation on airway nerves, mast cells and eosinophils.
• This results in cough inhibition, inhibition of early response to allergen challenge and inflammatory response.
• These drugs are poorly absorbed and are given as inhalations.
• Cromolyn and Nedocromil prevent asthmatic attacks in individuals with mild to moderate bronchial asthma.
• Nedocromil is recommended for use in asthmatic patients 12 years of age and above, while cromolyn can be used by both children and adults.
• They are relatively free from systemic toxicities.
• Minor localized adverse effects include cough, throat irritation, mouth dryness, wheezing, and chest tightness.

Antimuscarinic agents

• Examples include Ipratropium, tiotropium, umeclidium, glycopyrronium, and aclidinium.
• They are long acting muscarinic antagonists.
• The mechanism of action is competitive inhibition of acetylcholine at muscarinic receptors in the airways, resulting in bronchodilation.
• Antimuscarinic agents also reduce mucus secretion in the airways.
• Ipratropium is a quaternary amine derivative of atropine and is poorly absorbed from the GIT
• It does not cross the blood-brain barrier and is inhaled.
• Antimuscarinic agonists can be used for those that do not tolerate Beta agonists and in COPD.

Anti-IgE

• Omalizumab is a recombinant human monoclonal IgG antibody which is raised against IgE.
• Omalizumab binds to IgE, preventing it from binding to IgE receptors on mast cells and basophils.
• This prevents the allergic reaction at a very early step.
• Omalizumab is the first biological agent approved for asthma treatment.
• Omalizumab is given as a single sc injection every 2–4 weeks and is indicated for adults and adolescents >12 years of age with allergies and moderate-to-severe persistent asthma.
• It has a bioavailability of about 60% and peak plasma concentrations are reached between 7–8 days.
• Drug complex with IgE is eliminated by hepatic reticuloendothelial system.
• Intact omalizumab is excreted in the bile.
• Adverse reactions include injection site reactions (e.g., redness, stinging, bruising, and induration) and hypersensitivity reactions like anaphylaxis in some individuals.

Pneumonia

• Pneumonia is an inflammatory condition of the lungs, primarily the alveoli.
• It is commonly caused by bacterial or viral infections.
• More rarely, it is caused by other microorganisms, drugs, or autoimmune diseases.
• Symptoms include cough, chest pain, fever and difficulty breathing (dyspnoea).
• Conditions that predispose pneumonia are smoking, immunodeficiency, alcoholism, COPD, chronic disease and liver disease.
• The use of acid-suppressing medications- such as proton-pump inhibitors or H₂ blockers- is associated with an increased risk of pneumonia
• Old age can predispose someone to pneumonia.
• Community-acquired pneumonia (CAP) is most commonly caused by bacteria, including Streptococcus pneumoniae (50% of cases)
• Haemophilus influenzae (20%), Chlamydophila pneumoniae (13%), Mycoplasma pneumoniae (3%), Staphylococcus aureus; Moraxella catarrhalis; Legionella pneumophila also cause pneumonia.
• Commonly implicated viruses are, rhinoviruses, coronaviruses, influenza virus, respiratory syncytial virus (RSV), adenovirus, and parainfluenza.
• Viral infections can make the body more susceptible to bacterial infections, leading to bacterial pneumonia.
• Other organisms can cause atypical pneumonia, like fungi (e.g., Histoplasma capsulatum, blastomyces, Cryptococcus neoformans, Pneumocystis jiroveci) and parasites (e.g., Toxoplasma gondii, Strongyloides stercoralis, Ascaris lumbricoides, and Plasmodium malariae).
• For mild pneumonia the drugs of choice are Amoxicillin or doxycycline or clarithromycin.
• For moderate to severe conditions the drugs of choice are Amoxicillin + clarithromycin, or Amoxicillin + clavulanate or cefuroxime.
• Atypical pneumonia is mostly treated with clarithromycin or doxycycline.

Cough preparations

• Cough may be a symptom of an underlying disorder like asthma or COPD, gastroesophageal disease, rhinitis, drugs (ACEI), or environmental pollutants (e.g., tobacco smoking).
• Cough and other cold medicines are not recommended for children that are less than 6 years of age.

Expectorants

• Cause loosening or thinning of mucus or phlegm and expel it from the lungs.
• They decrease the viscosity of phlegm, increasing mucus flow and aiding its expulsion from the lungs.
• Examples include: guaifenesin, ammonia, sodium citrate, and ipecacuanha.
• Side effects include nausea, vomiting, diarrhea, dizziness, and headache.

Mucolytics

• Examples include bromhexidine, acetylcysteine, carbocisteine, erdosteine, and mecysteine.
• Mucolytics reduce sputum viscosity by breaking down thick, sticky chest phlegm, facilitating expectoration.
• They break down the chemical structures of the mucus molecule.
• Useful in patients with COPDs, especially with productive cough.
• Used with caution in patients with peptic ulcer since they may disrupt the gastric mucosal barrier.
• The following can also help to thin mucus and make it easy to cough up: drinking plenty fluids, taking a hot steamy shower, have plenty rest, and stop smoking if smoker

Cough suppressants (anti-tusives)

• Cough suppressants block the cough reflex, reducing the urge to cough, minimizing cough, and aid sleeping.
• They are indicated if the cough is not productive.
• Examples include opioids (codeine, dextromethorphan, pholcodine) and sedating antihistamines like diphenhydramine.
• Codeine is constipating and can cause dependence, while others have fewer adverse effects.
• Opioids are not used in children under 18 years.
• Cough suppressants should not be given with productive cough as this can cause build-up of mucus in the lungs and increase infection.
• Sedating antihistamines will dry up secretions and leave them in the lungs and so should be avoided when having productive cough.

Respiratory stimulants

• Respiratory stimulants cause stimulation of respiratory muscles and are effective in relieving symptoms in COPD
• They are often given intravenously.
• However, they have been replaced by ventilatory support.
• A typical example is doxapram.