Disorders Of Respiratory System General Pharmacology M212 Dr. Laila M. Matalqah Ph.D. Pharmacology

Classification Main disorders of the respiratory system are: Bronchial asthma Allergic Rhinitis: itchy, watery eyes, runny nose, and a nonproductive cough. Chronic obstructive pulmonary disease (COPD): includes emphysema and chronic bronchitis

Bronchial Asthma Asthma is an inflammatory disease of the airways characterized by recurrent episodes attack of acute bronchoconstriction causing shortness of breath, cough, chest tightness, wheezing, and rapid respiration Recurrent attack of airway obstruction in response to external stimuli. Chronic inflammatory disorder of airways. Airway hyper-reactivity; abnormal sensitivity to wide range of external stimuli.

Types of bronchial asthma Extrinsic asthma (Allergic asthma) Intrinsic asthma Infection Stress Cold air (Exercise asthma) Drug-induced, as by aspirin:

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Inhaler devices Inhaler devices can be divided into four main groups: Pressurised metered dose inhalers (MDIs). Breath-activated inhalers Inhalers with spacer devices. Nebulisers: are machines that turn the liquid form of short-acting bronchodilator medicines into an aerosol. 

Bronchial asthma - Montelukast - Zafirlukast Zileuton Pharmacology of agents used in the treatment of asthma β2-Adrenergic agonists Cholinergic antagonist: Ipratropium bronchodilator Methylxanthine drugs: Theophylline Corticosteroids Cromolyn & Nedocromil Anti-inflammatory agent Leukotriene inhibitors - Montelukast - Zafirlukast Zileuton Other drugs in the treatment of asthma

Asthma therapies - 1 Contraction of airway smooth muscle Bronchodilators Beta-adrenoceptor stimulants Methylxanthine drug Antimuscarinic agents “Short-term relievers”

1. Bronchodilator: β2-Adrenergic agonists A. Long-term control: Selective β2- agonists Salmeterol and formoterol are long-acting β2-agonists (LABAs). Salmeterol and formoterol have a long duration of action, providing bronchodilation for at least 12 hours, but have slower onsets of action and should not be used for quick relief of an acute asthma attack. Adjunctive therapy with inhaler

Bronchodilator: β2-Adrenergic agonists B. The short-acting β2-agonists: Treatment of choice for acute severe asthma and exercise-induced bronchospam The onset of action is less than 5 minutes and a duration of action of 4 to 6 hours Albuterol (Also Known as Salbutamol) Pirbuterol Terbutaline

Bronchodilator: β2-Adrenergic agonists Route of administration: 1. Inhalation formulations include: metered-dose inhaler – aerosol. aerosol administered via a nebulizer; In acute severe asthma, continuous nebulization of short-acting β-agonists (e.g., albuterol) is recommended for patients having an unsatisfactory response after three doses (every 20 minutes) of aerosolized 2. Oral formulations, including slow-release preparations 3. I.V

2. Bronchodilator: Anticholinergic agents: Ipratropium bromide By Inhaler poorly absorbed less systemic adverse effects Also effective in patients with chronic obstructive pulmonary disease (COPD) Adrenergeic agonist: Epinephrine For acute attack, rapid onset of action

3. Bronchodilator: Methylxanthine drugs Theophylline MOA: inhibiting phosphodiesterases, which result in antiinflammatory and bronchodilator activity through decreased mast cell mediator release, Narrow therapeutic window Overdose may cause seizures or potentially fatal arrhythmias. Methylxanthines are ineffective by aerosol and must be taken systemically (orally or IV). Theophylline is metabolized in the liver, is a CYP1A2 and 3A4 substrate, and interacts with inducers and inhibitors

Asthma Therapy 2 Mucosal thickening from edema and cellular infiltration Anti-inflammatory agent Corticosteroid Cromolyn or nedocromil Leukotriene antagonist “Long-term controllers”

Corticosteroids inhaled topical corticosteroids Beclomethasone dipropionate (BDP) Budesonide (BUD) Triamcinolone acetonide (TAA) ADR: Adrenal suppression, osteoporosis, cataracts, Oropharyngeal candidiasis, hoarseness Counseling: reduced by using spacer, rinse mouth with water

Mast cell mediator release

Cromolyn & Nedocromil; MOA: inhibits mast cell degranulation and release of histamine In nebulized solution: Nebulizer Prophylactic uses for asthma Before exercise Before unavoidable exposure to an allergen it is not useful in managing an acute asthma attack, because it is not a direct bronchodilator. Short duration of action Poorly absorbed - rare adverse effects Safe for children and pregnant

Leukotriene B4 is increases vascular permeability producing mucosal oedema. Leukotrienes C4, D4 and E4 are potent spasmogens and pro-inflammatory substances

Leukotriene Antagonist Block the synthesis of leukotriene 5-lipoxygenase inhibitor Zileuton Inhibit the action of leukotriene D4 (LTD4) Inhibition of the binding of LTD4 to its receptor on target tissue Zafirlukast and montelukast Inhibitors of CYP450: increase warfarin level ADR: increase hepatic enzyme

Other drugs in the treatment of asthma Omalizumab: Anti-IgE monoclonal antibodies- bind to AgE which activate mast cell to secrete histamine

Allergic Rhinitis Antihistamines (H1-receptor blockers) First generation (sedating): non-selective H1-receptor blocker diphenhydramine, chlorpheniramine, Hydroxyzine , Cyclizine , meclizine Antivertigo (meclizine) Antitussive (diphenhydramine) Second generation: selective H1- receptor blocker non-sedating: Cetrizine, loratadine, and fexofenadine, Orally, Ocular and nasal antihistamine delivery devices are available Combinations of antihistamines with decongestants Antihistamines differ in their ability to cause sedation and in their duration of.

NOTE: histamine receptors H1 – Smooth muscle, endothelium, CNS. Bronchoconstriction, vasodilation, separation of endothelial cells, pain and itching, allergic rhinitis, motion sickness. H2 – gastric parietal cell, vascular s.m. cell, basophils. Regulate gastric acid secretion, vasodilation, inhibition of IgE-dependent degranulation.

First Generation Agents Sedation Peripheral anticholinergic effects dry Mouth blurred Vision constipation urinary Retention

Allergic Rhinitis 2. α- Adrenergic agonists MOA: constrict dilated arterioles in the nasal mucosa and reduce airway resistance Short-acting α-adrenergic agonists (“nasal decongestants”), such as phenylephrine, Longer-acting: oxymetazoline 3. Corticosteroids: Nasal sprays such as beclomethasone, budesonide, and triamcinolone

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