Respiratory tract drugs LuTai Tien Ph D School

Respiratory tract drugs Lu-Tai Tien, Ph. D. School of Medicine Fu-Jen Catholic University

Classification of drugs Drugs used to treat asthma n Drugs used to treat allergic rhinitis n Drugs used to threat chronic obstruction pulmonary diseases (COPD) n Drugs used to treat cough n

From Lippincott’s 3 nd edition

Stimuli / Other Factors n allergens – not all atopic have asthma – dust mites, pollen n n exercise industrial chemicals and byproducts – aluminum smelters – cedar dust n pollutants n food additives n lung infection n cold air drugs n genetic predisposition n – SOx – bisulfite antioxidants – aspirin – predisposing before age of two – more boys than girls in childhood – more women than men from 2 nd decade onwards. – Familial risk of allergies

Control of Airway Diameter n Parasympathetic – ACh is the neurotransmitter at airway smooth muscle – it acts at M 3 receptors- activation causes formation of IP 3 (increasing Ca 2+) and diacylglycerol F tension is the result n No sympathetic innervation ● β 2 adrenoceptors are present in airway smooth muscle ● normally epinephrine released from adrenal medulla activates n Other nerves - bradykinin, neurokinins

Therapies for Asthma Treatments that mitigate an asthma attack n Treatments that relax airway smooth muscle n Treatments that mitigate chronic inflammation n

Relaxing airway contraction n Inhibition of Bronchoconstriction – Phosphodiesterase Inhibitors – Muscarinic receptor antagonists – β-adrenoceptor agonists

Phosphodiesterase Inhibitors n Methylxanthine (caffeine is in this group) – – – n Theophylline (aminophylline is the ethylenediamine complex) The therapeutic index of Theophylline is slow Causing severe toxicity (the conc. > 20 μg/m. L in blood) Inhibits the breakdown of cyclic AMP by inhibiting phosphodiesterase – c. AMP produced by β 2 -adrenoceptor activation initiates a phosphorylation cascade causing relaxation of airway smooth muscle n They are adenosine receptor antagonists

Clinical Use of Phosphodiesterase Inhibitors n n n Given orally Sustained release preparations are available Blood levels should be controlled – therapeutic range 5 -20 mg/L – below 5 no therapeutic effect – above 20 side effects become a problem n anorexia, headache, abdominal discomfort, anxiety n seizures and arrhythmias occur at high concentrations (>40 mg/L)

Muscarinic antagonists n n 阻斷迷走神經所傳導的呼吸道平滑肌收縮及黏液的分 泌 e. g. Ipratropium – 病人無法忍受 β-adrenergic agonists 時可用此藥代替 n Atropine is not used now – dries mucus membranes, too many side effects – doesn’t reverse bronchoconstriction n in asthma bronchoconstriction is mostly due to leukotrienes and other substances not muscarinic receptor stimulation – can cause viscid mucus plugs to form

Ipratropium n n n Quaternary muscarinic antagonist Given by nebulization (霧化) so effects limited to airway Not routinely used as the only drug in the treatment of asthma Has definite value in the treatment of acute asthma exacerbation when used in addition to β-agonists Used in the treatment of chronic obstructive pulmonary disease - COPD

Adrenergic agonists 擬腎上腺素 n β 2 -adrenergic agonist 治療輕度氣喘 n 直接作用在呼吸道平滑肌鬆弛，為一有 效的支氣管擴張劑 n Short and long acting drugs n

Short acting drugs n n n 15 -30 min可產生療效, 可緩解症狀 4 – 6 hours 治療急性支氣管收縮，因不具抗發炎作用，所以，不 可做為治療慢性氣喘的唯一藥物 Metaproterenol, albuterol, terbutaline, bitolterol, pirbuterol – – – n all can be given by inhalation – nebulization metaproterenol, terbutaline, albuterol can be given orally terbutaline injectable – subcutaneous 若由吸入途徑給藥可能會降低全身性給藥所造成的 心跳增快，血糖過高，血鉀過低，血鎂過低等副作用

Long acting drugs n Salmeterol, formoterol – – – long acting - 12 hours or more forms slow release depot in tissue (lipid soluble) long duration of action used to treat nocturnal asthma – not used as monotherapy always with inhaled steroids n 作為一般處方用藥，不用在急性症狀緩解治 療

Other b-Agonists n Epinephrine – good bronchodilator - not selective (all a and b) – short lived – used in emergencies, subcutaneous injection - severe asthma, hypersensitivity reactions, anaphylaxis – Available OTC (Over-The-Counter) n Ephedrine (麻黃素) – long history of use in China – β 2 selective, not used much in asthma now – Not as easily now available since methamphetamine can be made from this drug n CNS stimulant, amphetamine look-alike, “truck stop” pharmacology

Side Effects of β-agonists n Not completely selective – Can increase heart rate – Can cause arrhythmias n Headache - vasodilation

Anti-allergy agents - Omalizumab n n n Recombinant humanized antibody against the Cε 3 domain of Ig. E – Complexes Ig. E preventing activation of mast cells and basophils thus prevents the release of inflammatory mediators Market name: Xolair Used only after primary treatments have failed The drug is administered subcutaneously in 1 to 3 injections every 2 or 4 weeks Not recommended when living in environments where the presence of parasites is common

Inhibition of Leukotrienes n Inhibition of the formation of leukotrienes – – – n 5 -lipoxygenase inhibitor Zileuton Increases the lifetime of theophylline and drugs metabolized by CYP 3 A 4 Inhibition of the action of leukotrienes – leukotriene receptor antagonists (LTRA) – Zafirlukast (LTD 4), montelukast (LTD 4) n Zafirlukast (po), montelukast (po)

Zileuton Arachidonic acid - 5 -Lipoxygenase Leukotrienes Cyclooxygenase Prostaglandins LTB 4 LTC 4 LTD 4 LTE 4 LTC 4 LTD 4 + Cyst. LT 1 Contraction of airway smooth muscle cells Zafirlukast (Cyst. LT 1 antagonists) Montelukast

n Properties Leukotriene receptor antagonists – Not all patients respond – Aspirin sensitivity results from LTD 4 release n Aspirin (or NSAID) sensitivity may be caused by inhibiting cyclooxygenase and shunting of arachidonic acid metabolism into the leukotriene pathway – Takes 3 -14 days to work - used for chronic therapy – Contraindications - liver disease, pregnancy (crosses placenta), breast feeding (excreted) – Fewer of the above concerns with montelukast as compared to zafirlukast or zileuton

Steroids n Systemic steroids – – – corticosteroids (e. g. , prednisone, prednisolone) used to treat severe persistent asthma significant side effects n n n water retention - moon face (Cushingoid features) Immunosuppression Steroids reverse inflammation and reduce sensitivity of airway smooth muscle to stimulation n adrenal suppression-must taper dose when discontinuing after prolonged therapy

Inhaled Steroids n Beclomethasone, Budesonide, Flunisolide, Fluticasone, Mometasone and Triamcinolone – – given by inhaled route minimal systemic effects (better topical: systemic ratio) reduces need for oral steroids Used as first line therapy for newly diagnosed cases decreases chronic inflammation and might reverse remodeling of the airways – Oral candidiasis - thrush - gargle and spit, use a spacer

Corticosteroid Actions n Decrease the following – Secretion from, and numbers of eosinophils – Cytokines from T-lymphocytes – Number of mast cells – Secretion and production of cytokines by macrophages – Leakiness of endothelia (vasoconstriction) – Mucus secretion and hypertrophy of mucus cells – Upregulation of β-adrenergic receptors

Side effects of corticosteroids

Cromolyn/Nedocromil n Mechanism – inhibits the degranulation of mast cells - by inhibiting chloride conductance channels in the mast cell membranes which reduces intracellular calcium increases – works only prophylactically (預防性的) – cannot terminate an attack – Can reduce late phase response when given after an initial attack - inhibits eosinophil degranulation

Treatments by Cromolyn/Nedocromil n Given by nebulization – solution that is nebulized – Microfine powder - Spinhaler n n few side effects because it is poorly absorbed and not metabolized side effects primarily in airway – can induce bronchoconstriction, chest tightness, coughing, xerostomia – effects minimized by taking β 2 -agonist concomitantly n Used to treat allergic rhinitis – available OTC

Treatment of Asthma

THE END