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DRUGS IN RESPIRATORY SYSTEM

Pharmacology Department FACULTY OF MEDICINE – UNISSULA INTRODUCTION

Symptom of respiratory system : no sputum---antitussives Cough sputum --- expectorants Asthma ----- antiasthmatic drugs PHYSIOLOGY OF COUGH

• Batuk disebabkan oleh aktivasi reseptor sensorik di laring dan saluran pernapasan bagian bawah, mengirimkan impuls ke batang otak. • Ada banyak agen bervariasi yang bisa menimbulkan batuk: asam sitrat, bradikinin, air suling, SO2, capsaicin, metabisulfite, asap rokok dan inhibitor ACE. • Sensitivitas ujung saraf sensoris, yang menengahi refleks batuk yang ditimbulkan oleh agen tussive meningkat pada penderita asma dengan batuk, mengikuti infeksi saluran pernapasan bagian atas pada individu sehat dan pada pasien dengan batuk yang diinduksi ACE. PHYSIOLOGY OF COUGH

• Batuk biasanya terjadi ketika reseptor sensorik di saluran pernapasan menerima rangsangan dengan intensitas yang cukup untuk membangkitkan peningkatan aktivitas impuls saraf sensorik / aferen. Refleks batuk dapat dipicu dengan mudah oleh rangsangan mekanis dan kimia yang terjadi di laring atau trakeobronkial, karena di sinilah perlindungan terbesar terhadap masuknya bahan asing diperlukan. • Informasi sensorik dari saluran pernafasan yang memulai refleks batuk melalui nervus vagus. COUGH IN DISEASE

• Batuk sering terjadi pada asma dan selama infeksi saluran pernafasan bagian atas disertai dengan pembengkakan saluran udara. • Etiologi batuk pada anak berbeda dengan orang dewasa: virus URTI, bronkitis bakteri dan asma yang berkepanjangan sering menjadi penyebab anak- anak batuk. Jadi, pendekatan empiris yang biasa digunakan pada orang dewasa tidak sesuai untuk anak-anak. Evaluasi klinis batuk pada anak juga harus mencakup penilaian faktor lingkungan. ANTITUSSIVE AGENTS SITE AND MECHANISMS OF ACTION OF ANTITUSSIVE AGENTS

• Batuk dikaitkan dengan kelebihan produksi lendir di dalam paru-paru, penekanan refleks batuk umumnya tidak diperlukan, karena retensi lendir dapat terjadi yang dapat menyebabkan komplikasi serius. • Bila batuk tidak produktif dan menjadi gangguan, tidur dan istirahat, penekanan menjadi diperlukan, meski penekanan menyeluruh bisa berbahaya karena paru-paru kemudian kehilangan mekanisme pertahanan yang esensial SITE AND MECHANISMS OF ACTION OF ANTITUSSIVE AGENTS • Obat ideal akan mengurangi peningkatan sensitivitas refleks batuk normal, sebaiknya dengan mengeluarkan proses penyakit atau dengan mengurangi responsivitas reseptor sensorik saluran napas. • Reseptor sensori nafas yang paling jelas untuk ditargetkan adalah RAR. Obat yang mempengaruhi batuk juga bisa diberikan secara tidak langsung. Misalnya, obat yang menyebabkan bronkodilatasi, seperti agonis reseptor dan antagonis kolineptor yang digunakan pada asma, mengurangi refleks batuk tanpa memiliki efek sentral yang signifikan. SITE AND MECHANISMS OF ACTION OF ANTITUSSIVE AGENTS

• Obat dengan aktivitas antitusif secara longgar dikelompokkan menjadi dua kelompok: perifer atau pusat. • Obat antitusif sentral bertindak di dalam sistem saraf pusat untuk menekan satu atau lebih komponen jalur batuk sentral. • Agen yang bertindak secara periferal menggunakan cara kerjanya di luar sistem saraf pusat, mungkin dengan menghambat aktivasi reseptor sensorik saluran napas yang bertanggung jawab untuk memulai refleks batuk. • Penekan batuk yang paling sering digunakan adalah opiat, anestesi lokal, demulcents, ekspektoran, antihistamin dan dekongestan. SITE AND MECHANISMS OF ACTION OF ANTITUSSIVE AGENTS • Antitussive effects of the classical opiates, such as and morphine, were generally reported to be mediated centrally. • receptors on the afferent / sensory neurones of the vagus nerves. • Codein & morphine with opioid-receptor-mediated antitussive actions can modulate impulse activity in airway sensory neurones originating from RARs and C- fibre receptors. • Antitussive activity of drugs such as codeine is not restricted entirely to the central nervous system, but that some of its activity is also exerted peripherally. ANTITUSSIVES

Classification : A. Central Antitussives / Cough Supressants 1. Dependent Central Antitussives (Opioid) 2. Independent Central Antitussives (Non Opioid) B. Peripheral Antitussives

Note : codeine, and are among the most common central agents that inhibit cough primarily by their effect on the cough center. DEPENDENT CENTRAL ANTITUSSIVES

• Centrally acting antitussives  opioid / narcotic alkaloids. • Mechanism : suppressing of cough center. • Morphine is the most effective drug for the suppression of cough, but have addiction. • Ex : codeine, . INDEPENDENT CENTRAL ANTITUSSIVES

• Non opioid / narcotic alkaloids. • Stereoisomers of opioid molecules that are devoid of analgesic effects and addiction liability. • Classification : 1) Orphan – antitussives : dextromethorphan 2) Amido – antitussives : , 3) Piperidine – antitussives : cloperastine 4) Morpholine – antitussives : promolate, 5) Others : , PERIPHERAL ANTITUSSIVES Inhibiting receptor, afferent nerve, efferent nerve of cough reflex arc → cough suppression. 1. local anesthesia action : narcotine, 2. Alleviative action : extractum glycyrrhizae liquidum PERIPHERAL ANTITUSSIVES • is a non-opioid agent whose peripheral antitussive action may result from its modulation of sensory neuropeptide levels within the respiratory tract. •Locally acting agents (throat lozenges, cough drops) may suppress cough by increasing the flow of saliva and by containing demulcents or local anesthetics to decrease irritation of pharyngeal mucosa. ANTITUSSIVES Indication for use of antitussives : •A dry, hacking, nonproductive cough that interferes with rest and sleep. •It is not desirable to suppress a productive cough because the secretions need to be removed.. ANTITUSSIVES

• Penekanan berlebihan terhadap refleks batuk dengan antitusif (ketidakmampuan untuk batuk efektif saat ada sekresi). • Ini adalah efek samping yang berpotensi serius karena sekresi yang ditahan dapat menyebabkan atelektasis, pneumonia, hipoksia, dan gagal napas. • Mual, muntah, sembelit, pusing, kantuk, pruritus, kehilangan kesadaran, insomnia, sulit bernafas dan ketergantungan obat: berhubungan dengan agen narkotika. Ketika narkotika diberikan untuk efek antitusif, namun diberikan dalam dosis yang relatif kecil dan tidak menimbulkan reaksi yang merugikan. ANTITUSSIVES Drug interactions • Drugs that increase antitussive effects of codeine : CNS depressants (, antianxiety agents, , and other sedative-hypnotics) - Additive CNS depression. Codeine is given in small doses for antitussive effects, and risks of significant interactions are minimal. Drugs that alter effects of dextromethorphan : • MAO inhibitors  This combination is contra- indicated. Apnea, muscular rigidity, hyperpyrexia, laryngospasm, and death may occur. ANTITUSSIVES GENERAL PRECAUTION : • Anti cough agents that include codeine, dextromethorphan, butamirat are not recommended for using in kids (to 2 years of age), during pregnancy and lactation. • Agents that include glaucini hydrochloridum may provoke decreasing of arterial blood pressure in kids. • Anti cough agents that include dextromethorphan may cause CNS and breathing depression if using in hight doses or for a long period. • Anti cough agents that include butamirat, dextromethorphan may cause weakness, sleepiness, dizziness. CODEIN • Codeine phosphate is an opioid analgesic with uses similar to those of morphine, but is much << potent as an analgesic & has only mild sedative effects. Mechanism of Action and Effects : • Selectively suppress cough center in medulla oblongata. Its primary site of action is at the opioid receptors distributed throughout the central nervous system. • Codeine phosphate reduces intestinal motility through both a local and possibly central mechanism of action. • Codeine phosphate also suppresses the cough reflex by a direct central action, probably in the medulla or pons. CODEIN Potency : • Analgesia : 1/7 of morphine • Suppression of cough : 1/10 of morphine • Respiratory depression, constipation, tolerance, dependence ＜ that of morphine Clinical Uses : • Dry cough & moderate pain Pharmacokinetic : • Codeine is readily absorbed from the GI tract & metabolised by O- and N-demethylation in the liver  morphine & norcodeine which with codeine are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid. CODEIN • Codeine and its salts are absorbed from the gastro-intestinal tract and onset of analgesic action occurs 30 to 45 minutes after administration, when given orally. • Peak effect is reached within 1 to 2 hours and the duration of antitussive action is 4 hours and 4 to 6 hours respectively. CODEIN Dosage and administration : • Adults = for non-productive cough the usual dose is 10 mg – 20 mg every 4-6 hours to a maximum total of 120 mg in 24 hours. • Paediatric = for cough children may be given up to 0.25 mg per kg every 4 - 6 hours. • On the basis of available data, codeine and other opioid cough suppressants should rarely be administered to children less than 6 to 12 months old. • They should not be given in productive cough. CODEIN Contra Indications : • Known hypersensitivity to codeine • Acute respiratory depression (cyanosis and excessive bronchial secretion) • Obstructive airways disease • Acute alcoholism • Head injuries or conditions in which intracranial pressure ↑ • Patients at risk of paralytic ileus • Hepatic failure • Acute asthma attack • Heart failure secondary to chronic lung disease • Diarrhoea associated with pseudomembranous colitis or diarrhoea caused by poisoning • Patients taking MAOI DEXTROMETHORPHAN Chemistry : • Dextrorotatory stereoisomers of a methylated derivative of levorphanol. Clinical Use : • Dry cough and combined with drug. • Dextromethorphan is chemically related to codeine and acts on the brain to suppress cough, but does not have the pain-relieving and addictive properties of codeine Pharmacodynamics : • DMP acts centrally to elevate the threshold for coughing, and has no significant analgesic / sedative properties at antitussive doses. DEXTROMETHORPHAN • It is proposed that DMP is a glutamate and NMDA antagonist, and blocks the dopamine reuptake site. It may also increase 5HT 1A activity possibly via NMDA antagonism. Pharmacokinetics : • DMP is rapidly absorbed from the gastrointestinal tract and peak plasma concentrations are reached in approximately 2.5 hours. • DMP is widely distributed, and is rapidly and extensively metabolized by the liver. DMP is demethylated to , an active metabolite, and to 3- methoxymorphinan and 3-hydroxymorphinan. DEXTROMETHORPHAN • It is primarily excreted as unchanged parent drug and dextrorphan. • Route of Administration : oral. DEXTROMETHORPHAN

• Potency, Purity and Dose : • Adults & children aged ≥ 12 years = 60-120 mg daily in divided doses; • Children aged 6-12 years = 30-60 mg daily in divided doses; • Children aged 2-6 years = 15-30 mg daily in divided doses. PENTOXYVERINE •Suppression of cough : ≈1/3 of codeine. •Direct suppression of cough center CLOPERASTINE •Derivative of •Suppression of cough center

•Blocking H1-receptor LEVODROPROPIZINE Mechanism of Action : • Levodropropizine is a non-opioid agent whose peripheral antitussive action may result from its modulation of sensory neuropeptide levels within the respiratory tract. • In particular, levodropropizine exerts its antitussive effect through an inhibitory action at the level of the airway sensory nerves and it has been shown to be able to inhibit in vitro the release of neuropeptides from C- fibers. • The activity of levodropropizine on airway sensory units other than the C-fibres has not been investigated. LEVODROPROPIZINE Pharmacokinetics : • After oral administration of Levodropropizine, the drug is rapidly absorbed in the GIT. • The peak plasma concentration can be achieved within 40 minutes after administration of Levodropropizine. • The plasma protein-binding capability of Levodropropizine is about 13%. Precautions : • Levodropropizine is contraindicated in patients with excessive mucus discharge or limited mucociliary functions, severe hepatic disorders and allergy to levodroperizine. • Levodropropizine can cause dizziness. LEVODROPROPIZINE Other Drug Interactions : • Levodropropizine may interact with alcohol, sedatives, hypnotics and sedating anti- drugs. Dosage : • Adults : consider administration of 60 mg of Levodropropizine, thrice daily. The duration should not exceed more than seven days. • Pediatrics : children >2 years, consider administration of 1 mg/kg, thrice daily. Children >12 years, consider administration of 60 mg of Levodropropizine, thrice daily. The duration should not exceed more than seven days. LEVODROPROPIZINE Contra Indications : • USFDA pregnancy category D. Levodropropizine can harm the unborn fetus. • Avoid breast feeding. MUCOACTIVE AGENTS

1. EXPECTORANTS DEFINITION : • Expectorants are defined as that improve the ability to expectorate purulent secretions. This term is now taken to mean medications that increase airway water or the volume of airway secretions, including secretagogues that are meant to increase the hydration of luminal secretions (eg, hypertonic saline or ) and abhesives that decrease the adhesivity of secretions and thus unstick them from the airway (eg, surfactants). • Expectorants are agents given orally to liquefy respiratory secretions and allow for their easier removal. 1. EXPECTORANTS

MECHANISM OF ACTIONS : • Increase volume or hydration of airway secretion : Systemic hydration  no clinical effect Classic expectorant  no clinical effect Modifier of airway water transport (being investigated) • Expectorants do not alter ciliary beat frequency or mucociliary clearance. Oral expectorants were once thought to increase airway mucus secretion by acting on the gastric mucosa to stimulate the vagus nerve, but that is probably inaccurate. 1. EXPECTORANTS PREPARAT : The most commonly used expectorants are simple hydration, including :

• Bland aerosol / fog inhalation (1.8% NaCl, 2% ~ 7.5% NaHCO3) • Oral hydration • Iodide-containing compounds such as super-saturated or iodinated glycerol • Ammonium chloride • Glyceryl guaiacolate () • The more recently developed ion-channel modifiers such as the P2Y2 purinergic agonists 1. EXPECTORANTS GUAIFENESIN • Oral expectorant that is believed to increase the leaking of fluid out of the lung tissue and into the airways. This action thins (liquefies) the thick mucous in the airways and facilitates the clearing of the mucous by coughing. Clearing of mucous from the airways decreases cough. • Guaifenesin is the most commonly used expectorant. It is available alone and as an ingredient in many combination cough and cold remedies, although research studies do not support its effectiveness and many authorities do not recommend its use. 1. EXPECTORANTS OTHER EXPECTORANTS •Hot beverages, potassium iodide, and ipecac stimulate production of watery mucus. • In the first 2-3 days of reception of expectorants a cough and separation of sputum can increase : these phenomena testify to efficiency of preparation. • Plant decoctions and extracts render not only coughing up action, but also the regenerations of the damaged mucous membrane of bronchial tubes promote due to the contained microelements, vitamins and biogenic stimulators. 1. EXPECTORANTS EFFICACY • Expectorants show their clinical efficiency on 6-7 days of treatment. • At presence of acute inflammatory process herbal expectorants are preferable.

ADVERSE EFFECTS •At an overdose or prolonged reception of preparations, containing iodides, the origin of iodism is possible : rhinitis, somnolence, swelling; hyperthyroidism - tachicardia, tremor, insomnia, diarrhea are possible (more frequent at persons after 40 years). • Don’t combine expectorants with drugs that supress cough reflex. EXPECTORANTS 2. MUCOLYTICS MECHANISM OF ACTIONS : • Degrade polymers in secretion • Mucolytics are administered by inhalation to liquefy mucus in the respiratory tract. Solutions of mucolytic drugs may be nebulized into a face mask or mouthpiece or instilled directly into the respiratory tract through a tracheostomy.

CLASSIFICATIONS : A. Thiol with free sulphydryl groups (classic mucolytics) • N – Acetyl Cystein (NAC) : Disrupts disulfide bond  making mucus less resistant. 2. MUCOLYTICS NAC can be taken orally, inhalation or instillation Sodium chloride solution and are the only agents recommended for use as mucolytics. Oral acetylcysteine is widely used in the treatment of acetaminophen overdosage. Acetylcysteine is effective within 1 minute after inhalation, and maximal effects occur within 5 to 10 minutes. It is effective immediately after direct instillation. Side effects : • GIT irritation (oral) • Burning sensation in airways (inhalation) • Bronchospasm (inhalation) • Sulphorous taste & odor (inhalation) 2. MUCOLYTICS A. Thiol with free sulphydryl groups (classic mucolytics) • L – Cystein ethyl ester hydrochloride : Given orally Biotransformed in liver to NAC Used in COPD Has no GIT side effects B. Thiol with blocked sulphydryl group • Preparate : S-caboxymethyl (SCMC) Does not break mucin disulfide bonds Increases nasal mucociliary clearance in chronic sinusitis (not in chronic bronchitis) • Second generation mucolytic & free radical scavenging activity (antioxidant) : erdostein 2. MUCOLYTICS C. Proteolytic enzymes (peptide enzymes)  They decreases sputum viscidity

Indications •Indications : all forms of tracheobronchitis, emphysema with bronchitis pneumoconiosis, chronic inflammatory pulmonary conditions, bronchiectasis, bronchitis with bronchospasm asthma. During acute exacerbations of bronchitis it should be given with the appropriate antibiotic. •Contraindications : there are no absolute contraindications but in patients with gastric ulceration relative caution should be observed. 2. MUCOLYTICS Precaution • Acetylcysteine may cause pulmonary hemorrage, liver and kidney function disturbances, may provoke attack of asthma. 3. MUCOKINETICS Mechanism of Action : • Increase mucociliary efficiency or cough efficiency Agents : • Bronchodilators : they increase cough flow in patients with airway hyperactivity e.g. B2 agonist & theophylline  cilio-stimulant and bronchodilator • Ipratropium has no anti-mucokinetic • Abhesives : such as surfactants Pharmacological Action : • Decrease mucus attachment to cilia and epithelium • Increase cough and mucociliaryeffect 4. MUCOREGULATORY AGENT Mechanism of Action : • Decrease the volume of airway mucus secretion • Effective in hypersecretorystates (bronchorrhea and bronchial asthma) • Long-term oral administration causes decrease in water and mucus secretion in airway Agents : A. Anti-inflammatory agents : Iidomethacin & corticosteroids B. agents C. Macrolide antibiotics : erythromycin, clarithromycin, and azithromycin 5. OTHER MUCO – ACTIVE AGENTS A. Bromohexine & • Bromohexine increases expectoration of sputum in chronic bronchitis. • Ambroxol stimulates mucus secretion and causes normalization of mucus viscosity in viscid secretion. • / ambroxole may effectively decrease viscosity of bronchial secretions. • Ambroxol is a clinically proven systemically active mucolytic agent. When administered orally onset of action occurs after about 30 minutes. The breakdown of acid mucopolysaccharide fibers makes the sputum thinner and less viscous and therefore more easily removed by coughing. 5. OTHER MUCO – ACTIVE AGENTS A. Bromohexine & Ambroxol • Although sputum volume eventually decreases, its viscosity remains low for as long as treatment is maintained. • Bromhexine and ambroxole stimuly surfactant synthesis, making better alveolar cells function, and help clearing of mucous from the airways.

B. Saline solution (isotonic, 0.9%) • Uses :  For routine nebulisation therapy  Hydration of mucus 5. OTHER MUCO – ACTIVE AGENTS C. Sodium bicarbonate (2%) : alkaline environment causes decrease in mucus elasticity • If mucus secretion increases, viscidity decreases

Therapeutic Uses of Mucoactiveagents : • Respiratory mucostasis e.g. chronic bronchitis, asthma & cystic fibrosis • Chronic sinusitis (+ antibiotics) • With antibiotics for treatment of airway infections e.g. bronchiectasis • Prophylaxis of post-operative chest complications • Sputum production for diagnostic purposes e.g. T.B. 2. MUCOLYTICS

Precaution • Ambroxol is contraindicated in first term of pregnancy. • Don’t use ambroxol in kids to 3 years age. • Bromhexine and ambroxole may increase liver transaminase activity. Bromhexine and ambroxole are not combined with codeine including drugs.

TOPICAL COUGH

•Camphor and are topical cough medications. Camphor and menthol ointments are rubbed on the throat and the chest as a thick layer. The anesthetic action of their vapors is believed to relieve cough. They are also available as products for steam inhalation. Menthol is also available as lozenges and compressed tablets. ASMA BRONCHIALE

• Pathophysiology : • Asthma is a disease characterized by airway inflammation and episodic, reversible bronchospasm • Two characteristic features : 1) Inflammatory changes in the airway 2) Bronchial hyperreactivity to stimuli

• Important mediators : histamine, LTC4, LTD4, etc. ASTHMA BRONCHIALE

BASIC PHARMACOLOGY OF AGENTS USED IN THE TREATMENT OF ASTHMA MANAGEMENT OF ACUTE SEVERE ASTHMA

• Assessment of asthma severity • Life-threatening asthma (e.g. silent chest, exhaustion, cyanosis, peak flow 33% of predicted or best, saturation 92%) needs urgent treatment with : • High flow oxygen (FiO2 40–60% oxygen); • Glucocorticosteroids : hydrocortisone i.v., followed by prednisolone p.o.. • Nebulized β2-agonist (e.g. salbutamol) plus ipratropium; via oxygen-driven nebulizer. MANAGEMENT OF ACUTE SEVERE ASTHMA

– If the response to the above bronchodilator treatment is inadequate or not sustained, consider intravenous bronchodilator : β2-agonist (e.g. salbutamol by i.v. infusion), or aminophylline/theophylline (by slow i.v. injection). • Antibiotic (co-amoxiclav or clarithromycin), if bacterial infection is strongly suspected – beware potential interactions with theophylline. PRINCIPLES OF DRUG USE IN TREATING CHRONIC ASTHMA

1. Metered dose inhalers (MDIs) of β2-agonists • Convenient and with correct usage little drug enters the systemic circulation. • Inhalation formulations include : – Metered-dose inhaler – aerosol – Aerosol administered via a nebulizer – As a dry powder inhaler • Aerosols are particularly useful for treating an acute episode of breathlessness. PRINCIPLES OF DRUG USE IN TREATING CHRONIC ASTHMA • Long-acting β2-agonist (salmeterol) should be taken regularly with top-ups of ‘on-demand’ shorter- acting agents. • Oral preparations have a role in young children who cannot co-ordinate inhalation with activation of a metered-dose inhaler. Children over five years can use inhaled drugs with a ‘spacer’ device. Oral formulations, including slow-release preparations. PRINCIPLES OF DRUG USE IN TREATING CHRONIC ASTHMA

2. Patients should contact their physician promptly if their clinical state deteriorates or their β2-agonist use is increasing. 3. Inhaled glucocorticosteroids (beclometasone, fluticasone, budesonide) are initiated when symptoms are not controlled or when : • regular (rather than occasional, as needed) doses of short-acting β2-agonist bronchodilator are required • repeated attacks interfere with work or school. PRINCIPLES OF DRUG USE IN TREATING CHRONIC ASTHMA 4. Leukotriene receptor antagonists (e.g. montelukast) are used in adults and children for long-term maintenance therapy and can reduce glucocorticosteroid requirements. 5. In moderate to severe steroid-dependent chronic asthma, the anti-IgE monoclonal antibody omalizumab can improve asthmatic control and reduce the need for glucocorticosteroids. ANTI ASTHMATIC DRUGS I. Bronchodilators 1. β receptor agonists 2. Theophylline 3. Muscarinic antagonists II. Anti-inflammatory agents 1. Steroids 2. Anti-leukotriene agents III. Anti-allergic agents 1. Stabilizer of inflammatory cell membrane

2. H1 receptor blocker 3. Anti – IgE antibody BRONCHODILATORS BETA-ADRENOCEPTOR AGONISTS A. Prototypes and Pharmacokinetics • Adrenaline : α, β agonist • Ephedrine : α, β agonist

• Isoprenaline : β1 ,β2 agonist

• β2-selective agonists •Salbutamol •Terbutaline short / intermediate- •Clenbuterol acting •Formoterol •Salmeterol long-acting •Bambuterol BETA-ADRENOCEPTOR AGONISTS A. Prototypes and Pharmacokinetics • The most important sympathomimetics used to reverse asthmatic bronchoconstriction  direct-acting β2-selective agonists. • Short-acting agents : albuterol, terbutaline, metaproterenol (durations of action of 6 h or less). • Long-acting β2-selective agonists : salmeterol, formoterol, and indacaterol (act for 12–24 h), but indacaterol is currently approved only for COPD. • Given by inhalation, usually from pressurized aerosol canisters but occasionally by nebulizer  decreases the systemic dose (↓ adverse effects) & delivering an effective dose locally to the airway smooth muscle. B. Mechanism and Effects • Beta-adrenoceptor agonists stimulate adenylyl cyclase (via the β2-adrenoceptor–Gs-coupling protein-adenylyl cyclase pathway) and increase cyclic adenosine monophosphate (cAMP) in smooth muscle cells  results in a powerful bronchodilator response. C. Clinical Use • Shorter acting (albuterol, metaproterenol, terbutaline)  for acute episodes of bronchospasm. Their effects last for 4 h or less  not effective for prophylaxis. • Long-acting agents (salmeterol)  used for prophylaxis (12-h duration of action is useful). They should not be used for acute episodes  onset of action is too slow. • Furthermore, used alone  increase asthma mortality, whereas in combination with corticosteroids  improve control. • Shorter-acting β agonists : • most effective bronchodilators available • life-saving for acute asthma. • chronic obstructive pulmonary disease (COPD) also benefit D. Toxicity • Skeletal muscle : tremor is a common adverse β2 effect. • CV : beta2 selectivity is relative  at high clinical dosage, these agents have significant β1 effects. Even when they are given by inhalation, some cardiac effect (tachycardia) is common. Excessively  arrhythmias may occur. Loss of responsiveness (tolerance, tachyphylaxis) is an unwanted effect of excessive use of the short-acting sympathomimetics. • Metabolism disturbance : ketone bodies↑, acidosis

METHYLXANTHINES A. Prototypes and Pharmacokinetics • The methylxanthines are purine derivatives. 3 major methylxanthines are found in plants and provide the stimulant effects of 3 common beverages: caffeine (in coffee), theophylline (tea), and theobromine (cocoa). Theophylline is the only member of this group that is important in the treatment of asthma. • This drug and several analogs are orally active and available as various salts and as the base. Theophylline is available in both prompt-release and slow-release forms, eliminated by P450 drug-metabolizing enzymes in the liver. • Clearance varies with age (highest in young adolescents), smoking status (higher in smokers), and concurrent use of other drugs that inhibit or induce hepatic enzymes. B. Mechanism of Action and Effects • Methylxanthines inhibit phosphodiesterase (PDE), enzyme that degrades cAMP to AMP  cAMP accumulation. • Block adenosine receptors • Increase endogenous catecholamine (CA) releasing 2+ 2+ • Interfere with receptor-operated Ca channels → [Ca ]i↓ • Anti-inflammatory action C. Clinical Use • Slow-release theophylline (for control of nocturnal asthma). • Aminophylline is a salt of theophylline that is sometimes prescribed. D. Toxicity • Narrow margin of safety. Toxic effects are related to its plasma concentrations. • The common adverse effects : GI distress, tremor, insomnia. • Overdosage : severe nausea and vomiting, hypotension, cardiac arrhythmias, and seizures. • Very large overdoses (eg, in suicide attempts) : potentially lethal because of arrhythmias and seizures. • Beta blockers are useful in reversing severe cardiovascular toxicity from theophylline.

MUSCARINIC ANTAGONISTS A. Prototypes and Pharmacokinetics

• There are M1, M2, M3 receptor subtype in the airway.

• Selectively blocking M1, M3 receptor is resulted in bronchodilating effect.

• Ipratropium bromide binds to all M-R subtypes (M1, M2 and M3), and inhibits acetylcholine-mediated bronchospasm. • Atropine & other naturally belladonna alkaloids have been replaced by ipratropium, a quaternary antimuscarinic agent designed for aerosol use. • Ipratropium is delivered to the airways by pressurized aerosol  little systemic action. Tiotropium is a longer- acting analog. MUSCARINIC ANTAGONISTS B. Mechanism of Action and Effects • Ipratropium & tiotropium competitively block muscarinic receptors in the airways  effectively prevent broncho- constriction mediated by vagal discharge. • Muscarinic antagonists reverse bronchoconstriction especially children and in many patients with COPD. • They have no effect on the chronic inflammatory aspects of asthma. C. Clinical Use • Ipratropium and tiotropium are useful in one third to two thirds of asthmatic patients. • For acute bronchospasm, the β agonists are usually preferred than muscarinic antagonists. • In COPD, which is often associated with acute episodes of bronchospasm, the antimuscarinic agents may be more effective and less toxic than β agonists. D. Toxicity • Ipratropium and tiotropium are delivered directly to the airway and are minimally absorbed, systemic effects are small. • Excessive dosage  minor atropine-like toxic effects. • In contrast to the β2 agonists, muscarinic antagonists do not cause tremor or arrhythmias.

ANTI- INFLAMMATORY AGENTS GLUCOCORTICOIDS 319 343 346 A. Prototypes and Pharmacokinetics • All the corticosteroids are potentially beneficial in severe asthma. However, because of their toxicity, systemic (oral) corticosteroids (usually prednisone) are used chronically only when other therapies are unsuccessful. • In contrast, local aerosol administration of surface-active corticosteroids (eg, beclomethasone, budesonide, dexamethasone, flunisolide, fluticasone, mometasone) is relatively safe, and inhaled corticosteroids have become common first-line therapy for individuals with moderate to severe asthma. • Important intravenous corticosteroids for status asthmaticus include prednisolone (the active metabolite of prednisone) and hydrocortisone. B. Mechanism of Action & Effects • Corticosteroids reduce the synthesis of arachidonic acid by phospholipase A2 and inhibit the expression of COX-2, the inducible form of cyclooxygenase. It has also been suggested that corticosteroids increase the responsiveness of β adrenoceptors in the airway and they probably act by other mechanisms as well. • Glucocorticoids bind to intracellular receptors and activate glucocorticoid response elements (GREs) in the nucleus, resulting in synthesis of substances that prevent the full expression of inflammation and allergy. • Reduced activity of phospholipase A2 is thought to be particularly important in asthma because the leukotrienes that result from eicosanoid synthesis are extremely potent bronchoconstrictors and may also participate in the late inflammatory response. C. Clinical Use and Toxicity • Inhaled glucocorticoids are now considered appropriate (even for children) in most cases of moderate asthma that are not fully responsive to aerosol β agonists. • It is believed that such early use may prevent the severe, progressive inflammatory changes characteristic of long- standing asthma. This is a shift from earlier beliefs that steroids should be used only in severe refractory asthma. • In such cases of severe asthma, patients are usually hospitalized and stabilized on daily systemic prednisone and then switched to inhaled or alternate-day oral therapy before discharge. • In status asthmaticus, parenteral steroids are lifesaving. Patients with COPD tend to be more resistant to the beneficial effects of steroids. • The major systemic toxicities of the glucocorticoids are much more likely to occur when systemic treatment is required for more than 2 weeks, as in severe refractory asthma. Regular use of inhaled steroids does cause mild growth retardation in children, but these children eventually reach full predicted adult stature.

LEUKOTRIENE ANTAGONISTS A. Leukotriene Receptor Blockers • Mechanism of Action : Cysteinyl leukotrienes is a important inflammatory mediator of bronchoconstriction, increased bronchial reactivity, mucosal edema, mucus hypersecretion, etc. These drugs interfere with the synthesis or the action of the leukotrienes. Although their value has been established, they are not as effective as corticosteroids in severe asthma. • Prototypes : Zafirlukast and montelukast are antagonists at the LTD4 leukotriene receptor. The LTE4 receptor is also blocked. Orally active and effective in preventing exercise, antigen & aspirin-induced bronchospasm. • Toxicity : They are not recommended for acute episodes of asthma. Toxicity is generally low. Rare reports of allergic granulomatous angiitis, have appeared, but an association with these drugs has not been established.

B. Lipoxygenase Inhibitor • Mechanism of Action : Leukotrienes resulte from the action of 5-lipoxygenase on arachidonic acid. Zileuton (5-lipoxygenase inhibitor) is an orally active drug that selectively inhibits 5-lipoxygenase, a key enzyme in the conversion of arachidonic acid to leukotrienes. • Toxicity : Elevation of liver enzymes, and this drug is therefore less popular than the receptor blockers.

ANTI-ALLERGIC AGENTS DISODIUM CROMOGLYCATE A. Prototypes and Pharmacokinetics • Madiators release inhibitors & no bronchodilator action. • Cromolyn (disodium cromoglycate) and nedocromil are unusually insoluble chemicals, so that even massive doses given orally or by aerosol result in minimal systemic blood levels. • They are given by aerosol for asthma but are now rarely used in the United States. • Cromolyn is the prototype of this group. B. Mechanism of Action and Effects • The mechanism of action of these drugs is poorly understood but may involve IgE-mediated reactions in these tissues.  Stabilizer of mass cell membrane : decrease the release of mediators from mast cells (histamine).  Inhibit the function of sensory nerve ending and neurogenic inflammation in airway.  Decrease bronchial hyperreactivity. • The drugs have no bronchodilator action but can prevent bronchoconstriction caused by a challenge with antigen to which the patient is allergic. • Cromolyn and nedocromil are capable of preventing both early and late responses to challenge. • Because they are not absorbed from the site of administration, cromolyn and nedocromil have only local effects. C. Clinical Uses and Toxicity • Asthma (especially in children) was the most important use for cromolyn and nedocromil. Nasal and eyedrop formulations of cromolyn are available for hay fever. • When administered orally, cromolyn has some efficacy in preventing food allergy. Similar actions have been demonstrated after local application in the conjunctiva and the nasopharynx for allergic. D. Toxicity • Cromolyn and nedocromil may cause cough and irritation of the airway when given by aerosol. Rare instances of drug allergy have been reported.

H1 RECEPTOR BLOCKER A. Effects • H1 receptor—This Gq-coupled receptor is important in smooth muscle effects, especially those caused by IgE- mediated responses. Inositol trisphosphate (IP3) and diacylglycerol (DAG) are the second messengers. • Typical responses include pain and itching in the skin, bronchoconstriction, and vasodilation, the latter caused by release of . • Capillary endothelial cells, in addition to releasing nitric oxide (NO) and other vasodilating substances, also contract, opening gaps in the permeability barrier and leading to the formation of local edema. These effects occur in allergic reactions.

B. Mechanism and Effects • H1 blockers are competitive pharmacologic antagonists at the H1 receptor; these drugs have no effect on histamine release from storage sites. They are more effective if given before histamine release occurs. • As noted, most older first-generation agents are sedating. C. Clinical Use • H1 blockers have major applications in allergies of the immediate type (ie, those caused by antigens acting on IgE antibody sensitized mast cells). These conditions include hay fever and urticaria. • Adverse effects of the first-generation H1 blockers are sometimes exploited therapeutically (eg, in their use as hypnotics in over-the-counter sleep aids).

D. Toxicity and Interactions • Sedation is common, especially with diphenhydramine. It is much less common with second-generation agents, which do not enter the CNS readily. • Antimuscarinic effects such as dry mouth and blurred vision occur with some first generation drugs in some patients. • Alpha-adrenoceptor blockade, which is significant with phenothiazine derivatives such as , may cause orthostatic hypotension. • Interactions occur between older and other drugs with sedative effects ( and alcohol).

D. Toxicity and Interactions • Drugs that inhibit hepatic metabolism may result in dangerously high levels of certain antihistaminic drugs that are taken concurrently. For example, azole antifungal drugs and certain other CYP3A4 inhibitors interfere with the metabolism of and , 2 second- generation agents that have been withdrawn from the US market because high plasma concentrations of either antihistamine can precipitate lethal arrhythmias. ANTI-IgE ANTIBODY • Omalizumab is a humanized murine monoclonal antibody to human IgE. It binds to the IgE on sensitized mast cells and prevents activation by asthma triggers and subsequent release of inflammatory mediators. • Although approved in 2003 for the prophylactic management of asthma, experience with this drug is limited because it is very expensive and must be administered parenterally.

Salbutamol nebule 2,5 mg amp No. I Adult nebulizer mask No. I S imm Combivent nebule amp No. I Adult nebulizer mask No. I S imm Symbicort turbuhaler / MDI No. I S 2 dd puff I Thank you!

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