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 laringdan saluran pernapasan bagian bawah, mengirimkan impulske 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 refleksbatuk yang ditimbulkan oleh agen tussive meningkat padapenderita asma dengan batuk, mengikuti infeksi saluranpernapasan bagian atas pada individu sehat dan pada pasiendengan batuk yang diinduksi ACE.

PHYSIOLOGY OF COUGH

•Batuk biasanya terjadi ketika reseptor sensorik disaluran pernapasan menerima rangsangan denganintensitas yang cukup untuk membangkitkanpeningkatan aktivitas impuls saraf sensorik / aferen.Refleks batuk dapat dipicu dengan mudah olehrangsangan mekanis dan kimia yang terjadi di laringatau trakeobronkial, karena di sinilah perlindunganterbesar terhadap masuknya bahan asingdiperlukan.• Informasi sensorik dari saluran pernafasan yang

memulai refleks batuk melalui nervus vagus.

COUGH IN DISEASE

•Batuk sering terjadi pada asma dan selama infeksisaluran pernafasan bagian atas disertai denganpembengkakan saluran udara.

•Etiologi batuk pada anak berbeda dengan orangdewasa: virus URTI, bronkitis bakteri dan asma yangberkepanjangan sering menjadi penyebab anak-anak batuk. Jadi, pendekatan empiris yang biasadigunakan pada orang dewasa tidak sesuai untukanak-anak. Evaluasi klinis batuk pada anak jugaharus mencakup penilaian faktor lingkungan.

ANTITUSSIVE AGENTS

SITE AND MECHANISMS OF ACTION OF ANTITUSSIVE AGENTS

•Batuk dikaitkan dengan kelebihan produksi lendir didalam paru-paru, penekanan refleks batukumumnya tidak diperlukan, karena retensi lendirdapat terjadi yang dapat menyebabkan komplikasiserius.

•Bila batuk tidak produktif dan menjadi gangguan,tidur dan istirahat, penekanan menjadi diperlukan,meski penekanan menyeluruh bisa berbahayakarena paru-paru kemudian kehilangan mekanismepertahanan yang esensial

• Obat ideal akan mengurangi peningkatan sensitivitas refleksbatuk normal, sebaiknya dengan mengeluarkan prosespenyakit atau dengan mengurangi responsivitas reseptorsensorik saluran napas.

• Reseptor sensori nafas yang paling jelas untuk ditargetkanadalah RAR. Obat yang mempengaruhi batuk juga bisadiberikan secara tidak langsung. Misalnya, obat yangmenyebabkan bronkodilatasi, seperti agonis reseptor danantagonis kolineptor yang digunakan pada asma,mengurangi refleks batuk tanpa memiliki efek sentral yangsignifikan.

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

SITE AND MECHANISMS OF ACTION OF ANTITUSSIVE AGENTS•Antitussive effects of the classical opiates, such as

codeine and morphine, were generally reported to bemediated centrally.

•Opioid receptors on the afferent / sensory neurones ofthe vagus nerves.

•Codein & morphine with opioid-receptor-mediatedantitussive actions can modulate impulse activity inairway sensory neurones originating from RARs and C-fibre receptors.

•Antitussive activity of drugs such as codeine is notrestricted entirely to the central nervous system, but thatsome of its activity is also exerted peripherally.

Classification :

A. Central Antitussives / Cough Supressants

1. Dependent Central Antitussives (Opioid)2. Independent Central Antitussives (Non

Opioid)B. Peripheral Antitussives

Note : codeine, dextromethorphan and cloperastine areamong the most common central agents that inhibitcough primarily by their effect on the cough center.

ANTITUSSIVES

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, buthave addiction.

• Ex : codeine, hydrocodone.

INDEPENDENT CENTRAL ANTITUSSIVES

• Non opioid / narcotic alkaloids.

• Stereoisomers of opioid molecules that are devoidof analgesic effects and addiction liability.

• Classification :1) Orphan – antitussives : dextromethorphan2) Amido – antitussives : pentoxyverine,

clofedanol3) Piperidine – antitussives : cloperastine4) Morpholine – antitussives : promolate,

fominoben5) Others : eprazinone, zipeprol

PERIPHERAL ANTITUSSIVESInhibiting receptor, afferent nerve, efferent nerveof cough reflex arc → cough suppression.1. local anesthesia action : narcotine, benzonatate2. Alleviative action : extractum glycyrrhizae

liquidum

PERIPHERAL ANTITUSSIVES•Levodropropizine is a non-opioid agent whoseperipheral antitussive action may result from itsmodulation of sensory neuropeptide levelswithin the respiratory tract.

•Locally acting agents (throat lozenges, coughdrops) may suppress cough by increasing the flowof saliva and by containing demulcents or localanesthetics to decrease irritation of pharyngealmucosa.

Indication for use of antitussives :

•A dry, hacking, nonproductive cough that interfereswith rest and sleep.

• It is not desirable to suppress a productive coughbecause 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

ANTITUSSIVESDrug interactions

• Drugs that increase antitussive effects of codeine :CNS depressants (alcohol, antianxiety agents,barbiturates, and other sedative-hypnotics) -Additive CNS depression. Codeine is given in smalldoses for antitussive effects, and risks of significantinteractions are minimal.

Drugs that alter effects of dextromethorphan :

• MAO inhibitors This combination is contra-indicated. Apnea, muscular rigidity, hyperpyrexia,laryngospasm, and death may occur.

ANTITUSSIVESGENERAL PRECAUTION :• Anti cough agents that include codeine,

dextromethorphan, butamirat are notrecommended for using in kids (to 2 years of age),during pregnancy and lactation.

• Agents that include glaucini hydrochloridum mayprovoke decreasing of arterial blood pressure inkids.

• Anti cough agents that include dextromethorphanmay cause CNS and breathing depression if using inhight 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 asan 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 opioidreceptors distributed throughout the central nervoussystem.

• Codeine phosphate reduces intestinal motility throughboth a local and possibly central mechanism of action.

• Codeine phosphate also suppresses the cough reflexby a direct central action, probably in the medulla orpons.

CODEINPotency :

• 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.

CODEINDosage 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.

CODEINContra 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

DEXTROMETHORPHANChemistry :

•Dextrorotatory stereoisomers of a methylated derivativeof levorphanol.

Clinical Use :

•Dry cough and combined with antihistamine drug.

•Dextromethorphan is chemically related to codeine andacts on the brain to suppress cough, but does not havethe pain-relieving and addictive properties of codeine

Pharmacodynamics :

•DMP acts centrally to elevate the threshold for coughing,and has no significant analgesic / sedative properties atantitussive doses.

DEXTROMETHORPHAN• It is proposed that DMP is a glutamate and NMDA

antagonist, and blocks the dopamine reuptake site. It mayalso increase 5HT 1A activity possibly via NMDAantagonism.

Pharmacokinetics :

•DMP is rapidly absorbed from the gastrointestinal tractand peak plasma concentrations are reached inapproximately 2.5 hours.

•DMP is widely distributed, and is rapidly and extensivelymetabolized by the liver. DMP is demethylated todextrorphan, 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 diphenhydramine

•Suppression of cough center

•Blocking H1-receptor

LEVODROPROPIZINEMechanism of Action :

• Levodropropizine is a non-opioid agent whoseperipheral antitussive action may result from itsmodulation of sensory neuropeptide levels within therespiratory tract.

• In particular, levodropropizine exerts its antitussiveeffect through an inhibitory action at the level of theairway sensory nerves and it has been shown to be ableto inhibit in vitro the release of neuropeptides from C-fibers.

•The activity of levodropropizine on airway sensory unitsother than the C-fibres has not been investigated.

LEVODROPROPIZINEPharmacokinetics :

•After oral administration of Levodropropizine, the drug israpidly absorbed in the GIT.

•The peak plasma concentration can be achieved within40 minutes after administration of Levodropropizine.

•The plasma protein-binding capability ofLevodropropizine is about 13%.

Precautions :

• Levodropropizine is contraindicated in patients withexcessive mucus discharge or limited mucociliaryfunctions, severe hepatic disorders and allergy tolevodroperizine.

• Levodropropizine can cause dizziness.

LEVODROPROPIZINE

Other Drug Interactions :

• Levodropropizine may interact with alcohol, sedatives,hypnotics and sedating anti-histamine drugs.

Dosage :

• Adults : consider administration of 60 mg ofLevodropropizine, thrice daily. The duration should notexceed more than seven days.

•Pediatrics : children >2 years, consider administration of1 mg/kg, thrice daily. Children >12 years, consideradministration of 60 mg of Levodropropizine, thricedaily. The duration should not exceed more than sevendays.

LEVODROPROPIZINEContra Indications :

•USFDA pregnancy category D.Levodropropizine can harm theunborn fetus.

•Avoid breast feeding.

MUCOACTIVE AGENTS

1. EXPECTORANTSDEFINITION :

•Expectorants are defined as medications that improvethe ability to expectorate purulent secretions. This termis now taken to mean medications that increase airwaywater or the volume of airway secretions, includingsecretagogues that are meant to increase the hydrationof luminal secretions (eg, hypertonic saline or mannitol)and abhesives that decrease the adhesivity ofsecretions and thus unstick them from the airway (eg,surfactants).

•Expectorants are agents given orally to liquefyrespiratory secretions and allow for their easierremoval.

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 (beinginvestigated)

• Expectorants do not alter ciliary beat frequency ormucociliary clearance. Oral expectorants were oncethought to increase airway mucus secretion by actingon the gastric mucosa to stimulate the vagus nerve, butthat is probably inaccurate.

1. EXPECTORANTSPREPARAT :

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 potassium iodide or iodinatedglycerol

• Ammonium chloride

• Glyceryl guaiacolate (guaifenesin)

• The more recently developed ion-channel modifiers such as the P2Y2 purinergicagonists

GUAIFENESIN

•Oral expectorant that is believed to increase the leakingof fluid out of the lung tissue and into the airways. Thisaction thins (liquefies) the thick mucous in the airwaysand facilitates the clearing of the mucous by coughing.Clearing of mucous from the airways decreases cough.

•Guaifenesin is the most commonly used expectorant. Itis available alone and as an ingredient in manycombination cough and cold remedies, althoughresearch studies do not support its effectiveness andmany authorities do not recommend its use.

1. EXPECTORANTS

OTHER EXPECTORANTS

•Hot beverages, potassium iodide, and ipecacstimulate production of watery mucus.• In the first 2-3 days of reception of expectorants a

cough and separation of sputum can increase : thesephenomena testify to efficiency of preparation.•Plant decoctions and extracts render not only coughing

up action, but also the regenerations of the damagedmucous membrane of bronchial tubes promote due tothe contained microelements, vitamins and biogenicstimulators.

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 ofpreparations, containing iodides, the origin of iodismis possible : rhinitis, somnolence, swelling;hyperthyroidism - tachicardia, tremor, insomnia,diarrhea are possible (more frequent at persons after40 years).•Don’t combine expectorants with drugs that supress

cough reflex.

1. EXPECTORANTS

EXPECTORANTS

MECHANISM OF ACTIONS :

•Degrade polymers in secretion

•Mucolytics are administered by inhalation to liquefymucus in the respiratory tract. Solutions of mucolyticdrugs may be nebulized into a face mask or mouthpieceor instilled directly into the respiratory tract through atracheostomy.

CLASSIFICATIONS :

A. Thiol with free sulphydryl groups (classic mucolytics)

•N – Acetyl Cystein (NAC) :

Disrupts disulfide bond making mucus lessresistant.

2. MUCOLYTICS

NAC can be taken orally, inhalation or instillation

Sodium chloride solution and acetylcysteine are the onlyagents recommended for use as mucolytics.

Oral acetylcysteine is widely used in the treatment ofacetaminophen overdosage.

Acetylcysteine is effective within 1 minute afterinhalation, and maximal effects occur within 5 to 10minutes. It is effective immediately after directinstillation.

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 cysteine (SCMC)

Does not break mucin disulfide bonds

Increases nasal mucociliary clearance in chronic sinusitis(not in chronic bronchitis)

• Second generation mucolytic & free radical scavengingactivity (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 bronchospasmasthma. During acute exacerbations of bronchitis itshould be given with the appropriate antibiotic.•Contraindications : there are no absolute

contraindications but in patients with gastriculceration relative caution should be observed.

2. MUCOLYTICS

Precaution

•Acetylcysteine may cause pulmonary hemorrage, liverand kidney function disturbances, may provoke attackof asthma.

2. MUCOLYTICS

Mechanism of Action :

• Increase mucociliary efficiency or cough efficiency

Agents :

•Bronchodilators : they increase cough flow in patientswith airway hyperactivity e.g. B2 agonist & theophylline cilio-stimulant and bronchodilator

• Ipratropium bromide has no anti-mucokinetic

•Abhesives : such as surfactants

Pharmacological Action :

•Decrease mucus attachment to cilia and epithelium

• Increase cough and mucociliaryeffect

3. MUCOKINETICS

Mechanism of Action :

•Decrease the volume of airway mucus secretion

•Effective in hypersecretorystates (bronchorrhea andbronchial asthma)

• Long-term oral administration causes decrease in waterand mucus secretion in airway

Agents :

A. Anti-inflammatory agents : Iidomethacin &corticosteroids

B. Anticholinergic agents

C. Macrolide antibiotics : erythromycin, clarithromycin,and azithromycin

4. MUCOREGULATORY AGENT

A. Bromohexine & Ambroxol

•Bromohexine increases expectoration of sputum inchronic bronchitis.

•Ambroxol stimulates mucus secretion and causesnormalization of mucus viscosity in viscid secretion.

•Bromhexine / ambroxole may effectively decreaseviscosity of bronchial secretions.

•Ambroxol is a clinically proven systemically activemucolytic agent. When administered orally onset ofaction occurs after about 30 minutes. The breakdownof acid mucopolysaccharide fibers makes the sputumthinner and less viscous and therefore more easilyremoved by coughing.

5. OTHER MUCO – ACTIVE AGENTS

A. Bromohexine & Ambroxol

• Although sputum volume eventually decreases, itsviscosity remains low for as long as treatment ismaintained.

• Bromhexine and ambroxole stimuly surfactantsynthesis, making better alveolar cells function, andhelp 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.

5. OTHER MUCO – ACTIVE AGENTS

Precaution

•Ambroxol is contraindicated in first term of pregnancy.

•Don’t use ambroxol in kids to 3 years age.

•Bromhexine and ambroxole may increase livertransaminase activity. Bromhexine and ambroxole arenot combined with codeine including drugs.

2. MUCOLYTICS

•Camphor and menthol are topical coughmedications. Camphor and menthol ointments arerubbed on the throat and the chest as a thick layer.The anesthetic action of their vapors is believed torelieve cough. They are also available as products forsteam inhalation. Menthol is also available aslozenges and compressed tablets.

TOPICAL COUGH MEDICATION

ASMA BRONCHIALE

• Pathophysiology :

• Asthma is a disease characterized by airwayinflammation and episodic, reversiblebronchospasm

• Two characteristic features :1) Inflammatory changes in the airway2) 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, saturation92%) 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-drivennebulizer.

MANAGEMENT OF ACUTE SEVERE ASTHMA

– If the response to the above bronchodilator treatment is inadequate or notsustained, 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 entersthe 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 acuteepisode of breathlessness.

PRINCIPLES OF DRUG USE IN TREATING CHRONIC ASTHMA

• Long-acting β2-agonist (salmeterol) should be takenregularly with top-ups of ‘on-demand’ shorter-acting agents.

•Oral preparations have a role in young children whocannot co-ordinate inhalation with activation of ametered-dose inhaler. Children over five years canuse inhaled drugs with a ‘spacer’ device. Oralformulations, including slow-release preparations.

PRINCIPLES OF DRUG USE IN TREATING CHRONIC ASTHMA

2. Patients should contact their physician promptly iftheir clinical state deteriorates or their β2-agonist useis increasing.

3. Inhaled glucocorticosteroids (beclometasone,fluticasone, budesonide) are initiated whensymptoms are not controlled or when :

• regular (rather than occasional, as needed) doses of short-acting β2-agonistbronchodilator are required

• repeated attacks interfere with work or school.

PRINCIPLES OF DRUG USE IN TREATING CHRONIC ASTHMA4. Leukotriene receptor antagonists (e.g. montelukast)

are used in adults and children for long-termmaintenance therapy and can reduceglucocorticosteroid requirements.

5. In moderate to severe steroid-dependent chronicasthma, the anti-IgE monoclonal antibody omalizumabcan improve asthmatic control and reduce the need forglucocorticosteroids.

ANTI ASTHMATIC DRUGS

I. Bronchodilators1. β receptor agonists2. Theophylline3. Muscarinic antagonists

II. Anti-inflammatory agents1. Steroids2. Anti-leukotriene agents

III. Anti-allergic agents1. Stabilizer of inflammatory cell membrane2. H1 receptor blocker3. 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•Clenbuterol•Formoterol•Salmeterol•Bambuterol

short / intermediate-acting

long-acting

BETA-ADRENOCEPTOR AGONISTS

A. Prototypes and Pharmacokinetics

• The most important sympathomimetics used to reverseasthmatic bronchoconstriction direct-acting β2-selectiveagonists.

• 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 currentlyapproved only for COPD.

•Given by inhalation, usually from pressurized aerosol canistersbut occasionally by nebulizer decreases the systemic dose(↓ adverse effects) & delivering an effective dose locally tothe airway smooth muscle.

B. Mechanism and Effects

• Beta-adrenoceptor agonists stimulate adenylyl cyclase (via theβ2-adrenoceptor–Gs-coupling protein-adenylyl cyclasepathway) and increase cyclic adenosine monophosphate(cAMP) in smooth muscle cells results in a powerfulbronchodilator response.

C. Clinical Use

• Shorter acting (albuterol, metaproterenol, terbutaline) foracute episodes of bronchospasm. Their effects last for 4 h orless not effective for prophylaxis.

• Long-acting agents (salmeterol) used for prophylaxis (12-hduration of action is useful). They should not be used for acuteepisodes onset of action is too slow.

• Furthermore, used alone increase asthma mortality,whereas in combination with corticosteroids improvecontrol.

• Shorter-acting β agonists :•most effective bronchodilators available• life-saving for acute asthma.• chronic obstructive pulmonary disease (COPD) also

benefitD. 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 aregiven by inhalation, some cardiac effect (tachycardia) iscommon. Excessively arrhythmias may occur. Loss ofresponsiveness (tolerance, tachyphylaxis) is an unwantedeffect of excessive use of the short-actingsympathomimetics.•Metabolism disturbance : ketone bodies↑, acidosis

METHYLXANTHINES

A. Prototypes and Pharmacokinetics

• The methylxanthines are purine derivatives. 3 majormethylxanthines are found in plants and provide thestimulant effects of 3 common beverages: caffeine (incoffee), theophylline (tea), and theobromine (cocoa).Theophylline is the only member of this group that isimportant in the treatment of asthma.

• This drug and several analogs are orally active and availableas various salts and as the base. Theophylline is available inboth prompt-release and slow-release forms, eliminated byP450 drug-metabolizing enzymes in the liver.

• Clearance varies with age (highest in young adolescents),smoking status (higher in smokers), and concurrent use ofother drugs that inhibit or induce hepatic enzymes.

B. Mechanism of Action and Effects

•Methylxanthines inhibit phosphodiesterase (PDE), enzymethat degrades cAMP to AMP cAMP accumulation.

• Block adenosine receptors

• Increase endogenous catecholamine (CA) releasing

• Interfere with receptor-operated Ca2+ channels → [Ca2+]i↓

•Anti-inflammatory action

C. Clinical Use

• Slow-release theophylline (for control of nocturnal asthma).

•Aminophylline is a salt of theophylline that is sometimesprescribed.

D. Toxicity

•Narrow margin of safety. Toxic effects are related to itsplasma 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 severecardiovascular 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 inbronchodilating effect.

• Ipratropium bromide binds to all M-R subtypes (M1, M2and M3), and inhibits acetylcholine-mediatedbronchospasm.

•Atropine & other naturally belladonna alkaloids have beenreplaced by ipratropium, a quaternary antimuscarinicagent designed for aerosol use.

• Ipratropium is delivered to the airways by pressurizedaerosol little systemic action. Tiotropium is a longer-acting analog.

MUSCARINIC ANTAGONISTS

B. Mechanism of Action and Effects

• Ipratropium & tiotropium competitively block muscarinicreceptors in the airways effectively prevent broncho-constriction mediated by vagal discharge.

•Muscarinic antagonists reverse bronchoconstrictionespecially children and in many patients with COPD.

•They have no effect on the chronic inflammatory aspects ofasthma.

C. Clinical Use

• Ipratropium and tiotropium are useful in one third to twothirds of asthmatic patients.

•For acute bronchospasm, the β agonists are usuallypreferred than muscarinic antagonists.

• In COPD, which is often associated with acute episodes ofbronchospasm, the antimuscarinic agents may be moreeffective and less toxic than β agonists.

D. Toxicity

• Ipratropium and tiotropium are delivered directly to theairway and are minimally absorbed, systemic effects aresmall.

•Excessive dosageminor atropine-like toxic effects.

• In contrast to the β2 agonists, muscarinic antagonists donot cause tremor or arrhythmias.

ANTI-INFLAMMATORY

AGENTS

GLUCOCORTICOIDS 319 343 346

A. Prototypes and Pharmacokinetics

•All the corticosteroids are potentially beneficial in severeasthma. However, because of their toxicity, systemic (oral)corticosteroids (usually prednisone) are used chronically onlywhen other therapies are unsuccessful.

• In contrast, local aerosol administration of surface-activecorticosteroids (eg, beclomethasone, budesonide,dexamethasone, flunisolide, fluticasone, mometasone) isrelatively safe, and inhaled corticosteroids have becomecommon first-line therapy for individuals with moderate tosevere asthma.

• Important intravenous corticosteroids for status asthmaticusinclude prednisolone (the active metabolite of prednisone) andhydrocortisone.

B. Mechanism of Action & Effects

• Corticosteroids reduce the synthesis of arachidonic acid byphospholipase A2 and inhibit the expression of COX-2, theinducible form of cyclooxygenase. It has also been suggestedthat corticosteroids increase the responsiveness of βadrenoceptors in the airway and they probably act by othermechanisms as well.

•Glucocorticoids bind to intracellular receptors and activateglucocorticoid response elements (GREs) in the nucleus,resulting in synthesis of substances that prevent the fullexpression of inflammation and allergy.

• Reduced activity of phospholipase A2 is thought to be particularlyimportant in asthma because the leukotrienes that result fromeicosanoid synthesis are extremely potent bronchoconstrictors andmay also participate in the late inflammatory response.

C. Clinical Use and Toxicity

• Inhaled glucocorticoids are now considered appropriate (evenfor children) in most cases of moderate asthma that are notfully 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 thatsteroids should be used only in severe refractory asthma.

• In such cases of severe asthma, patients are usuallyhospitalized and stabilized on daily systemic prednisone andthen switched to inhaled or alternate-day oral therapy beforedischarge.

• In status asthmaticus, parenteral steroids are lifesaving.Patients with COPD tend to be more resistant to the beneficialeffects of steroids.

• The major systemic toxicities of the glucocorticoids are muchmore likely to occur when systemic treatment is required formore than 2 weeks, as in severe refractory asthma. Regularuse of inhaled steroids does cause mild growth retardation inchildren, but these children eventually reach full predictedadult stature.

LEUKOTRIENE ANTAGONISTS

A. Leukotriene Receptor Blockers

•Mechanism of Action :

Cysteinyl leukotrienes is a important inflammatorymediator of bronchoconstriction, increased bronchialreactivity, mucosal edema, mucus hypersecretion, etc.

These drugs interfere with the synthesis or the action ofthe leukotrienes. Although their value has beenestablished, they are not as effective as corticosteroids insevere asthma.

• Prototypes :

Zafirlukast and montelukast are antagonists at the LTD4leukotriene 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 ofasthma.

Toxicity is generally low. Rare reports of allergicgranulomatous angiitis, have appeared, but anassociation with these drugs has not been established.

B. Lipoxygenase Inhibitor

•Mechanism of Action :

Leukotrienes resulte from the action of 5-lipoxygenaseon arachidonic acid.

Zileuton (5-lipoxygenase inhibitor) is an orally activedrug that selectively inhibits 5-lipoxygenase, a keyenzyme in the conversion of arachidonic acid toleukotrienes.

• Toxicity :

Elevation of liver enzymes, and this drug is therefore lesspopular than the receptor blockers.

ANTI-ALLERGIC AGENTS

DISODIUM CROMOGLYCATE

A. Prototypes and Pharmacokinetics

•Madiators release inhibitors & no bronchodilator action.

•Cromolyn (disodium cromoglycate) and nedocromil areunusually insoluble chemicals, so that even massivedoses given orally or by aerosol result in minimalsystemic blood levels.

•They are given by aerosol for asthma but are now rarelyused 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 poorlyunderstood but may involve IgE-mediated reactions inthese 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 inairway.

Decrease bronchial hyperreactivity.

•The drugs have no bronchodilator action but can preventbronchoconstriction caused by a challenge with antigento which the patient is allergic.

•Cromolyn and nedocromil are capable of preventing bothearly and late responses to challenge.

•Because they are not absorbed from the site ofadministration, cromolyn and nedocromil have only localeffects.

C. Clinical Uses and Toxicity

•Asthma (especially in children) was the most important usefor cromolyn and nedocromil. Nasal and eyedropformulations of cromolyn are available for hay fever.

•When administered orally, cromolyn has some efficacy inpreventing food allergy. Similar actions have beendemonstrated after local application in the conjunctiva andthe nasopharynx for allergic.

D. Toxicity

•Cromolyn and nedocromil may cause cough and irritation ofthe airway when given by aerosol. Rare instances of drugallergy have been reported.

H1 RECEPTOR BLOCKER

A. Effects

•H1 receptor—This Gq-coupled receptor is important insmooth muscle effects, especially those caused by IgE-mediated responses. Inositol trisphosphate (IP3) anddiacylglycerol (DAG) are the second messengers.

•Typical responses include pain and itching in the skin,bronchoconstriction, and vasodilation, the latter causedby release of nitric oxide.

•Capillary endothelial cells, in addition to releasing nitricoxide (NO) and other vasodilating substances, alsocontract, opening gaps in the permeability barrier andleading to the formation of local edema. These effectsoccur in allergic reactions.

B. Mechanism and Effects

•H1 blockers are competitive pharmacologic antagonists atthe H1 receptor; these drugs have no effect on histaminerelease from storage sites. They are more effective if givenbefore histamine release occurs.

•As noted, most older first-generation agents are sedating.

C. Clinical Use

•H1 blockers have major applications in allergies of theimmediate type (ie, those caused by antigens acting on IgEantibody sensitized mast cells). These conditions includehay fever and urticaria.

•Adverse effects of the first-generation H1 blockers aresometimes exploited therapeutically (eg, in their use ashypnotics in over-the-counter sleep aids).

D. Toxicity and Interactions

•Sedation is common, especially with diphenhydramine. Itis much less common with second-generation agents,which do not enter the CNS readily.

•Antimuscarinic effects such as dry mouth and blurredvision occur with some first generation drugs in somepatients.

•Alpha-adrenoceptor blockade, which is significant withphenothiazine derivatives such as promethazine, maycause orthostatic hypotension.

• Interactions occur between older antihistamines andother drugs with sedative effects (benzodiazepines andalcohol).

D. Toxicity and Interactions

•Drugs that inhibit hepatic metabolism may result indangerously high levels of certain antihistaminic drugsthat are taken concurrently. For example, azole antifungaldrugs and certain other CYP3A4 inhibitors interfere withthe metabolism of astemizole and terfenadine, 2 second-generation agents that have been withdrawn from the USmarket because high plasma concentrations of eitherantihistamine can precipitate lethal arrhythmias.

ANTI-IgE ANTIBODY

•Omalizumab is a humanized murine monoclonalantibody to human IgE. It binds to the IgE on sensitizedmast cells and prevents activation by asthma triggersand subsequent release of inflammatory mediators.

•Although approved in 2003 for the prophylacticmanagement of asthma, experience with this drug islimited because it is very expensive and must beadministered parenterally.

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