Respiratory System Drugs PDF

RESPIRATORY SYSTEM DRUGS Drugs for Cough and Chapter 16 Bronchial Asthma DRUGS FOR COUGH to drain th e airway: its suppression is not Cough is a protective reflex, its pu rpose being desirable; may even be ha...

RESPIRATORY SYSTEM DRUGS Drugs for Cough and Chapter 16 Bronchial Asthma DRUGS FOR COUGH to drain th e airway: its suppression is not Cough is a protective reflex, its pu rpose being desirable; may even be harmful , except when expulsion of respiratory secretions a nd foreign the amount of expectoration achieved is small particles from ai r passages. It occurs due to com pared to the effort of continuous coughing. stimulation of mechano- or c hemo receptors The commonest cause of acute cough (lasting in throat and respiratory passages or stretch < 3 weeks) is respiratory vira l infections. Apart receptors in the lungs. Cough may be useful or from specific remedies (anti biotics, e tc. see useless. Useless (nonproductive) cough should box on p. 238), cough may be treated as a be suppressed. Useful (productive) cough serves symptom (nonspecific therapy) w ith: DRUGS FOR COUGH Expectorants (Mucokinetics) Lozenges Salbutamol Syrups Secretion Mucolytics Terbutaline Glycerine enhancers Liquorice Pot. citra te Bromhexine Antitusslves Pot. iodide Ambroxol (Cough centre Guaiphenesin Acetylcyste ine suppressants) Tolu balsam Carbocistcine Vasaka Ammon. chloride I I I I Opioids INonopioids Antihistaminics Codeine oscapine Chlorpheniramine Ethylmorphine Dextromethorphan Diphenhydramine Pholcodine Chlophcdianol Promethazine 238 RESPIRATORY SYSTEM DRUGS DEMULCENTS AND EXPECTORANTS Mucolytics Bromhexine A derivative of the alkalo id vasi- Phary ngeal demulcents soothe the th roat and cine obtained from Adhatoda vasica ( Vasaka), reduce afferent impulses fro m the i nnamed/ is a mucoly tic and mucokinetic. capab le of i rritated ph ary ngea l muco sa, thus p ro v ide i nduci ng thin copious bronchi al secret io n. It sy mpto m ati c re li ef i n dry co ug h ari s i ng depolymerises mucopolysaccharides directly as from throat. well as by liberating lysosomal enzymes- net- Ex pecto rants (Mucok inetics) arc drugs work o f fibres in tenacious sputum is broken. It believed to increase bronchial secretion or reduce is particularly usefu l i f mucus plugs ar e present. its v iscosity, facilitating its removal by coughing. Side effects are rhinorrhoea and lacrimation, Sodium and potassium citrate are considered nausea. gastric irritation, hy persensitiv ity. to increase bronchial secreti on by salt action. Dose: adults 8 mg TDS, children 1-5 years 4 mg BD. Potassium iodide is secreted by bronchial glands 5-10 years 4 mg TDS. and can irritate the airway mucosa. Prolonged BROMIIEXINE 8 mg tablet, 4 mg/5 ml cltxir. use can affect thy roid functio n and produce Ambroxol A metabolite of bromhex ine hav ing i odi sm. I t i s no t u sed now. Guai phenesin , si milar mucolytic action, uses and side effects. vasaka , tolu balsam are plant products w hich Dose: 15- 30 mg TDS. AMBRIL, AMBROLITE, AMBRODlL, MUCOLITE 30 are supposed to enhance bronchial secretion mg tab, 30 mg/5 ml liquid, 7.5 mg/ml drops, and mucociliary function while being secreted ACOCONTfN 75 mg CR tab. by tracheobronchial g lands. A mmonium salts Acetylcysteine I t opens di sulfide bo nds i n are nauseating- re fl exly increase respirator y mucoproteins prese nt in sputum and makes secretions. it less v isc id. It can be admi nistered orally A variety of expectorant formulations conta in- (200-600 mg TDS) as well as by i nhalatio n o f ing an assortment o f the above ingredients, o ften I 0-20% nebulized solution. In intubated patients, in combination w ith antitussi ves/ antihistaminics the thick sticky secretion can be l iquefied by are marketed and briskly promoted, but obj ective instillation o f I 0- 20% acetylcy stei ne sol ution evidence of effi cacy of expec torants is no n- directly into the respiratory tract. conclusive. The US-FDA has stopped marketing MUCOTAB 600 mg tab, FLUIMUCIL 200 mg, 600 mg of all expectorants, except guaiphenesin. Steam effervescent tab; "1UCOMIX 200 mg/ml inj in l,2,5 ml inhalation and proper hy dration may be more amps. The injectable solution can be nebu l ized/ helpful in clearing airway mucus. instilled through tracheo tomy tube. Specific treatment approaches to cough Etiology of cough Treatment approach Upper/lower respiratory tract infection Appropriate antibiotics Smoking/chronic bronchitis/ Cessation of smoking/avoidance of pollutants, steam inhalation, bronchiectasis postural drainage Pulmonary tuberculosis Antitubercular drugs Asthmatic cough Inhaled p2 agonists/corticosteroids/ipratropium Cough in pulmonary eosinophilia Diethyl carbamazine citrate, inhaled corticosteroids Postnasal drip due to sinusitis Antibiotic, nasal decongestant, H, antihistaminic Postnasal drip due to allergic/perennial Avoidance of precipitating factor(s), corticosteroid nasal spray, rhinitis H, antihistaminic Gastroesophageal reflux Bed head elevation, light dinner, diet modification, H2 blocker, proton pump inhibitor, mosapride ACE inhibitor associated cough Substitute AC E inhibitor by angiotensin receptor blocker, NSAI Ds may reduce cough Post-viral cough No specific treatment, subsides by itself.  DRUGS FO R COUGH AND BRONC HIAL ASTH MA 239 The gastric mucus barrier may be breached the receptors med iating the t\vo actions are not by orally administered acetylcystcine. idemical. Abuse lia bility is low, but present; Carbocisteine It liquefies viscid sputum in the constipation is t he chief drawback. At higher same way as acctylcysteine and is administe red doses respirato ry depression and drowsiness can orally (250- 750 mg TDS). Some pa tients of occur, especially in c hildren. Driving may be chronic bronchitis have been shown to benefit. impaired. Like morphi ne, it is contraindicated Jt may break the gastric mucus barrier; there- in asthmatics and in patients with diminished fore is contrai ndicated in peptic ulcer patients. respiratory reserve; should be avoided in children. Dose: Anti1ussivc dose is lesser than analgesic dose. I 0-30 Side efTects are gastric discomfort and rashes. mg; children 2- 6 years 2.5-5 mg, 6- 12 years 5 10 mg, MUCODY\/L 375 mg cap. 250 mg/5 ml syr frequently used as syrup codeine phos. 4-8 ml. It is available in combination with amoxicillin or cephalcxin CODD,1E 15 rng tab. 15 mg/5 ml linctu;,. for treatment of bronch itis, bronchiectasis, sinusitis, etc. CA RBOMOX : Carbocisteinc 150 mg amoxicilhn 250 Ethylmorphine It is closely re lated to code ine o r 500 mg caps. CARBICEF: Carboci,teinc 150 mg "'- which is methylmorph ine, and has antitussive, cephalexin 250 or 500 mg caps. respiratory depressant properties Iike it, but is Mucolytics are specifically useful in patie nts be lieved to be less constipat ing. with tracheostomy, asthmatic bronchitis, cystic Dose: 10-30 mg TDS; DIONIJ\DO!\ 16 mg tab. fi brosis, etc. who have thick tenacious sputum Pholcodine It has practically no analgesic or addict ing or mucus plugs. property, but is similar in emcacy as antitussive to codeine and is longer acting-acts for 12 ho urs; dose: 10-15 mg. ANTITUSSIVES Nonopioid antitussives These are drugs that act in the CNS to raise the Noscapine (Narcotine) An opium alkaloid thresho ld of cough centre or act peri pherally in of the benzoisoquin oline series (see Ch. 34), the respiratory tract to reduce tussal impulses, whi c h depresses cough but has no na rcotic, or both these acti ons. B eca use they a im to ana lges ic or depende nce indu cing propert ies. control rather than eliminate cough, antitussive It is nearly equipotent antitussive as code ine, drugs should be used only for dry nonproductive especially useful in spasmodic cough. Headache cough or if it is unduly tiring, disturbs sleep and nausea occur occasionally as side effect. or is hazardous (hernia, piles, cardiac d isease. It can re lease histamine and produce broncho- ocular surgery). constric tion in asthmatic. Dose: 15- 30 mg, children 2 6 years 7. 5 mg, 6 12 years Opioid antitussives 15mg. COSCOPJ 7 mg/5 ml syrup, COSCOTABS 25 mg tab. Morphine and its congeners are the most effective antitussives, but morph ine is not suitable for Dextromethorphan A synthetic central MDA treating cough, because of its strong addicting ( -methy l D-aspartate) receptor antagonist; the and respiratory depressant property. d-isomer has antitussive action while /-isomer is analgesic. Dextromethorphan does not depress Codeine (see Ch. 34) An o pium a lkaloid, mucociliary function of the airway mucosa and qualitatively similar to and less potent than is practically devoid of constipating action. morph ine, but is more se lect ive fo r cough Though cons idered nonaddi cting, some drug centre. Code ine is regard ed as the standard abusers indulge in it. antitussive; suppresses cough for about 6 hours. The antitussive action is blocked by naloxone Side effect: Dizziness, nausea, drowsiness; at indi cating that it is exerted through opioid high doses hallucinations and atax ia may occur. Dose: 10-20 mg, children, 6-12 years 5-10 m~. It is a receptors in the brain. That in certain opioid common ingredient of many proprietary cough fonnulations congeners. antitussive action can be dissociated (see antitussive comb inations below), but not advocated from the analgesic-addicting action, indicates that for children < 6 years. 240 RESP IRATORY SYSTEM DRUGS Ch/ophedianol It is a centrally acting anti- Aeromatic chest rub is widely advertized as a cough tussive with weak antihistami nic, anticholinergic remedy. Though it has been shown to reduce experimentally induced cough in healthy volunteers, there is no evidence and local anaesthetic properties. Onset of action of benefit in pathological cough. is slow and duration longer. Side effect: Dryness of mouth, vertigo, irritability. SOME ANTITUSSIVE-EXPECTORANT Dose: 20--40 mg. COMBINATIONS Prenoxdiazine A drug developed in Hungary which ASTHALI EXPECTORANT: Salbutamol 2 mg, guaiphc- acts as antitussive by desensitizing the pulmonary stretch ne,in 100 mg per 10 ml syr; dose 10 20 ml. receptors. Tussal impulses originating in the lungs arc ASCOR IL-C: Codeine 10 mg, chlorpheniraminc 4 mg suppressed. Efficacy, however, is not impressive. per 5 ml syr. Dose: I00-200 mg TDS; PRENOXID I00, 200 mg tab. AXALIN: Ambroxol 15 mg, guaiphenesin 50 mg. salbu- tamol I mg, menthol I mg per 5 ml syr. Antihistamines DRONCIIOSOLVl'J: Guaiphenesin 100 mg. tcrbutalin 2.5 Many H1 antihistamines have been conventionally mg, bromhexinc 8 mg per 10 ml susp. added to antitussive/expectorant formulations (see CADICOFf. GRILINCTLS; De>-1romcthorphan 5 mg, below). They afford relief in cough due to their chlorphcniraminc 2.5 mg, guaiphencsin 50 mg. Amm. sedative and anticholinergic actions, but lack chloride 60 mg per 5 ml syr. selectivity for the cough centre. They have no BENADRYL COUGH FORMULA: Diphenhydruminc 14 expectorant property, may even reduce secretions mg, amm. chlor. 138 mg, sod. citrate 57 mg, menthol I. I mg per 5 ml s}rup; dose 5- 10 ml, children 2.5 5 ml. by anticholinergic action. They have been specially BRO-ZEDEX: Dromhcxine 8 mg, guaiphcnesin 100 mg, promoted for cough in respiratory allergic states, tcrbutaline 2.5 mg. menthol 5 mg per IO ml :,yrup; dose though their lack of efficacy in asthma is legendary. 10 ml. Chlorpheniramine (2- 5 mg), Diphenhydra- CADISTI EXPECTORAJ\;T: Chlorphcniramine 2 mg. gl)c- mi ne ( 15- 25 mg) and Promethazine ( 15- eryl guaiacolatc 80 mg. amm. chi or. I00 mg, sod. citrate 25 mg; PIIENERGA 5 mg/5 ml cli-.ir) are com- 44 mg, menthol 0.8 mg, tcrpin hydrme 4 mg, tolu balsam monly used. Second generation antihistamines 6 mg, Vasaka syrup 0.13 1111 per 5 ml syrup: dose 10 ml. like fexofenadine, loratadine, etc. are ineffective. CHERICOF: Dextromcthorphan 10 mg, chlorpheniramine 2 mg. phenylpropanolam111e 12.5 mg per 5 ml liq. Bronchodilators Bronchospasm can induce CLISTN: Carbinoxaminc 4 mg, amm. chlor. 240 mg, sod. or aggravate cough. Stimulation of pulmonary citrate 240 mg per IO ml ,yrup. receptors can trigger both cough and broncho- COREX: Chlorphenirumine 4 mg, codeine phos. 10 mg, constriction, especially in individuals with bronchial menthol 0. 1 mg per 5 ml syrup; do:,c 5 ml. children hyperreactivity. Bronchodilators relieve cough in 1.15 2.5 ml. such individuals and improve the effectiveness of COSCOPI:-: LI CTUS: o:,capine 7 mg. chlorphcniraminc cough in clearing secretions by increasing surface 2 mg. citric acid 29 mg, 50d. citrate 3 mg, amm. chlor. velocity of airflow during the act of coughing. 28 mg, per 5 ml syrup; dose 10 20 ml. They should be used only when an element of COSOME: Dc,tromethorphJn IO mg, phcnylpropanolamine bronchoconstriction is present and not routinely. 25 mg. chlorphenir=inc 4 mg per 10 ml syr; dose 10 ml. Their fixed dose combinations with antitussives GRILll\('TUS: De:\trornethorphan 5 mg, chlorphcniraminc are not satisfactory because of differences in 2.5 mg, guaiphencsin 50 mg, ammon. chlor. 60 mg/5 ml time course of action of the components and syr; dose 5-10 ml. liability for indiscriminate use. GRILi 'CTUS SOFTCAPS: Dextromcthorphan 10 mg. chlor- Fixed dose combinations of a centrally acting antitussivc pheniramme 2 mg, phenylpropanolammc 12.5 mg softcap~. with a bronchodilator or with an antihistaminic having SOLVIN EXPECTORANT: Bromhc,ine 4 mg, pseudocphc- high atropinic activity have been banned in India, but drinc 30 mg tablet and in 10 ml liquid; dose I tablct/5 many are still marketed. ml liquid. Majority of the FDC cough formulations TOSSEX: Codcmc pho, JO mg, chlorphcnirami11e 4 mg. that are marketed and briskly advertized are menthol 1.5 mg, sod. citrate 75 mg per 5 ml liquid; irrational and have only placebo effect. dose 5 ml.  DRUGS FOR CO UGH AND BRONCH IAL ASTHMA 241 VCNTORLl'-i EXPECTORA T: Salbutamol 2 mg. guaiphc- perpetuates itself by cell-to-cell communication nesin I 00 mg per IO ml s) rup; c.Jose IO ml, children and recruitment of more and more lymphocytes, 2.5 7.5 ml. eosinophils and neutrophils. Bronchial smooth 21:.ET u,cTUS : Dextromcthorphan 10 mg. guaiphcnesm 50 mg, pbenylpropanolamin~ 25 mg per 5 ml syr; dose 5 ml. muscle hypertrophy, increase in the population of mucus secreting cells and blood vessels occurs DRUGS FOR BRONCHIAL ASTHMA over time and damage to bronchial epithelium accentuates the hyperreactivity. Vagal d ischarge Bronchial asthma is characterised by hyperres- to bronchial muscle is enhanced reflexly. Airway ponsiveness of tracheobronchial smooth muscle remodeling progressively worsens the disease. to a variety of stimuli, resulting in narrowing Chronic obstructive pulmonary disease (COPD) is also of air tubes, often accompanied by increased an inflammatory disease of the airways and lungs where secretion, mucosa! edema and mucus plugging. inflammation is dominated by neutrophils. macrophages and Symptoms include dyspnoea, wheezing, cough cytotoxic lymphocytes. It is characterized by progressive emphysema (alveolar destruction) and bronchiolar fibrosis in and may be limitation of activity. variable proportions. Loss of bronchiolar elasticity leads to Asthma is now recognized to be a primarily closure of smaller air tubes during expiration. The airway inflammatory condition: inflammation underlying obstruction is accentuated during exercise causing shortness hyperreactivity. An allergic basis can be demon- of breath. The expiratory airflow limitation does not fluctuate markedly over long periods of time, but there are exacerba- strated in many adult, and higher percentage of tions precipitated by respiratory infections, pollutants, etc. pediatric patients. In others, a variety of trigger COPD is clearly related to smoking and characteristically factors (infection, irritants, pollution, exercise, starts after the age of 40. Quiting smoking reduces the exposure to cold air, psychogenic) may be in- rate of decline in lung function. Bronchodilators prevent closure of peripheral air tubes during expiration and afford volved. Two principal varieties are recognised: symptomatic relief in COPD patients, but improvement in Extrinsic asthma: It is mostly episodic, less forced expiratory volume in 1st second (FEY,) following prone to status asthmaticus. inhalation of a shortacting [3, agonist is generally 9 cups o f co fTec per day has actions, but there are marked quantitative (Table been fou nd to be associated ,, ith increased inc idence of arrhythmias. moderate ingestion of cafTeinc (uplo 500 mg/ I 6.1) and pharmacokinetic di fTerences. day) does not increase frequency or severity of cardiac arrhythmias e,en in patients "ith ischaemic hean disease Table 16.1 : Comparative pharmacological actions or preexis1ing , entricular cxtrasyslolcs. of caffeine and theo h lhne ACTION GAFF. THEO. Meth y lxanthines, espec ia lly theophyl Iine, 1. CNS-stimulation (low dose) +++ ++ dilate systemic blood vessels. inc luding corona- - toxicity ++ +++ ries, by direct action: peripheral resistance is 2. Heart-stimulation ++ +++ reduced. However, cranial vessels are constric- 3. Blood vessel- relaxation + ++ 4. Bronchi -dilatation + +++ ted, especiall y by caffei ne; this is one of the 5. Kidney-diuresis + ++ basis of its use in migraine. 6. Sk. muscle-increased +++ ++ Effect o f methy lxanthines on BP is variable contractility and unpredictable- 7. Gastric mucosa- irritation + ++ 8. Phosphodiesterase inhibition ++ +++ Vasomotor centre a nd direct cardiac stimu- 9. Adenosine antagonism ++ +++ lation- tends to raise BP. GAFF-Caffeine; THEO-Theophylllne Vagal stimulation and direct vasodi latation- Theobromlne is of no therapeutic importance. tends to lower BP.  DRUGS FOR COUGH AND BRONCH IAL ASTHMA 245 Usually a rise in systolic and fall in diastolic to its therapeut ic effect in bronc hial asth ma BP is observed. and COPD. 3. Smooth muscles All smooth muscles arc Mechanism of action Three di stinct cellular relaxed; most promine nt cfTect is exerted on actions of methylxanthines have been defined- bronchi, especially in asthmatics. Theophylline is (a) Release of Ca2 ' from sarcoplasmic reticu- more potent bronchodi lator than caffeine. Slow lum, especially in skeletal and cardiac muscle. and sustained dose-related bronchodilatation is (b) Inhibition of phosphodiesterase (PDE) which produced, but the effect is much less marked degrades cycl ic nucleotides intracellularly. compared to that of inhaled ~. agonists. Vital A l I' adcm"(r/crc/ase cAMP phosphodie11erase 5-AMP capacity is increased. Biliary spasm is relieved, or - - - - -- or - -- -- - - or but effect on intestines and urinary tract is GTP l(Uan_,·(rln dase cGM P /.\ 1//BITED Ill 5-GMP TI/EOPIIILLI VE negligible. Consequently the concentration of cyclic 4. Kidney Methylxanthines are mild diuretics. nucleotides is increased. Bronchodilatation. They act by in hibiting tubular reabsorption of cardiac stim ulation and vasod ilatation occur and a' and water as well as increased renal blood mediator release is inhibited w he n cA MP level flow and g.f.r. However, the action is brief. rises in the bronchial/cardiac/ vascular smooth 5. Skeletal muscles Caffeine en hances muscle and in inflammatory cells, respectively. contracti le power of skeletal muscles. At high Several isoenzymcs of the PDE supcrfamily exist in dil~ concentrations it increases release of Ca2 ' from fcrent tissues o r which PDE3 and PDE4 appear to be sarcoplasmic reticulum by direct action. Al low involved in causing bronchodi latation and in inhibiting cytokine/inftammatory mediator release. doses, twitch response to nerve stimulation is Some selecti ve PDE4 mhibitors have been produced in augmented , whil e at toxic doses contraclure the hope of finding an effec11vc drug for asthma/COPD is produced. without the ancndant toxicuy as in Lheophyllinc. However, majority wcr~ clinically disappoint ing, hut one of the m In addition, caffeine facilitates neuromuscular Rojlumilast has been approved by US-FDA for symptomatic trans mission by increasing ACh release. The treatme nt of COPD (but not bronchial asthma). It exert, central action of caffeine relieves fatigue and antiin0ammatory action, primarily in the lungs. Lung func- increases muscular work. Enhanced diaphrag- tion i~ improved and risk of exacerbation, is reduced. Most common ad,·erse effect is diarrhoea. Psychiatric disturbances matic contractility noted with theophylline in and weight loss arc reported. Ronumilast appears to be a the therapeutic conce ntration range probably promis ing treatment option for moderate-to-severe cases of contributes to its beneficial effects in dyspnoea COPD. TI1eophy lline is a subtype nonselccti,c and weak and COPD. PDE inhibitor. (c) Blockade of adenosinc receptors: adenosine 6. Stomach Methy lxa nthines enhance secre- acts as a local mediator in CNS. CVS and tion of acid and peps in in stomach. even other organs. Adenosi ne co ntracts smoo th on parenteral injection. They arc also gastric irritants- thcophyllinc more than caffeine. muscles, especially bronchial; dilates cerebral blood vesse ls. depresses cardiac pacemaker 7. Metabolism Caffeine and to a smaller extent and inhibits gastric secretion. Mcthylxanthines theophylline increase BMR. Plasma free fatty produce opposite effects. acid levels a re raised. They induce release of Action (a) is exerted only at concentrations endogeno us catecholamines, wh ic h appears to much higher than therapeutic plasma concentra- be partly responsible for these effects. tions (range 5- 20 µg/ml) of caffeine and theo- 8. Mast cells and inflammatory cells Theo- phylline. Action (b) and act ion (c) are exerted phyll inc decreases release of histamine, othe r a t concentrations in the therapeutic range mediators and cytokines from mast cells and and appear to contribute to bronchodilatation. activated inflammatory cells. This may contribute Raised cAM P levels in inflammatory cells may 246 RESPIRATORY SYSTEM DRUGS atte nuate medi ator release and promote eo- early symptoms. Children are more liable to sinoph i I a poptosis, add ing to th e therapeutic develop C S tox icity. effect of theophylli ne in asthma. Adenosine A 1 receptor antagonism is considered responsible z l~#:it!Mof Death IM!Jtolii'I 0 for card iac arrhythmias a nd seizures occurring j:: Convulsions, shock, anilythmias in theophylline toxicity. Delirium, worsening cardiovascular sta1us Increased muscle lone, extrasystoles, c( Recent evidence suggests 1ha1 lo" concentrations of.J flashes of light seen 1heophylline enhance histonc dcace1yla1ion in airway inflam- B Agitation, tachypnoea. flushing, hypotension matory cells, suppressing proinflammatory gene transcription. 0 ResUessness. tremors. vomiting, Thus. even sub-bronchodilator doses of theophylline may I palpitation, diuresis l) exert ome beneficial effect in asthma. z Dyspepsia. headache, nervousness. insomnia (Phannacokinetics, adverse effects and uses of 0 ,..... a::: Minimal side effects caffeine are described in C h. 35) al Fig. 16.1 : Relationship between efficacy and toxicity of Theophylline theophylline with its plasma concentration. The depicted concentration ranges are approximate Pharmacokinetics Theophyllinc is well absor- bed orally; rectal absorption from suppositories The irritant property oftheophylline is reflected is erratic. It is distributed in al l tissues-crosses in gastric pai n (w ith oral), rectal inflammation placenta and is secreted in mi lk ( V 0.5 I/kg), (with suppositories) and pain at site of i.m. 50% plasma prote in bound and extensively injection. Rapid i. v. injection causes precordial metabo lized in l iver by demethylation a nd pai n, syncope and even sudden death- due to ox idation primarily by CY P IA2. Only 10% marked fa ll in BP, ventricula r arrhythmias or is excreted unc hanged in urine. Elimination asystole. rate of th eophylli ne varies considerably with age. At therapeutic concentrations, the t½ in Interactions ad ults is 7- 12 hou rs. Child ren eliminate it I. Agents which enhance theophy lline metabo- much faster (t½ 3-5 hours) and elderl y more lism primarily by inducing CYP I A2 lower its slowly. In premature infants the t½ is markedly p lasma level: dose has to be increased by the prolonged (24-36 hours). The re arc pronounced factor given in pare111hesis. interindividual variations in plasma concentrations Smoking ( 1.6), phcnytoin ( 1.5), rifampicin anai ned with the same dose. ( 1.5), phenobarbitone ( 1.2), c ha rcoal broiled T heop hy ll ine metabo lizing enzymes are meat meal ( 1.3). saturable, t½ is prolonged with higher doses 2. Drugs which inhibit thcophylline metabolism (to as much as 60 hours) as kinetics changes from firs t to zero order. Plasma concentrations, and increase its plasma level arc--erythromyci n, therefore, increase di sproportionately with dose. ciprofl oxacin , cimetidine, oral contraceptives, Factors which need dose reduction are- age allopurinol; dose shou ld be reduced to 2/3. > 60 yr ( x 0.6), CHF ( x 0.6), pneumonia 3. Theop hylline enhances the effects of- (x 0.4). liver fai lure (x 0.2- 0.4). furosem ide, sympathomi metics. d igitalis, oral Adverse effects Theophylli ne has a narrow anticoagulants, hypoglycaemics. margin of safety. Dose-dependent toxicity 4. Theophylline decreases the efTects of- pheny- starts from the upper part of therapeutic con- toin, lithium. 5. Aminophylline injection should not be mixed in the same centration range ( Fig. 16. 1). Ad verse effects infusion bonle/syringe with- ascorbic acid. chlorproma7ine, are primarily referable to the g.i.t., C S and prometha7ine, morphine. peth idine. phcnytoin. phenobarbi- CVS. Headache, nervousness and nausea are tone, insulin, penicillinG, tetracyclines, erythromycin.  DRUGS FOR COUGH AND BRONCHIAL ASTHMA 247 Preparations and dose severe asthma as an adjuvant drug, especially (i) Theophylline (Anhydrous) I 00-300 mg TDS (15 mg/kg/ in patients with nocturnal asthma. It is more day) oral, THEOLO'\G 100, 200 mg SR cap., DURALYN- useful in COPD, and often added to othe r drugs. CR 400 mg continuous release cap, UNICONTIN 400 mg, Use of intravenous aminophylline in status 600 mg CR tabs, TII EOBID 200 mg, 300 mg S R tabs. Only sustained release (SR) tab.leaps. whi ch produce asthmaticus is outmoded. effective blood levels for ~ 12 hours are used , because 2. Apnoea in premature infant: Theophylli ne fast release tabs. produce high peak and low trough plasma reduces the frequency and duration of episodes concentrations. of apnoea that occur in some preterm infants in Because solubility o f theophyllioc is low, a number of the first few weeks of life. Closely monitored soluble complexes and salts have been produced for oral and for parenteral use. oral or i.v. treatment is employed for 1- 3 weeks. Caffeine is equally effective. (ii) Aminophylline (Theophylline-ethylenediamine; 85% theophylline) water soluble, can be injected i. ,. but not i.m. or s.c.- highly irritating. 250-500 mg oral or slow ANTICHOLINERGIC DRUGS (see Ch. 8) i.v. injection; children 7.5 mg/kg i.v.; AMI NOPHYLLl'-IE 100 mg tab. 250 mg/10 ml inj. Atropinic drugs cause bronchodilatation by (iii) Hydroxyethyl theophyl/ine (Etophylline, 80% blocking M 3 receptor mediated choli nergic theophylline) water soluble; can be injected i. v. and constri ctor tone. They act primarily in the i.m. (but not s.c.), less irritating: 250 mg oral/i.m.li.v.; larger airways (Fig. 16.2) which receive vagal D ERIPIIY LLI 100 mg tab., 300 mg S R tab., 220 innervation. However, some recent evidence mg/2 ml inj. points to presence of M3 receptors on peripheral (iv) Theophylline ethanolate of piperazine 250-500 mg oral or i.v.; CA DIPIIYLLAT E 80 mg/5 ml elixir, ETO- bronchiolar muscles as well, though these are PHYLATE 125 mg/5 ml syrup. not vagally innervated. Doxophyl/ine A long-acting oral melhylxanthine that is claimed not to interfere with sleep or stimulate gastric secretion. adrenergic receptor ~2 Dose: 400 mg OD or BO, children 12 mg/kg/day; DOXOBID, e M3 muscarinic receptor DOXOVENT, DOXORIL 400 mg tab, 100 mg/5 ml syr. The double salts/derivatives of theophylline are claimed to be less gastric irritant and better a bsorbed. However, anhydrous tbeophylline is completely absorbed and gastric irritancy of the salts is the same in terms of theophyll ine content. Uses 1. Bronchial asthma and COPD: Theophylline may benefit by causing bronchodilatation as well as by decreasing release of inflammatory mediato rs, improvin g mucoci liary c learance, stimulating respiratory drive and by augmenting diaphragmatic contractility. However, it has Anticholinergics several lim itations, viz, poor tolerabi Iity, nar- row safety margin, lower e ffi cacy and wide Fig. 16.2: Primary sites of bronchodilator action of inhaled individual variability, because of which its use adrenergic ~. agonists and inhaled anticholinergics. Salbutamol mainly relaxes bronchio lar smooth muscle; has declined. Sustained release theophylline is lpratropium blocks b ronchoconstriction mainly in the occasionally employed in mild-to-moderate ly larger airways 248 RESPIRATORY SYSTEM DRUGS Jpratropium bromide is a short acting (dura- and other inflammatory cells in the lungs tion 4-6 hours) inhaled anticholinergic bron- are important mediators of bronchial asthma, chodilator, while tiotropium bromide is long efforts were made to develop their antagonists acting (duration 24 hours). Administered as and synthesis inhibitors. Two cysLTt receptor aerosol, they produce minimal antimuscarinic antagonists montelukast and zafirlukast are now side effects due to poor systemic absorption. established drugs for asthma. Anticholinergics are less efficacious than inhaled Montelukast and Zafirlukast Both have p2 sympathomimetics in bronchial asthma. s imilar actions and clinical utility. They However, patients of asthmatic bronchitis, competitively a ntagonize cysLTt receptor COPD and psychogenic asthma respond bet- (see p. 205) mediated bronchoconstriction, ter to anticholinergics. Reflex cholinergic tone airway mucus secretion, increased vascular appears to be the major reversible component permeability and recruitment of eosinophils. of airway obstructi on in COPD. Inhaled anti- Bronchodilatation, reduced sputum eosinophil cholinergics a re the bronchodilators of choice in count, suppression of bronchial inflammation, COPD. Tiotropium is rated more effective than mucus and hyperreactivity are noted in asthma ipratropium in COPD; more suitable for severe patients. Parameters of Iung function show cases (FEVt