Dr. Mahmoud H. Taleb1 Pharmacology II Lecture 1 Pharmacology of respiratory System Dr. Mahmoud H....

Dr. Mahmoud H. TalebDr. Mahmoud H. Taleb 11

Pharmacology IIPharmacology II

Lecture 1Lecture 1

Pharmacology of respiratory SystemPharmacology of respiratory System

Dr. Mahmoud H. TalebAssistant Professor of Pharmacology and Toxicology

Head of Department of Pharmacology and Medical Sciences, Faculty of Pharmacy- Al azhar University



Drugs affect on respiratory systemDrugs affect the respiratory system in a number of different ways:

Direct local action in the airways: the most important local drug effects on the airways are those that influence the volume and character of bronchial mucus secretion and degree of constriction or relaxation of bronchial smooth muscle.

Remote actions in the CNS with effects on the respiratory control mechanisms: the most important CNS effects are those that diminish the sensitivity of the cough reflex and those that alter the chemosensitivity of the respiratory control centers in the medulla and thus alter the rate and depth of respiration.


Infected or stagnant respiratory secretions contain DNA fibers from bacterial and phagocytic cells which give purulent sputum its yellow or green color.The respiratory-tract fluid is produced from three sources:Goblet cells of the epithelium.Bronchial glands in the mucosa.Serous transudate from the mucosal vasculature.

In bronchitis, goblet cells are greatly increased in number and produce extremely viscous sputum.. However, any agent that increases respiratory tract secretions or decreases their viscosity may act to the detriment of the patient unless the material is propelled upward by normal ciliary activity and either expecteorated by coughing or removed by mechanical suction. Otherwise, mobilized mucus will gravitate into the most dependent areas of the lungs. Where it may impair respiratory function.


Antimucokinetic Agents:The reduction of respiratory-tract fluid production may be accomplished by parasympatholytic drugs such as atropine. This is clinically useful in some situations, such as preparation for general anesthesia.

Mucokinetic Agents "Expectorants:"Agents that increase the production of respiratory tract fluid are often used in order to prevent the drying out of secretions and the plugging of the airways with mucus, and to increase the productiveness of coughing. The most important of these agents are water and saline given as aerosols. The traditional expectorants; whether given by mouth (e.g., glyceryl guaiacolate) or by vapor inhalation (e.g., menthol, camphor, and lemon oils) are of dubious value. However, Potassium iodide solution may be effective, and ipecacuanha (ipecac) apparently initiates a gastric reflex that results in vagal stimulation of the bronchial glands.


Mucolytic Agents:Mucolytic inhalants are mucokinetic substances that liquefy mucus and that are usually given by aerosol to aid the elimination of excess solidified mucus in patients with respiratory disease. Excess mucus may be liquefied by proteolytic agents and disulfide bond cleaving agents. Acetylcysteine ( Aerolin) is the N-acetyl derivative of the amino acid L-cysteine. It possesses a reactive sulfhydryl group that splits the disulfide bonds of the mucin molecule and thereby reduces the viscosity of mucus. This drug is an extremely effective mucokinetic agent, but it is little used because it causes many side effects such as stomatitis, nausea, vomiting,

rhinorrhea, and especially bronchospasm .Bromohexine ( Rx Bisolvon, Solvex , Movex, Mucocare)It stimulates lysosomal activity , leads to hydrolysis of mucopolysaccharides and decrease the viscosity of the mucus


Drugs affecting contraction of bronchial muscle "Antiasthmatic drugs:"

Asthma:Bronchial asthma is a condition characterized by repeated attacks of paroxysmal dyspnea. It is now recognizes that chronic asthma involves a characteristic inflammatory response in the airways that is present in patients with very mild asthma. Bronchial hyperresponsiveness or an exaggerated bronchoconstrictor response to many different stimuli is characteristic of asthma. There is remains considerable debate about the types of inflammatory cells and mediators involved in asthma. Presumably, mediators of inflammation also contribute to the hyperresponsiveness of the bronchi. Although mast cells may be important in the response to allergens and exercise, their exact role in chronic asthma remains less certain. Corticosteroids, which have no direct action on mast cells, inhibit the late response to allergens and thus may prevent or reduce bronchial hyperresponsiveness. Other inflammatory cells such as macrophages, eosinophils, neutrophils, and lymphocytes are also present in the mucusa of patients with asthma, and any of these cells may liberate inflammatory mediators. The most characteristic asthmatic cell is the eosinophil. Lymphokines may be important mediators in increasing the inflammatory response, and interleukin-5 release by lymphocytes also may be important in acting to prime the eosinophils in the mucusa.


Drugs Used in Asthma: Introduction

The clinical hallmarks of asthma are recurrent, episodic bouts of coughing, shortness of breath, chest tightness, and wheezing. In mild asthma, symptoms occur only occasionally, eg, on exposure to allergens or certain pollutants, on exercise, or after a viral upper respiratory infection. More severe forms of asthma are associated with frequent attacks of wheezing dyspnea, especially atرnight, and even chronic limitation of activity. Asthma is the most common chronic disabling disease of childhood, but it affects all age groups.


Asthma is physiologically characterized by increased responsiveness of the trachea and bronchi to various stimuli and by widespread narrowing of the airways that changes in severity either spontaneously or as a result of therapy. Its pathologic features are contraction of airway smooth muscle, mucosal thickening from edema and cellular infiltration, and inspissation in the airway lumen of abnormally thick, viscid plugs of mucus.

Of these causes of airway obstruction, contraction of smooth muscle is most easily reversed by current therapy; reversal of the edema and

cellular infiltration requires sustained treatment with anti-inflammatory agents.


Mechanisms of response to inhaled irritants.


Asthma therapies are thus sometimes divided into two categories: "short-term relievers" and

"long-term controllers".

Short-term relief is most effectively achieved with bronchodilators, agents that increase airway caliber by relaxing airway smooth muscle, and of these the -adrenoceptor stimulants ,Theophylline, a methylxanthine drug, and antimuscarinic agents are also used for reversal of airway constriction.

Long-term control is most often achieved with an anti-inflammatory agent such as an inhaled corticosteroid, with a leukotriene antagonist, or with an inhibitor of mast cell degranulation, eg, cromolyn or nedocromil.


Bronchodilator drugs:Activation of β2-adrenoceptors on the smooth muscle of the airways causes activation of adenylyl cyclase with a subsequent increase in the intracellular concentration of cyclic AMP. In turn, this leads to activation of protein kinase A, which lowers intracellular calcium concentration and thus results in relaxation of the bronchial sooth muscle. Β2-adrenoceptor agonists relax the bronchial smooth muscle from the trachea down to the terminal bronchioles, irrespective of the stimulus that has caused the bronchial smooth muscle to produce bronchoconstriction.

1 -Sympathomimetic agents:Stimulation of β2-adrenocerptors relaxes airway smooth muscle but does not produce the cardiac stimulation that results from β1-recptor activation. Therefore β2-selective drugs are the most important group of adrenoceptor agonists for the treatment of asthma.

Although adrenoceptor agonists may be administered by any route, delivery by inhalation results in the greatest local effect on bronchial smooth muscle with the least systemic toxicity. Aerosol deposition depends of the particle size, the pattern of

breathing (tidal volume and rate of airflow) ,


Epinephrine (adrenaline) stimulates β2-recptors and produces bronchodilation in asthma. It also stimulates β1- and α-adrenoceptors and thus prosuces hypertension, tachycardia, and cardiac arrhythmias. It's used for treating the acute asthmatic attack and can be given subcutaneously in a dose of 0.5-1mg. the drug has also used by inhalation but by this route it has been replaced by more selective β2 agonists.


Albuterol (salbutamol, RX Ventolin) is a selective β2-agonist. It's used as an aerosol, by i.v. infusion, and as an oral tablet. The aerosol administration minimizes side effects by delivering the drug directly to its site of action (thus permitting a lower dose) and is the method of choice for the use of this drug in the control of bronchoconstriction in chronic asthma or chronic obstructive pulmonary disease. The usual single dose delivered by an appropriate inhaler device (two puffs) is 200μg. The onset of action of the inhaled drug is almost immediate. When the drug is given by mouth as 5-mg tablets the action begins within 30 min., rises to a peak between 2 and 4 Hr., the drug causes an increase in heart rate and skeletal muscle tremor when given by mouth. Other selective β2-sympathomimetic agents with similar properties are terbutaline (Bricanyl), orciprenaline (metaproterenol, Alupent), fenoterol (Berotec), and isoetharine (Bronkosol).

These drugs are not inactivated by catehol-O-methyltransferase and so have a long duration of action compared to epinephrine. Specific β2 stimulants are currently the drugs of 1st choice, and larger doses in combination with methylxanthines and corticosteroids are used in treatment of status asthmaticus.


2-Anticholinergic drugs:Atropine is a competitive blocker of acetylcholine at muscarinic cholinergic receptors and thus can cause a variety of effects due to loss of parasympathetic activity, including blurring of vision, increase in heart rate, and drying of secretions in the salivary glands and respiratory tract. This limits its usefulness as a bronchodilator. Atropine is best used by inhalation, which reduces, but does not eliminate entirely, these unwanted side effects.

Ipratropium bromide (Atrovent) is a quaternary isopropyl-substituted derivative of atropine that can not cross the blood-brain barrier and therefore has practically no central effect; it also shows some degree of bronchoselectivity. The actions of ipratropium bromide are otherwise similar to those of atropine, and its therapeutic use is confined to aerosol administration. The drug is administered by inhaler and each puff contains 20μg, the exact place of ipratropium bromide in the treatment of asthma remains somewhat uncertain, and the drug appears to have little advantage over the selective β2-agonists.


3-MethylxanthinesThe 3 important are theopylline, theobromine, and caffeine. Their major source of intake by humans is beverages such as tea, cocoa, and coffee, respectively. Their effects are as follows:

CNS effects: in low to moderate doses, the methylxanthines, especially caffeine, cause mild cortical arousal with increased alertness and deferral of fatigue, in unusually sensitive individuals, the caffeine contained in beverages (e.g., 100mg in a cup of coffee) is sufficient to cause nervousness and insomnia. Nervousness and tremor are primary side effects in patients taking large doses of aminophylline for asthma.

Cardiovascular effects: the methylxanthines have direct positive chronotropic and inotropic effects on the heart. At low con., these effects appear to result from increased calcium influx, probably mediated by increased cyclic AMP. At higher con., sequestration of calcium by the sarcoplasmic reticulum is impaired, so intracellular calcium con. Is increased and myocardial contraction is strengthened. Methylxanthines have occasionally been used in the treatment of pulmonary edema associated with heart failure. These agents also relax vascular smooth muscle except in cerebral blood vessels, where they cause contraction.


GIT effects: they stimulate secretion of both gastric acid and digestive enzymes.Kidneys: they, especially theophylline, are weak diuretics. This effect may involve both increased glomerular filtration and reduced tubular sodium reabsorption. This effect is not sufficient therapeutically.

Smooth muscle: the bronchodilatation produced by the methylxanthines is the major therapeutic action. Tolerance does not develop, but side effects, especially in the CNS, may limit the dose. In addition to this direct effect on the airway smooth muscle, these agents inhibit antigen-induced release of histamine from lung tissue; their effect on mucociliary transport is unknown.

Skeletal muscle: the therapeutic actions of the methylxanthines may not be confined to the airways, for they also strengthen the contractions of isolated skeletal muscle in vitro and have potent effects in improving contractility and in reversing fatigue of the diaphragm in patients with chronic obstructive lung disease. This effect on diaphragmatic performance, rather than an effect on the respiratory center, may account for theophyllines's ability to improve the ventilatory response to hypoxia and to relieve dyspnea even in patients with irreversible airflow obstruction.


TheophyllineThis 1,3-dimethylxantine (fig. 40-2) is a plant alkaloid. Its poorly soluble and must be chemically complexed with other drugs to increase the solubility enough for clinical use (e.g., aminophylline = diethylamine + theophylline). It’s the most selective of the methylxanthines in its effects on smooth muscle.

Mechanism of action:As a bronchodialtor, it inhibits phosphodiestrase and the consequent increase in cAMP con. in smooth muscle. Alterations in smooth-muscle Ca2+ ion. may also be influenced by theophylline, and this may explain the relaxing effect on bronchial smooth muscles. Theopylline has also been shown to inhibit the effects of prostaglandins on smooth muscle and to inhibit the release of histamine and leukotrienes from mast cells. However, long-term administration doesn't reduce bronchial hyperresponsiveness or inhibit the release of mediators from eosinophils.


Pharmacokinetics:Theophylline is rapidly and completely absorbed orally and is distributed into all body compartments. There is marked interindividual variation in the hepatic transformation of theophylline. The clearance rate is influenced by so many factors that it is essentially unpredictable in an individual. Therefore the dose (27-82μmol/L, or 5-15mg/L) varies widely and must be controlled by actual measurement of the concentrations. The clearance of theophylline in males is 20-30% higher than that in females. There may also be a circadian variation in theophylline clearance. The major routes of biotransformation are 3-demethylation by CYP1A2 and 8-hydroxylation by CYP3A3. Cigarette smoking increases theophylline elimination by inducing these hepatic enzymes, and there is decreased biotransformation of theophylline in hepatic cirrhosis, congestive heart failure, and chronic pulmonary disease.


Theophylline toxicity: is largely related to dose and plasma concentration. Serious toxic effects are uncommon at concentrations blew 110μmol/L (20mg/L), although a significant percentage of patients have unacceptable side effects even when the plasma con. doesn't exceed the usual therapeutic range. The most serious toxicities are cardiac arrhythmias, seizures, and respiratory or cardiac arrest. Minor adverse effects occur frequently; the most common are headache, anorexia, nausea, vomiting, and anxiety.


Figure ( ) Bronchodilation is promoted by cAMP


4 -Calcium channel blockers:Calcium channel blockers are effective in relaxing bronchial smooth muscle and are particularly useful for the treatment of exercise-induced asthma.

Asthma prophylaxis:Anti-inflammatory steroids:

Glucocorticoid drugs such as prednisone, prednisolone, Budesonide, and dexamethasone are known empirically to relieve airway obstruction in bronchial asthma. The possible actions include:Anti-inflammatory activity.Reduction of tissue sensitivity to antigens.Inhibition of contraction of bronchial smooth muscle.Mucolytic action.Increased responsiveness of β2-adrenoceptors.

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Cromolyn sodium (sodium cromoglycate, R x Intal and others): Unlike the preceding drugs, this drug is used exclusively for the prophylaxis,

rather than the treatment, of asthmatic attacks. It inhibits the release of mediators such as histamine and leukotrienes from the secretory granules of mast cells following the challenge of antigen interacting with specific IgE antibodies. The exact mechanism underlying the action of cromolyn sodium is not clear, but the drug is active only against type I (immediate) allergic reactions and not against delayed or immune reactions. However, cromolyn sodium is also effective in asthma induced by exercise and by exposure to cold dry air. Interaction of antibodies with mast cells is probably not involved in either of these types of asthma, but both are associated with rapid respiratory loss of heat, which may be a physical stimulus to mast cell degranulation. Therefore it is suggested that cromolyn sodium acts as a nonspecific stabilizer of the mast cell membrane and/or granules.

Cromolyn sodium is absorbed poorly from the gastrointestinal tract and therefore is effective only when deposited directly into the airways. Two methods of administration are currently used for asthma. In adults, the drug can be given by a "Spinhaler" apparatus that causes a capsule to be punctured so that its powdered contents are entrained into inspired air and deposited in the airways. The usual dose is 20 mg inhaled four times daily. In children, who may have difficulty in using this device, the

drug may be given by aerosol .


Other formulations, for topical use in the eye or nose, are intended for the prophylaxis of allergic rhinitis and conjunctivitis (hay fever).

About 10% of the inhaled dose is gradually ab sorbed from the lungs into the blood, from which it is cleared, unchanged, by urinary and biliary excretion, with a plasma half-life of about 1.5 hours. There are very few toxic effects of cromolyn sodium, because very little is absorbed systemically. Local side effects such as throat irritation and cough may follow inhalation of the dry powder. Rashes have been reported, as well as rare cases of anaphylactic reaction.

Use of Inhaled Bronchodilator DrugsSelective β2-adrenoceptor agonists such as albuterol (salbutamol), terbutaline, and fenoterol have a rapid onset of action and are effective for up to 6 hours following inhalation, if the asthma is not se vere. Little difference exists between the various agents, as the duration of action and selectivity are similar. β2-adrenoceptor agonists such as formoterol and salmeterol (Serevent) may be effective for up to 12 hours and are therefore preferred by patients, particularly those with nocturnal symptoms.

Side effects are uncommon when the drugs are given by inhalation but are more frequent when they are taken orally Tremor, tachycardia, and palpita tions are the most common side effects; hypokalemia has been noted when higher doses are taken


Anticholinergic agents block muscarinic recep tors, thus inhibiting vagal cholinergic tone and re sulting in bronchodilatation. Although several types of muscarinic receptors have been recognized in bronchial smooth muscle, the currently available an ticholinergic inhalants do riot discriminate between these receptors. The anticholinergic drugs inhibit only the component of bronchoconstriction that is due to cholinergic stimulation. In contrast to β2-adrenoceptor agonists, they have no action against the direct effects of mediators on bronchial smooth muscle. Thus, anticholinergic agents are on the whole less effective than β2-adrenoceptor agonists in the

treatment of chronic asthma\. They are therefore used most frequently in combination with other

bronchodilators . Side effects are those caused by systemic anticholinergic activity,

such as dry mouth, blurred vision, and urinary retention, but they do not occur with ipratropium bromide because it is poorly ab sorbed.


Recently, glucocorticoid drugs such as beclomethasone dipropionate and beclomethasone valerate have been developed for administration by inhalation. Inhalation of these compounds is

as effec tive as oral prednisone in patients starting on ste roids. Only a small amount of the steroid adminis tered in this manner is

systemically absorbed. Therefore there is little or no systemic effect or adre nal suppression and the problem of growth suppres sion in

children may be avoided. The major problem with this form of therapy to date has been the devel opment of fungal infections

(candidiasis) in the oropharynx in about 10% of patients because of suppression of phagocytic activity by the high local concentrations

of corticosteroid.


The inhaled corticosteroids are remarkably ef fective in suppressing the inflammatory process occurring with asthma. In single doses, they do not block the early response to allergens but do block the late response and the bronchial hyperresponsiveness. This effect is gradual in onset but occurs to a greater extent with inhaled steroids than with orally adminis tered steroids. Inhaled corticosteroids produce a re duction in the number of mast cells in the airway. They also reduce the microvascular leakage caused by inflammatory mediators, although the exact mo lecular mechanism of their beneficial action is un clear.

Side effects are uncommon when low doses of inhaled steroids (less than 400μg daily) are given but become more frequent at higher doses.


Leukotriene Pathway Inhibitors

Because of the evidence of leukotriene involvement in many inflammatory diseases

considerable effort has been expended on the development of drugs that block

the synthesis of these arachidonic acid derivatives or their receptors.

Leukotrienes result from the action of 5-lipoxygenase on arachidonic acid and

are synthesized by a variety of inflammatory cells in the airways, including

eosinophils, mast cells, macrophages, and basophils. Leukotriene B4 is a potent

neutrophil chemoattractant, and LTC4 and LTD4 exert many effects known to

occur in asthma, including bronchoconstriction, increased bronchial reactivity,

mucosal edema, and mucus hypersecretion. Early studies established that

antigen challenge of sensitized human lung tissue results in the generation of

leukotrienes, while other studies of human subjects have shown that inhalation

of leukotrienes causes not only bronchoconstriction but also an increase in

bronchial reactivity to histamine that persists for several days.


Two approaches to interrupting the leukotriene pathway have been pursued: inhibition of 5- lipoxygenase, thereby preventing leukotriene synthesis; and inhibition of the binding of leukotriene D4 to its receptor on target tissues, thereby preventing its action. Efficacy in blocking airway responses to exercise and to antigen challenge has been shown for drugs in both categories:

zileuton, a 5-lipoxygenase inhibitor, and zafirlukast and montelukast, LTD4-receptor antagonists.

All have been shown to be effective when taken regularly in outpatient clinical trials.

Anti-IgE Monoclonal Antibodies Omalizumab



DRUGS AFFECTING THE COUGH REFLEXThe cough reflex is mediated by receptors located in the mucosa or deeper structures of the larynx, trachea, and major bronchi, and by mechanoreceptors that detect changes in bronchial intramural tension. Stimuli are transmitted via the vagus to the cough center in the medulla. Efferent impulses originating from the cough center are transmitted through cholinergic pathways to the abdominal and intercostal muscles and to the diaphragm, producing sudden explosive expiratory movements. The effect of coughing is to expel foreign particles that have entered the bronchial tree and to expectorate sputum from the bronchial lumen. This may be beneficial to the patient, protecting against damage by foreign bodies or bacteria and helping to clear the

airways . However, repeated nonproductive coughing (i.e., coughing that fails to clear

mucus from the lower respiratory tract) exhausts the patient and disturbs sleep. Long term coughing also may lead to the breakdown of elastic tissue in the lung or to damage to the tracheobronchial epithelium. It is therefore often helpful to give drugs to suppress the cough reflex.


Antitussive Drugs:Opioid antitussive agents:

Opioid analgesics are most effective in depressing the cough center. Although the precise mechanism by which they exert their effects is uncertain, they appear to react with a variety of receptors identified at numerous sites in the central and periph eral nervous systems. There is some specificity found among various opioids with respect to their antitussive potency. For example, the ED50 for analgesia compared to the ED50 for cough suppression yields a ratio of 6.62 for codeine, 4.60 for hydrocodone, and 2.87 for morphine, Codeine thus appears to be a more effective cough suppressant relative to its analgesic activity. The antitussive dose of codeine is relatively low, and 10 mg may produce a 62% eleva tion of threshold to ammonia-induced cough for 60 minutes. The usual antitussive dose is 15-20 mg as required. Codeine also has significantly less respira tory depressant effect than morphine. The development of tolerance and physical dependence is a major drawback to morphine-like drugs, and for this rea son, their long-term use as antitussive agents is dis couraged. They can, however, be used for short-term cough suppression. Because of the low dose of codeine required, and its relatively low addiction liability, it may be more suitable than other opioid drugs for long-term antitussive use.


Nonopioid antitussive agents:Dextromethorphan is a synthetic opioid derivative that is an effective antitussive agent, suppressing the response of the cough center but lacking analgesic or habituating properties. It is the d-isomer of levomethorphan, which is a potent opioid analgesic. This demonstrates that the analgesic activity, as well as the addictive properties, are exerted through recep tors with stereospecificity, while the antitussive recep tor sites lack the opioid stereospecificity. Levopropoxyphene is similarly an antitussive that lacks the analgesic activity of its isomer, dextropropoxyphene. Other nonopioid drugs that have some antitussive activity in addition to their other pharmacological actions include phenothiazines, antihistamines, and benzononatate,

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