PHARMACOLOGY OF RESPIRATORY

DRUGSby

Ma. Elizabeth V. Rey-Matias, M.D., PTRP, PTR, MHPEd, PhD SPED

RESPIRATORY DRUGSAcute, minor problems--nasal

congestion, coughing, and seasonal allergies

Chronic, serious airway obstructions, such as bronchial asthma, chronic bronchitis, and emphysema

Antitussivessuppress coughing related to common

cold and other minor throat irritations

often combined with aspirin or acetaminophen to treat cold as well as with other respiratory tract agents

Antitussives – for short-term use in relieving symptomatic coughing.

extensive use not advised

coughing -defense mechanism that expel mucus and foreign material from the URT.

antitussives -reduce the ability of coughing to raise secretions

helpful in treating annoying dry cough but extensive use not justified

codeine and similar opiate derivatives suppress the cough reflex by a central inhibitory effect

Other nonopioid antitussives inhibit the irritant effects of histamine on the respiratory mucosa or by a local anesthetic action on the respiratory epithelium.

adverse effect of most antitussives is

sedation. Dizziness and GI upset may also occur.

Decongestantstreat nasal congestion and mucous

discharge from theupper respiratory tract- usually alpha-

1–adrenergic agonists

bind to alpha-1 receptors located on the blood vessels of the nasal mucosa and stimulate vasoconstriction, drying up the mucosa and decreasing nasal congestion

Alpha-1 agonists used as decongestants Mimic effects of increased sympathetic

nervous system activity, and can cause serious cardiovascular and central nervous system (CNS) excitation.

abuse should be avoided

adverse effects- headache, dizziness, nervousness, nausea, and cardiovascular irregularities (increased blood pressure, palpitations).

AntihistaminesAntihistamines used for sedation or to

treat parkinsonism.

treat the respiratory allergies

Histamine -endogenous chemical involved in the normal regulation of certain physiologic functions (gastric secretion, CNS neural modulation), hypersensitivity (allergies)

Histamine exerts its effects on four receptor: the H1,H2, H3, and H4 receptors.

Antihistamines-are drugs that

specifically block the H1 subtype of histamine receptors; that is,

the effects of histamine during allergic reactions, respiratory infections,

H2 receptors -regulation of gastric acid secretion. H2 antagonists may help control gastric secretion in peptic ulcer

H3 receptor, involved in the local

regulation of histamine release from CNS nerve terminals.

Significance of H3 and H4 receptors remains to be determined.

antihistamine effects on the upper respiratory tissues -decrease nasal congestion, mucosal irritation and discharge (rhinitis, sinusitis), and conjunctivitis that are caused by inhaled allergens.

Antihistamines decrease the coughing and sneezing associated with

cold. do not reverse bronchospasm

associated with asthma, used as an adjunct in patients with

asthma to help control rhinitis and sinusitis

adverse effects associated with antihistamines are sedation, fatigue, dizziness, blurred vision, and incoordination.

“first-generation” antihistamines cross

the blood-brain barrier causing CNS-related side effects such as sedation and psychomotor slowing.

Newer “second-

generation”antihistamines, do not easily cross the bloodbrain

barrier, and the risk of sedation and other CNS side effects is reduced

nonsedating antihistamines, include cetirizine (Zyrtec), loratadine (Claritin), desloratidine (Clarinex), and fexofenadine (Allegra)

nonsedating antihistamines such as astemizole and terfenadine may be cardiotoxic, and may cause severe ventricular arrhythmias

Mucolytics and ExpectorantsMucolytic -decrease the viscosity of

respiratory secretions. Expectorant –facilitate production and

ejection of mucus. Prevent accumulation of thick, viscous

secretions that can clog respiratory passages and lead to pulmonary problems.

Expectorants and mucolytics are used

in acute disorders ranging from the common

cold to pneumonia, as well as in chronic disorders such as emphysema and chronic bronchitis.

often used in combination with other

agents (e.g., antitussives, decongestants, bronchodilators).

The primary mucolytic drug currently

in use is acetylcysteine (Mucomyst, Mucosil).

MUCOLYTIC drug Work by splitting the

disulfide bonds of respiratory mucoproteins, thus forming a less viscous secretion.

This drug has antioxidant effects, and

some of acetylcysteine’s benefits may be due to its ability to decrease free-radical damage in the respiratory tissues.

Acetylcysteine is usually administered

directly to the respiratory mucosa by inhalation or intratracheal instillation (through a tracheostomy).

Primary adverse effects with this drug

include nausea, vomiting, inflammation of the oral mucosa (stomatitis), and rhinorrhea.

Several expectorant agents have been

used in the past, but guaifenesin is the only drug currently

acknowledged by the FDA to have evidence of therapeutic effects.

increase the production of respiratory

secretions, thus encouraging ejection of phlegm and sputum.

Guaifenesin usually administered

orally in some form of syrup or elixir, is often combined with other agents in over-the-counter preparations, which are known by many different trade names.

primary adverse effect associated with

Guaifenesin is gastrointestinal upset,

Expectorants and mucolytics used to treat common cold, pneumonia, and chronic disorders such as emphysema and chronic bronchitis.

often used in combination with other

agents (e.g., antitussives, decongestants, bronchodilators).

The primary mucolytic drug currently in use is acetylcysteine (Mucomyst, Mucosil).

splitting the disulfide bonds of

respiratory mucoproteins, thus forming a less viscous secretion.

has antioxidant effects, and some of acetylcysteine’s benefits may be due to its ability to decrease free-radical damage in the respiratory tissues.

Acetylcysteine is usually administered

directly to the respiratory mucosa by inhalation or intratracheal instillation (through a tracheostomy).

Primary adverse effects with this drug

include nausea, vomiting, inflammation of the oral mucosa (stomatitis), and rhinorrhea.

Several expectorant agents have been

used in the past, but guaifenesin is the only drug currently

acknowledged by the FDA to have evidence of therapeutic effects.

increase the production of respiratory

secretions, thus encouraging ejection of phlegm and sputum.

Guaifenesin usually administered

orally in some form of syrup or elixir, is often combined with other agents in over-the-counter preparations, which are known by many different trade names.

primary adverse effect associated with

Guaifenesin is gastrointestinal upset,

adverse effects -nausea, vomiting, inflammation of the oral mucosa (stomatitis), and rhinorrhea.

guaifenesin -only drug acknowledged

as expectorant by the FDA to have evidence of therapeutic effects.

increase the production of respiratory secretions, thus encouraging ejection of phlegm and sputum.

Guaifenesin usually administered

orally in some form of syrup or elixir, often combined with other agents in

over-the-counter preparations

primary adverse effect associated with Guaifenesin is gastrointestinal upset

Drugs Used to Maintain Airway Patency in COPD

primary goal –prevent/ reverse bronchial constriction and obstruction of airways by • bronchodilators (beta-adrenergic agonists,

xanthine derivatives, anticholinergics)

• anti-inflammatory agents (glucocorticoids, others).

Beta-Adrenergic Agonists Rationale for

Use and Mechanism of ActionRespiratory smooth-muscle cells contain

the beta-2 subtype of adrenergic receptors. Stimulation of these beta-2 receptors results in relaxation of bronchiole smooth muscle.

drugs that stimulate these beta-2

adrenergic receptors (i.e., betaadrenergic agonists) produce bronchodilation and can be used to prevent or inhibit airway obstruction in bronchospastic diseases.

Beta-adrenergic agonists are believed to

induce smooth-muscle relaxation by, stimulation

of the beta-2 receptor increases activity of the adenyl cyclase enzyme. This enzyme increases the production of intracellular cyclic adenosine monophosphate (cAMP). The cAMP acts as an intracellular second messenger, which then increases the activity of other enzymes such as protein kinase. The increased protein kinase activity ultimately inhibits smooth-muscle contraction,

probably by adding a phosphate group to specific contractile proteins.

Specific Agents and Method of

Administration Beta-adrenergic agonists used to induce

bronchodilation some drugs are nonselective and stimulate alpha and beta receptors fairly equally. Other agonists are more selective and preferentially stimulate the beta-adrenergic receptors. Finally, the beta-2–specific agents are the most selective and tend to bind preferentially to beta-2 receptors.

Beta-2–selective agonists when

administered systemically - less chance of side effects caused by stimulation ofNother adrenergic receptors located on other tissues (e.g., beta-1 receptors on the myocardium).

When administered via inhalation,

however, the issue of adrenergic receptor selectivity becomes less important because the drug is applied directly to the respiratory

drugs (formoterol, salmeterol) - long-

acting beta-adrenergic agonists. may provide more stable and sustained bronchodilation in conditions such as asthma. Beta-adrenergic drugs can be administered

orally, subcutaneously, or by inhalation. Inhalation of these drugs is often the preferred method of administration in treating respiratory disorders. Inhalation allows the drug to be delivered directly to the respiratory tissues with a minimum of systemic side effects because of its absorption into the systemic circulation. 4 The onset of action is also more rapid with inhalation.

Oral or subcutaneous administration is

usually associated with more side effects. However, when administered orally or subcutaneously, beta agonists may reach the more distal branches of the airway to a greater extent. The bronchioles are usually constricted during an asthmatic attack, and the drug may not reach the distal respiratory passages when administered by inhalation.

Several beta agonists are available in metereddose inhalers (MDIs) for inhalation administration.

Another method of inhaling beta

agonists is through a nebulizer

Beta-Adrenergic AgonistsStimulation of beta-2 receptors results

in relaxation of bronchiole smooth muscle.

betaadrenergic agonists produce bronchodilation and can be used to prevent or inhibit airway obstruction in bronchospastic diseases.

Beta-adrenergic agonists Stimulation of beta-2 receptor

increases activity of the adenyl cyclase enzyme.

This enzyme increases the production of intracellular cyclic adenosine monophosphate (cAMP).

The cAMP acts as an intracellular second messenger, which increases the activity of protein kinase.

increased protein kinase activity ultimately inhibits smooth-muscle contraction

some drugs are nonselective and stimulate alpha and beta receptors fairly equally.

the beta-2–specific agents are the most selective and tend to bind preferentially to beta-2 receptors.

Beta-2–selective agonists when administered systemically - less chance of side effects

Do not stimulate other adrenergic receptors located on other tissues (e.g., beta-1 receptors on the myocardium).

drugs (formoterol, salmeterol) - long-acting beta-adrenergic agonists provide more stable and sustained bronchodilation

Beta-adrenergic drugs can be administered orally, subcutaneously, or by inhalation.

Inhalation -often the preferred method of administration in treating respiratory disorders.

-allows the drug to be delivered directly to the respiratory tissues with less side effects

-onset of action is also more rapid with inhalation.

Oral or subcutaneous administration is associated with more side effects.

when administered orally or subcutaneously, beta agonists may reach the more distal branches of the airway to a greater extent. The bronchioles are usually constricted during an asthmatic attack, and the drug may not reach the distal respiratory passages when administered by inhalation.

Several beta agonists are available in metereddose inhalers (MDIs) for inhalation administration.

Another method of inhaling beta

agonists is through a nebulizer.

Nebulizers- useful alternative for those who cannot master MDI delivery.

beta-2 drugs can be delivered via a dry powder inhaler (DPI).

DPIs may be easier for certain patients

who lack the coordination and timing needed to use an MDI.

Side Effectsexcessive use of beta-2 drugs promote

airway irritation, thus increasing the incidence and severity of bronchospastic attacks. Prolonged use of beta-2 drugs cause tolerance;

the dose must be increased to achieve therapeutic effects when this occurs.

Adrenergic agonists stimulate beta-1 receptors may cause cardiac irregularities if given through the systemic circulation.

stimulation of CNS adrenergic receptors -nervousness, restlessness, and tremor.

Adverse effects are less when beta-adrenergic agonists are used locally via inhalation.

Xanthine derivatives theophylline, caffeine, theobromine

Theophylline produce bronchodilation in asthma and other forms of reversible airway obstruction (bronchitis, emphysema)

Theophylline and caffeine -potent CNS stimulants

side effects -related to CNS excitation enhance bronchodilation by inhibiting

the phosphodiesterase (PDE) enzymeIn bronchial smooth-muscle cells.

PDE breaks down cAMP; inhibiting this enzyme results in higher intracellular cAMP concentrations.

cAMP -second messenger that brings about respiratorysmooth-muscle relaxation and subsequent bronchodilation.

By inhibiting PDE, theophylline prolongs effects of second messenger and increase bronchodilation.

PDE inhibition decrease function of inflammatory cells and inhibit production of inflammatory mediators

--theophylline has anti-inflammatory properties

theophylline’s benefits are the anti-inflammatory properties rather than to a direct bronchodilating effect.

Theophylline -act as an adenosine

antagonist. Adenosine bind toreceptors on the smooth-muscle cells

and cause contraction.

theophylline blocks this effect and facilitate smooth-muscle relaxation.

inhibit intracellular calcium release and stimulation of catecholamine release

Xanthine derivatives -treat bronchospastic disease

usually oral, may be given rectally or by injection if the oral route is not tolerated.

sustained-release preparations of theophylline improve patient’s compliance

Toxicity -plasma levels are between 15 and 20 _g/mL.

recommended levels -between 10 and 20 _g/mL, signs of toxicity may occur even when blood levels are in the therapeutic range.

Early signs of toxicity include nausea, confusion, irritability, and restlessness. When blood levels exceed 20 _g/mL, serious toxic effects such as cardiac arrhythmias and seizures may occur.

Theophylline-induced seizures -life-threatening

prone to theophylline toxicity- with liver disease, heart failure, alcohol consumption, cigarette smoking, concomitant use of other drugs (e.g., cimetidine), and patient age (older than 55)

Xanthine derivative bronchodilators

Anticholinergic Drugs The efferent fibers of the vagus nerve

release acetylcholine onto respiratory smooth-muscle cells, which contain muscarinic cholinergic receptors.

drugs that block muscarinic cholinergic receptors prevent acetylcholine-induced bronchoconstriction

anticholinergics – often drug of choice in treating COPD.

factors that cause bronchoconstriction in emphysema and chronic bronchitis -increased vagal tone and acetylcholine release.

reduce this vagal influence -control bronchoconstriction in COPD.

Anticholinergics –not first-line treatment of asthma

primary pathophysiology in asthma is airway inflammation rather than increased vagal tone.

can also be used to supplement anti-inflammatory drugs

treat acute episodes of moderate to severe asthma.

anticholinergic bronchodilators -ipratropium and tiotropium, muscarinic receptor blockers that are similar to atropine

atropine -prototype muscarinic antagonist, its use in respiratory conditions is limited--readily absorbed into the systemic circulation ,produce many side effects

ipratropium (Atrovent) is an anticholinergic agent -poorly absorbed into the systemic circulation and can be administered by an aerosol inhaler.

inhaled ipratropium -fewer systemic side effects.

Tiotropium (Spiriva) -anticholinergic bronchodilator similar to ipratropium, but with longer lasting effects.

needs to be inhaled once each day,

whereas ipratropium is often inhaled 3 or 4 times each day.

side effects associated with atropine -dry mouth, constipation, urinary retention, tachycardia, blurred vision, and confusion.

less with inhaled anticholinergics like ipratropium and tiotropium, which are not absorbed as readily into the systemic circulation.

GlucocorticoidsInflammation factor in the exaggerated

responsiveness of the respiratory passages in asthma and other obstructive pulmonary disorders.

glucocorticoids -used to control inflammation-mediated bronchospasm

most effective agents for controlling asthma.

Glucocorticoids (also known as corticosteroids) inhibit the inflammatory response

directly affect the genes and transcription factors that produce inflammatory components.

inhibit the production of proinflammatory products (cytokines, prostaglandins, leukotrienes) while increasing the production of anti-inflammatory proteins.

Glucocorticoids reverse the increase in vascular permeability and inhibit the migration of neutrophils and monocytes typically occurring during

the inflammatory response.

severe, acute episodes of bronchoconstriction (e.g., status asthmaticus)- glucocorticoids are given intravenously.

For prolonged use, glucocorticoids are given orally or by inhalation.

With beta agonists, the inhaled route is preferable because of the decreased chance of systemic side effects

Glucocorticoids via inhalation -beclomethasone, budesonide, flunisolide, and triamcinolone

by the inhalation route, the chance of adverse effects is greatly reduced, compared with the possible effects associated with systemic intake

Patients should be advised to rinse their mouth cavities

with water after using oral glucocorticoid inhalers to prevent local irritation of the oral mucosa.

Adverse Side Effectsglucocorticoids – has general catabolic

effect on supporting tissues, cause osteoporosis, skin breakdown, and muscle wasting – may occur during prolonged systemic administration.

systemic effects include retardation of growth in children, cataracts, glaucoma, hyperglycemia, aggravation of diabetes mellitus, and hypertension.

-may also become resistant to anti-

inflammatory effects during repeated exposure

Prolonged or excessive use can have a negative feedback effect on the adrenal gland, resulting in loss of adrenal function (adrenal suppression) while these drugs are being administered.

risk of these adverse effects is minimal when these drugs are administered by inhalation.

Inhalation provides a more direct and topical application of the glucocorticoid to the respiratory tissues, with fairly limited absorption of the drug into the systemic circulation.

periodically examine patients for bone mineral loss and other side effects when these drugs are used for prolonged

extremely effective in treating various types of bronchoconstriction, and they should be used judiciously

whenever possible.

Cromonescromolyn sodium (Intal, Nasalcrom)

and nedocromil sodium (Tilade) can help prevent bronchospasm in people with asthma.

not bronchodilators and will not reverse bronchoconstriction during an asthmatic attack.

must be taken prior to the onset of bronchoconstriction

Used prophylactically to prevent asthma attacks

regular use of these drugs several times each day for several months may decrease airway hyperresponsiveness so that the incidence of asthmatic

attacks decreases.

Cromolyn and nedocromil prevent bronchoconstriction by inhibiting the release of inflammatory mediators such as histamine and leukotrienes from pulmonary mast cells

can be administered by MDI and nebulizer.

cromolyn is available in a nonprescription nasal spray (Nasalcrom) that can be helpful in preventing allergic rhinitis

Adverse Side Effectsirritation of the nasal and upper

respiratory passages may occur following inhalation

cromolyn and nedocromil are often used preferentially to treat mild persistent asthma, especially in children or in individuals who are unable to tolerate the side effects of other antiasthma drugs.

Treatment of Bronchial AsthmaAsthma is a disease of the respiratory

system characterized by bronchial smooth-muscle spasm, airway inflammation, and mucous plugging of the airways.

These cells release proinflammatory chemical mediators such as prostaglandins, leukotrienes, bradykinin, histamine,

and platelet activating factor The chemicals irritate the respiratory

epithelium and stimulate the contraction of bronchiole smooth muscle.

localized inflammation sensitizes airway structures to asthmatic triggers

the bronchoconstriction and other features of asthma seem to be related directly to the inflammatory response

Airway inflammation -critical factor in initiating the exaggerated bronchial reactions in asthma

complex interaction between several different cells including macrophages, neutrophils, eosinophils, platelets, and the airway epithelial cells themselves.

Leukotriene InhibitorsLeukotrienes -inflammatory

compounds important in mediating the airway inflammation causing asthma.

-20-carbon fatty acids (eicosanoids) similar in structure and function to prostaglandins.

derived from the same precursor as prostaglandins (arachidonic acid), but leukotrienes are synthesized by the lipoxygenase enzyme rather than by the cyclooxygenase enzyme

zileuton (Zyflo) inhibits the lipoxygenase enzyme, thereby reducing the production of leukotrienes

montelukast (Singulair) and zafirlukast (Accolate) block the receptor for leukotrienes on respiratory tissues.

offer a fairly selective method for controlling a specific aspect of inflammation in bronchoconstrictive disease.

leukotriene inhibitors can be combined with other drugs (glucocorticoids, beta agonists) to provide optimal management in specific patients with asthma and COPD.

Enhance anti-inflammatory effects of glucocorticoids, provide therapeutic effects at a relatively lower dose of glucocorticoid (glucocorticoid sparing effect).

combination of a glucocorticoid and antileukotriene drug has become a popular option for mgt of bronchoconstrictive disease.

Adverse Side EffectsLeukotriene inhibitors are safer than

other anti-inflammatory agents such as the glucocorticoids.

hepatic impairment has been reported with these drugs, but cases of severe toxicity are relatively rare.

WAYS OF USING THE MDI

THE END