Respiratory Pharmacology Test Quiz! Trivia

Explanation
Ipratropium (Atrovent®)
o Tiotropium (Spiriva®)

•Chemistry
o Quaternary ammonium derivatives of atropine
• Pharmacokinetics
o Inhalational and nasal (ipratropium) administration
o Poor absorption when administered by inhalational administration and they do not readily distribute into the CNS
o Ipratropium onset of action is slow (30-60 min), but persists for up to 6-8 hrs
o Tiotropium is a long-acting agent (~24 hrs for a single inhaled dose)
• Pharmacodynamics
o Mechanism of Action
Competitive inhibition of acetylcholine (ACh) at muscarinic receptors
• In the airways, ACh is released from efferent endings of the vagus nerve
• Tiotropium selectively inhibits M1 and M3 receptors
o Thus it does not antagonize M2 receptor-mediated inhibition of ACh release

Pharmacological Actions/Effects
Blocks the contraction of airway smooth muscle mediated by ACh
Blocks the increase in mucus secretion that occurs in response to vagal activity
• Clinical Pharmacology

*********CLINICAL USES *************
Used as bronchodilator agents in asthma (not 1st line)
•Especially useful in enhancing the bronchodilating effects of B2-adrenoceptor agonists in cases of severe asthma

USED AS THE BRONCHODILATOR AGENTS OF CHOICE IN –COPD-- (BOTH)
• AS EFFECTIVE AS, OR EVEN SUPERIOR TO, B2-ADRENOCEPTOR AGONISTS
O DUE TO THEIR INHIBITORY EFFECT ON VAGAL TONE

• Reduce air trapping and improve exercise tolerance in these patients
Treatment of rhinorrhea due to allergic or non-allergic rhinitis

o Adverse Effects/Toxicity
Ipratropium
• Serious reactions
o Hypersensitivity reactions, anaphylaxis, angioedema, laryngospasm, paradoxical bronchospasm (due to antagonism of M2 receptor-mediated inhibition of ACh release), angle-closure glaucoma
• Common reactions
o Cough, nervousness, nausea, dry mouth/throat, GI upset, dizziness, headache, COPD exacerbation, oral/nasal irritation, rash/urticaria, URI, epistaxis, pharyngitis, nasal dryness, taste changes
Tiotropium
• Serious reactions
o Hypersensitivity reaction, angioedema, paradoxical bronchospasm, increased intraocular pressure, glaucoma, paralytic ileus
• Common reactions
o URI symptoms, dry mouth, pharyngitis, chest pain, UTI, dyspepsia, rhinitis, abdominal pain, edema, constipation, myalgia, vomiting, epistaxis, rash, infection, candidiasis, tachycardia, blurred vision, urinary hesitancy/retention
o Contraindications
Ipratropium
• Pregnancy/Lactation—Category B/precaution (safety unknown)
Tiotropium
• Acute bronchospasm
• Pregnancy/Lactation—Category C/precaution (safety unknown)

Explanation
The Pharmacology of B2-Adrenoceptor Agonists

Chemistry
o Chemical derivatives of the catecholamines norepinephrine and epinephrine
o Levalbuterol is the R-isomer of albuterol; arformoterol is the R,R-isomer of formoterol
• Pharmacokinetics
o Oral, parenteral, and inhalational administration
Drugs are best delivered inhalationally because this route leads to the greatest local effect in airway smooth muscle with the least toxicity
• Typically, 80-90% of the total aerosol dose is deposited in the mouth or pharynx
• Bronchial deposition is increased by slow inhalation of a nearly full breath and by more than 5 seconds of breath-holding at the end of inspiration
Duration of action ranges from 3-12 hrs depending on the chemical modifications present in the drug molecule (prevents degradation of the drug by catechol-O-methyl transferase—COMT)
• Pharmacodynamics
o Mechanism of Action
B2-ADRENOCEPTOR AGONIST
ESPECIALLY ON AIRWAY SMOOTH MUSCLE CELLS

•RECEPTOR ACTIVATES ADENYLYL CYCLASE AND STIMULATES FORMATION OF INTRACELLULAR cAMP

o This results in numerous biochemical changes in target cells
Lowering of [Ca2+]intracellular by active removal from the cytosol into intracellular stores and out of the cell
Potent inhibition of the phospholipase C-inositol triphosphate (PLC-IP3) pathway
Inhibition of myosin light chain kinase activation
Activation of myosin light chain phosphatase
Opening of large conductance Ca2+-activated K+ channels (KCa), which repolarizes the smooth muscle cell
Act as functional agonists
• Reverse bronchoconstriction irrespective of the contractile agent
o Extremely important fact in asthma, which has numerous bronchoconstriction-promoting agents

Pharmacological Actions/Effects
Relaxes airway smooth muscle
Rapidly decreases airway resistance
Inhibits release of bronchoconstricting mediators from mast cells
Inhibits microvascular leakage
Increases mucociliary transport by increasing ciliary activity
Reduces neurotransmission in human airway cholinergic nerves by inhibiting acetylcholine release (action on presynaptic 2-adrenoceptors)
• Major therapeutic MOA in COPD
• Clinical Pharmacology
o Clinical Uses
Bronchodilator treatment of choice in asthma
• Inhaled short-action drugs are the most widely used and effective due to their functional antagonism of bronchoconstriction
o Albuterol is the prototype of this group
o Drugs of choice in treatment of acute severe asthma
o Should be used on an “as needed” basis for the relief of symptoms in cases of mild asthma
o When inhaled from pressurized metered-dose inhalers (pMDI) or dry powder inhalers (DPI) they are convenient, easy to use, rapid in onset, and without significant systemic adverse effects
o Effective in protecting against various challenges, such as exercise, cold air, and allergens
• Inhaled long-acting drugs (LABA) improve asthma control and provide sustained bronchodilator action (>12 hrs) and bronchoprotection
o Salmeterol is the prototype of this group
o Should never be used alone because they do not treat the underlying chronic inflammation
Should be used in combination with inhaled corticosteroids (ICS), preferably in a fixed-dose combination inhaler
Bronchodilator treatment in COPD
• LABA are used for these cases
o Used “as needed” in mild COPD, or daily in severe COPD
o They are used alone or in combination with anticholinergics or ICS
o Adverse Effects/Toxicity

Most are dose related and due to stimulation of extrapulmonary B2-adrenoceptors
• Especially common with oral and parenteral administration
Possible development of tolerance (desensitization, subsensitivity)
• Seen with continuous therapy due to down-regulation of B2-adrenoceptors
• Can be prevented by corticosteroids
Albuterol
• Serious reactions
o Hypersensitivity reactions, paradoxical bronchospasm, HTN, angina, MI, hypokalemia, arrhythmias, metabolic acidosis (nebulized use)
• Common reactions
o Tremor, nervousness, headache, nausea, tachycardia, muscle cramps, palpitations, insomnia, dizziness, throat irritation, URI symptoms, cough, bad taste,
Salmeterol
• Serious reactions
o Paradoxical bronchospasm, asthma exacerbation, asthma-related death, anaphylaxis, angioedema, laryngospasm, arrhythmias, HTN
• Common reactions
o Headache, throat irritation, nasal congestion, rhinitis, tracheitis/bronchitis, pharyngitis, urticaria, rash, palpitations, tachycardia, tremor, nervousness
• Carries a Black Box Warning regarding asthma-related death risk and appropriate use in pediatric/adolescent patients
o Contraindications
Albuterol
• Drug Combinations
o Phenothiazines
• Pregnancy/Lactation—Category C/precaution (probably safe)
Salmeterol
• Asthma monotherapy, acute asthma
• Drug Combinations
o Phenothiazines
• Pregnancy/Lactation—Category C/precaution (safety unknown)

Explanation
Ipratropium (Atrovent®)

********Tiotropium (Spiriva®) **********

•Chemistry
o Quaternary ammonium derivatives of atropine
• Pharmacokinetics
o Inhalational and nasal (ipratropium) administration
o Poor absorption when administered by inhalational administration and they do not readily distribute into the CNS
o Ipratropium onset of action is slow (30-60 min), but persists for up to 6-8 hrs
o Tiotropium is a long-acting agent (~24 hrs for a single inhaled dose)
• Pharmacodynamics

************MECHANISM OF ACTION*****************
Competitive inhibition of acetylcholine (ACh) at muscarinic receptors
• In the airways, ACh is released from efferent endings of the vagus nerve
• Tiotropium selectively inhibits M1 and M3 receptors *****************
o Thus it does not antagonize M2 receptor-mediated inhibition of ACh release


Pharmacological Actions/Effects
Blocks the contraction of airway smooth muscle mediated by ACh
Blocks the increase in mucus secretion that occurs in response to vagal activity
• Clinical Pharmacology

CLINICAL USES
Used as bronchodilator agents in asthma (not 1st line)
•Especially useful in enhancing the bronchodilating effects of B2-adrenoceptor agonists in cases of severe asthma

USED AS THE BRONCHODILATOR AGENTS OF CHOICE IN –COPD-- (BOTH)
• AS EFFECTIVE AS, OR EVEN SUPERIOR TO, B2-ADRENOCEPTOR AGONISTS
O DUE TO THEIR INHIBITORY EFFECT ON VAGAL TONE

• Reduce air trapping and improve exercise tolerance in these patients
Treatment of rhinorrhea due to allergic or non-allergic rhinitis

o Adverse Effects/Toxicity
Ipratropium
• Serious reactions
o Hypersensitivity reactions, anaphylaxis, angioedema, laryngospasm, paradoxical bronchospasm (due to antagonism of M2 receptor-mediated inhibition of ACh release), angle-closure glaucoma
• Common reactions
o Cough, nervousness, nausea, dry mouth/throat, GI upset, dizziness, headache, COPD exacerbation, oral/nasal irritation, rash/urticaria, URI, epistaxis, pharyngitis, nasal dryness, taste changes
Tiotropium
• Serious reactions
o Hypersensitivity reaction, angioedema, paradoxical bronchospasm, increased intraocular pressure, glaucoma, paralytic ileus
• Common reactions
o URI symptoms, dry mouth, pharyngitis, chest pain, UTI, dyspepsia, rhinitis, abdominal pain, edema, constipation, myalgia, vomiting, epistaxis, rash, infection, candidiasis, tachycardia, blurred vision, urinary hesitancy/retention
o Contraindications
Ipratropium
• Pregnancy/Lactation—Category B/precaution (safety unknown)
Tiotropium
• Acute bronchospasm
• Pregnancy/Lactation—Category C/precaution (safety unknown)

Explanation
Zafirlukast (Accolate®)

Chemistry
o Cyclopentyl 3-{2-methoxy-4-[(o-tolylsulfonyl)carbamoyl]benzyl}-1-methyl-1H-indol-5-ylcarbamate
• Pharmacokinetics
o Oral administration (on an empty stomach)
Bioavailability reduced ~40% with food
o Wide distribution
o Undergoes extensive hepatic metabolism
o Excreted primarily in the feces
• Pharmacodynamics
o Mechanism of Action
Antagonist of CysLT1 (see Figure 18)
o Pharmacological Actions/Effects

BLOCKS LT-MEDIATED EFFECTS CORRELATED WITH ASTHMA

• Airway edema, smooth muscle contraction, pro-inflammatory cellular activity
• Clinical Pharmacology
o Clinical Uses
Prophylaxis and chronic treatment of asthma in adults and children ≥ 5 years of age

REDUCTION OF ASPIRIN-INDUCED ASTHMA IN ASPIRIN-SENSITIVE PATIENTS
o Adverse Effects/Toxicity

Serious reactions
• Hepatitis, hepatic failure (potentially fatal), Churg-Strauss syndrome, eosinophilia, vasculitis, hypersensitivity reaction, angioedema, depression
Common reactions
• Headache, infection, nausea, diarrhea, abdominal pain, ALT/AST elevation, insomnia
o Contraindications
Acute asthma attack, hepatic impairment
Pregnancy/Lactation—Category B/strong precaution (possibly unsafe)

Explanation
Inhaled albuterol is a bronchodilator medication commonly used to treat symptoms of asthma and chronic obstructive pulmonary disease (COPD). One of the most common adverse effects of albuterol is tachycardia, which refers to an increased heart rate. Albuterol stimulates beta-2 adrenergic receptors in the heart, leading to an increase in heart rate. This can cause palpitations, a racing heart, and potentially lead to an irregular heartbeat. Tachycardia is a known side effect of albuterol and is more likely to occur in patients who are sensitive to the medication or who use higher doses.

Explanation
Corticosteroids consistently demonstrate effectiveness in improving all indices of asthma control

Severity of symptoms
o Tests of airway caliber and bronchial reactivity
o Frequency of exacerbations
o Quality of life
• The primary mechanism of action in their control of asthma is their anti-inflammatory effect mediated by their modification of the gene expression of cells in the airways, particularly peripheral leukocytes (mainly lymphocytes, eosinophils, and macrophages)
o This remodeling of gene expression leads to:
Inhibition of the infiltration of asthmatic airways by lymphocytes, eosinophils, and mast cells
Increased expression of anti-inflammatory genes
Decreased expression of pro-inflammatory genes
Decreased synthesis of PGs and LTs
Potientiation of the effects of adrenoceptor agonists

Oral and parenterally administered corticosteroids are reserved only for asthma patients who require urgent therapy (those who have not improved adequately with bronchodilators or who experience worsening symptoms despite maintenance therapy)
o This is due to the fact that chronic corticosteroid use carries the risk of such serious adverse effects/toxicity
o Prednisolone and prednisone are the drugs of choice for oral administration
o Hydrocortisone is the drug of choice for parenteral administration; also prednisolone and methylprednisolone

*******************
ICS ARE 1ST LINE THERAPY FOR ALL PATIENTS WITH PERSISTENT ASTHMA
**********************
o Agents used are:
Beclomethasone (QVAR®)-- Prodrug that releases active corticosteroid after metabolism by lung esterases
Budesonide (Pulmicort Flexhaler®)
Ciclesonide (Alvesco®) -- Prodrug that releases active corticosteroid after metabolism by lung esterases
Flunisolide (Aerobid®; Aerospan™)
Fluticasone (Flovent®)
Mometasone (Asmanex® Twisthaler®)
Triamcinolone (Azmacort®)

Effective drugs for the therapy of mild, moderate, and severe asthma in children and adults
o Should be started in any patient who needs to use a 2-adrenoceptor agonist inhaler for symptom control more than twice weekly
o Early treatment is best because they cause a greater improvement in lung function
Due to the fact that these drugs modify the underlying inflammatory process and prevent structural changes in the airway resulting from chronic inflammation
o In cases of patients with severe asthma whose symptoms are not adequately controlled by a standard dose of ICS, modifications can be made:
ICS dose can be doubled

ICS can be combined with other drugs (methylxanthines, LT-pathway inhibitors, etc)
o Carry much less risk of systemic adverse effects than orally or parenterally administered corticosteroids
ICS may be absorbed from the airway and alveolar surface
Fraction of the ICS that is deposited in the oropharynx is swallowed and absorbed from the gut
• Use of a spacer chamber reduces oropharyngeal deposition, and thereby reduces systemic absorption of ICS
• Mouth rinsing and discarding the rinse also accomplish this feat
o Important note: Corticosteroids are not bronchodilators and cannot be used alone in cases of acute asthmatic attacks
In these cases they should be used in conjunction with 2-adrenoceptor agonists, because corticosteroids potentiate their effects
• ICS and oral corticosteroids can be used to treat acute exacerbations of COPD
o They do not have any effect on COPD disease progression or mortality, and do not appear to exert a significant anti-inflammatory effect in this disease
• Local adverse effects unique to ICS (due to steroid deposition in the oropharynx)
o Hoarseness, dysphonia (due to vocal atrophy; ~40%), throat irritation, coughing, oropharyngeal candidiasis, pneumonia (in COPD)

Explanation
Ipratropium (Atrovent®)

********Tiotropium (Spiriva®) **********

•Chemistry
o Quaternary ammonium derivatives of atropine
• Pharmacokinetics
o Inhalational and nasal (ipratropium) administration
o Poor absorption when administered by inhalational administration and they do not readily distribute into the CNS
o Ipratropium onset of action is slow (30-60 min), but persists for up to 6-8 hrs
o Tiotropium is a long-acting agent (~24 hrs for a single inhaled dose)
• Pharmacodynamics

************MECHANISM OF ACTION*****************
Competitive inhibition of acetylcholine (ACh) at muscarinic receptors
• In the airways, ACh is released from efferent endings of the vagus nerve
• Tiotropium selectively inhibits M1 and M3 receptors *****************
o Thus it does not antagonize M2 receptor-mediated inhibition of ACh release


Pharmacological Actions/Effects
Blocks the contraction of airway smooth muscle mediated by ACh
Blocks the increase in mucus secretion that occurs in response to vagal activity
• Clinical Pharmacology

CLINICAL USES
Used as bronchodilator agents in asthma (not 1st line)
•Especially useful in enhancing the bronchodilating effects of B2-adrenoceptor agonists in cases of severe asthma

USED AS THE BRONCHODILATOR AGENTS OF CHOICE IN –COPD-- (BOTH)
• AS EFFECTIVE AS, OR EVEN SUPERIOR TO, B2-ADRENOCEPTOR AGONISTS
O DUE TO THEIR INHIBITORY EFFECT ON VAGAL TONE

• Reduce air trapping and improve exercise tolerance in these patients
Treatment of rhinorrhea due to allergic or non-allergic rhinitis

o Adverse Effects/Toxicity
Ipratropium
• Serious reactions
o Hypersensitivity reactions, anaphylaxis, angioedema, laryngospasm, paradoxical bronchospasm (due to antagonism of M2 receptor-mediated inhibition of ACh release), angle-closure glaucoma
• Common reactions
o Cough, nervousness, nausea, dry mouth/throat, GI upset, dizziness, headache, COPD exacerbation, oral/nasal irritation, rash/urticaria, URI, epistaxis, pharyngitis, nasal dryness, taste changes
Tiotropium
• Serious reactions
o Hypersensitivity reaction, angioedema, paradoxical bronchospasm, increased intraocular pressure, glaucoma, paralytic ileus
• Common reactions
o URI symptoms, dry mouth, pharyngitis, chest pain, UTI, dyspepsia, rhinitis, abdominal pain, edema, constipation, myalgia, vomiting, epistaxis, rash, infection, candidiasis, tachycardia, blurred vision, urinary hesitancy/retention
o Contraindications
Ipratropium
• Pregnancy/Lactation—Category B/precaution (safety unknown)
Tiotropium
• Acute bronchospasm
• Pregnancy/Lactation—Category C/precaution (safety unknown)

Explanation
Theophylline (Elixophyllin®; Theo-24®)
Aminophylline
Chemistry
o Related to the compound caffeine
o Theophylline: 1,3-dimethylxanthine
o Aminophylline: theophylline-ethylenediamine complex
Salt form that has increased solubility at neutral pH
• Pharmacokinetics
o Oral and parenteral administration
o Rapidly and completely absorbed
Oral bioavailability ~100%
Absorption may be delayed at night related to patient being in a supine position
o Drug possesses a very narrow therapeutic window
Requires scheduled monitoring of plasma levels
o Large variation in drug clearance between patients due to differences in hepatic metabolism (requires individualization of dosage and plasma concentration monitoring)
Increased clearance is seen in children (1-16 years old), cigarette/marijuana smokers, and patients concurrently taking phenytoin, phenobarbital, and rifampin

DECREASED CLEARANCE IS SEEN IN PATIENTS WITH LIVER DISEASE, PNEUMONIA, AND HEART FAILURE (DOSES SHOULD BE CUT IN HALF AND PLASMA LEVELS MONITORED CLOSELY); CO-ADMINISTRATION WITH ERYTHROMYCIN, QUINOLONE ANTIBIOTICS, ALLOPURINOL, CIMETIDINE, FLUVOXAMINE, ZILEUTON, ZAFIRLUKAST; VIRAL INFECTIONS AND VACCINATION

Pharmacodynamics
o Mechanism of Action
Remains unclear
Several mechanisms have been proposed
• Nonselective inhibition of phosphodiesterases (PDE)
• Adenosine receptor antagonist

Adenosine induces bronchoconstriction in asthmatic patients by stimulating release of histamine and LTs
• Stimulation of release of interleukin-10 (IL-10)
o IL-10 possesses a broad spectrum of anti-inflammatory effects
• Inhibition of the pro-inflammatory transcription factor NF-B
• Induction of apoptosis in eosinophils and neutrophils
• Activation of histone deacetylases (HDAC)
o HDACs partially mediate corticosteroid-mediated suppression of pro-inflammatory genes
• Increase circulating catecholamines
• Inhibition of Ca2+ influx into inflammatory cells
• Inhibition of PG-mediated effects
• Antagonism of TNF-
o Pharmacological Actions/Effects
Induces bronchodilation
Exerts anti-inflammatory action
• Inhibits the late response to inhaled allergen
• Reduces infiltration of eosinophils and CD4+ lymphocytes into airways after allergen challenge
• Reduces the total number and production of neutrophils in induced sputum, [IL-8], and neutrophil chemotactic responses
Induces mild cortical arousal with increased alertness and deferral of fatigue (low-to-moderate doses); nervousness and tremor (large doses); medullary stimulation, convulsions, possible death (very high doses)
Positive chronotropic and inotropic effects on the heart
Stimulates secretion of both gastric acid and digestive enzymes
Exerts weak diuretic action
Improves contractility and reverses fatigue of the diaphragm (especially in COPD patients)

Clinical Pharmacology
o Clinical Uses
Therapy of acute and chronic asthma
• In cases of acute asthma, these drugs relieve airflow obstruction
o Rarely given, unless poor response to other therapies exist
• In cases of chronic asthma, these drugs reduce the severity of symptoms and time lost from work/school
o Particularly useful for the relief of nocturnal symptoms
• Improves long-term control of asthma when taken as the sole maintenance treatment or when added to ICS
• Removal of these drugs usually causes worsening of the disease
Bronchodilator therapy in COPD
• Usually added to other COPD drug regimens instead of being used alone
• Removal of these drugs usually causes worsening of the disease
Control of apnea of preterm infants
• Attributed to the immaturity of medullary respiratory center
Control of Cheyne-Stokes respiration
• Due to a decreased sensitivity of respiratory center to CO2
o Adverse Effects/Toxicity

Serious reactions
• Seizures, arrhythmias, hypotension, shock, exfoliative dermatitis
Common reactions
• Nausea/vomiting, headache, insomnia, diarrhea, irritability, restlessness, tremor, transient diuresis
o Contraindications
Pregnancy/Lactation—Category C/precaution (probably safe)

Explanation
Theophylline (Elixophyllin®; Theo-24®)
Aminophylline

Chemistry
o Related to the compound caffeine
o Theophylline: 1,3-dimethylxanthine
o Aminophylline: theophylline-ethylenediamine complex
Salt form that has increased solubility at neutral pH
• Pharmacokinetics
o Oral and parenteral administration
o Rapidly and completely absorbed
Oral bioavailability ~100%
Absorption may be delayed at night related to patient being in a supine position
o Drug possesses a very narrow therapeutic window
Requires scheduled monitoring of plasma levels
o Large variation in drug clearance between patients due to differences in hepatic metabolism (requires individualization of dosage and plasma concentration monitoring)
INCREASED CLEARANCE is seen in children (1-16 years old), cigarette/marijuana smokers, and patients concurrently taking phenytoin, phenobarbital, and rifampin

DECREASED CLEARANCE is seen in patients with liver disease, pneumonia, and heart failure (doses should be cut in half and plasma levels monitored closely); co-administration with erythromycin, quinolone antibiotics, allopurinol, cimetidine, fluvoxamine, zileuton, zafirlukast; viral infections and vaccination

Pharmacodynamics
o Mechanism of Action
Remains unclear
Several mechanisms have been proposed
• Nonselective inhibition of phosphodiesterases (PDE)
• Adenosine receptor antagonist

Adenosine induces bronchoconstriction in asthmatic patients by stimulating release of histamine and LTs
• Stimulation of release of interleukin-10 (IL-10)
o IL-10 possesses a broad spectrum of anti-inflammatory effects
• Inhibition of the pro-inflammatory transcription factor NF-B
• Induction of apoptosis in eosinophils and neutrophils
• Activation of histone deacetylases (HDAC)
o HDACs partially mediate corticosteroid-mediated suppression of pro-inflammatory genes
• Increase circulating catecholamines
• Inhibition of Ca2+ influx into inflammatory cells
• Inhibition of PG-mediated effects
• Antagonism of TNF-
o Pharmacological Actions/Effects
Induces bronchodilation
Exerts anti-inflammatory action
• Inhibits the late response to inhaled allergen
• Reduces infiltration of eosinophils and CD4+ lymphocytes into airways after allergen challenge
• Reduces the total number and production of neutrophils in induced sputum, [IL-8], and neutrophil chemotactic responses
Induces mild cortical arousal with increased alertness and deferral of fatigue (low-to-moderate doses); nervousness and tremor (large doses); medullary stimulation, convulsions, possible death (very high doses)
Positive chronotropic and inotropic effects on the heart
Stimulates secretion of both gastric acid and digestive enzymes
Exerts weak diuretic action
Improves contractility and reverses fatigue of the diaphragm (especially in COPD patients)

Clinical Pharmacology
o Clinical Uses
Therapy of acute and chronic asthma
• In cases of acute asthma, these drugs relieve airflow obstruction
o Rarely given, unless poor response to other therapies exist
• In cases of chronic asthma, these drugs reduce the severity of symptoms and time lost from work/school
o Particularly useful for the relief of nocturnal symptoms
• Improves long-term control of asthma when taken as the sole maintenance treatment or when added to ICS
• Removal of these drugs usually causes worsening of the disease
Bronchodilator therapy in COPD
• Usually added to other COPD drug regimens instead of being used alone
• Removal of these drugs usually causes worsening of the disease

***********CONTROL OF APNEA OF PRETERM INFANTS **********

• Attributed to the immaturity of medullary respiratory center
Control of Cheyne-Stokes respiration
• Due to a decreased sensitivity of respiratory center to CO2
o Adverse Effects/Toxicity

Serious reactions
• Seizures, arrhythmias, hypotension, shock, exfoliative dermatitis
Common reactions
• Nausea/vomiting, headache, insomnia, diarrhea, irritability, restlessness, tremor, transient diuresis
o Contraindications
Pregnancy/Lactation—Category C/precaution (probably safe)

Explanation
The Pharmacology of B2-Adrenoceptor Agonists

Chemistry
o Chemical derivatives of the catecholamines norepinephrine and epinephrine
o Levalbuterol is the R-isomer of albuterol; arformoterol is the R,R-isomer of formoterol
• Pharmacokinetics
o Oral, parenteral, and inhalational administration
Drugs are best delivered inhalationally because this route leads to the greatest local effect in airway smooth muscle with the least toxicity
• Typically, 80-90% of the total aerosol dose is deposited in the mouth or pharynx
• Bronchial deposition is increased by slow inhalation of a nearly full breath and by more than 5 seconds of breath-holding at the end of inspiration
Duration of action ranges from 3-12 hrs depending on the chemical modifications present in the drug molecule (prevents degradation of the drug by catechol-O-methyl transferase—COMT)
• Pharmacodynamics
o Mechanism of Action
B2-ADRENOCEPTOR AGONIST
ESPECIALLY ON AIRWAY SMOOTH MUSCLE CELLS

•RECEPTOR ACTIVATES ADENYLYL CYCLASE AND STIMULATES FORMATION OF INTRACELLULAR cAMP

o This results in numerous biochemical changes in target cells
Lowering of [Ca2+]intracellular by active removal from the cytosol into intracellular stores and out of the cell
Potent inhibition of the phospholipase C-inositol triphosphate (PLC-IP3) pathway
Inhibition of myosin light chain kinase activation
Activation of myosin light chain phosphatase
Opening of large conductance Ca2+-activated K+ channels (KCa), which repolarizes the smooth muscle cell
Act as functional agonists
• Reverse bronchoconstriction irrespective of the contractile agent
o Extremely important fact in asthma, which has numerous bronchoconstriction-promoting agents

Pharmacological Actions/Effects
Relaxes airway smooth muscle
Rapidly decreases airway resistance
Inhibits release of bronchoconstricting mediators from mast cells
Inhibits microvascular leakage
Increases mucociliary transport by increasing ciliary activity
Reduces neurotransmission in human airway cholinergic nerves by inhibiting acetylcholine release (action on presynaptic 2-adrenoceptors)
• Major therapeutic MOA in COPD
• Clinical Pharmacology
o Clinical Uses
Bronchodilator treatment of choice in asthma
• Inhaled short-action drugs are the most widely used and effective due to their functional antagonism of bronchoconstriction
o Albuterol is the prototype of this group
o Drugs of choice in treatment of acute severe asthma
o Should be used on an “as needed” basis for the relief of symptoms in cases of mild asthma
o When inhaled from pressurized metered-dose inhalers (pMDI) or dry powder inhalers (DPI) they are convenient, easy to use, rapid in onset, and without significant systemic adverse effects
o Effective in protecting against various challenges, such as exercise, cold air, and allergens
• Inhaled long-acting drugs (LABA) improve asthma control and provide sustained bronchodilator action (>12 hrs) and bronchoprotection
o Salmeterol is the prototype of this group
o Should never be used alone because they do not treat the underlying chronic inflammation
Should be used in combination with inhaled corticosteroids (ICS), preferably in a fixed-dose combination inhaler
Bronchodilator treatment in COPD
• LABA are used for these cases
o Used “as needed” in mild COPD, or daily in severe COPD
o They are used alone or in combination with anticholinergics or ICS
o Adverse Effects/Toxicity

Most are dose related and due to stimulation of extrapulmonary B2-adrenoceptors
• Especially common with oral and parenteral administration
Possible development of tolerance (desensitization, subsensitivity)
• Seen with continuous therapy due to down-regulation of B2-adrenoceptors
• Can be prevented by corticosteroids

*************************************
Albuterol SERIOUS REACTIONS
o Hypersensitivity reactions, paradoxical bronchospasm, HTN, angina, MI,*** HYPOKALEMIA***, arrhythmias, metabolic acidosis (nebulized use)
**********************************************
• Common reactions
o Tremor, nervousness, headache, nausea, tachycardia, muscle cramps, palpitations, insomnia, dizziness, throat irritation, URI symptoms, cough, bad taste,
Salmeterol
• Serious reactions
o Paradoxical bronchospasm, asthma exacerbation, asthma-related death, anaphylaxis, angioedema, laryngospasm, arrhythmias, HTN
• Common reactions
o Headache, throat irritation, nasal congestion, rhinitis, tracheitis/bronchitis, pharyngitis, urticaria, rash, palpitations, tachycardia, tremor, nervousness
• Carries a Black Box Warning regarding asthma-related death risk and appropriate use in pediatric/adolescent patients
o Contraindications
Albuterol
• Drug Combinations
o Phenothiazines
• Pregnancy/Lactation—Category C/precaution (probably safe)
Salmeterol
• Asthma monotherapy, acute asthma
• Drug Combinations
o Phenothiazines
• Pregnancy/Lactation—Category C/precaution (safety unknown)