Objectives
Understand the indications as well as contraindications of respiratory agents
Understand the adverse effects as well as the side effects of these agents
Understand the mechanism of action
Introduction: Asthma Airflow obstruction due to contraction of
bronchial smooth muscles, inflammation of the bronchial wall, increased mucus
Exposure to allergens or inhaled irritants, or exercise induced leading to bronchial hyperactivity and inflammation of the airway mucosa
. Pharmacologic agents are going to target the bronchoconstric2on as well as the inammatory aspect of the disease Studies have shown that there is increase of inammatory cells into the lung 2ssue
Introduction: Asthma
Chronic inflammatory disease of airways Characterized by increased responsiveness of
tracheobronchial tree to multiplicity of stimuli Characterized by activation of mast cells, infiltration of
eosinophils, and T helper2 lymphocytes The mast cells release bronchoconstrictor
mediators, such as histamine, leukotriene D4, and prostaglandinD2, which cause bronchoconstriction, microvascular leakage, and plasma exudation
Picture illustra2ng the process allergic rhini2s has same mechanism of ac2on as asthma but ususally not accompanied by asthma, because the allergens usually are contained in par2cles too large to be inhaled into the lower airways Histamine vasodila2on , leukotrines bronchocons2c2on, vasoldila2on, vasopermeability, cytokines to a?ract more cells 2 systems allergic hypersensi2vity and increased in parasympathe2c overtone which leads to brconchoconstric2on
Hypersensitivity Reaction Increase inflammatory cells in the lung tissue Allergen specific IgE bound to mast cells Triggers release of large number of inflammatory mediators Results in vasodilatation increased vasopermeablity,
increase lymphocytes in circulation Chronic results include increase in the number and
size of airway smooth muscle cells, blood vessels, mucus-sereting cells, and a characteristic feature of asthma is collagen deposition (fibrosis)
May also cause increase to the parasympathe2c tone resul2ng in bronchial narrowing Hyperreac2vity to nonspecic s2muli such as strong odors, cold air, pollutants and histamine
Changes in Airway Morphology in Asthma
Chronic Obstructive Pulmonary Disease Chronic inflammatory process Cigarette smoke other irritants activate
epithelial cells and macrophages in the lung to release mediators that attract circulatory inflammatory cells
Chronic Obstructive Pulmonary Disease Fibrogenic factors released from epithelial cells
and macrophages lead to fibrosis of small airways
Release of proteases results in alveolar wall destruction (emphysema)
Mucus hyper secretion (chronic bronchitis) Air way disease such as this have an dominant
parasympathetic overtone
Chronic Obstructive Pulmonary Disease
Irreversible obstruction of airflow Larger airways respond by increasing the number of
mucus-secreting glands and reducing mucociliary function
Smaller airways go through repeated cycles of injury and repair resulting in remodeling, scarring, thickening, and consolidation
Pharmacological Classification
Bronchodilators Beta2 Adrenergic agonists Theophylline Anticholinergic agents
Inflammatory Mediators Corticosteroids Mediator antagonists Immunotherapy
Pharmacological Targets
Beta2-adrenergic agonist Short acting relatively
selective SABA Albuterol (Proventil,
Ventolin) Levalbuterol (Xopenex) Pirbuterol (Maxair) Albuterol (Proventil
Repetabs, Volmax)
Long-acting relatively select LABA Salmeterol xinfoate
(serevent diskus) Formoterol Fumarate
(Foradil Brovana)
Repetabs are controlled release tablets, pirbuterol (maxair) and albuterol Metaproternol and isoetharine shorter ac2ng less selec2ve Isoproternol ac2vates beta1 & beta2 receptors equally
Inhaled Short-Acting Beta2-Agonists (SABA): Albuterol, Levalbuterol (Xopenex )
and Pirbuterol (Maxair)
Used for acute inhalation treatment of bronchospasm Can be diluted in saline for administration via nebulizer Not to be used as the sole therapeutic agent for patients with
persistent asthma Tolerance to the effects of beta2-agonist on airway tissue
occurs but uncommon with normal dosage Can be used as monotherapy for patients identified as having
intermittent asthma or pretreatment before exercise Used as required by symptoms and not on a regular
basis
Terbutaline (Brethine) has black box warning against pregnancy, can cause delay in uterine contrac2on up to 48 hours black box warning for pregnant females available as subcutaneous injec2on
Epinephrine is drug of choice for treatment of acute analphylaxis and status asthma2cus but past studies suggest high mortality if used constantly
Inhaled Short-Acting Beta2-Agonists (SABA): Albuterol, Levalbuterol (Xopenex )
and Pirbuterol (Maxair) Activates enzyme adenyl cyclase, which increases the
production of cyclic adenosine monophosphate (cAMP) Minor effect: indirectly inhibits the release of
bronchoconstrictor mediators from inflammatory cells via beta
Relax airway smooth muscle Increase in airflow within 35 minutes (relief for 4 -6 hours) All synthetic beta2-agonists exist chemically as racemic mixtures Levalbuterol contain only active enantiomer of albuterol
SABA: Toxicity Tachycardia Skeletal muscle tremor Hypokalemia Increased lactic acid Headache Hyperglycemia Inhaled route causes few systemic adverse effects
Muscle tremor (beta 2 muscle cells), tachycardia (atrial beta2 receptors) and refelex from peripheral vasodila2on, Hypokalemia (direct beta2 receptors on skeletal muscle uptake of k). Metabolic eects (increase fa?y acid, insulin, glucose, pyruvate, and lactate) only aRer large does
Long-Acting Beta2-Agonists (LABA)
Both drugs have a similar duration of effect Formoterol is a full agonist with a more rapid
onset of action, salmeterol is a partial agonist with a slower onset of action
Sustained improvement in lung function NOT APPROVED FOR MONOTHERAPY LABAs will mask inflammation by controlling
symptoms and will not modify disease progress Sustained effects may reduce events associated
with exercised induced asthma
Long-Acting Beta2-Agonists
Now combination inhalers are being widely used which combine LABA and a corticosteroid for persistent asthma Shown to have synergistic actions Patients get symptom relief and anti-inflammatory control Greater simplicity and convenience Steroids up regulate the number of beta2 receptors and
decrease beta2 receptor desensitization
Methylxanthines: Theophylline Xanthine derivative
Occurs naturally in tea Chemically similar to caffeine
Introduced in 1900 to treat asthma Use did not become widespread until after 1936 Approved by FDA in 1940
IR and SR oral dosage forms are marketed Inhibit phosphodiestarase (PDE), the
enzyme that degrades cAMP to AMP thus increase cAMP
Adenosine receptor antagonism
Sympathomimetic Agents
Methylxanthines: Theophylline Expert Panel recommends SR theophylline is an alternative but not preferred treatment
for mild persistent asthma May also be used as alternative but not preferred adjunctive
therapy with ICS Narrow Therapeutic Window Monitoring serum concentrations of theophylline is essential Target peak concentration range 1015 mcg/ml Unbound: 612 mcg/ml Levels should be obtained in patients with low levels of
binding proteins
Methylxanthines: Theophylline Serum concentration is obtained 35 days after
initiation of theophylline In middle of dosing interval At least 2 days after initiation of any factor known to affect
clearance Signs and symptoms of toxicity: severe
headache, tachycardia, n/v, convulsions or potentially fatal arrhythmias Discontinue drug and obtained serum concentration
Major substrate of cytochrome P450
Anticholinergics Ipratropium Bromide (Atrovent) Tiotropium Bromide (Spiriva)
Nonselective competitive antagonists of muscarinic receptors Blocks the vagally mediated contraction of airway smooth
muscles and mucus secretion
More effective for COPD due to belief that cholinergic tone is increased Response based on strength of parasympathetic tone
Not recommended for the routine treatment of acute bronchospasm in asthma due to slow onset
Anticholinergic
Anticholinergics Ipratropium Bromide (Atrovent) Tiotropium Bromide (Spiriva)
Bronchodilation produced by ipratropium develops more slowly and is usually less intense than that produced by adrenergic agonists
Minor adverse effects related to local anticholinergic effects xerostomia and bitter tasted
Used with caution in patients with narrow angle glaucoma, prostatic hypertrophy, or bladder neck obstruction
Corticosteroids Inhaled Corticosteroid
(ICS) Beclomethasone
(Vanceril, Beclovent, Q-VAR)
Budesonide (Pulmicort) Flunisolide (Aerobid) Fluticasone (Flovent) Triamcinolone acetonide
(Azmacort)
Systemic Prednisone/
Prednisolone Methylprednisolone
(Solu-Medrol, Medrol)
Inhaled Corticosteroids (ICS)
Benefit of Daily Use And Therapeutic Properties Controlling inflammation Facilitate long-term prevention of symptoms Reduce need for oral steroids Decrease exacerbations Prevent hospitalization Decrease economic burden Reduce use of quick-relief medicine
ICS: Mechanisms of Action
Inhibit Cytokine production Adhesion protein activation Inflammatory cell migration and activation
Block late reaction to allergen and reduce airway hyper responsiveness
Reverse beta2-receptor down-regulation Inhibit microvascular leakage
Estimated Comparative Dosages of Inhaled Corticosteroids (ICS)
Preparations are not equivalent per puff or per microgram No fixed dose benefits all patients Most important determinant of dosing is clinician judgment Therapeutic onset seen in 1 2 weeks
Toxicity of Inhaled Corticosteroids Local (oropharyngeal) Candidiasis Hoarseness
Systemic toxicity in adults Suppression of adrenal pituitary axes at doses > 1000
mcg/day Little effect on bone mineral density in studies
Monitor for hypercor2cism and HPA axis suppression. If these occur, discon2nue drug gradually Neuroendocrine system that controls reac2ons to stress and regulates many body processes, including diges2on, the immune system, mood and emo2ons, sexuality and energy storage and expenditures
Schematic Representations of the Disposition of Inhaled Drugs
Systemic Corticosteroids Expert Panel of National Asthma Education and
Prevention Program recommends Use of oral systemic corticosteroids in moderate or
severe exacerbations Multiple courses of oral systemic corticosteroids,
especially more than three courses per year, should prompt a reevaluation of the asthma management plan for a patient
Dose Prednisone 3060 mg PO per day Methylprednisolone 1 mg/kg IV every 6 hours Administer early in the morning For prevention of nocturnal asthma: give in the late
afternoon
Systemic if taken for 5 to 10 days has li?le dose related side eects
Mast CellStabilizing Agent: Cromolyn sodium
Stable but extremely insoluble salts
Inhibit degranulation of mast cells Prevent release of chemical
mediators of anaphylaxis Administer by inhalation
Dosing recommendations
Administration four times a day Due to its short duration of
action
Nebuliza2on, meterdose aerosol slow onset therapeu2c eects occur in about a week, 2-4 weeks to maximum therapeu2c eect Cromolyn sodium (Intal) Nedocromil sodium (Tilade)
Mast CellStabilizing Agents
Adverse effects minor and include cough, irritation, and unpleasant taste
Leukotriene Modifiers
Leukotriene receptor antagonists: Montelukast (singulair), Zafirlukast (Accolate)
5-Lipoxygenase inhibitor: Zileuton (Zyflo) Leukotrienes are a more potent and longer-acting
bronchoconstrictor then histamine
Leukotriene Modifiers: Potential Clinical Use Add-on therapy in patients not controlled by ICS +
LABA As steroid sparing agent As alternative to ICS in patients Not using MDIs correctly Those who fear inhaled steroids
In aspirin sensitive asthmatics Exercise induced asthma
Anti-IgE Therapy: Omalizumab (Xolair )
First "biological drug" approved for treatment of asthma Recombinant humanized monoclonal antibody targeted
against IgE IgE bound to omalizumab cannot bind to IgE receptors on mast
cells and basophils ]preventing allergic reaction at a very early step in the process
Omalizumab:
Pharmacology and Use in Asthma
Delivered as single subcutaneous injection every 2 to 4 weeks
Peak serum levels:7 to 8 days
Elimination half-life: 26 days
Upper Respiratory Agents
Rhinitis Allergic Rhinitis Cough
Rhinitis o Often viral in origin o Disturbs normal physiologic processes
o Production of mucus dramatically increases but thick with dehydration
o Mucociliary mechanism is inhibited, cilia become sticky and unable to move
o Characterized by itching, nasal discharge, sneezing, nasal airway obstruction, sometimes nonproductive cough
Body mounts a defence to a?ack it leading to these symptoms, Coughing may also occur, if its bacterial may display ue like symptoms, and be accompanied by fever
Allergic Rhinitis q Induction of rhinitis symptoms after allergen exposure
by an IgE-mediated immune reaction q Accompanied by inflammation of the nasal mucosa
and nasal airway hyper reactivity q Sneezing, injected conjunctiva, watery itchy eyes, red
edematous eyelids Same mechanism of ac2on as asthma but usually not accompanied by asthma because the allergens usually are contained in par2cles too large to be inhaled into the lower airways Consider the dynamics of inamma2on and the ANS this 2me regarding vasculature
Mechanism
Histamine: pruritis, sneezing, rhinorrhea Acetylcholine: stimulates glandular secretion
Mediator Effects
Vasodilation and increased vascular permeability Nasal congestion
Increased glandular secretion Mucus rhinorrhea
Stimulation of afferent nerves Pruritis & sneezing
Agents and Actions Oral
antihistamines
Nasal antihistamines
LT1 receptor
antagonists
Nasal steroids
Nasal decongestan
ts
Oral decongestnts
Nasal ipratropium
Rhinorrhea + + ++ ++ +++ 0 0 +++ Congestio
n + + + +++ ++++ ++ 0
Sneezing ++ ++ ++ +++ 0 0 0 Pruritus ++ ++ + +++ 0 0 0 Ocular
symptoms ++ 0 ++ ++ 0 0 0
Onset of action 1 hr 15 min 48 hr 12 hr 5-15 min 1 hr
15-30 min
Duration 12-24 hr 6-12 hr 24 hr 12-48 hr 3-6 hr 12-24 hr 4-12 hr
Oral Antihistamines
First Generation Agents Diphenhydramine
(Benedryl) Clemastine Fumarate
(Tavist) Chlorpheniramine
Maleate (Chlor-Trimeton)
Second Generation Agents Certrizine (Zyrtec) Fexofenadine (Allegra) Loratidine (Claritin) Desloratadine (Clarinex)
Benedryl (OTC), Tavist (OtC)), Chlor-trmeton (OTC), Calri2n (OTC), Clari2n D or Allegra D has a pseudoephedrine
Non Oral Antihistamines
Levocabastine (Livostin): applied topically to relieve allergic conjunctivitis
Olopatadine (Patanol): applied topically for allergic pink eye
Azelastine (Astelin): intranasal antihistamines
Antihistamines
Compete for histamine at the H1-receptor sites and used to treat IgE-mediated allergy
Helpful in treating urticaria H2 receptor blockers used in gastrointestinal system Found to be helpful in vestibular associated nausea
and vomiting Have anticholinergic properties Produce sedation in varying degrees
Benedryl topical formula2ons for hives , skin rash (ur2caria)
H3 receptors in neuro terminals that deal with histamine feed back
An2cholinergic eects such as dry eyes/ mouth, diculty urina2ng and/ or defeca2ng especially with the rst genera2on an2histamines
Antihistamine Generation Comparison
First Generation Second Generation Lipophyllic Lipophobic Side effects
Sedation Anticholinergic effects
Side effects Less sedation Anticholinergic effects
Antihistamines Not to be used with alcohol, sleeping pills, sedatives or
tranquilizers may cause drowsiness Caution exercised when driving or operating
dangerous machinery Viral or bacterial infec2ons uses other
mechanisms, deconges2ons are preferred for cold symptoms, an2histamines are op2mal for allergic reac2ons
Antihistamines
Some OTC preparations contain antihistamine to help patients sleep Combine with decongestant to counter side effects
Contra indicated in patients with narrow-angle glaucoma, prostatic hyperplasia, bladder neck obstruction
Nyquill night 2me medica2on contains an2histamine such as diphenydramine or other an2histamine, other variatons manipulate dextromethorphan, psuedoephirine decongestant, tylenol for fever various combina2on. The dayquil prepara2on does not contain an2histamines
Intranasal Antihistamine: Azelastine (Astelin)
Second generation Only antihistamine that also reduces nasal
congestion Rapid onset of action Side effects Bitter taste Anticholinergic effects Sedation
Decongestants: Alpha-2 Adrenergic Agonists
Oral Decongestants Pseudoephedrine
(Sudafed ) Phenylephrine (Sudafed)
Topical Nasal decongestants Phenylephrine (Neo-
synephrine Oxymetazoline (Afrin,
Neo-synephrine 12-hour
Decongestants
Stimulate alpha adrenergic receptors leading to constriction of dilated arterioles in the nasal mucosa and reduced airway resistance
Reduces tissue edema and nasal congestion, increases nasal airway patency, promotes drainage of sinus secretions
Decongestants o Adverse Effects: o Oral decongestants: insomnia, tachycardia, tremor, increased blood pressure o Nasal decongestants: tachyphylaxis, rebound congestion, nasal hyperresponsiveness, rhinitis medicamentosa oNot for chronic therapy no longer then 3 days of use oTreatment rest cycles could be used
Decongestants
Contra indicated in patients with mitral valve prolapse and cardiac palpitations, severe hypertension, or on MAOIs For people with hypertension Coricidin is alternatve cold & flu
perparation Precautions: diabetes, hypertension, cardiovascular disease,
prostatic hypertrophy, or hyper reactivity to ephedrine Many over the counter products have this ingredient added to it
eg. Allegra-D ( antihistamine/ decongestant), Guaifed PD (antitussive/ decongestiant), Robitussin DM
Anticholinergic Treatment: Ipratropium Bromide (Atrovent) Nasal Spray
Indications: .03% strength rhinorrhea (runny nose) .06% strength rhinorrhea from common cold
Nasal glands are activated by muscarinic, cholinergic receptors Nonselective muscarinic receptor antagonist Applied intranasally Blocks rhinorrhea induced by cholinergic stimulation
Has negligent systemic anticholinergic activity Topical adverse effects: excessive dryness, epistaxis
Leukotriene Antagonist: Montelukast (Singular ) Only leukotriene inhibitor approved for allergic
rhinitis Nasal congestion correlates mainly with leukotriene
levels Sneezing and nasal itching correlates with
histamine release Can be used in patients that can not tolerate
intranasal corticosteroids
For both seasonal and periannel rhini2s
Mast Cell Stabilizers: Cromolyn Sodium (NasalCrom)
OTC intranasal mast stabilizer used as a preventative agent taken in advance of allergen exposure Very effective in intermittent allergies (seasonal allergies) Should start 3 to 4 weeks before peak allergy season Several doses are needed per day
Side Effects: nasal stinging or sneezing occurs rarely Start up to 1 week before contact with cause of allergy By inhibi2ng calcium from entering the mast cell, results in preven2on of mediator release
Intranasal Steroids
Triamcinolone Acetonide (Nasacort AQ) Beclomethasone Dipropionate (Beconase, Vancenase) Fluticasone Propionate (Flonase)
Nasal Corticosteroids
reduction of symptoms and exacerbations
reduction of mucosal inflammation
reduction of late phase reactions
priming nasal hyperresponsiveness
1
reduction of mucosal mast cells
reduction of acute allergic reactions
2
suppression of glandular activity and vascular leakage induction of vasoconstriction
3
Nasal Corticosteroids
Most potent anti-inflammatory agents Effectively control the four major symptoms of allergic
rhinitis rhinorrhea, congestion, sneezing, and nasal itch
Effective in treatment of all nasal symptoms including obstruction
Superior to anti-histamines and anti-leukotienes Can be used consistently on a daily basis for
effectiveness Effect may not be noted for several weeks
Nasal Corticosteroids Overall safe to use Adverse Effects Nasal irritation Epistaxis Septal perforation (extremely rare) HPA axis suppression (inconsistent and not clinically significant) Suppressed growth (only in one study with
beclomethasone)
Exceeding the recommended dose may result in systemic eects but less likely with intranasal cor2costeriods
Antitussives Used to control or suppress cough caused by
respiratory tract irritation, colds or allergies Narcotic Medications used Low dose Codeine/ Hydrocodone Decreases the sensitivity of cough centers in the central
nervous system to peripheral stimuli and decreases mucosal secretion
S/E rash , sedation, constipation, fatigue Low dose codeine is combine with guaifensesin as an2tussive syrup with
10mg codeine/ 100 mg guaifenesin Poten2al for habit forming Has analgesic eects allowing it to be used for pain associated with
coughs, seda2on could be used to help person to sleep
Antitussives Non narcotic
Dextromethorphan (Benyin, Delsym, Robitussin Maximum Strength)
D-isomer of codeine that lacks the analgesic and addictive properties of codeine
Not as effective as codeine Benzonatate (Tessalon Perles) has anesthetic
action similar to that of benzocaine and numbs the stretch sensors in the lungs Often used in frail elderly who must continue to perform
activities that require maximum mental alertness such as driving
(Dextromethorphan) Available as lozenges Stretching of these sensors of these sensors with breathing causes the cough Benzonate released in the mouth can produce temporary local anesthesia of the oral mucosa that could cause choking
Expectorants
Guaifenesin (Robitussin, Humibid LA, Mucinex) Increases respiratory tract fluid secretions and helps to
loosen bronchial secretions by reducing adhesiveness and tissue surface tension
THE END Feel free to email me your questions:
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