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:

liu_ag@yahoo.com