Drugs used in disorders of the respiratory system

Marc Imhotep Cray, M.D.

Learning Objectives Treatment of Asthma and COPD 1. The indications, mechanism of action, adverse effects and contraindications for the different anti-asthmatics including the preference for certain drugs in certain situations.

2. The pharmacokinetics of anti-asthmatics and the rapidity of their onset of action.

3. Describe the strategies of drug treatment of asthma and COPD. 4. List the major classes of drugs used in asthma and COPD. 5. Describe the mechanisms of action of these drug groups.

6. List the major adverse effects of the prototype drugs used in airways disease.

Marc Imhotep Cray, M.D.

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Learning Objective cont.

7. To provide a global overview of the drugs affecting the respiratory system as a prerequisite to deeper layered discussions and case-based learning in subsequent lectures, including:  Classification and class prototype/s  Mechanism of action  Indications (therapeutic use)  Side effects (adverse effects)  Drug-drug interactions and contraindications  Pharmacokinetic properties and drug-disease (patient) interactions  Toxicities and antidotes (or) treatment

Marc Imhotep Cray, M.D.

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Learning Objectives cont.

8. Histamine and its Antagonists    

The physiological and pathophysiological role of histamine The pharmacology of histamine receptors The mechanisms of histamine release The indications, mechanism of action, adverse effects and contraindications of histamine H1 and H2 receptor antagonists.

See: Histamine and Antihistamines in Autocoids, Ergots, Anti-inflammatory and Immunosuppressive Agents Notes

Marc Imhotep Cray, M.D.

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Organization of the Nervous System CENTRAL NERVOUS SYSTEM (CNS)

BRAIN & SPINAL CORD

AFFERENT

EFFERENT

(Sensory)

(Motor)

NERVES

NERVES

EXTEROCEPTORS

INTEROCEPTORS

EFFECTOR ORGANS

SKELETAL MUSCLES VOLUNTARY Monosynaptic

Marc Imhotep Cray, M.D.

SOMATIC

AUTONOMIC

PERIPHERAL NERVOUS SYSTEM (PNS)

SMOOTH MUSCLE, CARDIAC MUSCLES AND GLANDS INVOLUNTARY Pre & Post Ganglionic Fiber

Classes of Chemical Messengers 1. Autocrine chemical messengers An autocrine chemical messenger stimulates the cell that originally secreted it  Examples are those secreted by white blood cells during an infection o Several types WBCs can stimulate their own replication, so that total number of white blood cells increases rapidly 2 Paracrine chemical messengers Paracrine chemical messengers act locally on nearby cells  These chemical messengers are secreted by one cell type into extracellular fluid and affect surrounding cells o An is histamine, released by certain white blood cells during allergic reactions Histamine stimulates vasodilation in nearby blood vessels Marc Imhotep Cray, M.D.

Classes of Chemical Messengers (2) 3 Neurotransmitters Neurotransmitters are chemical messengers secreted by neurons that activate an adjacent cell, whether it is another neuron, a muscle cell, or a glandular cell  NTs are secreted into a synaptic cleft, rather than into bloodstream Therefore, in strictest sense NTs are paracrine agents, but for our purposes it is most appropriate to consider them as a separate category 4 Endocrine chemical messengers Endocrine chemical messengers are secreted into bloodstream by certain glands and cells, which together constitute endocrine system  These chemical messengers travel through general circulation to their target cells Marc Imhotep Cray, M.D.

Summary of drugs affecting the respiratory system

Marc Imhotep Cray, M.D.

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Summary of drugs affecting the respiratory system MEDICATION

INDICATION

SHORT-ACTING β2 ADRENERGIC AGONISTS Albuterol PROAIR, PROVENTIL, VENTOLIN

Asthma, COPD

Levalbuterol XOPENEX

Asthma, COPD

LONG-ACTING β2 ADRENERGIC AGONISTS Arformoterol BROVANA

COPD

Formoterol FORADIL, PERFOROMIST

Asthma, COPD

Indacaterol ARCAPTA

COPD

Salmeterol SEREVENT

Asthma, COPD

Marc Imhotep Cray, M.D.

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Summary of drugs affecting respiratory system (2) MEDICATION

INDICATION

INHALED CORTICOSTEROIDS Beclomethasone BECONASE AQ, QVAR

Allergic rhinitis, Asthma, COPD

Budesonide PULMICORT, RHINOCORT

Allergic rhinitis, Asthma, COPD

Ciclesonide ALVESCO, OMNARIS, ZETONNA

Allergic rhinitis

Fluticasone FLONASE, FLOVENT

Allergic rhinitis, Asthma, COPD

Mometasone ASMANEX, NASONEX

Allergic rhinitis, Asthma

Triamcinolone NASACORT AQ

Allergic rhinitis

Marc Imhotep Cray, M.D.

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Summary of drugs affecting respiratory system (3) MEDICATION

INDICATION

LONG-ACTING β2 ADRENERGIC AGONIST /CORTICOSTEROID COMBINATION Formoterol/budesonide SYMBICORT

Asthma, COPD

Formoterol/mometasone DULERA

Asthma, COPD

Salmeterol/futicasone ADVAIR

Asthma, COPD

Vilanterol/futicasone BREO ELLIPTA

COPD

SHORT-ACTING ANTICHOLINERGIC Ipratropium ATROVENT

Allergic rhinitis, COPD

LONG-ACTING ANTICHOLINERGIC Aclidinium bromide TUDORZA PRESSAIR

COPD

Tiotropium SPIRIVA

COPD

Marc Imhotep Cray, M.D.

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Summary of drugs affecting respiratory system (4) MEDICATION

INDICATION

LEUKOTRIENE MODIFIERS Montelukast SINGULAIR

Asthma, Allergic rhinitis

Zafirlukast ACCOLATE

Asthma

Zileuton ZYFLO CR

Asthma

ANTIHISTAMINES (H1-RECEPTOR BLOCKERS) Azelastine ASTELIN, ASTEPRO

Allergic rhinitis

Cetirizine ZYRTEC

Allergic rhinitis

Desloratadine CLARINEX

Allergic rhinitis

Fexofenadine ALLEGRA

Allergic rhinitis

Loratadine CLARITIN

Allergic rhinitis

Marc Imhotep Cray, M.D.

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Summary of drugs affecting respiratory system (5) MEDICATION

INDICATION

Îą-ADRENERGIC AGONISTS Oxymetazoline AFRIN, DRISTAN

Allergic rhinitis

Phenylephrine NEOSYNEPHRINE, SUDAFED PE

Allergic rhinitis

Pseudoephedrine SUDAFED

Allergic rhinitis

AGENTS FOR COUGH Benzonatate TESSALON PERLES Codeine (with guaifenesin) VARIOUS Dextromethorphan VARIOUS Dextromethorphan (with guaifenesin) VARIOUS Guaifenesin VARIOUS

Marc Imhotep Cray, M.D.

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Summary of drugs affecting respiratory system (6) MEDICATION

INDICATION

OTHER AGENTS Cromolyn NASALCROM

Asthma, Allergic rhinitis

Omalizumab XOLAIR

Asthma

Roflumilast DALIRESP

COPD

Theophylline ELIXOPHYLLIN, THEO-24, UNIPHYL

Asthma

Marc Imhotep Cray, M.D.

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Overview  Common respiratory diseases include:  Asthma  chronic obstructive pulmonary disease(COPD includes emphysema and chronic bronchitis)  acute bronchitis  dyspnea(difficult breathing) and  pneumonia  Drugs for treating respiratory system are used primarily to open bronchial tubes, either  By reversing effects of histamines (which are released by body when exposed to substances that cause allergic reactions) or  By relaxing muscle bundles surrounding bronchial tubes

Marc Imhotep Cray, M.D.

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Overview (2)  Asthma, which involves constriction of pulmonary passages and secretion of excess mucus, is characterized by  Dyspnea  Coughing and  wheezing  Asthma is precipitated by triggers such as  Allergens  cold air  viral infections  bacterial infections and  Exercise  Anti-IgE antibodies, mast cell degranulation blockers, smooth muscle relaxants, and antiinflammatory agents are major drug classes used for asthma Marc Imhotep Cray, M.D.

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Overview (3)  Emphysema results from breakdown of alveolar walls, which leads to reduced alveolar surface area and impaired cellular respiration and gas exchange  Acute bronchitis results from inflammation of bronchial passages and has causes similar to those of asthma  Chronic bronchitis is characterized by persistent production of excess mucus in bronchial tubes  Cough, shortness of breath, and lung damage are typical of chronic bronchitis  Medications for COPD include short-acting β2 agonists and other bronchodilators  Pneumonia is an acute lung inflammation that results in collapse of lung tissue and can be treated with antibiotics only when cause is bacterial Marc Imhotep Cray, M.D.

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Respiration: Introduction to Physiology and Pathology

Marc Imhotep Cray, M.D.

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Respiration Overview  Respiration means ventilation, or breathing  2 phases of breathing are inspiration (inhalation) and expiration (exhalation)

 Primary functions of respiratory system are to provide oxygen to tissues and to expel carbon dioxide from body  Respiration is classified into 3 functional categories:  external respiration exchange of gas between atmosphere and blood  internal respiration exchange of gas between blood and cells, and  cellular respiration process whereby cells use oxygen and convert energy into useful forms

 Major waste product of cellular respiration= carbon dioxide diffuses from cells into blood transported to lungs and expelled during expiration  Pharmacologic intervention becomes necessary when respiratory system functions improperly Marc Imhotep Cray, M.D.

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Respiratory Diseases  Most common respiratory disorders are asthma, cough, COPD (emphysema; chronic bronchitis), and pneumonia  Less common disorders are hyperventilation (excessive inspiration and expiration); apnea (temporary breathing cessation that may follow hyperventilation); and rhinitis (nasal mucosa inflammation)

 Drugs used for these conditions normally given by inhalation (metereddose or nebulized inhaler) or by oral means  Inhalation is preferred because of direct drug delivery to lungs, avoidance of first-pass metabolism by liver and intestine, and minimization of adverse effects of systemic distribution 

Certain drugs used to treat asthma (eg, theophylline, albuterol, terbutaline) can be given orally

 Parenteral dosing (intravascular, subcutaneous, or intramuscular) may be needed, especially when rapid onset of action is critical or drug absorption from GI tract is poor controls dose delivered, but adverse effects can result Marc Imhotep Cray, M.D.

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Allergy Allergic rhinitis affects approximately 20% of the American population. It is characterized by itchy, watery eyes, runny nose, and a nonproductive cough that can significantly decrease quality of life.

Marc Imhotep Cray, M.D.

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Allergy Term allergy, from Greek allos (altered state) and ergon (reactivity), was first used to describe patients who had reactions caused by effect of external factors, or allergens, on body’s immune system  Often defined as hypersensitive reactions of immune system to substances (allergens) that are usually innocuous in most people food, animal dander, pollen, bee stings, mold, ragweed, and drugs

Marc Imhotep Cray, M.D.

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Allergy (2)  Allergic person’s immune system recognizes something as foreign mounts a specific reaction to identify allergen and destroy it via inflammation  Thus, a sensitivity to a material that causes a symptom is allergic only if it has an identifiable mechanism  Distinction between allergic and nonallergic disorders is important because it determines evaluation and treatment  Treatment of an allergy as if it were nonallergic will fail and vice versa  In asthma, allergens increase sensitivity of bronchial smooth muscle, thereby creating an allergic state Marc Imhotep Cray, M.D.

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Mechanism of Type 1 (Immediate) Hypersensitivity

Marc Imhotep Cray, M.D.

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Leukocyte Function  Humans have a special immune system to combat infectious and toxic agents (eg, bacteria and viruses)  Major cells involved in defense against foreign substances are leukocytes (WBCs)  Like all blood cells synthesized in bone marrow

 Leukocytes can be classified into 2 basic classes:  granular store mediators in granules, and  mononuclear or agranular have no granules  Three types of granular leukocytes exist:  neutrophils  eosinophils and  basophils Marc Imhotep Cray, M.D.

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Leukocyte Function (2)  Eosinophils, which phagocytize antigen-antibody complexes (antigen-IgE complexes that initiate an asthmatic reaction), and  Basophils, which release  heparin (clotting)  serotonin (clotting) and  histamine (immune reaction) play primary roles in asthma  Agranular cells are  monocytes, which phagocytize foreign particles, and  lymphocytes, which play a critical role in delayed asthmatic response o T cells (a subtype of lymphocytes) synthesize cytokines (Interleukins) o B cells (another subtype) synthesize IgE antibodies

Marc Imhotep Cray, M.D.

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Leukocyte Function (3)

Marc Imhotep Cray, M.D.

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Leukocyte Function (4)

Marc Imhotep Cray, M.D.

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Allergic Rhinitis  Allergic rhinitis (hay fever), an inflammation or irritation of mucous membranes lining nose initiated when allergens cause body to defend itself by producing antibodies  allergen-antibody combination prompts histamine release and allergic response  Symptoms are o o o o o o o

sneezing stuffy or runny nose itchy eyes noisy breathing chronic fatigue poor appetite and nausea

 seasonal disorder is caused by pollen and normally wanes during winter  perennial disorder occurs year-round and is caused by indoor allergens(eg, animal dander, mold spores, dust mites) Marc Imhotep Cray, M.D.

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Allergic Rhinitis (2)  Treatments are:  Antihistamines (H1 antagonist) (Treatment of choice; blocks histamine action but can cause drowsiness) o Diphenhydramine (1st Gen.), Loratadine (2nd Gen.= less sedation) o See: Histamine and Antihistamines in Autocoids, Ergots, Anti-inflammatory and Immunosuppressive Agents Notes

 Nasal decongestants (relieve nasal stuffiness but can increase histamine release and worsen congestion) o Short-acting α-adrenergic agonists, such as phenylephrine, constrict dilated arterioles in nasal mucosa and reduce airway resistance o Longer-acting oxymetazoline

 corticosteroids (desensitize cellular response to histamine and minimize allergic reaction) and  cromolyn sodium (inhibits histamine release, which reduces or stops allergic response) Marc Imhotep Cray, M.D.

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General Management Principles for Allergic Rhinitis

Marc Imhotep Cray, M.D.

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Asthma Asthma is a chronic disease characterized by hyperresponsive airways, affecting over 25 million patients in U.S , and resulting in 2 million emergency room visits and 500,000 hospitalizations annually.

Marc Imhotep Cray, M.D.

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Introduction to Asthma Bronchial asthma, known simply as asthma, is a chronic lung disease characterized by inflammation and obstruction of lower airways  Affects approximately 10% of the US population, or 25 million people  Most common symptoms are o acute constriction of bronchial smooth muscle o cough High-Yield Tip: Chronic cough in a young o chest tightness adult, particularly a cough that worsens at o wheezing and night and is associated with dyspnea and o rapid breathing chest tightness, is classic for asthma.

Marc Imhotep Cray, M.D.

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Types of Asthma  Older classification: Extrinsic and Intrinsic Asthma  Newer (preferred) Classification  Atopic (Extrinsic) : A type I hypersensitivity reaction with strong familial tendencies  Nonatopic (Intrinsic): Asthma associated with viral infection (e.g. rhinovirus, parainfluenza virus) in patients with no family history of allergies and who have normal levels of IgE  Drug-induced asthma  Occupational asthma  Cardiac asthma Marc Imhotep Cray, M.D.

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Types of Asthma (2) Alternative classification:  Allergic asthma versus Nonallergic asthma  Allergic asthma o o o o

Epidemiology: Occurs more frequently in children Associated conditions: Patients may have hay fever or eczema Mechanism of allergic asthma: Type I hypersensitivity reaction Causes: Pollens, dust, drugs

 Nonallergic asthma o Epidemiology: Occurs more frequently in adults o Mechanism of nonallergic asthma: Not type I hypersensitivity reaction; IgE levels are normal o Causes: Exercise, cold air, drugs, gastroesophageal reflux, viral infections Marc Imhotep Cray, M.D.

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Clinical presentation of asthma Symptoms:  Classic triad is persistent wheezing, chronic episodic dyspnea, and chronic nonproductive cough  Symptoms may be worse, or only present at night, due to physiologic drop in cortisol secretion  Night-time cough, which may be only symptom, is a classic symptom of asthma  Dark rings under the eyes (“allergic shiners”) and a dark transverse crease on nose (“allergic salute”) are often seen, especially in children  Status asthmaticus is a prolonged asthmatic attack, which can be fatal Otherwise deaths caused by asthma are infrequent Marc Imhotep Cray, M.D.

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Clinical presentation of asthma (2) Laboratory studies:  Low peak expiratory flow (PEF)  FEV1/FVC is often decreased as in other obstructive lung diseases, and residual volume is increased  Carbon dioxide is usually low in an acute asthma exacerbation secondary to hyperventilation  a rising carbon dioxide concentration in this setting often precedes respiratory failure  Eosinophilia may be present Marc Imhotep Cray, M.D.

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Asthma Capsule

Marc Imhotep Cray, M.D.

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Extrinsic and Intrinsic Asthma  Pharmacotherapy of asthma depends on understanding disease pathogenesis  extrinsic (allergic, type I) or intrinsic (nonallergic, type II) asthma  In immunologic, or antigen challenge, model IgE antibodies produced by airway mucosa mast cells mediate asthma  B lymphocytes synthesize IgE antibodies after exposure to an antigen  IgE antibodies attach to mast cells  with re-exposure to antigen form antigen-antibody complexes complexes trigger synthesis and release of mediators from mast cells, including  Histamine  Leukotrienes (LTC4 and LTD4) and  Prostaglandins  Bronchoconstriction and vascular leakage result Marc Imhotep Cray, M.D.

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Extrinsic and Intrinsic Asthma (2)  Other substances (eg, cytokines) mediate late response (IgE release)  Corticosteroids reduce bronchial responses by inhibiting cytokine production  In some asthmatic patients who are not hypersensitive to antigens infections and non-antigenic stimuli can evoke symptoms (Intrinsic asthma)  Intrinsic asthma develops later in life, has unclear causes, is associated with a worse prognosis, and is less responsive to treatment than extrinsic asthma

Marc Imhotep Cray, M.D.

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Extrinsic Allergic Asthma: Clinical Features  Features common to both extrinsic allergic and intrinsic asthma:              

respiratory distress dyspnea wheezing flushing cyanosis cough flaring of alae use of accessory respiratory muscles apprehension tachycardia perspiration hyperresonance distant breath sounds and rhonchi eosinophilia

Marc Imhotep Cray, M.D.

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Intrinsic Asthma: Clinical Features  Features common to both extrinsic allergic and intrinsic asthma:              

respiratory distress dyspnea wheezing flushing cyanosis cough flaring of alae use of accessory respiratory muscles apprehension tachycardia perspiration hyperresonance distant breath sounds and rhonchi eosinophilia

Marc Imhotep Cray, M.D.

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Asthma Pharmacotherapy Major classes of drugs for asthma: I. II. III. IV. V.

Anti-lgE Antibodies Mast Cell Degranulation Blockers Bronchodilators Methylxanthine β-Adrenergic Agonists: o Nonselective o Selective VI. Antimuscurinic Antagonists VII. Anti-inflammatory Agents: o Corticosteroids o Leukotriene Antagonists Marc Imhotep Cray, M.D.

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Asthma Pharmacotherapy Capsule

Marc Imhotep Cray, M.D.

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Asthma Pharmacotherapy (2)  When exposure to allergens cannot be avoided, drug therapy is needed  Major goals being to reverse asthmatic symptoms and prevent recurrent episodes by disrupting actions of endogenous agents that worsen bronchospasm and inflammation  Bronchodilators were first and most effective treatment, but a better approach is prophylactic use of antiinflammatory agents to control bronchial inflammation  With these agents, patients with asthma are rarely hospitalized, seriously ill, or in need of emergency treatment  Patients can control their disease, and therapy is much less expensive than previous emergency management Marc Imhotep Cray, M.D.

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Asthma Pharmacotherapy (3)  Now, antiinflammatory agents are first-line therapy [(Inhaled corticosteroids (ICS)] for patients who have more than occasional symptoms  Bronchodilators are still used but only when antiinflammatory therapy is inadequate, and then in smaller amounts  SABA manage symptoms (rescue therapy) and does not address underlying cause, which is airway inflammation  LABA still useful as in prophylaxis /control therapy, particularly in combination with ICS

Marc Imhotep Cray, M.D.

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Guidelines for Treatment of Asthma Classification

Bronchoconstrictive Episodes

Results of Peak Flow or Spirometry

Long-term Control

Quick Relief of Symptoms

Intermittent

Less than 2 days per week

Near normal*

No daily medication

Short-acting β2 agonist

Mild persistent

More than 2 days per Near normal* week, not daily

Low-dose ICS

Short-acting β2 agonist

Moderate persistent

Daily

60% to 80% of normal

Low-dose ICS + LABA OR Med-dose ICS

Short-acting β2 agonist

Severe persistent

Continual

Less than 60% of normal

Med-dose ICS + Short-acting β2 LABA OR High- agonist dose ICS + LABA ICS = inhaled corticosteroid. LABA = long-acting β2 agonist. *Eighty percent or more of predicted function.

Redrawn from: Whalen K. Lippincott Illustrated Reviews: Pharmacology Sixth Ed., 2015.

N.B. In all asthmatic patients, quick relief (“rescue” therapy) is provided by a SABA as needed for symptoms.

Marc Imhotep Cray, M.D.

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I. Anti-lgE Antibodies  One of the more novel therapies is use of anti-IgE antibodies  In theory, drugs acting as anti-IgE antibodies would prevent IgE binding to mast cell surfaces

 Action reduces formation of activated antigen-IgE complexes and suppress release of mediators that induce immediate bronchoconstriction in early phase  Mediators such as histamine, prostaglandins, and leukotrienes are unable to cause sneezing, wheezing, itching, and coughing

Marc Imhotep Cray, M.D.

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Immunologic basis of anti-IgE antibodies MOA

Marc Imhotep Cray, M.D.

Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014. Figure 7-9

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Anti-lgE Antibodies (2) Most notable anti-IgE antibody, omalizumab, is a recombinant humanized monoclonal antibody to human immunoglobulin E (IgE)  By binding to circulating IgE in blood, omalizumab blocks release of inflammatory mediators by keeping IgE from binding to mast cells and basophils  Reduction in surface-bound IgE limits release of mediators of allergic response Indicated for treatment of moderate to severe persistent asthma in patients who are poorly controlled with conventional therapy Marc Imhotep Cray, M.D.

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Anti-lgE Antibodies (3) ď ą Rhumab-E25 (Omalizumab) blocks release of inflammatory mediators by keeping IgE from binding to mast cells

Marc Imhotep Cray, M.D.

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Anti-lgE Antibodies (4) ď ąOmalizumab use is limited by high cost, route of administration (subcutaneous), and adverse effect profile  Adverse effects include: o serious immediate- or delayed-onset anaphylactic reactions pose the greatest risk (rare) o arthralgias o fever, and rash o secondary malignancies have been reported

Marc Imhotep Cray, M.D.

High-Yield Pearl: Anaphylaxis or less severe untoward immunologic reactions have been reported 24 hours or longer post administration, so patient should have an epinephrine autoinjector (self-injector) (prescribed by physician) handy for at least several days after an omalizumab dose.

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II. Mast Cell Degranulation Blockers (Chromones)  Cromolyn block mast cell degranulation by suppressing release of mediators of immediate bronchoconstriction (early response) and reduce eosinophil recruitment that causes airway inflammation  Does not directly alters smooth muscle tone or reverses bronchospasm

 Inhaled as aerosols, can be used for intrinsic or extrinsic asthma Marc Imhotep Cray, M.D.

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Mast Cell Degranulation Blockers (2)  Poorly absorbed, so adverse effects are restricted to deposition site  Cromolyn (nasal spray) is preferred for young patients  Cromolyn alter Cl− channel function, which 1) on airway neurons underlies cough inhibition 2) on mast cells delays antigen-evoked bronchoconstriction and 3) on eosinophils prevents inflammatory responses to antigens

Marc Imhotep Cray, M.D.

NB: Cromolyn and related compounds do not posses bronchodilator activity and are therefore not useful in acute asthma attacks.

Neither cromolyn and nedocromil, is available in the USA.

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Mast Cell Degranulation Blockers MOA

Marc Imhotep Cray, M.D.

Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014

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III. Bronchodilators (smooth muscle relaxants)  Drugs that expand pulmonary airways (bronchi)-bronchodilators-block early response by inhibiting immediate bronchoconstriction  Some agents, especially theophyline and β2-adrenergic agonists, inhibit late response inflammation  These drugs are usually used when a persistent cough and bronchial constriction are present  In addition to relaxing smooth muscles and reducing airway reactivity, bronchodilators reduce coughing, wheezing, and shortness of breath  Agents are usually given via inhalation, but some can be given orally or parenterally (intravenous, intramuscular, or subcutaneous route) Marc Imhotep Cray, M.D.

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Bronchodilators (2)  Most drugs have a rapid onset of action (within minutes), but effect usually wanes in 5 to 7 hours (short duration of action)  Some agents, especially theophylline, inhibit delayed response to antigen  Most common bronchodilators are 1) methylxanthines (eg, theophylline, caffeine) 2) β-adrenergic agonists (eg, isoproterenol, albuterol, epinephrine) 3) cholinergic antagonists (eg. ipratropium, tiotropium)

Marc Imhotep Cray, M.D.

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G protein linked 2nd messenger mechanism (β2-Receptor) Receptor Beta 2

G-Protein Class Gs

Major Function Vasodilation, Bronchodilation, Increase Heart Rate, Increase Contractility, Increase Lipolysis, Increase Insulin release, Decrease Uterine Muscle tone

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

Marc Imhotep Cray, M.D.

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Marc Imhotep Cray, M.D.

Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.

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IV. Methylxanthines  The methylxanthines theophylline, caffeine, and theobromine, found in cola, tea, and coffee, are bronchodilators that reduce bronchial smooth muscle activity by causing increase intracellular cAMP levels  Mechanism of Action (MOA):  Signal molecules (eg, transmitters, drugs) activate GPCRs on airway smooth muscle cells and increase conversion rate of ATP to cAMP  increased cAMP levels relax bronchial muscle and reduce airway reactivity  Phosphodiesterase stops cAMP effects and reduces cAMP levels by catalyzing hydrolysis of cAMP to AMP o Methylxanthines prevent cAMP hydrolysis (PDE Inhibitor) o Or, theophylline may block cell surface receptor effects of adenosine, which may induce bronchoconstriction and inflammation Marc Imhotep Cray, M.D.

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Methylxanthines (2)  These drugs may also be antiinflammatory  Theophylline, the most widely prescribed and of low cost, comes as:  short-acting tablets and syrups,  sustained-release capsules and tablets, and  intravenous doses  Synthetic dyphylline may help patients who are unable to use theophylline  Previously the mainstay of asthma therapy, has been largely replaced with β2 agonists and corticosteroids due to narrow therapeutic window, adverse effect profile, and potential for drug interactions Marc Imhotep Cray, M.D.

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Methylxanthines

Marc Imhotep Cray, M.D.

Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.

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Methylxanthine: Adverse Effects  Methylxanthine doses and bld levels must be closely watched 

Low therapeutic index Serum concentration monitoring should be performed when theophylline is used chronically  Low doses have little effect, if any, whereas high doses can affect central nervous (seizures), cardiovascular (arrhythmias), skeletal muscle, GI, and renal system  Theophylline is most selective at sm. mm.; caffeine induces most marked CNS effects  Even at low to moderate doses, they enhance cortical arousal & alertness & defer fatigue  In hypersensitive patients, insomnia and nervousness may occur  Methylxanthines reduce blood viscosity increase blood flow increase cardiac output & induce tachycardia in healthy subjects Marc Imhotep Cray, M.D.

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Methylxanthine: Adverse Effects(2) In sensitive persons, cardiac arrhythmias are common These drugs strengthen contractions of isolated skeletal muscles in vitro and improve contractility & reverse fatigue of diaphragm in pts with COPD accounts for their usefulness in COPD

 Although methylxanthines enhance gastric acid and digestive enzyme secretion in GI tract and induce a slight diuresis, these effects are minor Note: metabolism of theophylline depends on age; the half-life of drug in children is much shorter than in adults Marc Imhotep Cray, M.D.

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Marc Imhotep Cray, M.D.

Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.

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V. β-Adrenergic Agonists  Another class of drugs that enhance sympathetic discharge, β-adrenergic agonists, are used to relieve a sudden asthma attack or block exerciseinduced asthma  relax bronchial smooth muscle, inhibit mediator release, increase transport of mucus, and alter composition of mucus by stimulating β adrenoceptors  Bronchodilation is mediated by β2 adrenoceptors located on smooth muscle cells in human airways  Nonselective β-adrenoceptor agonists (eg, epinephrine, ephedrine, isoproterenol) stimulate all β adrenoceptors (β1 and β2 classes)  These nonselective actions often produce adverse effects, particularly in CNS and cardiovascular system

 Selective drugs activate only β2 receptors (eg, albuterol, terbutaline, salmeterol) are most commonly prescribed sympathomimetic agents Marc Imhotep Cray, M.D.

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Nonselective β-Adrenergic Agonists  Agents that activate both β1 and β2 adrenoceptors have long been used to treat asthma

 These drugs are potent, rapidly acting bronchodilators, but their stimulation of cardiac system is a serious drawback  Major agents are epinephrine, ephedrine, and isoproterenol  Epinephrine is either inhaled or given subcutaneously and is active agent in many over-the-counter (OTC) preparations 

Maximal bronchodilation is achieved 15 minutes after injection and lasts approximately 90 minutes  Because this drug stimulates cardiac output, increases heart rate, and exacerbates angina, physicians rarely prescribe it Marc Imhotep Cray, M.D.

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Nonselective β-Adrenergic Agonists  Ephedrine, used in China more than 2000 years ago, has longest history of use of any antiasthmatic  It has a longer duration of action, lower potency, and greater oral activity than epinephrine  However, has marked adverse effects, particularly in CNS, and is rarely administered  Isoproterenol is characterized by a rapid onset of action, with peak bronchodilation occurring within 15 minutes of injection

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β-Adrenergic Agonists MOA

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Selective β-Adrenergic Agonists  Selective β2-adrenoceptor activators are most widely prescribed sympathomimetic drugs because of their…  β2 selectivity  oral activity  rapid onset and long duration of action (4 hours)

 Major drugs: metaproterenol, terbutaline, albuterol, salmeterol, and formoterol  have minimal β1-mediated effects on nervous and cardiac systems  Inhalation route allows greatest local effects with fewest adverse effects  Inhaled agents cause bronchodilation equal to isoproterenol and persists for 4 hours (metaproterenol, terbutaline, albuterol) Marc Imhotep Cray, M.D.

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Selective β-Adrenergic Agonists (2)  Terbutaline, metaproterenol, and albuterol can be given orally as tablets  Terbutaline, the only drug that can be used subcutaneously, is given for severe asthma attacks or if insensitivity to inhaled agents exists  Two newest drugs, salmeterol and formoterol, have a long duration of action and high lipid solubility  Both drugs at high concentrations move slowly into airway smooth muscle so effects can last up to 12 hours  Both also enhance antiasthmatic actions of corticosteroids

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Catecholamine Action on ι and β Receptors of Heart and Bronchial Tree

Marc Imhotep Cray, M.D.

Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.

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VI. Antimuscarinic Agents (Muscarinic Antagonists)  Acetylcholine mediates its physiologic effects via 2 types of receptors:  muscarinic and nicotinic  Muscarinic receptors are GPCRs that are densely expressed in airways  When stimulated AChM receptors cause muscle contraction leads to narrowing of airways bronchoconstriction  Muscarinic antagonists, or anticholinergics, prevent acetylcholine from producing smooth muscle contractions & excess mucus in bronchi Marc Imhotep Cray, M.D.

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Antimuscarinic Agents (2)  Ipratropium bromide and atropine are most commonly used  Antimuscarinic agents are less effective than β2-adrenergic activators  However, these drugs enhance bronchodilation induced by β2-adrenoceptor agonists, so patients often take both anticholinergics and β2 agonists  Major adverse effects = dry mouth, bitter taste, scratchy throat, and headache Marc Imhotep Cray, M.D.

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Antimuscarinic Agents MOA

Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.

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Leukotriene Modulators (LTMs) ď ą Leukotrienes (LTs) are potent inflammatory mediators generated from metabolism of arachidonic acid through the 5lipoxygenase (5-LOX) pathway ď ą These compounds, along with prostaglandins and related compounds, belong to a group of substances termed the eicosanoids Marc Imhotep Cray, M.D.

Wecker L etal. Brady's Human Pharmacology, Molecular to Clinical, 5th Ed. Philadelphia: Mosby, 2010 76

Inflammatory mediators

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015) Marc Imhotep Cray, M.D.

See Eicosanoids in Autocoids, Ergots, Anti-inflammatory and Immunosuppressive Agents Notes

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VII. Anti-inflammatory Agents: Corticosteroids  Corticosteroids are antiinflammatory drugs similar to natural corticosteroid hormones produced by the adrenal cortex  Tx with these agents improves symptoms of asthma, allergic rhinitis, eczema, and rheumatoid arthritis  Corticosteroids inhibit late phase allergic reactions (including late asthmatic response to antigen challenge) by various mechanisms, eg., reduced 1) number of mast cells lining surfaces of airway mucosal cells; 2) chemotaxis and activation of eosinophils; and 3) cytokine production by eosinophils, monocytes, mast cells, and lymphocytes

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Corticosteroids (2)  Corticosteroids taken regularly have the following effects:  reduce bronchial reactivity  enhance airway quality  decrease severity & frequency of asthma attacks o However, corticosteroids do not directly relax smooth muscle o They would be only agents needed to treat asthma if their adverse effects were not so pronounced  Commonly used agents prednisone, methylprednisone, beclomethasone, flunisolide, budesonide, and mometasone

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Corticosteroids: Clinical Uses  Corticosteroids have marked adverse effects on nonrespiratory systems, so inhalation (maintenance therapy in asthma, via inhaler) or intranasal (in allergy, as nasal spray) route is preferred  Intranasal corticosteroids relieve stuffy nose, nasal irritation, and other discomforts  Corticosteroids inhaled by mouth effectively prevent asthma attacks  Regular doses of aerosol agents are smaller than doses used in pill form  Smaller, regular doses reduce side effect risk and may eliminate a need for oral steroids

 Oral prednisone or IV methylprednisone is used only when pts are insensitive to inhaled drugs or need urgent treatment for severe asthma attacks

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Corticosteroids: Clinical Uses (2)  Spacers (chambers) can be attached to metered-dose inhalers to reduce velocity & particle size of drug amount of drug reaching lungs maximized,  quantity of drug deposited in mouth is minimized  Spacers are crucial for Tx with corticosteroids, which have many adverse effects Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.

Marc Imhotep Cray, M.D.

Corticosteroid Actions in Bronchial Asthma

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Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.

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Corticosteroids: Adverse Effects  Taking corticosteroids orally (prednisone) and intravenously (methylprednisone) can cause unwanted side effects  Short-term use (days) of prednisone can lead to  increased appetite  weight gain  diarrhea  headache  mood changes & insomnia  possibly hyperglycemia & hypertension o Cessation of short term corticosteroid use or taking smaller doses usually minimizes or eliminates effects Marc Imhotep Cray, M.D.

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Corticosteroids: Adverse Effects (2)  Adverse effects that accompany long-term (months to years) oral and IV therapy are:    

suppressed immune system increased cholesterol levels rapid weight gain May also promote osteoporosis, cataracts, and thinning of skin

 Efforts to develop safer corticosteroids with antiinflammatory properties but lacking adverse effects are ongoing  Lipophilic inhaled steroids, such as beclomethasone, flunisolide, budesonide, and mometasone, have a strong safety profile and are almost devoid of orally precipitated systemic effects Marc Imhotep Cray, M.D.

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Corticosteroids: Adverse Effects

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Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.

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Leukotrienes  Leukotrienes are arachidonic acid derivatives involved in inflammatory processes including asthma and anaphylaxis

 The enzyme 5-lipoxygenase catalyzes synthesis of arachidonic acid into unstable intermediates which are converted into leukotrienes  A number of airway cells (including mast cells, macrophages, eosinophils, and basophils) synthesize, store, & secrete several subtypes of proinflammatory leukotrienes  Leukotriene B4 (LTB4) attracts additional leukocytes, and LTC4 and LTD4 increase bronchial reactivity, bronchoconstriction, and secretion of mucus See Eicosanoids in Autocoids, Ergots, Anti-inflammatory Agents, and Immunosuppressive Agents Notes Marc Imhotep Cray, M.D.

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Leukotriene (2) ď ąEvidence that inhaled leukotrienes increase bronchial reactivity and that antigen challenge in sensitized airways augments leukotriene synthesisďƒ supports a role for these mediators in asthma and a rationale for development of drugs that block leukotriene or 5-lipoxygenase action

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Newly generated lipid mast cell mediators depicting sites of action of LTMs Inhibitory actions of LTMs are shown in red

ď ąZileuton inhibits 5-lipoxygenase, thereby inhibiting synthesis of leukotrienes ď ąZafirlukast and Montelukast are antagonists at CysLT1 receptor

Marc Imhotep Cray, M.D.

Wecker L etal. Brady's Human Pharmacology, Molecular to Clinical, 5th Ed. Philadelphia: Mosby, 2010

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Leukotrienes Synthesis

Marc Imhotep Cray, M.D.

Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.

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Anti-inflammatory Agents: Leukotriene Antagonists  Efforts to develop drugs that disrupt proinflammatory actions of leukotrienes produced 2 types of drugs: 1) 5-lipoxygenase inhibitors and 2) leukotriene antagonists  Zileuton reduces leukotriene synthesis rate by blocking 5-lipoxygenase  can cause increases in hepatic enzymes and altered liver function It decreases rate of heparin metabolism, leaving patients prone to easy bruising

 Zafirlukast and montelukast, LTD4 antagonists, block leukotriene receptors and prevent these mediators from causing an asthmatic response  taken orally, easy to administer and are used more regularly than inhaled corticosteroids in USA (especially in children ) because of concerns over possible longterm toxicity of systemic absorption of ICSs Marc Imhotep Cray, M.D.

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Leukotriene Antagonists (2)  When taken regularly, these drugs work as well as inhaled corticosteroids in reducing frequency of asthma attacks  However, leukotriene antagonists are less successful for relieving symptoms, reducing bronchial reactivity, and improving airway quality  These drugs are effective and safe when taken orally, an advantage compared with inhaled corticosteroids  Strong safety profile and excellent oral activity account for popularity of leukotriene antagonists for children  Leukotriene antagonists also reduce responses in aspirin-induced asthma, a disorder affecting nearly 10% of patients with asthma Marc Imhotep Cray, M.D.

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Leukotriene Antagonists MOA

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Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.

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Question A woman who has asthma and is recovering from a myocardial infarction is on several medications including a baby aspirin a day. She complains of large bruises on her arms and legs and some fatigue. A standard blood panel reveals markedly elevated alanine aminotransferase (ALT). Which of the following is most likely responsible for the increase in liver enzymes?

(A)Heparin (B)Zileuton (C)Zafirlukast (D)Albuterol (E)Aspirin

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Management of Acute Asthmatic Attack

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Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.

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The National Asthma Education and Prevention Program 1997 Guidelines (Updated) RECOMMENDATIONS FOR PHARMACOLOGIC MANAGEMENT OF ASTHMA IN ADULTS AND CHILDREN OLDER THAN 5 Asthma Severity

Symptom Frequency

Medications

Mild intermittent

<2 days/week, <2 nights/month

No regular therapy; short-acting β2 –agonists as needed for symptom relief

Mild persistent

>2 per week but <once per day >2 nights/month

Low-dose inhaled glucocorticoids. Alternate: cromolyn, nedocromil, leukotriene modifier, or sustained release theophylline

Moderate persistent

Daily, >1 night/week

Low- to medium-dose glucocorticoids and long-acting inhaled β2 -agonists. Alternate: leukotriene modifier or theophylline

Severe persistent

Continual during day, frequent at night

High-dose glucocorticoids and long-acting inhaled β2 -agonist and (if needed) systemic glucocorticoids. Consider omalizumab for allergy sufferers

Ressel GW, Centers for Disease Control and Prevention, National Asthma Education and Prevention Program. NAEPP updates guidelines for the diagnosis and management of asthma. Am Fam Physician . 2003;68:169–70.

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Respiratory Drugs Summary Short-Acting β2-Adrenoceptor Agonists Albuterol Levalbuterol Metaproterenol Long-Acting β2-Adrenoceptor Agonists Salmeterol Formoterol Terbutaline Other Adrenoceptor Agonists for Asthma Epinephrine Isoproterenol Ephedrine Methylxanthines Theophylline Muscarinic Antagonists Ipratropium bromide Tiotropium Atropine Chromones Cromolyn sodium Nedocromil sodium Inhaled Glucocorticoids Beclomethasone Triamcinolone acetate Budesonide Flunisolide Fluticasone propionate Marc Imhotep Cray, M.D.

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Respiratory Drug Summary cont.

Leukotriene Inhibitors Zafirlukast Montelukast Zileuton Enzyme Inhibitors Îą1-Proteinase inhibitor Anti-IgE Antibody Omalizumab Antihistamines (selected H1-receptor antagonists Diphenhydramine Loratadine Chlorpheniramine Brompheniramine Îą-Adrenoceptor Agonists (selected) Oxymetazoline Phenylephrine Pseudoephedrine Antitussives Codeine Hydrocodone Hydromorphone Dextromethorphan Benzonatate Expectorants Guaifenesin Mucolytics Acetylcysteine Marc Imhotep Cray, M.D.

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Further study: eLearning:  Unit 7: Drugs Used In Disorders Of The Respiratory System. In: Digital Guidebook 2015 Integrated Scientific and Clinical Pharmacology  IVMS MedPharm Cloud Folder Notes:  Drugs Used In Disorders Of The Respiratory System Notes  Autacoids, Ergots, Anti-inflammatory Agents, and Immunosuppressive Agents Notes o Histamine and its Antagonists o Eicosanoids

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e-Medicine (Medscape) Articles Obstructive Airway Diseases  Alpha1-Antitrypsin Deficiency  Asthma  Bronchiectasis  Bronchiolitis  Bronchitis  Chronic Bronchitis  Chronic Obstructive Pulmonary Disease  Emphysema  Status Asthmaticus Marc Imhotep Cray, M.D.

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