Pulmonary System - Drugs for Asthma

What occurs to bronchiole smooth muscle from sympathetic stimulation?

Sympathetic stimulation via beta 2 adrenergic receptors results in relaxation of bronchiole smooth muscles - bronchodilation

What occurs to bronchiole smooth muscle from parasympathetic sitmulation?

Parasympathetic stimulation results in constriction of bronchiole smooth muscle - bronchoconstriction

What are 3 pathophysiological processes in asthma?

1. Airway obstruction from narrowed bronchioles

2. Inflammation (Significant role)

3. Airway irritability caused by hyperresponsiveness, resulting in the bronchioles being narrowed easily in response to stimulus

What is the main pathophysiological process in asthma?

Airway inflammation

What is the role of IgE in asthma?

Allergens binds to IgE receptors in the lungs, which is linked to a Gq protein and causes release of IP3 and PIP, which increase calcium levels.

Increased calcium levels causes degranulation of mast cells, resulting in histamine release and subsequent bronchoconstriction

IP3 also causes activation of phospholipase A2, which converts arachidonic acids into COX prostaglandins, which causes increased inflammation, and leukotrienes, which causes increased immune cell recruitment

What is the role of mast cells in asthma?

Mast cells degranulate from increased calcium levels caused by allergen binding to IgE receptors.

Mast cell degranulation releases histamine, which causes bronchoconstriction

Mast cells also cause direct synthesis of inflammatory cytokines, which recruits eosinophils to secrete inflammatory mediators, bronchoconstrictors, and cytotoxins (damage to lungs)

What is the role of IP3 in asthma?

IP3, activated by IgE receptors, causes increased calcium levels, which leads to activation of phospholipase A2, resulting in the conversion of arachidonic acids into COX prostaglandins, which causes increased inflammation, and leukotrienes, which causes increased immune cell recruitment

How does histamine cause bronchoconstriction in asthma?

Histamine binds to its receptors in lung smooth muscles, which are linked to Gq proteins. The Gq proteins activates IP3, which increases Ca2+ levels inside of the smooth muscle. The increased calcium levels directly lead to contraction of the smooth muscle, leading to bronchoconstriction

What are the overall pharmacotherapy goals for asthma?

Reduce intensity and frequency of asthma symptoms

-Reduce symptoms of asthma

-Reduce need for reliever medications

-Reduce night time awakenings due to asthma

-Ensure ability to perform normal daily activities

Reduce risk of adverse effects associated with asthma

-Prevent exacerbations and need for hospital care

-Prevent reduced lung growth in children

-Prevent loss of lung function in adults

What are reliever medications for asthma?

Used to help terminate an asthma attack

Includes

Beta adrenergic agonists

Corticosteroids

Muscarinic antagonists

What are controller medications for asthma?

Used to help prevent an asthma attack

Includes

Corticosteroids

Monoclonal Antibodies (anti IgE, anti IL5,

Leukotriene antagonists

Lipoxygenase Inhibitors

Mast Cell Stabilizers

Methylxanthines

What is the first-line treatment for immediate relief of an asthma attack?

Low dose inhaled corticosteroids and long acting beta agonists

What are beta2 adrenergic agonists for treatment for asthma treatment? (Use, Mechanism of Action, Dosing, Routes of Administration, Adverse Effects)

Use

Used in combination with inhaled glucocorticoids (long acting) to provide relief and control of asthma

Mechanism of Action

Beta2 agonists bind to it's associated receptor on airway smooth muscles. It directly inhibits the Ip3 effects on increasing calcium levels from the sarcoplasmic reticulum, leading to lower calcium levels and smooth muscle relaxation (bronchodilation)

Dosing

Short acting beta agonists

Long acting beta agonists (combined with inhaled glucocorticoids is best practice for asthma relief)

Routes of Administration

Inhaled

Nebulized for severe asthma attacks - ensures drug will be used

Adverse Effects

Associated with activation of the SNS

-Tremors

-Tachycardia

What are dosing options for beta2 adrenergic agonists for asthma treatment?

Short acting beta agonists

Long acting beta agonists (combined with inhaled glucocorticoids is best practice for asthma relief)

What is the use of beta2 adrenergic agonists for asthma treatment?

Used in combination with inhaled glucocorticoids (long acting) to provide relief and control of asthma

What is the mechanism of action of beta2 adrenergic agonists for asthma treatment?

Beta2 agonists bind to it's associated receptor on airway smooth muscles. It directly inhibits the Ip3 effects on increasing calcium levels from the sarcoplasmic reticulum, leading to lower calcium levels and smooth muscle relaxation (bronchodilation)

What are adverse effects of beta2 adrenergic agonists for asthma treatment?

Associated with activation of the SNS

-Tremors

-Tachycardia

What are muscarinic antagonists for treatment of pulmonary disorders (Use, Mechanism of action, Dosing Adverse Effects)

Use

Used as add on therapy to asthma maintenance (on top of long acting beta agonists and corticosteroid therapy)

Effective for treatment of COPD and chronic bronchitis

Mechanism of Action

Blocks parasympathetic input to bronchial smooth muscles, resulting in reduced bronchoconstriction

Dosing

Combined with short acting beta agonists for COPD management

Long acting muscarinic antagonists as add on therapy for asthma maintenance management

Adverse Effects

Few via inhaled route

-Dry mouth

-Sedation

What is the use of muscarinic antagonists for treatment of pulmonary disorders?

Used as add on therapy to asthma maintenance (on top of long acting beta agonists and corticosteroid therapy)

Effective for treatment of COPD and chronic bronchitis

What is the mechanism of action of muscarinic antagonists for treatment of pulmonary disorders?

Blocks parasympathetic input to bronchial smooth muscles, resulting in reduced bronchoconstriction

What are dosing strategies for muscarinic antagonists for treatment of pulmonary disorders?

Combined with short acting beta agonists for COPD management

Long acting muscarinic antagonists as add on therapy (w/ long acting beta agonists and corticosteroid therapy) for asthma maintenance management

What are adverse effects for muscarinic antagonists for treatment of pulmonary disorders?

Few adverse effects for the inhaled route

-Dry mouth

-Sedation

What are corticosteroids for asthma treatment? (Use, Mechanism of Action, Dosing, Adverse Effects)

Use

Extremely effective for limiting asthma exacerbations (asthma maintenance)

Mechanism of Action

Multipronged approach

1. Corticosteroids directly inhibit transcription factors that activate genes which produce inflammatory factors

2. Corticosteroids downregulate genes which produce inflammatory factors

3. Corticosteroids inhibit phospholipase A2 activity, which is responsible for activating COX enzymes to produce prostaglandins and lipoxygenase to produce leukotrienes

4. Corticosteroids inhibit activation of COX enzymes to produce prostaglandins

Dosing

Low dose for mild to moderate asthma treatment

Medium to high dose for severe asthma treatment

Adverse Effects

Low dose = local effects -> throat irritation, oral candidiasis (yeast infection -> immunosuppression)

High dose = systemic effects -> osteoporosis, infection (immunosuppresion)

What is the use of corticosteroids for asthma treatment?

Extremely effective for limiting asthma exacerbations (asthma maintenance)

What is the mechanism of action of corticosteroids for asthma treatment?

Multipronged approach

1. Corticosteroids directly inhibit transcription factors that activate genes which produce inflammatory factors

2. Corticosteroids downregulate genes which produce inflammatory factors

3. Corticosteroids inhibit phospholipase A2 activity, which is responsible for activating COX enzymes to produce prostaglandins and lipoxygenase to produce leukotrienes

4. Corticosteroids inhibit activation of COX enzymes to produce prostaglandins

What is the dosing strategy of corticosteroids for asthma treatment?

Low dose for mild to moderate asthma treatment

Medium to high dose for severe asthma treatment

What are the adverse effects of corticosteroids for asthma treatment?

Low dose = local effects -> throat irritation, oral candidiasis (yeast infection -> immunosuppression)

High dose = systemic effects -> osteoporosis, infection (immunosuppresion)

What are antiIgE monoclonal antibodies? (Use, Mechanism of Action, Adverse Effects)

Use

Reserved for treatment of moderate to severe persistent allergic asthma who do not respond to other treatments -due to its high costs, associated with developing a tailored dose for each patient by assessing IgE receptors

Mechanism of Action

Attaches to IgE receptors and causes downregulation, which decreases recruitment of mast cells, prostaglandins, and leukotrienes during the asthma response

Adverse Effects

Upper respiratory tract infection

Headache

Anaphylaxis (caused by predisposition to allergic reaction due to hypersensitive immune system)

Includes Omalizumab

What is the use of antiIgE monoclonal antibodies

Reserved for treatment of moderate to severe persistent allergic asthma who do not respond to other treatments -due to its high costs, associated with developing a tailored dose for each patient by assessing IgE receptors

What is the mechanism of action of antiIgE monoclonal antibodies?

Attaches to IgE receptors and causes downregulation, which decreases recruitment of mast cells, prostaglandins, and leukotrienes during the asthma response

What are the adverse effects of antiIgE monoclonal antibodies?

Upper respiratory tract infection

Headache

Anaphylaxis (caused by predisposition to allergic reaction due to hypersensitive immune system)

What are anti IL-5 monoclonal antibodies? (Use, Mechanism of Action, Adverse Effects, Dosing, Route of Administration)

Use

Used for severe persistent asthma in patients who are 18 years or older and with an eosinophilic subtype of asthma (where sputum contains high concentration of eosinophils - resistant to normal asthma treatments)

Mechanism of Action

Binds to IL-5, which is responsible for recruiting eosinophils, thus reducing the inflammatory actions of eosinophils that contribute to the asthma response

Dosing

Once every 4 weeks

Route of Administration

IV

Adverse Effects

Oropharyngeal pain

Anaphylaxis (caused by predisposition to allergic reaction due to hypersensitive immune system)

What is the use of anti IL-5 monoclonal antibodies?

Used for severe persistent asthma in patients who are 18 years or older and with an eosinophilic subtype of asthma (where sputum contains high concentration of eosinophils - resistant to normal asthma treatments)

What is the mechanism of action of anti IL-5 monoclonal antibodies?

Binds to IL-5, which is responsible for recruiting eosinophils, thus reducing the inflammatory actions of eosinophils that contribute to the asthma response

What are the adverse effects of anti Il-5 monoclonal antibodies?

Oropharyngeal pain

Anaphylaxis (caused by predisposition to allergic reaction due to hypersensitive immune system)

What are leukotriene receptor antagonists? (Use, Mechanism of Action, Route of Administration, Adverse Effects)

Use

Effective for management of night time exacerbations/awakenings from asthma

Mechanism of Action

Binds to leukotriene receptors, preventing leukotrienes from binding and preventing bronchoconstriction and immune effects

Route of Administration

Oral

Chewable Tablets available for children

Adverse Effects

-Abdominal Pain

-Headaches

What is the use of leukotriene receptor antagonists?

Effective for management of night time exacerbations/awakenings from asthma

What is the mechanism of action of leukotriene receptor antagonists?

Binds to leukotriene receptors, preventing leukotrienes from binding and preventing bronchoconstriction and immune effects

What are lipoxygenase inhibitors? (Use, Mechanism of Action, Routes of Administration)

Use

Used for maintenance of asthma symptoms

Mechanism of Action

Inhibits formation of all leukotrienes, preventing immune recruitment and reducing inflammation during an asthma attack

Routes of Administration

Oral

What is the use of lipoxygenase inhibitors?

Used for maintenance of asthma symptoms

What is the mechanism of action of lipoxygenase inhibitors?

Inhibits formation of all leukotrienes, preventing immune recruitment and reducing inflammation during an asthma attack

What are methylxanthines? (Use, Mechanism of Action, Route of Administration, Adverse Effects)

Use

Used to control COPD and nocturnal exacerbations of asthma

Mechanism of Action

Inhibits phosphodiesterase, which results in increased CAMP activity and leads to less sequestering of calcium, resulting in less twitching of lungs

Route of Administration

Oral

Adverse Effects

GI distress

Irritability

Insomina

Headache

Nausea

Vomiting

What is the use of methylxanthines?

Used to control COPD and nocturnal exacerbations of asthma

What is the mechanism of action of methylxanthines?

Inhibits phosphodiesterase, which results in increased CAMP activity and leads to less sequestering of calcium, resulting in less twitching of lungs

What are mast cell stabilizers? (Use, Mechanism of Action, Route of Administration)

Use

Effective if used prior to known exposure to an allergen, "prophylaxis"

Mechanism of Action

Prevents increase of calcium release caused by Gq linked IgE receptors in mast cells, preventing mast cell degranulation, which would release histamines, prostaglandins, and leukotrienes, resulting in reduced inflammation and bronchoconstriction

Route of Administration

Inhaled

What is the use of mast cell stabilizers?

Effective if used prior to known exposure to an allergen, "prophylaxis"

What is the mechanism of action of mast cell stabilizers?

Prevents increase of calcium release caused by Gq linked IgE receptors in mast cells, preventing mast cell degranulation, which would release histamines, prostaglandins, and leukotrienes, resulting in reduced inflammation and bronchoconstriction