Lapinsky Pulmonary

MDI

Metered Dose Inhaler

DPI

Dry Powder Inhaler

Brand Name Identifiers of MDIs vs. DPIs

MDIs

• HFA, Respimat, or no suffix

DPIs

• Diskus, Ellipta, Pressair, HandiHaler, RespiClick, Flexhaler

Dose Delivery of MDIs vs. DPIs

MDIs

• Aerosolized liquid

• Some use a propellant (Ex. HFA)

DPIs

• Fine powder

• No propellant (Pt is propellant)

How should patients be counseled to use MDIs vs. DPIs?

MDIs

• Hand-breath coordination

• Slow, deep inhalation while pressing the canister

• Must shake before use (some exceptions)

• Must be primed before first use and if not used for a certain period of time

DPIs

• Breath-activated, no need to press anything

• Quick, forceful inhalation

• Do not shake

• No need to prime (except for Flexhaler prior to first use)

Spacer Use in MDIs vs. DPIs

MDIs

• Can be used for most MDIs

• Helpful if patient is incapable of hand-breath coordination

• Decreases risk of thrush with ICS

DPIs

• Cannot be used

• Does not fit on most DPIs and powder would get stuck

Why are inhaled forms of drugs preferred for treatment of respiratory disorders vs. oral forms?

Inhaled forms deliver the drug directly into the lungs, so they generally have reduced toxicity/systemic side effects

Development of COPD vs. asthma

COPD

• Age of onset - usually > 40 years

• Smoking history - usually >= 20 years

Asthma

• Age of onset - usually <= 40 years

• Smoking history - uncommon

Characteristics of COPD

Sputum/mucus production is common

Usually not triggered by allergies

Persistent, chronic, and progressive loss of lung function

Worsens over time

Exacerbations/attacks are common

NOT fully reversible with medication

Characteristics of asthma

Infrequent sputum/mucus production

Commonly triggered by allergies

Intermittent and variable symptoms

Stable, does not worsen over time

Exacerbations/attacks are common

Reversible with medication/spontaneous

First-line treatment for COPD

Bronchodilators

First-line treatment for asthma

Inhaled Corticosteroids (ICS)

Symptoms of asthma

Recurrent episodes of:

• Wheezing

• Breathlessness

• Chest tightness

• Coughing

Symptoms of COPD

• Chronic and progressive shortness of breath (dyspnea)

• Chronic cough

• Sputum production

• Wheezing

Most common cause of COPD

Tobacco smoke

#1 way to reduce the morbidity and mortality of COPD

Smoking cessation

In COPD, long-term exposure to tobacco smoke or other air pollutants leads to:

Destruction of alveoli (the small passages in the lungs) = emphysema

AND/OR

Chronic inflammation and narrowing of bronchial tubes resulting in mucus production and a chronic cough = bronchitis

Elastin

A protein that contributes to lung elasticity

Neutrophil Elastase

A protease enzyme that chops up elastin

One specific disease risk factor unique to COPD but not asthma

Alpha-1 Anti-Trypsin (A1AT) deficiency

A1AT, also known as A1PI, functions as a protease inhibitor to inhibit Neutrophil Elastase

Without this inhibition, Neutrophil Elastase chops up Elastin, causing the lungs to lose their elasticity → COPD

COPD patients with Alpha-1 Anti-Trypsin (A1AT) deficiency typically undergo _____

Chronic weekly IV augmentation therapy with an Alpha-1 Protease Inhibitor (A1PI)

• Ex. Prolastin, Aralast, Zemaira

Two main disease components of asthma

Airway inflammation

• Therefore, treat/manage using anti-inflammatory drugs (ICS)

Bronchial smooth muscle contraction/bronchoconstriction

• Therefore, treat/manage by:

  • Inhibiting bronchial smooth muscle contraction/bronchoconstriction

  • Bronchial smooth muscle relaxation/bronchodilation

Asthma causes airflow obstruction typically resulting in _____

Expiratory airflow limitation/difficulty with exhalation

Most common complication of asthma

Exacerbations/attacks

• Can vary in length

• Can range from mild to severe, and in some cases can potentially be fatal

Most types of asthma result from:

An activation of inflammatory mediators

• Histamine

• Cytokines

• Leukotrienes (LTs)

  • One of the most important

Increase in the number of inflammatory cells

• Mast cells

• Eosinophils

Patients with a genetic predisposition for severe allergic asthma have abnormally high blood levels of:

Immunoglobulin E (IgE) antibody

OR

Eosinophils → severe eosinophilic asthma

• Can require specialized treatment in addition to routine inhaled medications

Asthma generally causes inflammation of the airways of the lungs, but severe eosinophilic asthma causes inflammation of _____

The ENTIRE respiratory system, from the nose down to the tiniest airways

Three most important chemical mediators of an asthma attack or asthma symptoms

IgE

Leukotrienes

Acetylcholine (ACh)

• Neurotransmitter associated with bronchial smooth muscle contraction

Mechanism of Action of Omalizumab

Monoclonal antibody that binds to IgE, preventing it from properly interacting with IgE receptors on the surface of mast cells, basophils, and eosinophils

Drug target is NOT the IgE receptor

Indication for Omalizumab

Severe allergic asthma

Used in patients with high levels of IgE

Omalizumab Administration

Given subcutaneously every 2 or 4 weeks

Not oral because antibodies have poor oral pharmacokinetic properties

Dose and frequency of omalizumab is based on _____

Pre-treatment body weight and IgE blood serum levels

Boxed warning for Omalizumab

Anaphylaxis

Can occur at any point during treatment (NOT just after the first dose)

Typically the first three doses are given in a healthcare setting under medical supervision

After 3 doses, self-administration can be considered if specific criteria are met

Common asthma triggers

• Allergens

• Exercise

  • EIB (Exercise Induced Bronchoconstriction)

• Aspirin/NSAIDs

• Cold air

Triggers cause activation of Phospholipase A2 (PLA2) → increased arachidonic acid

Activation of leukotriene receptors results in:

Bronchoconstriction

Eosinophil recruitment

Mucus secretion

Plasma exudation (leaking fluid)

How do NSAIDs induce asthma exacerbations?

NSAIDs inhibit COX1 and/or COX2, decreasing conversion of arachidonic acid to prostaglandins, including Prostaglandin E2 (PGE2)

PGE2 uniquely functions as an “anti-inflammatory” prostaglandin and suppresses production of leukotrienes

• NSAID inhibition of COX1 and COX2 “releases the brake” on the leukotriene pathway within mast cells and eosinophils in the airways

This also causes a “shunting” of arachidonic acid toward leukotriene production → overproduction of leukotrienes

Overproduction of leukotrienes leads to:

Bronchoconstriction

Mucus secretion

Increased vascular/blood vessel permeability

Recruitment of eosinophils to the site of inflammation

Mechanism of Action of Corticosteroids

Function as Glucocorticoid Receptor (GCR) agonists to indirectly inhibit PLA2

Corticosteroid binds to GCR → increased synthesis of lipocortin-1, which inhibits PLA2

Does not result in shunting of arachidonic acid down the leukotriene pathway, so can be used for managing asthma

Why are corticosteroids significantly more potent anti-inflammatory agents than NSAIDs?

Corticosteroids decrease prostaglandins and leukotrienes, while NSAIDs only decrease prostaglandins

Asthma Relievers (“Rescue Drugs”)

Inhaled forms of these drugs rapidly open airways within minutes of inhalation to treat acute asthma symptoms

If an ICS + Formoterol combination inhaler is used, asthma control is assesses based on frequency of asthma symptoms

If a SABA is used, frequency of SABA use can be incorporated into assessment of asthma control

Some of these drugs can be used preventively for EIB (Exercise-Induced Bronchoconstriction/Bronchospasm)

Asthma Controllers (“Maintenance Drugs”)

Often taken on a daily basis to reduce airway inflammation and maintain asthma control

ICS doses are categorized as low, medium, or high

• Can be escalated if indicated based on asthma severity

Asthma Drugs Classified as Relievers

ICS + Formoterol combination inhalers

Inhaled SABAs

Systemic corticosteroids

Inhaled epinephrine

Inhaled SAMAs

ICS + Formoterol Combination Inhalers

Used as needed to treat acute asthma symptoms

Formoterol is used compared to other LABAs because it has a shorter onset of action

• Formoterol onset of action = about 5 minutes

• Salmeterol onset of action = about 30 minutes

Better at reducing the risk of asthma exacerbations compared to a SABA alone

Inhaled SABAs

Short-Acting Beta-2 Adrenergic Receptor Agonists

Prototype = Albuterol

Used as needed to treat acute asthma symptoms

Quickly reverses bronchoconstriction as an alternative to the preferred therapy of ICS + Formoterol

Albuterol, Salmeterol, and Formoterol are structural derivatives of _____

Epinephrine

Systemic Corticosteroids

Injections (used in asthma exacerbations) or oral (used in asthma exacerbations or for severe asthma that is difficult to control with other drug combinations

Used to “support a rescue”

Use should be limited as much as possible to avoid systemic side effects

Inhaled epinephrine

Available OTC as Primatene Mist

Can be used intermittently for acute treatment of mild asthma ONLY

Typically not included in asthma guidelines

Inhaled SAMAs

Short-Acting Muscarinic-3 Receptor Antagonists

Prototype = Ipratropium Bromide

Can be used in combination with a SABA during asthma exacerbations

Ipratropium and Tiotropium are structural derivatives of _____

Atropine

Asthma Drugs Classified as Controllers

Inhaled Corticosteroids (ICS)

Inhaled LABAs

Oral Leukotriene Receptor Antagonists (LTRA)

Theophylline and Aminophylline

Inhaled LAMAs

Injectable Monoclonal Antibodies

Inhaled Corticosteroids (ICS)

Glucocorticoid receptor agonists

First-line treatment for all patients with asthma

Mainstay of treatment as the most effective anti-inflammatory agents

Prototype = Fluticasone

Inhaled corticosteroids are structural derivatives of _____

Hydrocortisone

Inhaled LABAs

Long-Acting Beta-2 Adrenergic Receptor Agonists

Used in combination with and preferred add-on agents to ICS

Should never be used alone due to an increased risk of serious adverse outcomes

• Long acting structural derivatives of epinephrine

Prototypes = Formoterol and Salmeterol

Oral Leukotriene Receptor Antagonists (LTRA)

Alternative option to, and can be added to, ICS + LABA treatment

Prototype = Montelukast

No inhaled forms available (not a rescue drug)

Most commonly used in children

PDE (Phosphodiesterase) Inhibitors

Theophylline (oral) and aminophylline (IV)

• Nonselective PDE Inhibitors

• Theophylline is a prodrug for caffeine → adenosine receptor antagonist

• Least desirable option for add-on treatment due to significant adverse effects, drug interactions, and the need to monitor serum drug concentrations

Roflumilast

• Selective PDE-4 inhibitor for bronchodilation in COPD only, not clinically indicated for asthma

Inhaled LAMAs

Long-Acting Muscarinic-3 Receptor Antagonists

Can be used as add-on treatment in patients with a history of exacerbations despite ICS + LABA treatment

Prototype = Tiotropium Bromide

Injectable Monoclonal Antibodies for Pulmonary Treatment

Add-on treatment for persistent severe asthma

• For severe allergic asthma → omalizumab

• For severe eosinophilic asthma → mepolizumab, reslizumab, benralizumab, and dupilumab

• For severe asthma regardless of eosinophil counts or biomarkers → tezepelumab

How do SABAs and LABAs cause bronchodilation?

Bind to β-2 Adrenergic Receptor → stimulates adenylyl cyclase → increases conversion of ATP to cAMP → increased levels of cAMP cause bronchodilation

How do PDE Inhibitors cause bronchodilation?

Inhibition of PDE → decreases conversion of cAMP to AMP → increased levels of cAMP cause bronchodilation

Antagonists of leukotriene receptors, mucarinic-3 receptors, and adenosine receptors decrease _____

Bronchial smooth muscle contraction/bronchoconstriction

Structural advantages and disadvantages of epinephrine vs. SABAs

Epinephrine

• Non-selective adrenergic receptor agonist (α1,α2,β1,β2,) leads to dangerous side effects such as cardiac stimulation

• Rapid inactivation by COMT and MAO leads to short half life (~3-5 minutes)

SABA

• β2-selective adrenergic receptor agonist leads to decreased side effects

• Decreased inactivation by COMT and MAO leads to longer half life

Structural advantages and disadvantages of hydrocortisone vs. ICS

Hydrocortisone

• Non-selective GCR agonist → mineralocorticoid receptor agonism leads to cardiovascular side effect

• Low agonist potency

ICS

• Selective GCR agonist leads to decreased side effects

• Very potent GCR agonist

Structural advantages and disadvantages of atropine vs. SAMAs

Atropine

• Non-selective muscarinic receptor antagonist leads to cardiovascular side effects

• Crosses the BBB to produce dangerous CNS side effects

SAMAs

• Improved selectivity for muscarinic-3 receptor as an antagonist leads to decreased side effects

• Does not cross the BBB to produce CNS side effects (lung/peripheral nervous system selective)

Effects of SABAs and LABAs outside the lung

• Direct agonist on skeletal muscle β2ARs → muscle contraction → nervousness and muscle tremors

  • Use with caution in patients with seizures

• Direct agonist on atrial β2ARs + reflex effect from increased peripheral vasodilation from blood vessel β2ARs → tachycardia and heart palpitations

  • Use with caution in patients with cardiovascular disease

• Direct agonist on skeletal muscle β2ARs → increase uptake of K+ from the blood → hypokalemia → heart palpitations

  • Use with caution in patients with cardiac arrhythmias

• Direct agonist on liver β2ARs causes increased glycogenolysis → hyperglycemia

  • Use with caution in patients with diabetes

SABAs and LABAs should be used with caution in patients with:

Seizures

Cardiovascular Disease

Cardiac Arrhythmias

Diabetes

Boxed warning for salmeterol

Increased risk of asthma-related deaths and hospitalizations (particularly in pediatric and adolescent patients)

Why are nonselective beta blockers unsafe in asthma patients with cardiovascular disease?

Antagonize β1ARs and β2ARs, which increases the risk of a beta-blocker-induced asthma attack

Why are selective beta blockers safe in asthma patients with cardiovascular disease?

Antagonize β1ARs but not β2ARs, which decreases the risk of a beta-blocker-induced asthma attack

Propranolol is a _____ beta blocker

Nonselective

Metoprolol is a _____ beta blocker

β1 Selective

Effect of epinephrine/norepinephrine in the heart/kidneys vs. lungs

Heart/kidneys

• Increased heart rate and force of contraction

• Increased renin and blood pressure

Lungs

• Decreased bronchoconstriction

• Increased bronchodilation

Effect of beta blockers in the heart/kidneys vs. lungs

Heart/kidneys

• Decreased heart rate and force of contraction

• Decreased renin and blood pressure

Lungs (Propranolol, but not metoprolol)

• Increased bronchoconstriction

• Decreased bronchodilation

What pharmacological advantages do ICS have over hydrocortisone?

Selective for glucocorticoid receptor, no activity at mineralocorticoid receptor

Higher potency

Effect of ICS on airway inflammatory cells and structural cells

Suppression of the immune system

Upregulation of β2 receptors

Why is a combination inhaler of an ICS and a LABA beneficial?

Increases patient convenience and adherence

Ensures both drugs are delivered simultaneously to the same cells

Reciprocal drug synergy

• Both drugs help each other

• Uncommon, usually only 1 drug helps the other

How do LABAs enhance ICS drug action?

LABAs activate β2 receptors on bronchial smooth muscle cells → increases cAMP → increases GCR activity

Result: LABAs make ICS work better via more suppression of pro-inflammatory genes

How do ICS enhance LABA drug action?

ICS increases the number of β2 receptors on bronchial smooth muscle cells, allowing use of a lower and safer dose of LABA

ICS also prevent downregulation and desensitization of β2 receptors, which can occur after chronic LABA exposure

Result: ICS make LABAs work more reliably and for longer periods of time

Indications of ICS/LABA combination inhalers

Asthma and COPD

• Symbicort

• Advair Diskus

• Breo Ellipta

Asthma only

• Dulera

• Advair HFA

Why is vilanterol considered an ulra-LABA?

It has an even longer duration of action compared to other LABAs

After using ANY inhaler containing an ICS, patients should _____

Gargle and rinse their mouth with warm water

• Prevents the development of thrush, or oral candidiasis

  • Can also use a spacer and proper inhalation technique to reduce risk

• Swallowing the rinse can lead to undesired systemic side effects

How do ICS lead to the development of thrush?

Corticosteroid can deposit on the mucus membranes of the mouth, tongue, and throat instead of reaching the lungs

Inhibits cytokine production, T cell activation, and antigen presentation, which dampens local immune system activity, especially antifungal defenses

Candida albicans, part of the normal oral flora, begins to overgrow due to weakened immunity

• Causes formation of white, creamy patches often on the tongue, inner cheek, or palate

Advantages of Montelukast vs. Zafirlukast

QD dosing with or without food vs. BID dosing on an empty stomach (1 hour before or 2 hours after a meal)

Can be used in ages 1+ vs. ages 5+

Comes as a tablet, chewable tablet, or packet of granules for breast milk/formula vs. only as a tablet

Safe concerning the liver, no LFTs vs. Contraindicated with liver impairment, required LFTs

Less drug interactions

Also approved for allergic rhinitis and exercise-induced bronchoconstriction

Warning for Leukotriene Receptor Antagonists

Neuropsychiatric Events

• Serious behavior and mood-related changes, including suicidal thoughts or actions

• Monitor for signs of aggressive behavior, hostility, agitation, hallucinations, depression, suicidal thinking

Atropine

Prototype muscarinic ACh receptor antagonist

• Causes altered mental state (upon crossing BBB), dry mouth, tachycardia, etc.

Cholinergic Crisis

Too much Acetylcholine as an agonist

How can you change the structure of an agonist to make an antagonist?

Add bulk

Why is atropine not used to treat asthma or COPD?

Nonselective muscarinic ACh receptor antagonist → sidee effects outside of the lung + unionized form can cross the BBB

• Antagonism of M2 receptors in the heart → ventricular tachycardia

• Antagonism of M1, M4, and M5 receptors in the CNS → confusion and deliriant hallucinations

Key functional group in ipratropium and tiotropium

Quaternary ammonium group

• Permanently ionized

• These drugs are m3/lung-selective and cannot cross the BBB

Symptoms of muscarinic ACh agonism

Diarrhea/Defecation

Urination

Miosis (eye pupil constriction)

Muscle Contraction

Bronchoconstriction

Bradycardia

Emesis

Lacrimation (secretion of tears)

Salivation/Sweating

SAMAs and LAMAs should be used with caution in patients with:

Narrow-angle glaucoma

• Antagonist of miosis, lacrimation

• Caused by too much fluid in eye, ACh antagonist traps fluid

Myasthenia gravis

• Antagonist of muscle contraction

BPH, urinary retention, bladder neck obstruction

• Antagonist of muscle contraction, urination

Direct drug interaction with SAMAs and LABAs

Muscarinic ACh Receptor Agonists

Acetylcholinesterase Inhibitors

Most common side effect of inhaled SAMAs and LAMAs

Dry mouth

• Antagonist of salivation

Benefit of SABA + SAMA combination inhaler

Creation of additive bronchodilation vs. dangerously increasing the dose of a SABA alone

Patient counseling for Spiriva Handihaler

Do NOT swallow the capsules associated with this DPI

While breathing in deeply and fully, you should hear or feel the capsule rattle/vibrate

To get the full dose, you must inhale TWICE from each capsule