Pharmacology - DRUGS FOR ASTHMA AND COPD (MADE EASY)

Summary

This lecture delves into the pharmacology of asthma and COPD treatments, highlighting the distinct pathophysiologies of both diseases. It explains the roles of mast cells in asthma and macrophages in COPD, detailing the inflammatory processes and bronchoconstriction. The video outlines various drug classes used in treatment, such as inhaled beta-2 agonists, muscarinic antagonists, leukotriene modifiers, and corticosteroids, emphasizing their mechanisms of action in managing airway inflammation and constriction.

Takeaways

• 🌟 Asthma and COPD are chronic lung diseases characterized by inflammation and narrowing of the airways, but they have distinct pathophysiologies.
• 🔬 Mast cells are key in asthma, activated by inhaled allergens to release bronchoconstrictor mediators, while macrophages orchestrate inflammation in COPD, often due to cigarette smoke.
• 💊 Inhaled beta-2 adrenergic agonists are used in both asthma and COPD to improve airflow by increasing cAMP levels and relaxing smooth muscles.
• 🍃 Muscarinic antagonists, or anticholinergics, block the effects of acetylcholine, reducing bronchial smooth muscle contraction in asthma and COPD.
• 🧬 Leukotriene modifiers target the action of leukotrienes, which are potent bronchoconstrictors produced by mast cells in asthma.
• ⚗️ Phosphodiesterase inhibitors like Theophylline and Roflumilast affect bronchodilation by influencing the breakdown of cAMP in smooth muscle cells.
• 💉 Omalizumab is a monoclonal antibody for allergic asthma that binds to free IgE, preventing mast cell degranulation and release of bronchoconstrictor mediators.
• 💦 Antihistamines reduce histamine-mediated responses by inhibiting the function of H1 receptors in allergic asthma.
• 🌿 Corticosteroids are used to suppress airway inflammation by affecting gene expression at the genetic level, both in asthma and COPD.
• 🛡️ Corticosteroids' anti-inflammatory effects involve binding to coactivators and histone deacetylase to suppress inflammatory genes or activate anti-inflammatory genes.
• 💥 Theophylline and Roflumilast differ in their mechanism of PDE inhibition, with Roflumilast being more selective and potentially safer.

Q & A

What are the main characteristics of asthma and COPD?

Asthma and COPD are chronic lung diseases characterized by inflammation and narrowing of the airways. They share some features but have distinct pathophysiologies.

What role do mast cells play in the pathophysiology of asthma?

Mast cells are key in asthma pathophysiology, being abundant in the airways of asthmatic patients and releasing bronchoconstrictor mediators upon activation by inhaled allergens.

How do inhaled allergens activate mast cells in asthma?

Inhaled allergens activate sensitized mast cells by crosslinking surface-bound IgE molecules, leading to the release of various bronchoconstrictor mediators.

What is the significance of thymic stromal lymphopoietin (TSLP) in the pathophysiology of asthma?

TSLP is secreted by epithelial and mast cells and conditions dendritic cells to release chemokines that attract T helper 2 cells, contributing to the allergic response in asthma.

What are the main mediators released by activated mast cells that contribute to bronchoconstriction and inflammation?

Activated mast cells release granule-derived mediators like histamine and newly formed metabolites of arachidonic acid, such as prostaglandins and leukotrienes, which promote inflammation and induce bronchoconstriction.

Why are cysteinyl leukotrienes considered potent bronchoconstrictors?

Cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are potent bronchoconstrictors because they activate Gq protein-coupled CysLT1 receptors on bronchial smooth muscle cells, increasing intracellular calcium concentration and causing smooth muscle contraction.

How do adenosine and histamine contribute to bronchoconstriction?

Adenosine activates Gi protein-coupled adenosine A1 receptors on bronchial smooth muscle cells, decreasing cyclic AMP levels and leading to smooth muscle contraction. Histamine causes smooth muscle contraction by activating Gq protein-coupled H1 receptors.

What is the role of inhaled beta-2 adrenergic agonists in treating asthma and COPD?

Inhaled beta-2 adrenergic agonists improve airflow by increasing cAMP levels upon receptor activation, leading to smooth muscle relaxation and bronchodilation.

What are the two types of beta-2 adrenergic agonists and their duration of action?

There are short-acting beta-2 agonists (SABAs) that provide bronchodilation for about 4 to 6 hours, and long-acting beta-2 agonists (LABAs) that provide bronchodilation for about 12 hours.

How do muscarinic antagonists, or anticholinergics, work in the treatment of asthma and COPD?

Muscarinic antagonists block the effects of acetylcholine on muscarinic receptors involved in bronchial smooth muscle contraction, leading to reduced intracellular calcium concentrations and airway smooth muscle relaxation.

What is the primary effect of corticosteroids in suppressing airway inflammation?

Corticosteroids primarily affect the genetic level by suppressing activated inflammatory genes and activating anti-inflammatory genes, which helps to reduce airway inflammation.

How do corticosteroids influence the inflammatory gene activation process?

Corticosteroids, depending on the dose, can bind to cytoplasmic glucocorticoid receptors and translocate to the nucleus, where they inhibit histone acetyltransferase activity, recruit histone deacetylase, or bind to glucocorticoid response elements to activate anti-inflammatory genes.

What is the mechanism of action of Theophylline and Roflumilast in treating airway constriction?

Theophylline binds to adenosine A1 receptors to block adenosine-mediated bronchoconstriction and nonselectively inhibits phosphodiesterases, contributing to bronchodilation. Roflumilast selectively inhibits phosphodiesterase-4 (PDE-4), improving therapeutic efficacy and safety profile compared to Theophylline.

What are the two pharmacotherapeutic options specifically for patients with allergic asthma mentioned in the script?

Omalizumab, a monoclonal antibody that binds to free IgE and prevents mast cell degranulation, and antihistamines, which inhibit the function of H1 receptors to reduce histamine-mediated responses.

Outlines

00:00

😷 Pathophysiology of Asthma and COPD

This paragraph delves into the chronic lung diseases asthma and COPD, highlighting the inflammation and narrowing of airways as a common feature. It emphasizes the distinct pathophysiology of both conditions, particularly the role of mast cells in asthma, activated by inhaled allergens and cytokines like SCF. The paragraph explains the process of IgE sensitization, eosinophil-mediated inflammation, and the release of bronchoconstrictor mediators from mast cells. It also covers the effects of leukotrienes and histamine on bronchoconstriction and the role of adenosine and autonomic nervous system in airway function. The paragraph concludes with a brief introduction to the drugs used in treating these diseases, focusing on the importance of addressing pathological constriction of smooth muscle.

05:04

💨 Inhaled Medications for Asthma and COPD

The second paragraph focuses on the pharmacological treatment of asthma and COPD, discussing the use of inhaled beta-2 adrenergic agonists, which increase cAMP levels leading to bronchodilation. It differentiates between short-acting beta-2 agonists (SABAs) like Albuterol and Levalbuterol, and long-acting beta-2 agonists (LABAs) such as Arformoterol and Salmeterol. The paragraph also covers muscarinic antagonists or anticholinergics, which block acetylcholine's effects, including short-acting muscarinic antagonist (SAMA) Ipratropium and long-acting muscarinic antagonists (LAMAs) like Tiotropium. Leukotriene modifiers that target CysLT1 receptors and lipoxygenase, such as Montelukast and Zileuton, are also discussed. Theophylline and Roflumilast, which inhibit phosphodiesterases, are mentioned for their bronchodilating effects. The paragraph concludes with a mention of Omalizumab for allergic asthma and antihistamines, which inhibit H1 receptors.

10:07

🌿 Corticosteroids in Asthma and COPD Treatment

The final paragraph discusses the use of corticosteroids to suppress airway inflammation in asthma and COPD, either as monotherapy or in combination with other medications. It explains the genetic level action of corticosteroids, which involves suppression of inflammatory genes and activation of anti-inflammatory genes. The paragraph describes the inflammatory process involving IL-1β or TNF-α, IKK2, MAPK, and NF-kB, and how corticosteroids at different doses affect this process. It details the binding of corticosteroids to glucocorticoid receptors and their subsequent actions in the nucleus, including the inhibition of histone acetyltransferase activity and the activation of anti-inflammatory genes. The paragraph concludes with examples of inhaled and oral corticosteroids used in treating lung inflammation.

Keywords

💡Asthma

Asthma is a chronic lung disease characterized by inflammation and narrowing of the airways. It is a key theme of the video as it discusses the pathophysiology and treatment of asthma. The script mentions that mast cells play a key role in asthma, and their activation by allergens leads to the release of bronchoconstrictor mediators, contributing to the disease's symptoms.

💡Chronic Obstructive Pulmonary Disease (COPD)

COPD is another chronic lung disease highlighted in the video, with a distinct pathophysiology from asthma. The script explains that while both diseases involve airway inflammation and narrowing, COPD's inflammation is primarily orchestrated by macrophages rather than mast cells, and is often associated with cigarette smoke and other inhaled irritants.

💡Mast Cells

Mast cells are crucial in the pathophysiology of asthma, as defined in the script. They are abundant in the airways of asthmatic patients and are activated by inhaled allergens, leading to the release of mediators that cause bronchoconstriction and inflammation. The video emphasizes their role in the activation of T-helper cells and the production of IgE antibodies.

💡Cytokines

Cytokines are signaling proteins that mediate and regulate immunity and inflammation, as mentioned in the script. In the context of asthma, stem cell factor (SCF) is a cytokine released by epithelial cells that interacts with mast cells upon encountering allergens, contributing to the disease's pathophysiology.

💡Bronchoconstriction

Bronchoconstriction refers to the narrowing of the airways, which is a central feature of both asthma and COPD as discussed in the video. It is caused by various mediators released from activated mast cells, such as histamine and leukotrienes, leading to smooth muscle contraction and reduced airflow.

💡Leukotrienes

Leukotrienes are potent bronchoconstrictors derived from the metabolism of arachidonic acid, as explained in the script. They are formed through the lipoxygenase (LOX) pathway and are particularly significant in the pathophysiology of asthma. The script specifically mentions cysteinyl leukotrienes (LTC4, LTD4, and LTE4) as the most potent bronchoconstrictors.

💡Corticosteroids

Corticosteroids are a class of drugs used to suppress airway inflammation in both asthma and COPD, as detailed in the script. They work at the genetic level by suppressing activated inflammatory genes and activating anti-inflammatory genes, which is crucial for managing the inflammation associated with these respiratory diseases.

💡Beta-2 Adrenergic Agonists

Beta-2 adrenergic agonists are a class of drugs that are central to the treatment of asthma and COPD, as discussed in the video. They work by activating beta-2 receptors, leading to an increase in cAMP levels and resulting in smooth muscle relaxation and improved airflow. The script differentiates between short-acting beta-2 agonists (SABAs) and long-acting beta-2 agonists (LABAs), providing examples of each.

💡Muscarinic Antagonists

Muscarinic antagonists, also known as anticholinergics, are drugs used in the treatment of asthma and COPD to mitigate the effects of increased parasympathetic neuronal activity. As explained in the script, these drugs block acetylcholine's effects on muscarinic receptors, leading to airway smooth muscle relaxation and reduced bronchoconstriction.

💡Leukotriene Modifiers

Leukotriene modifiers are a class of drugs that target the leukotrienes produced by mast cells, as mentioned in the script. They function by either blocking the binding of leukotrienes to CysLT1 receptors or by inhibiting the lipoxygenase enzyme, both of which contribute to reducing bronchial smooth muscle contraction and treating asthma symptoms.

💡Phosphodiesterase Inhibitors

Phosphodiesterase inhibitors, such as Theophylline and Roflumilast, are drugs that affect the contraction of bronchial smooth muscle cells, as discussed in the video. They work by inhibiting phosphodiesterases, the enzymes that break down cAMP, thus contributing to bronchodilation. Roflumilast, in particular, selectively targets phosphodiesterase-4 (PDE-4), improving therapeutic efficacy and safety.

Highlights

Asthma and COPD are chronic lung diseases characterized by inflammation and narrowing of the airways.

Mast cells are key in asthma pathophysiology, activated by inhaled allergens to release bronchoconstrictor mediators.

Cytokines like stem cell factor (SCF) play a role in mast cell activation in asthma.

T helper 2 cells induce B cells to produce IgE antibodies in asthma, contributing to inflammation.

Cysteinyl leukotrienes, such as LTC4, LTD4, and LTE4, are potent bronchoconstrictors in asthma.

Histamine and adenosine contribute to bronchoconstriction in asthma through different receptor activations.

In COPD, macrophages are the primary orchestrators of inflammation, unlike in asthma.

Cigarette smoke activates alveolar macrophages and airway epithelial cells in COPD, leading to chemokine release.

Neutrophils in COPD produce proteases that stimulate mucus secretion and cause alveolar wall destruction.

Corticosteroids are used to suppress airway inflammation in both asthma and COPD.

Corticosteroids affect inflammatory gene expression at the genetic level by binding to coactivators and histone deacetylase.

Inhaled beta-2 adrenergic agonists improve airflow by increasing cAMP levels, leading to smooth muscle relaxation.

Muscarinic antagonists, or anticholinergics, block acetylcholine effects to reduce bronchial smooth muscle contraction.

Leukotriene modifiers target CysLT1 receptors and lipoxygenase to reduce bronchoconstriction in asthma.

Phosphodiesterase inhibitors like Theophylline and Roflumilast contribute to bronchodilation by affecting cAMP metabolism.

Omalizumab is a monoclonal antibody that binds to free IgE, inhibiting allergic responses in asthma.

Antihistamines reduce histamine-mediated responses by inhibiting H1 receptors in allergic asthma.

Transcripts

In this lecture we’re gonna cover the pharmacology of drugs for asthma and COPD

so let’s get right into it.

Asthma and chronic obstructive pulmonary disease (COPD) are chronic lung diseases

marked by an inflammation and narrowing of the airways.

Although both diseases share some features, the pathophysiology of asthma and COPD are distinct.

Mast cells play a key role in the pathophysiology of asthma and are abundant in the airways

of asthmatic patients.

They are orchestrated by several interacting cytokines, one of which is stem cell factor

(SCF) released by epithelial cells upon encounter with inhaled allergens.

Inhaled allergens activate sensitized mast cells by crosslinking surface-bound IgE molecules

to release various bronchoconstrictor mediators.

The allergens are also processed by dendritic cells, which are conditioned by thymic stromal

lymphopoietin (TSLP) secreted by epithelial and mast cells to release several chemokines

that attract T helper 2 cells.

These T-helper cells, in turn, induce B cells to produce and secrete IgE antibodies that

sensitize mast cells, induce eosinophil-mediated inflammation, and stimulate mast cell proliferation.

All right, now that we have a big picture, let’s take a closer a look at how the mediators

derived from activated mast cells contribute to bronchoconstriction and inflammation.

So, when mast cells are activated, stored granule-derived mediators such as histamine

are released alongside newly formed metabolites of the phospholipid arachidonic acid.

During immunologic activation arachidonic acid is liberated from the membrane phospholipids

with the help of phospholipase A2 and is rapidly oxidized by either the cyclooxygenase (COX)

or the lipoxygenase (LOX) pathways to form prostaglandins and leukotrienes, respectively.

Now, these mediators not only promote inflammation but also induce bronchoconstriction.

The so-called cysteinyl leukotrienes; LTC 4, LTD 4 and LTE 4 have been shown to be the

most potent bronchoconstrictors.

Specifically, they activate Gq protein-coupled CysLT1 receptors expressed on bronchial smooth

muscle cells, and increase the intracellular calcium concentration producing smooth muscle

contraction.

Likewise, but to a lesser degree, histamine causes smooth muscle contraction by activating

Gq protein-coupled H1 receptors.

Now, asthmatic individuals also have been found to have elevated levels of adenosine

in their lungs.

Adenosine exerts its effects on bronchial smooth muscle cells by activating Gi protein-coupled

adenosine A1 receptors causing decrease in cyclic AMP levels leading to smooth muscle

contraction.

Finally, in addition to this, airway smooth muscle is also innervated by both sympathetic

and parasympathetic nerve fibers that regulate contractions and relaxations.

Specifically, endogenous catecholamines such as epinephrine and norepinephrine released

from the sympathetic fibers activate Gs protein-coupled β2-adrenergic receptors causing increase

in cyclic AMP levels leading to smooth muscle relaxation.

On the other hand, acetylcholine released from the parasympathetic fibers activate

Gq protein-coupled muscarinic M3 receptors causing increase in intracellular calcium leading

to smooth muscle contraction.

Now, let’s switch gears and let’s talk about COPD.

So, when it comes to COPD, mast cells do not seem to play a significant role.

Instead, the primary orchestrators of inflammation are macrophages.

Cigarette smoke and other irritants inhaled into the lungs may activate alveolar macrophages

and airway epithelial cells to release multiple chemokine mediators, which attract monocytes,

neutrophils, and T lymphocytes.

Monocytes are attracted into the lung to differentiate into macrophages thereby leading to increased

macrophage numbers.

Neutrophils produce proteases, which are potent stimulants of mucus secretion, and are associated

with chronic bronchitis.

In addition to that, these proteases as well as other proteolytic enzymes produced by macrophages

and cytotoxic T-cells drive structural cells into apoptosis causing alveolar wall destruction

leading to emphysema.

Lastly, chronic inflammation of the interstitial lung tissue along with other triggers activates

the proliferation of fibroblasts leading to pulmonary fibrosis.

Now that we covered the basic pathophysiology of asthma and COPD, let’s move onto discussing

drugs used in treatment of these diseases.

So pathological constriction of smooth muscle is one of the main causes of airway narrowing

in patients with asthma and COPD.

Therefore, some of the same drug classes are often used in treatment of both, as there

are many shared mechanisms.

One such class of drugs is inhaled beta-2 adrenergic agonists.

The pathway of beta-2 receptor action begins when an agonist activates the receptor, thereby

triggering a signaling cascade that causes increase in cAMP levels, which in turn leads

to smooth muscle relaxation and improved airflow.

There are two types of β2 adrenergic agonists: the short-acting β2 agonists (SABAs), which

produce bronchodilation for about 4 to 6 hours.

The examples of drugs that belong to this group are Albuterol and Levalbuterol.

And we also have the long-acting β2 agonists (LABAs), which produce bronchodilation for

about 12 hours.

The examples of drugs that belong to this group are Arformoterol, Formoterol, Vilanterol,

and Salmeterol.

Now, another class of drugs that is used in treatment of asthma and COPD is

muscarinic antagonists also known as anticholinergics.

So, research has shown that parasympathetic neuronal activity, through acetylcholine signaling,

is increased in the pathophysiology of asthma and COPD.

To mitigate this problem, muscarinic antagonists were developed to block the effects of acetylcholine

on muscarinic receptors that are involved in contraction of bronchial smooth muscle.

Specifically, binding of these drugs to M3 receptors results in reduced intracellular

calcium concentrations thereby leading to airway smooth muscle relaxation.

Just like β2 adrenergic agonists, muscarinic antagonists include short- and long-acting agents.

The example of short-acting muscarinic antagonist (SAMA) is Ipratropium, and the examples of

long-acting antagonists (LAMAs) are Tiotropium, Aclidinium and Umeclidinium.

All right, moving on the next class of drugs that affect the contraction of bronchial smooth

muscle cell, that is leukotriene modifiers.

So as previously discussed, mast cells are the primary producers of cysteinyl leukotrienes.

Therefore drugs that alter their action are typically reserved for treatment of asthma.

Now, the medications in this class function in two ways.

First is by blocking the binding of leukotrienes to CysLT1 receptors, which reduces bronchial

smooth muscle contraction.

Examples of drugs that target CysLT1 receptors are Montelukast and Zafirlukast.

The second mechanism of action involves inhibition of lipoxygenase, the enzyme that converts

arachidonic acid into leukotrienes.

Example of drug that targets lipoxygenase is Zileuton.

Now, moving on to another pharmacotherapeutic option that directly affects contraction of

bronchial smooth muscle cells, that is phosphodisterase inhibitors.

One of the most well known drugs in this group is an agent called Theophylline.

Theophylline exerts its effects mainly through two distinct mechanisms.

First, it binds to the adenosine A1 receptors and blocks adenosine mediated bronchoconstriction.

Secondly, Theophylline targets phosphodiesterases (PDE), the enzymes responsible for breaking

down cAMP in smooth muscle cell, by nonselectively inhibiting their activity thereby contributing

to bronchodilation.

Another drug similar to Theophylline, called Roflumilast also inhibits phosphodiesterase,

however it does it in a selective manner by specifically targeting phosphodiesterase-4 (PDE-4).

Because phosphodiesterase-4 (PDE-4) is the primary enzyme involved in metabolism of cyclic

AMP in smooth muscle, selective inhibition of phosphodiesterase-4 (PDE-4) by Roflumilast

results in better therapeutic efficacy and improved safety profile when compared to Theophylline.

Lastly, before we move on, I wanted to briefly mention couple more pharmacotherapeutic options

that are available specifically for patients with allergic asthma.

The first one is a drug called Omalizumab that targets the root cause of the allergic response.

Omalizumab is a recombinant monoclonal antibody that selectively binds to free IgE thus preventing

them from binding to the mast cell receptors.

As a result, Omalizumab inhibits IgE-dependent cellular events such as mast cell degranulation

thereby preventing the release of chemical mediators that cause the clinical symptoms

such as bronchial constriction.

The second option is a class of drugs called antihistamines, which work by inhibiting the

function of H1 receptors thereby reducing histamine-mediated responses.

If you wan to learn more about these drugs make sure to check out my other video about

the pharmacology of antihistamines.

Now in addition to airway narrowing, airway inflammation is a major component of both

asthma and COPD and thus represents another important target for treatment.

To suppress airway inflammation a class of drugs called corticosteroids is often used

as monotherapy or in combination therapy typically with long-acting β2-agonists

or long-acting muscarinic antagonists.

The primary effect of corticosteroids appears to be at the genetic level, involving suppression

of activated inflammatory genes and activation of anti-inflammatory genes.

So to gain better understanding of these mechanisms of action,

let’s take a closer look at typical inflammatory cell.

The activation of inflammatory genes involves a signaling cascade which is initiated by

inflammatory stimuli, such as interleukin 1β (IL-1β) or tumor necrosis factor α (TNF-α),

that binds to the cell’s surface receptor leading to activation of

inhibitor kappa B kinase 2 (IKK2) and mitogen-activated protein kinase (MAPK) pathway.

Now, inhibitor kappa B kinase 2 (IKK2) activates transcription factor nuclear factor kappa B (NF-kB),

which then leads to formation of a dimer of p50 and p65 nuclear factor kappa B.

This dimer then translocates to the nucleus and binds to specific recognition sites and

coactivators such as CREB-binding protein (CBP) or p300/CBP-associated factor (pCAF).

Mitogen-activated protein kinases (MAPK) also contribute to the association of this coactivator

complex by phosphorylating CREB-binding protein (CBP).

Now, these coactivators possess intrinsic histone acetyltransferase (HAT) activity,

meaning they are able to acetylate core histone residues, causing unwinding of DNA and thereby

increase expression of genes encoding multiple inflammatory proteins such as cyclooxygenase 2 (COX-2).

All right, so how do corticosteroids affect this cascade?

Well, it depends on the dose.

So upon entry into the cell, low-dose corticosteroids bind to cytoplasmic glucocorticoid receptors (GR)

that translocate to the nucleus, where they work by binding to these coactivators

and inhibiting histone acetyltransferase activity as well as recruiting histone deacetylase (HDAC),

which reverses histone acetylation, leading to suppression of activated inflammatory genes.

On the other hand, at higher doses, corticosteroids bound to cytoplasmic glucocorticoid receptors

that translocate to the nucleus, bind to glucocorticoid response elements in the promoter region of

steroid-sensitive genes and also directly or indirectly bind to coactivator molecules

CBP, pCAF or steroid receptor coactivator (SRC).

This binding in turn causes acetylation of specific lysine residues on histone-4, which

leads to activation of genes encoding anti-inflammatory proteins.

One of these anti-inflammatory proteins is annexin A1 also known as lipocortin-1, which

inhibits the action of phospholipase A2, thereby limiting the availability of arachidonic acid

that is needed for synthesis of prostaglandins and leukotrienes.

Examples of corticosteroids used to treat lung inflammation include inhaled agents such as

Beclomethasone, Budesonide, Ciclesonide, Fluticasone, Mometasone, and Triamcinolone,

and oral agents such as Dexamethasone, Methylprednisolone, Prednisone, and Prednisolone.

And with that I wanted to thank you for watching, I hope you enjoyed this video and as always

stay tuned for more.