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.