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.