Pharmacology - DRUGS FOR ASTHMA AND COPD (MADE EASY)

In this lecture we will cover the

pharmacology

of

asthma

and COPD medications, so let's jump right into it. Asthma and chronic obstructive pulmonary disease (COPD) are chronic lung diseases characterized by inflammation and narrowing of the airways. Although both diseases share some characteristics, the pathophysiology of

asthma

and COPD are different. 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 encountering inhaled allergens. Inhaled allergens activate sensitized mast cells by cross-linking surface-bound IgE molecules to release various bronchoconstrictor mediators.

Allergens are also processed by dendritic cells, which are conditioned by thymic stromal lymphopoietin (TSLP) secreted by mast and epithelial cells to release various chemokines that attract T helper 2 cells. In turn, they induce B cells to produce and secrete IgE antibodies that sensitize mast cells, induce eosinophil-mediated inflammation, and stimulate mast cell proliferation. Alright, now that we have the big picture, let's take a closer look at how mediators derived from activated mast cells contribute to bronchoconstriction and inflammation. Then, when mast cells are activated, stored granule-derived mediators, such as histamine, are released along with newly formed metabolites of the phospholipid arachidonic acid.

During immune activation, arachidonic acid is released from membrane phospholipids with the help of phospholipase A2 and is rapidly oxidized by the cyclooxygenase (COX) or 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 intracellular calcium concentration producing smooth muscle contraction. Likewise, but to a lesser extent, histamine causes smooth muscle contraction by activating Gq protein-coupled H1 receptors.

Now, asthmatic people have also 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 a decrease in cyclic AMP levels leading to smooth muscle contraction. Finally, in addition to this, airway smooth muscle is also innervated by sympathetic and parasympathetic nerve fibers that regulate contractions and relaxations. Specifically, endogenous catecholamines such as epinephrine and norepinephrine released by sympathetic fibers activate G protein-coupled β2 adrenergic receptors, causing an increase in cyclic AMP levels leading to smooth muscle relaxation. On the other hand, acetylcholine released by parasympathetic fibers activates muscarinic M3 receptors coupled to the Gq protein, causing an increase in intracellular calcium leading to smooth muscle contraction.

Now, let's change the subject and talk about COPD. So when it comes to COPD, mast cells don't seem to play a big role. Instead, the main orchestrators of inflammation are macrophages. Cigarette smoke and other irritants inhaled into the lungs can activate alveolar macrophages and airway epithelial cells to release multiple chemokine mediators, which attract monocytes, neutrophils, and T lymphocytes. Monocytes are attracted to the lung to differentiate into macrophages, which increases the number of macrophages. Neutrophils produce proteases, which are potent stimulants of mucous 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 to apoptosis, which causes destruction of the alveolar wall and causes emphysema.

Finally, chronic inflammation of the interstitial lung tissue together with other triggers activates the proliferation of fibroblasts leading to pulmonary fibrosis. Now that we've covered the basic pathophysiology of asthma and COPD, let's move on to discuss the medications used in the treatment of these diseases. Therefore, pathological smooth muscle constriction is one of the main causes of airway narrowing in patients with asthma and COPD. Therefore, some of the same classes of

drugs

are often used in the treatment of both, as there are many shared mechanisms. One such class of

drugs

is inhaled beta-2 adrenergic agonists. The beta-2 receptor pathway of action begins when an agonist activates the receptor, triggering a signaling cascade that causes an increase in cAMP levels, which in turn leads to smooth muscle relaxation and improved blood flow. of air.

There are two types of β2 adrenergic agonists: short-acting β2 agonists (SABA), which produce bronchodilation for approximately 4 to 6 hours. Examples of medications that belong to this group are Albuterol and Levalbuterol. And we also have long-acting β2 agonists (LABA), which produce bronchodilation for about 12 hours. Examples of drugs that belong to this group are Arformoterol, Formoterol, Vilanterol and Salmeterol. Now, another class of drugs used in the treatment of asthma and COPD are muscarinic antagonists, also known as anticholinergics. Thus, research has shown that parasympathetic neuronal activity, through acetylcholine signaling, increases in the pathophysiology of asthma and COPD. To mitigate this problem, muscarinic antagonists were developed to block the effects of acetylcholine on muscarinic receptors involved in bronchial smooth muscle contraction.

Specifically, binding of these drugs to M3 receptors results in reduced intracellular calcium concentrations, leading to relaxation of airway smooth muscle. Like β2-adrenergic agonists, muscarinic antagonists include short- and long-acting agents. Example of short-acting muscarinic antagonist (SAMA) is ipratropium, and examples of long-acting antagonists (LAMA) are tiotropium, aclidinium, and umeclidinium. Okay, moving on to the next class of drugs that affect the contraction of bronchial smooth muscle cells, namely leukotriene modifiers. So, as discussed above, mast cells are the main producers of cysteinyl leukotrienes. Therefore, drugs that alter its action are usually reserved for the treatment of asthma. Now, medications in this class work in two ways.

The first is by blocking the binding of leukotrienes to CysLT1 receptors, which reduces the contraction of bronchial smooth muscle. Examples of drugs that target CysLT1 receptors are montelukast and zafirlukast. The second mechanism of action involves the inhibition of lipoxygenase, the enzyme that converts arachidonic acid to leukotrienes. An example of a drug that targets lipoxygenase is Zileuton. Now, let's move on to another pharmacotherapeutic option that directly affects the contraction of bronchial smooth muscle cells: phosphodisterase inhibitors. One of the best-known drugs in this group is an agent called theophylline. Theophylline exerts its effects primarily through two distinct mechanisms.

First, it binds to adenosine A1 receptors and blocks adenosine-mediated bronchoconstriction. Second, theophylline targets phosphodiesterases (PDEs), the enzymes responsible for breaking down cAMP in smooth muscle cells, non-selectively inhibiting their activity, thereby contributing to bronchodilation. Another drug similar to theophylline, called Roflumilast, also inhibits phosphodiesterase, however, it does so selectively by specifically targeting phosphodiesterase-4 (PDE-4). Because phosphodiesterase-4 (PDE-4) is the main enzyme involved in cyclic AMP metabolism in smooth muscle, selective inhibition of phosphodiesterase-4 (PDE-4) by Roflumilast results in improved therapeutic efficacy and a better safety profile compared to theophylline. Finally, before we continue, I wanted to briefly mention a couple more pharmacotherapeutic options that are available specifically for patients with allergic asthma.

The first is a drug called Omalizumab that attacks the root cause of the allergic response. Omalizumab is a recombinant monoclonal antibody that selectively binds to free IgE, thus preventing it from binding to 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 clinical symptoms such as bronchial constriction. The second option is a class of medications called antihistamines, which work by inhibiting the function of H1 receptors, thereby reducing histamine-mediated responses. If you would like to learn more about these medications, be sure to watch my other video on the

pharmacology

of antihistamines.

Now, in addition to airway narrowing, airway inflammation is an important component of both asthma and COPD and therefore represents another important target for treatment. To suppress airway inflammation, a class of medications called corticosteroids is often used as monotherapy or in combination therapy, typically with long-acting β2-agonists or long-acting muscarinic antagonists. The main effect of corticosteroids appears to be at the genetic level, involving the suppression of activated inflammatory genes and the activation of anti-inflammatory genes. So, to better understand these mechanisms of action, let's take a closer look at typical inflammatory cells. Activation of inflammatory genes involves a signaling cascade that is initiated by inflammatory stimuli, such as interleukin 1β (IL-1β) or tumor necrosis factor α (TNF-α), which binds to the cell surface receptor and causes the activation of the inhibitor kappa B.

Kinase 2 (IKK2) and mitogen-activated protein kinase (MAPK) pathway. Now, the inhibitor kappa B kinase 2 (IKK2) activates the transcription factor nuclear kappa B (NF-kB), which then leads to the formation of a dimer of p50 and p65 of 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 (MAPKs) 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 that they are able to acetylate core histone residues, causing DNA unwinding and thus increasing the expression of genes encoding multiple inflammatory proteins such as cyclooxygenase 2 (COX-2).

Okay, so how do corticosteroids affect this cascade? Well, it depends on the dosage. Then, upon entering the cell, low-dose corticosteroids bind to cytoplasmic glucocorticoid receptors (GRs) that translocate to the nucleus, where they function 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 bind to cytoplasmic glucocorticoid receptors that translocate to the nucleus, bind to glucocorticoid response elements in the promoter region of steroid-responsive genes, and also bind directly or indirectly to molecules coactivators CBP, pCAF or steroid receptor. coactivator (SRC).

This binding, in turn, causes acetylation of specific lysine residues on histone-4, leading to the 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, thus limiting the availability of arachidonic acid that is needed for the 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.