Drugs for asthma

Now that I've explained the pathology of asthma, let's get on to talking about drugs!

There is no cure for asthma, so treatment generally aims at reducing symptoms. This is usually by preventing or relieving bronchoconstriction, suppressing inflammation and/or reducing the hypersecretion of mucus.

Preventing or relieving bronchoconstriction: "Relievers"

As there are many different agents that cause vasoconstriction (histamine, acetylcholine, neuropeptides, endothelin etc.), it would be very difficult to target all of them at once. Instead, we use medications that directly cause vasodilation. The most common ones are the β₂-adrenoceptor agonists, which I've also spoken about here. As their name suggests, they stimulate β₂-adrenoceptor agonists, causing vasodilation through a series of steps (converting ATP to cAMP, which activates PKA, which phosphorylates some proteins). These drugs do not, however, have any effect on inflammation or on mucus hypersecretion.

One example of a short-acting β₂-adrenoceptor agonist is salbutamol. Like many other asthma drugs, it is given by inhalation so that it gets to the target site quickly and has few systemic effects. Salbutamol kicks in after 5-10 minutes, making it suitable for relieving bronchoconstriction during an asthma attack. Its effects, however, only last for 4-6 hours.

Eformoterol and salmeterol are long-acting β₂-adrenoceptor agonists. Their actions last for 12 hours. Eformoterol, like salbutamol, kicks in pretty quickly (5-10 minutes), so it can also double as a reliever. Salmeterol, however, takes around 15-20 minutes to kick in, so it is not as suitable as a reliever medication. Long-acting β₂-adrenoceptor agonists are often used as an add-on therapy in patients already taking inhaled corticosteroids (ICS). In fact, a lot of "combination inhalers" package together an ICS and a long-acting β₂-adrenoceptor agonist.

Targeting inflammation: "Preventers"

Some drugs target the inflammatory processes in asthma so as to prevent future asthma attacks. The most important of these medications are the inhaled corticosteroids, which I just mentioned above. These drugs can directly reduce airway wall swelling and airway narrowing, and indirectly reduce contraction and hypersecretion by reducing production of inflammatory mediators. However, since they don't cause bronchodilation directly, they're not good relievers. Just like other asthma medications, these are taken by inhalation.

ICS bind to glucocorticoid receptors (GR) in the cytoplasm of the cell. This allows the glucocorticoid receptors to translocate into the nucleus and act as transcription factors, as discussed here. GR dimers can bind to positive glucocorticoid response elements (pGRE), upregulating the transcription of anti-inflammatory proteins. GR dimers can also bind to negative GREs (nGRE), decreasing levels of pro-inflammatory proteins. Alternatively, monomers of GR can inactivate pro-inflammatory transcription factors, such as NF-κB, also decreasing levels of pro-inflammatory proteins.

ICS are not the only "preventers." There are also leukotriene receptor agonists, such as montelukast, and anti-IgE antibodies, such as omalizumab. (There are also some newer IL-5 antagonists, and the reason I know that is because that's what our group project is on :P Specifically, our group is learning about reslizumab (Cinqair), which was only approved in the US last year.)

Targeting hypersecretion of mucus

There is no fancy name for drugs that target the hypersecretion of mucus, mainly because there are no specific effective drugs that actually do so. Before we talk about drugs, however, let's talk about the mucus first.

As you should know, airways are lined by mucus, which helps to trap pathogens and other unwanted stuff that we breathe in so that it can all be swept out by the ciliated cells. Mucus consists of mucins, which give mucus its sticky, gel-like structure, antimicrobial molecules, such as defensins, lysozymes and IgA, water, and salts. In some airway diseases, especially in cystic fibrosis, mucus can be quite abnormal, with elevated amounts of these components, as well as contaminants such as DNA, actin and bacteria. Abnormal mucus can be difficult to clear.

As mentioned above, ICS can reduce production of inflammatory mediators that cause mucus hypersecretion, but unfortunately steroid resistance is an issue in some patients. More direct inhibitors of mucin production and secretion have not been successfully developed yet. An alternative approach to this problem is promoting the clearance of mucus. Mannitol and hypertonic saline can make the mucus more hydrated, effectively increasing its ability to "wash out" of the lungs. N-acetylcysteine and dornase alpha can also break down mucins and contaminating DNA, but while these have had some benefit in patients with cystic fibrosis, there is no evidence of their efficacy in patients with asthma.

Believe it or not, macrolides, which you might remember from PHAR2210 as protein synthesis inhibitors, have also been explored as a potential treatment for mucus hypersecretion. In fact, macrolides have been found to greatly increase survival rates of patients with diffuse panbronchiolitis (DPB), in which patients have extensive mucus hypersecretion which they cough up.

Macrolides have anti-inflammatory and mucoregulatory effects. They are anti-inflammatory in that they suppress the secretion of some cytokines, such as IL-8 (which activate neutrophils), suppress the recruitment of neutrophils, and promote the removal of neutrophils via macrophages. In other words, it's Pick-On-Neutrophils Day. But why neutrophils? Well, neutrophil elastase promotes mucus synthesis and secretion. Hence, when macrolides suppress neutrophils, they also suppress mucus production. Macrolides can also directly inhibit mucin production.

Aaaaaaaaaand that's all, folks! Next week we'll be getting into talking about the central nervous system!