With a survey of drugs pertaining to inflammation and immune activity complete, it’s time to switch
gears and look at pulmonary activity. There are many drugs that address issues pertaining
to the lungs and breathing, so let’s start by examining a class of drugs called bronchodilators.
These are very important drugs that treat asthma and a variety of chronic obstructive pulmonary
diseases like emphysema and bronchitis, so they are crucial in making sure that millions of
affected people are able to breathe properly. Broncho-dilating drugs, or bronchodilators,
are used in instances of increased airway resistance, which occurs when there is
luminal narrowing of the bronchus and bronchioles. Airway resistance is modelled using a law called
“Poiseuille’s law” published by Jean Léonard Marie Poiseuille in 1838. This law accurately
models the flow of a fluid, such as a liquid or gas, through a tube. This law is generally used
in physics applications concerning fluid dynamics. However, we can also use this law to understand
air flowing through the respiratory system, and for later reference, blood flowing through the
cardiovascular system, which will be relevant in later tutorials discussing antihypertensive drugs.
The law states that: Q = ΔPπr4/8ηl, where Q is the volume flow rate, ΔP is the pressure
gradient along the tube or pipe, r is the radius of the pipe, η is the viscosity of the fluid,
and l is the length of the tube or pipe. The general goal of bronchodilators is to decrease
airway resistance and improve the flow of air in and out of the respiratory system. This is done by
influencing the ‘r’ variable, the luminal radius of the bronchus and bronchioles. From glancing at
the equation, it can be appreciated how much the radius of the pipe influences flow rate,
given that the radius is raised to the fourth power. In other words,
relatively small increases to the radius of these vessels dramatically increase air flow rate, Q.
Bronchodilation is primarily achieved through the relaxation of smooth muscle
cells located in the wall of the bronchus and bronchioles. As the smooth muscle cells relax,
the lumen of the airway increases in radius and resistance is reduced. The luminal radius can be
increased via bronchodilation pharmacologically using three main mechanisms. Those are beta-2
adrenoceptor agonism, muscarinic receptor antagonism, and glucocorticoids to reduce
inflammation. This tutorial will focus on the first two of these, since the
anti-inflammatory action of glucocorticoids was already covered in an earlier tutorial.
Let’s start with beta-2 adrenoceptor agonists. The beta-2 adrenoceptor is part of a general family
of receptors known as adrenoceptors. These receptors are widespread, and play multiple
roles in physiology. They are activated by endogenous agonists adrenaline and noradrenaline.
Although adrenaline and noradrenaline are effective bronchodilators, adrenaline even
being used clinically for anaphylaxis, they are unselective across adrenoceptors. Due to this
lack of selectivity, they can activate both types and all subtypes of the adrenoceptor family. This
leads to promiscuous pharmacology causing multiple side effects as a consequence of activating
the whole family of receptors, rather than one specific target, making this an undesirable course
of action. With one specific pharmacological target, fewer adverse effects will be prevalent.
It’s worth bearing in mind that certain receptors for adrenaline regulate different biological
processes and are drug targets for different purposes. In future tutorials we will discuss
how other adrenoceptors signal, function, and can be modulated for therapeutic purposes,
so expect to see these receptors again when we discuss drugs pertaining to the heart,
synaptic transmission, and other topics. Now, unlike adrenaline and noradrenaline,
bronchodilators in this class are selective for the beta-2 adrenoceptor. The selectivity
arises primarily from the alkyl group next to this nitrogen atom, and also partly from the extension
of the carbon chain on the phenol moiety. This is clear when compared with nonselective alpha/beta
adrenoceptor agonist adrenaline, which lacks these structural features. Resolving the
molecular structure of selective drugs is a very complicated and challenging endeavour that relies
on an experimental strategy known as structural activity relationship studies, or SAR for short.
Essentially, this involves modifying the molecular structure incrementally and testing
the new modified compounds in a functional receptor assay to investigate their affinity
and efficacy at different receptors. With this data in mind, new structures are synthesised and
tested in precisely the same experimental setup. The end goal of this activity is to better
understand which structural aspects of the drug are important for activity and interaction at a
given receptor or receptor group in cases of selectivity screening. These aspects include
functional groups, length of carbon chains between groups, and more. This doesn’t just
apply to bronchodilators but pharmacological science in general, and in a future tutorial
we will go into more detail about this process, but for now the important thing to understand
is that specific structural differences lead to different pharmacology and receptor selectivity,
so this should give us an appreciation of how these new drugs are discovered.
In the instance of the drug salbutamol, this has not only beta selectivity over alpha
adrenoceptors, but also specifically beta-2 over receptors 1 and 3. The R enantiomer is the active
salbutamol structure, having approximately 150 fold increased affinity over the S enantiomer for
the beta-2 receptor. Unfortunately, even though an enantiomerically pure drug has been developed,
called levalbuterol, it is more expensive and difficult to synthesize a pure enantiomer,
so a racemic mixture of salbutamol is used much more commonly. In the next tutorial we will talk
in more detail about how beta-2 adrenoceptor agonism and M3 muscarinic receptor antagonism
results in bronchodilation, so let’s move forward and get a better understanding of this pathway.