Over the past few tutorials we have been discussing respiratory pharmacology,
so let’s continue by examining antitussives, which are drugs that halt the coughing reflex. Tussis,
or coughing, is a complicated physiological reflex that can be somewhat simplified by breaking
it down into three connected neurological pathways. These are the afferent pathway,
the central pathway, and the efferent pathway. The afferent pathway is triggered by cough
receptors, also known as rapidly adapting irritant receptors, located in the trachea and pharynx.
These receptors are not well-understood but what is known is that they respond to both mechanical
stretching and chemical irritants. Following stimulation, an increased frequency of action
potentials are conducted via the laryngeal nerves toward the vagus nerve, then arriving
in the medulla of the brain. Unlike the clearly defined region of the medulla responsible for the
mediation of swallowing, we currently aren’t aware of a clearly defined cough center in the medulla.
Following processing in the medulla, the cough reflex enters the efferent pathway via the vagus
nerve where impulses innervate the diaphragm and external intercostal muscles in between the ribs,
causing them to contract and establishing negative pressure around the lungs.
Due to this newly established pressure gradient, air rushes into the lungs via
rapid inhalation to ablate the negative pressure which closes the glottis. Expiratory and abdominal
muscles contract, which increases the pressure inside the lungs. Due to the increased pressure,
the glottis opens and air is rapidly released in the form of a cough. With this process,
the physiological aim is to remove irritants in the lining of the respiratory system.
Causes of cough that may be treated by antitussive drugs are most commonly respiratory infections,
followed by chronic obstructive pulmonary disease and lung cancer. It is worth noting that
antitussive drugs do not treat the cause of the cough, they only offer symptomatic relief for the
cough, and may be used in combination with other drugs that treat the root cause where appropriate.
Now that we understand the basics regarding the mechanism behind coughing,
and the situations where antitussive drugs may be used, we can discuss mechanisms of action
behind antitussive drugs. The most commonly used antitussives are codeine, a mu opioid receptor
agonist, dextromethorphan, a drug with a very promiscuous pharmacodynamic profile,
and benzonatate, better known by its brand name, Tessalon. This drug’s mechanism of
action is through its ability to induce blockage of voltage gated sodium channels.
Because of the ambiguity of the cough reflex in general, it is difficult to be definitive
on the mechanism of action of antitussives, but we will discuss some mechanisms and pharmacology
which are most likely to be contributing to efficacy. Let’s first discuss codeine. Codeine
is a prodrug that requires hepatic metabolism via UDP-Glucuronosyltransferase-2B7 and cytochrome
P450 enzyme CYP2D6, to form the major active metabolites codeine-6-glucuronide and morphine.
Following metabolism, codeine-6-glucuronide and morphine mediate their effects through agonism
of the mu opioid receptor, or μOPR. The mu opioid receptor is a G protein coupled receptor which
signals through Gαi. The receptor is widely expressed in the body, but especially present
on neurons in the GI tract. Here it has a wide range of effects including euphoria,
analgesia, constipation, and respiratory suppression, but most relevant to this
tutorial is cough suppression. The other pharmacodynamic effects we just mentioned
will be expanded upon in future tutorials, namely those about drug abuse and analgesia.
Cough suppression is likely achieved through hyperpolarization of neurons
through activation of potassium ion channels, via the βγ G protein subunit following dissociation
from the Gαi/βγ heterotrimer following receptor activation. This causes an efflux of positively
charged potassium ions. Hyperpolarization of the pre-synaptic neurons in the cough reflex reduces
neurotransmission and inhibits action potential generation in this reflex arc, likely both in the
peripheral and central nervous system in the medulla. To add to the antitussive mechanisms
mediated through the mu opioid receptor, there is likely a role for its coupling to Gαi, and that is
inhibition of adenylate cyclase and subsequent reduction of intracellular cAMP concentration,
but little is understood about the relative contributions of cellular signalling and
antitussive phenotypes. It’s also worth noting that due to the high adverse effect profile of
codeine, including respiratory suppression and addiction liability, prescriptions to treat cough
are rare, and in general are saved for the most extreme cases where the pharmacological benefits
of cough suppression outweigh the risks the side effects present. There is a lot more to be said
about codeine and other opioids, but this is outside the scope of this tutorial. Opioids
will be discussed at great length in future tutorials regarding analgesia and drug abuse.
Dextromethorphan, or DXM, is an over-the-counter antitussive that has a very promiscuous
pharmacological profile. Due to this profile, it is difficult to anticipate what the mechanism of
action for the drug is, with regard to cough suppression, and it is not known what the
main mechanism of cough suppression is. The mechanism is likely related to sigma opioid
receptor agonism, which has the same canonical signaling as codeine since the σOPr is also a Gαi
coupled GPCR. However, its mechanism may also be related to its N-Methyl-D-Aspartate, or NMDA,
receptor antagonism. NMDA is a ligand-gated cation channel that responds endogenously to glutamate.
When DXM is present it inhibits glutamate binding, hence reducing the neuronal depolarization that
an influx of cations would cause, those being sodium ions and to a lesser extent calcium ions.
This overall inhibition of neuronal transmission in the cough centers
could contribute to the antitussive effect seen with DXM. It is worth
mentioning at this stage that like codeine, DXM has abuse potential as a dissociative,
hallucinogen, and sedative, due to its NMDA receptor antagonism. Other NMDA receptor
antagonists will be discussed in future tutorials concerning analgesia and antidepressants.
Finally, we will briefly discuss benzonatate, better known as Tessalon. Unlike DXM and codeine,
benzonatate is a non-narcotic antitussive drug. The mechanism of action for benzonatate
is mediated through its blockage of voltage gated sodium channels.
Voltage gated sodium channels are important in propagating action potentials down neurons,
as we recall from the biopsychology tutorial on neural conduction and synaptic transmission.
Following oral admission and distribution of benzonatate,
the molecule blocks voltage gated sodium channels in the bronchi and alveoli of the airways
reducing action potential frequency output from the afferent cough pathway via the vagal
fibers. Benzonatate is also able to have some impact on voltage gated sodium channels at the
level of the medulla, which is thought to impact central processing of the cough reflex response.
To summarize, we have just explored compounds that inhibit the cough reflex.
Although the mechanism of the cough reflex as well as the mechanism of
action of some of these drugs can be unclear, their effects are reproducible
and highlight an area of active mechanistic and neuro-physiological research.