The Neuro-Endocrine Pathway
The release of epinephrine and norepinephrine are regulated primarily by the nervous system. Epinephrine and norepinephrine are hormones, which means that once released they end up in the bloodstream and reach target organs with the appropriate receptors, they will carry out their functions. This is in contrast to cells being activated directly by nervous system control, where nerves connect or are close to the effector cells and release their neurotransmitters to produce effects in a localized area. Epinephrine and norepinephrine release are examples of a neuro-endocrine pathway.
How do individual cells regulate binding of epinephrine and norepinephrine?
An important concept to understand is regardless of how much endogenous (from within) epinephrine or norepinephrine is released or exogenous (from outside) vasopressor we administer, the body still has ways of regulating its response. One of the primary ways this occurs is by regulating the number of available receptors on target cells.
Epinephrine and norepinephrine bind receptors such as alpha-1 and beta-1. These receptors are in a class of receptors called G-protein coupled receptors (which are discussed later.. but yes they are gangsta). Individual cells can regulate how many of these receptors are activated or how many are available to be bound in an effort to control its response.
This is accomplished primarily in two ways, either existing receptors in the membrane are phosphorylated (a phosphate group is attached to a specific part of the molecule in an effort to inactivate it), or the messenger RNA (the production template for new receptors) that is used to make new receptors is inactivated by phosphorylation as well.
The Binding of a Receptor
Now that we have epinephrine and norepinephrine circulating, let’s talk about how it binds to cells and carries out its function. This occurs when it reaches a cell that is expressing the appropriate receptors that it can bind. For example, a cell expressing alpha-1 or beta-1 receptors is likely to bind both of these drugs. We must then answer the questions, what happens when the drug binds and why do some receptors bind one drug or molecule better than another?
Let’s first define affinity, specificity, and selectivity.
Affinity – refers to how avidly a drug binds a specific receptor
Selectivity – the ability of a drug to produce a specific effect related to its structural specificity and binding of binding a specific receptor
Specificity – the type of mechanism the drug carries out
You can further familiarize yourself with these terms here. Although a veterinary article, these definitions and explanations are very clear and understandable.
Remember those functional groups and the molecular structure we talked about earlier? This is where they become important. The receptor structure and how it interacts with the molecule it is binding (a ligand) is often dependent on which functional groups are present and how they fit into the site on the receptor. This is why you may here about drugs like phenylephrine being a pure alpha-1 agonist because it has high affinity for the alpha-1 receptor, but a drug like norepinephrine binds well to alpha-1 receptors but also has some effects at the beta-1 receptors. If you are unfamiliar with the different effects of the subtypes of alpha- and beta-adrenergic receptors I suggest that you look into this to reinforce your knowledge.
What Happens on the Outside of the Cell
Receptors exist on the outside of cells that bind these drugs/hormones and once the receptors are activated, they carry out functions inside the cell that result in the actions we know these drugs to perform. For example, a beta-2 agonist causes bronchodilation. There is a cellular process to get to that point that we will discuss.
G-Protein coupled receptors (GPCRs) are proteins that span the lipid bilayer membrane of cells as pictured below. The proteins vary based on the type of the receptor which allows them to exert their specific characteristics and be selective about what they bind and have different binding affinity.
Different agents will bind different GPCRs based on their subtype. Remember that the adrenergic subtypes we care about with vasopressors are alpha-1, alpha-2, beta-1, and beta-2. These are further divided into certain G-Protein subtypes that will in turn determine what action is taken inside the cell. Alpha-1 receptors are Gq receptors, Alpha-2 receptors are Gi receptors, and beta receptors are all Gs receptors.
What Happens Inside the Cell
Once bound, each individual receptor triggers a cascade within the cell that ultimately result in the various receptor functions being performed. This is based on the G-protein subtypes above. Let’s look at each individually.
Alpha-1 – Gq Receptors
Once bound, Gq receptors activate a molecule called phospholipase C, this results in an increase in calcium concentration within the cell and this rise in intracellular calcium has a stimulatory function. In alpha-1 cells, this ultimately results in vasoconstriction.
Alpha-2 – Gi Receptors
When you see “i” think of it as an inhibitor. When alpha-2 receptors are bound, the intracellular molecule adenylate cyclase is inhibited, this decreases the concentration of cyclic adenosine monophosphate (cAMP) and has an overall inhibitory function on the cell.
Beta-1 and Beta-2 – Gs Receptors
Once bound, Gs receptors activate the molecule adenylate cyclase. This increases the intracellular cAMP and ultimately stimulates the cell to perform its effector function. In the case of vasopressors beta-1 receptors are specifically targeted to increase heart rate. When we use agents that target beta-2 receptors we are often looking for bronchodilation.
Do pH and Temperature Matter?
In the critical care environment one of the factors we have to deal with is patients who are often in less than optimal physiologic states and have disrupted homeostasis. This is the part of critical care that makes it so interesting and these patients so challenging but rewarding to manage because we must overcome and/or manage their altered physiology in the midst of taking care of their illness. Many of the enzymes and substrates involved in the synthesis, binding, and activation of the effects we are looking for occur best at physiologic pH (7.35-7.45). Each of the specific molecules has a pH in which it works optimally at. Remember those functional groups again? The -OH and the NH2we talked about earlier? They have their own specific acid base characteristics. For example, -OH is a basic functional group. In acidic environments it often reacts with the excess hydrogen. Reactions are also carried out optimally at certain temperatures and like most things in the body, function best within a specific range. Therefore, it is important to consider that our critical care patients are often outside of these “optimum” ranges and that may alter the effectiveness of the drugs we administer. In looking at the whole patient, we often have to manage things like acidosis to make our other treatments more effective.
What happens to our vasopressors when our body is done with them?
There are many different metabolic mechanisms in the body, many people are most aware of the cytochrome P450 enzyme system in the liver that is responsible for a lot of our drug metabolism. All of our catecholamines including epinephrine, norepinephrine, and dopamine are broken down primarily using catechol-O-methyl transferase (COMT) or monoamine oxidase (MAO). Remember that both of these are enzymes because they contain -ase and that they either add or remove functional groups. This results in the creation of metabolites that do not have the same affinity for the target receptors as they once did. When we look at this metabolism, it is a great way to tie together everything you just learned about affinity, specificity, molecular changes, enzymes, and more.
There is no need to remember the specifics, this is just to reinforce how much you just learned and make sure you see the whole picture!
One important point to consider though is MAO inhibitors are still in use for depression and COMT inhibitors are sometimes used in Parkinson’s disease patients and this can impair the metabolism of the vasopressors we give, just one more thing to consider in the management of your critically ill patient.
A Note Regarding Science
The many areas of science including biology, chemistry, biochemistry, physiology, and others are vast and the depth of scientific understanding is immense in this modern era. Considering that, only so much can be covered in one article. Sometimes a deeper understanding of these concepts requires more intense study or explanation than can feasibly presented in this format or context. It is my hope that you will seek out further information from reliable sources to help answer your questions regarding these topics.
Now that you understand the science, go back to treating your patients with some additional information to improve your clinical care!
Tom Latosek, MS, NRP, CCP-C
Tom is a practicing paramedic and EMS educator who is interested in EMS research, and advancing the profession of EMS through education. Tom has practiced in a variety of EMS clinical settings and teaches a variety of courses for a healthcare education company. Tom holds an MS in neuroscience and a bachelor’s degree in biology and psychology and is currently a first-year medical student.