Steph’s Note: This week, we here at tl;dr are SUPER excited to introduce the newest member of our team, Dr. Josef Nissan. He’s happily filling the critical care hole in our pharmacy hearts (that many of you may have noticed in our content to date). So y’all better get ready to learn some critical care - starting now! We’re also really excited to continue our pharmacology series. (If you haven’t seen our previous posts on statins, ACE-inhibitors, and thiazide diuretics and you love knowing how medications work, you should check those out too.)

Josef graduated from Ohio Northern University in May of 2020. He completed a PGY1 residency at The MetroHealth System and is currently completing his PGY2 critical care pharmacy residency at Cleveland Clinic Hillcrest Hospital. Upon graduation, Josef will begin his career as the ICU/ED clinical specialist at Indiana University Health. When not watching Derrick Rose be the best basketball player of all time, Josef enjoys spending time with his family, hanging out with friends, and playing basketball.

If you’re looking for a handy guide to carry around with you when you’re covering the ICU/ED, check out our Pocket Guide to Pharmacotherapy Management of Acute Medical Emergencies. It covers vasopressors and a bunch of other essential critical care topics.

Ahh yes. Vasopressors. The topic that every pharmacy student tries to avoid until your ICU/ED rotation sneaks up on you, and you have no choice but to acknowledge its presence. Well, hopefully by the end of this article (if you make it to the end…), you'll learn that vasopressors really aren't so bad after all!

Alright, let's start. To get a better understanding of how vasopressors work, we need to dig a little bit deeper into the pathophysiology of the peripheral nervous system. Throwing it back to physiology 101, the peripheral nervous system is broken down into somatic and autonomic divisions. The somatic nervous system controls our voluntary skeletal muscle movement. This is how we walk, run, chew, type articles, etc. You get the picture.

On the other hand, the autonomic nervous system controls involuntary movements, such as our heart beat, breathing, digestive smooth muscle (aka pooping), coughing, pupil constriction/dilation, and so on. Why is this important?

It's important because our autonomic nervous system is what controls our sympathetic (aka "fight or flight") and parasympathetic (aka "rest and digest") responses. And where do vasopressors work? You guessed it, on the sympathetic nervous system!

Now that we’ve reviewed the basics of the sympathetic nervous system, let's talk about the specific receptors that the catecholamines agonize during a sympathetic response (“fight or flight”): primarily Alpha-1, Beta-1, Beta-2, Dopamine (DA), Vasopressin-1 (V1), and Vasopressin-2 (V2). These are the common receptors that our endogenous neurotransmitters bind to during a "fight or flight" reaction.

Imagine being punched in the face by Mike Tyson… Yowsers. (Image)

For example, if Mike Tyson threatened to punch me in the face, then my sympathetic nervous system is going to activate and release a bunch of endogenous neurotransmitters, including epinephrine, norepinephrine, and dopamine to help with my "fight or flight" reaction.

Let’s be honest. Probably flight because there's no way I'm fighting Mike Tyson.

But anyway, yes, these endogenous neurotransmitters (aka catecholamines) are the compounds that we have synthetically created as drugs to help treat patients with certain shock syndromes. These are our vasopressors!!!

So, how do vasopressors work? Before we go there, let's go back and review where our catecholamine receptors are primarily found in our bodies.

Catecholamine Receptors and the Effects of Agonism

Alpha-1: blood vessels
Beta-1: heart
Beta-2: lungs and blood vessels
- To keep your beta receptors straight, remember we have ONE heart and TWO lungs!
DA: renal smooth muscle
V1: blood vessels
V2: renal collecting ducts

Now that we know where these receptors are located, let’s talk about their systemic effects under agonist conditions, in the setting of preserving my lovely life from Mike Tyson:

Alpha-1 agonist: Vasoconstriction
- Back to the Mike Tyson wanting to punch me in the face scenario... Seeing Mike Tyson getting ready to punch me is going to activate my sympathetic nervous system to trigger my fight or flight response. As a result, I’m going to release endogenous catecholamines, which will agonize alpha-1 receptors. This leads to vasoconstriction and an increase in my blood pressure. Increased blood pressure means I can get more blood to my vital organs such as my heart, lungs, brain, etc. More blood flow to my organs means I can run away from Mike Tyson.
Beta-1 agonist: Increase in heart rate (chronotropy) and heart contractility force (inotropy)
- Increasing my heart rate and contractility increases my cardiac output. This in turn provides my vital organs with more blood and nutrients so that I can run away from Mike Tyson.
Beta-2 agonist: Bronchodilation and vasodilation
- Dilating my lungs allows me to get more oxygen into my bloodstream for my tissues to use. More oxygen means my muscles have more energy to continue to help me to run away from Mike Tyson.
V1 agonist: Vasoconstriction
- Same as the alpha-1 agonist effects noted above. Increased vasoconstriction means higher blood pressure, leading to better tissue perfusion.
V2 agonist: Increased water reabsorption from the kidneys
- Increasing water reabsorption from my kidneys increases my blood volume, meaning higher blood pressure and again, better tissue perfusion.
DA agonist: Renal vasodilation, leading to potential nephroprotective properties (ehhhh, not great literature supporting this but whatever)
- There’s not really a benefit to protecting my kidneys when it comes to fleeing from Mike Tyson, but you know, it’s good to try to protect them for future endeavors after I survive this harrowing encounter.

Phew. That’s a lot to take in. But if you know the pathophysiology behind each receptor, then understanding vasopressors is a breeze. Speaking of vasopressors, the ones we’re going to focus on today are epinephrine, norepinephrine, phenylephrine, vasopressin, and dopamine. (To be totally fair and honest, there is also that one oral vasopressor that no one ever likes to acknowledge: midodrine. There are also angiotensin II and ephedrine, but since those aren’t really widely used, we’re sticking to the meat and potatoes today.)

SooOOooOOO shall we dig deeper into each vasopressor? I think we shall.

BTW - This is a lot of information. We’ve got a downloadable (and printer-friendly) PDF of this article that you can download here. It’s great for offline viewing and for writing notes.

Vasopressor #1: Epinephrine

Good ol’ epi. Probably the one you have heard of the most - and usually the one most dramatically called for on TV. (“I need an amp of epi, STAT!” Hollywood loves that one.) Anyway, let’s review.

Epinephrine equally agonizes the alpha-1, beta-1, and beta-2 receptors, which leads to peripheral vasoconstriction, increased inotropy and chronotropy, and bronchodilation, respectively. These effects are what make it so widely used in various emergency situations, including during cardiac arrest, anaphylactic shock, distributive shock, cardiogenic shock, and as an adjunct agent for septic shock.

As an IV infusion, epinephrine is generally dosed around 2-10 mcg/minute and can be rapidly titrated to the necessary maintenance rate. Even though drug references note higher maximum rates (even up to 40 or 80 mcg/minute!!), usually you should consider an additional or alternative pressor if you’re not getting the desired effect by 10 mcg/minute. Rapid titration every 2-3 minutes is possible because of epinephrine’s immediate onset of action and short, 5 minute duration of effect.

Check out how the catecholamines are inter-related here. (Image)

PAY ATTENTION!!! Each institution handles infusion rates differently. Here we are talking in mcg/minute, but some places do still discuss vasopressor rates in terms of weight-based dosing, aka mcg/kg/minute. Which, as you can imagine, makes the rates drastically different. Make sure you’re familiar with how your institution handles these so that you are talking apples to apples.

So what’s the downside to this staple catecholamine?

Think about it. Anytime you agonize receptors on the heart that impact rate and contractility, including the beta-1 receptors agonized by epinephrine, there’s an increased risk of tachyarrhythmias. Given its MOA, epinephrine does carry the potential of overloading the heart and causing a tachyarrhythmia. Monitoring heart rate and blood pressure is essential, as well as inspecting the extremities for any signs of necrosis (from peripheral vasoconstriction).

Vasopressor #2: Norepinephrine

Ah yes. My personal favorite. Let’s review.

Norepinephrine primarily agonizes the alpha-1 receptor with some beta-1 and beta-2 agonism - but to a much lesser degree than epinephrine. Therefore, you will primarily see peripheral vasoconstriction, but it is also possible to see an increase in inotropy, chronotropy, and bronchodilation. (Again, to a much lesser extent than epinephrine.)

This is typically the FIRST-LINE vasopressor for ALL shock types. Yes, it’s that awesome :) Starting infusion rates are about 2 mcg/minute with usual maximums around 30 mcg/minute. Like epinephrine, drug references allow for much higher infusion rates (in the 80 mcg/minute range), but you should probably be thinking of alternatives if you’re not where you need to be by 30 mcg/minute. Also like epinephrine, norepinephrine’s onset of action is immediate, and its duration of effect is very short, only about 1-2 minutes. This is why it’s also a rapidly titratable infusion.

Norepi’s main adverse effect is development of a tachyarrhythmia. However, given the relatively weaker beta-1 agonism, it is LESS likely to induce a tachyarrhythmia when compared to epinephrine. Win.

The not-so-winning part? Acidosis can diminish the effects of norepinephrine, and guess what kind of serum pH many non-perfusing/arrest patients experience when they are also in need of vasopressor support? You got it - acidosis. Bummer. But it’s still an awesome and widely used supportive med. Just don’t forget to listen for the ABG results, specifically the pH, and to consider an alternative if escalating infusion rates aren’t producing the desired effects.

Vasopressor #3: Phenylephrine

Another lovely vasopressor. WHY do they all have to sound so similar?!? Let’s review and figure out what makes this one distinct.

Phenylephrine is a PURE alpha-1 agonist, leading to peripheral vasoconstriction and increases in the mean arterial pressure (MAP). That’s right, this one is selective, unlike the previous pressors we’ve reviewed.

Given it ONLY has alpha-1 effects with no beta-1 or beta-2 effects, phenylephrine is a great option to use for the treatment of hypotension in the setting of tachycardia (with or without other vasopressors). It also is usually the vasopressor of choice for neurogenic shock.

Phenylephrine infusions usually start around 40-160 mcg/minute and range up to 300-400 mcg/minute for maintenance. Like the previous options, onset of action is immediate (do you see a recurring theme here?). But really, think about it. Would you want a vasopressor that takes 24 hours for onset of action?

(“Um, please hold this code for a while, could you? We need to give this infusion time to reach steady state.” Meanwhile, everyone is staring at you, the pharmacist, wondering why the BP is still so low. Wouldn’t that be TERRIBAD…).

Phenylephrine’s duration of action is 15-30 minutes (that’s right, its duration of action is much longer than epinephrine and norepinephrine!). Its adverse effects are also slightly different than the previously discussed catecholamines, and they include reflex bradycardia and tachyphylaxis. Tachyphylaxis means that your body will begin to become resistant and develop tolerance if it is exposed to phenylephrine for too long, leading to loss of effect.

Vasopressor #4: Vasopressin

Well that’s just a confusing header, now isn’t it? Looks like a jumble of "“vasopress—” with different endings. They can’t just make it easy, can they…

Vasopressin is a V1 and V2 agonist, leading to peripheral vasoconstriction and water reabsorption. It is typically only used as an ADJUNCT vasopressor to norepinephrine in the setting of refractory shock (e.g., septic shock) .

For the love of God, please don’t ever use it as the initial or sole vasopressor. Thank you.

Vasopressin doses often look like 0.01-0.04 units/minute. Unlike the other vasopressors, this one is NOT titratable. This is due to its relatively longer onset of action (15-20 minutes) and duration of action (30-60 minutes). So pick a dose and stick to it. And also note that this one is dosed in UNITS/minute, not MCG/minute. Very different.

Unfortunately, vasopressin can reduce cardiac output and should therefore be avoided in cardiogenic and hemorrhagic shock. On the plus side, it maintains its effects even in acidotic conditions.

Vasopressor #5: Dopamine

First, let’s get something straight. Dopamine is not the same as dobutamine. Yes, this is incredibly confusing and an unfortunate SALAD drug moment. But dobutamine is an inotrope, not a vasopressor.

Ok, moving on.

I know what you’re thinking. How is dopamine a vasopressor? Doesn’t dopamine have something to do with Parkinson's disease or Restless Legs Syndrome? Maybe schizophrenia? Something like that?

Well, yes… it does when it crosses the blood brain barrier and reaches the central nervous system (CNS). However, an IV dopamine infusion does NOT cross the blood brain barrier, and therefore you see no CNS effects. It remains in the peripheral system where it agonizes multiple receptors providing the vasopressor effects. Let’s review.

Dopamine’s mechanism of action is tricky. Why? Because the mechanism of action is dose-dependent, meaning that it acts on different receptors depending on the dose that is infused. Check this out:

○ 0.5-2 mcg/kg/min: primarily DA agonism, leading to potential nephroprotective effects

○ 5-10 mcg/kg/min: primarily beta-1 agonism, leading to increased chronotropy and inotropy

○ 10-20 mcg/kg/min: primarily alpha-1 agonism, leading to increased peripheral vasoconstriction and mean arterial pressure (MAP)

Dopamine is typically one of the last-line adjunct options when all other vasopressors have failed and the patient continues to experience refractory hypotension. Like norepinephrine, dopamine’s effects are diminished in an acidotic environment, which can make its utility limited in certain types or degrees of shock. As you might expect from the receptors agonized, it can lead to tachyarrhythmias. Other adverse effects include pulmonary congestion and peripheral necrosis (at higher infusion rates from the vasoconstriction).

The tl;dr of Vasopressors

Now was that so bad? Come on, it wasn’t terrible. As long as you understand the pathophysiology of the sympathetic nervous system and where its receptors are located within the body, then vasopressors are easy to remember!

In case you didn’t take the time to read through the whole post and just want the tl;dr version of vasopressors, see below. You’re welcome.

And don’t forget to check out our Pocket Guide to Pharmacotherapy Management of Acute Medical Emergencies. It covers vasopressors and a bunch of other essential critical care topics.

Pharmacology 101: Vasopressors