phenylephrine mechanism of action

[epidural man]

Does phenylephrine primarily constrict arterial side, or venous side?

It depends on your source -

My Cardiac Anesthesia (albeit third edition 2003) says it is mostly arterial.

OpenAnesthesia keywords claims it is mostly venous constriction (references this article
Thiele, Robert H., Edward C. Nemergut, and Carl Lynch III. "The clinical implications of isolated alpha1 adrenergic stimulation." Anesthesia & Analgesia 113.2 (2011): 297-304.)

I had always thought it was venous, but then two residents told me it was arterial and Hensley's book (as mentioned above) agrees with this.

So....

Does anyone REALLY know the answer?

It probably doesn't matter - but if I am going to pimp residents, I probably should be correct.

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[deleted171991]

If it were venous constriction, it would not induce reflex bradycardia, but (increased preload -> Bainbridge reflex ->) tachycardia.

 

[cchoukal]

Or, if venous, as I've heard, an auto-transfusion of splanchnic, unstressed venous blood might increase the stroke volume, which would lower the heart rate.

 

[Planktonmd]

It is an alpha 1 agonist, so it should work where smooth muscles exist: Arteries, arterioles, and to a much lesser degree veins.
But I guess the correct answer would be it works both on arteries and veins but more predominantly on arteries.

 

[GravelRider]

It increases afterload. That's more important to understand than the other minutiae.

 

[pgg]

I thought this was a trick question when I read the OP, never really thought about it or questioned that it was arteriolar constriction.

I can't say I've ever noticed a more full heart on TEE after giving phenylephrine.

And it still works, though certainly not as well, in hypovolemic patients.

It's not the drug of choice for hypotensive patients with AS because it fills the right side of the heart.

 

[deleted171991]

It's not the drug of choice for hypotensive patients with AS because it fills the right side of the heart.

Pardon? So what's your drug of choice?

 

[Robotic Wis-Hipple]

But it could explain why it's the drug of choice in HOCM as well....

I think the point here is that pharmacology is extremely complex in vivo, we simplify it into the expected effects of a given drug based on the predominant action as dictated by the proportion/prevalence of particular receptor subtypes. As another closely related example, there are papers that show alpha 1 receptors present in the myocardium which stimulates increased inotropy yet nobody is pushing phenylephrine with that aim.

Phenylephrine causes arterial vasoconstriction with a resultant increase in SVR as the predominant action.

 

[Robotic Wis-Hipple]

Pardon? So what's your drug of choice?

He's saying it is the drug of choice in AS, but not because it increases preload.

 

[deleted171991]

He's saying it is the drug of choice in AS, but not because it increases preload.

Thanks. I misunderstood at first.

 

[Ezekiel2517]

Propofol's arch nemesis

 

[vector2]

both, but i think venous predominates when the pt is euvolemic. think about the logic of asking for a neo bump when doing a difficult a-line...it would make no sense if it was a pure arteriolar constrictor. the bump works because autotransfusion leads to increased preload which leads to increased contractility and stroke volume, in addition to increased arteriolar tone which should increase the reflectance. the final effect is a usually dilated artery secondary to a larger arterial blood volume that feels like it's pulsating harder

 

[deleted171991]

I think the point here is that pharmacology is extremely complex in vivo, we simplify it into the expected effects of a given drug based on the predominant action as dictated by the proportion/prevalence of particular receptor subtypes. As another closely related example, there are papers that show alpha 1 receptors present in the myocardium which stimulates increased inotropy yet nobody is pushing phenylephrine with that aim.

That would explain why phenylephrine doesn't decrease cardiac output except in really bad hearts (opposite of what most of the books say).

 

[WholeLottaGame7]

Also look at what happens to your SVV after you bolus phenylephrine or start an infusion: almost always goes down. Doesn't make sense if it were purely arterial.

 

[deleted171991]

both, but i think venous predominates when the pt is euvolemic. think about the logic of asking for a neo bump when doing a difficult a-line...it would make no sense if it was a pure arteriolar constrictor. the bump works because autotransfusion leads to increased preload which leads to increased contractility and stroke volume, in addition to increased arteriolar tone which should increase the reflectance. the final effect is a usually dilated artery secondary to a larger arterial blood volume that feels like it's pulsating harder

Why wouldn't it work with pure arteriolar constriction? Increased arteriolar tone means increased pressure proximal to the increased resistance, e.g. in the radial artery.

 

[GravelRider]

both, but i think venous predominates when the pt is euvolemic. think about the logic of asking for a neo bump when doing a difficult a-line...it would make no sense if it was a pure arteriolar constrictor. the bump works because autotransfusion leads to increased preload which leads to increased contractility and stroke volume, in addition to increased arteriolar tone which should increase the reflectance. the final effect is a usually dilated artery secondary to a larger arterial blood volume that feels like it's pulsating harder

Phenylephrine increasing contractility and stroke volume? I don't think so. That "neo bump" is purely from an increase in blood pressure. The phenylephrine doesn't magically turn the arteries into lead pipes that you wouldn't be able to feel a pulse through.

I prefer a small dose of ephedrine for a tricky a-line.

 

[GravelRider]

Also look at what happens to your SVV after you bolus phenylephrine or start an infusion: almost always goes down. Doesn't make sense if it were purely arterial.

Those things are inaccurate when a patient is on pressors for this very reason. They measure stroke volume variation...in the the artery. You take away that variation when you use a pressor.

 

[sevoflurane]

Good discussion and obviously a source of debate.

I come from a school of thought where it depends on the volume status of the patient:

In hypovolemic patients and at high doses, phenylephrine is mostly arterial as there is no reservoir in the venous capacitance vessels.

In patients who are euvolemic and have received a neuraxial anesthetic or are in septic shock with decreased SVR or those who have been overdosed with a venodilator, phenylephrine at normal doses has both arteriolar and venous constriction with both an increase in afterload and preload.

In these patients, as alpha-1 receptors in the venous capacitance vessels get hit with phenylephrine they get squeezed down on and have an immediate push into the venous circulation and consequently into the right heart. Still, at this piont, arteriolar vasoconstriction is dominant, but with a venous return component.

 

[vector2]

Phenylephrine increasing contractility and stroke volume? I don't think so. That "neo bump" is purely from an increase in blood pressure. The phenylephrine doesn't magically turn the arteries into lead pipes that you wouldn't be able to feel a pulse through.

I prefer a small dose of ephedrine for a tricky a-line.

In a difficult a-line situation when you have a low blood pressure after induction of general anesthesia with systemic vasodilation, you've essentially made the heart preload dependent. When you administer phenylephrine with a preload dependent heart, you get an increase in MAP, CO, and IVC flow (autotransfusion). Per starling mechanism, increased preload should lead to associated increase in contractility and stroke volume

https://www.ncbi.nlm.nih.gov/pubmed/22556399

arteriolar

Pure arteriolar vasoconstriction should lead to increased resistance and pressure, but a narrower lumen. The pulse would be stronger, but I think it would be self-defeating since you have a smaller target to hit. Venoconstriction and autotransfusion helps maintain arteriolar bloodflow, so you should be getting a high pressure with a maintained lumen diameter.

 

[Planktonmd]

In a difficult a-line situation when you have a low blood pressure after induction of general anesthesia with systemic vasodilation, you've essentially made the heart preload dependent. When you administer phenylephrine to a preload dependent heart, you get an increase in MAP, CO, and IVC flow (autotransfusion). Per starling mechanism, increased preload should lead to associated increase in contractility and stroke volume

https://www.ncbi.nlm.nih.gov/pubmed/22556399



Pure arteriolar vasoconstriction should lead to increased resistance and pressure, but a narrower lumen. The pulse would be stronger, but I think it would be self-defeating since you have a smaller target to hit. Venoconstriction and autotransfusion helps maintain arteriolar bloodflow, so you should be getting a high pressure with a maintained lumen diameter.

Could the inotrope effect be explained by improved coronary perfusion secondary to improved BP?

 

[vector2]

Could the inotrope effect be explained by improved coronary perfusion secondary to improved BP?

In the absence of significant CAD, LVH, valve dz, and if the low MAP is still in the heart's autoregulatory range, I doubt it.

 

[GravelRider]

In a difficult a-line situation when you have a low blood pressure after induction of general anesthesia with systemic vasodilation, you've essentially made the heart preload dependent. When you administer phenylephrine with a preload dependent heart, you get an increase in MAP, CO, and IVC flow (autotransfusion). Per starling mechanism, increased preload should lead to associated increase in contractility and stroke volume

https://www.ncbi.nlm.nih.gov/pubmed/22556399



Pure arteriolar vasoconstriction should lead to increased resistance and pressure, but a narrower lumen. The pulse would be stronger, but I think it would be self-defeating since you have a smaller target to hit. Venoconstriction and autotransfusion helps maintain arteriolar bloodflow, so you should be getting a high pressure with a maintained lumen diameter.

But is this a direct effect of phenylephrine or more of a downstream effect of increased MAP?

 

[vector2]

But is this a direct effect of phenylephrine or more of a downstream effect of increased MAP?

Which effect? CO doesn't augment with phenylephrine when the heart isn't in a preload dependent state. There's not really a better alternative explanation for increased MAP other than venous autotransfusion leading to increased preload leading to increased CO (in addition to some increased arteriolar tone/SVR).

More simply said, if you look at MAP = CO X SVR . In a full heart that's euvolemic, SVR goes up and CO goes down when you administer phenylephrine. In an empty heart with adequate venous volume reserve, both CO and SVR go up.

 

[GravelRider]

Which effect? CO doesn't augment with phenylephrine when the heart isn't in a preload dependent state. There's not really a better alternative explanation for increased MAP other than venous autotransfusion leading to increased preload leading to increased CO (in addition to some increased arteriolar tone/SVR).

More simply said, if you look at MAP = CO X SVR . In a full heart that's euvolemic, SVR goes up and CO goes down when you administer phenylephrine. In an empty heart with adequate venous volume reserve, both CO and SVR go up.

Increasing afterload increases LVEDP (i.e. increases preload). You are correct that an increase in preload activates the Frank-Starling mechanism in order to compensate for the reduction in stroke volume caused by the increase in afterload. Phenylephrine primarily works on afterload (the most important takeaway point). Everything else is just a downstream affect of that increased afterload.

 

[vector2]

Increasing afterload increases LVEDP (i.e. increases preload).

The mechanism you describe is correct for the scenario of a preload independent heart, but I don't think the takeaway should solely be that phenylephrine = afterload since the real effect seems to be more nuanced (see Sevo's post above). The vast majority of times we administer phenylephrine are to patients under general anesthesia who are vasodilated, preload dependent, and who have had their baroreceptor reflexes blunted. In addition to increasing arteriolar tone, phenylephrine acts like a quick fluid bolus to these people assuming they are not hypovolemic and still have venous reserve. If it were pure afterload increase (acute afterload increase -> acute LVEDP rise -> acute decrease diastolic filling), you'd essentially cause a hypotensive s/p induction patient to arrest since CO would drop to 0.

 

[GravelRider]

The mechanism you describe is correct for the scenario of a preload independent heart, but I don't think the takeaway should solely be that phenylephrine = afterload since the real effect seems to be more nuanced (see Sevo's post above). The vast majority of times we administer phenylephrine are to patients under general anesthesia who are vasodilated, preload dependent, and who have had their baroreceptor reflexes blunted. In addition to increasing arteriolar tone, phenylephrine acts like a quick fluid bolus to these people assuming they are not hypovolemic and still have venous reserve. If it were pure afterload increase (acute afterload increase -> acute LVEDP rise -> acute decrease diastolic filling), you'd essentially cause a hypotensive s/p induction patient to arrest since CO would drop to 0.

So now Frank-Starling doesn't exist? The situation you speak of here is a decompensated heart failure where the patient has fallen off the Frank-Starling curve and you need an inotrope.

I think you give phenylephrine too much credit. It is not a smart drug that differentiates between hypovolemia and euvolemia and changes it's mechanism of action accordingly. Rather, the effects you speak of are downstream effects that are measurable in the hypovolemic patient.

Let's agree to disagree. I've made my point. Phenylephrine causes an increased afterload. Every other nuanced thing you speak of is the result of increasing afterload on the physiology of the heart/vascular system.

 

[deleted171991]

The mechanism you describe is correct for the scenario of a preload independent heart, but I don't think the takeaway should solely be that phenylephrine = afterload since the real effect seems to be more nuanced (see Sevo's post above). The vast majority of times we administer phenylephrine are to patients under general anesthesia who are vasodilated, preload dependent, and who have had their baroreceptor reflexes blunted. In addition to increasing arteriolar tone, phenylephrine acts like a quick fluid bolus to these people assuming they are not hypovolemic and still have venous reserve. If it were pure afterload increase (acute afterload increase -> acute LVEDP rise -> acute decrease diastolic filling), you'd essentially cause a hypotensive s/p induction patient to arrest since CO would drop to 0.

The increase in aortic pressures also improves coronary perfusion, i.e. contractility. I don't think there is a significant venous component here either.

 

[deleted171991]

Which effect? CO doesn't augment with phenylephrine when the heart isn't in a preload dependent state. There's not really a better alternative explanation for increased MAP other than venous autotransfusion leading to increased preload leading to increased CO (in addition to some increased arteriolar tone/SVR).

More simply said, if you look at MAP = CO X SVR . In a full heart that's euvolemic, SVR goes up and CO goes down when you administer phenylephrine. In an empty heart with adequate venous volume reserve, both CO and SVR go up.

MAP = HR x SV x SVR.

SV rarely drops significantly with phenylephrine. HR may drop because of reflex bradycardia. Overall CO stays the same, or drops mostly because of bradycardia (if any), but still less than the increase in SVR. So MAP goes up. End-effect on critical organs depends on MAP, not CO. What's so complicated here?

 

[vector2]

So now Frank-Starling doesn't exist? The situation you speak of here is a decompensated heart failure where the patient has fallen off the Frank-Starling curve and you need an inotrope.

I think you give phenylephrine too much credit. It is not a smart drug that differentiates between hypovolemia and euvolemia and changes it's mechanism of action accordingly. Rather, the effects you speak of are downstream effects that are measurable in the hypovolemic patient.

Let's agree to disagree. I've made my point. Phenylephrine causes an increased afterload. Every other nuanced thing you speak of is the result of increasing afterload on the physiology of the heart/vascular system.

Increases in LVEDP do not cause increased preload. Increased end diastolic pressure actually impedes diastolic filling. Here is a picture

If you've had longstanding increased LVEDP from something like AI where eventually your LV becomes eccentrically hypertrophied, then yea, you will finally have some increased preload.

And I disagree that phenylephrine can't differentiate between hypovolemia and euvolemia. It's a classic CRNA occurrence when they continue giving phenylephrine bumps to hypovolemic pts...BP goes up for 30 seconds and immediately drops again. If the patient is euvolemic with venous reserve, BP stays elevated for dozens of minutes because you've autotransfused them.

 

[vector2]

The increase in aortic pressures also improves coronary perfusion, i.e. contractility. I don't think there is a significant venous component here either.

Under a volatile anesthetic with vasodilation, your coronary bloodflow is already maximal and your myocardial oxygen demand is minimal since you're typically not tachycardic due to diminished baroceptor reflexes. Increasing your DBP won't improve myocardial performance unless your MAP was critically low (like less than 50), or you have severe LVH, CAD, AS etc

MAP = HR x SV x SVR.

SV rarely drops significantly with phenylephrine. HR may drop because of reflex bradycardia. Overall CO stays the same, or drops mostly because of bradycardia (if any), but still less than the increase in SVR. So MAP goes up. End-effect on critical organs depends on MAP, not CO. What's so complicated here?

My entire point is that phenylephrine's effects vary based on the volume status of the patient. Yes, it's a pig study (https://www.ncbi.nlm.nih.gov/pubmed/22556399) but preload (IVC flow), stroke volume, and CO increase when the heart is preload dependent. When preload indepdent, MAP may still go up but CO goes down.

I think I've made this point enough times, up to you all whether you think it's a believable mechanism.

 

[epidural man]

So now Frank-Starling doesn't exist? The situation you speak of here is a decompensated heart failure where the patient has fallen off the Frank-Starling curve and you need an inotrope.

I think you give phenylephrine too much credit. It is not a smart drug that differentiates between hypovolemia and euvolemia and changes it's mechanism of action accordingly. Rather, the effects you speak of are downstream effects that are measurable in the hypovolemic patient.

Let's agree to disagree. I've made my point. Phenylephrine causes an increased afterload. Every other nuanced thing you speak of is the result of increasing afterload on the physiology of the heart/vascular system.

GravelRider (and others),

Why are you so sure that it is mostly an increased afterload? Where is this coming from (and by that I mean...is it updated articles?) Because it seems like anything published more recent points more to the venous side, and old teachings are more towards the arterial side.

 

[deleted171991]

GravelRider (and others),

Why are you so sure that it is mostly an increased afterload? Where is this coming from (and by that I mean...is it updated articles?) Because it seems like anything published more recent points more to the venous side, and old teachings are more towards the arterial side.

I wonder if the cardiac guys see bumps in CVP after giving phenylephrine (not that the blasted CVP corelates with a lot, but one would expect it to bump, at least initially, from increased venous return).

 

[GravelRider]

I wonder if the cardiac guys see bumps in CVP after giving phenylephrine (not that the blasted CVP corelates with a lot, but one would expect it to bump, at least initially, from increased venous return).

Of course you are going to see a "bump" in CVP with a bolus of phenylephrine, but keep a hypovolemic patient on phenylephrine long enough and the preload will decrease. This increased CVP is a transient effect. The most important effect of phenylephrine is on afterload.

 

[GravelRider]

GravelRider (and others),

Why are you so sure that it is mostly an increased afterload? Where is this coming from (and by that I mean...is it updated articles?) Because it seems like anything published more recent points more to the venous side, and old teachings are more towards the arterial side.

Yes, I have read articles regarding phenylephrine and its effects on the myocardium. My argument is that any increase in contractility that you see is a result of an increased afterload causing an increase in LVEDV and the associated Frank-Starling mechanism. As pointed out, you certainly don't see increased contractility with phenylephrine in a patient with heart failure.

 

[sevoflurane]

So how does PE increase CO and MAP with an 100% occluded L main lesion + a 90% RC obstruction?

How do u explain that? Collaterals?

Just asking...

 

[GravelRider]

So what happens when CO and MAP increase with an 100% occluded L main lesion + a 90% RC obstruction?

How do u explain that? Collaterals?

Just asking...

Not for long...

Is this related to phenylephrine?

 

[sevoflurane]

Not for long...

Is this related to phenylephrine?

Yes. Cuz it still works.

 

[sevoflurane]

If you were to only increase afterload wouldn't it just make things worse? Just wondering.

 

[GravelRider]

Yes. Cuz it still works.

Too many confounding variables to use as an example. I certainly hope you are not just using phenylephrine to treat a STEMI. Phenylephrine may have a role in maintaining whatever coronary perfusion you can get, but you should be doing a lot of other things to treat a STEMI before the cath lab gets there or you get to the OR. If you have an inferior MI like you present here then you should be dumping in fluids while you are giving phenylephrine.

 

[sevoflurane]

Too many confounding variables to use as an example. I certainly hope you are not just using phenylephrine to treat a STEMI. Phenylephrine may have a role in maintaining whatever coronary perfusion you can get, but you should be doing a lot of other things to treat a STEMI before the cath lab gets there or you get to the OR. If you have an inferior MI like you present here then you should be dumping in fluids while you are giving phenylephrine.

Yeah thanks big guy... I've been doint this for a while and am quite comfortable with all cardiac disasters. My point is that phenylephrine has SOME venous return properties in some settings. Usually NOT the hypovolemic ones. Why so black and white?

 

[GravelRider]

If you were to only increase afterload wouldn't it just make things worse? Just wondering.

A severe left main lesion and a severe aortic stenosis share some similar physiology here. This is important for residents to read...the role of phenylephrine in these situations is to maintain afterload in order to maintain coronary perfusion. Reducing afterload will result in a downward spiral that we do not want to go down.

 

[Robotic Wis-Hipple]

Lol at this thread blowing up. We know it's alpha 1, we know (or can look up) where alpha 1 receptors are located. The pharmacodynamics will depend on dose, receptor predominance, and hemodynamic variables (fluid status, myocardial contractile state and perfusion, etc).

The largest effect of an a1 is going to be on your resistance vessels, but certainly any increased tone in capacitance vessels will serve to redistribute that volume centrally so sure the increase in preload in certain conditions may make this effect just as, if not more important than the increase in SVR, reflexive bradycardia, etc.

 

[GravelRider]

Yeah thanks big guy... I've been doint this for a while and am quite comfortable with all cardiac disasters. My point is that phenylephrine has SOME venous return properties in some settings. Usually NOT the hypovolemic ones. Why so black and white?

No need to take offense, I just don't think using a severe situation such as you describe proves anything regarding the venous return properties of phenylephrine. You are doing a lot of other things to that patient. I am also not denying that phenylephrine results in some venous return properties...in someone who is not hypovolemic (again I agree with you). I just think those are more downstream effects from the direct action of phenylephrine.

 

[sevoflurane]

Lol at this thread blowing up. We know it's alpha 1, we know (or can look up) where alpha 1 receptors are located. The pharmacodynamics will depend on dose, receptor predominance, and hemodynamic variables (fluid status, myocardial contractile state and perfusion, etc).

The largest effect of an a1 is going to be on your resistance vessels, but certainly any increased tone in capacitance vessels will serve to redistribute that volume centrally so sure the increase in preload in certain conditions may make this effect just as, if not more important than the increase in SVR, reflexive bradycardia, etc.

 

[sevoflurane]

No need to take offense, I just don't think using a severe situation such as you describe proves anything regarding the venous return properties of phenylephrine. You are doing a lot of other things to that patient. I am also not denying that phenylephrine results in some venous return properties...in someone who is not hypovolemic (again I agree with you). I just think those are more downstream effects from the direct action of phenylephrine.

 

[sevoflurane]

Well, yeah brahs... that's all we are saying here. Look at my original post. Arteriolar>venous. Volume dependeant. I think it's a good learning point and goes to @epidrual man question. It's clearly a good one.

 

[GravelRider]

Well, yeah brahs... that's all we are saying here. Look at my original post. Arteriolar>venous. Volume dependeant. I think it's a good learning point and goes to @epidrual man question. It's clearly a good one.

I think I got hung up on the preload/afterload thing. When I want preload for my patient, I am not reaching for phenylephrine. When you are looking at the TEE as you are coming off bypass and see an empty ventricle are you bolusing phenylephrine?

 

[Robotic Wis-Hipple]

If you look at my original post I said SVR as predominant action, and the full actions were dictated by the distribution of alpha receptors and the relative predominance in various tissues. I never said there was no venous contribution. I still think you need a pretty specific set of circumstances for the venous action to be even close to dominant, which is why you don't throw phenylephrine at sick hearts.

 

[sevoflurane]

I think I got hung up on the preload/afterload thing. When I want preload for my patient, I am not reaching for phenylephrine. When you are looking at the TEE as you are coming off bypass and see an empty ventricle are you bolusing phenylephrine?

No.

I don't come off until I'm satisfied with volume.

 

[sevoflurane]

If you look at my original post I said SVR as predominant action, and the full actions were dictated by the distribution of alpha receptors and the relative predominance in various tissues. I never said there was no venous contribution. I still think you need a pretty specific set of circumstances for the venous action to be even close to dominant, which is why you don't throw phenylephrine at sick hearts.

Sorry. Too many posts. I agree with you.