CV Effects of Autonomic Agonists

Question 0

What changes happen in heart in response to parasymp stimulation (via muscarinic receptors)?

Answer 0

SA node: less automaticity (slower spontaneous depolarization)
Atrial myocardium: lower inotropy
AV node: increased refractoriness (slower AV conduction)
The His-Purkinje and ventricular myocardium aren’t affected much.

Question 1

Review: What neurotransmitter do both the sympathetic and parasympathetic nervous system use at ganglionic synapses?

Answer 1

Acetylcholine.

And yet… Ach is really talked about as stimulating the PSNS, not SNS.

Question 2

What effect does muscarinic have on the systemic vasculature?

Answer 2

Causes arterioles to vasodilate.

Not much effect on veins.

Question 3

Putting the effects on the heart together with the effects on the vasculature, what happens when you have a “parasympathetic discharge” (i.e. lots of PSNS signaling)?

Answer 3

Vaso-vagal reaction: bradycardia + vasodilation = significant drop in bp -> syncope.
(why some people faint when frightened)

Question 4

Why can’t you just give people acetylcholine?

Answer 4

It gets cleared too rapidly by acetylcholinesterase.

So you give an acetylcholinesterase inhibitor to create this effect.

Question 5

Usefulness of edrophonium, an acetylcholinesterase inhibitor?
Duration of effect?

Answer 5

Edrophonium is a short-acting (i.e. 30s per bolus).
It induces AV block, and can be used to aid diagnosis of supraventricular tachycardia.
It isn’t used more because it causes GI parasympathetic stimulation (cramps and diarrhea).
(Most places use adenosine, because it doesn’t have GI side effects.)

Question 6

Longer acting acetylcholinesterase drugs?

Answer 6

-stigmine drugs (they came up in B&B for Alzheimer’s)

Insecticides and sarin….

Question 7

Agonism of both alpha-1 and alpha-2 causes what?

What does each cause the other doesn’t?

Answer 7

Vasoconstriction
Alpha-1 causes GU smooth muscle constriction.
Alpha-2 causes platelet aggregation.

Question 8

Effects of beta-1 agonism?

Answer 8

Increased inotropy and chronotropy.

Activation of renin secretion by juxtoglomerular cells.

Question 9

Effects of beta-2 agonism?

Answer 9

Vasodilation

Bronchodilation

Question 10

Effect of beta-3 agonism? (don’t worry about it)

Answer 10

Increased lipolysis.

Question 11

Which adrenergic receptor mediates direct effects on the heart? (increased inotropy, decreased AV refractoriness, increased SA rate)

Answer 11

beta-1

Question 12

Which adrenergic receptor mediates constriction of veins, and vasoconstriction of arterioles leading to skin, kidneys, and gut?

Answer 12

alpha-1

Question 13

Which adrenergic receptor mainly mediates vasodilation of skeletal muscle and bronchodilation?

Answer 13

beta-2

Question 14

How does receptor specificity vary between endogenous and synthetic adrenergic agonists?

Answer 14

Endogenous agonists have affinity for multiple receptors.

Synthetic agonists have been designed to have more specificity.

Question 15

Epinephrine receptor affinity?

Answer 15

mixed alphia, beta-1, beta-2 agonist

Question 16

Norepinephrine (NE) receptor affinity profile?

Answer 16

mixed alpha, beta-1 agonist

little beta-2 activity

Question 17

Dopamine receptor affinity profile?

Answer 17

mixed alphia, beta-1 affinity (little beta-2 affinity)
Isolated delta activity at low levels.

I.e. it acts pretty much like NE at high levels.

Question 18

What’s the effect of epinephrine on HR, CO, and SVR?

Answer 18

HR and CO increased.

SVR doesn’t change much.

Question 19

Effect of epineprhine on mean arterial pressure (MAP)?

Answer 19

It increases it (due to increases in CO and not changing SVR - MAP = CO * SVR, roughly)

Question 20

What’s probably the reason why epinephrine doesn’t change SVR much?

Answer 20

Vasoconstriction from alpha agonism balances the vasodilation from beta-2.

Question 21

Why doesn’t NE cause vasodilation?

Answer 21

It doesn’t have beta-2 activity.

Question 22

What’s the effect of NE on SVR, HR, and CO?

Answer 22

SVR is increased.
HR is decreased (due to baroreceptor reflex)
CO is unchanged. (increases in SVR, vagal signaling balance beta-1 effects)

Question 23

What are the effects of dopamine on vasculature at low, intermediate, and high doses?

Answer 23

Low: delta-1 agonism vasodilates renal arterioles.
Intermediate: beta-1 + delta-1 activity increases CO without increasing SVR much.
High: acts like NE, with increased SVR, decreased HR, and unchanged CO.

Question 24

So… what is dopamine really good for at low to intermediate doses?

Answer 24

It acts as a pressor without decreasing renal blood flow.
You would think that this would make it a great for various kinds of shock e.g. septic, but there’s a lot of data out there that shows NE has a lower mortality rate vs. dopamine when used for shock….

Question 25

Primary receptor activity of phenylephrine?

Answer 25

Alpha agonist

Question 26

Primary receptor activity of dobutamine?

Answer 26

Beta-1 agonist

Question 27

Primary receptor activity of isoproterenol?

Answer 27

Mixed beta-1, beta-2 agonist

Question 28

Effect of phenylephrine on SVR, HR, and CO?

Answer 28

Increased SVR
Decreased HR
Decreased CO
Increased MAP, but shunts blood away from skin, gut, kidneys.
(not sure what advantage this has over dopamine as a vasopressor)

Question 29

Effect of isoproterenol on SVR, HR, and CO? Utility?

Answer 29

SVR decreased
HR increased
CO increased
doesn’t change MAP much, maybe small increase.
Useful for transplanted hearts… and not much else.

Question 30

Dobutamine effects?

Answer 30

Relatively pure inotrope.

Increases CO, and slightly increases HR, but has little effect on systemic circulation.

Question 31

Say you have a patient in septic shock. What receptor(s) do you want to agonize, and which adrenergic agonists would accomplish this?

Answer 31

You want to increase SVR by agonizing alpha receptors -and you don’t want beta-2 activity.
This makes norepinephrine and phenylephrine viable choices here (and dopamine, one would think).

Question 32

Preferred adrenergic agonist for cardiogenic shock?

Answer 32

Dobutamine - beta-1 activity increases inotropy and chronotropy.
(but I suppose you want to be careful of “whipping the heart” and increasing metabolic demand if it’s ischemic)
You don’t want isoproterenol here, as it would cause BP to drop.