Vasopressors

Question 1

Alpha 1 receptors do more than just vasoconstrict-explain.

Answer 1

The positive inotropy helps explain why cardiac output only slightly decreases with the large associated increase in afterload (due to vasoconstriction) and, even more so, bradycardia (remember cardiac output is stroke volume X heart rate).

Question 2

60 year-old man with coronary heart disease (CAD) is hypotensive following an induction dose of propofol with pronounced ST depressions. The CRNA administers ephedrine without resolution of the ST depressions. She states that she did not want to administer phenylephrine for fear of constricting coronary arteries. You explain:

Answer 2

Therefore, in this situation, the treatment would be aimed at increasing coronary perfusion pressure (AoDP – LVEDP) and decreasing heart rate. Phenylephrine accomplishes both of these goals (answer E). Phenylephrine can constrict coronary arteries, but metabolic vasodilators (nitric oxide) in the coronary arteries easily override the weak vasoconstrictive effects and the coronaries remain maximally vasodilated

Question 3

Epi vs norepinephrine as far as receptors? How is dopamine affected?

Answer 3

Both epinephrine and norepinephrine have agonistic effects at the alpha-1, alpha-2, and beta-1 receptors, but only epinephrine has a clinically significant effect on beta-2. You can remember this easily, because you give epinephrine for bronchospasm, not norepinephrine. Neither drug agonizes the dopamine receptors.

Question 4

A healthy 30 year-old test subject is given an infusion of epinephrine until his mean arterial blood pressure (MAP) increases by 20 mm Hg, and then the same is done with a norepinephrine gtt (increase the MAP by 20 mm Hg). Compared to the norepinephrine gtt, the epinephrine gtt does what?

Answer 4

To answer the question correctly, you need understand that norepinephrine, due to its absence of beta-2 mediated vasodilation, results in a marked increase in both systolic and diastolic blood pressures. Epinephrine, on the other hand, vasoconstricts (alpha-1) and vasodilates (beta-2), leading to more pronounced increases in systolic blood pressure (SBP) and minimal changes in diastolic blood pressure (DBP)..reread that sentence again! Because MAP is mostly dependent on DBP (MAP = 2/3 DBP + 1/3 SBP), for epinephrine to raise the MAP by 20 mm Hg, the SBP must sky rocket since the DBP begrudgingly budges up. Norepinephrine, having a pronounced effect on both DBP and SBP can produce the same MAP at a lower SBP.

Question 5

Epi vs norepi on hr and cardiac output

Answer 5

Because of norepinephrine’s pronounced effects on SVR (answer E), baroreceptor mediated bradycardia offsets beta-1 mediated chronotropic effects, with the net effect being minimal changes to heart rate (answer C). Furthermore, the increased afterload also limits increase in stroke volume despite increased beta-1 mediated inotropy. Epinephrine, however, has a pronounced effect on heart rate (answer C) and its effects on afterload are less so than norepinephrine

Question 6

Dopamine and renal flow:

Answer 6

Dopamine, the obvious choice, has been conclusively shown not to be renal protective in ICU patients. Its effects on splanchnic circulation at doses needed to reverse marked hypotension are also very unfavorable.

Question 7

Renal arteries-are they autoregulated?

Answer 7

Because the renal arteries are autoregulated, perfusion is pressure dependent below a certain point (somewhere around 70-80 mm Hg).

Question 8

Norepi-cardiac output and renal artery perfusion:

Answer 8

Norepinephrine raises blood pressure while preserving cardiac output, and thus far has been shown with the most evidence to maintain urine output and preserve kidney function (for sepsis, it will decrease renal perfusion in otherwise healthy patients through vasoconstriction).

Question 9

Dobutamine works in beta receptors, but explain.

Answer 9

beta-1 > beta-2

Question 10

Most recent guidelines for sepsis can be boiled down to the following.

Answer 10

If the patient is hypotensive use norepinephrine. If the cardiac performance is compromised, add an ionotrope (dobutamine). In most cases, cardiac performance is not compromised and the second line treatments are epinephrine or vasopressin, although the authors of the 2012 surviving sepsis guidelines seemed to have a “thing” for epinephrine. Under “special” circumstances, consider dopamine. Never use dopamine for renal protection. Phenylephrine is reserved for refractory cases.

Question 11

The primary advantage of a norepinephrine gtt as compared to a dopamine gtt for the treatment of severe hypotension is that norepinephrine: ____. Which one causes more of an increase in cardiac output?

Answer 11

Fewer arrhythmia.
While it is true that norepinephrine does not require further metabolism for its receptor-ligand effects (answer C) and that it does not stimulate DA receptors (answer D), this is not the reason for its preference for treating severe hypotension. Endogenous dopamine is converted into norepinephrine (within storage vesicles of some tissues), but exogenously administered dopamine is converted to a lesser extent. Both dopamine and norepinephrine can result in significant alpha-1 receptor stimulation, and the degree to which these drugs do that is dose dependent (answer E). Dopamine, more than norepinephrine, at various doses, increases cardiac output to a greater extent than norepinephrine (see question 4), which typically has mild effects (at best) on cardiac output.

Question 12

Metabolism of catechilamones in liver vs neurons: ____. Final result of the metabolism: _______. Dosing for people on MAOIs: ______

Answer 12

In the liver, catecholamines are first metabolized by COMT, then MAO. In nerve endings, catecholamines are first metabolized by MAO and then COMT. In either tissue, both enzymes are used
Patients on MAO inhibitors (MAOIs) theoretically will require lower doses because of inhibition of the metabolic pathways, but response in an individual to catecholamines is very variable among individuals for numerous reasons that no broad generalizations can be made (answer D), but if you had to guess, the ABA would be looking for lower doses, not higher doses.

Question 13

Dopamine at low, moderate, and high doses. Also-low dose dopamine and renal stuff?

Answer 13

At low doses of dopamine (<3 mcg/kg/min), dopamine has significant agonistic effects on DA1 receptors (renal artery vasodilatation) and relatively weak effects at other adrenergic receptors. The overall effect of this is a minimal increase in heart rate & contractility (both major determinants of myocardial oxygen consumption) and significant diuresis. In the past, low dose dopamine infusions were considered to be renal protective, but that has since been strongly disputed (essentially disproven in ICU patients as a whole). Although urine output increases, kidneys continue to fail at the same rate, with or without low dose dopamine. Moderate doses of dopamine (answer B) tend to have beta > alpha receptor effects (increased heart rate, contractility, vasodilatation) leading to increased cardiac output. Unfortunately, myocardial oxygen demand often outpaces myocardial oxygen delivery (set up for non-STEMIs). At even higher doses of dopamine (answer C & D), alpha-1 effects start to predominate with increased systemic vascular resistance and renal blood flow starts to decrease. Answer E is an unusually high dose of dopamine.

Question 14

What drug is inverted dobutamine? When should you use it, when should you not?

Answer 14

Dooexamine. Think of dopexamine as an inverted dobutamine: in that instead of dobutamine’s B1»>B2 effects, dopexamine has B2»>B1 effects as well as potent DA effects as well. Dopexamine is used to increase cardiac output in the setting of CHF. The strong beta 2 effects reduces afterload and with combined weak beta-1 mediated increases in contractility, stroke volume increases (answer B). However, since beta-2 (vasodilatory) effects are pronounced, it should not be used in the setting of already low systemic vascular resistance states such as sepsis, as blood pressure will significantly decrease

Question 15

Dobutamine-all of the receptors it hits, and what happens with SVR

Answer 15

Dobutamine is a racemic mixture, with one enantiomer having beta-1»>beta-2 agonism and the other enantiomer having alpha-1 agonism. The overall effect is strong beta-1 effects, and nearly equal vasodilatation (beta-2) and vasoconstriction (alpha-1) effects (minimal reduction of systemic vascular resistance*).

*Its a minor point, but the “minimal” reduction of SVR can be (over)emphasized by some texts. In practice, dobutamine will often lower the BP a bit in some situations, but less so than milrinone. What that means is that the increase in CO is not so great to overcome the decrease in SVR (remembering that BP = CO X Resistance

Question 16

How does ephedrine work? How does its tachyphylaxis work? How do pts on MAOIs respond?

Answer 16

Ephedrine is an indirect adrenergic agonist and its mechanism of action likely involves increased post-synaptic norepinephrine release and/or decreased norepinephrine reuptake. As these stores of norepinephrine are depleted, the efficacy with each subsequent dose tends to decrease. Patients on norepinephrine reuptake inhibitors or MAOIs can have unpredictable responses to ephedrine.

Question 17

What is dromotrophy?

Answer 17

Dromotropic effects relate to the conduction speed of electrical impulses within the heart

Question 18

The pressors that work on Beta receptors work through which second messenger system?? What about milrinone?

Answer 18

The beta receptors (which answers A, B, & D activate) lead to a G-protein (Gs to be specific) mediated stimulation of adenylate cyclase which converts adenosine triphosphate (ATP) to cAMP, which has downstream effects, ultimately leading to increased intracellular calcium concentrations. cAMP is metabolized by phosphodiesterases, which milrinone (answer E) inhibits the action of this enzyme. Therefore, beta-1 or -2 receptor activation increases cAMP production and phosphodiesterase inhibitors decrease the degradation of cAMP. In either case, cAMP levels rise.

Question 19

Give me the phenylephrine receptor breakdown situation:

Answer 19

Alpha-1 receptor agonism also leads to increased intracellular calcium levels, but not through cAMP. The alpha receptor, also a member of the g-protein receptor family, stimulates phospholipase C, splitting phosphatidyl inositol (into inositol triphosphate and 1,2-diacylglycerol), leading to release of calcium from the sarcoplasmic reticulum.

Question 20

cAMP works how? Like what does it activate to increase I tracellukar calcium?

Answer 20

cAMP activates protein kinase A, which acts at multiple sites of the sarcoplasmic reticulum (responsible for the majority of calcium release used for contraction). The released calcium binds to troponin (answer D), allowing actin/ myosin (answer E) mediated contraction

Question 21

Tell me about milrinone and its effects. What does it do with chronotropy? Lusitropy? Preload and afterload?

Answer 21

Milrinone is selective for phosphodiesterase 3, resulting in increased intracellular cAMP. In the heart this leads to increases in contractility (answer C) and probably lusitropy (answer D, see question 14). At very high levels, heart rate can increase, not decrease (answer E). Milrinone leads to significant arterial and venous vasodilation, decreasing afterload and preload

Question 22

On transesophageal echocardiogram (TEE), a hypotensive patient is seen with a failing right heart and increasing tricuspid regurgitant jet, despite the absence of overt left heart failure. Which of the following medications is the next BEST step:
Milrinone 
Nitric Oxide 
Nitrous oxide 
Dobutamine 
Fenoldopam

Answer 22

Inhaled nitric oxide is a direct vasodilator. By delivering it through the respiratory tract, in primarily effects the vasculature near the site of the alveoli, thereby lowering pulmonary artery pressures (which are leading to the right ventricular failure in this patient). Because nitric oxide is metabolized almost immediately (in seconds) systemic decreases in blood pressure are minimal. Milrinone (answer A), and far less so dobutamine (answer D), can also have vasodilatory properties leading to decreased pulmonary artery pressures, but both (especially milrinone) can lead to systemic hypotension. Fenoldopam (answer E) is a pure DA1 agonist, leading to systemic vasodilation and increased renal blood flow. Nitrous oxide (answer C) increases pulmonary artery pressures.

Question 23

Tell me about Nitric oxide-how does it work, why are pts with pulm HTN on viagra pills? What other type of hemoglobin can they make?

Answer 23

Nitric oxide (NO) stimulates guanylate cyclase (answer D), increasing cGMP levels (answer A). cGMP leads to the relaxation of smooth muscle (by several mechanisms) leading to vasodilation. cGMP is broken down by the 5th isoform of phosphodiesterase (PDA5, answer B), which sildenafil is an inhibitor of (and is why pulmonary hypertension patients are on “Viagra” pills). Because the NO is inspired, it is only active at vasculature near the alveoli, increasing perfusion to well ventilated alveoli, decreasing V/Q mismatch (answer C). NO can bind to the haeme moiety in haemoglobin, leading to methaemoglobin,

Question 24

Tell me about Nesitride. What does it do? How does it compare to a spinal? How does it affect contractility?

Answer 24

Nesiritide is a recombinant BNP, leading to stimulation of guanylate cyclase (and increased cyclic guanosine monophosphate (cGMP)) with resultant vasodilation (answer C). It is indicated for part of the treatment for severe decompensated heart failure (answer D) by decreasing afterload and encouraging forward flow. Both spinal anesthesia and nesiritide will decrease afterload, although spinal anesthesia is difficult to titrate and may have profound preload effects as well. Nesiritide has no effect on contractility (answer B). Although nesiritide is essentially BNP, a BNP level does not need to be obtained prior to its use. Notice that this question did not say that spinal anesthesia and nesiritide have the same effects overall, just that they both decrease afterload.

Question 25

Vasopressin should not be used to replace epi-T/F?

Answer 25

True-it should not!

Question 26

Breakdown SVR and PVR for me:

Answer 26

Lets get this down crystal clear:

SVR = (MAP - CVP) / CO. ——> Normally a bit over 1,000
PVR = (PAP - Wedge) / CO —-> Normal a bit lower than 100
NOTE: Remember both are multiplied by 80, but the more junk you throw in equations, the harder it is to remember!

Question 27

Phentolamine vs prazosin vs labetalol moa:

Answer 27

Phentolamine is relatively easily titrated alpha blocker that can be used intraoperatively, with a single dose lasting only about 15 minutes. Prazosin is a pure alpha-1 antagonist. Labetalol is a non-selective beta blocker with weak alpha-1 antagonism.

Question 28

I know you hate this, but what does notroprusside have to do with ferrous to ferric? Is it oxidized or reduced? What happens to the nitroprusside molecules with the additional electron? And what three things can it become?

Answer 28

Everyone hates chemistry, but there are some things that have high potential of coming up on the boards, met-Hb and cyanide toxicity being two big ones. Nitroprusside produces both of these phenomenon. Nitroprusside is a nitrate that acts by a series of steps, first by entering red blood cells (RBCs). Inside the RBC, the chemical accepts an electron from the 2+ ferrous oxy-Hb and oxidizes it to a +3 Met-Hb.

The nitroprusside molecule becomes unstable with the additional electron and breaks into five cyanide molecules (CN-) and nitric oxide. The nitric oxide goes on to stimulate guanylate cyclase, increasing cGMP (see Vasopressor question 20), producing vasodilation. The CN- molecules go on to bind one of three things. It can bind the met-Hb, producing cyanmet-Hb (answer C), it can bind cytochrome oxidase in the electron transport chain (answer E) or bind with thiosulfate, producing thiocyanate. The thiocyanate is cleared by the kidney, but is moderately toxic in itself.

Question 29

Nitroprusside toxicity-explain how it ends up increasing mixed venous o2

Answer 29

As discussed above in Vasopressor Question 25, free CN- can bind to a variety of things, with cytochrome oxidase being the most dangerous. Without the electron transport chain, ATP cannot be produced from aerobic metabolism; and anaerobic metabolism occurs, with the production of lactic acid and resulting acidosis. The inability of mitochondria to utilize oxygen results in decreased oxygen consumption (despite unchanged oxygen delivery and cellular level hypoxia) leading to elevated venous oxygen partial pressures

Question 30

What’s the treatment for cyanide toxicity from nitroprusside?

Answer 30

Treatment relies on increasing the other sinks of CN-. The first treatment is increasing the level of methaemoglobin (met-Hb) with sodium nitrite. The met-Hb can therefore act as a sink for CN- by the production of cyanmet-Hb. At high levels, this could lead to hypoxia (answer D), and is treated with methylene blue (answer B).
The other classic treatment is sodium thiosulfate, which binds with CN- producing thiocyanate (answer E). This molecule is moderately toxic but is slowly excreted by the kidneys. The other cornerstones of therapy are discontinuation of nitroprusside and 100% oxygen to make oxygen as available to tissues as possible. This has very little efficacy compared to the other measures and mechanical ventilation for cyanide toxicity alone is unlikely to help significantly.

Question 31

Why would anyone use sodium nitroprusside in a patient with ARDS? What’s the normal dose of nitroprusside?

Answer 31

With ARDS V/Q mismatch results in significant hypoxia. The vasodilating effects of sodium nitroprusside on pulmonary vasculature can counteract hypoxic pulmonary vasoconstriction (HPV), thereby increasing blood flow to poorly oxygenated alveoli (shunt). Lower doses of nitroprusside (< 500 mcg/kg/min) and short infusion times are unlikely to result in significant cyanide toxicity (answer A) or met-Hb (answer B).

Normal doses of sodium nitroprusside are usually more along the lines of 4 mcg/kg/min and maybe 40 mcg/kg/min. In the question, the dose was 400 which is why there was shunt.

Question 32

Is nitroprusside more active on arteries or veins?

Answer 32

Veins

Question 33

How does nitroprusside cause rebound HTN? Thiocyanate can lead to dysfunction of which organ? Does it result in baroreceptor dysfunction?

Answer 33

During nitroprusside treatment, there is increased catechol and renin-angiotensin release. When nitroprusside is discontinued these factors lead to rebound hypertension. Thiocyanate (formed from cyanide and sodium thiosulfate) can lead to thyroid dysfuction, not hyperthyroidism (answer A). Nitroprusside does not result in baroreceptor dysfunction and there is no such thing as vasoconstrictive memory.

Question 34

NTG is best for subendocardial ischemia. Why?

Answer 34

NTG, more than other vasodilators, helps to redistribute blood flow to the subendocardium, where the ischaemia typically first presents during oxygen delivery/ consumption mismatch.

Question 35

What are the 2 ways that NTG can improve the myocardial oxygen delivery

Answer 35

The most significant of which is decreased preload (left ventricular end diastolic pressure (LVEDP), decreased wall tension) which does two important things. First decreased LVEDP decreases myocardial oxygen consumption and secondly it allows for improved myocardial perfusion (remember that perfusion of the LV is aortic diastolic pressure minus LVEDP during diastole), assuming diastolic pressures are preserved. NTG is famous for being a coronary artery dialator, but in the setting of ischaemia, most if not all non-stenosed coronary arteries are maximally dilated. NTG, more than other vasodilators, helps to redistribute blood flow to the subendocardium, where the ischaemia typically first presents during oxygen delivery/ consumption mismatch.

Question 36

Nicardioine is a potent ___ _____ but how does it affect the aorta?

Answer 36

Nicardipine is a potent coronary artery vasodilator but can also drop aortic diastolic pressures as well

Question 37

Hydralazine negatives:

Answer 37

Hydralazine is classically associated with rebound hypertension and has precipitated myocardial ischaemia

Question 38

Between SNP, NTG, and nicardipine-put them in order of most venodilating to arterial dilating

Answer 38

NTG is primarily a venodilator (far more than arterial), leading to significant decreases is preload and smaller decreases in afterload. SNP potently dilates both arterial and venous vascular beds with significant reductions in afterload and preload. In most cases, its preload effects account for most of its hypotensive effects (thus explaining why the renin angiotensin and sympathetic systems are revved up with prolonged therapy!). Nicardipine is a calcium channel blocker that nearly exclusively dilated only the arterial bed (like hydralazine).

Question 39

Pt is on SNP and has cerebral hemorrhage and malignant HTN. Which drug do you want to switch to?

Answer 39

Nicardipine can be easily titrated and does not have significant metabolite concerns and is not prone to any significant tachyphylaxis concerns (like NTG and especially SNP). Nicardipine, SNP, and NTG all lead to increased cerebral vasculature dilation which can be detrimental (but less detrimental than malignant hypertension!). Esmolol is a beta-1selective blocker and can reduce heart rate and contractility.