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Flashcards in Vasopressors Deck (37):
1

Alpha 1 receptor mechanism and effects

-G protein dependent increases in intracellular calcium (through phosphatidyl inositol)
-densely found on smooth muscle
-vasoconstriction, mydriasis, bronchoconstriction, sphincter contraction, uterine contraction
-insulin and lipolysis is inhibited (anabolic effects inhibited)
-mild positive inotropy (effects easily overshadowed by pronounced vasoconstriction, because receptors in myocardium much less densely populated)

2

Epinephrine vs norepinephrine

-only epi has beta-2 receptor agonism
*epi given for bronchospasm, not norepi
-epi vasoconstricts (alpha-1) and vasodilates (beta-2) leading to more pronounced increases in SBP and minimal changes in DBP; whereas norepi has pronounced effect on both SBP and DBP (no beta-2 activity)
-MAP more dependent on DBP (2/3 DBP + 1/3 SBP) so for an equal increase in MAP, epi causes a huge increase in SBP (and small increase in DBP) while norepi can produce the same MAP at a lower SBP

3

Norepinephrine and epinephrine effect on HR

-norepinephrine- pronounced SVR and subsequent baroreceptor mediated bradycardia is offset by beta-1 chronotropic effects, leading to minimal changes in heart rate
-epinephrine- pronounced effects on HR, and thus increase in CO

4

Best vasopressor to preserve renal function in sepsis

Norepinephrine- best evidence to maintain UOP and preserve kidney function
*raises BP while preserving CO
*in healthy patients, norepi decreases renal perfusion through vasoconstriction

5

Best vasopressor in patient with coexisting cardiogenic and septic shock

Norepinephrine + dobutamine

-Septic shock- low SVR state, so increasing SVR and DBP (for pressure dependent perfusion) with norepi ideal
-Cardiogenic shock- low contractility, so increasing CO with dobutamine is ideal

6

Surviving Sepsis vasopressor guidelines

1. If hypotensive, use norepinephrine
-Second line treatments for hypotension are epinephrine or vasopressin

2. If cardiac performance compromised, add an inotrope (dobutamine)

3. Consider dopamine under "special" circumstances only
*never use dopamine for renal protection

4. Phenylephrine reserved for refractory cases

7

Primary advantage of norepinephrine gtt compared to dopamine gtt

Norepi is associated with a lower rate of arrhythmias, especially high grade tachyarrhythmias (eg. a fib)

8

Catecholamine metabolism (hepatic v neural)

-Liver: COMT then MAO ("Liver contains
-Nerve endings: MAO then COMT
*Final product in both: VMA

9

Dopamine doses and effects

2 mcg/kg/min: significant DA1 agonism (renal artery dilation) and relatively weak effects at other adrenergic receptors
-overall effect is minimal increase in HR and contractility and significant diuresis (increased UOP but no improvement in renal protection)

5 mcg/kg/min: beta > alpha effects (increased HR, contractility, vasodilation) leading to increased CO
-unfortunately, myocardial oxygen demand outpaces oxygen delivery (set up for non-STEMIs)

10 mcg/kg/min: alpha-1 effects predominate (increased SVR)
-renal blood flow decreases

10

Dopamine doses and effects

2 mcg/kg/min: significant DA1 agonism (renal artery dilation) and relatively weak effects at other adrenergic receptors
-overall effect is minimal increase in HR and contractility and significant diuresis (increased UOP but no improvement in renal protection)

5 mcg/kg/min: beta > alpha effects (increased HR, contractility, vasodilation) leading to increased CO
-unfortunately, myocardial oxygen demand outpaces oxygen delivery (set up for non-STEMIs)

10 mcg/kg/min: alpha-1 effects predominate (increased SVR)
-renal blood flow decreases

11

Mechanism and effects of dopexamine

-B2>>>B1 effects as well as potent DA agonism
*think of as inverted dobutamine

-used to increase CO in setting of CHF: strong beta 2 effects reduces afterload and weak beta 1 increases contractility and SV
-however, since beta-2 (vasodilatory) effects are pronounced, BP will significantly decrease

12

Dobutamine MOA

-racemic mixture: one enantiomer has beta 1>>>beta 2, the other has alpha-1 agonism
*overall effect is strong beta 1 effects and minimal reduction in SVR (nearly equal beta-2 and alpha-1)

13

Isoproterenol MOA

Beta-1 roughly equals beta-2
*"chemical pacemaker"

14

Dromotropy

Conduction speed of electrical impulses within the heart
*primarily a result of AV node, as conduction through the his-purkinje system is far less variable
*beta-1 agonism leads to increased dromotropy

15

Lusitropy

Definition: active process of myocardial relaxation in diastole
-calcium increases isotropy (contractility) but decreases lusitropy
-beta-1 agonism increases both isotropy (increasing calcium in myocyte during systole) and lusitropy (increasing rate of calcium uptake into SR during diastole)

16

SERCA

Sarco-endoplasmatic reticulum calcium ATPase
-regulates uptake of calcium into the SR
-impaired SERCA is a part of diastolic function (impaired lusitropy)

17

Ephedrine MOA

Increased post-synaptic NE release and/or decreased NE reuptake

18

Ephedrine MOA

Increased post-synaptic NE release and/or decreased NE reuptake

19

Adrenergic receptor effect

Beta: G-protein (Gs) mediated stimulation of adenylate cyclase which converts ATP to cAMP, leading to increased intracellular calcium concentrations
Alpha-1: G-protein mediated stimulation of phospholipase C which splits phosphatidyl inositol into IP-3 and 1,2-DAG, leading to release of calcium from the SR

20

Adrenergic receptor effect

Beta: G-protein (Gs) mediated stimulation of adenylate cyclase which converts ATP to cAMP, which activates PKA, which acts at the SR, leading to increased intracellular calcium concentrations
Alpha-1: G-protein mediated stimulation of phospholipase C which splits phosphatidyl inositol into IP-3 and 1,2-DAG, leading to release of calcium from the SR

21

Calcium mediated contraction

Calcium released from SR binds to troponin, allowing actin/myosin mediated contraction

22

Milrinone MOA and effects

-Selective inhibition of PDE3, resulting in increased intracellular cAMP
-increased isotropy (contractility), increased lusitropy (relaxation), increased chronotropy (HR), and significant arterial AND venous vasodilation (decreasing afterload AND preload)

23

Fenoldopam MOA and effects

-Pure DA1 agonist
-systemic vasodilation and increased renal blood flow

24

Fenoldopam MOA and effects

-Pure DA1 agonist
-systemic vasodilation and increased renal blood flow

25

Nitric Oxide MOA, effects, metabolism, side effect

-stimulates guanylate cyclase leading to increased cGMP levels, causing smooth muscle relaxation and vasodilation
-broken down by PDE5 (inhibited by sildenafil)
*inhaled NO: only active at vasculature near alveoli, increasing perfusion to well ventilated alveoli, decreasing V/Q mismatch
-methhemoglobinemia (NO binds to heme moiety in hemoglobin)

26

Nesiritde MOA, effects, indications

-recombinant BNP- leads to stimulation of guanylate cyclase-->cGMP-->vasodilation
-indicated as part of treatment in severe decompensated CHF for afterload reduction and improved forward flow

27

SVR equation

SVR = (MAP-CVP)/CO *80

28

PVR equation

PVR = (PAP-wedge)/CO *80

29

Phentolamine MOA

Alpha blocker (both alpha-1 and alpha-2)

30

Sodium nitroprusside MOA and two major side effects

-nitrate that acts by a series of steps, first by entering RBCs, then accepting an electron from the 2+ ferrous oxy-Hb and oxidizes it to a +3 Met-Hb
*heme in Hb has an iron atom which can have more electrons (Fe 2+) or less electrons (Fe 3+); oxygen only likes heme with more electrons, giving it a lower charge (+2) also known as ferrous state
-when nitroprusside is exposed to ferrous (2+) hb, it takes an electron away, leaving iron in the ferric (3+) state, which is called met-Hb (ferr-IC state is ICky oxygen)
-nitroprusside becomes unstable with the additional electron and breaks info five cyanide molecules (CN-) and nitric oxide
-CN- binds one of three things: met-Hb (cyanmet-Hb), cytochrome oxidase (part of electron transport chain), or thiosulfate (thiocyanate- cleared by kidney)

31

Sodium nitroprusside MOA and two major side effects

-nitrate that acts by a series of steps, first by entering RBCs, then accepting an electron from the 2+ ferrous oxy-Hb and oxidizes it to a +3 Met-Hb
*heme in Hb has an iron atom which can have more electrons (Fe 2+) or less electrons (Fe 3+); oxygen only likes heme with more electrons, giving it a lower charge (+2) also known as ferrous state
-when nitroprusside is exposed to ferrous (2+) hb, it takes an electron away, leaving iron in the ferric (3+) state, which is called met-Hb (ferr-IC state is ICky oxygen)
-nitroprusside becomes unstable with the additional electron and breaks info five cyanide molecules (CN-) and nitric oxide
-CN- binds one of three things: met-Hb (cyanmet-Hb), cytochrome oxidase (part of electron transport chain), or thiosulfate (thiocyanate- cleared by kidney)

32

Cyanide toxicity
-cause and mechanism
-treatment

Cause: nitroprusside
-free CN- can bind to three things, with cytochrome oxidase being the most dangerous (ETC shuts down-->ATP not produced-->only anaerobic metabolism-->lactic acidosis)
*inability of mitochondria to utilize oxygen resluts in decreased oxygen consumption and elevated mixed venous pO2

Treatment: increase other sinks of CN-
-sodium nitrite- increases levels of methemoglobin (met-Hb) which acts as a sink for CN- by the production of cyan met-Hb
*high levels of cyanmet-Hb leads to hypoxia, and is treated with methylene blue

-sodium thiosulfate- binds with CN- to form thiocyanate (which is moderately toxic but slowly excreted by kidneys)

-100% and discontinuation of nitroprusside

33

Nitroprusside effects on lungs and in ARDS

-vasodilates pulmonary vasculature and can counteract hypoxic pulmonary vasoconstriction (HPV), thereby increasing blood flow to poorly oxygenated alveoli (shunt)

34

Cause of rebound HTN following sodium nitroprusside

Increased catecholamines
-during nipride treatment, there is increased catechol and renin-angiotensin release

35

Nitroglycerin (NTG) MOA, function, and side effects

-improves myocardial oxygen delivery to consumption ratio through multiple mechanisms
*most important is through decreased preload (decreased LVEDP and wall tension)
-in setting of ischemia, non-stenosed coronaries are maximally dilated, so NTG helps to redistribute blood flow to the subendocardium (where ischemia typically first presents during oxygen delivery/consumption mismatch)

36

Venodilation versus arterial dilation with NTG, SNP and Nicardipine

NTG>SNP>nicardipine

-NTG: primarily venodilator-->significant decreases in preload and small decreases in afterload
-SNP: potently dilates both A and V-->significant reductions in afterload and preload (hypotension accounted for mostly by preload though)
-Nicardipine: nearly exclusively dilates arterial bed (like hydralazine)

37

Drug of choice in malignant hypertension and cerebral hemorrhage

Nicardipine- easily titrated, no metabolite concerns (like SNP), no tachyphylaxis (like SNP), and just as effective as SNP