Vasopressors Flashcards
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)
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
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
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
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
Surviving Sepsis vasopressor guidelines
- If hypotensive, use norepinephrine
- Second line treatments for hypotension are epinephrine or vasopressin - If cardiac performance compromised, add an inotrope (dobutamine)
- Consider dopamine under “special” circumstances only
* never use dopamine for renal protection - Phenylephrine reserved for refractory cases
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)
Catecholamine metabolism (hepatic v neural)
- Liver: COMT then MAO (“Liver contains
- Nerve endings: MAO then COMT
- Final product in both: VMA
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
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
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
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)
Isoproterenol MOA
Beta-1 roughly equals beta-2
*“chemical pacemaker”
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
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)
SERCA
Sarco-endoplasmatic reticulum calcium ATPase
- regulates uptake of calcium into the SR
- impaired SERCA is a part of diastolic function (impaired lusitropy)
Ephedrine MOA
Increased post-synaptic NE release and/or decreased NE reuptake
Ephedrine MOA
Increased post-synaptic NE release and/or decreased NE reuptake
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
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
Calcium mediated contraction
Calcium released from SR binds to troponin, allowing actin/myosin mediated contraction
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)
Fenoldopam MOA and effects
- Pure DA1 agonist
- systemic vasodilation and increased renal blood flow
Fenoldopam MOA and effects
- Pure DA1 agonist
- systemic vasodilation and increased renal blood flow
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)
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
SVR equation
SVR = (MAP-CVP)/CO *80
PVR equation
PVR = (PAP-wedge)/CO *80
Phentolamine MOA
Alpha blocker (both alpha-1 and alpha-2)
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)
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)
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
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)
Cause of rebound HTN following sodium nitroprusside
Increased catecholamines
-during nipride treatment, there is increased catechol and renin-angiotensin release
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)
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)
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
