ANS Pharm: Adrenergic Agonists Flashcards
(151 cards)
1
Q
Which vasopressors are removed from the cleft by reuptake? Which aren’t?
A
Dopamine, Epi, Norepi
NOT phenylephrine
1
Q
How is phenylephrine removed from the synapse?
A
metabolized by MAO
This is why MAOIs with phenylephrine = HTN
2
Q
which pressors are synethetic noncatecholamine vs endogenous catecholamines?
A
synethetic NONcatecholamine: neosynephrine
endogenous catecholamines: DA, epi, NE
3
Q
The endogenous catecholamines are normally reuptaken via transporters, but what if they escape?
A
metabolized by MAO and COMT
4
Q
T/F:
Both the SNS and PNS are response for fight or flight, as the ANS.
A
True
5
Q
Phenylephrine receptor activity
A
selective and direct A1 agonist
sympathomimetic
6
Q
Clonidine and Precedex both act ____ to produce sedation, anxiolysis, decrease BP & HR and cause analgesia
A
centrally
7
Q
Classes of drugs that modify the ANS
A
8
Q
T/F:
The SNS and PNS usually work on the same end-organ at the same time.
A
False
usually do not
9
Q
The ANS relies on these 2 NTs
A
ACh & NE
10
Q
Which NTs work at each location?
-ganglionic
-postganglionic PNS
-postganglionic SNS
A
-ganglionic: ACh
-postganglionic PNS: ACh
-postganglionic SNS: NE
ACh is the PNS NT
NE is the SNS NT
(exceptions do exist)
11
Q
the PNS and SNS of the ANS both target these organs/tissues
A
smooth muscle, cardiac muscle, glands
12
Q
The somatomotor system is part of which nervous system?
A
CNS
somatic motor system: voluntary movements
13
Q
In the (PNS/SNS) the ganglion is located closer to the target organ/tissue.
A
PNS
14
Q
Which division of the nervous system targets skeletal muscle?
A
Somatomotor system of the CNS
15
Q
A
16
Q
Which Alpha selective drug affects Renal blood flow?
A
Neosynephrine; decreases it
(others do not)
17
Q
How are the Alpha selective drugs each metabolized?
A
- Neo = MAO
- Clonidine = half life, half kidney UNCHANGED
- Precedex = Liver CYP
18
Q
Abruptly stopping which alpha selective agent may cause rebound HTN?
A
clonidine
19
Q
Phenylephrine is especially useful in …… states
A
low vascular resistance
20
Q
Phenylephrine is almost exclusively a pure stimulant at A1 adrenoreceptors, causing….
A
venous AND arterial vasoconstriction
21
Q
Neo vs. Norepi
A
Neo has similiar effects to NE
but
less potent and longer acting
BOTH risk end-organ damage (high dose/prolonged drip)
22
Q
Why do you see bradycardia with Neo?
A
baroreceptor activity
23
Q
Neo
dosing & gtt
A
24
How does Neo affect pulmonary circulation?
Pulmonary artery pressure increases
due to direct vasoconstrictive action of the drug in the lung vasculature and an increase in venous return.
25
T/F:
Unlike natural and synthetic catecholamines, phenylephrine is not arrhythmogenic.
True
26
T/F:
The dose of phenylephrine needed to stimulate the a 1 receptor is much more than that for the a2 receptor.
False
LESS
27
Sometimes drug like phenylephrine treat the BP number instead of the actual physiological process. When could this happen?
hypotensive patient with CAD may increase BP by increasing peripheral vasoconstriction
but
this decreases CO and may worsen ischemia!
(decreased CO is d/t strong baroreceptor reflex (bradycardia) & abrupt increase in afterload)
28
Phenylephrine overdose
* phentolamine (nonselective A-adrenergic antagonist)
* or maybe just wait it out since Neo doA is short
* DO NOT use a Beta blocker
29
Phenylephrine overdose
What is CONTRAINDICATED?
Beta blockers
may induce pulm edema & catastrophic, irreversible CV collapse
30
Where can we find Alpha-2 receptors?
1. Presynaptic: NE-releasing neurons in the CNS and PNS (negative feedback mechanism reduces NE release)
2. Postsynaptic: Smooth muscle and several organs
3. Nonsynaptic: platelets
31
Alpha-2 receptors by location and their effect
32
The a2 agonists have long been used in treating...
* hypertension
* ADHD
* panic disorders
* drug and alcohol withdrawal
* sedation
* sympatholysis
* reducing anesthetic requirements
## Footnote
these agents can modify the ANS!
33
Clondine vs. Precedex
A2:A1 binding ratio
34
partial agonist of the A2 receptor
clonidine
35
T/F:
Clondine can reduce IV anesthetic and volatile requirements.
True
but only mild effect
36
T/F:
Clondine will not cause respiratory depression, but Precedex can.
False
neither do
37
clonidine vs. precedex
Where do they act?
clonidine: central presynaptic receptors (medulla & locus coeruleus)
precedex: brain and SC; inhibits neuronal firing
## Footnote
both alpha2 agonists
38
Clonidine & Precedex both block ___ release
norepinephrine
this is how clonidine causes vasodilation this way & precedex modifies pain signal propigation
39
Clonidine
Its **central** action is its predominant clinical activity. What effects does this have?
decreases SNS outflow ➡️ sympatholysis, lowering HR & BP
40
How does clonidine cause centrally induced sedation?
via a2 receptors in the locus coeruleus
41
Clonidine produces **centrally** mediated pain modification and analgesia via ...
activity at the dorsal horn of the spinal cord
42
Aside from rebound HTN, what can happen when abruptly stopping clonidine?
tachycardia and arrhythmia
taper it!
43
Clonidine has been in use for decades and with demonstrated utility in various conditions:
* diagnosing pheochromocytoma
* opiate and nicotine withdrawal manifestations
* HTN
## Footnote
in general, A2 agonists treat
* hypertension
* ADHD
* panic disorders
* drug and alcohol withdrawal
* sedation
* sympatholysis
* reducing anesthetic requirements
44
T/F:
Clonidine's ANS effects are strong enough that sedative/hypnotic effects can happen in anti-hypertensive doses.
True
## Footnote
its action centrally in the locus coeruleus provides the sedative/hypnotic
45
T/F:
A2 agonists have a distinctive place in anesthesia, partly because of early observations of the effect of clonidine on the ANS.
True
patients reported altered pain signals so a2 agonist drug research and development ensued
46
How does Precedex cause hypotension, bradycardia, sedation, and analgesia?
Dexmedetomidine stimulates a2 receptors in the brain and spinal cord, leading to inhibition of neuronal firing
=
decreased sympathetic drive!
## Footnote
dose-dependent sedation, analgesia, and sympatholytic effects
47
T/F:
Dexmedetomidine is a postsynaptic a2 agonist at peripheral receptors.
false!
PREsynaptic
CENTRAL receptors
48
T/F:
dexmedetomidine can cause very concerning hypotension and bradycardia, especially with higher and rapid dosing.
True
49
Prcedex
Hypertension, tachycardia, and dysrhythmias show us that....
a complex distribution of central a2 receptors at which the drug acts.
50
less appreciated ANS effects of dexmedetomidine
* dry mouth,
* impaired Gl motility,
* inhibition of renin release,
* increased GFR,
* decreased insulin release
51
inhibition of norepinephrine release by dexmedetomidine
plays a role in modifying the propagation of pain signals.
52
Dexmedetomidine's central sympatholytic effect exerts these 2 effects
* anti-shivering
* overall reduction in the neuroendocrine stress response to surgery
53
T/F:
Precedex can reduce emergence agitation in both adults and children.
True
54
How can Precedex cause transient HTN?
1. Giving Precedex rapidly can stimulate postsynaptic A2 receptors
1. these receptors are on arterial and venous circulations = vasoconstriction & HTN
1. CNS effect (vasodilation) lags behind the peripheral response
1. the CNS effect eventually catches up and overpowers the peripheral effect
55
Which A2 agonist is more protein bound?
precedex
## Footnote
Prece loves protein
56
T/F:
Ephedrine is a non-endogenous direct acting synthetic sympathomimetic.
False
indirect acting
non-endogenous & synthetic
noncatecholamine
## Footnote
DA, NE, Epi are endogenous
57
Ephedrine
receptor activity & effects
stimulates both A & B
myocardial stimulation, bronchodilation, vasoconstriction
58
the synthetic catecholamines
dobutamine
isoproterenol
59
adverse effects of using endogenous and synthetic catecholamines
HTN, arrhthymia and myocardial ischemia
## Footnote
EPI, NE, DA
Isoproterenol, dobutamine
60
the effects of endogenous and synthetic agonists are dependent on their specificity for which receptors?
a-and -adrenoreceptors and dopaminergic subtypes.
61
Appreciating the metabolism of the endogenous catecholamines helps us predict (2)
their clinical use and dosing.
62
Epinephrine and norepinephrine metabolism
catechol-O-methyl transferase & monoamine oxidase
⬇️
common metabolite, vanilly mandelic acid (VMA)
63
assayed as part of pheochromocytoma work-up
vanilly mandelic acid (VMA)
## Footnote
Epi & NE are metbolized to this common metabolite
64
noncatecholamine with both direct and indirect activity at adrenoceptors
Ephedrine
65
isoproterenol
vs
dobutamine
the synthetic catecholamine isoproterenol has a modified version, dobutamine
both have B1 & *some* B2 activity
66
Short-and long-acting B2-adrenoceptor agonists
short: albuterol
long: salmeterol
asthma, COPD, and airway hyperactivity during anesthesia
67
Dobutamine used more than isoproterenol due to its novel ability to...
enhance cardiac contractility and simultaneously reduce arterial vasomotor tone
68
Why give albuterol and salmeterol in aerosolized form?
minimizes side effects such
as anxiety, tremor, and restlessness
69
A non-selective adrenergic agonist acts...
on BOTH alpha and beta receptors
70
Why do we closely monitor patients on adrenergic agonists?
adverse events such as ischemia and arrhythmias
71
adrenergic agonists
can mimic the SNS in 1 of 2 ways
1. direct receptor activation
1. encourage endogenous catecholamine release
72
Aside from vasoconstriction, what 2 effects can adrenergic agonists give that are clinically desirable?
1. bronchodilation
1. myocardium stimulation
73
Which adrenergic agonists are metabolized by COMT?
entirely: Iso & dobutamine
partially: Epi, NE, DA
74
Which adrenergic agonist will cause the greatest decrease in airway resistance?
isoproterenol
lesser extent: Epi & ephedrine
none: NE, DA, dobutamine
75
Which adrenergic agonist will cause the greatest change in renal blood flow?
reduces: norepi
increases: dopamine
76
Which agent is best for vasoplegia?
norepi
77
Which adrenergic agonist cannot be given as an infusion?
ephedrine
## Footnote
Isoproterenol is rapidly metabolized by COMT, so infusion is the preferred route of administration.
78
drug of choice for cardiogenic shock and stress testing
dobutamine
79
80
the prototype sympathomimetic
epi
81
Epi infusion dose
0.01 - 0.2 mcg/kg/min
82
Epi receptor activity and effects
* a1, ß1, and B2
* more potent than norepinephrine at beta
* potent vasoconstrictor and bronchodilator
* may cause significant metabolic changes! ↑POCT
* HypoK due to a transcellular shift
83
The net effect of Epi depends on
1. the balance of the receptor types in the individual tissues and organs
1. dose
84
Organ response to epi
* more B2r (skeletal muscle): vasodilation
* more a1r (mesentery, kidneys): vasoconstrict
85
epi
Low dose vs high dose
* Low doses = beta (↑ HR, CO, inotropy, and pulse pressure; ↓SVR)
* High doses = alpha (↑SVR, ↓CO)
86
Epi is the ideal drug for..
anaphylaxis, shock, and ACLS
87
"epinephrine-reversal"
A-mediated pressor response
⬇️
B2-mediated depressor response
88
Epi will (reduce/prolong) the doA of locals.
prolong
89
should you use Epi to treat hypoTN from A2 blockers??
it can but may counterproductive due to "epinephrine-reversal"
## Footnote
A-mediated pressor response becomes B2-mediated depressor response
90
Norepi
receptor activity and effects
* mostly a1 & B; minimal B2
* minimal metabolic effect; no △POCT
* △HR may be insignificant; vasoconstriction stimulation of the baroreceptors to slow HR is countered by its B1 positive chronotropic effect.
* STRONGER systemic vasoconstriction then epi! (ischemia skeletal muscle, bowel, liver, kidney, and cutaneous)
* ↑ venous return by venous vasoconstriction
91
Are HR changes from Norepi clinically significant?
may be insignificant
its vasoconstriction stimulates baroreceptors to slow HR but its countered by its B1 positive chronotropic effect
## Footnote
mostly a1 and B1 effects. It has minimal B2 effects.
92
Norepi IV infusion dose
0.01 - 0.22 mcg/kg/min
93
The net effect of NE depends on..
the dose
## Footnote
epi net effect depends on both dose and organ's receptors
94
Hgih vs low dose Norepi
Low: B1 (↑ HR, CO, inotropy, dromotropy)
High: B1 & A (↓HR, systemic constriction, except for the coronary arteries)
## Footnote
dromotropy: conduction speed
95
T/F:
Epinephrine causes greater systemic vasoconstriction than Norepi.
False
opposite
96
T/F:
High doses of Norepi will cause systemic vasoconstriction including coronary arteries.
False!
the coronaries are spared
## Footnote
Low: B1 (↑ HR, CO, inotropy, dromotropy)
High: B1 & A (↓HR, systemic constriction, except for the coronary arteries)
97
NE's principal use
* ↑ total peripheral vascular resistance ➡️ ↑BP
* first-line therapy in distributive shock refractory to hypotension
98
Norepinephrine is a double-edged sword as its potent vasoconstriction risks (2)
volume depletion
&
ischemia to bowel, kidneys, liver
99
Dopamine receptor activity
by dose range
* Low (< 3 ug/kg/min): D1 (dilation, ↑ renal & splanchnic flow)
* Moderate (3 - 8 ug/kg/min): a1 & B1 in the heart & periphery (↑ contractility & BP)
* High (> 10 ug/kg/min): pure a1 agonist → BP
100
DA's complex functionality
wide range of dopaminergic & adrenergic receptors
101
How does dopamine increase CO?
positive chronotropic, inotropic, and dromotropic activity via B1
102
The dose-response to DA varies widely in the general population due to
genetics, individual pharmacokinetic differences, and comorbidity.
103
Types of dopamine receptors
* Postsynaptic D1: dilate renal, Gl, coronary, and cerebral
* Presynaptic D2: inhibit norepi release = dilate
* D2: pituitary gland, emetic center, kidney
104
What causes Dopamine's highly variable effect on different vascular beds ?
depends on dose used, receptor type & density on the vessels
105
Rapid metabolism of ___ necessitates administration as an infusion.
dopamine
106
DA has a useful & unique clinical effect to increase contractility and BP while increasing renal blood flow and urine output
but...
"Renal dose dopamine"/renal-protective effects are highly variable and largely unproven
107
T/F:
Dopamine may the prevent but not reverse acute kidney injury or failure.
False
the data are conclusive that dopamine **does not prevent or reverse** acute kidney injury or failure.
108
Due to unlikely benefit and the potential for these adverse effects, using dopamine to protect the kidneys should be abandoned
evidence that low-dose dopamine can be associated with CV, pulmonary, Gl, immune, and endocrine complications
109
Why is Renal-dose dopamine a thing even though its not proven?
* evidence of low dose infusions (< 3 ug/kg/min) increasing renal blood flow & urine output in healthy ppl
* dopamine increases renal blood flow via D1r & inhibits D2r norepi release
* people to try to apply this to renal patients & those at risk of decreased renal blood flow due to anesthesia or surgery
110
How are Epi and Norepi metabolized into vanilly mandelic acid?
111
Dopamine undergoes similar mechanisms (to epia nd norepi) of metabolic degradation by COMT and MAO. The end-product of DA metabolism is
homovanillic acid (HVA)
112
B3 receptors
locations & effects
primarily in adipose tissue
thermoregulation and lipolysis
but
effects of catecholamines stimulation are unclear
113
Non-selective Adrenergic Agonists: Synthetic Catecholamines
ISOPROTERENOL
DOBUTAMINE
114
T/F:
Dopamine is derived from Isoproterenol.
FALSE
Isoproterenol is derived from dopamine.
## Footnote
Dobutamine is derived from isoproterenol.
115
Isoproterenol
IV infusion dose
0.015 - 0.15 mcg/kg/min
## Footnote
*Barash 8th edition incorrectly states the dose of isoproterenol as 2 - 10 mcg/kg/min.
116
describe the potency of Isoproterenol
potent sympathomimetic with 1 and 2 activity.
2 - 3 times the potency of epinephrine and has **no A activity**.
117
Isoproterenol
she used to be popular but...
* was viewed as ideally suited to increase HR in those patients with heart block
* It tends to precipitate supraventricular and ventricular arrhythmias
* largely been replaced by transcutaneous or transvenous pacing
limited clinical use.
118
Isoproterenol
uses
right ventricular dysfunction and pulmonary congestion
though NO and prostaglandin I2 are more effective with fewer side effects.
119
For the most part, these agents have replaced isoproterenol as bronchodilators.
selective B2 agonists
120
Isoproterenol is rapidly metabolized by ___, so infusion is the preferred route of administration.
COMT
121
In terms of the adrenergic agonists, who's derived from who?
Dopamine
⬇️
isoproterenol
⬇️
dobutamine
122
Dobutamine
drip dose
2 - 20 mcg/kg/min
123
acts as a "pharmacological stress test"
Dobutamine
Chemical pacing with dobutamine is used in place of the patient exercising - this procedure illustrates how dobutamine affects the ANS.
124
Dobutamine is now less commonly used in cardiac surgery because
extending a cardiac infarction
&
increasing AV conduction (may turn AFIB into AFIB w/ RVR)
125
Dobutamine
receptor activity & effects
* synthetic, selective B1 agonist with some mild B2 effects
* ↑ HR & **inotropy**
* inotropic agent for pulmonary HTN as it decreases pulmonary arterial pressures & vascular resistance via B2
126
When to use dobutamine
* inotropic agent for pulmonary HTN as it decreases pulmonary arterial pressures & vascular resistance via B2
* organic heart disease, MI, and depressed myocardial states
127
Ephedrine exerts both direct and indirect actions on adrenoceptors with ___ actions predominating.
indirect
128
ephedrine
IV & IM dose
IV dose = 5 -25 mg
IM dose = up to 50 mg.
129
Ephedrine
direct vs indirect action
direct: both a and & receptors
direct B2 limits the increase in BP from a1-adrenoceptor activation
indirect: Norepi release
1. endocytosis of ephedrine into adrenergic presynaptic terminals
1. displaces norepi from secretory vesicles
1. NE activates A1 & B1 as usual
130
Ephedrine Tachyphylaxis
repeat administrations
deplete presynaptic norepi
so ephedrine is released from synaptic vesicles as a false neurotransmitter instead
131
T/F:
Ephedrine is not given as an infusion due to its metabolism.
False
tachyphylaxis
## Footnote
repeat administrations
deplete presynaptic norepi
so ephedrine is released from synaptic vesicles as a false neurotransmitter instead
132
T/F:
Ephedrine has potential for abuse.
True
It crosses the BBB with mild stimulating effects that may invite misuse
133
Ephedrine is typically dosed as a bolus, which onsets rapidly and may have a duration of
up to an hour based on the dose
134
T/F:
Ephedrine does not produce clinically worrisome hyperglycemia like epinephrine.
True
135
Ephedrine's effects are less pronounced and more prolonged than those of ___
epinephrine
136
Ephedrine vs Neo
OB
* Ephedrine was long preferred due to *incorrect* concerns about decreasing uterine blood flow
* Neo may now be preferable in treating anesthetic-induced hypotension in the parturient.
137
Ephedrine has multiple actions (positive inotropy and chronotropy). Who may this not be good for?
can increase 02 demand in those with coronary artery disease
138
Phenylephrine is structurally like ephedrine except that....
phenylephrine possesses a 4-hydroxyl group on the benzene ring
139
phenylephrine is almost purely ___-selective.
a 1
140
Beta-2 agonists are classified by doA
What are the classes?
short: albuterol, terbutaline, levalbuterol.
Long: salmeterol and formoterol
141
Pros and Cons of
Aerosolized B2-selective agents
bronchodilation and minimize cardiac stimulation/arrhythmias
but
*pure B2 selectivity does not occur!*
142
How do B2-selective drugs duplicate the functionality of the endogenous catecholamines on the ANS?
help to isolate the effect on the smooth muscle of the airway, uterus, GI tract, and systemic vasculature
143
___ properties of drugs such as albuterol and salmeterol are of primary value in our perioperative care of the patient
bronchodilatory
144
Chronic B agonist therapy
* may lead to receptor down-regulation = tachyphylaxis
* evidence of airway **hyperresponsiveness**
* chronic high doses: B2 selectivity wanes, and B1 effects such as tachycardia and arrhythmias may become apparent
145
Beta-2 agonists moA
increased intracellular cAMP
in uterine muscle, ↑cAMP = ↓Ca = uterine smooth muscle relaxation & tocolytic effect
146
Which Beta-2 agonists have a black box warning? why?
longer-acting agents; risk of asthma-related death
reports of severe asthma exacerbations in some patients using **salmeterol and formoterol**, possibly from developing airway hyperresponsiveness
147
What potent alpha agonist is the chemical precursor of epinephrine?
Norepi
## Footnote
precursor of norepi = dopamine
148
Which adrenoreceptor agonist is metabolized by the liver?
ephedrine
149
Would epi or norepi give you the greatest increase in MAP?
Norepi
150
Ephedrine metab
liver
* oxidative deamination
* demethylation
* aromatic hydroxylation
* conjugation
Metabolites: norepi & benzoic acid
## Footnote
Unlike the endogenous catecholamines, it is resistant to MAO & COMT.
