ANS Pharm: Adrenergic Agonists Flashcards
Which vasopressors are removed from the cleft by reuptake? Which aren’t?
Dopamine, Epi, Norepi
NOT phenylephrine
How is phenylephrine removed from the synapse?
metabolized by MAO
This is why MAOIs with phenylephrine = HTN
which pressors are synethetic noncatecholamine vs endogenous catecholamines?
synethetic NONcatecholamine: neosynephrine
endogenous catecholamines: DA, epi, NE
The endogenous catecholamines are normally reuptaken via transporters, but what if they escape?
metabolized by MAO and COMT
T/F:
Both the SNS and PNS are response for fight or flight, as the ANS.
True
Phenylephrine receptor activity
selective and direct A1 agonist
sympathomimetic
Clonidine and Precedex both act ____ to produce sedation, anxiolysis, decrease BP & HR and cause analgesia
centrally
Classes of drugs that modify the ANS
T/F:
The SNS and PNS usually work on the same end-organ at the same time.
False
usually do not
The ANS relies on these 2 NTs
ACh & NE
Which NTs work at each location?
-ganglionic
-postganglionic PNS
-postganglionic SNS
-ganglionic: ACh
-postganglionic PNS: ACh
-postganglionic SNS: NE
ACh is the PNS NT
NE is the SNS NT
(exceptions do exist)
the PNS and SNS of the ANS both target these organs/tissues
smooth muscle, cardiac muscle, glands
The somatomotor system is part of which nervous system?
CNS
somatic motor system: voluntary movements
In the (PNS/SNS) the ganglion is located closer to the target organ/tissue.
PNS
Which division of the nervous system targets skeletal muscle?
Somatomotor system of the CNS
Which Alpha selective drug affects Renal blood flow?
Neosynephrine; decreases it
(others do not)
How are the Alpha selective drugs each metabolized?
- Neo = MAO
- Clonidine = half life, half kidney UNCHANGED
- Precedex = Liver CYP
Abruptly stopping which alpha selective agent may cause rebound HTN?
clonidine
Phenylephrine is especially useful in …… states
low vascular resistance
Phenylephrine is almost exclusively a pure stimulant at A1 adrenoreceptors, causing….
venous AND arterial vasoconstriction
Neo vs. Norepi
Neo has similiar effects to NE
but
less potent and longer acting
BOTH risk end-organ damage (high dose/prolonged drip)
Why do you see bradycardia with Neo?
baroreceptor activity
Neo
dosing & gtt
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.
T/F:
Unlike natural and synthetic catecholamines, phenylephrine is not arrhythmogenic.
True
T/F:
The dose of phenylephrine needed to stimulate the a 1 receptor is much more than that for the a2 receptor.
False
LESS
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)
Phenylephrine overdose
- phentolamine (nonselective A-adrenergic antagonist)
- or maybe just wait it out since Neo doA is short
- DO NOT use a Beta blocker
Phenylephrine overdose
What is CONTRAINDICATED?
Beta blockers
may induce pulm edema & catastrophic, irreversible CV collapse
Where can we find Alpha-2 receptors?
- Presynaptic: NE-releasing neurons in the CNS and PNS (negative feedback mechanism reduces NE release)
- Postsynaptic: Smooth muscle and several organs
- Nonsynaptic: platelets
Alpha-2 receptors by location and their effect
The a2 agonists have long been used in treating…
- hypertension
- ADHD
- panic disorders
- drug and alcohol withdrawal
- sedation
- sympatholysis
- reducing anesthetic requirements
these agents can modify the ANS!
Clondine vs. Precedex
A2:A1 binding ratio
partial agonist of the A2 receptor
clonidine
T/F:
Clondine can reduce IV anesthetic and volatile requirements.
True
but only mild effect
T/F:
Clondine will not cause respiratory depression, but Precedex can.
False
neither do
clonidine vs. precedex
Where do they act?
clonidine: central presynaptic receptors (medulla & locus coeruleus)
precedex: brain and SC; inhibits neuronal firing
both alpha2 agonists
Clonidine & Precedex both block ___ release
norepinephrine
this is how clonidine causes vasodilation this way & precedex modifies pain signal propigation
Clonidine
Its central action is its predominant clinical activity. What effects does this have?
decreases SNS outflow ➡️ sympatholysis, lowering HR & BP
How does clonidine cause centrally induced sedation?
via a2 receptors in the locus coeruleus
Clonidine produces centrally mediated pain modification and analgesia via …
activity at the dorsal horn of the spinal cord
Aside from rebound HTN, what can happen when abruptly stopping clonidine?
tachycardia and arrhythmia
taper it!
Clonidine has been in use for decades and with demonstrated utility in various conditions:
- diagnosing pheochromocytoma
- opiate and nicotine withdrawal manifestations
- HTN
in general, A2 agonists treat
* hypertension
* ADHD
* panic disorders
* drug and alcohol withdrawal
* sedation
* sympatholysis
* reducing anesthetic requirements
T/F:
Clonidine’s ANS effects are strong enough that sedative/hypnotic effects can happen in anti-hypertensive doses.
True
its action centrally in the locus coeruleus provides the sedative/hypnotic
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
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!
dose-dependent sedation, analgesia, and sympatholytic effects
T/F:
Dexmedetomidine is a postsynaptic a2 agonist at peripheral receptors.
false!
PREsynaptic
CENTRAL receptors
T/F:
dexmedetomidine can cause very concerning hypotension and bradycardia, especially with higher and rapid dosing.
True
Prcedex
Hypertension, tachycardia, and dysrhythmias show us that….
a complex distribution of central a2 receptors at which the drug acts.
less appreciated ANS effects of dexmedetomidine
- dry mouth,
- impaired Gl motility,
- inhibition of renin release,
- increased GFR,
- decreased insulin release
inhibition of norepinephrine release by dexmedetomidine
plays a role in modifying the propagation of pain signals.
Dexmedetomidine’s central sympatholytic effect exerts these 2 effects
- anti-shivering
- overall reduction in the neuroendocrine stress response to surgery
T/F:
Precedex can reduce emergence agitation in both adults and children.
True
How can Precedex cause transient HTN?
- Giving Precedex rapidly can stimulate postsynaptic A2 receptors
- these receptors are on arterial and venous circulations = vasoconstriction & HTN
- CNS effect (vasodilation) lags behind the peripheral response
- the CNS effect eventually catches up and overpowers the peripheral effect
Which A2 agonist is more protein bound?
precedex
Prece loves protein
T/F:
Ephedrine is a non-endogenous direct acting synthetic sympathomimetic.
False
indirect acting
non-endogenous & synthetic
noncatecholamine
DA, NE, Epi are endogenous
Ephedrine
receptor activity & effects
stimulates both A & B
myocardial stimulation, bronchodilation, vasoconstriction
the synthetic catecholamines
dobutamine
isoproterenol
adverse effects of using endogenous and synthetic catecholamines
HTN, arrhthymia and myocardial ischemia
EPI, NE, DA
Isoproterenol, dobutamine
the effects of endogenous and synthetic agonists are dependent on their specificity for which receptors?
a-and -adrenoreceptors and dopaminergic subtypes.
Appreciating the metabolism of the endogenous catecholamines helps us predict (2)
their clinical use and dosing.
Epinephrine and norepinephrine metabolism
catechol-O-methyl transferase & monoamine oxidase
⬇️
common metabolite, vanilly mandelic acid (VMA)
assayed as part of pheochromocytoma work-up
vanilly mandelic acid (VMA)
Epi & NE are metbolized to this common metabolite
noncatecholamine with both direct and indirect activity at adrenoceptors
Ephedrine
isoproterenol
vs
dobutamine
the synthetic catecholamine isoproterenol has a modified version, dobutamine
both have B1 & some B2 activity
Short-and long-acting B2-adrenoceptor agonists
short: albuterol
long: salmeterol
asthma, COPD, and airway hyperactivity during anesthesia
Dobutamine used more than isoproterenol due to its novel ability to…
enhance cardiac contractility and simultaneously reduce arterial vasomotor tone
Why give albuterol and salmeterol in aerosolized form?
minimizes side effects such
as anxiety, tremor, and restlessness
A non-selective adrenergic agonist acts…
on BOTH alpha and beta receptors
Why do we closely monitor patients on adrenergic agonists?
adverse events such as ischemia and arrhythmias
adrenergic agonists
can mimic the SNS in 1 of 2 ways
- direct receptor activation
- encourage endogenous catecholamine release
Aside from vasoconstriction, what 2 effects can adrenergic agonists give that are clinically desirable?
- bronchodilation
- myocardium stimulation
Which adrenergic agonists are metabolized by COMT?
entirely: Iso & dobutamine
partially: Epi, NE, DA
Which adrenergic agonist will cause the greatest decrease in airway resistance?
isoproterenol
lesser extent: Epi & ephedrine
none: NE, DA, dobutamine
Which adrenergic agonist will cause the greatest change in renal blood flow?
reduces: norepi
increases: dopamine
Which agent is best for vasoplegia?
norepi
Which adrenergic agonist cannot be given as an infusion?
ephedrine
Isoproterenol is rapidly metabolized by COMT, so infusion is the preferred route of administration.
drug of choice for cardiogenic shock and stress testing
dobutamine
the prototype sympathomimetic
epi
Epi infusion dose
0.01 - 0.2 mcg/kg/min
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
The net effect of Epi depends on
- the balance of the receptor types in the individual tissues and organs
- dose
Organ response to epi
- more B2r (skeletal muscle): vasodilation
- more a1r (mesentery, kidneys): vasoconstrict
epi
Low dose vs high dose
- Low doses = beta (↑ HR, CO, inotropy, and pulse pressure; ↓SVR)
- High doses = alpha (↑SVR, ↓CO)
Epi is the ideal drug for..
anaphylaxis, shock, and ACLS
“epinephrine-reversal”
A-mediated pressor response
⬇️
B2-mediated depressor response
Epi will (reduce/prolong) the doA of locals.
prolong
should you use Epi to treat hypoTN from A2 blockers??
it can but may counterproductive due to “epinephrine-reversal”
A-mediated pressor response becomes B2-mediated depressor response
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
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
mostly a1 and B1 effects. It has minimal B2 effects.
Norepi IV infusion dose
0.01 - 0.22 mcg/kg/min
The net effect of NE depends on..
the dose
epi net effect depends on both dose and organ’s receptors
Hgih vs low dose Norepi
Low: B1 (↑ HR, CO, inotropy, dromotropy)
High: B1 & A (↓HR, systemic constriction, except for the coronary arteries)
dromotropy: conduction speed
T/F:
Epinephrine causes greater systemic vasoconstriction than Norepi.
False
opposite
T/F:
High doses of Norepi will cause systemic vasoconstriction including coronary arteries.
False!
the coronaries are spared
Low: B1 (↑ HR, CO, inotropy, dromotropy)
High: B1 & A (↓HR, systemic constriction, except for the coronary arteries)
NE’s principal use
- ↑ total peripheral vascular resistance ➡️ ↑BP
- first-line therapy in distributive shock refractory to hypotension
Norepinephrine is a double-edged sword as its potent vasoconstriction risks (2)
volume depletion
&
ischemia to bowel, kidneys, liver
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
DA’s complex functionality
wide range of dopaminergic & adrenergic receptors
How does dopamine increase CO?
positive chronotropic, inotropic, and dromotropic activity via B1
The dose-response to DA varies widely in the general population due to
genetics, individual pharmacokinetic differences, and comorbidity.
Types of dopamine receptors
- Postsynaptic D1: dilate renal, Gl, coronary, and cerebral
- Presynaptic D2: inhibit norepi release = dilate
- D2: pituitary gland, emetic center, kidney
What causes Dopamine’s highly variable effect on different vascular beds ?
depends on dose used, receptor type & density on the vessels
Rapid metabolism of ___ necessitates administration as an infusion.
dopamine
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
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.
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
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
How are Epi and Norepi metabolized into vanilly mandelic acid?
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)
B3 receptors
locations & effects
primarily in adipose tissue
thermoregulation and lipolysis
but
effects of catecholamines stimulation are unclear
Non-selective Adrenergic Agonists: Synthetic Catecholamines
ISOPROTERENOL
DOBUTAMINE
T/F:
Dopamine is derived from Isoproterenol.
FALSE
Isoproterenol is derived from dopamine.
Dobutamine is derived from isoproterenol.
Isoproterenol
IV infusion dose
0.015 - 0.15 mcg/kg/min
*Barash 8th edition incorrectly states the dose of isoproterenol as 2 - 10 mcg/kg/min.
describe the potency of Isoproterenol
potent sympathomimetic with 1 and 2 activity.
2 - 3 times the potency of epinephrine and has no A activity.
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.
Isoproterenol
uses
right ventricular dysfunction and pulmonary congestion
though NO and prostaglandin I2 are more effective with fewer side effects.
For the most part, these agents have replaced isoproterenol as bronchodilators.
selective B2 agonists
Isoproterenol is rapidly metabolized by ___, so infusion is the preferred route of administration.
COMT
In terms of the adrenergic agonists, who’s derived from who?
Dopamine
⬇️
isoproterenol
⬇️
dobutamine
Dobutamine
drip dose
2 - 20 mcg/kg/min
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.
Dobutamine is now less commonly used in cardiac surgery because
extending a cardiac infarction
&
increasing AV conduction (may turn AFIB into AFIB w/ RVR)
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
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
Ephedrine exerts both direct and indirect actions on adrenoceptors with ___ actions predominating.
indirect
ephedrine
IV & IM dose
IV dose = 5 -25 mg
IM dose = up to 50 mg.
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
Ephedrine Tachyphylaxis
repeat administrations
deplete presynaptic norepi
so ephedrine is released from synaptic vesicles as a false neurotransmitter instead
T/F:
Ephedrine is not given as an infusion due to its metabolism.
False
tachyphylaxis
repeat administrations
deplete presynaptic norepi
so ephedrine is released from synaptic vesicles as a false neurotransmitter instead
T/F:
Ephedrine has potential for abuse.
True
It crosses the BBB with mild stimulating effects that may invite misuse
Ephedrine is typically dosed as a bolus, which onsets rapidly and may have a duration of
up to an hour based on the dose
T/F:
Ephedrine does not produce clinically worrisome hyperglycemia like epinephrine.
True
Ephedrine’s effects are less pronounced and more prolonged than those of ___
epinephrine
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.
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
Phenylephrine is structurally like ephedrine except that….
phenylephrine possesses a 4-hydroxyl group on the benzene ring
phenylephrine is almost purely ___-selective.
a 1
Beta-2 agonists are classified by doA
What are the classes?
short: albuterol, terbutaline, levalbuterol.
Long: salmeterol and formoterol
Pros and Cons of
Aerosolized B2-selective agents
bronchodilation and minimize cardiac stimulation/arrhythmias
but
pure B2 selectivity does not occur!
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
___ properties of drugs such as albuterol and salmeterol are of primary value in our perioperative care of the patient
bronchodilatory
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
Beta-2 agonists moA
increased intracellular cAMP
in uterine muscle, ↑cAMP = ↓Ca = uterine smooth muscle relaxation & tocolytic effect
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
What potent alpha agonist is the chemical precursor of epinephrine?
Norepi
precursor of norepi = dopamine
Which adrenoreceptor agonist is metabolized by the liver?
ephedrine
Would epi or norepi give you the greatest increase in MAP?
Norepi
Ephedrine metab
liver
- oxidative deamination
- demethylation
- aromatic hydroxylation
- conjugation
Metabolites: norepi & benzoic acid
Unlike the endogenous catecholamines, it is resistant to MAO & COMT.
