Alpha and Beta Adrenergic Receptor Antagonists Flashcards
What are the 2 Non-selective A1 and A2 receptor antagonists ?
1) Phentalomine
2) Phenoxybenzamine
What are the 4 Selective A1 Antagonists?
1) Prazosin (Minipress)
2) Terazosin (Hytrin)
3) Doxazosin (Cardura)
4) Alfuzosin (Uroxatral)
What are the 2 Selective A1a antagonists?
1) Tamsulosin (Flomax)
2) Silodosin (Rapaflo)
What is the only A2 antagonist?
Yohimbine
Alpha-1 Adrenergic Receptor Blockade Effects
1) Inhibits endogenous catecholamines or sympathomimetics amine induced vasoconstriction resulting in vasodilation
2) Vasodilation causes ↓ BP due to ↓ in PVR
3) Baroreceptor-mediated reflex response cause ↑ in HR, CO and fluid retention
4) Baroreflexes are exaggerated if the antagonist also blocks alpha 2 receptors (binding alpha2 receptors on nerve endings usually inhibits NE release)
Alpha-2 Adrenergic Receptor Blockade Effects
↑ Sympathetic flow from CNS and release of NE from nerve endings which in turn stimulates A1 and B1 receptors leading to ↑ BP and HR.
Effect of using the following Sympathomimetic when the patient has been on an Alpha-1 Blocker chronically:
1) Phenylephrine + Alpha-1 Blocker
2) Norepinephrine + Alpha-1 Blocker
3) Epinephrine + Alpha-1 Blocker
1) Phenylephrine (A1) + Alpha-1 Blocker = pressor response can be almost completely suppressed
2) Norepinephrine (A1,A2,B1) + Alpha-1 Blocker = Causes maximal cardiac stimulation and pressor response is only incompletely blocked b/c of residual stimulation of cardiac β1 receptors by NE
3) Epinephrine (A1, A2, B1, B2) + Alpha-1 Blocker = pressor response may be transformed to vasodepressor effects (↓ blood pressure) b/c of residual stimulation of β2 receptors in the vasculature with resultant vasodilation by epinephrine
Non-cardiovascular effects of Alpha Adrenergic Receptor Antagonists
1) A2 antagonist - Inhibition of insulin secretion
2) A1 antagonist - ↑ GI motility and prevention of ejaculation or cause impotence
Phentolamine Characteristics
1) Nonselective (A1 and A2), competitive, reversible antagonist.
2) IV form causes vasodilation and ↓ in BP within 2 mins and lasts 10 to 15 mins
3) ↓ in BP causes baroreceptor response which ↑ CO and HR
4) Can be administered IV or IM
Phentolamine Metabolization
Primarily by the liver
~13% of drug is excreted unchanged in the urine
Phentolamine Clinical Uses
1) Prevention or Tx of acute HTN due to pheochromocytoma and ANS hyperreflexia
2) Pre-op prevention of HTN - 5mg IV or IM (1mg for children) 1 or 2 hrs before surgery
3) Prevention or Tx of dermal necrosis following extravasation of catecholamines (5-10 mg
Which class of drugs should never be used in conjunction with Phentolamine?
Beta Blockers
Phenoxybenzamine (Dibenzyline) Characteristics
1) Nonselective (A1 and A2), irreversible antagonist.
2) Binding is insurmountable - once alpha blockade has been established, even massive doses of sympathomimetics are ineffective until Phenoxybenzamine is terminated by metabolism
3) Only available PO
4) Slow onset of action (up tp 60 mins to reach peak effect)
Phenoxybenzamine (Dibenzyline) cardiovascular effects
1) Hypotension (most common)
2) Orthostatic hypotension
3) Tachycardia
4) ↑ CO via baroreceptorreflex
5) ↑ Blood flow to skin, mucosa
Phenoxybenzamine (Dibenzyline) non- cardiovascular effects
1) Crosses the placenta
2) decreases blood sugar
3) Glycogenolysis
4) Miosis
5) Sedation, drowsiness and fatigue
6) Nasal stuffiness
7) Unable to ejaculate
Explain the warning for Phenoxybenzamine relating to the administration of B1 and B2 agonists?
Phenoxybenzamine binds and IRREVERSIBLY blocks A1 and A2 receptors, which leaves beta-adrenergic receptors unopposed. Administration of agonist that stimulate B1 and B2 receptors may, therefore, produce an exaggerated hypotensive response (B2) and tachycardia (B1).
Phenoxybenzamine Clinical Uses
1) Pre-op Tx of pressure and sweating in PTs with pheochromocytoma (start 1-3 wks prior to surgery)
2) Control of autonomic hyperreflexia in PTs with spinal cord transection
Phenoxybenzamine Dosing
1) Initially 10mg PO BID
2) Increase dose every other day to 20-4mg 2 to 3 times a day until optimal dosage is obtained
Under which circumstances should you NEVER operate on a phenochromocytoma patient?
If they have not had adequate blockade first
Yohimbine Caracteristics
1) Selective A2 receptor antagonist
2) Blocks A2 receptors on presynaptic nerve endings
3) Allows more release of NE from nerve ending
4) Causes increase in HR and BP
5) Used for body building and impotence
Selective A1 Adrenergic Receptor Antagonists characteristics
1) Competitive and reversible
2) Inhibit all 3 subtypes of post synaptic receptors (A1a, A1b, A1d)
3) They do not bind A2 receptors and release NE from nerve endings
Selective A1 Adrenergic Receptor Antagonists clinical uses
Tx of HTN and BPH
Selective A1 Adrenergic Receptor Antagonists Cardiovascular Effects
1) ↓ SVR which ↓ after load and BP
2) ↓ Venous return = ↓ preload, can ↓ CO
3) Greater vasodilation at veins when compared to arteries
4) No baroreceptor reflex
Selective A1 Adrenergic Receptor Antagonists Adverse Effects
Dizziness, headache and hypotension(most common)
Tamsulosin (Flomax) and Siladosin (Rapaflo) MOA
1) Both selective, competitive postsynaptic A1a antagonist
2) Slecetively inhibits A1a receptors in bladder and prostate
3) Improves urinary flow without causing peripheral vascular smooth muscle relaxation
4) Both have minimal effect on BP
Tamsulosin (Flomax) and Siladosin (Rapaflo) Side Effect
1) Nasal decongestion/rhinitis
2) Headache
3) Dizziness
4) Low risk of Hypotension
Beta Adrenergic Receptor Antagonist Effect
Antagonism results in decreased activation of the adenylate cyclase which decreases the concentrations of cAMP
How can Beta Adrenergic Receptor Antagnists agents be distinguished from one another?
By the following properties:
1) Relative affinity for B1 and B2 receptors (Beta selectivity)
2) Intrinsic Sympathomimetic activity (ISA)
3) Differences in lipid solubility
4) Membrane-stabilizing effects (Local anesthetic activity)
5) Differences in pharmacokinetic profile (ADME)
Examples of Non-selective Beta Antagonists agents
1) Propanolol
2) Nadolol
3) Sotalol
4) Timolol
5) Carvedolol
6) Labetalol
7) Carteolol
8) Pindolol
Which pts are safer with cardioselective drugs vs nonselective
Asthma COPD Asthma diabetes PAD (prevents B2 action of vasodilation)
Is selectivity pure in B blockers
no, it just means that they are less likely to affect non selective receptor.
drugs tend to lose their selectivity with higher doses
Which receptors do the following sympathomimetics bind to:
1) NE
2) EPI
3) Dopamine
4) Isoproterenol
5) Phenylephrine
6) Dobutamine
7) Ephedrine
1) NE - A1, A2, B1
2) EPI - A1, A2, B1, B2
3) Dopamine - A1, A2, B1
4) Isoproterenol - B1, B2
5) Phenylephrine - A1
6) Dobutamine - A1, A2, B1
7) Ephedrine - A1, B1, B2
Why do Tamsulosin (Flomax) and Siladosin (Rapaflo) Side Effect have such a low risk of hypotension?
Because they target A1a receptors only located in bladder and prostate. A1b and A1d are located in arteries and veins do not get affected by this these 2 drugs.
If PT has intraop hypotension who’s been on flomax, and you want to correct BP with phenylephrine, would you give a lower, normal or higher dose of phenylephrine?
normal - hypotension was not caused by antagonism of A1b and A1d receptors in blood vessels. Flomax only antagonizes A1a receptors in bladder and prostate.
Would you give a lower, normal, or higher dose to someone who has overdosed on beta blockers and is experiencing symptomatic bradycardia?
Higher does - because you have to out-compete the antagonist (BB) already onboard.
Examples of Selective Beta-1 Antagonists (aka cardioslelective agents)
1) Metoprolol
2) Atenolol
3) Esmolol
4) Acebutolol
5) Bisoprolol
6) Nebivolol
7) Betaxolol
Why are Selective Beta-1 Antagonists (aka cardioslelective agents) a better choice for OR use by anesthesia than over their non-selective counter parts
They do not antagonize B2 receptors and have less chance of causing bronchospasm
What is Intrinsic Sympathomimetic Activity (ISA) regarding Beta Antagonists
Means the BB has a partial agonist effect if concentration of endogenous NE is low (as in resting states)
when endogenous NE is high, BB effects will still be present
ISA agents can cause less direct myocardial depression and less brady
bottom line for ISA B blockers in anesthesia
never use ISA BBs in anesthesia unless as a last resort
pure antagonist vs partial antagonist
partial antagonist signifies the presence of ISA
Effect of Beta blockers with high lipid solubility
Cross BBB and decrease SNS outflow (↓ HR and CO)
at risk for neurologic sequelae such as:
seizures (overdose)
delerium
lethargy
nightmares/vivid dreams
Highly lipophilic Beta Blockers
1) Prpanolol
2) Nebivolol
Membrane Stabilizing Effect (MSA)
membrane stabilizing effect
ability to inhibit myocardial fast Na+ channels, which widens QRS and potentiates arrhythmias
only detectable in overdose situations
B Blockers with MSA
Acebutolol Betaxolol Metoprolol Pindolol Propanolol Carvedilol Labetalol
B Blockers with primary Hepatic and secondary Renal clearance
Timolol, Pindolol, Acebutolol, Betaxolol
B blockers with Hepatic clearance only
Propanolol, Metoprolol, Labetalol, Nebivolol
B Blockers that undergo Renal clearance only
Cartelol, Nadolol, Atenolol, Sotalol
halflife of esmolol
9 mins
B-blockers with intrinsic sympathomimetic activity (ISA)
Labetalol
Acebutolol
Pindolol
B blocker uses
essential HTN manage CHF angina pectoris Acute coronary syndrome hypertrophic obstructive coronary syndrome intraoperative myocardial ischemia suppress cardiac dysrhythmias ventricular rate control in afib/flutter migraine prophylaxis pheochromocytome (always alpha-block first) open angle glaucoma (topical)
perioperative Beta blocker Use
sometimes used perioperatively in pts at risk for myocardial ischemia and to decrease mortality associated with the operation. i.e.
known CAD
positive preop stress test
LV hypertrophy
Diabetes
General resting HR goal with perioperative B blockade
65 to 80 bpm
Beta Blockers’ MOA
- 1) ↓ Slope of phase 4 spontaneous depolarization
2) ↓ Automaticity
3) ↓ Sinus rate
4) Slows AV nodal conduction velocity, ↑refractory period of the AV node, and lengthens PR interval
5) Negative chronotropic , dromotropic and inotropic effects
Effect of Beta blockers with high lipophilicity (propranolol) on baroreceptor reflex?
resets the baroreceptor reflex downward, leading to a decreased total PVR (meaning its harder for the reflex to respond to decreases in TPR)
(T/F?) ALL Beta Blockers lower BP?
True - its due to ↓ PVR which leads to ↓ afterload
do B blockers reduce BP in pt with normal BP?
not generally
they work best in the presence of preexisting increased SNS activity
Why is a beta blocker use in reduced EF a core measure?
they reduce rate of LV hypertrophy development by:
decreasing PVR (afterload) and thereby reducing myocardial oxygen demand
decreased HR increases diastolic filling time, improving vent function and coronary perfusion
overall, relationship between myocardial oxygen supply and demand is improved
When is the effect of B blockers highest?
In the presence of increased SNS outflow:
exercise
cardiac failure
Can B blockers block the effects of Ca++, glucagon, or digoxin?
No, they all used alternate pathways that do not involve the B receptors
which agents reduce portal pressure
classic nonselective B blockers (blocking B2 reduces splachnic vasoconstriction, reducing blood flow)
propanolol
nadolol
what B blockers are avoided in diabetic pts
non selective (use Lopressor if possible) B2 blockade decreases glycogenolysis and pancreatic glucagon stimulation
B blockers in hypoglycemia
all B blockers all can mask effect of catecholamine secreted during hypoglycemia, blunting visible effects (tachy, tremor, nervousness)
B blocker induced hyperkalemia
very rare, really only pertinent in overdose
which drug has highest risk of CNS effects
Propanolol? (most lipophilic)
can cause memory loss and depression in addition to fatigue, lethargy and vivid dreams
preferred B blockers in gestation
low lipophilic (will not cross placenta)
adverse side effects in B antagonists
similar for all, but vary in magnitude and selectivity, ISA, degree of CNS penetration, method of excretion, etc.
relationship between B blocker effects and anesthesia drugs
additive effects may occur
B antagonist contraindications
sinus brady
2nd of 3rd degree HB
cardiogenic shock
decompensated HF
sick sinus syndrome
non selective B antagonists are contraindicated in bronchial asthma/bronchospastic disease
cardioselective B blockers may be used, but should be used with caution
Why are non-selective BBs avoided in the PT with PVD
Can cause cold hands and feet syndrome - bind and blocks B2 receptors in veins and arteries, causing vasoconstriction which ↓ circulation in the periphery.
all B blockers have what non life threatening side effect with a potentially negative psychosocial effect
sexual dysfunction
B blockers with anesthetic agents
myocardial depression exacerbation (enflurane is the worst) (least with isoflurane, sevoflurane, desflurane)
always avoid ketamine
can be used safely in perioperative period
Is B blocker held for surgery
never hold without a good reason
IV dose can be given if pt was NPO
risk of SNS overactivity with missed doses, increases risk of MI
which B blcoker should not be used perioperatively with inhaled anesthetics
Timolol - profound bradycardia has been observed in concomitant use
interaction of ketamine and B blockers
ketamine stimulates SNS, increasing SVR and afterload
B blockers prevent myocardial contractility increase, and HF may ensue
(similar to reason Epi is not used with B blockers)
which inhaled anesthics have the least additive effects with B blockers?
isoflurane
sevoflurane
desflurane
B blocker use in rebound HTN with withdrawal of clonidine
B1 and B2 receptors will be blocked, but not Alpha receptors, causing an unopposed alpha vasoconstriction, making their HTN worse.
B blockers with digoxin or Ca Channel blockers
use with caution: risk of bradycardia and heart block since both slow AV conduction and decrease HR
B blocker overdose treatment
First - Glucagon 2-10 mg IVP followed by 5 mg/hr (drug of choice)
Second - IV fluids, Atropine, CaCL2, catecholamines (high doses)
four B blockers that must know because they are commonly used in anesthesia setting
non selecrtive: propranolol, labetalol
selective: esmolol, metoprolol
Propanolol
lacks ISA
equal B1 and B2
highly lipophilic
strong membrane stabilizing at high doses
extensive FPE (multiple CYP 450 ezymes in liver)
high degree of individual variation of FPE
Propanolol’s active metabolite
4-Hydroxypropanolol
Propanolol clearance
primarily CYP 450
active metabolite 4-hydroxypropranolol
inactive metabolites
can reduce its own clearance due to decreased hepatic blood flow
high FPE necessitates much higher oral dose
what is the major factor in metabolization of propranolol
clearance greatly decreased in decreased blood flow
Propranolol protein binding
~90%
heparin and other high protein binding drugs increase free drug
propranolol onset and administration rate
onset: up to 15 min IV
no faster than 1mg/min, or slow IV infusion over 30 min.
Propanolol Dosing
0.25mg to 5mg IV
propranolol effects on coronary perfusion
B2 blockade causes some coronary vasoconstriction
decrease in HR and contractiliy decreaases myocardial oxygen demand
net effect is still a decrease in myocardial ischemia
propanolol effects with local anesthetics
decreases -amide clearance due to decreased hepatic blood flow AND inhibiting metabolism in liver
increases toxicity of bupivicaine and lidocaine
propanolol and clearance of opioids
substantially decreases FPE effect of fentanyl (2-4x as much reaches systemic circulation)
Should you decrease, keep the same, or increase the dose of fentanyl when a patient is on propranolol?
decrease it
Metoprolol pharmacokinetics
Dose 1-5mg IV onset: 1-5 min peak effect: 20 min duration: 5-8 hrs (highly variable) highly metabolized in liver (CYP 450)
Atenolol
no ISA
no MSA
low lipophilic
highly hydrophilic (high renal clearance)***
Esmolol dosing
ventricular rate control in Afib/flutter
noncompensatory sinus tach
short term treatment of tachycardia/HTN in periop based on physician’s judgment
Esmolol Immediate control dosing for tachy/HTN in OR
1 mg/kg bolus over 30 sec followed by 150 mcg/kg/min infusion if needed max infusion rate: 200 mcg/kg/min for tachy 300 mcg/kg/min for HTN
Esmolol Gradual control dosing for tachy/HTN in OR
500 mcg/kg IV over 1 min
followed by 4 min infusion at 50 mcg/kg/min
Esmolol Metabolism
metabolism occurs via esterases in cytosol of RBC’s
Esmolol in gestation
can cross placental barrier in high doses and/or extended use
Esmolol half life/duration/onset
9 min
10-30 min
2-5 min
Esmolol most common side effects
hypotension (dose related)
diaphoresis
Esmolol in hypovolemic patients
can attenuate reflex tachycardia, increasing risk of hypotension
Esmolol and Sux
blockade is prolonged
moderately prolonged clinical duration and recovery in mivacurium as well
Esmolol and propofol
significantly decreases propofol required to prevent pt movement in response to surgical skin incision
esmolol potentiates propofol (decreasing the dosing requirements)
Esmolol effect on injectable anesthetics
decreases dosing requirements
specifically propofol as well as others
Esmolol and catecholamines
B Blocking in presence of A stimulation can cause reduced CO in face of high SVR even in low doses
most highly cardiac selective agent
Nebivolol
Nebivolol
highest degree of B1 selectivity
endothelial NO-mediated vasodilation activity and antioxidant properties
Labetalol MOA
comptetitive antagonist at A1, B1, B2, and partial B2 agonist
Labetalol vs phentolamine and propranolol
1/10th to 1/5th A1 effect as phentolamine
1/4th to 1/3rd B effect as propranolol
ratio of Labetolol Beta to A1 blockade in oral and IV doses
3: 1 in oral dose
7: 1 in IV dose
Best clinical use for labetalol
when a pt is both tachycardic and hypertensive
what is the dose for continuous IV infusion for labetalol
It is NEVER given continuously
Labetalol onset/peak/duration
onset: 2-5 min IV
peak: 5-15
duration: 2-4 hrs
Labetalol starting dose
5-20 mg IV repeated every 10-15 min until desired effect is achieved
Labetalol uses
drug of choice when A and B blockade are needed:
catecholamine overdose
rebound HTN after clonidine withdrawal
pheochromocytoma
Other uses:
angina pectoris
aortic dissection
attenuate surgical stimulation of SNS (HR and BP)
Labetalol use in pregnancy
little placental transfer due to poor lipid solubility
no change in uterine blood flow
Labetalol adverse effects
hypotension (most common)
Coreg (Carvedilol)
competitive antagonist at A1, B1, B2
coreg uses
CHF management
LV dysfunction following MI
HTN
Drug of choice for pregnancy induced hypertensive crisis
Labetalol
poor lipid solubility
uterine blood flow not altered
