M&m: Adrenergic Agonists & Antagonists

Front 1

key concept regarding the classification of adrenergic agonists

Back 1

-adrenergic agonists can be categorized as direct or indirect
-direct agonists bind to the receptor, indirect agoists increase endogenous neurotransmitter activity

Front 2

key concept regarding the primary effect of phenylephrine

Back 2

-it is peripheral vasoconstriction with a concominant rise in systemic vascular resistance and arterial blood pressure

Front 3

key concept regarding clonidine

Back 3

-it appears to decrease anesthetic and analgesic requirements and to provide anxiolysis and sedation

Front 4

key concept regarding dexmedetomidine

Back 4

-its a novel lipophylic a-methylol derivative with a higher affinity for a2-receptors than clonidine
-it has sedative, analgesic, and sympatholytic effects that blunt many of the cardiovascular responses seen during the perioperative period

Front 5

key concept regarding long term use of clonidine or dexmedetomidine

Back 5

-it leads to super-sensitization and up-regulation of the receptors
-abrupt discontinuation of either one causes an acute withdrawl syndrome manifested by hypertensive crisis can occur

Front 6

key concept regarding the use of ephedrine during anesthesia

Back 6

-it is commonly used as a vasopressor during anesthesia, but its use should be viewed as a temprizing measure while the cause of hypotension is determined and remedied

Front 7

key concept regarding small doses of dopamine

Back 7

-doses of <2 ug/kg/min have minimal adrenergic effects, but activate dopaminergic receptors (specifically DA1), which are nonadrenergic receptors that vasodilate the renal vasculature and promote diuresis

Front 8

key concept regarding dobutamine

Back 8

-it has favorable effects on myocardial oxygen balance, which makes it a good choice for patients with CHF and CAD, especially if peripheral vascular resistance and heart rate are already elevated

Front 9

key concept regarding labetolol

Back 9

-lowers blood pressure without reflex tachycardia because of its combination of a- and B-effects

Front 10

key concept regarding esmolol

Back 10

-its an ultra short-acting B1-antagonist which reduces heart rate, and to a lesser extent blood pressure

Front 11

key concept regarding discontinuation of B-blockers

Back 11

-if discontinued for 24-48 hrs it may trigger a withdrawl syndrome characterized by hypertension, tachycardia, and angina

Front 12

the term adrenergic

Back 12

-originally referred to the effects of epinephrine (adrenaline), as opposed to the cholinergic effects of acetylcholine

Front 13

what is now known, though, about the sympathetic nervous system?

Back 13

-norepinephrine (noradrenaline) is the neurotransmitter responsible for most adrenergic activity

Front 14

neurotransmitters release in the SNS and PNS, both pre and postsynaptically

Back 14

parasympathetic nervous system:
-presynaptic: ACh
-postsynaptic: ACh

sympathetic nervous system:
-presynaptic: ACh
-postsynaptic: NE

Front 15

what is the exception to norepinephrine being the neurotransmitter of choice at postsynaptic sympathetic ganglia?

Back 15

-eccrine sweat glands and some blood vessels

Front 16

what are the anatomic differences between the sympathetic and parasympathetic nervous systems?

Back 16

-the sympathetic chain originates in the thoracolumbar (T1-L3) spinal cord (vs. craniosacral for parasympathetics)
-the postganglionic sympathetics are longer (ie. there is a greater distance between the ganglia and the effector organs for sympathetics) than parasmpathetics

Front 17

where are the main sympathetic ganglia?

Back 17

-superior cervical
-middle cervical
-inferior cervical
-celiac ganglion


*********************12-1******************************
-inferior mesenteric

Front 18

what sympathetic receptors are found in the eye, and what is the response to them?

Back 18

alpha1: causes contraction of the radial muscle (mydriasis)

B: causes ciliary muscle relaxation (far vision)

Front 19

adrenergic receptors in the salivary glands and response to them

Back 19

alpha1 and B2: increased secretion

Front 20

adrenergic receptors in the heart and response to them

Back 20

B1:
-increased heart rate
-increased conduction velocity
-inceased contractility

Front 21

adrenergic receptors in the lungs and response to them

Back 21

alpha1: bronchoconstriction

B2: bronchodilation

Front 22

adrenergic receptors in the pancreas and response to them

Back 22

alpha 1: decreased insulin secretion

B2: increased insulin secretion

Front 23

adrenergic receptors in the upper GI tract and response to them

Back 23

alpha1: sphincter contraction

B2: decreased tone and motility

Front 24

adrenergic receptors in the liver and response to them

Back 24

alpha 1 and B2: glycogenolysis and gluconeogenesis

Front 25

adrenergic receptors in the gallbladder and response to them

Back 25

B3: unknown

Front 26

adrenergic receptors in the abdominal blood vessels and response to them

Back 26

alpha1: constriction

B2: dilation

Front 27

adrenergic receptors in the bladder and response to them

Back 27

alpha 1: sphincter contraction

B2: detrusor relaxation

Front 28

synthesis of norepinephrine and epinephrine

Back 28

********************12-2*********

-the amino acid phenylalanine is made into tyrosine in the liver, then tyrosine is converted into Dopa in the postganglionic cytoplasm, where dopa is converted into dopamine, which is put into storage vesicles, where the dopamine is made into NE, which can be converted into epinephrine in the adrenal medulla
-NE is then released into the synaptic cleft by exocytosis

Front 29

what is the rate limiting step in norepinephrine synthesis

Back 29

hydroxylation of tyrosine to dopa

Front 30

termination of action of norepinephrine

Back 30

done in 3 ways:

-reuptake into the postganglionic nerve ending
-diffusion away from receptor sites
-metabolism by monoamine oxidase or catechol-O-methyltransferase

Front 31

what can be said about the step where norepinephrine is taken back up by the postganglionic nerve ending?

Back 31

its inhibited by TCAs

Front 32

metabolism of norepinephrine and epinephrine

Back 32

************12-3****************

-is done in either the nerve endings or the liver, with the common end product of MAO or COMT being VMA (vanillylmandelic acid)
-in the liver NE is made into normetanephrine and epi into metanephrine by COMT, and these are converted by MAO into VMA
-in nerve endings both NE and Epi are converted by MAO into 3,4-dihydroxymandelic acid, which is converted by COMT into VMA

Front 33

what does prolonged adrenergic activation lead to?

Back 33

-desensitization and hyporesponsiveness to further stimulation

Front 34

division of types of adrenergic receptors

Back 34

-into 2 general categories: alpha and beta
-each has at least 2 subtypes

Front 35

alpha receptor subtypes

Back 35

-divided into a1 and a2, which have been further divided by molecular cloning techniques into a1A, a1B, a1D, a2A, a2B, a2C

Front 36

B receptor subtypes

Back 36

-divided into B1,2,3

Front 37

what are all a and B receptors linked to?

Back 37

G proteins

Front 38

G proteins

Back 38

-heterotrimeric receptors made up of a,b, and y subunits

*********************12-4*****************************

Front 39

adrenergic receptor linkage to G proteins

Back 39

-each different adrenoreceptor is linked to a specific G protein, each of which has a unique effector

Front 40

what is common about all of the G proteins adrenoreceptors are linked to?

Back 40

they all use GTP as a cofactor

Front 41

which G protein are a1 receptors linked to, and what is its action?

Back 41

-Gq
-activates phospholipases

Front 42

what G protein is a2 linked to, and what is its action?

Back 42

-Gi
-inhibits adenylate cyclase

Front 43

what G protein are B receptors linked to, and what is its action?

Back 43

-Gs
-activates adenylate cyclase

Front 44

a1-receptors in the body

Back 44

-they are postsynaptic adrenoreceptors located in smooth muscle throughout the body, including in the:

eye
lung
blood vessels
uterus
gut
GU system

Front 45

what does activation of a1 receptors lead to?

Back 45

-an increase in intracellular Ca, leading to muscle contraction

thus their activation causes:
-mydriasis: pupillary dilation due to contraction of the radial eye muscles
-bronchoconstriction
-vasoconstriction
-uterine contraction
-contraction of sphincters in the GI and GU systems
-also inhibition of insulin secretion and lipolysis

Front 46

a1 receptors and the heart

Back 46

-the myocardium has a1 receptors, which cause slightly positive inotropic and negative chronotropic effects

Front 47

with this said, what is the most important cardiovascular effect of a1 receptors?

Back 47

-vasoconstriction, which causes increased peripheral vascular resistance, inc LV afterload, and an inc in arterial BP

Front 48

what happens with a1 receptors during myocardial ischemia?

Back 48

-an enhanced coupling of a1 receptors with agonists

Front 49

location of a2 receptors

Back 49

-in contrast to a1 receptors, are primarily located on presynaptic nerve terminals

Front 50

activation of a2 receptors

Back 50

-their activation leads to inhibition of adenylate cyclase activity, which leads to decreased entry of Ca into the nerve terminal, which limits exocytosis of storage vesicles that contain NE, thus creating a negative feedback loop that inhibits further NE release from the nerve terminal (further meaning after the initial NE that is released due to adrenergic/sympathetic activation)

Front 51

where else are a2 receptors located?

Back 51

-vascular smooth muscle the CNS contain postsynaptic a2 receptors

Front 52

what do vascular smooth muscle a2 receptors cause?

Back 52

vasoconstriction

Front 53

what do CNS postsynaptic a2 receptors cause?

Back 53

-sedation and a reduction of sympathetic outflow, which leads to peripheral vasodilation and lower blood pressure

Front 54

where is the most important place B1 receptors are found?

Back 54

-the heart

Front 55

stimulation of cardiac B2 receptors

Back 55

-activates adenylate cyclase, which converts ATP tp cyclic AMP and initiates a kinase phosphorylation cascade, which has positive chronotropic (increased HR), dromotropic (increased conduction), and inotropic (increased contractility) effects

Front 56

B2 receptor location

Back 56

-postsynaptically in smooth muscle and gland cells

Front 57

mechanism of action of B2 receptor activation

Back 57

-same as B1, activation of adenylate cyclase

Front 58

despite the commonality of action after activation with B1 receptors, what does activation of B2 receptors produce?

Back 58

relaxation of smooth muscle, resulting in:

-bronchodilation
-vasodilation
-relaxation of the uterus, gut, GU tract

-also stimulates glycogenolysis, lipolysis, gluconeogenesis, and insulin release

Front 59

what else do B2 agonists do?

Back 59

-activate the sodium-potassium pump, which drives K intracellularly, and can lead to hypokalemia and dysrhythmias

Front 60

B3 receptors

Back 60

-found in the gallbladder and brain adipose tissue
-role is unknown, but thought to play a role in lipolysis and thermogenesis in brown fat

Front 61

general point about adrenergic agonists

Back 61

-they can interact with varying degrees with different adrenergic receptors, with overlapping effects that can make their end result difficult to predict, for example epi stimulates a1, a2, B1, and B2, and the net effect will depend on the vasoconstriction of a1, positive inotropicity of B1, versus the vasodilation of a2 and B2, and futhermore these differences will change at changing doses

Front 62

classification of adrenergic agonists

Back 62

direct or indirect

Front 63

mechanism of action of direct agonists

Back 63

bind directly to the receptor, and stimulate it

Front 64

mechanism of indirect agonists

Back 64

-they increase endogenous neurotransmitter activity, by either increased release or decreased reuptake

Front 65

why is the differentiation of the mechanism of action between direct and indirect agonists important?

Back 65

-because some patients can have abnormal endogenous norepinephrine stores

Front 66

what can cause abnormal endogenous NE stores?

Back 66

-some antihyperensives
-MAOIs

Front 67

treatment of these patients

Back 67

-should treat hypotension with direct agonists, as their response to indirect agonists will be altered

Front 68

what is another feature distinguishing adrenergic agonists from each other?

Back 68

their chemical structure

Front 69

adenergic agonist structure

Back 69

********************12-5*********

-adrenergic agonists with a 3,4-dihydroxybenzene structure are known as catecholamines

Front 70

catecholamine metabolism

Back 70

-catecholamines are typically short acting due to metabolism by monoamine oxidase and COMT (therefore patients taking MAOIs or TCAs may have an exaggerated response to them)

Front 71

what are the naturally occuring catecholamines?

Back 71

-epinephrine
-norepinephrine
-dopamine

Front 72

synthetic catecholamines

Back 72

-developed by changing the side chain structure (R1, R2, or R3)
-include isoproterenol and dobutamine
-tend to be more receptor specific

Front 73

phenylephrine

Back 73

-a noncatecholamine with primarily direct a1 agonist activity (though at high doses may stimulate a2 and B receptors)

Front 74

primary effect of phenylephrine

Back 74

-peripheral vasoconstriction with a concomitant rise in SVR and arterial BP

Front 75

effect of phenylephrine on the heart

Back 75

-a reflex bradycardia can reduce cardiac output
-coronary blood flow increases, because any vasoonstriction of the coronaries is overridden by vasodilation induced by the release of metabolic factors

Front 76

summary of phenylephrine effects

heart rate
MAP
CO
PVR
bronchodilation
renal blood flow

Back 76

HR: ↓
MAP: ↑↑↑
CO: ↓
PVR: ↑↑↑
bronchodilation: 0
renal blood flow: ↓↓↓

Front 77

giving phenylephrine

Back 77

-can give small IV boluses of 50-100 ug (0.5-1 ug/kg) to reverse hypotension causes by peripheral vasodilation (ie. from a spinal)
-can use a continuous infusion of 100 ug/ml at a rate of 0.25-1 ug/kg/min

Front 78

what is the problem with an infusion of phenylephrine?

Back 78

-it will maintain the BP at the expense of renal blood flow
-also get tachyphylaxis requiring increasing doses of the infusion

Front 79

what is the prototypical a2-agonist?

Back 79

methyldopa

Front 80

methyldopa

Back 80

-an analog of levodopa, which enters the norepinephrine synthesis pathway and is converted to a-methylnorepinephrine and a-methylepinephrine, false transmitters which activate a-adrenoreceptors, particularly central a2 receptors

Front 81

effects of methyldopa

Back 81

-activation of central a2-receptors results in diminished norepinephrine release and sympathetic tone, and the resulting fall in peripheral vascular resistance leads to a drop in arterial BP
-renal blood flow is maintained or increased

Front 82

when does methyldopa reach its peak effect?

Back 82

within 4 hours

Front 83

use of methyldopa in the real world

Back 83

-since it relies on metabolites to work, it is being replaced by direct acting a2-agonists
-is still indicated for treating high blood pressure in pregnancy

Front 84

direct a2-agonists

Back 84

clonidine and dexmedetomidine

Front 85

uses of clonidine

Back 85

-used for its antihypertensive effect (by decreasing SVR) and negative chronotropic effects
-also used for its sedative properties

Front 86

clonidine use in anethetics

Back 86

-has been investigated for use given oral, IM, IV, transdermal, intrathecal, and epidural
-decreases anesthetic and analgesic requirements (decreases MAC)

Front 87

clonidine dose (oral, IM, IV transdermal, intrathecal, and epidural)

Back 87

-oral: 3-5 ug/kg

-IM: 2 ug/kg

-IV: 1-3 ug/kg

-transdermal: 0.1-0.3mg released per day

-intrathecal: 75-150 ug

-epidural: 1-2 ug/kg

Front 88

what has clonidine been shown to do during general anesthesia?

Back 88

-enhance intraoperative circulatory stability by reducing catecholamine levels

Front 89

clonidine in regional anesthesia

Back 89

-prolongs the duration of the block, including in peripheral nerve blocks
-its direct effects on the spinal cord are mediated through postsynaptic receptors in the dorsal horn

Front 90

other benefits of clonidine

Back 90

-decreased postop shivering
-inhibition of opioid-induced muscle rigidity
-attenuation of opioid withdrawl syndromes
-treatment of some chronic pain syndromes

Front 91

side effects of clonidine

Back 91

-bradycardia
-hypotension
-sedation
-respiratory depression
-dry mouth

Front 92

dexmedetomidine

Back 92

-a novel lipophylic a-methylol derivative with a higher affinity for a-receptors than clonidine
-similar to clonidine and amethyldopa, it reduces sympathetic outflow

Front 93

dexmedetomidine effects

Back 93

-has sedative, analgesic, and sympatholytic effects that blunt many of the CV responses seen during surgery
-reduces IV and inhaled anesthetic requirements when used intraoperatively
-reduces need for analgesics and sedatives postoperatively, and also may be useful for sedating ventilated patients postoperatively or in the ICU

Front 94

what does the typical dexmedetomidine patient look like?

Back 94

-will appear sedated when undisturbed, but will arouse readily with stimulation

Front 95

side effects of dexmedetomidine

Back 95

-get hypotension and bradycardia, though rapid administration can elevate blood pressure

Front 96

common side effect with a2-agonists

Back 96

-although they are technically adrenergic agonists, they are sympatholytics since they reduce sympathetic outflow
-long term use can lead to supersensitization and up-regulation of receptors, and abrupt discontinuation can cause an acute withdrawl syndrome with a hypertensive crisis
-since dex has a higher affinity for the a2-receptors than clonidine, this syndrome might occur after discontinuation of dex after only giving it for 48 hours

Front 97

effects of epinephrine

Back 97

-eptors will raise cardiac output and myocardial oxygen demand by increasing contractility and heart rate (increases rate of spontaneous phase IV depolarization)
-a1 stimulation will decrease splanchnic and renal blood flow, but will increase coronary and cerebral perfusion pressure
-even though systolic blood pressure rises, B2 vasodilation in skeletal muscle will cause a drop in diastolic blood pressure
-B2 stimulation will also cause dilation of bronchial smooth muscle

Front 98

what is epi the principal treatment for?

Back 98

-anaphylaxis
-v-fib

Front 99

complications of epinephrine

Back 99

-cerebral hemorrhage
-coronary ischemia
-ventricular dysrhythmias

Front 100

what can be said about epi and anesthesia?

Back 100

-volatile anesthetics, especially halothane, potentiate the dysrhythmic effects of epi

Front 101

epi in emergency situations (ie shock, allergic reactions)

Back 101

-given as an IV bolus of 0.5-1 mg (depends on the situation severity)

Front 102

epi infusion

Back 102

-used to improve myocardial contractility and heart rate
-1mg in 250 ml dextrose 5% H2O, and run at 2-20 mcg/min

Front 103

epi in local anesthetics

Back 103

-used to decrease systemic absorption and increase the duration of action of local
-in concentrations of 1:200,000 (5 ug/ml) or 1:400,000 (2.5 ug/ml)

Front 104

epi vials

Back 104

-available in a concentration of 1:1000 (1mg/ml), 1:10000 (0.1 mg/ml; 100ug/ml); 1:100,000 (10 ug/ml) for peds

Front 105

summary of epinephrines effects

HR
MAP
CO
PVR
bronchodilation
renal blood flow

Back 105

HR: ↑↑

MAP: ↑

CO: ↑↑

PVR: ↑/↓

bronchodilation: ↑↑

renal blood flow: ↓↓

Front 106

effects of ephefrine

Back 106

-cardiovascular effects similar to epi: increased heart rate, blood pressure, contractility, and cardiac output
-is also a bronchodilator

Front 107

how does ephedrine differ from epi?

Back 107

-is much less potent
-has a longer duration of action since its a noncatecholamine
-has both direct and indirect effects
-stimulates the CNS (raises MAC)

Front 108

indirect actions of ephedrine

Back 108

may be due to:

-central stimulation
-peripheral postsynaptic norepinephrine release
-inhibition of norepinephrine reuptake

Front 109

using ephedrine during anesthesia

Back 109

-its often used as a vasopressor during anesthesia, and should be viewed as a temporizing measure while the cause of hypotension is identified and fixed

Front 110

for what type of patient is ephedrine the preferred vasopressor and why?

Back 110

-for obstetrics, because unlike direct acting a1-agonists it does not decrease uterine blood flow

Front 111

what other property has ephedrine been reported to have?

Back 111

-antiemetic, especially when treating hypotension following a spinal