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CA-1 > Adrenergic Agonist And Antagonists > Flashcards

Adrenergic Agonist And Antagonists Flashcards

1
Q

What is the difference between direct and indirect adrenergic agonists

A

Direct adrenergic agonists
- bind to the receptor
Indirect adrenergic agonists
- increase endogenous neurotransmitter activity

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2
Q

What is the structure of all G protein coupled receptors

A

They are 7 transmembrane helices connected by extracellular and intracellular loops

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3
Q

Describe the subunits of G proteins

A
  • G proteins are trimmers
    • abg trimers
  • In resting state abg- trimmer is bound to GDP
  • when activated
    - GDP dissociates from the a subunit
    - GTP binds to the bg subunits
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4
Q

What are the functions of the Ga subunit

A
  • the Ga subunit has many different subtypes
    - inhibits or stimulates adenylyl cyclase
    - activates phospholipase C
    - inhibits voltage-gated ca++ channels
    - activates GPCR kinases
    - activates nitrogen activated protein kinase cascade
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5
Q

What are the functions bg dimmer subunit of GPCR

A
  • Bg subunit dimer
    - activates potassium channels
    - activates protein kinases
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6
Q

What receptors and what are the main effects of the Gai subunit

A
  • inhibits adenylyl cyclase to decrease cAMP formation
  • associates with
    • cannabinoid
    • catecholamine
    • histamine
    • opioid and
    • serotonin receptors
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7
Q

What receptors and what are the resulting effects of the Gas subunit

A

Gas
- stimulates adenylyl cyclase
- increases cAMP formation
- binds to
- catecholamines
- histamines
- serotonin and
- other receptors

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8
Q

What are the receptors and effects of Gaq binding

A
  • Gaq
    - activates phospholipase C
    - increases the production of a second messenger IP3 and DAG => activates PLC
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9
Q

What neurotransmitter is released by all preganglionic sympathetic fibers and all parasympathetic (pre and post ganglionic) fibers

A

Acetylcholine

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10
Q

What neurotransmitter is released by postganglionic sympathetic fibers

A

Norepinephrine

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11
Q

What are the 3 ways in which the activity of norepinephrine is terminated after its release

A
  • reuptake into post ganglionic nerve endings (primary)
  • norepinephrine diffuses from receptor site to non-neuronal cells and is metabolized by COMT to
    - MAOIs or
    - repackaged into vesicles
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12
Q

How do cocaine amphetamine and TCAs affect the activity of the norepinephrine transporter on neuronal cells

A
  • Norepinephrine transporter on neuronal cells facilitate the removal norepinephrine from synapse
    - cocaine amphetamine and TCAs
    - inhibit the activity of this transporter
    - dec norepinephrine reuptake from synapse
    - hence the sympathomimetic or stimulatory side effects of these meds
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13
Q

What is the pathway of phenylalanine conversion to epinephrine and what are the catalysts

A
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14
Q

What G protein is the a1 receptor linked to and what is the function

A
  • a1 adrenergic receptor
    • linked to Gq
    • stimulates phospholipase
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15
Q

What G protein is the a2 receptor linked to and what is the function

A

A2 adrenergic receptor is linked to
- Gi which
- inhibits cAMP

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16
Q

What G protein is the b receptor linked to and what is the function

A

B adrenergic receptors are linked to Gs
- which stimulates cAMP

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17
Q

What is the effect of a1 activation

A
  • Activation of a1 receptors leads to
    • Gq => phospholipase
    • releases intracellular ca++
    • leads to constriction of smooth muscles
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18
Q

Where are a1 receptors primarily located and what is the effect of their activation

A
  • a1 receptors are located on post synaptic nerve terminals ==> ie on smooth muscle cells
    • activation causes smooth muscle constriction on the ff. organs
  • eye radial muscles => dilation/mydriasis
  • lung => bronchoconstriction
  • blood vessels => vasoconstriction
  • uterus => uterine contractions
  • GI/GU => sphincter constriction
  • inhibits insulin secretion
  • inhibits lipolysis
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19
Q

What is the primary effect of a1 receptor stimulation on the heart

A
  • vasoconstriction which
    • increases systemic vascular resistance
    • increases arterial blood pressure
    • increases left ventricular afterload
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20
Q

Where are a2 adrenergic receptors located and what are the effects of their stimulation

A
  • a2 adrenergic receptors are located
    • presynaptic nerve terminals
    • coupled with Gi => inhibits cAMP
    • dec intracellular ca++
    • limits exocytosis of norepinephrine for vesicles
  • acts as a neg feedback loop for norepinephrine
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21
Q

How does post synaptic a2 receptor stimulation cause vascular vasoconstriction

A
  • a2 receptor is coupled with Gi which inhibits cAMP
  • low cAMP => decrease the activation on protein kinase A
    • PKA is normally activated by cAMP => results in vasodilation
      - by inhibiting cAMP and PKA a2 activation results in vasoconstriction
  • cAMP usually inhibits ca influx
    • dec cAMP =>inc ca influx
    • smooth muscle contraction
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22
Q

What are the central effects of a2 receptor stimulation

A

In the CNS postsynaptic a2 receptor stimulation
- causes sedation
- reduces sympathetic outflow
- causes peripheral vasodilation and
- lower blood pressure

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23
Q

On which b receptors are epinephrine and norepinephrine equipotent

A

B1

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24
Q

On which b receptors is epi > norepinephrine . How is this difference obscured

A
  • epi is more potent than norepinephrine on b 2 receptors
  • the more potent actions of norepinephrine on alpha receptors obscured this difference
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25
Q

Where are b1 receptors primarily located

A
  • b1 receptors
    • postsynaptic membranes of the heart
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26
Q

What are the effects of b1 receptor stimulation

A
  • b1 stimulation
    • activates cAMP formation
    • initiates PKA activation
    • In the heart PKA phosphorylates L type ca++ channels and causes
    • ca++ influx in the cardiac action potential
      - this increases cardiac contractility (ionotropy )
      - leads increased depolarization of SA and AV nod=> inc heart rate (chronotropy)
  • inc ionotropy and chronotropy indirectly increases CO and inc blood pressure
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27
Q

Where are beta 2 receptors located

A

B2 receptors are located on
- smooth muscle cells
- gland cells
- ventricular myocardial

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28
Q

What is the pathway for b2 activation and what are the effects

A
  • b2 stimulation results in
    • Gs pathway => inc cAMP
    • which relaxes smooth muscles and leads to
    • bronchodilation
    • vasodilation
    • uterine tocolysis
    • gut and bladder relaxation
  • lipolysis
  • gluconeogenesis
  • insulin release
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29
Q

What is the result of D1 receptor activation

A

D1 activation
- vasodilation of
- kidney
- intestine and
- heart

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30
Q

What is the effect of D2 receptor stimulation

A

D2 receptor stimulation
- antiemetic action of
- droperidol and
- haloperidol

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31
Q

Direct adrenergic agonists

A

Bind receptor directly

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32
Q

Indirect adrenergic agonists

A

Increase endogenous neurotransmitter activity
For example
- increase release of norepi or
- dec reuptake of norepi

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33
Q

Which subset of pts should be treated with only direct acting agonists only

A
  • pts with abnormal endogenous norepi stores
  • those on MAOIs and certain antihypertensives
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34
Q

What are catecholamines

A

Adrenergic receptors with 3,4 dihydroxybezene structure

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35
Q

Why are catecholamines short acting

A

Because they are metabolized rapidly by
- monoaminde oxidase and
- catecholamines O methyltransferase

36
Q

What are the naturally occurring catecholamines

A
  • norepi
  • epi
  • dopamine
37
Q

Why are MAOIs and TCAs dangerous for pts being given catecholamines

A
  • they inhibit MAO and COMT
    • thereby preventing the metabolism of catecholamines and
    • leads to exaggerated catecholamine responses
38
Q

Discuss reflex bradycardia

A

This is a carotid baroreceptor response to increased blood pressure
- eg administering phenylephrine causes vasoconstriction which increases blood pressure
- rise in blood pressure is sensed by carotid baroreceptors which signal the brain stem =>parasympathetic nervous system is activated via vagus nerve => Acetylcholine is released which results in dec heart rate and reflex bradycardia

39
Q

What class of drug is phenylephrine

A
  • selective a1 agonist
  • non catecholamine
40
Q

What’s the difference between vasopressors and vasoactive agents

A
  • vasopressors act specifically to vasoconstriction peripheral vasculature
  • epi
  • nopepi
  • dopamine
  • phenylephrine
  • ephedrine
41
Q

What is the duration of action of phenylephrine

A
  • short 15min
42
Q

What kind of hypotension is phenylephrine effective for

A
  • hypotension that results from peripheral vasodilation
    • does not act on the heart. Is a true pressor => peripheral vasculature only
    • treat mechanism not number
    • aortic stenosis - heart pushing against fixed defect
    • goal: dec HR for inc LV filling
      • phenylephrine will inc SVR with reflex bradycardia
43
Q

What is the dosing of phenylephrine

A
  • blouses 50 -100mcg
    • comes as a 1% soln
      • 10mg/1mL = 10000mg/mL => dil 1/10
      • 100mcg/mL
44
Q

What adrenergic receptor agonist is clonidine

A

Clonidine is a2 agonist

45
Q

What are the uses of clonidine by mechanism

A
  • Antihypertensive and negative chronotrope
    • a2 activity neg feedback via Gi
    • peripheral vasodilation
  • Sedation and anxiolysis
    • central a2 activity
    • enhances intraoperative circulation stability by reducing catecholamine levels
46
Q

what are the effects of clonidine on regional anesthesia

A
  • clonidine prolongs the duration of blocks
47
Q

what are the postoperative benefits of clonidine

A
  • dec postoperative shivering
    • a2 receptors in the hypothalamus => temperature modulating center of brain
    • a2 stimulation leads to thermoregulation
  • inhibition of opioid -induced muscle rigidity
  • attenuation of opioid withdrawal symptoms
  • tx for acute post operative pain
48
Q

What are the side effects of clonidine

A
  • respiratory depression
  • dry mouth
  • hypotension
  • sedation
49
Q

What is the half life of clonidine

A

12-14hrs

50
Q

What is the a2:a1 receptor specificity ratio for clonidine vs Dexmedetomidine

A

Clonidine a2:a1
- 200: 1
Dexmedetomidine a2:a1
- 1600: 1

51
Q

What is the half life of Dexmedetomidine

A

2-3hrs

52
Q

What are the effects of dexmedetomidine

A
  • sedation and analgesia
    • a2 receptors in locus ceruleus and spinal cord
  • sympatholytic
    • blunts cardiovascular responses
53
Q

What are the advantages of using dexmedetomidine

A
  • reduces the need for iv and inhaled anesthetics
54
Q

What makes dexmedetomidine particularly safe for PACU use

A
  • does not cause respiratory depression
55
Q

What is the dosing of dexmedetomidine

A

Loading dose
- 1mcg/kg over 10min
Infusion
- 0.2 — 1mg/kg/hr (sedation)

56
Q

Does phenylephrine have any effect on the heart

A

NO
It is a pure vasopressors

57
Q

What are the effects of long term clonidine and dexmedetomidine use

A
  • receptor upregulation
  • super sensitization of receptors
  • these cause acute withdrawal syndrome with abrupt discontinuation of med
  • can occur in only 48hrs of dexmedetomidine use
58
Q

Where is epinephrine synthesized

A

Adrenal medulla

59
Q

Vasopressin is a pure pressor discuss mechanism of action

A
  • V1 receptor binding on vascular smooth muscle
    • coupled with phospholipase C => inc intracellular ca++ => vasoconstriction
  • V2 receptor binding renal cells
    • renal water retention (antidiuretic)
    • increases preload
    • this is only with the administration of DDVAP not the vasopressin drips we use for shock and hypotensive states which are predominantly V1
60
Q

What is the dosing of vasopressin for adults

A

0.01 - 0.1U/min
- Infusion dose => 0.01- 0.04 U/min

61
Q

What is the half life of vasopressin ?

A

20 min
(Note that it takes about 3 half life’s or more for majority of a drug to be cleared

62
Q

What are the effects of vasopressin

A
  • In SVR
63
Q

How is vasopressin metabolized

A
  • primarily kidney
  • also liver
64
Q

How is vasopressin excreted

A
  • urine
65
Q

What receptors do epinephrine stimulate

A
  • a1 a2 b1 b2
    • in a dose dependent manner
66
Q

Describe the dose dependent receptor activity of epinephrine

A
  • low dose epi
    • 0.01 - 0.04mcg/kg/min
    • primarily beta
  • higher doses
    • start to exact alpha receptor activity
67
Q

What are the effects of epinephrine

A

Stimulation of myocardial beta 1 receptors
- raises blood pressure
- inc cardiac output
- inc cardiac contractility and inc heart rate
- which increase myocardial oxygen demand
Stimulation of a1 receptors
- decreases splanchnic and renal blood flow
- increases coronary perfusion
Stimulation of B2 receptors
- relaxes bronchial smooth muscle

68
Q

Complications of epi

A
  • cerebral hemorrhage
  • myocardial ischemia
69
Q

What is the concerning outcome of using halothane with epinephrine

A

Halothane potentiates arrhythmogenic effects of epinephrine

70
Q

What is the cardiac arrest dose of epi

A

1mg

71
Q

What class of drug is ephedrine

A
  • non catecholamine
  • indirect sympathomimetic
  • similar to epinephrine
72
Q

What are the effects of ephedrine

A
  • same effects as epi
  • inc BP HR CO and contractility
  • bronchodilator
73
Q

What is the indirect agonist mechanism of ephedrine

A
  • it induces release of endogenous catecholamines
  • it induces peripheral postsynaptic norepinephrine release and
    Inhibits its reuptake
74
Q

Why is ephedrine only a temporizing agent

A
  • it is only effective until the catecholamine stores are depleted
75
Q

What is the dosing of ephedrine

A

Bolus dosing 2.5 - 10mg in adults

76
Q

Which receptors do norepi stimulate

A
  • primarily a1 with
  • limited B2 activity
77
Q

what is the primary clinical difference between norepi and phenylephrine

A
  • there is less/ no reflex bradycardia with norepi compared to phenylephrine
78
Q

What is norepi the first line agent for

A
  • septic shock
79
Q

How is norepi dosed and why

A
  • dosed as a continuous infusion
    • 2 — 20mcg/min
  • because it has a short half-life
80
Q

How does dopamine achieve its clinical effects

A
  • it is nonselective
  • both direct and indirect
    - adrenergic and dopaminergic agonist
  • low dose => renal dilation ***
  • mid dose => b1
  • high dose => a1
    • however the dose does not correlate with the clinical receptor activation effects
    • does not have a clean profile
81
Q

What is the mechanism of action for isoproterenol

A
  • pure B agonist
    • b1
      • inc HR contractility CO
    • b2
      • inc myocardial oxygen demand&raquo_space;» supply
  • poor ionotropic choice
82
Q

What is the selectivity of Dobutamine based on its constitution

A
  • racemic mixture of two isomers
  • both b1 and b2 receptor affinity
  • b1 selectivity&raquo_space;»> b2
83
Q

Describe the effects of dobutamine and its clinical significance

A
  • increases cardiac output as a result of increased cardiac contractility ==> b1
  • b2 ==> inc perineural vascualr resistance ==> attenuates inc in blood pressure ==> LV filling pressure decreases while coronary blood flow increases
  • used for stress tests
  • used for low output cardiogenic shock but be careful with hypotensive pts as it will exacerbate hypotension
84
Q

What is the dosing of dobutamine

A

Infusion rate
- 2-20mcg/kg/min

85
Q

How does fenoldopam achieve its clinical effects

A
  • selective D1 receptor agonist
  • many of the benefits of dopamine without a or b effects
86
Q

What are the clinical benefits of fenoldopam

A
  • exerts hypotensive effects
    • dec peripheral vascular resistance
    • inc renal blood flow
    • inc diuresis and naturesis
  • reduces blood reassure but helps maintain renal blood flow *****

CA-1 (8 decks)

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