Adrenergic Agonist And Antagonists Flashcards
What is the difference between direct and indirect adrenergic agonists
Direct adrenergic agonists
- bind to the receptor
Indirect adrenergic agonists
- increase endogenous neurotransmitter activity
What is the structure of all G protein coupled receptors
They are 7 transmembrane helices connected by extracellular and intracellular loops
Describe the subunits of G proteins
- 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
What are the functions of the Ga subunit
- 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
What are the functions bg dimmer subunit of GPCR
- Bg subunit dimer
- activates potassium channels
- activates protein kinases
What receptors and what are the main effects of the Gai subunit
- inhibits adenylyl cyclase to decrease cAMP formation
- associates with
- cannabinoid
- catecholamine
- histamine
- opioid and
- serotonin receptors
What receptors and what are the resulting effects of the Gas subunit
Gas
- stimulates adenylyl cyclase
- increases cAMP formation
- binds to
- catecholamines
- histamines
- serotonin and
- other receptors
What are the receptors and effects of Gaq binding
- Gaq
- activates phospholipase C
- increases the production of a second messenger IP3 and DAG => activates PLC
What neurotransmitter is released by all preganglionic sympathetic fibers and all parasympathetic (pre and post ganglionic) fibers
Acetylcholine
What neurotransmitter is released by postganglionic sympathetic fibers
Norepinephrine
What are the 3 ways in which the activity of norepinephrine is terminated after its release
- 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
How do cocaine amphetamine and TCAs affect the activity of the norepinephrine transporter on neuronal cells
- 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
What is the pathway of phenylalanine conversion to epinephrine and what are the catalysts
What G protein is the a1 receptor linked to and what is the function
- a1 adrenergic receptor
- linked to Gq
- stimulates phospholipase
What G protein is the a2 receptor linked to and what is the function
A2 adrenergic receptor is linked to
- Gi which
- inhibits cAMP
What G protein is the b receptor linked to and what is the function
B adrenergic receptors are linked to Gs
- which stimulates cAMP
What is the effect of a1 activation
- Activation of a1 receptors leads to
- Gq => phospholipase
- releases intracellular ca++
- leads to constriction of smooth muscles
Where are a1 receptors primarily located and what is the effect of their activation
- 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
What is the primary effect of a1 receptor stimulation on the heart
- vasoconstriction which
- increases systemic vascular resistance
- increases arterial blood pressure
- increases left ventricular afterload
Where are a2 adrenergic receptors located and what are the effects of their stimulation
- 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
How does post synaptic a2 receptor stimulation cause vascular vasoconstriction
- 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
- PKA is normally activated by cAMP => results in vasodilation
- cAMP usually inhibits ca influx
- dec cAMP =>inc ca influx
- smooth muscle contraction
What are the central effects of a2 receptor stimulation
In the CNS postsynaptic a2 receptor stimulation
- causes sedation
- reduces sympathetic outflow
- causes peripheral vasodilation and
- lower blood pressure
On which b receptors are epinephrine and norepinephrine equipotent
B1
On which b receptors is epi > norepinephrine . How is this difference obscured
- epi is more potent than norepinephrine on b 2 receptors
- the more potent actions of norepinephrine on alpha receptors obscured this difference
Where are b1 receptors primarily located
- b1 receptors
- postsynaptic membranes of the heart
What are the effects of b1 receptor stimulation
- 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
Where are beta 2 receptors located
B2 receptors are located on
- smooth muscle cells
- gland cells
- ventricular myocardial
What is the pathway for b2 activation and what are the effects
- 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
What is the result of D1 receptor activation
D1 activation
- vasodilation of
- kidney
- intestine and
- heart
What is the effect of D2 receptor stimulation
D2 receptor stimulation
- antiemetic action of
- droperidol and
- haloperidol
Direct adrenergic agonists
Bind receptor directly
Indirect adrenergic agonists
Increase endogenous neurotransmitter activity
For example
- increase release of norepi or
- dec reuptake of norepi
Which subset of pts should be treated with only direct acting agonists only
- pts with abnormal endogenous norepi stores
- those on MAOIs and certain antihypertensives
What are catecholamines
Adrenergic receptors with 3,4 dihydroxybezene structure
Why are catecholamines short acting
Because they are metabolized rapidly by
- monoaminde oxidase and
- catecholamines O methyltransferase
What are the naturally occurring catecholamines
- norepi
- epi
- dopamine
Why are MAOIs and TCAs dangerous for pts being given catecholamines
- they inhibit MAO and COMT
- thereby preventing the metabolism of catecholamines and
- leads to exaggerated catecholamine responses
Discuss reflex bradycardia
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
What class of drug is phenylephrine
- selective a1 agonist
- non catecholamine
What’s the difference between vasopressors and vasoactive agents
- vasopressors act specifically to vasoconstriction peripheral vasculature
- epi
- nopepi
- dopamine
- phenylephrine
- ephedrine
What is the duration of action of phenylephrine
- short 15min
What kind of hypotension is phenylephrine effective for
- 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
What is the dosing of phenylephrine
- blouses 50 -100mcg
- comes as a 1% soln
- 10mg/1mL = 10000mg/mL => dil 1/10
- 100mcg/mL
- comes as a 1% soln
What adrenergic receptor agonist is clonidine
Clonidine is a2 agonist
What are the uses of clonidine by mechanism
- 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
what are the effects of clonidine on regional anesthesia
- clonidine prolongs the duration of blocks
what are the postoperative benefits of clonidine
- 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
What are the side effects of clonidine
- respiratory depression
- dry mouth
- hypotension
- sedation
What is the half life of clonidine
12-14hrs
What is the a2:a1 receptor specificity ratio for clonidine vs Dexmedetomidine
Clonidine a2:a1
- 200: 1
Dexmedetomidine a2:a1
- 1600: 1
What is the half life of Dexmedetomidine
2-3hrs
What are the effects of dexmedetomidine
- sedation and analgesia
- a2 receptors in locus ceruleus and spinal cord
- sympatholytic
- blunts cardiovascular responses
What are the advantages of using dexmedetomidine
- reduces the need for iv and inhaled anesthetics
What makes dexmedetomidine particularly safe for PACU use
- does not cause respiratory depression
What is the dosing of dexmedetomidine
Loading dose
- 1mcg/kg over 10min
Infusion
- 0.2 — 1mg/kg/hr (sedation)
Does phenylephrine have any effect on the heart
NO
It is a pure vasopressors
What are the effects of long term clonidine and dexmedetomidine use
- receptor upregulation
- super sensitization of receptors
- these cause acute withdrawal syndrome with abrupt discontinuation of med
- can occur in only 48hrs of dexmedetomidine use
Where is epinephrine synthesized
Adrenal medulla
Vasopressin is a pure pressor discuss mechanism of action
- 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
What is the dosing of vasopressin for adults
0.01 - 0.1U/min
- Infusion dose => 0.01- 0.04 U/min
What is the half life of vasopressin ?
20 min
(Note that it takes about 3 half life’s or more for majority of a drug to be cleared
What are the effects of vasopressin
- In SVR
How is vasopressin metabolized
- primarily kidney
- also liver
How is vasopressin excreted
- urine
What receptors do epinephrine stimulate
- a1 a2 b1 b2
- in a dose dependent manner
Describe the dose dependent receptor activity of epinephrine
- low dose epi
- 0.01 - 0.04mcg/kg/min
- primarily beta
- higher doses
- start to exact alpha receptor activity
What are the effects of epinephrine
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
Complications of epi
- cerebral hemorrhage
- myocardial ischemia
What is the concerning outcome of using halothane with epinephrine
Halothane potentiates arrhythmogenic effects of epinephrine
What is the cardiac arrest dose of epi
1mg
What class of drug is ephedrine
- non catecholamine
- indirect sympathomimetic
- similar to epinephrine
What are the effects of ephedrine
- same effects as epi
- inc BP HR CO and contractility
- bronchodilator
What is the indirect agonist mechanism of ephedrine
- it induces release of endogenous catecholamines
- it induces peripheral postsynaptic norepinephrine release and
Inhibits its reuptake
Why is ephedrine only a temporizing agent
- it is only effective until the catecholamine stores are depleted
What is the dosing of ephedrine
Bolus dosing 2.5 - 10mg in adults
Which receptors do norepi stimulate
- primarily a1 with
- limited B2 activity
what is the primary clinical difference between norepi and phenylephrine
- there is less/ no reflex bradycardia with norepi compared to phenylephrine
What is norepi the first line agent for
- septic shock
How is norepi dosed and why
- dosed as a continuous infusion
- 2 — 20mcg/min
- because it has a short half-life
How does dopamine achieve its clinical effects
- 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
What is the mechanism of action for isoproterenol
- pure B agonist
- b1
- inc HR contractility CO
- b2
- inc myocardial oxygen demand»_space;» supply
- b1
- poor ionotropic choice
What is the selectivity of Dobutamine based on its constitution
- racemic mixture of two isomers
- both b1 and b2 receptor affinity
- b1 selectivity»_space;»> b2
Describe the effects of dobutamine and its clinical significance
- 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
What is the dosing of dobutamine
Infusion rate
- 2-20mcg/kg/min
How does fenoldopam achieve its clinical effects
- selective D1 receptor agonist
- many of the benefits of dopamine without a or b effects
What are the clinical benefits of fenoldopam
- exerts hypotensive effects
- dec peripheral vascular resistance
- inc renal blood flow
- inc diuresis and naturesis
- reduces blood reassure but helps maintain renal blood flow *****
