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Pharm Exam 1
Set 13: Adrenergics thru Cardiovascular system as a whole
161
Pharmacology
Graduate
10/12/2011

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Term
A 67 yo pharmacologist was stung on the hand and forehead by bees. In less than 5 min, the sites were inflamed & developed lg. swelling. He felt restless & itchy all over. In the next 5-10 min., his entire body was bright red, skin was itchy & he developed hives. Soon his sight was blurred & he was feeling dizzy. In his medical cabinet there were antihistaminic, anticholinergic & adrenergic classes.

What drugs shoul be taken for immediate relief of his anaphylaxis?

What would be DOC?
Definition
Adrenergics (to increase BP & improve breathing to prevent anaphylactic shock)

DOC: Epi (can be self-injected IM for rapid action)
Term
What are the adrenergics?
Definition
catecholamines s.a. NE & Epi
Term
What is the main neurotransmitter of sensory neurons?
Definition
substance P
Term
What is the main neurotransmitter of presynaptic neurons?
Definition
Ach (cholinergic)
Term
What is the main neurotransmitter of postsynaptic neurons?
Definition
NE (adrenergic)
Term
What are the co-trasnmitters used in addition to the principal transmitters?
Definition
peptigergic
Term
What peptidergic cotransmitter is used in cholineric neurons?
Definition
VIP (vasoactive intestinal polypeptide)
Term
What peptidergic cotransmitter is used in adrenergic neurons?
Definition
NPY (neuropeptide Y)
Term
Function

Co-transmitters
Definition
under investigation
Term
What type of cell are adrenergic neurons?
Definition
multipolar cells w/ long axon & characteristic "beaded" terminal nerve endings
Term
What is the functional unit of the neuron?
Definition
nerve endings
Term
Where in the adrenergic neuron is the highest concentration of NE?
Definition
nerve endings
Term
Where is NE synthesized in the adrenergic neuron?
Definition
all regions => transported by vesicle to terminals by fast axoplasmic transport
Term
Why is it important to know that adrenergic neurons display fast transport?
Definition
Fast transport can be blocked by such drugs as colchicine & vinca alkaloids via inhibition of polymerization of microtubules/microfilaments
Term
def

varicosity
Definition
nerve terminal
Term
What is contained in adrenergic varicosities?
Definition
lg # of vesicles storing NE (500-2000)
Term
What is the range of synaptic clefts from adrenergic nerve endings to their target organs?
Definition
small (10-20 nm vas deferens, SA node) to large (100-500 nm lg blood vessels, GI smooth muscle)
Term
When will adrenergic neurons produce faster & greater response?
Definition
more narrow synaptic junctions
Term
What are the 5 major events of the "life" of NE?
Definition
1) storage
2) release
3) action
4) inactivation
5) recycling
Term
How is NE synthesized?
Definition
Tyrosine -> L DOPA -> DA -> NE (-> Epi)

[true love does not exist]
Term
What is the end product of catecholamine synthesis in CNS?
Definition
DA
Term
What is the end product of catecholamine synthesis in sympathetic neurons?
Definition
NE
Term
Where is Epi the end product of catecholamine synthesis?
Definition
adrenal gland
Term
What enzyme converts Tyrosine -> L DOPA?
Definition
tyrosine hydroxylase (TH)
Term
What enzyme converts L DOPA -> DA?
Definition
DOPA decarboxylase (DD)
Term
What enzyme converts DA -> NE?
Definition
DA-β-hydroxylase (DBH)
Term
What enzyme converts NE -> Epi?
Definition
PNMT
Term
Where are the catecholamine synthesis enzymes TH, DD & DBH synthesized & transported to?
Definition
adrenergic nerve cell bodies & transported to nerve endings (where much of NE synthesis is carried out)
Term
What is the rate limiting enzyme of catecholamine synthesis?
Definition
TH
Term
What 2 mechanisms regulate NE synthesis by TH activation regulation?
Definition
1) phosphorylation of existing enzyme
2) induction or synthesis of new TH
Term
What balances the increased rate of NE release in enhanced frequency of sympathetic nerve impulses?
Definition
increased rate of NE synthesis via phosphorylation of TH
Term
What balances the increased rate of NE release in chronic activation of sympathetic nervous system (daily exercise, long exposure to cold, stress, etc)?
Definition
increased rate of NE synthesis via increasing synthesis of TH
Term
What does it mean that DBH is a vesicular enzyme?
Definition
~75% of the enzyme is located in the membranes of storage granules & remaining in the soluble contents of the vesicles
Term
Why is the concentration of DBH used as an idication of sympathetic nerve activity of a patient?
Definition
DBH is released with NE
Term
Where can PNMT mostly be found?
Definition
chromaffin cells of adrenal gland
Term
Why is PNMT found in the chromaffin cells of the adrenal gland?
Definition
It's where NE is methylated to form Epi
Term
What is the methyl donor to form Epi?
Definition
S-adenosyl methionine
Term
What incudes PNMT in the adrenal medulla?
Definition
corticosteroids
Term
How can glucocorticoids perfuse the adrenal medulla?
Definition
via adrenal cortical sinusoids
Term
What mechanism type is used to store NE & DA?
Definition
voltage & pH dependent mechanism
Term
What co-factors are required by VMAT (vesicular monoamine transporter) for NE & DA storage?
Definition
Mg2+ & ATP
Term
def

VMAT
Definition
vesicular pump for NE & DA storage
Term
What are the 2 types of VMAT?
Definition
VMAT 1 & 2
Term
What do VMAT 1 & 2 transport?
Definition
5-HT (serotonin), histamine & catecholamines
Term
Where is VMAT 1 mostly found?
Definition
periphery (esp. endocrine cells)
Term
Where is VMAT 2 found?
Definition
CNS (esp. neuronal cells)
Term
What molecule is NE to be found in association with within storage vesicles?
Definition
ATP (~ 4NE:1ATP)
Term
Besides ATP, what is also found in the NE vesicle?
Definition
DBH, acidic proteins (chromogranins), ascorbic acid, Ca2+, etc.
Term
What cells in the adrenal medulla store Epi?
Definition
cells that have induced PNMT (in a similar way NE is stored)
Term
What are the only places chromogranins are found?
Definition
1) adrenal medullary secretion granules
2) adrenergic nerve synaptic vesicles
3) endocrine tissues
Term
What is chromogranin A a marker for?
Definition
tumors of tissues containing chromogranins => over-expression & secretion of chromogranin A
Term
Function

chromogranin A
Definition
unknown
Term
What channels open following adrenergic memebrane depolarization?
Definition
Ca2+ => extracellular Ca2+ to enter neurons
Term
What does increased [Ca2+] at the mouth of Ca2+ channels of adrenergic neurons allow?
Definition
docked vesicles to exocytose via association of complex machinery
Term
What is released with NE?
Definition
everything contained in it's vesicle (DBH, chromogranins, ATP, ascorbic acid, etc)
Term
What happens to substances of high molecular wt. in the extracellular space?
Definition
uptaken into storage granules
Term
What are the 4 types of Ca2+ channels?
Definition
P, T, N, L

(Pity Those who Never Love)
Term
Where are T Ca2+ channels found?
Definition
cardiac SA & AV node
Term
Where are N Ca2+ channels found?
Definition
neuron (inc. sympathetic neurons!)
Term
Where are L Ca2+ channels found?
Definition
muscle, endocrine, exocrine glands
Term
Where are P Ca2+ channels found?
Definition
cerebellar Purkinje neurons
Term
What 2 Ca2+ channels are found in sympathetic neurons?
Definition
Mostly: N
soma may contain some: L
Term
What happens to the cytosolic [Ca2+] after massive influx?
Definition
goes from 100-200nM to over 10,000nM
Term
Why is the massice rise of [Ca2+] transient?
Definition
Ca2+ channels rapidly close & mechanisms regulate the intracellular Ca2+ via pumps & buffers to bring [Ca2+] back to basal levels in a few seconds
Term
what action does NE have of the presynatpic nerve after its release in the synaptic cleft?
Definition
inhibitory to its own release
Term
What specific adrenergic receptor is responsible for NE feedback inhibition?
Definition
α2
Term
How do α2 receptors turn off subsequent NE release?
Definition
either decrease in cAMP or inhibition of Ca2+ entry
Term
What adrenergic receptors are located postsynaptically?
Definition
α1
Term
Why is it useful to know that α1 receptors differ from α2 receptors?
Definition
They have their own agonists and therefore can be used as pharmacologic targetrs (i.e. α2 agonists are useful in controlling high BP)
Term
What are the 3 paths NE can take once it's released into the synapse?
Definition
1) diffusion
2) extraneuronal uptake
3) neuronal uptake via NET
Term
Where can NE diffue to?
Definition
liver vis capillaries or lymphatics => metabolized by COMT & MAO
Term
How can NE be uptaken by effector cells?
Definition
via extraneuronal uptake (Uptake2) which is specific for catecholamines
Term
What inhibits Uptake2 of NE?
Definition
supra-physiological amounts of estrogens & corticosteroids
Term
What metabolizes NE in the effector cells?
Definition
COMT
Term
What does COMT metabolize NE to in the effector cells?
Definition
inactive nor-metanephrine
Term
What is the fate of inactive nor-metanephrine?
Definition
diffuse out of effector cell & either be eliminated in urine or further metabolized in liver by MAO
Term
How much of NE released into the synapse diffuse or are uptaken by effector cell?
Definition
30% total
Term
What happens to the 70% of NE not uptaken by the effector cell nor diffused?
Definition
taken back up into the releasing nerve terminals
Term
What pump is needed for reuptake (Uptake1) of NE?
Definition
amine pump NET (NE transporter)
Term
Does NET uptake other catecholamines?
Definition
yes, but affinity NE>Epi
Term
Is the synthetic catecholamine isoproterenol (Iso) transported by NET?
Definition
no
Term
What other function does NET have (for amines & other drugs)?
Definition
concentrate other amines & drugs (i.e. a variety of drugs can rapidly & effectively block NET)
Term
What antidepressants are known to block NET?
Definition
TCAs
Term
What 2 enzymes metabolize NE?
Definition
monoamine oxidase (MAO
catcechol-o-methyl transferase (COMT)
Term
Where is MAO found?
Definition
nerve terminal (mitochondrial outer membrane), brain, liver, interstinal mucosa, & neuronal tissue
Term
Why is there MAO in nerve terminals?
Definition
to regulate NE content in cytosol
Term
Where is COMT found?
Definition
effector cells & liver (NOT brain or neuronal cells)
Term
Does MAO or COMT metabolize NE first?
Definition
either
MAO first in nerve terminal -> COMT in liver
or
COMT first in effector cells -> MAO liver
Term
What catecholamine products are found excreted in the urine?
Definition
mixture of catacholatimes, COMT NE & Epi products, MAO products, and COMT & MAO products
Term
What is the primart pathway of NE metabolism?
Definition
inactivation by COMT then oxidation by MAO
Term
What is the the metabolic pathway of Epi?
Definition
same as NE
Term
How do the metabolic products differ if MAO or COMT metabolizes NE (or Epi) first?
Definition
they don't. they lead to the same end products if are metabolized by both (but individual products differ)
Term
What are the 2 end products of MOA & COMT metabolism together?
Definition
MOPEG & VMA
Term
What are the 2 types of adrenergic receptors?
Definition
α & β
Term
Fuction

α receptor agonists
Definition
contraction/excitation

(except in intestinal smooth muscle, pre-synaptic nerve terminals, platelets & brain where it inhibits)
Term
Function

β receptor agonists
Definition
relaxation/inhibition

(except in the heart & kidney where it stimulates)
Term
Can organs/cells have α & β receptors, or only one or the other?
Definition
can have both
Term
Can both α & β receptors be activated simultaneously, or only one or the other?
Definition
some adrenergic agoniss can stimulate both simulateneously
Term
Since both α & β receptors can be on a cell & both can be activated by the same agonists, what determines the final response?
Definition
dominance of receptor type & adrenergic agonist used.
Term
What are the 2 α receptors?
Definition
α1 & α2
Term
Where are α1 receptors found?
Definition
postsynaptic smooth muscles of blood vessels, salivary glands, pancreas, internal sex organ, etc.
Term
Where are α2 found?
Definition
presynaptic sympathetic nerve terminals, blood platelets & CNS
Term
What are the potencies of the 2 α agonists that affect only α1?
Definition
Phenylephrine (PE) > methoxamine
Term
What are the potencies of the 3 α agonists that affect only α2?
Definition
Clonidine > α-methyl-NE >> oxymetazoline
Term
What are the potencies of the 3 α aginists that affect α1 & α2?
Definition
naphazoline = Epi = NE
Term
What are α & β receptors coupled with?
Definition
second messanger systems
Term
What are the 2 β receptor types?
Definition
β1 & β2
Term
What are the potencies of the 4 β agonists on β1 receptors?
Definition
Isoproterenol (Iso) > Epi > NE >>> Phenylephrine (PE)
Term
What are the potencies of the 4 β agonists on β2 receptors?
Definition
Iso > Epi >>> NE >>> PE
Term
What adrenergic receptors does DA activate?
Definition
none, it activates DA receptors (distinct from adrenergic α & β receptors)
Term
Where are the major effects of DA exerted?
Definition
CNS (therefore a lg # of antipsychotic & neuroleptic drugs target DA receptors)
Term
What are the 2 types of DA receptors?
Definition
D1 & D2
Term
What are the 2 DA receptor subtypes in the D1 family?
Definition
D1 & D5
Term
What are the 3 DA receptor subtypes in the D2 receptor family?
Definition
D2, D3, D4
Term
Function

DA1 family
Definition
increase cAMP
Term
Where are D1 family receptors found?
Definition
Mainly CNS (striatum, hypothalamus, hippocampus)
also: smooth muscle cells of blood vessels (esp. renal vasculature)
Term
What does D1 stiumlation do to the periphery?
Definition
vasodilation, natriuresis & diursis
Term
Function

D2 family
Definition
inhibits cAMP, blocks Ca2+ channels & opens K+ channels
Term
Where are D2 receptors found?
Definition
sympathetic ganglia, sympathetic nerve terminals & CNS (pituitary gland, substantia nigra, frontal cortex, medulla, hypothalamus, etc)
Term
What does stimulation of D2 family receptors do to the periphery?
Definition
hypotention, bradycardia, vasodilation
Term
What are the 2 DA agonists?
Definition
DA & fenoldopam
Term
What is the potency of the DA agonist DA on DA receptors & adrenergic receptors?
Definition
D1 = D2 >> β >> α
Term
What is the potency of the DA agonist fenoldopam on DA receptors & adrenergic receptors?
Definition
D1 >> D2
Term
What are the 3 ways DA produces cardiovascular actions?
Definition
1) releasing NE from adrenergic neurons
2) interacting with α & β adrenergic receptors
3) interacting with specific DA receptors
Term
Function

DA on heart
Definition
Increase HR, contraction, & cardiac output
Term
What is the main mechanism DA uses to increase HR, contraction & cardiac output?
Definition
activation of β receptors via NE release from sympathetic neurons in the heart
Term
Why is it important to know the relative potency of the neutrotransmitter at each receptor?
Definition
better prediction of the effects on the organ/organ system
Term
What with an amine that is indirectly acting on adrenergic receptors response look like?
Definition
NE response
Term
What receptor mediates all actions on the heart?
Definition
β1
Term
Function β1 agonist in the heart
Definition
1)increased HR
2)increased contractile force
3)increased conduction
4)decreased cardiac efficency
5)arrhythmia induced
Term
What cells do β1 agonists bind to when affecting HR?
Definition
pacemaker cells of SA node
Term
What does activation of pacemaker cells of SA node via β1 agonists do to increase HR?
Definition
=> more rapid diastolic depolarization & increase of frequency of APs via accelerating potassium leak in the diastolic interval decreasing threshold time for depolarization
Term
How can β1 agonists produce a decrease in HR (counterintuitive)?
Definition
if amine involved also causes an increase in BP (s.a. NE or PE) => vagus reflex activation can override direct action of amine on HR to decrease BP
Term
What cells with β1 receptors are activated to increae contractile force of the heart?
Definition
myocardial cells
Term
How does activation of β1 agonists on myocardial cells increase contractile force?
Definition
=> increase Ca2+ influx with each AP => greater force of contraction
Term
How is conduction of the heart increased by β1 agonists?
Definition
velocity of impulse transfer from SA to AV nodes is increased
refractory period of AV node is decreased
Term
Which 2 β1 agoinsts are more likely to cause arrhythmias? Why?
Definition
NE & Epi bc they cause increase in BP too

BP increase => greater workload on heart => greater possibility of arrythmia

(further enhanced by general anesthetics)
Term
What adrenergic receptor mediates the kidney vascular beds?
Definition
α1
Term
Effect α1 agonist in the kidney vascular beds
Definition
vasoconstriction with Epi & NE
slight vasodilation with Iso
Term
What adrenergic receptor is seen in skeletal muscle vascular beds?
Definition
α1 & β2
Term
Effect

PE & NE on skeletal muscle vascular beds
due to what receptor?
Definition
vasocontriction due to α1
Term
Effect

Epi on skeletal muscle vascular beds
due to what receptors?
Definition
vasodilation at lower concentration, but vasoconstriction at higher concentrations Epi has higher affinity for β2 receptors than α1 receptors. At low concentrations, β2 receptors are activated => vasodilation At high concentrations, both α1 & β2 are activated, but the α1 receptors mediate the response.
Term
Effect

Iso on skeletal muscle vascular beds
due to what receptors?
Definition
vasodilation due to β2 receptors
Term
What adrenergic receptor mediates the liver & spanchnic area vascular beds?
Definition
α1 (+ sm. β receptor component)
Term
Effect

Epi & NE on liver & spanchnic area vascular beds
Definition
vasocontriction: higher concentrations of Epi & NE
vasodilation: lower concentration of Epi
Term
Effect

NE, Epi, & Iso on coronaries
due to what receptors?
Definition
vasodilation due to β2 receptors
Term
What is also a contributor to vasodialtion of the coronaries?
Definition
adenosine on smooth smuscles of coronaries during exercise
Term
Whaat adrenergic receptor mediates effect of pulmonary circulation?
Definition
Both α & β receptors, but α receptors dominate
Term
Effect

Epi & E on pulmonary circulation
Definition
some relatively weak vasoconstriction
Term
What adrenergic receptors are seen in the α cells on the pancreas?
Definition
β receptors
Term
What adrenergic receptors are seen in the β cells on the pancreas?
Definition
α receptors
Term
Effect

α cell β receptor agonist in pancreas
Definition
stimulation of glucagon secretion
Term
Effect

β cell α receptor agonist in pancreas
Definition
inhibition of insulin secretion
Term
Effect

low [Epi] on BP
Definition
systolic increase, diastolic decrease => little to no change in overall BP
Term
Effect

low [Epi] on cardiac output
Definition
increased
Term
Effect

low [Epi] on total peripheral resistance
Definition
decreased (due to vasodilation in skeletal muscle)
Term
Effect

NE & higher [Epi] on BP
Definition
increase of both systolic & diastolic pressure => increased BP
Term
Effect

NE & higher [Epi] on total peripheral resistance
Definition
increased (due to vasoconstriction in skeletal muscle)
Term
Effect

Iso on BP
Definition
sm. increase in systolic, lg. decrease in diastolic => decrease in BP
Term
When can Iso cause decrease in cardiac output?
Definition
if vasodilation is too extreme => decrease in venous return
Term
Effect

Iso on total peripheral resistance
Definition
decreased (due to vasodilation in skeletal muscle)
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