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? |
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Definition
Adrenergics (to increase BP & improve breathing to prevent anaphylactic shock)
DOC: Epi (can be self-injected IM for rapid action) |
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Term
What are the adrenergics? |
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Definition
catecholamines s.a. NE & Epi |
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Term
What is the main neurotransmitter of sensory neurons? |
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Definition
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Term
What is the main neurotransmitter of presynaptic neurons? |
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Definition
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Term
What is the main neurotransmitter of postsynaptic neurons? |
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Definition
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Term
What are the co-trasnmitters used in addition to the principal transmitters? |
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Definition
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Term
What peptidergic cotransmitter is used in cholineric neurons? |
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Definition
VIP (vasoactive intestinal polypeptide) |
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Term
What peptidergic cotransmitter is used in adrenergic neurons? |
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Definition
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Term
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Definition
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Term
What type of cell are adrenergic neurons? |
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Definition
multipolar cells w/ long axon & characteristic "beaded" terminal nerve endings |
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Term
What is the functional unit of the neuron? |
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Definition
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Term
Where in the adrenergic neuron is the highest concentration of NE? |
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Definition
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Term
Where is NE synthesized in the adrenergic neuron? |
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Definition
all regions => transported by vesicle to terminals by fast axoplasmic transport |
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Term
Why is it important to know that adrenergic neurons display fast transport? |
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Definition
Fast transport can be blocked by such drugs as colchicine & vinca alkaloids via inhibition of polymerization of microtubules/microfilaments |
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Term
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Definition
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Term
What is contained in adrenergic varicosities? |
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Definition
lg # of vesicles storing NE (500-2000) |
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Term
What is the range of synaptic clefts from adrenergic nerve endings to their target organs? |
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Definition
small (10-20 nm vas deferens, SA node) to large (100-500 nm lg blood vessels, GI smooth muscle) |
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Term
When will adrenergic neurons produce faster & greater response? |
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Definition
more narrow synaptic junctions |
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Term
What are the 5 major events of the "life" of NE? |
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Definition
1) storage 2) release 3) action 4) inactivation 5) recycling |
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Term
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Definition
Tyrosine -> L DOPA -> DA -> NE (-> Epi)
[true love does not exist] |
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Term
What is the end product of catecholamine synthesis in CNS? |
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Definition
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Term
What is the end product of catecholamine synthesis in sympathetic neurons? |
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Definition
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Term
Where is Epi the end product of catecholamine synthesis? |
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Definition
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Term
What enzyme converts Tyrosine -> L DOPA? |
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Definition
tyrosine hydroxylase (TH) |
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Term
What enzyme converts L DOPA -> DA? |
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Definition
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Term
What enzyme converts DA -> NE? |
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Definition
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Term
What enzyme converts NE -> Epi? |
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Definition
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Term
Where are the catecholamine synthesis enzymes TH, DD & DBH synthesized & transported to? |
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Definition
adrenergic nerve cell bodies & transported to nerve endings (where much of NE synthesis is carried out) |
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Term
What is the rate limiting enzyme of catecholamine synthesis? |
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Definition
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Term
What 2 mechanisms regulate NE synthesis by TH activation regulation? |
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Definition
1) phosphorylation of existing enzyme 2) induction or synthesis of new TH |
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Term
What balances the increased rate of NE release in enhanced frequency of sympathetic nerve impulses? |
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Definition
increased rate of NE synthesis via phosphorylation of TH |
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Term
What balances the increased rate of NE release in chronic activation of sympathetic nervous system (daily exercise, long exposure to cold, stress, etc)? |
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Definition
increased rate of NE synthesis via increasing synthesis of TH |
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Term
What does it mean that DBH is a vesicular enzyme? |
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Definition
~75% of the enzyme is located in the membranes of storage granules & remaining in the soluble contents of the vesicles |
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Term
Why is the concentration of DBH used as an idication of sympathetic nerve activity of a patient? |
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Definition
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Term
Where can PNMT mostly be found? |
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Definition
chromaffin cells of adrenal gland |
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Term
Why is PNMT found in the chromaffin cells of the adrenal gland? |
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Definition
It's where NE is methylated to form Epi |
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Term
What is the methyl donor to form Epi? |
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Definition
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Term
What incudes PNMT in the adrenal medulla? |
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Definition
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Term
How can glucocorticoids perfuse the adrenal medulla? |
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Definition
via adrenal cortical sinusoids |
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Term
What mechanism type is used to store NE & DA? |
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Definition
voltage & pH dependent mechanism |
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Term
What co-factors are required by VMAT (vesicular monoamine transporter) for NE & DA storage? |
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Definition
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Term
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Definition
vesicular pump for NE & DA storage |
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Term
What are the 2 types of VMAT? |
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Definition
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Term
What do VMAT 1 & 2 transport? |
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Definition
5-HT (serotonin), histamine & catecholamines |
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Term
Where is VMAT 1 mostly found? |
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Definition
periphery (esp. endocrine cells) |
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Term
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Definition
CNS (esp. neuronal cells) |
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Term
What molecule is NE to be found in association with within storage vesicles? |
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Definition
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Term
Besides ATP, what is also found in the NE vesicle? |
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Definition
DBH, acidic proteins (chromogranins), ascorbic acid, Ca2+, etc. |
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Term
What cells in the adrenal medulla store Epi? |
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Definition
cells that have induced PNMT (in a similar way NE is stored) |
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Term
What are the only places chromogranins are found? |
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Definition
1) adrenal medullary secretion granules 2) adrenergic nerve synaptic vesicles 3) endocrine tissues |
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Term
What is chromogranin A a marker for? |
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Definition
tumors of tissues containing chromogranins => over-expression & secretion of chromogranin A |
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Term
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Definition
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Term
What channels open following adrenergic memebrane depolarization? |
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Definition
Ca2+ => extracellular Ca2+ to enter neurons |
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Term
What does increased [Ca2+] at the mouth of Ca2+ channels of adrenergic neurons allow? |
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Definition
docked vesicles to exocytose via association of complex machinery |
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Term
What is released with NE? |
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Definition
everything contained in it's vesicle (DBH, chromogranins, ATP, ascorbic acid, etc) |
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Term
What happens to substances of high molecular wt. in the extracellular space? |
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Definition
uptaken into storage granules |
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Term
What are the 4 types of Ca2+ channels? |
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Definition
P, T, N, L
(Pity Those who Never Love) |
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Term
Where are T Ca2+ channels found? |
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Definition
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Term
Where are N Ca2+ channels found? |
|
Definition
neuron (inc. sympathetic neurons!) |
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Term
Where are L Ca2+ channels found? |
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Definition
muscle, endocrine, exocrine glands |
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Term
Where are P Ca2+ channels found? |
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Definition
cerebellar Purkinje neurons |
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Term
What 2 Ca2+ channels are found in sympathetic neurons? |
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Definition
Mostly: N soma may contain some: L |
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Term
What happens to the cytosolic [Ca2+] after massive influx? |
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Definition
goes from 100-200nM to over 10,000nM |
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Term
Why is the massice rise of [Ca2+] transient? |
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Definition
Ca2+ channels rapidly close & mechanisms regulate the intracellular Ca2+ via pumps & buffers to bring [Ca2+] back to basal levels in a few seconds |
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Term
what action does NE have of the presynatpic nerve after its release in the synaptic cleft? |
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Definition
inhibitory to its own release |
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Term
What specific adrenergic receptor is responsible for NE feedback inhibition? |
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Definition
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Term
How do α2 receptors turn off subsequent NE release? |
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Definition
either decrease in cAMP or inhibition of Ca2+ entry |
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Term
What adrenergic receptors are located postsynaptically? |
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Definition
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Term
Why is it useful to know that α1 receptors differ from α2 receptors? |
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Definition
They have their own agonists and therefore can be used as pharmacologic targetrs (i.e. α2 agonists are useful in controlling high BP) |
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Term
What are the 3 paths NE can take once it's released into the synapse? |
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Definition
1) diffusion 2) extraneuronal uptake 3) neuronal uptake via NET |
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Term
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Definition
liver vis capillaries or lymphatics => metabolized by COMT & MAO |
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Term
How can NE be uptaken by effector cells? |
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Definition
via extraneuronal uptake (Uptake2) which is specific for catecholamines |
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Term
What inhibits Uptake2 of NE? |
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Definition
supra-physiological amounts of estrogens & corticosteroids |
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Term
What metabolizes NE in the effector cells? |
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Definition
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Term
What does COMT metabolize NE to in the effector cells? |
|
Definition
inactive nor-metanephrine |
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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 |
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Term
How much of NE released into the synapse diffuse or are uptaken by effector cell? |
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Definition
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Term
What happens to the 70% of NE not uptaken by the effector cell nor diffused? |
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Definition
taken back up into the releasing nerve terminals |
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Term
What pump is needed for reuptake (Uptake1) of NE? |
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Definition
amine pump NET (NE transporter) |
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Term
Does NET uptake other catecholamines? |
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Definition
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Term
Is the synthetic catecholamine isoproterenol (Iso) transported by NET? |
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Definition
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Term
What other function does NET have (for amines & other drugs)? |
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Definition
concentrate other amines & drugs (i.e. a variety of drugs can rapidly & effectively block NET) |
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Term
What antidepressants are known to block NET? |
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Definition
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Term
What 2 enzymes metabolize NE? |
|
Definition
monoamine oxidase (MAO catcechol-o-methyl transferase (COMT) |
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Term
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Definition
nerve terminal (mitochondrial outer membrane), brain, liver, interstinal mucosa, & neuronal tissue |
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Term
Why is there MAO in nerve terminals? |
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Definition
to regulate NE content in cytosol |
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Term
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Definition
effector cells & liver (NOT brain or neuronal cells) |
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Term
Does MAO or COMT metabolize NE first? |
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Definition
either MAO first in nerve terminal -> COMT in liver or COMT first in effector cells -> MAO liver |
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Term
What catecholamine products are found excreted in the urine? |
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Definition
mixture of catacholatimes, COMT NE & Epi products, MAO products, and COMT & MAO products |
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Term
What is the primart pathway of NE metabolism? |
|
Definition
inactivation by COMT then oxidation by MAO |
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Term
What is the the metabolic pathway of Epi? |
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Definition
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Term
How do the metabolic products differ if MAO or COMT metabolizes NE (or Epi) first? |
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Definition
they don't. they lead to the same end products if are metabolized by both (but individual products differ) |
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Term
What are the 2 end products of MOA & COMT metabolism together? |
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Definition
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Term
What are the 2 types of adrenergic receptors? |
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Definition
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Term
Fuction
α receptor agonists |
|
Definition
contraction/excitation
(except in intestinal smooth muscle, pre-synaptic nerve terminals, platelets & brain where it inhibits) |
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Term
Function
β receptor agonists |
|
Definition
relaxation/inhibition
(except in the heart & kidney where it stimulates) |
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Term
Can organs/cells have α & β receptors, or only one or the other? |
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Definition
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Term
Can both α & β receptors be activated simultaneously, or only one or the other? |
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Definition
some adrenergic agoniss can stimulate both simulateneously |
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Term
Since both α & β receptors can be on a cell & both can be activated by the same agonists, what determines the final response? |
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Definition
dominance of receptor type & adrenergic agonist used. |
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Term
What are the 2 α receptors? |
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Definition
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Term
Where are α1 receptors found? |
|
Definition
postsynaptic smooth muscles of blood vessels, salivary glands, pancreas, internal sex organ, etc. |
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Term
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Definition
presynaptic sympathetic nerve terminals, blood platelets & CNS |
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Term
What are the potencies of the 2 α agonists that affect only α1? |
|
Definition
Phenylephrine (PE) > methoxamine |
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Term
What are the potencies of the 3 α agonists that affect only α2? |
|
Definition
Clonidine > α-methyl-NE >> oxymetazoline |
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Term
What are the potencies of the 3 α aginists that affect α1 & α2? |
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Definition
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Term
What are α & β receptors coupled with? |
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Definition
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Term
What are the 2 β receptor types? |
|
Definition
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Term
What are the potencies of the 4 β agonists on β1 receptors? |
|
Definition
Isoproterenol (Iso) > Epi > NE >>> Phenylephrine (PE) |
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Term
What are the potencies of the 4 β agonists on β2 receptors? |
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Definition
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Term
What adrenergic receptors does DA activate? |
|
Definition
none, it activates DA receptors (distinct from adrenergic α & β receptors) |
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Term
Where are the major effects of DA exerted? |
|
Definition
CNS (therefore a lg # of antipsychotic & neuroleptic drugs target DA receptors) |
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Term
What are the 2 types of DA receptors? |
|
Definition
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Term
What are the 2 DA receptor subtypes in the D1 family? |
|
Definition
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Term
What are the 3 DA receptor subtypes in the D2 receptor family? |
|
Definition
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Term
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Definition
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Term
Where are D1 family receptors found? |
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Definition
Mainly CNS (striatum, hypothalamus, hippocampus) also: smooth muscle cells of blood vessels (esp. renal vasculature) |
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Term
What does D1 stiumlation do to the periphery? |
|
Definition
vasodilation, natriuresis & diursis |
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Term
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Definition
inhibits cAMP, blocks Ca2+ channels & opens K+ channels |
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Term
Where are D2 receptors found? |
|
Definition
sympathetic ganglia, sympathetic nerve terminals & CNS (pituitary gland, substantia nigra, frontal cortex, medulla, hypothalamus, etc) |
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Term
What does stimulation of D2 family receptors do to the periphery? |
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Definition
hypotention, bradycardia, vasodilation |
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Term
What are the 2 DA agonists? |
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Definition
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Term
What is the potency of the DA agonist DA on DA receptors & adrenergic receptors? |
|
Definition
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Term
What is the potency of the DA agonist fenoldopam on DA receptors & adrenergic receptors? |
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Definition
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Term
What are the 3 ways DA produces cardiovascular actions? |
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Definition
1) releasing NE from adrenergic neurons 2) interacting with α & β adrenergic receptors 3) interacting with specific DA receptors |
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Term
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Definition
Increase HR, contraction, & cardiac output |
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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 |
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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 |
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Term
What with an amine that is indirectly acting on adrenergic receptors response look like? |
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Definition
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|
Term
What receptor mediates all actions on the heart? |
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Definition
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Term
Function
β1 agonist in the heart |
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Definition
1)increased HR 2)increased contractile force 3)increased conduction 4)decreased cardiac efficency 5)arrhythmia induced |
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Term
What cells do β1 agonists bind to when affecting HR? |
|
Definition
pacemaker cells of SA node |
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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 |
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Term
How can β1 agonists produce a decrease in HR (counterintuitive)? |
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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 |
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Term
What cells with β1 receptors are activated to increae contractile force of the heart? |
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Definition
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Term
How does activation of β1 agonists on myocardial cells increase contractile force? |
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Definition
=> increase Ca2+ influx with each AP => greater force of contraction |
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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 |
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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) |
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Term
What adrenergic receptor mediates the kidney vascular beds? |
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Definition
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Term
Effect
α1 agonist in the kidney vascular beds |
|
Definition
vasoconstriction with Epi & NE slight vasodilation with Iso |
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Term
What adrenergic receptor is seen in skeletal muscle vascular beds? |
|
Definition
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Term
Effect
PE & NE on skeletal muscle vascular beds due to what receptor? |
|
Definition
vasocontriction due to α1 |
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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. |
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Term
Effect
Iso on skeletal muscle vascular beds due to what receptors? |
|
Definition
vasodilation due to β2 receptors |
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Term
What adrenergic receptor mediates the liver & spanchnic area vascular beds? |
|
Definition
α1 (+ sm. β receptor component) |
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Term
Effect
Epi & NE on liver & spanchnic area vascular beds |
|
Definition
vasocontriction: higher concentrations of Epi & NE vasodilation: lower concentration of Epi |
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Term
Effect
NE, Epi, & Iso on coronaries due to what receptors? |
|
Definition
vasodilation due to β2 receptors |
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|
Term
What is also a contributor to vasodialtion of the coronaries? |
|
Definition
adenosine on smooth smuscles of coronaries during exercise |
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|
Term
Whaat adrenergic receptor mediates effect of pulmonary circulation? |
|
Definition
Both α & β receptors, but α receptors dominate |
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|
Term
Effect
Epi & E on pulmonary circulation |
|
Definition
some relatively weak vasoconstriction |
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Term
What adrenergic receptors are seen in the α cells on the pancreas? |
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Definition
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|
Term
What adrenergic receptors are seen in the β cells on the pancreas? |
|
Definition
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Term
Effect
α cell β receptor agonist in pancreas |
|
Definition
stimulation of glucagon secretion |
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|
Term
Effect
β cell α receptor agonist in pancreas |
|
Definition
inhibition of insulin secretion |
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|
Term
|
Definition
systolic increase, diastolic decrease => little to no change in overall BP |
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|
Term
Effect
low [Epi] on cardiac output |
|
Definition
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|
Term
Effect
low [Epi] on total peripheral resistance |
|
Definition
decreased (due to vasodilation in skeletal muscle) |
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|
Term
Effect
NE & higher [Epi] on BP |
|
Definition
increase of both systolic & diastolic pressure => increased BP |
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|
Term
Effect
NE & higher [Epi] on total peripheral resistance |
|
Definition
increased (due to vasoconstriction in skeletal muscle) |
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Term
|
Definition
sm. increase in systolic, lg. decrease in diastolic => decrease in BP |
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|
Term
When can Iso cause decrease in cardiac output? |
|
Definition
if vasodilation is too extreme => decrease in venous return |
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|
Term
Effect
Iso on total peripheral resistance |
|
Definition
decreased (due to vasodilation in skeletal muscle) |
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|