Adrenergics Flashcards
Autonomic Adrenergic Transmission
SNS Postganglionic fibers release
norepinephrine (NE) (sometimes Epi and dopamine/DA)
Catecholamine Synthesis
dopamine neurons
1) adrenergic neurons uptake L-tyrosine (blood)
2) L-tyrosine→L-dopa
(tyrosine hydroxylase/TH)
3) L-dopa→dopamine
(dopa decarboxylase/DD/l-amino acid decarboxylase)
4) dopamine into storage granules (vesicles) via active transport carrier.
5) can be released from dopamine neurons.
the rate-limiting step in synthesis
L-tyrosine→L-dopa
(by tyrosine hydroxylase/TH)
Where is phenylethanolamine n-methyltransferase (PNMT) found?
cytoplasm
Catecholamine Synthesis
Norepi neurons
NE neurons:
1) dopamine β-hydroxylase (DBH) is in the vesicles.
2) dopamine→norepi
(DBH)
3) cytoplasmic norepi (reuptake/internal release from vesicles)
↓
epinephrine
(phenylethanolamine n-methyltransferase (PNMT)
Dopa decarboxylase
specificity
what can it convert?
fairly non-selective (broad substrate specificity)
L dopa→DA
5-hydroxytryptophan→5-hydroxytryptamine
αmethyldopa→αmethyldopamine
false transmitters
α-methylnorepinephrine
α-methyldopa
Dopa decarboxylase converts α-methyldopa to α-methyldopamine, which can be further converted to….
α-methylnorepinephrine (false transmitter)
acts in feedback loop on the enzymes TH and DD to decrease excessive production
Cytoplasmic NE
if there is excessive NE release, there is (more/less) NE in the cytoplasm, thus (more/less) feedback, and (more/less) rapid synthesis
excessive NE release
less NE in cytoplasm
less feedback
more rapid synthesis
main contributor to the NE pool
NE re-uptake
the NE pools
two cytoplasmic pools
(rapid & slow turnover)
cytoplasm (ie renal medulla chromaffin cells)
In the cytoplasm, NE acts to feedback on ___ production
DA
NE in the ________ is converted to EPI before packaging in vesicles
cytoplasm of the adrenal medulla chromaffin cells
In the chromaffin cells, both EPI and NE are stored and released in the ratio of ….
80% EPI, 20% NE
important d/t receptor specificity differences between EPI and NE
Epi vs NE
which has longer doA?
Epi
Catecholamine storage is mainly in ___
granular vesicles
making granular vesicles
in cell body & carried to terminal for filling
endocytosis (pinching off) of the nerve terminal membrane.
NE in the granules is in a complex with…
-ATP (4NE:1ATP)
-proteins (NTs & neuromodulators)
-DBH/dopamine β-hydroxylase
-DA
Neuropeptide Y
protein** stored with NE**
released with NE as a co-transmitter
potent local vasoconstrictor
increases fat deposition
Two cytoplasmic pools of NE
fast and slow turnover pools
fast:
used as transmitter
stored or released directly from cytoplasm
slow:
reserve pool
use when NE too low
Adrenergic enzyme inhibitors
experimental determination of the system mechanics
α-methyl-p-tyrosine
(inhibits TH, α-methyldopa, which inhibits DD)
Disulfiram (Antabuse)
(inhibits DBH)
post synaptic receptors
A1
A2 (also pre-synpatic)
B1
B2
B3
Presynaptic A2
control mechanism to prevent overrelease
sense too much/enough NT in synapse
once stimulated, shuts off further release
prevents overstimulation of post synaptic neuron
presynaptic A2
cholinergic vs adrenergic
cessation of action
cholinergic: destroy ACh by AChE
adrenergic: reuptake transporters (rapid acting; high affinity)
presynaptic A2r prevents the ___ dependent release of NT.
Ca
T/F
NE reuptake is a slower process.
False
NE in synapse for very short time
MAO & COMT
location
MAO: mostly terminal; mitchondria external wall
COMT: ECF
After NE is taken back up, it is subject to metabolism by ___ before its safely repackaged in vesicles.
MAO (outside wall of mitochondria)
T/F
MAO contributes to the 20% of NE that is not reuptaken by metabolizing it in the synapse.
False
COMT is in synapse
MAO is inside terminal
NE
% reuptake
% lost (how?)
80% reuptaken and survives MAO
20%
diffuses away, metab by MAO or COMT
Tyrosine hydroxylase
converts ___ to ___
L-tyrosine to L-dopa
(adds OH group)
catecholamine nucleus
2 hydroxy groups
dopa decarboxylase
converts ___ to ___
L dopa to dopamine
(remove carbox acid group)
Dopamine B hydryxolase
converts ___ to ___
dopamine to L-norepi
adds OH group the B carbon (beta from amine)
phenylethanolamine n-methyltransferase (PNMT)
converts ___ to ___
L-Norepi to L-epi
(adds methyl group onto N)
The catecholamines
L-dopa
dopamine
L-Norepi
L-Epi
❌L-tyrosine
Adrenergics Release
neuron vs adrenal chromaffin cells
Ca inflow @ terminal
exocytosis of vesicles
synaptic release of NT
adrenal chromaffin cells:
same but NT released directly to blood stream
most important mechanism in stopping neurotransmitter action at the receptor sites
re-uptake pumps back into the cytoplasmic pool
retrieved neurotransmitter is then taken up ____ concentration gradient back into vesicles
against
Some of the released neurotransmitter in the synapse can act on presynaptic α2 autoreceptors to…
inhibit further release via feedback loop
catecholamine depletion
done by preventing reuptake
initial & transient increase in activity
pheochromocytoma
tumor of the adrenal medulla
increase in circulating catecholamines
T/F
small amounts of neuronally released NT gets free to enter circulation but this isnt significant a amount.
True
rapidly destroyed
The 2 principle enzymes responsible for the degradation of catacholamines
monoamine oxidase (MAO)
catechol-o-methyltransferase (COMT)
MAO major forms
Type A: most active
metabolism of NE
(& DA, EPI, 5-HT/serotonin, tyramine)
Type B: less active
more selective for DA
found in red wine
tyramine
allows the liver the rapidly metab circulating catecholamines
has a lot of MAO and COMT
can be assayed in blood to show adrenergic activity
(ie: adrenergic tumors)
VMA
MHPG
MAO and COMT metabolizes NE into which compounds?
MAO
NE→DHMA & DHPG
COMT:
VMA & MHPG
Which are found in blood?
DHPG
MHPG
DHMA
VMA
MHPG
VMA
Adrenergic receptors
Characterized over 50 years ago based on
effects of NE, EPI and Isoproterenol (ISO) (Isuprel) - as α and β.
α and β
Receptor types further broken down as
α1 α2
β1, β2, β3
agonist comparative potencies
α1-agonist: NE > EPI > DA > ISO
α2-agonist: EPI > NE > DA > ISO
β1-agonist: ISO > EPI = NE > DA
β2-agonist: ISO > EPI > NE > DA
β3-agonist: ISO = NE > EPI > DA
Selective antagonists
α: phenoxybenzamine
β: propranolol
(finalizes classical characterization of these receptors)
T/F
Pre-junctional (α2) receptors are identical to post-junctional (α1)
False
T/F
Clonidine has higher selectivity for A1 than A2.
False
more selective for A2 > A1
Phenylephrine (Neo-Synephrine) is more potent at ___ than at __ receptors.
α1 > α2
Selective A antagonists
α1: prazosin
α2: yohimbine
A2 agonist post jxnl actvity
contraction of smooth muscles
platelet aggregation
etc
α1 and α2 receptors
subgroups
α1 → α1A, α1B, α1D
(3 subgroups)
α2: 4 subgroups (so far)
All α2 receptors have which moA?
inhibit adenyl cyclase by G protein interaction, causing a hyperpolarization
α1 stimulation
increased ICF Ca release by activation of phospholipase C, (G protein mediated)
A2r inhibit adenyl cyclase
&
A1r increases ICF Ca release
this is medicated thru _____
G proteins
β receptors subclasses
β1 and β2
β1 β2 β3
locations
1: mainly cardiac tissue
2: everywhere else
3: colon, bladder, adipose tissue
β-receptor potencies
β1 receptor potency: NE >= EPI
β2 receptor potency: EPI > NE
β3 agonist potency: NE > EPI
B Selective antagonists
β1- atenolol and metoprolol
β2– butoxamine
β3 selective antagonist is unknown at present
B Selective agonists
β1- dobutamine
β2– albuterol
B3 stimulation
lipolysis
relaxation of bladder detrusor muscle
propranolol does not block the action of __ at __ .
isoproterenol @ β3
All β receptors moA
via stimulatory G protein to stimulate adenyl cyclase.
B agonism
cardiac fx
increased inotropy & chronotropy
controlled by increased Ca++ release
B agonism
smooth muscle fx
increased cAMP → relaxation as membrane hyperpolarizes
Tissue response is often a balance of
several effects
Usually, the SNS postganglionic NT is norepi. Whats the exception?
Sweat glands
in symp: post ganglionic fiber is cholinergic (Ach; and not NE)
radial vs. sphincter muscle
radial muscle: contract to pull iris open
sphincter muscle: around rim of pupil; contracts to close iris (miosis)
parasympathetic effect on lens/vision
sympathetic effect on lens/vision
NE blocks the normal release of ___ by acting at ___.
NE
A2 (presyn)
also has post synaptic action
Directly acting adrenergic agents
NE
phenylephrine
isoproterenol
phenylephrine & isoproterenol
act on..
post synaptic A1 & B’s
tyramine
indirect agent
triggers NE release
NE acts as normal
Mixed action agents
Amphetamine
Ephedrine
indirect: triggers NE release
AND
direction: action @ post syn (less than NE)
prolonged use of indirectly acting agents
catecholamine depletion d/t it stimulating NE release
tyramine
amphetamine
ephedrine
Reuptake blocking agents
Cocaine
imipramine*
amitriptyline*
*TCAs
increases stimulation
Inhibitors of NA storage
acts on & destroys vesicles
severe decrease in activity
Why dont we use reserpine anymore
effects way too broad
affects adrenergic, cholinergic, etc
Adrenergic receptor blockers
dont prevent release but occupy the post-synaptic receptor
phentolamine (A1 & 2)
Propanolol (B1 & 2)
Prazosin (A1)
T/F
Adrenergic receptor blockers act by preventing release of NE.
False
dont prevent release but occupy the post-synaptic receptor
False transmitter moA
release in place of normal NT
A-methyldopa
uptaken and converted into AmethylNE
released w/ NE
acts at post syn (<NE)
Blocking NE release
prevents vesicle fusion with membrane
Clonidine (A2; blocks release)
Bretylium (doesnt let vesicle fuse with NT)
Guanethidine (releases NT intracellularly)
Clonidine vs Reserpine
Reserpine destroys vesicle
Clonidine prevents its fusion with NT
(Bretylium & Guanethidine)
Norepinephrine is the ___ isomer
L
“Levophed”
Norepinephrine (Levophed) (l-isomer)
a & b
Potent vasoconstrictor and inotropic agent
L> d potency
More α than β activity
α: ↑ PVR, SBP, coronary flow
Some β1:
lower doses = cardiac stimulatory effects
larger doses = vasoconstrictive effects (α1) predominate cause of increased BP
Like other catacholamines, NE increases cAMP in cells via _____, and decreases cAMP via _____.
increases: β stimulation
decreases: α stimulation
Glycogenolysis
NE vs Epi
(inhibits insulin release & lipolysis)
Epi has more
Levo
other fx
Reflexive vagal stimulation
(increased TPR & BP = ↓HR & ↑SV)
↓ Blood to abd organs & skeletal muscle
(coronary blood flow is increased indirectly due to alpha stimulation)
Does Levop increase myocardial O2 consumption?
no
Does levo cross the BBB?
no
When to use Levo
limited
mainly shock & severe hypoTN
Epinephrine (Adrenalin)
routes
IV
inhalation(more selective compounds available)
opthalmic
Epi
uses
cardiac stimulant and bronchodilator (anaphylactic shock)
w/ LAs & topical eye preps (prolong by vasoconstriction)
Epi
receptor activity
Potent α & β agonist
(non-selective adrenergic agonist)
α1: arteriolar vasoconstriction
α2: ↓ NE release
β1: ↑ chrono & inotrope; ↓ mast hist. release
β2: arteriolar vasodilation, bronchial smooth muscle relaxation & increased glycogenolysis
Epi
major therap. fx
Major therapeutic effects:
bronchodilation
cardiac stimulation
skeletal muscle vasodilation
glycogenolysis
Epi
other fx
Smooth muscle:
depend on receptor density & hormonal fx
↓ IOP (wide-angle glaucoma) + brief mydriasis
Topical/local: constricts blood vessels (hemostasis)
Epi
effect on SBP & DBP
SBP increased (increased inotropy)
DBP decreased (vasodilation)
Epi
coronary effects
MDO2
coronary vasodilation
↑ myocardial O2 demand
has further local effect (via NO) to increased coronary vasodilation
Epi
Increased risk of arrhythmias due to __ activity
β1
___ doses of Epi will give mostly contstrictive effects
high
