I
"Pharmacology
Adrenergic System
Lecture (1)
Adrenergic System
General Notes:
 ANS is subdivided into: Sympathetic and Parasympathetic systems.
 The efferent preganglionic fibers of sympathetic comes from thoracic and
lumber regions of spinal cord, they synapse in the paravertebral ganglia.
 All preganglionic autonomic efferent fibers (sympathetic and
parasympathetic) are "CHOLINERGIC" which means they synthesize and
release ACh.
 Axons of Postganglionic fibers extend from the ganglia to glands and viscera.
 Most postganglionic "sympathetic" fibers release (Norepinephrine) or also
named (Nor-adrenaline), so they called noradrenergic or simply "Adrenergic
Fibers".
 Few sympathetic fibers release ACh and some peripheral sympathetic fibers
release Dopamine.
 Adrenal medulla, which is embryologically analogous to postganglionic
sympathetic neurons, release epinephrine (adrenaline) and lesser amounts of
norepinephrine so usually adrenal gland cells may be considered as
Postganglionic neurons.
 During emergency, body undergoes several reactions totally named (fight or
flight) response. These are triggered either by direct sympathetic activation
of the effector organ or by stimulation of adrenal medulla to release
epinephrine and lesser amount of norepinephrine.
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Adrenergic System
Neurotransmitters at adrenergic neurons:
Tyrosine
mediated by Noradrenaline, this process involves 5
steps:
Tyrosine
Hyrdoxylase
1) Synthesis of noradrenaline:
Dopa
tyrosine is transported by sodium linked carrier into
the axoplasm of adrenergic neuron.
Dopa
decarboxylase
The conversion of Tyrosine  Dopa is the rate
limiting step of noradrenaline synthesis.
Dopamine
Dopamine
β-hydroxylase
 Phenyethanolamine N-methylatransferase is
found only in adrenal medulla therefore the
conversion of noraldrenaline to adrenaline
happens in adrenal medulla not neurons.
Noradrenaline
Phenyethanolamine
N-methylatransferase
2) Storage of Noradrenaline:
Dopamine is transported into the synaptic vesicles by
an amine transporter system that is also involved in
the reuptake of pre-formed Noradrenaline.
Adrenaline
This carrier system is blocked by "Reserpine" which is
the oldest antihypertensive drug.
Depletion of the transmitter stores results. Synaptic vesicles contain dopamine
or Noradrenaline plus adenosine triphosphate ATP and the β-hydroxylase.
In the adrenal medulla, Noradrenaline is methylated to yield adrenaline both are
stored in the Chromaffin cells of adrenal gland.
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Adrenergic System
3) Release of Noradrenaline:
An action potential arriving triggers the influx of Ca2+ ions into the cytoplasm of
neurons causes vesicles to fuse with the cell membrane and expel their contents
into the synaptic space.
This release is blocked by drugs as "Bretylium" which is also an antihypertensive
agent.
Another drug is "Guanethidine", this inhibits the transport into vesicles and also
blocks release of Noradrenaline so it acts like both "Reserpine and Bretylium".
Indirectly acting "Sympathomimetics" are capable of releasing stored
Noradrenaline from nerve endings. They may displace free Noradrenaline in
cytoplasmic pool which is in equilibrium with that in storage vesicles.
4) Binding by receptors:
Noradrenaline released from synaptic vesicles diffuses across synaptic space and
binds either to:
Postsynaptic receptor on the effector organ or,
Presynaptic receptor on the nerve endings
 resulting in formation of intracellular 2nd messenger.
Adrenergic receptors use both the cAMP 2nd messenger and phosphoionsitide
cycle to transmit signals to effects.
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Adrenergic System
5) Removal of Noradrenaline:
The termination of noradrenergic transmission results from several processes:
a) Reuptake into the nerve terminal (Reuptake 1) or into perisynaptic glia cells
or smooth muscle cells (Reuptake 2).
The reuptake by neural membrane involves Na+ - K+ activated ATPase that
can be inhibited by "tricylic antidepressants TCA" or "Cocaine".
Once adrenaline re-enters cytoplasm of the adrenergic neurons it may be
taken into adrenergic vesicles by amine transporter system, or persist in a
protected pool,
Alternatively, it can be oxidized by "Monoamine Oxidase MAO" present in
neuronal mitochondria.
About 80% of released Noradrenaline is removed by reuptake.
b) Metabolism to O-methylated derivatives by postsynaptic cell membrane
associated "Catechol O-Methyl Transferase COMT".in the synaptic space.
c) Diffusion out of synaptic space to enter the general circulation.
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Adrenergic System
The metabolism of Catecholamines:
Norepinephrine
Epinephrine
MAO
MAO
COMT
Dihydroxy Mandelic Acid
Normetanephrine
COMT
COMT
MAO
Metanephrine
MAO
3-Methoxy-4-Hydroxy Mandelic Acid
(Vanillyl Mandelic Acid VMA)
The inactive product of Noradrenaline metabolism are excreted in urine as VMA,
metanephrine and normetanephrine are excreted in urine too.
Their concentration increase up to 95% in patients with Phenochromacytoma.
Sympathomimetics: are compounds that simulate or mimic the action of
sympathetic nerves.
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Adrenergic System
The Adrenoceptors (Adrenergic Receptors):
The term Adrenoceptors is widely used to describe receptors that respond to
catecholamines.
Receptors were also named After nerves that usually innervate them,thus
adrenergic receptors.
In 1948, Ahlquist proposed two different types of Adrenoceptors: α alpha and β
Beta.
There are three steps to prove or discover a receptor:
1) Structure-Activity Analyses.
2) Careful comparison of potency with series of agonists and antagonists.
3) Molecular biology provides a new approach by making possible the discovery
and expression of genes that code for related receptors.
So, by these means it was found that there are two types of adrenergic
receptors: Alpha and Beta.
Alpha Adrenoceptors:
These are subdivided into:
1) Alpha 1  A, B, D and L
2) Alpha 2  A, B and C
1) Alpha 1 Adrenoceptors:
They're present on postsynaptic membrane of effecter organ.
Their function:
 On Vessels: cause smooth muscle contraction so there will be
Vasoconstriction of blood vessels found in skin, splanchnic vessels and
skeletal muscles, this will cause pallor and increase peripheral vascular
resistance.
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Adrenergic System
 On Eyes: contraction of radial muscles of the iris (papillary dilatory muscle)
this will lead to dilation of the pupil  Mydriasis.
 Genitourinary Smooth muscles: contraction of sphincter of the bladder and
contraction of prostate and prostatic capsule causing difficulty to urination.
Besides, contraction of smooth muscles of Vas Deferens and seminal vesicle
 ejaculation.
Pregnant uterus contraction affects blood flow to fetus  low placental
blood flow.
 Skin: contraction of Pilo erector muscle  goose flesh skin  erection of hair.
 Sweat glands: are of two types:
1) Apocrine gland involved in stress has alpha receptor so stimulation of this
gland leads to increased secretion.
2) Acrine gland or thermoregulatory gland has muscarinic receptor even
though they’re innervated by adrenergic nerves.
 Metabolic functions: the effect on the liver is stimulation of lipolysis,
Gluconeogenesis and Glycogenlysis and K+ release.
 Heart: increase force of contraction ( not so important).
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Adrenergic System
Mechanism of Activation of alpha 1 receptors:
1)
2)
3)
4)
5)
Stimulation of alpha 1 receptor 
Activation of a G-coupling protein 
Activation of phospholipase C 
It acts om phosphotidyl inositol biphosphate 
The release of :
a) Diacylglycerol (DAG)
b) Inositol triphosphate (IP3)
IP3 stimulates the release of sequestrate
Stores of Ca2+ leading to increased concentration of
Cytoplasmic calcium
DAG activates protein Kinase C
Ca2+ activates Ca2+ dependant protein kinase
Phosphorylates their substrate and the effect happens
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Adrenergic System
2) Alpha 2 Adrenoceptors:
The location and actions are:
Location
1 Presynaptic receptor on adrenergic
nerve terminal (auto receptor)
2 Presynaptic receptor are present on
cholinergic nerve terminal, they are
called “Hetero receptors”
5 On platelets
Function
They inhibit the release of
noradreanline
The relaxation of GIT smooth muscles
is probably due to Presynaptic
inhibition of parasympathetic activity
(because of the presence on alpha 2
receptors on cholinergic terminal on
GIT)
Decrease sympathetic stimulation.
Some drugs used as Antihypertensive
act on these receptors for example
“Clonidine”
Alpha 2 receptors are inhibitory, they
decrease the insulin release.
They produce aggregation
6 On vascular smooth muscles
contraction
7 On fat cells
Inhibition of lipolysis
3 Postsynaptic CNS adrenoceptors are
present in the brain, e.g.: brain stem
vasomotor center
4 On the beta cells of pancreas
Mechanism of Activation of alpha 2 receptors:
Alpha 2 receptors (with the help of inhibitory regulatory protein Gi)  inhibit
adenyl cyclase enzyme activity  causing decrease in intracellular cAMP.
In addition there are other mechanisms include:
1) Activation of Potassium channels.
2)Closing of Calcium channel.
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