2. METABOLIC SYNTHESIS OF
NOREPINEPHRINE AND EPINEPHRINE
Tyrosine (from ECF cytoplasm)
Tyrosine hydroxylase (mitochondrial)
Tetrahydrobioterin (cofactor)
DOPA
Decarboxylase (cytoplasmic)
Pyridoxine PO4 (cofactor)
DOPAMINE
Dopamine B-oxidase (in specific granules)
Ca
Mg + ATP
Ascorbic acid (cofactor)
Exocytosis:
Mechanism whereby Ca brings about the
release of NE
NE
Phenylethanolamine
N-methyltransferase (in adrenal medulla)
EPINEPHRINE
Ca++ is needed for membrane excitation and release of catecholamines for
adrenergic neurons and adrenal medullary cells.
3. NEUROTRANSMISSION AT
ADRENERGIC NEURONS
I.
II.
III.
IV.
V.
Synthesis of NE – Tyrosine is transported cytoplasm of
adrenergic neuron DOPA Dopamine.
Storage of NE in Vesicles – Dopamine is transported into
synaptic vesicles using an amine transporter (carrier)
DOPAMINE NE.
Release of NE – Action potential at nerve ending triggers
calcium influx cytoplasm of neuron causing fusion of
vesicles with cell membrane releasing NE synapse .
Binding to Receptor – NE diffuses across the synaptic
space and binds to either: 1) post-synaptic receptors on
the effector organs or 2) pre-synaptic receptors on the
nerve ending. This triggers a cascade of events resulting in
the formation of intracellular 2nd messenger (cyclic AMP).
Removal of NE – NE diffuses out of the synaptic space
general circulation or it may be recaptured by an uptake
system then back into the neuron.
4. TERMINATION OF ACTIVITY OF
NEUROTRANSMITTER
1.
2.
3.
•
Reuptake into the neuron (uptake I)
Enzymatic inactivation (MAO, COMT)
Diffusion away from synapse and uptake at extraneuronal sites
(perisynaptic glia and smooth muscle cells) (uptake II)
STORAGE VESICLES OF NOREPINEPRHINE
–
Pool I
•
•
•
–
Rapid turnover of NE
T ½ of 2 hrs.
NE released into synaptic cleft, metabolized by COMT.
Pool II
•
•
•
Slow turnover of NE
T ½ of 24 hrs.
NE released into neuronal cytoplasm, metabolized by MAO.
5. ADRENERGIC AGONISTS
A.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Direct-acting (Release of NE
after binding to receptors)
Epinephrine (Adrenaline)
Norepinephrine
(Noradrenaline, Levarterenol)
Isoproterenol
Isoetharine
Dobutamine
Phenylephrine
Methoxamine
Clonidine
Metaproterenol
Terbutaline
Ritodrine
Albuterol
B.
1.
Indirect-acting (Release of
NE followed by binding to
receptors)
Tyramine
C.
1.
2.
3.
4.
5.
Mixed-acting
Ephedrine
Metaraminol
Dopamine
Phenylpropanolamine
Amphetamines
12. PARTICULAR NEURONAL-BLOCKERS
•
•
RESERPINE
– Blocks the ability of adrenergic neurons to transport NE from the
cytoplasm into storage vesicles.
– Causes ultimate NE depletion in adrenergic neurons, causing
impairment of adrenergic function.
– Effects: Gradual decline in BP
Slows cardiac rate simultaneously
– ADR:
Insomnia, nightmares, hallucinations, depression,
suicidal tendencies
GUANETHIDINE
– Blocks the release of stored NE.
– Gradual lowering of BP.
– Displaces NE from storage vesicles – acting as false
neurotransmitter.
– ADR:
Orthostatic hypotension
Impairs male sexual function
