AUTONOMIC

NERVOUS SYSTEM
ADRENERGIC
MECHANISMS
 LEARNING OBJECTIVES
The Students should be able to:
- describe the synthesis, release and
metabolism of noradrenaline

- describe the characteristics of

neuronal and extraneuronal uptake
of catecholamines

- differentiate between directly and

indirectly acting sympathomimetic
amines
 Learning Objectives (contd)
- describe the pharmacological
actions of sympathomimetic
amines

- identify the receptors upon

which sympathomimetic amines
act

- describe the uses of α- and β-

Neurotransmitters Used in the Peripheral Nervous System
 Synthesis of
Noradrenaline
Synthesis of Noradrenaline
Tyrosine, a dietary amino acid is the substrate
for the synthesis of noradrenaline.
It is taken up into adrenergic nerves by an
active transport system.
Catecholamine Synthesis, Storage, Release, and Reuptake Pathways
Inhibitors of Noradrenaline Synthesis
These include:
α-methyl-p-tyrosine: inhibits the conversion of
tyrosine to L-DOPA.
Carbidopa, benserazide: these agents inhibit
dopa-decarboxylase activity. They are used as
adjuncts in the treatment of Parkinsonism.
α-methyldopa: is converted into a false
transmitter. It is used in the treatment of
hypertension.
Storage of Noradrenaline
 Noradenaline is stored in storage vesicles in
association with ATP (ratio 1 to 4).
 Other contents of the vesicles include
dopamine-β-hydroxylase and chromogranins.
 These are released along with noradrenaline
when the nerve is stimulated.
 Storage of noradrenaline and other monoamines
in the vesicles is inhibited by reserpine and
related rauwolfia alkaloids.
Release of Noradrenaline
 Release of noradrenaline from the nerve
terminals, when stimulated, is by the process
of exocytosis.
Steps in Synaptic Transmission
Noradrenaline can also be released from
adrenergic nerve terminals by
c) Displacement from the storage site: this is the
mechanism of action of indirectly acting
sympathomimetic amines eg tyramine.
b) Impairment of storage mechanisms leading to
release and subsequent depletion of the
vesicles. Reserpine acts in this manner.
Inhibitors of Noradrenaline Release
Negative feedback mechanism
Noradrenaline can act on specific receptors
on adrenergic nerve terminals producing a negative
feedback effect that limits the amount of
transmitter released. Inhibition of this negative
feedback mechanism would result in increased
release of the neurotransmitter.
Adrenergic Neurone Blockers
Examples: guanethidine, bethanidine and bretylium
These drugs
• have local anaesthetic properties
• are substrates for the uptake1 process
• prevent the uptake of noradrenaline by competing
for the same transport system
d) deplete neuronal stores of noradrenaline by
preventing the uptake of noradrenaline.
Uses
2) Treatment of hypertension
3) Treatment of cardiac arrhythmias
(especially bretylium).

Side effects
7) Diarrhoea
8) Postural hypotension
9) Failure of ejaculation
10) Nasal congestion
Noradrenergic Depleting Agents
Eg. Reserpine
Reserpine: It is an alkaloid from the Rauwolfia
sp. It depletes catecholamine
(and other monoamines) stores peripherally
and centrally.

Reserpine enters the nerve terminal by passive

diffusion. Inside the cytoplasm, it prevents the
uptake of noradrenaline into the storage vesicles.
Uses
 Reserpine can be used (though not much
nowadays) in the treatment of hypertension.
 It can also be used in psychiatric disorders such
as schizophrenia.
Inactivation of Noradrenaline
 Noradrenaline released from the nerve
terminal is inactivated by enzymatic or
non-enzymatic pathways.
Enzymatic Pathway
 This involves two enzymes, monoamine
oxidase (MAO) and catechol-o-methyl
transferase (COMT) acting in concert.
 MAO is present in almost all tissues.
 Very high levels are found in the intestine where
they inactivate biologically active monoamines
in the diet.
 MAO in the lungs and kidneys inactivate
circulating monoamines while in neuronal
tissues, MAO inactivate noradrenaline that is
present in the cytoplasm.
 MAO is inhibited by selegiline, pargylline and
iproniazid.
 COMT is widely distributed in tissues.
 High activity in liver, kidney, smooth and
cardiac muscle cells and other tissues innervated
by adrenergic nerves.
 COMT is inhibited by pyrogallol and tropolones.
Norepinephrine Metabolism
Non-Enzymatic pathway
This involves the uptake of noradrenaline and
related amines into neuronal and extraneuronal
tissues.

Two uptake processes

• Uptake1 (neuronal uptake)
• Uptake2 (extraneuronal uptake)
Uptake1: This is uptake followed by storage. It

b) Is an active transport process

c) is sodium dependent
d) is proportional to the density of adrenergic
innervations
f) is saturable
g) conserves transmitter
This process is inhibited by cocaine, tricyclic
antidepressants and adrenergic neuron blockers.
Other substrates for the process include dopamine
and tyramine.
Mechanisms of Action of Cocaine and reserpine
Uptake2: This is uptake followed by destruction. It
• occurs at high substrate concentrations

• becomes important when uptake1 is blocked

or saturated
c) is inhibited by steroids