Drugs affecting synthesis, storage, release or removal of noradrenaline

Drugs which affect the synthesis or storage of noradrenaline will affect all sympathetic nerves, thereby causing a diverse range of effects.  In addition, because there is an overlap in the mechanisms involved in the synthesis, storage, release and removal of noradrenaline, adrenaline and dopamine, drugs which affect noradrenergic neurotransmission will have similar effects on adrenergic and dopaminergic neurotransmission in the periphery and the CNS.  Drugs which target noradrenaline synthesis and storage, therefore, have limited value as therapeutics.

Drugs can affect the release of noradrenaline by:

• affecting the available stores of noradrenaline in the sympathetic nerve terminals. Stores of noradrenaline within the nerve terminal can be affected by changes in metabolism e.g. by inhibition of the main metabolic pathway via monoamine oxidase (MAO) or inhibiting catechol-O-methyltransferase (COMT).  However, because reuptake rather than metabolism is the major mechanism for terminating the action of noradrenaline in the peripheral nervous system, inhibition of MAO and/or COMT may have little effect on the responses to sympathetic nerve stimulation.​​
• directly blocking release from the nerve terminal. Noradrenergic neurone blocking drugs, such as bretylium, can inhibit the release of noradrenaline from the nerve terminal.  Actions contributing to this effect include uptake into the nerve terminal and displacement of NA from the synaptic vesicles, along with a membrane stabilizing action.  The result of this is a decrease in the amount of noradrenaline released with each nerve stimulation.   While noradrenergic neurone blocking drugs were used in the treatment of hypertension, they had a number of adverse effects associated with effects on multiple sympathetically innervated organs and interference with cardiovascular reflexes.  They have been superseded by safer, more selective drugs.
• causing release of noradrenaline from the nerve terminal. Indirectly acting sympathomimetics enter the nerve via the uptake process and trigger the release of noradrenaline.  This release is due to the indirectly acting sympathomimetic displacing noradrenaline from the synaptic vesicles into the cytoplasm and then out of the nerve terminal via the reverse action of the uptake  transporter.  Once in the neuroeffector junction, the noradrenaline can interact with adrenoceptors and produce effects similar to those seen with activation of the sympathetic nervous system (including increased blood pressure and increased heart rate). Amphetamine is an example of an indirectly acting sympathomimetic. 

As the major mechanism for terminating the action of noradrenaline released from sympathetic nerves is via reuptake into the nerve terminal (Uptake 1), inhibition of this transport system will result in potentiation of sympathetic activity.  Drugs such as cocaine act as Uptake 1 inhibitors.  Their stimulant effects and addictive potential are due to action within the CNS.