By Duy Thai, 1997 Pharmacology Semester 1 page 1 of 3

ADRENERGIC PHARMACOLOGY II

Release processes
1. Exocytotic
• Triggered by an action potential
• The action potential opens up a Ca2+ channel, causing an influx of Ca2+ into the nerve terminal which is
required for release of the vesicle containing the neurotransmitter.
• Recall that the vesicle contains other chemicals apart from NA. These are:
• Dopamine β hydroxylase
• ATP and NPY
• Chromogranins
• Drugs which can act to inhibit this process are:
• Local anaesthetics which block the Na+ channels, preventing the propagation of an action
potential
• Ca2+ channel antagonists, which block the opening of the Ca2+ channel
• The problem with these drugs is that they are not selective, they block neurotransmission is all
nerves, not just adrenergic nerves.
• An example of a drug which is specific for adrenergic nerves (adrenergic neuron blocking drugs) is
guanethidine.
• Guanethidine is used as an anti-hypertensive drug since it prevents the release of NA
• It works by the following mechanisms
• They selectively accumulate into sympathetic nerves
• They are inhibited by ISA’s
• As well as inhibiting the release of NA, they also prevent the release of ATP and NPY,
which means they must act on the vesicle as a whole.
• They may limit Ca2+ entry into the nerve following depolarisation.
• As with reserpine, can have side effects such as depression and impotence.
2. Non exocytotic
• Drug induced release of stored noradrenaline
• The drugs belong to a class known as Indirectly acting sympathomimetic amines (ISA)
A. Tyramine
• Tyramine is a natural product, present in wines, cheeses, banana skins
• Tyramine can also be a substrate of dopamine β hydroxylase.
• The product of the reaction is octamine, which acts as a false transmitter
having no action
B. Ephedrine
• Found in decongestants
C. Amphetamine
• Commonly a drug of abuse
• ISA’s are able to release NA from the vesicle, but unlike reserpine, the NA is not broken down when it is
released. The drugs displace NA from the vesicles in high enough concentration so as to be able to elicit a
response.
• Reserpine acts by disrupting membrane integrity, causing NA to leak out, but when it does so, it
is inactivated.

Indirectly acting sympathmimetic amines

• Act by displacing noradrenaline from the vesicle
• The release of NA is no Ca2+ dependent
• The drugs enter the nerve terminal by an uptake mechanism
• Inside the nerve terminal, they may possible be substrates for enzymes which break down noradrenaline, which
explains the reason why when NA is displaced from the vesicle, it is not degraded.

Prejunctional modulation
• When noradrenaline is released into the synaptic space, it acts on α or β receptors located on the tissues.
• However, it may also act on a receptor which is located on the nerve terminal itself - an α2 receptor, which inhibits
the release of further NA (a classic negative feedback mechanism, very similar to the prejunctional modulation of
5HT) - Autoinhibition
By Duy Thai, 1997 Pharmacology Semester 1 page 2 of 3

• ATP and NPY can also act on this receptor to inhibit the release of NA
• Since lots of energy is required to synthesise and release NA, the nerve must have a mechanism to stop excessive
release of NA, and so it uses autoinhibition.
• Drugs which can exploit this are the α2 agonists, which depress the release of NA
• e.g. Clonidine

• There are other chemicals which can augment a NA response

• e.g. Constriction of a blood vessel
• Sympathetic activation releases NA from nerve terminals which act on α receptors on the blood
vessels to cause constriction
• Sympathetic activation of β receptors in the kidney also stimulates the release of renin, which
cleaves angiotensinogen to angiotensin which is converted to angiotensin II.
• Angiotensin II can also increase blood pressure by causing constriction of blood vessels
• In addition, prostaglandins may increase the release of NA from nerves, augmenting the direct
action of AII.

Inactivation of noradrenaline
• Inactivation can occur via 2 mechanisms:
• Uptake into the nerve terminal or tissues
• Metabolism

Neuronal (uptake 1)

NA
Extraneuronal (uptake 2)

• Uptake
• 95% of release NA is recycled
• The nerves have evolved a way of conserving energy by:
1. Modulating the release of NA during heavy use by autoinhibtion
2. Recycling NA
• The reuptake of NA is via a Na+ dependent facilitated diffusion
• Other substrates for the reuptake mechanism are;
• Adrenaline
• Adrenaline is the preferred substrate for extraneuronal uptake
• ISA’s
• Adrenergic neuron blocking drugs (AND)
• Apart from saving energy, reuptake maintains stores of NA so that there will always be sufficient levels to
cause a response under any circumstances. If there were no uptake mechanism, when all the NA was
depleted, we would have to wait a long time for it to be synthesised, stored and released again.
• Uptake blockers have been developed which prevent reuptake of NA.
• This causes NA to accumulate in the synaptic space and so the response you get is bigger and
lasts longer.
• Example of uptake blockers are;
• Desipramine
• Used to treat depression
• Depression is the result of low levels of amines (hence reserpine, and
guanethidine cause depression by lowering the amount of NA
released in the brain)
• Serotonin is also an amine and so it too can cause depression in low
levels (reserpine can act on serotonergic nerves as well)
By Duy Thai, 1997 Pharmacology Semester 1 page 3 of 3

• Amphetamines increase levels of serotonin, and can elevate mood.

• Prozac (fluoxetine) is a serotonin uptake inhibitor (much like
desipramine) and so prolongs the action of serotonin.
• Cocaine
• Local anaesthetic
• Extraneuronal uptake blockers are corticosteroids
• e.g. In asthma, which is an inflammatory disorder of the bronchi, it is better to treat the
inflammation causing the constriction of the airways, rather than just treating the
constriction.
• Corticosteroids are useful in asthma because they do 2 things:
1. They treat the inflammation
2. They block extraneuronal uptake, which is selective for adrenaline.
• Recall that adrenaline acts on β receptors on the bronchi (there is no
sympathetic innervation) to cause dilation
• Metabolism

MAO

NA

Catechol O methyl transferase

• The primary inactivation process is reuptake

• Metabolism is secondary to reuptake
• If breakdown of NA is inhibited, then NA can accumulate in the nerve terminal and some of it may leak
out into the synaptic space if the concentrations in the nerve terminal are too great.
• MAO inhibitors are used as antidepressants
• There are 2 forms of MAO - MAO A and MAO B

Substrates Inhibitor drug

MAO A/B Dopamine, tyramine Paragyline (irreversible)
MAO A NA, 5HT Moclobemide (reversible)
MAO B Selegiline

• Catechol O methyl transferase inhibitor drugs are not clinically important (pyrogallol)
• Paragyline:
• Is an irreversible inhibitor of MAO. Since it is irreversible, it takes time to replenish stores of
MAO.
• It is used to treat patients with depression
• It takes 4 - 6 weeks for NA levels to accumulate to sufficient concentrations in the nerve terminal
to be able to leak out and cause a response.
• MAO is also present in the GI flora.
• The GI MAO is important in breaking down natural products e.g. tyramine (remember
that tyramine is an ISA)
• If you inhibit the GI MAO by taking paragyline (irreversible inhibitor), and you go to a
party where there is lots of wine and cheese (foods rich in tyramine) then tyramine will
not be broken down and so will be absorbed.
• If tyramine gets to a sympathetic nerve terminal, it will cause displacement of NA and
result in a hypertensive crisis!
• Irreversible MAO inhibitors (moclobemide) is good because it allows competition with tyramine,
so that tyramine is able to be broken down in the gut if the concentrations are high enough to
displace moclobemide.
• The reason why NA and tyramine are not given as oral drugs is because they will be rapidly broken down in the gut
by GI MAO.