By Duy Thai, 1997 Pharmacology Semester 1 page 1 of 5

ADRENERGIC PHARMACOLOGY III

More on the metabolism of NA

• The enzymes MAO and COMT, although present at different locations (MAO is present in the nerve terminal on
the mitochondrial membrane, COMT is present in the target tissue), tend to work together.

COMT
Normetanephrine Noradrenaline
MAO MAO
Aldehyde Aldehyde

DOMA DOPEG
Diffuse out of nerve
terminal and act on
COMPT in external
VMA tissues MOPEG
(in periphery) (in CNS)

Urine

• NA is taken up by the nerve terminal and degraded by MAO into intermediates. The intermediates diffuse out of
the nerve terminal where they are taken up by the target tissue and further degraded by COMT.
• The products of COMT are VMA and MOPEG which are excreted in the urine.
• Alternatively, NA can be taken up by uptake 2 and metabolised by COMT directly. The product of this is
normetanephrine, which is broken down by MAO into aldehyde which gets converted to VMA and MOPEG.

• Note that uptake 2 mechanisms (tissue uptake) are more sensitive to adrenaline rather than adrenaline. That is why
uptake 2 blockers (corticosteroids) are useful in treating asthma. They block uptake 2 in the bronchi, allowing
adrenaline to have prolonged action, and so you get more bronchodilation.
• Uptake 1 blockers are desipramine and work mainly in the CNS.
By Duy Thai, 1997 Pharmacology Semester 1 page 2 of 5

Summary of drugs used to affect synthesis and degradation

Process Drug Drug action Clinical relevance

Synthesis L DOPA • Natural substrate of DOPA • Treat Parkinsons
decarboxylase, therefore
increasing the amount of NA
produced in the brain

Storage Reserpine • Disrupts vesicle membrane so NA • Treat hypertension. Has

leaks out and degraded, reducing side effects: depression,
NA stores impotence
Release:
Exocytosis Guanethidine • Specific for adrenergic neurons. • Hypertension. Side
Blocks Ca2+ mediated release of effects: depression,
NA impotence
• Displaces NA from the vesicle in • Increases blood pressure.
ISA Tyramine sufficient amounts to cause it to Present in foods and can
leak out of the nerve cause hypertensive crisis
if irreversible MAO
inhibitor used
Amphetamine • Same as above • CNS stimulant, keeping
people awake
(narcolepsy)
Inactivation:
Uptake Desipramine • Blocks uptake 1 mechanisms into • Antidepressant
the nerve, prolonging NA action
Corticosteroids • Blocks uptake 2 mechanisms into • Cause bronchodilation in
the tissues, prolonging adrenaline asthmatics
action
Metabolism Moclobemide • Reversible MAO inhibitor, which • Antidepressant
allows competition with tyramine
for MAO

Adrenoreceptors
• α effects tend to cause constriction, β effects tend to cause dilation or have specialised effects on special organs.
• α adrenoreceptors:
• Blood vessels Constricts
• GIT Constricts sphincters
• Pupil Constricts radial muscle (pupil dilation)
• β adrenoreceptors:
• Heart Increase heart rate and force
• Skeletal blood vessels Dilation
• Kidney Renin release
• Liver Glycogenolysis
• Bronchi Dilation (via adrenaline)
• Recall that NA and adrenaline have slightly different effects when injected:
• Noradrenaline
• Increases blood pressure (vasoconstricts)
• Increases heart rate
• Adrenaline
• Increases blood pressure (vasoconstricts) but also causes a slight fall in blood pressure
afterwards (vasodilate)
• Increases heart rate.
• This suggests that adrenaline and noradrenaline act on the same receptors in the heart but may act on different
receptors on the blood vessels.
• Adrenaline and noradrenaline have the same effect on β1 receptors of the heart
By Duy Thai, 1997 Pharmacology Semester 1 page 3 of 5

• Adrenaline and noradrenaline have the same effect on α1 receptors on blood vessels (constriction), but
adrenaline can also act on β2 receptors, causing vasodilation.
• The distribution of α and β receptors on different tissues can be illustrated using sympathomimetic agonists.

Blood pressure (α effect) Heart rate (β effect)

NA

Phenylephrine

Isoprenaline

Phenylephrine is an α agonist
Isoprenaline is a β agonist

Adrenoreceptor classification
• α receptors
• Present in smooth muscle which can be contracted
• Phenylephrine > NA ≥ Adrenaline >>> Isoprenaline
• β receptors
• Present in the heart
• Isoprenaline > Adrenaline ≥ NA >>> Phenylephrine
• Also present on smooth muscle which can be relaxed (e.g. bronchi, blood vessels to skin and muscle)
• Isoprenaline > Adrenaline >>> NA > Phenylephrine

• See how adrenaline has a much higher affinity for the β receptors in the smooth muscles which relax than
noradrenaline, while in the heart, adrenaline and noradrenaline have the same affinity for the β receptor. This has
led to the discovery of receptor subtypes:
• The β receptors on the heart are β1
• The βreceptors on the smooth muscles are β2

• Generally, it is better to classify receptors according to antagonists. Why?

• It is easier to measure the affinity of an antagonist (KB) than it is to measure the affinity of an agonist
(KA). All you need to do is construct a Schild plot.
• The different affinity of an antagonist to different tissues means that there may be different receptor
subtypes on the tissues.

Adrenoreceptor antagonists
Blood pressure (α effect) Heart rate (β effect)
Noradrenaline alone:

Noradrenaline + phentolamine:

Noradrenaline + Propranalol:

Phentolamine is an alpha antagonist

Propranalol is a beta antagonist
By Duy Thai, 1997 Pharmacology Semester 1 page 4 of 5

Subtypes of α and β receptors

β1 Heart Increase HR
Kidney Cause renin release
β2 Bronchial smooth muscle Relaxation
Vascular smooth muscle Relaxation
Uterine smooth muscle Relaxation
α1 Vascular smooth muscle Constriction
Radial muscle of pupil Constriction (pupil dilation)
Genitourinary muscles Impotence
α2 Nerves on vascular smooth muscle Inhibition of NA release
Vascular smooth muscle

• Recall that adrenaline is a better β2 agonist than noradrenaline!

• On β1, the two are the same.

• Most tissues have a mixture of the receptor subtypes.

α1 agonists
• Found on blood vessels, eye, genitourinary
• Phenylephrine Was the drug responsible for finding α1 receptor
Mydriatic (dilates the pupil for ophthalmic procedures).
Generally, cholinergic antagonists are better!
• Oxymetazoline Ocular decongestant
Increased blood flow to the eye leads to dilation of the vessel and buildup of fluid.
The alpha1 agonist causes constriction of the vessels.
• Methoxamine Nasal decongestant
Runny nose and excess mucous is due to excess blood flow.

• Direct decongestants vs indirect (ISAs)

• Direct decongestants have an advantage because they work quickly, are more specific, have no CNS
effect. However, they tend to overdo the vasoconstriction, and so when the effects wear off, there tends to
be a reactive hyperemia (rebound effect).
• ISAs (e.g. pseudoephedrine) may be better as decongestants because they have a slower onset, release a
natural product (NA) which can be removed naturally, at a slower rate, thus preventing the reactive
hyperemia.
• Why are there so many different drugs for different conditions, if they all have the same effect?
• Because, each drug has a different pharmacokinetic profile which makes it more suitable for some
conditions than others. e.g. Methoxamine would not be suitable as an ocular decongestant because it does
not cross the corneal membrane very well.

α2 agonists
• Found on nerves, blood vessels
• Clonidine
• Was the drug used to identify the α2 receptor
• Is used to treat hypertension by reducing the sympathetic outflow in the CNS (centers
controlling blood pressure).
• It is a partial agonist at α2 receptors, and so is weaker than NA at causing
vasoconstriction. Hence, it is acting as a partial antagonist as well, preventing NA
from exerting its full effects. Also, clonidine is a very effective α2 agonist on nerves
and so it acts to reduce NA release.
• α methyl DOPA
• Is a substrate for DOPA decarboxylase.
• Its product is α methyl NA, which acts as a false transmitter.
• It is a partial agonist at α1, β1 and β2 receptors. However, it is a very effective α2
agonist, and so prevents the release of NA.
• It is used as an antihypertensive.
By Duy Thai, 1997 Pharmacology Semester 1 page 5 of 5

α antagonists
• α1 and α2 adrenoreceptor antagonists
• Phentolamine
• Competetive
• Used to reverse hypertensive crisis due to tyramine
• Also used in peripheral vascular diseases (Reynaud phenomenon)
• Phenoxybenzamine
• Non competitive
• Used in phaeochromocytoma (in conjunction with β antatagonists)
• Selective α1 antagonist
• Prazosin
• Treat hypertension (its major use – very good at it!)
• Side effects:
• 1st dose effect (if an initial dose is too high, it is possible to get too much vasodilation
resulting in a hypotensive crisis)
• Postural hypotension (failure of the reflex vasoconstriction upon standing up)
• Nasal stuffiness
• Failure of ejaculation due to inhibition of α1 receptors in the vas (which constricts to
propel semen)
• Involuntary micturition
• Selective α2 antagonist
• Yohimbine
• No clinical uses
• Possible aphrodesiac?

Competitive
Non - Competitive

Response Response

• What are the benefits of an irreversible inhibitor like phenoxybenzamine?

• Sometimes irreversible inhibitors are beneficial. They cause a long term blockage which cannot be
overcome by increasing agonist concentration.
• e.g. Phenoxybenzamine can be used to treat phaeochromocytoma, which is a benign tumor of
the adrenal glands causing increased release of adrenaline. If a competitive antagonist were
used, the excess levels of adrenaline would overcome the inhibition. That is why an irreversible
antagonist is used. Furthermore, treatment of the condition is usually surgical removal. Removal
of the adrenal gland causes marked rises in adrenaline levels in the blood, which will not be able
to overcome the irreversible inhibition.
• Sometimes, irreversible antagonists are not beneficial, for example irreversible MAO inhibitors are not
good because ingested tyramine will not be able to compete with the antagonist for MAO and so it is
absorbed in the blood, and cause release of NA (it is an ISA), possibly resulting in hypertensive crisis.