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

ADRENERGIC PHARMACOLOGY I

• When adrenaline is injected into a person we see 2 things happening:

• A rise in blood pressure (and maybe a small drop in blood pressure)
• A rise in heart rate
• Adrenaline causes these effects by acting on 2 different receptors - one on the peripheral blood vessels and one on
the heart.
• The peripheral receptor is the α receptor and causes vessel constriction
• There is also a β receptor which adrenaline can act on to cause a small degree of vessel dilation,
but the α effect predominates.
• The heart receptor is β1 and causes increased force and rate of contraction.
• When ergot alkaloids (α antagonists) are given in conjunction with adrenaline, we see a fall in blood pressure but
the heart rate remains increased.
• The ergot alkaloids inhibit the α receptor
• Hence, adrenaline cannot act on the α receptors in the vessels and so acts on the β receptors, which causes
vasodilation and a drop in blood pressure.

• Noradrenaline causes:
• A rise in blood pressure with no drop afterwards
• A rise in heart rate
• Noradrenaline presumably works on the same receptors as adrenaline described above, but noradrenaline does not
act on the β receptor in the vessels (and so does not cause vasodilation)
• When ergot alkaloids are added, we still see a rise in heart rate, but the blood pressure does not rise or fall
(noradrenaline has no effect on the vessels since the α receptors are blocked and noradrenaline cannot work on the
β receptors.

Noradrenergic neurons
• Tissues that receive sympathetic nerves have lots of noradrenalin associated with them.
• A typical noradrenergic neuron has its cell body in the sympathetic trunk and a long axon, ending with branching
networks containing swellings (varicosities) where the noradrenalin is concentrated.
• The criteria for chemical transmission are:
1. The chemical neurotransmitter must be synthesised by the nerve
2. The neurotransmitter must be stored in the nerve
3. Upon excitation, the neurotransmitter must be released from the nerve.
4. The neurotransmitter must act on specific receptors on the target tissue which leads to a response.
5. The neurotransmitter must have some way of being inactivated (either by reuptake or metabolism).

Synthesis of noradrenaline
• L tyrosine, an essential amino acid is the initial precursor.

L tyrosine
Tyrosine hydroxylase

L dihydroxyphenylalanine (L DOPA)
DOPA decarboxylase

Dopamine
Dopamine β hydroxylase

Noradrenaline

• Dopaminergic nerves use the same synthetic pathway, but they lack the enzymes that further degrade dopamine
(e.g. dopamine B hydroxylase). Hence dopamine is the final synthetic product.
• In the adrenal medulla, the chromaffin cells have an enzyme which can convert noradrenaline into adrenaline.
• This enzyme is phenylethanolamine N methyltransferase (PNMT)
By Duy Thai, 1997 Pharmacology Semester 1 page 2 of 3

Drugs affecting synthesis

• The targets of drugs affecting the synthesis of noradrenaline are the enzymes.
• Tyrosine hydroxylase
• No therapeutic drugs work here although it may be possible to develop drugs which are structural
analogues of L tyrosine.
• This enzyme is the rate limiting step in the synthesis of catecholamines (therefore it would be nice to have
a drug which inhibits it)
• It is a cytoplasmic enzyme
• DOPA decarboxylase
• The proper name for this is L aromatic aminoacid decarboxylase
• Is also involved in the synthesis of serotonin
• The drugs affecting this enzyme are:
• L DOPA
• Used in the treatment of Parkinsons
• It is not metabolised in the gut
• It can pass through the blood brain barrier
• It is the natural substrate for this enzyme
• carbidopa
• Often given in conjunction with L DOPA
• Does not cross the blood brain barrier so it inhibits DOPA decarboxylase in the
peripheral nerves. By doing this, it prevents peripheral side effects of L DOPA.
• We want L DOPA to act in the CNS, and so we inhibit its effects in the periphery by
giving it in conjunction with carbidopa.
• α methyl DOPA
• Is a synthetic substrate for DOPA decarboxylase.
• Its product is α methyl noradrenaline
• a methyl noradrenaline is a weak agonist of the alpha receptors and so acts as a partial
antagonist of noradrenaline (it prevents noradrenaline from acting on the α receptors
and giving a full response)
• It is often used as an anti hypertensive
• (α2 selective, therefore inhibits NA release)
• Dopamine B hydroxylase
• Present in the vesicle
• Released in conjunction with NA

Storage
• Vesicles contain:
• Noradrenaline
• Dopamine B hydroxylase
• Chromogranins
• Proteins that give the black staining appearance of the granules
• May act as binding proteins for the NA to prevent NA leaking out of the vesicle.
• ATP
• Provides the energy to maintain the high concentrations of NA in the vesicle
• The ration of NA:ATP is 1:4. This may indicate that ATP is involved in the binding of NA and
preventing its loss.
• There are other, larger more dense vesicles which contain cotransmitters (neurotransmitters released in conjunction
with noradrenaline).
• ATP and neuropeptide Y
• Released in conjunction with noradrenaline but acts on different receptors.
• Drugs affecting storage:
• Reserpine
• Depletes NA stores by interfering with the uptake of NA into the vesicles and may also disrupt
the integrity of the membrane so that NA can leak out.
• Leads to decreased blood pressure, depression and impotence.
• The decrease in blood pressure is due to the reduction in NA released.
By Duy Thai, 1997 Pharmacology Semester 1 page 3 of 3

• Depression is due to the effects reserpine has on the reduced uptake of serotonin in
vesicles.
• Impotence is also due to reduced NA release.
• Ejaculation is caused by and α constriction in the genitalia.

Release
• Noradrenaline can be released via 2 mechanisms
• Exocytotic
• An action potential arrives at the axon terminal and causes an influx of Ca ions. Ca2+ causes the
exocytosis of the vesicle.
• Non exocytotic
• Ca2+ independent
• Via Indirectly Acting Sympathomimetic Amines (IASA)
• Tyramine
• Ephedrine
• Phenylpropanolamine
• Amphetamine
• IASAs displace the NA from the vesicle quickly, so that NA is not deactivated and can be
released from the nerve directly. Hence, IASAs deplete stores but can cause an effect, unlike
reserpine which depletes stores but noradrenaline is inactivated when it leaks out of the vesicle.