PHAR0004/9/7 - General and Systematic Pharmacology/

Intermediate Pharmacology/Introductory Pharmacology

Adrenergic Pharmacology II Dr. Richard Burt

Aim
To understand the mechanisms by which drugs may interfere with or mimic the effects of the sympathetic nervous system.

Objectives
By the end of this session you should be able to:
 Understand the mechanism of action and know the therapeutic uses of ergot alkaloids.
 To know the physiological consequence of α-adrenoceptor blockade.
 To be aware that blocking centrally located α-adrenoceptors can affect the level of sympathetic outflow.
 To know the classification of -adrenoceptor antagonists, their therapeutic uses and when they are contra-
indicated.
 To list and explain the main therapeutic uses and side effects of adrenoceptor antagonists.
 To be able to describe the synthetic pathway for the catecholamines and the action of drugs at different points.
 To know the possible sites, mechanisms and names of drugs that can act to affect the release of noradrenaline
 Demonstrate an understanding of what is meant by an ‘adrenergic neurone blocking agent’
 To appreciate the roles played by the neuronal and extra-neuronal uptake mechanisms in terminating the actions
of noradrenaline and adrenaline and the consequences of blocking these mechanisms
 Give a named example of each class of drugs in the two preceding objectives
 Explain the routes by which noradrenaline is metabolised, the importance of the isoenzymes MAO-A and MAO-B
and the "cheese reaction".

Further reading
Supplement the lecture by reading Rang, Ritter, Flower & Henderson (8th Ed) Chapters 12 & 14 (P143-154 & P-177-
195) Ergot – Chapter 15 P202-P203

Ergot alkaloids
The first α -adrenoceptor antagonist to be described was a mixture of alkaloids extracted from ergot which is product of
Clacviceps purpurea, a fungal contaminant of rye grain. The main alkaloids found in this extract are in fact amine
derivatives of d-lysergic acid (LSD). As well as having α -adrenoceptor antagonist actions they have agonist actions on
5-HT (5-hydroxytryptamine) and dopamine receptors. They are used to treat migraine (ergotamine) and postpartum
haemorrhage (ergometrine).
Differences between adrenoceptor antagonists
Antagonists vary in their selectivity for α or  adrenoceptors. They also differ in their interaction with the receptor.
Phentolamine acts as a reversible competitive receptor antagonist at α-adrenoceptors as does propranolol at -adrenoceptors.
However, phenoxybenzamine is an irreversible non-competitive antagonist that acts by forming a co-valent bond with α-
adrenoceptors. This type of antagonism is characterised by a reduction in the slope of the log-dose response curve and a
decrease in the maximum response to an agonist.
Some of the -adrenoceptor antagonists e.g. oxprenolol are partial agonists. They are weak agonists at -adrenoceptors but
can antagonise the effects of a full agonist e.g. noradrenaline. The partial agonist action is termed "intrinsic sympathomimetic
activity". In addition, they can be grouped into whether they are lipid soluble and have a local anaesthetic action.

Physiological consequences of α -adrenoceptor blockade

α -adrenoceptor antagonists in general produce vasodilation which will cause a fall in blood pressure and nasal stuffiness. The
fall in blood pressure will evoke a baroreceptor reflex which will cause an increase in sympathetic drive. As this increase in
sympathetic drive is unopposed on β-adrenoceptors there will be a resultant tachycardia and increase in renin secretion from
the juxtaglomerular apparatus of the kidney (this results in sodium and water retention - oedema). Interestingly, sympathetic
tone is controlled by α -adrenoceptors in the brain, activation of α 1-adrenoceptors causes excitation while activation of α 2-
adrenceptors causes inhibition. This probably explains why α 1-adrenoceptors cause less of the reflex tachycardia and sodium
and water retention than non selective α -adrenoceptor antagonists. Another problem of α -adrenoceptor blockade is postural
hypotension i.e. the inability to venoconstrict when changing position. Venoconstriction is mediated by both types of α-
adrenoceptor and this again is probably why α1-adrenoceptor antagonists cause less postural hypotension that non-selective α-
adrenoceptor antagonists.

Department of Neuroscience, Physiology and Pharmacology, UCL

-adrenoceptor antagonists
There are 16 different types of these drugs in the BNF. They can be divided into whether they are lipid or water soluble, have
intrinsic sympathomimetic activity and are selective for 1-adrenceoptors (cardioselective) and if they also have -
adrenoceptor antagonist actions. They are used in the treatment of angina, hypertension, glaucoma, myocardial infarction,
arrhythmias, thyrotoxicosis, congestive heart failure, anxiety and for the prophylaxis of migraine. The major contraindication
is in ASTHMATICS in which they cause bronchospasm.

Effect of drugs on adrenergic neurons

A Synthesis
The synthetic pathway for noradrenaline is shown in Figure 1. The rate of synthesis can be increased by giving L-DOPA (as
in Parkinsonism) as this by-passes the rate-limiting step (a tyrosine hydroxylation inhibitor is α-methyltryosine -Metirosine).
Dopa decarboxylase is more correctly termed aromatic L-amino acid decarboxylase which emphasises the enzyme's lack of
substrate specificity. This is demonstrated by the conversion of α-methyl dopa (an anti-hypertensive agent) by the
decarboxylase enzyme to α -methyl dopamine, which is subsequently converted by dopamine β-hydroxylase to α-methyl
noradrenaline. The latter is a false transmitter as it can be released from the sympathetic nerve terminals by nerve stimulation.
The α-methyl group makes this false transmitter resistant to degradation by the enzyme MAO (see below). The decarboxylase
enzyme is inhibited by the polar compound, carbidopa (used in Parkinsonism). Disulfiram, used to alter ethanol metabolism,
is a copper chelating agent and it is this property that leads to its inhibition of dopamine -hydroxylase.

Figure 1 the synthetic pathway for noradrenaline

(b) Storage (see Figure 2)
Noradrenaline is stored in vesicles together with ATP and the protein chromogranin A. Vesicular transporters (with 12
transmembrane spanning domains) facilitate the accumulation of dopamine and noradrenaline in the vesicles. These
transporters are affected by reserpine and related drugs whose action leads to the depletion of noradrenaline by preventing
the passage of the catecholamines into the storage vesicles. Therefore the catecholamines escape into the cytoplasm of the
nerve terminal and are inactivated (by MAO, see below). Tetrabenazine is a short acting noradrenaline and dopamine
depletory, which is reversible and is used to treat hyperkinetic movement disorders, such as Huntington’s disease.

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 Noradrenergic
varicosity

Figure 2 showing how noradrenaline is stored in a varicosity and released.

c) Release
The effects of sympathetic nerve stimulation are due to the release of noradrenaline and also to the effects of any co-
transmitters e.g. ATP and NPY.
The release of noradrenaline from postganglionic sympathetic nerves can be regulated through receptors situated on
the sympathetic nerve terminal. There are pre-junctionally (synaptically) located α2-adrenoceptors on all sympathetic nerve
terminals. Noradrenaline released from the nerves can act on these receptors to inhibit its own subsequent release (Fig. 3).
This is termed auto-inhibition. However other agonists with affinity for α 2-adrenoceptors e.g. clonidine (an antihypertensive
agent) can also inhibit transmitter release. There are many other presynaptic receptors on sympathetic nerve terminals through
which the release of noradrenaline (and any co-transmitters) can be either increased or reduced.
Noradrenaline can also be released by drugs in the absence of nerve stimulation. For example, tyramine produces its
effects via the displacement of neuronal noradrenaline (termed an indirect acting sympathomimetic). Some drugs can act
partly indirectly via noradrenaline release and partly directly on post-junctional adrenoceptors e.g. ephedrine and
amphetamine.
The release mechanism for noradrenaline can be inhibited by guanethidine and related drugs, the adrenergic neurone
blocking agents (anti-hypertensive agents). These enter via the uptake1 mechanism and accumulate in the sympathetic
neurones to block neurotransmission.

d) Uptake
Much of the noradrenaline released into the neuroeffector junction is recaptured by the sympathetic nerve terminals.
Noradrenaline has a higher affinity than adrenaline for this uptake1 (or neuronal uptake ; norepinephrine transporter (NET),
also known as solute carrier family 6 member 2 (SLC6A2)) process. This is the main route by which the effects of neuronally
released noradrenaline are terminated. The transporter protein of the uptake1 mechanism is different from those involved in
transporting catecholamines into vesicles (see above). The uptake1 mechanism can be inhibited by cocaine and by tricyclic
antidepressants e.g. desmethylimipramine. Blockade of this mechanism can potentiate the effects of sympathetic nerve
stimulation and also prevent the action of the adrenergic neurone blocking drugs (see above).

There is an uptake2 or extra-neuronal uptake process (e.g. into smooth muscle cells) for which noradrenaline has a lower
affinity than adrenaline. This mechanism can be inhibited by some steroids e.g. β-oestradiol.

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(e) Metabolism
Noradrenaline and adrenaline are metabolized in the body by two enzymes, monoamine oxidase (MAO) and catechol-
O-methyl transferase (COMT).
MAO is found in mitochondria in sympathetic nerve terminals, in the liver and in intestinal epithelium. There are two
isoenzymes, MAO-A and MAO-B. Many inhibitors of MAO e.g. the antidepressant phenelzine, are non-selective unlike
recent drugs e.g. MAO-B selective selegiline (used in Parkinsonism).
Foods formed by bacteria e.g. some cheeses, contain large amounts of tyramine. This is normally metabolized by
MAO in the intestinal epithelium. In the presence of MAO inhibition (as in the patient taking the non-selective phenelzine)
the tyramine is absorbed and reaches sympathetic nerve terminals. The tyramine enters via uptake1 and displaces
noradrenaline which evokes vasoconstriction at the post-junctional α-adrenoceptors causing a large rise in peripheral
resistance. This can be lethal due to sub-arachnoid haemorrhage. This is the "cheese reaction". The likelihood of this reaction
is reduced if a patient is on a selective MAO-B inhibitor. COMT occurs in neuronal and non-neuronal tissues. As its name
implies it will only metabolize catechols unlike MAO which metabolizes the catecholamines (dopamine, noradrenaline and
adrenaline) and other amines e.g. 5-hydroxytryptamine
The metabolite of noradrenaline formed by the action of MAO and then COMT (or vice versa) is 3-methoxy-4-hydroxy
mandelic acid (vanillyl mandelic acid or VMA) which is found in urine. High levels of VMA are an indicator of the presence
of phaeochromocytoma (a tumour of chromaffin tissue).

FIGURE 3
Schematic diagram of adrenergic neurone showing sites of drug action