17. Agents acting on the biosynthesis, storage, release and elimination of catecholamines

Last updated on January 8, 2019 at 19:21

Drugs influencing catecholamine biosynthesis Drugs influencing noradrenaline storage Indirectly acting adrenergic drugs Noradrenergic neuron blocking agents
Banserazide Reserpine Cocaine Bretylium
Carbidopa Tetrabenazine Ephedrine Guanadrel
Levodopa Amphetamine Guanethidine
Methyldopa Tyramine
Methyltyrosine
Noradrenaline
Ach = acetylcholine, NA = noradrenaline, AM = adrenal medulla, A = adrenaline

In the sympathetic nervous system, preganglionic neurons activate postganglionic neurons with acetylcholine, and postganglionic neurons activate the innervated tissues with noradrenaline. In other words, noradrenaline is the postganglionic neurotransmitter in the sympathetic nervous system. By controlling the release and function of noradrenaline, we can block or enhance certain functions of the sympathetic nervous system.

As learned in biochemistry, the catecholamines (dopamine, noradrenaline and adrenaline) are synthesized from tyrosine. The postganglionic neuron takes up tyrosine through a transporter, the tyrosine is hydroxylated in to DOPA, which is decarboxylated into dopamine. Dopamine is then transported into a vesicle by an important transporter called VMAT. Inside the vesicle is dopamine hydroxylated into noradrenaline. The vesicles now contain ATP, noradrenaline, a protein called chromogranin A and dopamine β-hydroxylase. The vesicle waits at the nerve ending for an action potential to arrive.

When an action potential arrives will it cause voltage-gated Ca2+ channels to open, causing an influx of Ca2+ into the cell. This triggers exocytosis of the vesicle, causing it to releasing its content into the synaptic cleft. In the synaptic cleft can the released noradrenaline have three different fates:

  1. It can diffuse over the synaptic cleft to bind to postsynaptic noradrenaline receptors, which carry the signal to the innervated tissue.
  2. It can be recycled into the presynaptic nerve ending by norepinephrine transporter (NET). NET is also called uptake-1.
  3. Lastly, it can bind to special α2-adrenergic receptors on the presynaptic nerve ending.
An unnecessarily complicated figure that shows how noradrenaline is synthesized and its three different fates in the synaptic cleft. MAO is monoamine oxidase

These α2-adrenergic receptors work as a negative feedback mechanism. When noradrenaline released from the nerve ending binds to the α2-receptors (on the same nerve ending) will adenylyl cyclase inside the axon be inhibited, which inhibits further NA release.

Monoamine oxidase (MAO) will degrade catecholamines into a compound called DOPGAL.

Enzymes called aldehyde reductase, COMT, alcohol dehydrogenase, aldehyde dehydrogenase and sulfotransferase are involved in the breakdown of DOPGAL into the final end-products to be excreted in urine.

Drugs influencing catecholamine synthesis

Methyltyrosine is a false substrate for the tyrosine hydroxylase enzyme, that usually uses normal tyrosine. Methyltyrosine will inhibit the enzyme, which inhibits the noradrenaline and adrenaline synthesis. It’s used in therapy of pheochromocytoma.

Levodopa, or L-DOPA, is used in the treatment of Parkinson’s disease. In Parkinson’s is dopamine deficient, so increasing dopamine is essential. Dopamine doesn’t cross the blood-brain barrier, however L-DOPA, dopamine’s precursor, does so we give that instead. It often given with carbidopa or bensarazide.

Carbidopa and benserazide are DOPA decarboxylase inhibitors. They don’t cross the blood-brain barrier either, so when we give it together with levodopa we can ensure that the levodopa isn’t decarboxylated into dopamine in the periphery, which would cause side-effects.

Methyldopa is a false substrate for DOPA carboxylase. The enzyme converts it to methyldopamine, which is converted by dopamine β-hydroxylase into methylnoradrenaline. Methyl-NA has a high effect on α2-receptors and little effect on α1-receptors, meaning that it increases the negative feedback. Also, as a false substrate methyldopa will reduce the capacity DOPA carboxylase has to convert normal DOPA into dopamine, which reduces the amount of noradrenaline formed.

Drugs influencing noradrenaline storage

Reserpine is an irreversible inhibitor of VMAT. This causes dopamine and noradrenaline to remain in the cytosol instead of entering the vesicle. They will therefore be degraded by MAO. The end effect is that reserpine depletes NA and dopamine in the nerve ending. It’s not used clinically anymore.

Tetrabenazine is a selective VMAT2 inhibitor used to treat Huntington’s chorea. VMAT2 is a type of VMAT only found in the CNS.

Indirectly acting sympathomimetic agents

These drugs enter the adrenergic nerve ending by acting as false substrates for NET. They are also taken up into the vesicles by VMAT. This causes noradrenaline to be released from the cytosol into the synaptic cleft by reversing the mechanisms of uptake-1 and VMAT. Noradrenaline will then stimulate α1, α2 and β1 receptors.

Tachyphylaxis often develops, as the pool of noradrenaline inside the cytosol of the presynaptic neuron quickly empties.

Amphetamine has this indirect sympathomimetic effect, however it also has a strong psychomotor effect and appetite-reducing effect because of the release of dopamine, adrenaline and serotonin in the CNS.

Ephedrine is also indirectly sympathomimetically acting. It is also a direct β receptor agonist. It has a slight psychomotor and appetite-reducing effect. It is used to treat nasal congestion, haemorrhoids, hypotension, nocturnal enuresis and to produce mydriasis.

Tyramine is the last drug of this type. It’s broken down by MAO in the gut mucosa and liver, so it’s not effective orally. It’s found in cheese and red wine. If MAO for some reason is inhibited and you eat cheese you may develop the cheese reaction, characterized by severe hypertension.

Cocaine doesn’t work the same way. It instead inhibits the NET altogether, so that noradrenaline cannot be removed from the synaptic cleft. This causes the effect of noradrenaline to last for much longer.

Noradrenergic blocking agents

These drugs enter the presynaptic noradrenergic neurons by serving as alternative substrates for NET. Inside the cytoplasm will they block the voltage-gated Na+ channels, thereby preventing the propagation of a nerve signal along the neuron and therefore inhibiting the exocytosis of the vesicles containing noradrenaline.

The overall effect is the inhibition of physiological, exocytotic noradrenaline release. These drugs are therefore sympatholytic in action. The important drugs here are bretylium, guanethidine and guanadrel.

These drugs are all hydrophilic, meaning they have poor gastrointestinal absorption and don’t pass the blood-brain barrier. They used to treat hypertension but are now not used in practice.


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