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Adrenergic antagonists: Presynaptic



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Yifan Xiao, MD

Peripheral presynaptic anti-adrenergics are a class of medication that’s not very commonly used these days. Their mechanism of action is to target the presynaptic adrenergic neurons in the peripheral nervous system, and prevent them from effectively releasing the catecholamines, norepinephrine, and epinephrine.

The nervous system is divided into the central nervous system, so the brain and spinal cord; and the peripheral nervous system, which includes all the nerves that connect the central nervous system to the muscles and organs. The peripheral nervous system can be divided into the somatic nervous system, which controls voluntary movement of our skeletal muscles; and the autonomic nervous system, which is further divided into the sympathetic and the parasympathetic, and controls the involuntary movement of the smooth muscles and glands of our organs.

Now, the autonomic nervous system - which includes both the sympathetic and parasympathetic nervous system - is made up of a relay that includes two neurons. We’ll focus on just the sympathetic nervous system. Signals for the autonomic nervous system start in the hypothalamus, at the base of the brain. Hypothalamic neurons have really long axons that carry signals all the way down to the thoracic and lumbar spinal cord nuclei, where they synapse with preganglionic neuron cell bodies. From there, the signal goes from the preganglionic neurons down its relatively short axon, exits the spinal cord, and reaches the nearby sympathetic ganglion, which is made up of lots of postganglionic neuron cell bodies. The postganglionic neurons are also called adrenergic neurons because they release the neurotransmitter norepinephrine, which is also called noradrenalin; and to a much lesser degree, epinephrine, or adrenaline. These two catecholamines activate the adrenergic receptors on many different organs, which allow the sympathetic nervous system to trigger the fight or flight response that increases the heart rate and blood pressure, as well as slowing digestion. All of this maximizes blood flow to the muscles and brain, and can help you either run away from a threat, or fight it, which is why it’s also called the fight or flight response.

Now, let’s zoom into an adrenergic synapse. The presynaptic terminal contains loads of tiny synaptic vesicles, each of which stores thousands of norepinephrine molecules. But for norepinephrine to be there in the first place, a precursor amino acid, called tyrosine, is taken up by the adrenergic neuron and gets converted to L-dihydroxyphenylalanine, or L-DOPA for short, by an enzyme called tyrosine hydroxylase. Next, L-DOPA is converted to dopamine, which is then packaged into the synaptic vesicles with the help of a transporter, called Vesicular Monoamine Transporter, or VMAT for short. The remaining dopamine will be broken down by a class of enzymes called monoamine oxidases, or MAOs for short. Okay, now once inside the vesicles, dopamine get converted by dopamine β-hydroxylase into norepinephrine. And then, whenever the appropriate signal travels down the axon to the axon terminal, these vesicles fuse with the presynaptic membrane in order for norepinephrine to get released (or exocytosed), into the synaptic cleft and take action on the adrenergic receptors of the postsynaptic neuronal membrane. Now, each of these presynaptic neurons has small reuptake proteins, called Norepinephrine Transporters, or NETs for short, which pump norepinephrine from the synaptic cleft back into presynaptic neurons. Once inside the neuron, with the help of Vesicular Monoamine Transporter, or VMAT, norepinephrine gets packaged into pre-existing vesicles, waiting to be released once more. Just like dopamine, any bit of norepinephrine that’s left behind in the cytoplasm will be broken down by monoamine oxidases or MAOs.

Alright, so medications that act on peripheral presynaptic adrenergic neurons to inhibit adrenergic signal transmission are called peripheral presynaptic anti-adrenergics. What these do, is collectively oppose the effects of the sympathetic nervous system - so, overall, heart rate and blood pressure decrease, digestion speeds up and the fight-or-flight response gets blocked.


Adrenergic antagonists are a type of drug that blocks the action of certain neurotransmitters, such as adrenaline. They work by preventing the release of stored neurotransmitters from the presynaptic neuron. This reduces the number of available neurotransmitters at the synapse and prevents them from binding to and activating postsynaptic receptors. This ultimately reduces the excitatory response of the neuron and results in a decrease in nerve activity.

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