Adrenergic antagonists: Presynaptic

Definitions & Key takeaways

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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Introduction0:00–0:27

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.

Physiology0:27–4:23

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.

Mechanism of action4:23–5:05

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.
Okay, so peripheral presynaptic anti-adrenergics are further subdivided into those affecting norepinephrine synthesis, norepinephrine storage, and norepinephrine release.
Now, there are inhibitors of norepinephrine synthesis, which include alpha-methyl-p-tyrosine or metyrosine. Metyrosine looks like tyrosine, and it can bind to and inhibit the enzyme tyrosine hydroxylase.

Norepinephrine synthesis inhibitors5:05–5:55

This means less tyrosine gets converted to L-DOPA, so, down the road, less norepinephrine is produced, and less gets released into the synaptic cleft.
Metyrosine can be given to lower the blood pressure in individuals with pheochromocytoma. Pheochromocytoma is a rare tumor of the adrenal medulla, which secretes too much catecholamines, causing extreme peaks of high blood pressure, or hypertension.
The main side effect, though, is that blood pressure may fall too low, causing hypotension. Now, norepinephrine storage is mainly inhibited by another medication called reserpine.

Norepinephrine storage inhibitors5:55–6:59

Reserpine’s job is to block the Vesicular Monoamine Transporter, or VMAT. What this means is that dopamine is prevented from getting stored into the synaptic vesicles and turning into norepinephrine.
At the same time, recirculated norepinephrine from the synaptic cleft cannot get repackaged into the synaptic vesicles. Instead, both dopamine and norepinephrine build up in the cytoplasm, where they get chopped up by monoamine oxidases, or MAOs.
The end result is a decrease in both norepinephrine and dopamine. This makes reserpine effective in controlling high blood pressure.
However, it’s almost never used today, due to its poor absorption, slow metabolism, and most importantly, its long-term side effects on the central nervous system, where it causes the same depletion of dopamine and norepinephrine.
This results in depression, drowsiness, fatigue, and difficulty concentrating. Alright, now norepinephrine release is directly inhibited by guanethidine.

Norepinephrine release inhibitors6:59–8:09

Guanethidine gets gobbled up by the presynaptic terminal through norepinephrine transporters, so it directly competes with norepinephrine during its reuptake.
So essentially, more norepinephrine remains active in the synaptic cleft, causing a transient increase in adrenergic signals, and thus, an increase in blood pressure.
As guanethidine enters the presynaptic nerve, it accumulates in the synaptic vesicles, where it displaces norepinephrine.
And soon enough, norepinephrine stores get depleted. At the same time, guanethidine blocks the fusion of synaptic vesicles with the presynaptic membrane, preventing norepinephrine release into the synaptic cleft.
All this leads to less stimulation of the postsynaptic adrenergic receptors, which can be useful in terms of lowering the blood pressure.
However, just like reserpine, guanethidine is almost obsolete today, due to its poor absorption, slow metabolism, and most importantly, its initial hypertensive effect.
Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharm facts! Okay, so let’s have a toy factory with three workers.

Memory palace8:09–10:03

The first worker is building a toy black cat holding a cola can, for catecholamine synthesis. He’s about to be attacked by a tyrannosaurus holding a slab of meat, for metyrosine.
It’s also snapping at a bird that’s half-crow and half-phoenix, since it’s used to treat hypertension in pheochromocytoma.
The next worker represents storage, so he’s packing boxes. Since the medications in this class affect both catecholamines and dopamine, let’s put a cola cat and a doberman doll in the box.
He’s about to be attacked by a robot serpent, for reserpine. The robot serpent has a biological brain on its head to help you remember this medication is very active in the central nervous system, and could cause side effects like depression, so let’s have the robot serpent cry big sad tears.
Finally, the last worker is pushing a cart full of cola cats out of the factory, which represents catecholamine release.
Waiting for him is an iguana, who’s ready to have him for dinner, which represents guanethidine. Let’s put a pumped up blood pressure cuff on his tail, so you remember that this drug could initially worsen hypertension as a side effect.
There’s also a worker who passed out from orthostatic hypotension in the middle of the factory, since all 3 groups of medications can cause this as a side effect.
Due to the unsafe condition of the factory, many of the non-essential workers, like the box packer and the cart pusher, eventually quit, so those medications filling those roles like reserpine and guanethidine are rarely used.
All right, as a quick recap, peripheral presynaptic anti-adrenergics act on presynaptic neurons of the peripheral nervous system.

Recap10:03–10:45

Metyrosine inhibits the enzyme tyrosine hydroxylase and prevents catecholamine synthesis; Reserpine prevents the storage of dopamine and norepinephrine in the synaptic vesicles; and guanethidine blocks the release of norepinephrine in the synaptic cleft.
These medications are mainly used for treating hypertension, but reserpine and guanethidine are rarely used, due to their side effects.
But wait, there’s more: Here’s a mind map with all of the mnemonics. Go ahead and pause the video so you can test yourself to see what you remember.

Mind map10:45–10:54

Stay tuned for the answers after the credits.
Adrenergic antagonists: Presynaptic: Video, Causes | Osmosis