Sympatholytics: Alpha-2 agonists

Definitions & Key takeaways

Alpha-2 agonists are a class of drugs that bind to alpha-2 adrenergic receptors and activate them, resulting in a range of physiological effects. Alpha-2 adrenergic receptor agonists include clonidine, guanabenz, and guanfacine. These medications stimulate alpha-2 adrenergic receptors on the presynaptic neurons in the CNS, especially those in the medulla. This decreases the release of norepinephrine in the sympathetic neurons, which leads to lower blood pressure. Alpha-2 agonists are used to treat various conditions such as anxiety, depression, attention deficit hyperactivity disorder (ADHD), and pain. Common side effects associated with the use of alpha-2 agonists include dry mouth, constipation, headache, dizziness, drowsiness, and fatigue.

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Introduction0:00–0:20

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

Physiology0:20–3:51

So, 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 controls the involuntary movement of smooth muscles and glands of our organs.
Now, the autonomic nervous system - which includes both the sympathetic and parasympathetic nervous systems - 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.
Here, they release the neurotransmitter norepinephrine, which causes the preganglionic neurons to transmit the signals down their relatively short axon, which exits the central nervous system via the spinal cord.
These short nerve fibers reach the nearby sympathetic ganglion, which consists of many postganglionic neuron cell bodies.
The postganglionic neurons are also called adrenergic neurons, because they release the neurotransmitter norepinephrine, which is also called noradrenaline; 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.” Alright, so let’s zoom into the synapse between the hypothalamic neurons and the preganglionic neurons, which can be found throughout the brainstem and spinal cord.
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 by an enzyme called DOPA decarboxylase to dopamine, which is then packaged into the synaptic vesicles.
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 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.
Okay, but this release of norepinephrine is controlled through negative feedback inhibition. So when a pre-synaptic nerve terminal is stimulated to release a bunch of norepinephrine in the synapse, some of it will bind to a special type of receptor called an alpha-2 adrenergic receptor, located on the presynaptic membrane.
These alpha-2 receptors then inhibit further release of norepinephrine into the synapse, so the postsynaptic neuron doesn’t get over stimulated.
Alright, so medications that act on adrenergic neurons of the brainstem to inhibit adrenergic signal transmission are called central anti-adrenergics.

Mechanism of action3:51–4:21

What these do, is collectively oppose the effects of the sympathetic nervous system. So overall, the heart rate and blood pressure decrease, digestive processes speed up, and the fight-or-flight response gets blocked.
Okay, so central anti-adrenergics are divided into alpha-2 adrenergic receptor agonists and a special drug called methyldopa.

Alpha-2 adrenergic receptor agonists4:21–5:35

Alpha-2 adrenergic receptor agonists include clonidine, guanabenz, and guanfacine. These medications stimulate alpha-2 adrenergic receptors on the presynaptic neurons in the CNS, especially those in the medulla.
This decreases the release of norepinephrine in the sympathetic neurons, which leads to lower blood pressure. At the same time, alpha-2 receptor agonists, clonidine in particular, act on alpha-2 adrenergic receptors present in a special region at the front of the brain, called the prefrontal cortex, where they exert the same inhibitory effect on norepinephrine release.
Moderating the amount of norepinephrine in this part of the brain helps tune out irrelevant stimuli and sharpens focus, so it’s useful in the treatment of attention deficit hyperactivity disorder, or ADHD for short.
Now, the main side effect of these medications is that blood pressure may fall too low and cause orthostatic hypotension.
Also, if someone quits taking them too abruptly, blood pressure may climb over the roof and cause severe rebound hypertension due to a rebound in sympathetic activity.
Other side effects include sedation, fatigue, as well as nausea and gastric upset. Now, another central anti-adrenergic medication is methyldopa.

Methyldopa5:35–6:51

Methyldopa looks like L-DOPA, so much that it fools the enzyme DOPA decarboxylase to convert it to methyldopamine. Methyldopamine can’t get broken down by monoamine oxidases, so it builds up and moves into the synaptic vesicles and gets converted to methylnorepinephrine!
Methylnorepinephrine then builds up inside the vesicles and pushes the true norepinephrine into the cytoplasm where they get chopped up by monoamine oxidases.
So when a signal comes, methylnorepinephrine is released instead. And methylnorepinephrine not only can’t activate adrenergic receptors of the postsynaptic neuron, but it can circle back to act on alpha-2 adrenergic receptors on the presynaptic neuron membrane, leading to further inhibition of norepinephrine release.
So, methyldopa can be given to lower blood pressure during pregnancy, since it’s safe for the baby. In general though, it’s not so commonly used due to its several side effects, ranging from mild ones, like drowsiness, fatigue, nausea, and gastric upset, to pretty severe ones like liver toxicity, allergic reactions, and hemolytic reactions or red blood cell breakdown.

Memory palace6:51–8:27

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 an iguana driving a Benz, for guanabenz and another iguana is powdering her face, for guanfacine.
In the backseat is a clown for clonidine. And they head down a highway lane, called alpha-2, to remind you that they are alpha-2 adrenergic agonists, and there’s a billboard with a giant brain to help you remember they act on the central nervous system.
In the middle of the lane, a black cat trapped in a cage is drinking from a cup of cola, which represents the inhibition of catecholamine release.
For the indications of these drugs, there’s a large blood pressure cuff sticking out of the trunk to represent hypertension.
The clown is jumping up and down to show that clonidine is used to treat ADHD. For the major side effects, let’s use a billboard on the side of the road.
So on the sign, there’s a picture of a basketball player getting a rebound, which represents rebound hypertension. And the fans are fainting from excitement to represent orthostatic hypotension.
Okay, moving onto the next drug! Further down the alpha-2 highway, there’s a pregnant doberman carrying a slab of meat, for methyldopa, which is safe for use during pregnancy.
It’s bullying a black kitty out of its box, to represent how this medication can displace catecholamines from their vesicles.
For indications, let’s put a blood pressure cuff around the box for hypertension. Behind the doberman, we have a chewed up liver and some shredded red blood cells, since methyldopa causes liver toxicity and hemolysis.
All right, as a quick recap, central anti-adrenergics act in the central nervous system to block sympathetic outflow. They include alpha-2 agonists, like clonidine, guanabenz, and guanfacine, which inhibit catecholamine release through negative feedback control and are used to treat hypertension.

Review8:27–9:09

Clonidine in particular, can also be used to treat ADHD. There's also methyldopa, which gets converted to the false neurotransmitter methylnorepinephrine which displaces norepinephrine, but also stimulates alpha-2 receptors.
Methyldopa is effective in hypertension and is safe for use during pregnancy. But wait, there’s more: Here’s a mind map with all of the mnemonics.

Mind map9:09–9:19

Go ahead and pause the video so you can test yourself to see what you remember. Stay tuned for the answers after the credits.
Sympatholytics: Alpha-2 agonists: Video and Causes | Osmosis