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Sympathomimetics: Direct agonists

Sympathomimetics: Direct agonists


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Sympathomimetics: Direct agonists

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Content Reviewers:

Yifan Xiao, MD

Alpha agonists and beta agonists are two types of adrenergic medications that stimulate their respective receptors and mimic the effect of endogenous catecholamines, like norepinephrine and epinephrine.

The nervous system is divided into the central nervous system and the peripheral nervous system.

The peripheral nervous system can be further 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 the smooth muscles and glands of our organs; this system is then further divided into the sympathetic and parasympathetic nervous systems.

Now, the autonomic 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 also known as adrenaline.

These two catecholamines activate the adrenergic receptors on many different organs, which allows the sympathetic nervous system to trigger the fight or flight response that increases the heart rate and blood pressure, as well as slowing down digestion.

This response 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, there are two main groups of adrenergic receptors: the alpha receptors, and beta receptors.

There are 2 types of alpha receptors: alpha-1 and alpha-2.

Alpha-1 adrenergic receptors are mainly located on the walls of blood vessels, and when stimulated, they cause vasoconstriction, thus decreasing blood flow to tissues.

In the eyes, alpha-1 adrenergic receptors also trigger mydriasis, or pupil dilation.

In the bladder, they cause sphincter constriction and urinary retention, or holding the urine within the bladder.

And in males, they trigger ejaculation.

Now, alpha-2 adrenergic receptors are primarily found on the presynaptic neuron. So when a presynaptic nerve ending is stimulated to release noradrenaline in the synaptic cleft, some of that norepinephrine turns around and binds to alpha-2 receptors on the presynaptic membrane. This inhibits further release of norepinephrine and serves as a mechanism of negative feedback control.

On the other hand, beta receptors have two main subtypes: beta-1 (β1) and beta-2 (β2).

Beta-1 adrenergic receptors are mainly located in the heart, where they increase the heart rate and contractility, which helps pump out more blood.

Beta-1 receptors are also found in the kidney, where they stimulate a very special kind of cell, called juxtaglomerular cells, to release renin. Renin is a part of the renin- angiotensin- aldosterone system, which increases sodium and water retention by the kidneys and helps increase blood pressure.

Moving on to beta-2 adrenergic receptors, these are found on smooth muscle cells in the walls of blood vessels supplying skeletal muscles and the brain, which leads to vasodilation and increased blood flow to these tissues.

In the lungs, beta-2 adrenergic receptors cause bronchodilation, and that increases oxygen delivery to cells.

In the gastrointestinal tract, they decrease motility and slow digestion.

In the eyes, they act on the ciliary body to promote the secretion of aqueous humor, which provides support and helps to maintain the shape of the eye.

Now, in the liver, they cause more glucose to be released into the blood; and in the pancreatic islets of Langerhans, they promote the release of glucagon, which again, helps raise blood glucose levels.

Finally, beta-2 receptors stimulate an enzyme found on the surface of the cells lining capillary walls called lipoprotein lipase, which breaks down triglycerides into free fatty acids and cholesterol.

Alright, so medications that stimulate adrenergic receptors are called sympathomimetic medications or sympathomimetic agonists; and based on their mechanism of action, they are subdivided into three main categories: direct-acting agonists, which directly activate adrenergic receptors to produce the desired effect; indirect-acting agonists like amphetamines and cocaine, which increase the release of endogenous catecholamines and enhance their effect; and mixed-acting agonists like ephedrine, which utilize both of these mechanisms.

Now, we’re going to focus only on direct-acting agonists and we’ll subdivide them into three main groups: alpha agonists; beta agonists; and catecholamines and dobutamine.

First let’s start with alpha agonists, which are subdivided into two groups of their own; alpha-1 agonists and alpha-2 agonists.

Alpha-1 agonists, as their name implies, activate alpha-1 adrenergic receptors and they include phenylephrine and midodrine.

So, by activating alpha-1 receptors, phenylephrine causes systemic vasoconstriction and increases blood pressure, therefore it’s used to treat hypotension.

But, when blood pressure increases, the body compensates by lowering the heart rate, leading to compensatory bradycardia, which is a slower than normal heart rate.

Besides hypotension, phenylephrine can also be used as a nasal spray and decongestant in the treatment of rhinitis, since it causes vasoconstriction of submucosal nasal blood vessels.

Moreover, it can also be used as a topical agent in ophthalmological procedures to cause mydriasis.

Common side effects of phenylephrine include hypertension, stroke, and myocardial infarction.

On the other hand, midodrine is primarily used to treat autonomic dysfunction and orthostatic hypotension, which is a condition in which the blood pressure falls significantly when a person stands up too quickly.


Sympathomimetics are drugs that act on the sympathetic nervous system to produce their effects. They include classes of drugs like alpha agonists and beta-agonists. Both alpha agonists and beta-agonists bind to receptors in the body and activate them.

Alpha agonists activate alpha receptors, which are found primarily in the smooth muscles of the blood vessels and lungs. Alpha agonists are divided into alpha-1 agonists, like phenylephrine and midodrine; and alpha-2 agonists, like clonidine. Phenylephrine is used to treat hypotension, but it can also be used as a decongestant to treat rhinitis, or as a topical agent to cause mydriasis. Midodrine is used to treat orthostatic hypotension; while intravenous and nasal administration of clonidine causes vasoconstriction.

On the other hand, beta-agonists activate beta receptors, which are found in the heart, lungs, and other organs. Beta-agonists are subdivided into non-selective beta agonists like isoproterenol; and selective beta-2 agonists, like albuterol, salmeterol, and terbutaline. Isoprenaline is used to stimulate the heart in individuals with bradycardia or heart block, while albuterol, salmeterol, and terbutaline are used in the treatment of asthma, chronic obstructive pulmonary disease, and hyperkalemia.

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