Alpha agonists: Uses, common brands, and safety info

Alpha agonists are a class of drugs that have a diverse range of benefits. Some alpha agonists such as epinephrine and norepinephrine are life-saving drugs that act quickly in critical conditions such as anaphylaxis or myocardial infarction (heart attack). Other alpha agonists are used as long-term treatments for cardiovascular, psychiatric, allergic, or eye conditions. Certain drugs in this class also provide analgesia (pain relief) and can be used for opioid withdrawal or migraines. Most alpha agonists require a prescription, but many are available over the counter to treat nasal congestion and eye conditions.

This article will detail the different drugs within this class, outlining their names, uses, and side effects. 

What are alpha agonists?

Alpha agonists bind to alpha receptors, which can be found in the heart and blood vessels, among other areas. Alpha agonists belong to a larger class of drugs called sympathomimetics, which mimic the effects of the sympathetic nervous system. This part of the nervous system is responsible for the “fight or flight” response. Many alpha agonists are used in the ICU setting to support patients who are hemodynamically unstable, meaning that there is not enough pressure in the circulatory system to keep blood flowing reliably to the whole body. Examples of conditions characterized by hemodynamic instability include cardiac arrest, decompensated heart failure, and circulatory shock.

Alpha agonists vary in their effects depending on where they work in the body. In addition to the heart and blood vessels, alpha receptors are also located in the airways, eyes, and brain, making alpha agonists useful for a variety of conditions. Uses for this drug class can range from cardiac conditions to eye, allergy, psychiatric, and other conditions. Alpha agonists vary in their site of action and the specific types of alpha receptors they bind, which is why they differ so greatly in their effects. For example, one alpha agonist targeting receptors in blood vessels might increase blood pressure, whereas another alpha agonist targeting receptors in the central nervous system can lower blood pressure.

How do alpha agonists work?

Alpha agonists bind to alpha-1 and alpha-2 receptors located on vascular smooth muscle cells. When alpha agonists reach their receptors, they cause the smooth muscle to contract. When this occurs in blood vessels, it causes veins and arteries to constrict, which raises blood pressure (alpha agonists cause both arteries and veins to constrict, however, they have a greater effect on arteries). Constricting blood vessels can have other benefits besides increasing blood pressure. For example, constricting the blood vessels in the nasal passageways can allow more room for airflow, which decreases nasal congestion.

Alpha agonists that act directly on the heart and blood vessels have the same effects as the naturally occurring hormones norepinephrine and epinephrine because they bind to the same receptors. But alpha agonists that act on other parts of the body may cause the opposite effect of these hormones. For example, alpha-2 receptors are also located at nerve terminals in the central nervous system. When alpha agonists bind receptors on nerve terminals, it decreases the amount of norepinephrine released by nerves via a negative feedback mechanism. This basically means that when these receptors get activated, the nervous system thinks it has enough norepinephrine and so it stops producing it. Therefore, alpha agonists that primarily target central alpha-2 receptors (i.e., clonidine) have the opposite effect of alpha-1 agonists, which work directly on the heart and blood vessels. This is why drugs such as clonidine can be useful for lowering blood pressure.

Alpha2 agonists also can also affect behavior. Alpha2 receptors are located throughout the prefrontal cortex of the brain. Major functions of the prefrontal cortex include regulating attention, behavior, and emotion. Norepinephrine sends signals throughout the prefrontal cortex by binding to alpha-2 receptors. Psychiatric conditions such as ADHD are partly caused by norepinephrine imbalances in the prefrontal cortex. Clonidine and guanfacine are thought to improve ADHD by mimicking or modulating the effects of norepinephrine at alpha2 receptors in the prefrontal cortex.

Alpha receptors at other locations in the body allow for the other uses of alpha agonists. For example, alpha 2 receptors in the eye help reduce eye fluid production and increase drainage of eye fluid, which in turn lowers the pressure in the eye. Thus, the alpha-2 agonist brimonidine is useful for treating high intraocular pressure and glaucoma.

What are alpha agonists used for?

• Intraocular pressure

• Severe allergic reactions

• Opioid withdrawal

•  Glaucoma

•  Muscle spasms

•  Myocardial infarction

• Asthma

• Anxiety

• Pain

• Chest congestion

• Orthostatic hypotension

• Nasal/sinus congestion

• Rhinitis

• Otitis media

• Sinusitis

• Hypoperfusion

• Low blood pressure (hypotension)

•  Vasodilatory shock (e.g., septic shock)

• Cardiac arrest

Types of alpha agonists

Alpha-1 adrenergic receptor agonists

There are numerous alpha-1 receptors found on the smooth muscles of blood vessels and on muscle tissue of the heart. Alpha agonists that primarily target the alpha-1 receptors are used to treat vasodilatory shock, low blood pressure, and hypoperfusion (insufficient oxygen supply to organs). Their primary effect is to constrict blood vessels (raising blood pressure) and increase the forcefulness of heart contractions.

Examples of alpha-1 adrenergic agonists:

• Midodrine

• Phenylephrine

Alpha-2 adrenergic receptor agonists

Alpha-2 adrenergic receptors are found in abundance in the central nervous system. Stimulation of these receptors is responsible for different drug effects such as sedation, analgesia, etc. Stimulating the central alpha-2 receptors has the general effect of reducing the activity of the sympathetic nervous system, which is responsible for the “fight or flight” response. Thus, alpha agonists that predominantly target alpha-2 receptors have a very different effect than those primarily targeting alpha-1 receptors. Alpha-2 agonists have sympatholytic effects such as reducing blood pressure, anxiety, panic disorder, or PTSD. Alpha agonists that stimulate alpha-2 receptors in the eye are effective at reducing intraocular pressure and glaucoma.

Examples of alpha-2 adrenergic agonists:

• Brimonidine

• Clonidine

• Dexmedetomidine

• Guanfacine

• Methyldopa

• Naphazoline

• Lofexidine

• Tizanidine

Nonspecific alpha adrenergic receptor agonists

Some alpha agonists target both types of alpha receptors equally. These typically have similar effects to alpha-1 agonists, such as increased blood pressure. Some nonspecific alpha agonists can treat glaucoma by binding to alpha-1 receptors in the conjunctiva, although most of their effect is by alpha-2 receptor stimulation.

Examples of nonspecific alpha-adrenergic agonists:

• Apraclonidine

• Norepinephrine

• Oxymetazoline

• Pseudoephedrine

• Epinephrine

Who can take alpha agonists?

Children and infants

Children under the age of 4 years old should not use Sudafed (pseudoephedrine). Children under the age of 6 months should not use phenylephrine, and children under the age of 6 years should not use oral phenylephrine (they can use phenylephrine nasal drops). Children under the age of 12 years should not use long-acting forms of Sudafed (i.e. extended-release tablets).  

Certain alpha agonists are contraindicated in children. For example, Alphagan (brimonidine eye drops) should not be used in children under two years according to the manufacturer’s labeling.

Children should not use a regular Epipen (0.3 mg dose) unless they meet the weight requirements (at least 30 kg, or about 66 lbs). EpiPen Jr. (0.15 mg dose) is indicated for children who weigh between 33 and 66 lbs. Children who weigh less than 33 lbs may require a smaller dose of epinephrine than can be delivered by an EpiPen Jr kit. For example, the epinephrine pen Auvi-Q can deliver as little as 0.1 mg per injection and can be used in patients weighing 16.5 lbs or greater. However, in an emergency, a child weighing less than 33 lbs should still receive EpiPen Jr. if that is the only product available.

Central alpha-2 agonists like guanfacine and clonidine are approved for children with ADHD aged six years and older, although non-oral formulations such as transdermal patches may not be approved for the same age group.

Certain alpha agonists such as midodrine, lofexidine, tizanidine, and dexmedetomidine have not been approved by the FDA for use in children. However, this does not necessarily mean that their use in children is inappropriate. Physicians frequently prescribe medications for “off-label” uses, meaning they are used outside of the FDA approved indications or age groups.

Adults

Alpha agonists are approved for adult use for a wide range of conditions. In some cases, they are prescribed for short-term use of acute conditions (i.e., anaphylaxis, circulatory shock). In many cases, they are prescribed long-term for treatments such as hypertension, ADHD, glaucoma, etc. Adults should always use alpha agonists as prescribed and discuss their current medications and allergies with a physician in order to ensure safe use.

Seniors

Alpha agonists may be used in the elderly, although extra caution is warranted due to increased adverse effects. For example, elderly patients are at an increased risk of falls due to the sedating and hypotensive effects of alpha 2 agonists. Alpha agonists that rely on the kidney for metabolism (e.g., clonidine, methyldopa) may require dose adjustments in the elderly due to age-related deterioration of the kidney.

Can you take alpha agonists while pregnant or breastfeeding?

Ergotamine is contraindicated during pregnancy due to the possible risk of birth defects and fetal toxicity. It should also be avoided during breastfeeding. Caution is advised when taking clonidine or guanfacine during pregnancy, although there is no known risk of fetal harm based on limited human data (other than possible decreased birth weight). Consider alternatives to these two drugs while breastfeeding, since safety data is lacking. Women should not take pseudoephedrine or phenylephrine during the first trimester, and caution is advised during the second and third trimesters due to the possible risk of birth defects. Limit the use of pseudoephedrine and phenylephrine while breastfeeding. Oxymetazoline nasal spray is an alternative nasal decongestant that is safe to use during pregnancy. Many alpha agonists lack human safety data in pregnancy, so their use should be avoided if possible. For example, there is inadequate data available for Lucemryra, tizanidine, and midodrine, so caution is advised during pregnancy. Finally, epinephrine carries a possible risk of birth defects based on limited human data, but its benefits for anaphylaxis use greatly outweigh these risks.

Are alpha agonists safe?

A black box warning, or “boxed warning,” is an FDA warning to alert consumers about serious or life-threatening side effects the drug may have. These are found on the package insert for prescription drugs. A few alpha agonists carry black box warnings. These can be summarized as followed:

Levophed can cause sloughing and necrosis in areas in which extravasation has occurred. To treat extravasation, infiltrate the ischemic area as soon as possible with a fine hypodermic needle with 5 to 10 mg of phentolamine in 10 ml of saline.

Midodrine can cause significant supine blood pressure elevation. It should only be used for the treatment of symptomatic orthostatic hypotension in patients whose lives are considerably impaired despite standard clinical care. The evidence for use in treating orthostatic hypotension is based on surrogate markers only.

The 500 mcg/mL strength of injectable clonidine must be diluted prior to use. Epidural clonidine should only be used if a physician determines that benefits outweigh risks. Its use is generally not recommended for obstetrical, postpartum, or perioperative pain management due to the risk of hemodynamic instability, such as low blood pressure and low heart rate.

Ergotamine is contraindicated in patients with peripheral vascular disease, coronary artery disease, luetic arteritis, arteriosclerosis, thrombophlebitis, and Raynaud’s phenomenon, sepsis, malnutrition, or uncontrolled hypertension, due to its vasoconstrictive effects.

The combination product containing ergotamine and caffeine can also cause severe peripheral ischemia when given drugs categorized as “CYP3A4 inhibitors” which increase the levels of ergotamine in the bloodstream. This product should never be used with CYP3A4 inhibitors, including protease inhibitors and macrolide antibiotics.

Recalls

• Apotex Corporation voluntarily recalled guanfacine 2 mg extended-release tablets (NDC 60505-3928-10) due to trace amounts of quetiapine fumarate present in lot# RX1663 (March 31, 2021). Quetiapine is an entirely different medication for the treatment of schizophrenia or bipolar disorder. Recalled lots expire in November 2022. 

• Dr. Reddy’s Laboratories Inc. voluntarily recalled tizanidine 4 mg tablets (NDC 55111-1800-15) due to failed tablet specifications and lower weight of tablets (March 23, 2021). Affected lots expire in September of 2023. 

• Fresenius Kabi USA voluntarily recalled two lots of dexmedetomidine Hcl 0.9% injection due to trace amounts of lidocaine present in affected lots (July 22, 2020). Affected lots expired in May and June of 2021.

Restrictions

Alpha 1 agonists should not be used in patients with hypertension, bradycardia (slow heart rate), or benign prostatic hyperplasia (BPH). Patients with coronary artery disease may experience worsening chest pain due to increased demands of the heart after taking alpha-1 agonists.

Alpha 2 agonists should be used cautiously in patients with low blood pressure. Elderly patients may be at increased risk of falls due to the sedating and hypotensive effects of alpha 2 agonists. Certain alpha agonists, such as epinephrine, should not be used in patients with angle-closure glaucoma.

General contraindications to adrenergic drugs that increase sympathetic activity (i.e., epinephrine, pseudoephedrine) include cardiac arrhythmia, angina pectoris, hyperthyroidism, and cerebrovascular disease. Dose adjustments may be necessary for patients with impaired kidney function.

Ergotamine is contraindicated in patients with peripheral vascular disease, coronary artery disease, luetic arteritis, arteriosclerosis, thrombophlebitis, Raynaud’s phenomenon, sepsis, malnutrition, or uncontrolled hypertension due to its vasoconstrictive effects.

Levophed should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOIs) or antidepressants because prolonged hypertension may result. Levophed should not be used with cyclopropane or halothane anesthesia due to the risk of ventricular tachycardia or fibrillation.

Levophed should not be used in patients with sulfite sensitivity.

Alpha agonists constitute a wide group of medications that vary greatly in their uses and side effects. This is not an exhaustive list of medical precautions surrounding the use of alpha agonists. Always consult a physician or pharmacist when starting therapy with an alpha agonist. 

Are alpha agonists controlled substances? 

Alpha agonists are not controlled substances according to the DEA. However, there are laws in place that create extra restrictions on the purchase of pseudoephedrine. The U.S. Food and Drug Administration (FDA) banned over-the-counter sales of pseudoephedrine in the Combat Methamphetamine Epidemic Act. While a prescription is not required in most states, products containing ephedrine, pseudoephedrine, or phenylpropanolamine must be kept behind the pharmacy counter and sales must occur at the pharmacy register. Purchase amounts are restricted to 3.6 grams per day, 9 grams per month, and no more than 7.5 grams per month if purchased through a mail-order pharmacy.

Common alpha agonists side effects

The side effects of alpha agonists differ depending on which alpha receptor is predominantly affected. For example, some side-effects are specific to alpha-2 agonists and are due to their sympatholytic effects. Examples include constipation, nausea, and GI upset. Common side effects of alpha-1 agonists are mainly due to their sympathomimetic effects.

Common side effects of alpha-1 adrenergic agonists:

• Headache

• Reflex bradycardia

• Restlessness

• Angina (chest pain) in patients with coronary artery disease

Common side effects of alpha-2 adrenergic agonists:

• Sedation

• Dry mouth and nose

• Bradycardia

• Orthostatic hypotension

• Impotence

• Constipation

• Nausea

• G.I. upset

How much do alpha agonists cost?

Alpha agonists vary widely in cost. Fortunately, alpha agonists can be more affordable with a SingleCare discount. On the higher end of the price range is Lucemyra, which is not available as a generic. The brand name costs around $900 for 36 tablets, which can be reduced to approximately $736 with a SingleCare Lucemyra coupon. Epinephrine can be expensive without insurance, costing nearly $750 out-of-pocket for a single Epipen 2-pak. Fortunately, a SingleCare coupon can lower the cost to less than $200.