Alpha-1 adrenergic receptors are present on vascular smooth muscle and myocardial tissue; therefore, stimulation causes vasoconstriction and positive inotropic effects, respectively. Higher acuity indications for alpha-1 receptor agonists include cases of vasodilatory shock, hypotension, and hypoperfusion. Often patients receiving an alpha-1 agonist are concurrently undergoing fluid resuscitation, for example, sepsis or septic shock, cardiopulmonary arrest, and heart failure decompensation.[1] Other lower acuity indications for alpha-1 agonists would include glaucoma (to lower intraocular pressure) and the use of nasal decongestants. Nasal decongestive effects occur by the induction of local vasoconstrictive effects in the respiratory microvasculature, which leads to a decrease in edema and airflow resistance.[2] The ability to decrease intraocular pressure primarily takes place by lowering aqueous production along with a slight effect from inducing vasoconstriction in the conjunctiva. It is worth noting that the alpha agonist often used for this indication, apraclonidine, lowers aqueous production through concurrent alpha-2 effects while vasoconstriction occurs through alpha-1 effects.[3]

FDA approved indications for selected alpha-1 agonists (off-label uses indicated when applicable):

Apraclonidine:

• Indications: Elevated intraocular pressure and as a diagnostic tool for Horner syndrome
• Administration: Eye drops
• Notes: Apraclonidine is also called iopidine. Often the elevated intraocular pressure that necessitates its use is caused by glaucoma. This drug is primarily an alpha-2 adrenergic agonist but does also produce alpha-1 agonist effects.

Epinephrine:

• Indications: Mucosal congestion, glaucoma, asthma, and emergency treatment of severe hypersensitivity reactions. Epinephrine is also the primary drug used to aid the reversal of cardiac arrest during cardiopulmonary resuscitation (CPR).
• Administration: Intravenous, inhalation, nebulization, intramuscular injection, and subcutaneous injection
• Notes: Epinephrine is a hormone and a neurotransmitter, also known as adrenaline, that is secreted endogenously by the adrenal medulla as part of the sympathetic response. It is also used in lidocaine drug formulations to prolong the local anesthetic effects of lidocaine and provide local hemostasis.[4]

Methoxamine:

• Indications: Hypotension (especially due to spinal anesthesia), hemorrhage, adverse medication reaction, and shock caused by surgery, brain damage or trauma
• Administration: Injection and intravenous
• Notes: Methoxamine causes prolonged peripheral vasoconstriction but has little to no effect on the central nervous system. Unlike many alpha-1 agonists that have mixed alpha-1 or alpha-2 activity and beta action, methoxamine is a selective alpha-1 agonist.
• Discontinued in the USA

Norepinephrine:

• Indications: Vasodilatory shock (i.e., septic shock and neurogenic shock), acute hypotension (used as a vasopressor), and cardiac arrest (used as an adjunct therapy)
• Administration: Intravenous drip and injection
• Notes: The neurotransmitter, norepinephrine, is the precursor to epinephrine and is also secreted by the adrenal medulla. Norepinephrine and epinephrine are known as catecholamines.

Oxymetazoline:

• Indications: Nasal congestion, facial erythema due to rosacea, and ophthalmic allergic reactions
• Administration: Topical cream, nasal spray, eye drops

Phenylephrine:

• Indications: Anesthesia-associated and shock-associated hypotension, conditions or procedures necessitating dilation of the pupil, and nasal congestion (provides local vasoconstrictive effects)
• Administration: Oral, intravenous, and topical (eye drops and rectal ointment)
• Notes: Phenylephrine is used off-label as a first-line treatment for ischemic priapism.

Pseudoephedrine:

• Indications: Nasal congestion, rhinitis, otitis media, sinusitis, and tracheobronchitis
• Administration: Oral tablet or syrup
• Notes: Medications containing pseudoephedrine are often offered as a combined product with ibuprofen and/or an antihistamine

Tetryzoline:

• Indications: Minor eye irritation (provides short-term relief) or inflammation
• Administration: Eye drops

Xylometazoline:

• Indications: Nasal congestion and minor nasal inflammation
• Administration: Nasal spray or drops
• Notes: This agent decreases congestion through vasoconstriction effects

It is worth noting that many agents that are “alpha-1 agonists” have at least some mixed alpha-1 and alpha-2 activity, and others have mixed alpha and beta-agonistic activity.

Adrenergic receptors are G-protein-coupled receptors (GPCR) that play a central role in the sympathetic nervous system. The alpha-1 adrenergic receptors respond to norepinephrine and epinephrine and act through the Gq signaling pathway to facilitate several effects, some specific to the alpha-1 receptor and other effects shared with alpha-2 receptors.[5] When the alpha-1 receptor is activated, the Gq signaling pathway kicks off. This activation leads to phospholipase C activation, and the second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG) cause smooth muscle contraction and glycogenolysis by increasing intracellular calcium.[6] Many of the desired effects of alpha-1 agonists are a result of the vascular smooth muscle contraction resulting in increased systemic vascular resistance, thereby increasing afterload on the heart, which in turn increases blood pressure and decreases cardiac output.[4]

In conditions involving the eyes (such as elevated intraocular pressure, irritation of the eye, or procedures requiring dilation of the pupil), an alpha-1 agonist will most often be administered topically via eye drops. Medications for nasal congestion are often a combination of multiple active agents, and the route of administration will vary from oral tablets or capsules, oral liquid in pediatric patients, nasal sprays for local effect, as seen with oxymetazoline. Epinephrine is given intravenously during CPR and via intramuscular injection during anaphylactic shock.

In general, alpha agonists can cause decreased renal perfusion, increased cardiac afterload, and decreased venous compliance. Phenylephrine, specifically, has documented cases of renal failure. Researchers have also conducted several studies indicating that alpha-1 agonists cause adverse effects on gastrointestinal blood flow due to their inherent vasoconstriction.[4] Epinephrine, while used as an adjunctive to lidocaine injections for local anesthetic effect, has been shown to cause a clinically significant increase in pain when compared to placebo injections.[7]

The suggested general guideline is that each patient’s situation is taken into account when considering the use of alpha-1 agonists. The indications described above often have specific benefits outweighing the potential risks. Still, in general, an alternative vasopressor should be used when possible to avoid adverse effects such as increased cardiac afterload. Catecholamines (norepinephrine and epinephrine) are contraindicated for the treatment of hypotension in the setting of increased serotonin as they can exacerbate the release of serotonin that is already occurring in the underlying disease state. In patients with carcinoid tumors, it is advisable for phenylephrine, octreotide, antihistamines, and hydrocortisone to merit consideration for use instead of a catecholamine.[4]