Vasoactive agents were recognized in 1895 by H.D. Rollerston, when he described a suprarenal extract as a “powerful vascular tonic.”¹ Today, these drugs have an important role in anesthetics and critical care.

Adrenergic receptors are classified into two commonly recognized subtypes, α and β. Many subtypes of these receptors have been described, but the most clinically important subtypes are α₁, α₂, β₁, and β₂. α₁ receptors are found primarily on smooth muscle in the vasculature where activation leads to vasoconstriction. They are also found in the genitourinary tract, intestine, as well as cardiac and liver tissue. α receptors are found in pancreatic beta cells, nerves, and platelets. They are also present on vascular smooth muscle, although to a lesser extent than α₁ receptors. β₁ receptors are found primarily in the heart and kidney. In the heart their stimulation leads to an increase in chronotropy, inotropy and atrial-ventricular node conduction velocity. Their activation in the kidney causes renin release. β₂ Receptors are prominent in smooth muscle. Activation of β₂ receptors in the vasculature results in vasodilation, while activation of the same receptors in the airways leads to bronchodilation.

Dopamine, norepinephrine, and epinephrine are endogenous adrenergic agonists synthesized from the enzymatic alteration of phenylalanine. They are most frequently used for the acute management of hypotension, although epinephrine is also indicated for use in acute bronchoconstriction and anaphylaxis. By causing vasoconstriction, these agents will alter perfusion and oxygen delivery to different organs. The clinical significance of this altered blood flow varies dramatically between patients but sometimes results in organ ischemia or ischemia of the distal extremities necessitating amputation. Tachycardia and increased myocardial oxygen consumption can lead to dysrhythmias if cardiac oxygen delivery is inadequate. Cerebral hemorrhage can occur if vasoconstriction leads to severe systemic hypertension.

Epinephrine

Epinephrine is the prototypical sympathomimetic drug and is active at both α and β receptors. At very low doses the vasodilatory effects of β₂ activation can be most prevalent, but as the dose increases the β₂ and α₁ effects dominate. Its vasoconstriction and bronchodilation properties make it an excellent drug for the treatment of anaphylaxis and it may be administered intramuscularly (IM) for the treatment of bronchoconstriction or anaphylaxis. Typical IM dosing is 300 mcg for adults and 150 mcg in children. When given IM, peak effects are seen within 15 minutes.² Intravenous (IV) bolus dosing effects are seen within seconds after reaching the circulation, and these effects typically last less than 5 minutes. Inhaled epinephrine can cause bronchodilation within 1 minute, but tachycardia and other systemic effects may be seen at high doses. Epinephrine is primarily eliminated by hepatic metabolism. Epinephrine causes a rise in blood glucose levels by increasing hepatic gluconeogenesis and decreasing pancreatic insulin secretion.

Norepinephrine

Norepinephrine activates both α and β receptors. It is active at α₁ receptors, although it is less potent than epinephrine and has no clinically significant β₂ effects. Its β₁ stimulation effects are equipotent to those of epinephrine. IV doses of norepinephrine have a rapid onset and offset time similar to epinephrine. It is eliminated via the same pathways as epinephrine. It is indicated for use in patients with severe hypotension due to vasodilation. In septic shock, norepinephrine causes less tachycardia and may case less splanchnic vasoconstriction than epinephrine. Although epinephrine has not been associated with worse outcomes, norepinephrine is preferred over epinephrine in the treatment of septic shock.³

Dopamine

Dopamine is the precursor to norepinephrine and epinephrine in catecholamine synthesis. Though it is an important neurotransmitter, it does not cross the blood-brain barrier after IV administration and is therefore not associated with clinically important central nervous system effects. It acts on α, β, and dopaminergic (D₁ and D₂) receptors. In addition to the CNS, D₁ receptors are found in the renal tubules as well as renal and mesenteric blood vessels. At low doses (< 3 mcg/kg/min), the predominant effect is vasodilation resulting from D₁ receptor activation. The increased renal blood flow is apparently offset by peripheral vasodilation via D₂ receptor attenuation of norepinephrine release shunting blood away from the kidneys. At higher doses the β₁ activity becomes more prominent, with increased myocardial contractility and a rise in systolic blood pressure. At high doses (> 10 mcg/kg/min), vasoconstriction caused by activation of α₁ receptors becomes the predominant clinical effect.

Dopamine has a rapid onset and elimination similar to epinephrine. Dopamine is metabolized by monoamine oxidase (MAO) in the liver and kidney. Its duration of action is prolonged up to 1 hour in patients taking MAO inhibitors. Dopamine is indicated in the treatment of shock states, including cardiogenic shock where its β₁ agonism could increase a low cardiac output.

Dopamine can increase urine output, and low-dose dopamine (1–3 mcg/kg/min) has been widely studied for its possible ability to prevent renal damage in low perfusion states by improving renal perfusion. However, most recent clinical data do not support the use of low-dose dopamine to preserve renal function.³

Fenoldopam

Fenoldopam is a dopamine analog that is only active on the D₁ receptor. It does not have any α or β activity, and it does not cross the blood-brain barrier. It has poor oral bioavailablity and is currently only available for parenteral administration. Its primary clinical effects are vasodilation and diuresis. It can rapidly and predictably lower blood pressure, which makes it a useful agent to treat acute and severe hypertension. It is recommended that it be administered only by continuous infusion. It has a rapid onset reaching full effect after 15 minutes of continuous infusion and it has a half-life of 10 minutes.⁴

Fenoldopam should be used with caution in patients with glaucoma, as it has been shown to raise intraocular pressure. Like other vasodilating agents, it can also cause tachycardia and headaches.

Phenylephrine

Phenylephrine is a synthetic sympathomimetic agent that exhibits potent vasoconstriction activity via α₁ receptor activation. Its hemodynamic effects are seen almost immediately after IV administration, and these effects persist for up to 15 minutes. At very high doses, it may activate β receptors but at commonly used doses only the α effects are seen. These effects include a rise in systemic blood pressure and reflex bradycardia.

Phenylephrine is indicated for use in patients with hypotension due to vasodilation. It must be used cautiously in patients with poor left ventricular function as cardiac output may be further decreased by the increased peripheral vascular resistance caused by phenylephrine.

Ephedrine

Ephedrine is a sympathomimetic that has both direct α and β activity. Its effects are similar to epinephrine, although ephedrine is much less potent and has a longer duration of action. Ephedrine exhibits indirect activity as well due to its ability to release norepinephrine from presynaptic nerve terminals. Ephedrine can be used for the short-term treatment of vasodilatory hypotension and is often the first choice among vasoconstrictors to counteract the vasodilation associated with spinal or epidural anesthesia. Its effects on hemodynamics are seen almost immediately after IV administration, and these effects last for up to 10 minutes. The effects may last for up to 1 hour after IM or subcutaneous administration. Ephedrine is metabolized by hepatic enzymes as well as excreted unchanged in the urine.

Ephedrine has become the preferred vasoconstrictor in obstetric patients because it is believed to cause less reduction in uterine blood flow when compared to phenylephrine.^5,6

Dobutamine

Dobutamine is a synthetic analog of dopamine and has predominantly β₁ effects. Hemodynamic effects occur immediately after IV administration, and peak effects occur with 10 minutes after starting a continuous infusion. It has a half-life of 2 minutes and is primarily cleared by hepatic metabolism. In healthy patients, dobutamine has been shown to increase cardiac output in a linear fashion. At low doses (2.5 mcg/kg/min) cardiac output rises due to increased stroke volume. At higher doses the stroke volume is unchanged, and the increased heart rate accounts for the continued rise in cardiac output.⁷

Dobutamine has the ability to increase cardiac output without the vasoconstriction and tachycardia associated with other agents. This has made it particularly useful in the treatment of congestive heart failure. It is also useful for improving ventricular function after cardiopulmonary bypass or acute myocardial infarction when the cardiac output is low but may recover within hours to days after the injury.

Isoproterenol

Isoproterenol is a nonselective β agonist and causes vasodilation, tachycardia, and increased cardiac output. It is a very short-acting medication after IV bolus dosing, with effects lasting only a few minutes. The availability of β₁-selective agents has limited its use, but it can be used in situations where increased inotropy and chronopy are desirable. It may also be useful in treating symptomatic bradycardia when atropine has failed. Isoproterenol may also be considered in the treatment of overdosage of β blockers and calcium channel blockers.⁸ It can also be used to treat acute bronchospasm during general anesthesia.⁹

Selective α receptor blocking agents are used in the treatment of hypertension, benign prostatic hyperplasia, and preoperatively to decrease the effects of pheochromocytoma. The only agent with a parenteral formulation is phentolamine. Phentolamine is a competitive antagonist at both α₁ and α₂ receptors and is used to counteract the effects of excessive catecholamine secretion seen in patients with pheochromocytoma. Phentolamine is given as an IM or intravenous dose of 5 to 15 mg. It has an onset of action of 1 to 2 minutes and a duration of 10 to 30 minutes.¹⁰ It is typically dosed every 1 to 2 hours for the treatment of acute hypertension due to pheochromocytoma. It can also be used when a vasoconstrictive agent is inadvertently infused into tissue rather than the circulation. Phentolamine diluted to 0.5 to 1.0 mg/mL can be injected directly into the affected tissue and may restore enough circulation to limit or prevent tissue necrosis.¹¹

Agents that block β–adrenergic receptors are used in the treatment of hypertension and tachycardia. Propranolol is a nonselective β blocker in that it blocks both β₁ and β₂ receptors. Atenolol, esmolol, and metoprolol are β₁-selective agents. They have much less activity at β₂ receptors compared to β₁, but they still activate β₂ receptors to a small degree.

Nonselective β agonists are contraindicated in patients with reactive airway disease or chronic obstructive pulmonary disease as β₂ blockade may cause symptomatic bronchoconstriction in these patients. β₁-selective agents may still exhibit activity at β₂ receptors, so these agents should be used cautiously in this patient group as well.

Propranolol

IV propranolol is indicated for the treatment of life-threatening supraventricular dysrhythmias. It may be given as a 1- to 3-mg bolus dose. It has an immediate onset of action and a duration of action of less than 5 minutes.