Ephedrine is an indirect (stimulation of release of endogenous norepinephrine) and direct (stimulates - and -adrenergic receptors) acting synthetic sympathomimetic. The slow inactivation and excretion of ephedrine are responsible for the prolonged duration of action of this sympathomimetic.

1. Clinical Uses

   1. Ephedrine, 5 to 10 mg IV administered to adults, is a commonly selected sympathomimetic to increase systemic blood pressure in the presence of sympathetic nervous system blockade produced by regional anesthesia or hypotension due to inhaled or injected anesthetics.

   2. Until recently, ephedrine was considered the preferred sympathomimetic for administration to parturients experiencing decreased systemic blood pressure owing to spinal or epidural anesthesia. Recent reviews of trials of ephedrine versus phenylephrine have concluded that systemic blood pressure control is similar with both drugs but phenylephrine is associated with a higher umbilical artery pH at delivery than ephedrine (seems that agonists such as phenylephrine may be preferable to ephedrine for treatment of maternal hypotension).

2. Cardiovascular effects of ephedrine resemble those of epinephrine, but its systemic blood pressure-elevating response is less intense and lasts approximately 10 times longer.

   1. IV ephedrine results in increases in systolic and diastolic blood pressure, heart rate, and cardiac output.

   2. The principal mechanism for cardiovascular effects produced by ephedrine is increased myocardial contractility due to activation of ₁ receptors. In the presence of preexisting -adrenergic blockade, the cardiovascular effects of ephedrine may resemble responses more typical of -adrenergic receptor stimulation.

   3. A second dose of ephedrine produces a less intense systemic blood pressure response than the first dose (tachyphylaxis, occurs with many sympathomimetics).

Phenylephrine mimics the effects of norepinephrine but is less potent and longer lasting (principally stimulates ₁-adrenergic receptors by a direct effect, with only a small part of the pharmacologic response being indirect-acting due to its ability to evoke the release of norepinephrine). Phenylephrine exerts minimal effects on -adrenergic receptors. The dose of phenylephrine necessary to stimulate ₁ receptors is far less than the dose that stimulates ₂ receptors. Phenylephrine primarily causes venoconstriction rather than arterial constriction.

1. Clinical Uses

   1. Phenylephrine, 50 to 200 μg IV bolus, is often administered to adults to treat systemic blood pressure decreases that accompany sympathetic nervous system blockade produced by a regional anesthetic and peripheral vasodilation following administration of injected or inhaled anesthetics.

   2. Phenylephrine is believed to be particularly useful in patients with coronary artery disease and in patients with aortic stenosis because it increases coronary perfusion pressure without chronotropic side effects, unlike most other sympathomimetics.

   3. Phenylephrine has been used as a continuous infusion (20 to 100 μg per minute) in adults to maintain normal blood pressure during surgery.

   4. The reflex vagal effects produced by phenylephrine can be used to slow heart rate in the presence of hemodynamically significant supraventricular tachydysrhythmias.

   5. Topically applied, phenylephrine is a widely available nasal decongestant (brand name Neo-Synephrine).

2. Cardiovascular Effects

   1. Rapid IV injection of phenylephrine to patients with coronary artery disease produces dose-dependent peripheral vasoconstriction and increases in systemic blood pressure that are accompanied by decreases in cardiac output (Fig. 18-5).

   2. Decreases in cardiac output may reflect increased afterload but more likely are due to baroreceptor-mediated reflex bradycardia in response to drug-induced increases in diastolic blood pressure.

   3. Pulmonary artery pressure is increased by phenylephrine.

3. Metabolic Effects. Stimulation of receptors by a continuous infusion of phenylephrine during acute potassium loading interferes with the movement of potassium ions across cell membranes into cells (Fig. 18-6). Administration of phenylephrine in the absence of an acute potassium load does not change the plasma potassium concentration.

4. Treatment of Overdose

   1. Systemic manifestations of sympathetic nervous system activation (systemic hypertension, tachycardia, baroreceptor-mediated bradycardia) may accompany vascular absorption of agonists (phenylephrine, epinephrine) when used as topical or injected vasoconstrictors in the surgical field.

   2. Because ₁ receptor blockades reduces cardiac output, treatment of phenylephrine-induced hypertensive crisis with -adrenergic blocking drugs is contraindicated.

   3. Systemic hypertension induced by intravenously administered agonists may not require treatment. The duration of action of IV phenylephrine and epinephrine is brief and hypertension may resolve spontaneously without pharmacologic interventions. Severe hypertension may require pharmacologic interventions but treatment must not decrease the ability of the stressed myocardium to increase contractility and heart rate (vasodilating drugs such as nitroprusside or nitroglycerin are indicated).