Direct-Acting Adrenergic Agonists (Catecholamines)

Each of these drugs is or has previously been used in the treatment of shock.  All of the drugs in this group are catecholamines.  

Note: Each drug will be considered in isolation in this section.  Class Drugs

• Epinephrine

• Norepinephrine

• Dopamine

• Dobutamine

• Phenylephrine

• Isoproterenol

Physiology Review

Direct-Acting Adrenergic Agonists directly stimulate adrenergic receptors (α and β).  α and β receptors are found in the sympathetic nervous system.  The following table is a reminder of the effects of stimulation of α and β receptors.

Alpha Adrenoreceptors

Receptor Type	Physiologic Response	Signal Transduction
α1	GI Relaxation; Mydriasis (pupillary dilatation); Vasoconstriction;      - ↑ PVR;      - ↑ BP; ↑  Bladder sphincter tone	Gq, activated. Results in IP3 (Calcium influx) and DAG (PKC activation) release
α2	↓  Norepinephrine release; ↓  Insulin release; ↓  Lipolysis; ↓  Aqueous humor production; ↓  ACh release	Gi, g-protein linked receptor, which inhibits adenylyl cyclase, which decreases cAMP levels

Beta Adrenoreceptors

Receptor Type	Physiologic Response	Signal Transduction
β1	↑  Chronotropy; ↑  Inotropy; ↑  Lipolysis; ↑  Renin release	Gs, Activates adenylyl cyclase, increasing cAMP levels
β2	Vasodilation;      - ↓ PVR; Bronchodilation; Mobilizes glucose;      - ↑ Glycogenolysis;      - ↑ Glucagon release; ↓  Uterine tone	Gs, Activates adenylyl cyclase, increasing cAMP levels
β3	↑ - Lipolysis; Bladder relaxation	Gs, Activates adenylyl cyclase, increasing cAMP levels

Drugs

Epinephrine

Epinephrine is a naturally occurring catecholamine that is produced in the adrenal medulla and released when the adrenal medulla is stimulated.  In the vascular system, low-dose epinephrine primarily results in β effects (vasodilation) and at higher doses, α effects (vasoconstriction) predominate.

When administered, epinephrine causes an increase in heart rate and contractility (β1). The β1 effects result in an increased systolic blood pressure. Diastolic blood pressures tend to decrease due to the stimulation of β2 receptors, which results in vasodilation of skeletal muscle and liver blood vessels having a slightly larger effect on diastolic blood pressures than the vasoconstriction caused by stimulation of α1 receptors. Overall, peripheral vascular resistance decreases.

Therapeutic Uses

Anaphylaxis: Reverses Type 1 Hypersensitivity reactions.

Cardiac arrest: Restores cardiac function in cardiac arrest.

Bronchospasm: Reverses bronchospasm in asthma and allergic reactions.

Septic Shock: Treatment of hypotension in septic shock by increasing cardiac output.

Croup: Inhaled epinephrine is used to decrease supra-glottic swelling in croup.

Local Anesthetic: Increases duration of action of local anesthetic via local vasoconstriction.

Adverse Effects

• Tachycardia

• Headache

• Tremor

• Anxiety

• Local tissue ischemia

Norepinephrine

Norepinephrine is a naturally occurring catecholamine that is both excreted from the adrenal medulla and used as a neurotransmitter in adrenergic nerves.  

Norepinephrine primarily stimulates α receptors and has weak β activity. Stimulation of α receptors results in vasoconstriction, which results in increased peripheral vascular resistance and systolic and diastolic blood pressure.  As norepinephrine is a weak β stimulator, pulse rate tends to decrease in response to the increased blood pressure (reflex bradycardia).

Therapeutic Uses

Shock

• Increased blood pressure (SBP & DBP) by increasing systemic vascular resistance

Adverse Effects

• Headache

• Tremor

• Anxiety

• Local tissue ischemia

Dopamine

Dopamine differs from NE and epinephrine in that it interacts with dopamine receptors in the renal and splanchnic arterioles.  Activation Dopamine-1 and Dopamine-2 receptors results in increased blood flow to the kidneys, GI tract, liver, and spleen.  Dopamine stimulates β receptors and α receptors as well.

Therapeutic Uses

• Cardiogenic shock

• Septic shock

Adverse Effects:

• Tachycardia

• Headache

• Tremor

• Anxiety

Dobutamine

Dobutamine is a direct β1 agonist, which results primarily in increased cardiac output with increased heart rate and contractility.

Therapeutic Uses

• Acute Heart Failure, increases cardiac output

• Post-cardiac surgery

Adverse Effects

• May precipitate atrial fibrillation with rapid ventricular response

• Tachycardia

• Tremor

• Anxiety

Isoproterenol

Isoproterenol is rarely used clinically.  There is possible indication in AV block.  Isoproterenol is non-selective to β1 and β2. Isoproterenol does not significantly stimulate alpha receptors.  Due to isolated beta effects, isoproterenol results in increased heart rate and contractility and decreased peripheral vascular resistance (vasodilation of smooth muscle vasculature).  These effects result in mildly increased systolic blood pressure and a decrease in diastolic blood pressure.

Adverse Effects:

• Tachycardia

• Headache

• Tremor

• Anxiety

Physiologic response comparison of catecholamines

Drug/Receptor/Response Table

Drug	Receptors	Physiologic Response	Therapeutic Indications
Epinephrine	β > α	↑HR & Contractility; Overall ↓ PVR	Anaphylaxis, cardiac arrest, shock, vasoconstriction, croup, bronchospasm
Norepinephrine	α>>β	Vasoconstriction; ↑PVR; reflex bradycardia	Shock
Dopamine	D1, D2, α, β	Vasodilation of renal & splanchnic arterioles	Cardiogenic shockSeptic shock
Dobutamine	β1	↑HR & Contractility	Acute heart failure
Isoproterenol	Β1 & β2	↑HR & Contractility; ↓ PVR	Heart block

Drug Table

Drug Name	Application	Comments	Image
Epinephrine	Anaphylaxis; Shock; Cardiac Arrest; Bronchospasm; Croup; Local anesthesia	β1; β2	"EpiPen"
Norepinephrine	Shock	α1; α2; 'weak' β1	"North" and "F"
Dopamine	Cardiogenic Shock	Dopamine-1; Dopamine-2; β1; α1	"Dope"
Dobutamine	Acute Heart Failure	β1	"Doe" and "Butane Torch"