Autonomic Pharmacology II: Adrenergic

Adrenergic Receptors: Alpha I- Excitation

Vascular smooth muscle, eyes, GI/GU sphincters

Adrenergic Receptors: Alpha 2- Relaxation

Vascular smooth muscles, GI systems, skin, and mucosa

Adrenergic Receptors: Beta 1- Excitation

Heart, kidneys

Adrenergic Receptors: Beta 2- Relaxation

Eyes, blood vessels, lungs, liver, pancreas, and GI/GU systems

Agonists do what?

Activates receptors

Antagonists do what?

Blocks receptors, producing no effects

Alpha 1 Main effects: Smooth muscle contraction

Indications of Agonists: Vasodilatory shock, hypotension

Indication of Antagonists: Hypertension, benign prostatic hyperplasia

Alpha II Main effects: Inhibition of norepinephrine

Indications of Agonist: Hypertension, pain and panic disorders

Indications of Antagonists: Erectile dysfunction, depression

Beta: Main Effects:

B1: Cardiac stimulation

B2: Bronchodilation

B3: Increased lipolysis

Indications of Agonists: Cardiogenic shock, heart failure, asthma, overactive bladder

Indications of Antagonists: Heart failure, arrhythmias, hypertension

A1 Selective Adrenergic Receptor Agonists: Phenylephrine and Oxymetazoline

Nasal Decongestant

A1 Selective Adrenergic Receptor Agonists: Metaraminol

Hypotension

A1 Selective Adrenergic Receptor Agonists: Midodrine

Postural hypotension

A1 Selective Adrenergic Receptor Antagonists: Prazosin

Hypertension

A1 Selective Adrenergic Receptor Antagonists: Terazosin, Doxazosin

Hypertension

Benign Prostatic hyperplasia

A1 Selective Adrenergic Receptor Antagonists: Alfuzosin, Tamsulosin, Silodosin

Benign Prostatic hyperplasia

Alpha 2 Selective Adrenergic Receptor Agonist: Clonidine

Hypertension

Alpha 2 Selective Adrenergic Receptor Antagonists: Yohimbine

Prior use for male sexual dysfunction (replaced by PDE5 inhibitors)

• Current use as dietary supplement

Non-Selective Alpha-Adrenergic Receptor Antagonists: Phenoxybenzamine

Treatment of sweating and hypertension associated with pheochromocytoma

Non-Selective Alpha-Adrenergic Receptor Antagonists: Phentolamine

Treatment of sweating and hypertension associated with pheochromocytoma

Prevention and treatment of dermal necrosis after the inadvertent extravasation of an alpha receptor agonist (dopamine)

Reversal of soft tissue (lip, tongue) anesthesia

Beta-Selective Adrenergic Receptor Agonists: Dobutamine

Acute decompensated heart failure

Beta 1-Selective Adrenergic Receptor Antagonists: Metoprolol

Hypertension, angina, myocardial infraction, heart failure

Beta 1-Selective Adrenergic Receptor: Atenolo

Hypertension, angina, myocardial infraction

Beta 2- Selective Adrenergic Receptor Agonists: Short Acting

Metaproterenol, Albuterol, Levalbuterol, Pirbuterol, Terbutaline

• Bronchodilators (primarily for asthma)

Beta 2- Selective Adrenergic Receptor Agonists: Long Lasting

Salmeterol, Formoterol, Arformoterol

• Bronchodilators (primarily for COPD)

Beta 2- Selective Adrenergic Receptor Agonists: Very Long Lasting

Indacaterol, Olodaterol

• Bronchodilators (ONLY for COPD)

Are there Beta 2 antagonists receptors?

NO!!

There are no FDA-approved selective B2 antagonists

What is the Non-Selective Beta-Adrenergic Receptor Antagonist Propranolo used for?

Hypertension, angina, myocardial infarction, cardiac dysrhythmias, migraine preventions

• Off-label use: Performance anxiety disorder

What is the Non-Selective Beta-Adrenergic Receptor Antagonist Labetalol used for?

Hypertension

Nonselective Adrenergic Agonists: Norepinephrine and Dopamine

MOA

Nonselective Adrenergic Agonists: Epinephrine

MOA

Anaphylaxis and other severe immediate hypersensitivity reactions; hypotension and shock; induction and maintenance of mydriasis during intraocular surgery

Sympathomimetic Nasal Decongestant: Oxymetazoline and phenylephrine- MOA are?

Alpha 1- adrenoceptor agonist = Constricts blood vessels in the nasal = reduced nasal congestion and promotes easier breathing

Sympathomimetric Nasal Decongestant: Pseudoephedrine- MOA acts?

INDIRECTLY acting sympathomimetic = acts primarily or exclusively by including the release of norepinephrine = activation of a1, a2, b1 » b2; has a mixed mechanism of action consisting of both indirect and direct effects by binding to and acting as an agonist of adrenergic receptors.

• The affinity of pseudoephedrine for adrenergic receptors is described as very low or negligible

What are Positive Inotropes: Dopamine (IV) for RENAL DOSE

Low doses: <5 mcg/kg/min

Primary Effects: Vasodilation in renal, mesenteric, coronary, and cerebral arteries

• Increase renal blood flow and urine output

What are Positive Inotropes: Dopamine (IV) for CARDIAC DOSE?

Intermediate Doses: 5-10 mcg/kg/min

Primary effects: Increases heart rate (chronotropy), Cardiac contractility (inotropy), and Cardiac output

What are Positive Inotropes: Dopamine (IV) for VASOPRESSOR DOSE?

High Doses: >10 mcg/kg/min

Primary Effects: Vasoconstrictions

• Increases systemic vascular resistance (SVR)

• Increase Blood Pressure

Higher arrhythmia risk

Positive Inotropes Dopamine (IV): Clinical Indicators

Severe hypotension or shock (septic shock and other vasodilatory shock states, acute decompensated heart failure)

Positive Inotropes Dopamine (IV): Adverse Effects

Cardiovascular (hypertension, palpitations, tachycardia), peripheral gangrene, GI symptoms, CNS symptoms (headache, axiety)

• Tolerance: Long-term use NOT recommended

Positive Inotropes: Dobutamine (IV) Primary Effects?

Dobutamine’s effects are not strongly dose-dependent in terms of receptor selectivity.

• Its pharmacologic profile is relatively consistent across therapeutic dose, but the magnitude of its effects changes with dose

Primarily beta-1, minimally alpha 1

Less likely to cause excessive tachyarrhythmias than dopamine

Provides more predictable cardiac support with less vasoconstriction

Positive Inotropes Dobutamine (IV) Clinical Indications:

Cardiogenic shock, acute decompensated heart failure

Positive Inotropes Dobutamine (IV): Adverse Effects

Cardiovascular (tachycardia (less likely than dopamine), hypertension), GI symptoms, CNS symptoms (headache);

• Tolerance: Long term used NOT recommended

Norepinephrine (IV) Primary Effects:

Primarily alpha-1, moderate beta-1

Alpha 1: Restores perfusion pressure in hypotensive patients by increasing systemic vascular resistance (SVR)

• Has B1 effects, so it may modestly support contractility without causing as much tachycardia as dopamine

Benefit: Better safety profile than dopamine- lower risk of arrhythmias

Limitation: Does not directly increase contractility as much as dobutamine

Norepinephrine (IV) Clinical Indications:

Often the first-line vasopressor when hypotension in severe in cardiogenic shock, especially when dobutamine alone does not maintain blood pressure

Norepinephrine (IV): Adverse Effects

Cardiovascular (reflex bradycardia, hypertension), Gi symptoms (reduced gut perfusion), CNS symptoms (headache, anxiety)