Alpha Agonists: Types and Functions

Alpha Agonists Overview

• Alpha agonists activate alpha receptors, a type of adrenergic receptor.
• These receptors exist in various body tissues.
• There are two primary categories of alpha receptors: alpha-1 and alpha-2.

Alpha-1 (α1) Receptors

• Located on smooth muscles, predominantly in blood vessels, the bladder, eye and prostate.
• Activation causes vasoconstriction.
• It also leads to increased blood pressure.
• Contraction of smooth muscles occurs, affecting the bladder and causing mydriasis in the eye.

Alpha-2 (α2) Receptors

• Primarily located in the central nervous system (CNS) and presynaptic terminals, specifically in the brainstem.
• Activation inhibits norepinephrine release through negative feedback.
• Results in decreased sympathetic outflow.
• Causes reduced blood pressure, sedation, and decreased heart rate.

Selective Alpha-1 Agonists

• Example includes phenylephrine, a vasoconstrictor.
• Phenylephrine raises blood pressure and treats nasal congestion via nasal spray.
• Phenylephrine induces mydriasis.
• Midodrine treats orthostatic hypotension.
• This is achieved by constricting peripheral blood vessels to elevate blood pressure.
• The mechanism mainly involves vasoconstriction through α1 receptor activation.

Selective Alpha-2 Agonists

• Clonidine treats hypertension and withdrawal symptoms such as in opioid withdrawal.
• It acts centrally to decrease sympathetic nervous system activity.
• Methyldopa is another centrally acting antihypertensive, often used during pregnancy.
• Mechanism: acts on α2 receptors in the CNS.
• α2 receptor activation leads to decreased sympathetic outflow.
• This results in vasodilation and lowered blood pressure.

Non-Selective Alpha Agonists

• Epinephrine activates α1, α2, β1, and β2 receptors.
• It is used in emergencies like anaphylactic shock and cardiac arrest.
• Norepinephrine is primarily an α1 and α2 agonist with some β1 activity.
• It is used in critical care settings to increase blood pressure.
• Mechanism involves stimulation of both α1 and α2 receptors.
• These drugs exert broad actions on vascular tone, heart rate, and smooth muscle.

Clinical Uses: Vasoconstriction

• Phenylephrine treats hypotension.
• It is effective in surgical settings or shock by increasing vascular resistance and blood pressure.

Clinical Uses: Nasal Decongestion

• Phenylephrine and oxymetazoline are used topically in nasal sprays.
• They cause vasoconstriction in the nasal mucosa, reducing nasal congestion.

Clinical Uses: Mydriasis

• Phenylephrine dilates pupils during eye examinations.

Clinical Uses: Hypertension

• Clonidine and Methyldopa manage hypertension through reduced sympathetic outflow.
• Alpha-2 agonists treat withdrawal symptoms from opioids and other drugs.

Clinical Uses: Orthostatic Hypotension

• Midodrine treats orthostatic hypotension by increasing blood pressure upon standing.

Clinical Uses: Anaphylaxis and Shock

• Epinephrine treats anaphylactic reactions and some shock syndromes.

Alpha-1 Agonists: Side Effects

• Vasoconstriction leads to hypertension.
• Reflex bradycardia occurs due to increased blood pressure.
• Tissue necrosis can occur if phenylephrine is administered outside the vein.

Alpha-2 Agonists: Side Effects

• Sedation occurs due to CNS depression, causing drowsiness.
• Rebound hypertension may occur upon abrupt discontinuation of clonidine.
• Dry mouth is a frequent side effect of clonidine.
• Bradycardia and hypotension result from central reduction in sympathetic outflow.

Non-Selective Alpha Agonists: Side Effects

• Stimulation of β1 receptors can cause tachycardia.
• Epinephrine and norepinephrine can precipitate arrhythmias.
• Epinephrine can cause hyperglycemia by promoting glycogenolysis and inhibiting insulin release.
• Excessive vasoconstriction from these drugs may lead to tissue ischemia.

Contraindications and Precautions

• Alpha agonists that cause vasoconstriction should be used cautiously in patients with hypertension.
• Alpha agonists that increase heart rate or blood pressure should be used with caution in patients with heart disease, such as arrhythmias or coronary artery disease.
• Certain alpha agonists like clonidine and methyldopa are safer during pregnancy, while others like phenylephrine should be used cautiously or avoided.

Beta-1 (β1) Receptors

• Located in the heart and kidney.
• Stimulation increases heart rate (chronotropy), force of contraction (inotropy).
• Action increases renin release, leading to increased blood pressure.

Beta-2 (β2) Receptors

• Found in smooth muscles of the lungs, vasculature, and uterus.
• Stimulation causes smooth muscle relaxation (bronchodilation, vasodilation).
• Action inhibits release of inflammatory mediators.
• This process result in glycogenolysis and increased glucose levels.

Beta-3 (β3) Receptors

• Located in adipose tissue.
• Stimulation increases lipolysis and thermogenesis.

Mechanism of Action: Beta Agonists

• Beta agonists activate beta-adrenergic receptors via catecholamine binding (e.g., norepinephrine and epinephrine).
• Activation leads to increased intracellular cyclic adenosine monophosphate (cAMP).
• Subsequently, protein kinase A (PKA) is activated.
• PKA activates pathways depending on the tissue type, leading to smooth muscle relaxation (especially in airways and blood vessels), increased heart rate and contractility in the myocardium, and metabolic effects such as glycogenolysis and lipolysis.

Beta-1 Selective Agonists: Examples

• Dobutamine is a selective β1 agonist.
• Dobutamine is used primarily in managing heart failure, cardiogenic shock, and during cardiac stress testing.
• Increased heart rate, contractility, and cardiac output occur without significant effects on the vasculature or lungs.

Beta-1 Selective Agonists: Clinical Uses

• Useful to improve cardiac output in heart failure.
• Beta-1 agonists help to support blood pressure and circulation in acute heart failure or shock.
• They simulate the effects of exercise on the heart during cardiac stress testing.

Beta-2 Selective Agonists: Examples

• Albuterol (Salbutamol) is a short-acting β2 agonist (SABA).
• Albuterol is commonly used as a bronchodilator in asthma and COPD treatment.
• Salmeterol and Formoterol are long-acting β2 agonists (LABAs).
• Salmeterol and Formoterol treat asthma and COPD maintence.

Beta-2 Selective Agonists: Mechanism

• Selective Beta-2 agonists stimulate β2 receptors in bronchial smooth muscles.
• This causes bronchodilation.
• They are often administered via inhalation to minimize systemic effects.

Beta-2 Selective Agonists: Clinical Uses

• Beta-2 selective agonists relieve bronchospasm and improve airflow in asthma and COPD.
• SABAs such as albuterol are effective for acute asthma exacerbations.
• LABAs like salmeterol are used for chronic asthma management.
• Beta-2 Selective agonists prevent exercise-induced bronchoconstriction like LABA.

Non-Selective Beta Agonists: Examples

• Epinephrine activates β1 and β2 receptors.
• It is used in emergencies like anaphylaxis, severe asthma exacerbations, and cardiac arrest.
• Isoproterenol is a non-selective β1 and β2 agonist used historically for bradycardia and heart block.
• Isoproterenol is less common now due to the availability of more selective agents.

Non-Selective Beta Agonists: Clinical Uses

• Epinephrine rapidly reverses symptoms like bronchoconstriction and vasodilation from anaphylaxis.
• It treats cardiac arrest by increasing myocardial contractility and improving blood flow during resuscitation.
• Epinephrine is effective in emergency settings for acute asthma exacerbations.

Beta Agonists: Pharmacokinetics

• Inhaled beta agonists (e.g., albuterol, salmeterol) have localized effects in the lungs with minimal systemic absorption.
• Oral and intravenous formulations (e.g., isoproterenol, epinephrine) have greater systemic effects.
• There may be varying half-lives depending on the drug's formulation.
• Beta agonists are excreted in the urine, and dose adjustments may be necessary for patients with renal impairment.

Beta Agonists: Clinical Applications for Asthma and COPD

• Beta-2 agonists are the cornerstone of bronchodilation therapy for acute and chronic management.
• SABAs give immediate relief of bronchospasm.
• LABAs give long-term control

Beta Agonists: Clinical Applications for Cardiogenic Shock

• Dobutamine, a selective β1 agonist, improves cardiac output in heart failure or shock.

Beta Agonists: Clinical Applications for Anaphylaxis

• Epinephrine reverses bronchospasm and vasodilation, and prevents airway edema..

Beta Agonists: Clinical Applications for Arrhythmias and Heart Block

• Beta agonists like isoproterenol were historically used to treat bradycardia and heart block by increasing heart rate.
• More specific interventions are now preferred.

Beta Agonists: Clinical Applications for Preterm Labor

• Beta-2 agonists such as terbutaline have been used off-label to delay premature labor by relaxing uterine smooth muscle.
• Use is now limited due to safety concerns.

Beta Agonists: Adverse Effects - Cardiovascular

• Drugs like tachycardia, and arrhythmias with non-selective beta agonists can arise.
• Can cause increased blood pressure.

Beta Agonists: Adverse Effects - Respiratory

• Can cause tremors, nervousness, and palpitations (common with inhaled beta-2 agonists).

Beta Agonists: Adverse Effects - Metabolic

• Beta agonists elevate glucose levels by promoting glycogenolysis and inhibiting insulin release (especially in high doses).
• They drive potassium into cells, leading to decreased serum potassium levels.

Beta Agonists: Adverse Effects - Tolerance

• Chronic use of beta-2 agonists, especially LABAs, may lead to tolerance or "tachyphylaxis".

Beta Agonists: Contraindications and Cautions

• Patients with heart disease should exhibit caution, particularly with non-selective beta agonists.
• Beta agonists should be used cautiously in diabetic patients because they increase blood glucose levels.
• Patients with hyperthyroidism may have increased sensitivity.
• Monitoring for excessive cardiac stimulation is critical.
• Some beta agonists (e.g., terbutaline) are used to manage preterm labor.
• Monitor closely for maternal and fetal safety.