Adrenergic Agonists Overview

Overview

This lecture covers adrenergic agonists, detailing their synthesis, receptor mechanisms, physiological effects, and clinical uses, including relevant drugs and their indications.

Adrenergic Neuron & Neurotransmitter Synthesis

• Norepinephrine is synthesized from the dietary amino acid tyrosine via tyrosine → L-DOPA → dopamine → norepinephrine.
• Release occurs following action potential-induced calcium influx and vesicle exocytosis.
• Norepinephrine binds adrenergic receptors on target organs, causing specific physiological effects.
• Norepinephrine is either reuptaken into the neuron or metabolized by COMT (catechol-O-methyltransferase) and MAO (monoamine oxidase).

Adrenergic Receptors and Intracellular Effects

• Alpha-1 receptors: Activate phospholipase C pathway, increasing IP3 and DAG, leading to smooth muscle contraction.
• Alpha-2 receptors: Inhibit adenylyl cyclase via Gi, reducing cAMP, inhibiting neurotransmitter/hormone release.
• Beta-1/2/3 receptors: Stimulate adenylyl cyclase via Gs, increasing cAMP; beta-1 increases cardiac contraction, beta-2/3 relax smooth muscle.

Norepinephrine & Epinephrine

• Both released by sympathetic system; epinephrine mainly from adrenal medulla.
• Both act on alpha and beta receptors but with different affinities and effects.

Types of Adrenergic Agonists

• Direct agonists: Bind and activate adrenergic receptors (e.g., phenylephrine, dobutamine).
• Indirect agonists: Increase norepinephrine in synapse by preventing breakdown or reuptake (e.g., amphetamines, cocaine).
• Mixed agonists: Do both, e.g., pseudoephedrine (used as decongestant).

Receptor-specific Effects & Drug Examples

Alpha-1 Agonists (e.g., phenylephrine, midodrine)

• Cause vasoconstriction, increase blood pressure, inhibit urination/defecation, dilate pupils.
• Used for hypotension (phenylephrine for general/shock, midodrine for orthostatic hypotension), nasal decongestion, pupil dilation.
• Adverse: reflex bradycardia, rebound nasal congestion.

Alpha-2 Agonists (e.g., clonidine, alpha-methyldopa)

• Inhibit norepinephrine release, reduce CNS sympathetic outflow.
• Used for hypertension, ADHD, withdrawal symptoms; alpha-methyldopa safe in pregnancy.
• Adverse: sedation, lethargy, decreased respiratory drive.

Beta-1 Agonists (e.g., dobutamine)

• Increase heart rate and contractility, raising cardiac output.
• Used for bradycardia, acute heart failure, cardiogenic shock.
• Adverse: tachyarrhythmias, increased angina.

Beta-2 Agonists (e.g., albuterol, salmeterol, terbutaline)

• Relax bronchial and uterine smooth muscle.
• Used for asthma/COPD (albuterol = short-acting, salmeterol = long-acting), preterm labor (terbutaline), hyperkalemia (albuterol).
• Adverse: tremor, hypokalemia, hyperglycemia, mild tachycardia.

Beta-3 Agonists (e.g., mirabegron)

• Relax detrusor muscle of bladder, inhibit urination.
• Used for overactive bladder, urinary urgency/frequency.

Mixed Alpha/Beta Agonists

• Norepinephrine: Primarily alpha-1 (vasoconstriction, BP ↑), mild beta-1 (HR/contractility ↑ at high doses); used in shock.
• Epinephrine: More beta than alpha; increases HR, contractility, bronchodilation; used in anaphylaxis, asthma, cardiac arrest, shock.
• Dopamine: Dose-dependent effects; low = beta, high = alpha; used for heart failure, shock, bradycardia.
• Isoproterenol: Non-selective beta agonist; strong HR/contractility ↑, vasodilation (↓ diastolic BP); used for bradycardia.

Hemodynamic Effects Summary

• Norepinephrine: ↑ systolic/diastolic BP, ↑ SVR, neutral cardiac output, reflex bradycardia.
• Epinephrine: ↑ cardiac output, ↑ HR, ↑ systolic, slight ↓ diastolic BP, mild ↑ MAP.
• Isoproterenol: ↑ HR/output, ↓ SVR/diastolic BP, ↓ MAP, ↑ pulse pressure.

Key Terms & Definitions

• Adrenergic agonist — drug that stimulates adrenergic receptors.
• Alpha-1 receptor — causes smooth muscle contraction (e.g., vasoconstriction).
• Alpha-2 receptor — decreases release of norepinephrine.
• Beta-1 receptor — increases heart rate and contractility.
• Beta-2 receptor — relaxes smooth muscle (bronchioles, uterus).
• Beta-3 receptor — relaxes bladder muscle (detrusor).
• Indirect agonist — increases norepinephrine without binding receptor directly.

Action Items / Next Steps

• Review adrenergic receptor types, locations, and effects.
• Memorize major drugs and their main clinical indications/adverse effects.
• Study hemodynamic response patterns for major agonists.
• Complete assigned textbook readings on adrenergic pharmacology.