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Adrenergic agonist

An adrenergic agonist is a medication that binds to and activates adrenergic receptors in the body, mimicking the physiological effects of endogenous catecholamines such as norepinephrine and epinephrine to stimulate the sympathetic nervous system.^[1]^[2] These drugs, also known as sympathomimetics or adrenomimetics, exert their actions through G-protein-coupled receptors, including alpha-1, alpha-2, beta-1, beta-2, and beta-3 subtypes, leading to diverse responses such as vasoconstriction, increased heart rate, bronchodilation, and smooth muscle relaxation.^[1]^[2] Adrenergic agonists are classified by their receptor selectivity and mechanism of action. Receptor-selective types include alpha-1 agonists (e.g., phenylephrine), which primarily cause vasoconstriction and are used for hypotension and nasal decongestion; alpha-2 agonists (e.g., clonidine), which reduce sympathetic outflow and treat hypertension and attention-deficit/hyperactivity disorder; beta-1 agonists (e.g., dobutamine), which enhance cardiac contractility in conditions like cardiogenic shock; beta-2 agonists (e.g., albuterol), which promote bronchodilation for asthma and chronic obstructive pulmonary disease; and beta-3 agonists (e.g., mirabegron) for overactive bladder.^[1] Non-selective agonists like epinephrine and norepinephrine activate multiple receptor types and are employed in emergencies such as anaphylaxis, cardiac arrest, and septic shock.^[1]^[2] Additionally, they can be categorized as direct-acting (binding directly to receptors), indirect-acting (promoting norepinephrine release), or mixed, with catecholamine-based drugs (e.g., epinephrine) differing from noncatecholamines in metabolism and duration of action.^[2] The physiological effects of adrenergic agonists vary by receptor: alpha-1 activation increases intracellular calcium to contract vascular and pupillary smooth muscle; alpha-2 stimulation inhibits neurotransmitter release; beta-1 enhances cyclic AMP to boost heart rate and force; beta-2 relaxes smooth muscle via cyclic AMP elevation; and beta-3 promotes lipolysis in adipose tissue.^[1] Clinically, these agents are vital for managing acute conditions like allergic reactions, glaucoma, and preterm labor, but their use requires caution due to potential side effects including hypertension, tachycardia, tremors, and arrhythmias, which arise from excessive sympathetic stimulation.^[1]^[3]

Receptor Fundamentals

Adrenergic Receptor Types

Adrenergic receptors, which mediate the effects of catecholamines such as epinephrine and norepinephrine, were initially classified into two main types—alpha (α) and beta (β)—by pharmacologist Raymond P. Ahlquist in 1948. This classification arose from observations of differential responses in isolated tissues to sympathomimetic amines, revealing distinct potency orders: for α receptors, epinephrine and norepinephrine exhibited similar high potency, surpassing isoproterenol, whereas for β receptors, isoproterenol was most potent, followed by epinephrine and then norepinephrine.^[4] These relative potencies—epinephrine > norepinephrine for β receptors and epinephrine ≈ norepinephrine for α receptors—provided the pharmacological basis for distinguishing the receptor classes and explained varied physiological responses like vasoconstriction versus bronchodilation.^[4] Building on this foundation, adrenergic receptors were further subdivided in subsequent decades into five primary subtypes—α1, α2, β1, β2, and β3—using criteria including selective agonist/antagonist affinities, G-protein coupling mechanisms, and specific tissue distributions.^[5] The α1 subtype couples to Gq proteins and is predominantly expressed in vascular smooth muscle, where it promotes contraction and vasoconstriction.^[5] In contrast, the α2 subtype couples to Gi/Go proteins and is mainly located on presynaptic neurons, modulating neurotransmitter release through feedback inhibition.^[5] The β subtypes all couple to Gs proteins but differ in distribution and function. β1 receptors are primarily found in cardiac tissue, driving increased heart rate and contractility.^[5] β2 receptors are abundant in the lungs and bronchi, facilitating smooth muscle relaxation and bronchodilation, while also present in vascular and uterine smooth muscle.^[5] β3 receptors, though less studied historically, are concentrated in adipose tissue, where they stimulate lipolysis and thermogenesis.^[5] Each subtype retains the broad binding preferences of its parent class, with β subtypes showing higher affinity for epinephrine relative to norepinephrine.^[4]

Receptor Signaling Pathways

Adrenergic receptors are a subclass of G protein-coupled receptors (GPCRs), seven-transmembrane domain proteins that transduce extracellular signals from catecholamines such as norepinephrine and epinephrine into intracellular responses via heterotrimeric G proteins.^[6] Upon agonist binding, these receptors undergo conformational changes that facilitate GDP-GTP exchange on the Gα subunit, leading to dissociation of Gα from the Gβγ complex and activation of downstream effectors.^[6] All nine adrenergic receptor subtypes—α1A, α1B, α1D, α2A, α2B, α2C, β1, β2, and β3—operate through this GPCR mechanism, but they couple to distinct G protein families, resulting in diverse signaling cascades.^[7] The α1-adrenergic receptors (α1ARs) couple primarily to Gq proteins, activating phospholipase C-β (PLC-β), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).^[8] IP3 binds to receptors on the endoplasmic reticulum, triggering Ca²⁺ release into the cytosol, while DAG activates protein kinase C (PKC), which phosphorylates targets to amplify signaling.^[8] This pathway promotes vasoconstriction in vascular smooth muscle by enhancing Ca²⁺-dependent myosin light chain phosphorylation and contraction.^[9] In contrast, α2-adrenergic receptors (α2ARs) couple to Gi/o proteins, inhibiting adenylyl cyclase and thereby reducing cyclic adenosine monophosphate (cAMP) levels, which decreases protein kinase A (PKA) activity.^[10] Gi/o activation also releases Gβγ subunits that can modulate ion channels, such as opening GIRK potassium channels or inhibiting voltage-gated Ca²⁺ channels, contributing to presynaptic inhibition of neurotransmitter release.^[11] β-adrenergic receptors (βARs) predominantly couple to Gs proteins, stimulating adenylyl cyclase to increase cAMP production and activate PKA, which phosphorylates targets like ion channels and contractile proteins.^[12] The β1AR subtype drives increased heart rate (positive chronotropy) and contractility (positive inotropy) via enhanced Ca²⁺ influx through L-type channels and faster relaxation through phospholamban phosphorylation.^[12] β2AR activation leads to bronchodilation in airway smooth muscle by reducing intracellular Ca²⁺ and promoting relaxation via myosin light chain phosphatase activation.^[13] The β3AR primarily signals through Gs but can also couple to Gi in certain contexts, such as in adipocytes, where it modulates lipolysis and thermogenesis.^[14] To prevent prolonged signaling, adrenergic receptors undergo desensitization primarily through phosphorylation by G protein-coupled receptor kinases (GRKs), such as GRK2 for β2ARs, which targets serine/threonine residues in the receptor's C-terminus upon agonist binding.^[15] This phosphorylation recruits β-arrestins, which sterically hinder G protein coupling and promote clathrin-mediated endocytosis, leading to receptor internalization and temporary sequestration from the plasma membrane.^[15] Arrestin binding can also initiate alternative signaling, such as MAPK pathway activation, independent of G proteins.^[16]

Pharmacological Mechanisms

Direct Agonists

Direct adrenergic agonists are synthetic or naturally derived compounds that bind directly to adrenergic receptors on postsynaptic cells, thereby mimicking the physiological effects of endogenous catecholamines such as norepinephrine and epinephrine without relying on the modulation of neurotransmitter release or reuptake.^[17] These agents activate specific receptor subtypes to elicit targeted responses, such as vasoconstriction or bronchodilation, depending on their selectivity profile.^[1] The development of direct adrenergic agonists traces back to the early 1900s, following the isolation of epinephrine from adrenal extracts in 1901 by Jokichi Takamine, which paved the way for synthetic analogs aimed at treating conditions like hypotension and shock.^[18] Early compounds, including epinephrine itself and its derivatives, were introduced for vasopressor effects to counteract low blood pressure, marking a significant advancement in cardiovascular pharmacology during that era.^[19] At the molecular level, direct agonists exert their effects through orthosteric binding to the primary ligand recognition site within the transmembrane domain of adrenergic receptors, which are G-protein-coupled receptors (GPCRs).^[20] This binding stabilizes the receptor in its active conformation, facilitating the exchange of GDP for GTP on the associated G-protein and initiating downstream signaling cascades, such as increased cyclic AMP production via Gs proteins for beta receptors.^[21] Selectivity for alpha or beta receptor subtypes is largely determined by structural modifications to the core phenylethylamine scaffold of catecholamines. For instance, alpha-1 selective agonists like phenylephrine feature a meta-hydroxy substitution on the phenyl ring and a secondary (N-methyl) amine group, which enhance binding affinity to alpha-1 receptors while minimizing beta activity.^[22] In contrast, beta-selective agonists such as isoproterenol incorporate N-alkylation, including N-methylation or larger isopropyl groups on the amine, which sterically hinder interactions with alpha receptors and favor beta-1 and beta-2 activation, resulting in non-selective beta agonism without significant alpha effects.^[23] These tweaks allow for precise therapeutic targeting, as seen in phenylephrine's use for nasal decongestion via alpha-1 mediated vasoconstriction and isoproterenol's application in cardiac stimulation through beta receptor pathways.^[24]

Indirect Agonists

Indirect adrenergic agonists, also known as indirect sympathomimetics, are pharmacological agents that amplify adrenergic signaling by elevating synaptic levels of norepinephrine (NE) and epinephrine without directly interacting with adrenergic receptors. These compounds primarily act by either blocking the reuptake of catecholamines into presynaptic neurons or facilitating their release from intracellular stores, thereby prolonging or intensifying neurotransmission at sympathetic nerve terminals.^[1]^[25] A prominent subclass includes amphetamine-like drugs, which are substrates for neuronal transporters and enter presynaptic terminals to displace stored catecholamines into the cytoplasm. Once inside, these agents reverse the function of the vesicular monoamine transporter 2 (VMAT2), causing NE to leak from synaptic vesicles into the cytosol and subsequently promoting its efflux into the synaptic cleft via reversal of the norepinephrine transporter (NET). This VMAT2-mediated mechanism is exemplified by amphetamines, which dissipate the proton gradient across vesicular membranes, leading to non-exocytotic release independent of neuronal firing.^[26]^[27] In contrast, reuptake inhibitors like cocaine primarily target the NET on the plasma membrane, preventing the clearance of released NE from the synapse and allowing accumulation in the extracellular space. Cocaine binds to the outward-facing conformation of NET, acting as a competitive inhibitor that blocks NE transport back into the neuron, thereby enhancing synaptic NE concentrations and downstream adrenergic effects. The serotonin transporter (SERT) can also be affected by some agents, contributing to broader monoamine modulation, though NET inhibition predominates in adrenergic contexts.^[28] The discovery of indirect mechanisms dates to 1960s research on tyramine, a naturally occurring amine shown to exert sympathomimetic effects by releasing NE from sympathetic nerve stores, an action potentiated by precursors like dopamine and abolished by depletion agents such as reserpine. Tyramine enters neurons via NET and promotes vesicular release similar to amphetamines, highlighting early insights into indirect agonism.^[29] Pharmacokinetically, indirect agonists exhibit rapid onset of action due to immediate synaptic flooding of catecholamines, often within minutes of administration, driven by their high affinity for transporters and efficient cellular uptake. However, chronic use risks neuronal depletion of NE stores, as repeated release without adequate replenishment leads to diminished responsiveness (tachyphylaxis) and potential downregulation of vesicular storage, emphasizing the need for cautious therapeutic application.^[25]^[30]

Mixed and Indirect-Plus-Direct Agonists

Mixed and indirect-plus-direct agonists are sympathomimetic compounds that exert their effects through a combination of direct stimulation of adrenergic receptors and indirect enhancement of endogenous catecholamine activity.^[31] These agents, such as ephedrine and pseudoephedrine, weakly bind to alpha and beta adrenergic receptors while simultaneously promoting the release of stored norepinephrine from presynaptic neurons.^[32] This dual profile distinguishes them from purely direct or indirect agonists, allowing for amplified physiological responses in targeted tissues.^[33] The dual mechanism involves partial direct agonism at alpha-1, beta-1, and beta-2 adrenergic receptors, alongside indirect actions that include inhibition of the norepinephrine transporter (NET) to prevent reuptake and displacement of catecholamines from vesicular monoamine transporter (VMAT) storage sites.^[31] For instance, ephedrine directly activates alpha-1 receptors to increase vascular resistance and beta-2 receptors for bronchodilation, while its indirect effects elevate synaptic norepinephrine levels, further potentiating these responses.^[32] Similarly, pseudoephedrine demonstrates modest direct agonism at alpha-1 and beta receptors but primarily relies on norepinephrine release from cytoplasmic pools to stimulate peripheral adrenergic signaling.^[34] This combined approach results in sustained sympathomimetic activity, particularly in conditions requiring enhanced catecholamine tone. Clinically, the synergistic effects of these mixed agonists provide broader therapeutic utility, such as in asthma where ephedrine induces bronchodilation through both direct beta-2 receptor stimulation and indirect norepinephrine-mediated airway relaxation.^[31] This dual pathway enhances efficacy in hypotensive states or respiratory distress by simultaneously boosting cardiac output and vascular tone without solely depending on depleted endogenous stores.^[35] However, their lack of receptor subtype selectivity often leads to off-target cardiovascular effects, including tachycardia, hypertension, and arrhythmias due to non-specific alpha and beta activation.^[1] These challenges necessitate careful monitoring, as the indirect release of catecholamines can exacerbate sympathetic overdrive in susceptible patients.^[31]

Prodrugs and Precursors

Prodrugs and precursors of adrenergic agonists are pharmacologically inactive compounds that undergo metabolic activation in vivo to yield active catecholamine-like agonists, such as norepinephrine or epinephrine derivatives, thereby modulating adrenergic signaling indirectly through enzymatic conversion.^[1] These agents are designed to enhance bioavailability, facilitate tissue-specific delivery, or circumvent limitations in endogenous synthesis pathways, such as those involving dopamine beta-hydroxylase (DBH), the enzyme that hydroxylates dopamine to norepinephrine.^[36] Unlike direct agonists, prodrugs and precursors rely on host metabolism for activity, often leveraging decarboxylases or hydroxylases to generate the pharmacologically active moiety.^[37] A prominent example is methyldopa (α-methyldopa), developed in the late 1950s as an antihypertensive agent, which is decarboxylated by aromatic L-amino acid decarboxylase to α-methyldopamine and subsequently β-hydroxylated by DBH to α-methylnorepinephrine.^[38] This metabolite functions as a false neurotransmitter, displacing norepinephrine from storage vesicles and acting as a selective α2-adrenergic agonist to inhibit central sympathetic outflow.^[39] The conversion occurs primarily in the central nervous system, allowing methyldopa to penetrate the blood-brain barrier more effectively than polar catecholamines, thus providing sustained adrenergic modulation with reduced peripheral side effects.^[40] Droxidopa (L-threo-3,4-dihydroxyphenylserine, or L-threo-DOPS), a synthetic amino acid analog, serves as an immediate precursor to norepinephrine, bypassing the dopamine intermediate by direct decarboxylation via DOPA decarboxylase.^[36] This pathway is particularly advantageous in conditions with impaired DBH activity, as it restores norepinephrine levels without requiring the hydroxylase step, leading to enhanced adrenergic tone in deficient states.^[41] Similarly, dipivefrin (dipivalyl epinephrine) is a lipophilic prodrug of epinephrine, esterified with pivalic acid groups to improve corneal penetration; once absorbed, ocular esterases hydrolyze it to the active β-adrenergic agonist, facilitating localized intraocular pressure reduction.^[42] These prodrugs offer pharmacokinetic benefits, such as prolonged half-life and targeted activation, exemplified by the slower metabolic clearance of α-methylnorepinephrine compared to native norepinephrine, which supports extended receptor stimulation.^[39] Historically, the exploration of such precursors in the 1950s, including early analogs of L-DOPA for catecholamine synthesis, laid the foundation for modern adrenergic therapies by addressing challenges in neurotransmitter delivery and stability.^[38]

Structure-Activity Relationships

Core Chemical Structures

Adrenergic agonists are primarily derived from the catecholamine backbone, which consists of a phenylethylamine core featuring a beta-hydroxy group on the chiral carbon adjacent to the aromatic ring and an alpha-amino group at the terminus of the ethylamine side chain, as exemplified by norepinephrine (also known as 3,4-dihydroxyphenethylamine).^[43]^[44] This structural motif allows for interaction with adrenergic receptors through key functional groups that mimic the endogenous ligands epinephrine and norepinephrine.^[45] The essential pharmacophore of these agonists includes an aromatic ring attached to an ethanolamine side chain, represented by the general formula C₆H₃(OH)₂-CH(OH)-CH₂-NH₂, where the catechol moiety (3,4-dihydroxyphenyl) provides hydrogen bonding capabilities critical for receptor binding.^[46]^[43] The beta-hydroxyl group on the chiral center and the protonated amine are indispensable for efficacy, as modifications disrupting these elements abolish agonistic activity.^[44] Variations on this core include non-catechol structures that enhance receptor subtype selectivity; for instance, salbutamol lacks the meta-hydroxyl group of the catechol system, conferring high beta-2 selectivity while retaining the ethanolamine pharmacophore.^[47]^[45] The isolation of epinephrine, the prototypical catecholamine agonist, in pure form was achieved in 1901 by Jokichi Takamine from bovine adrenal glands, marking the first successful purification of a hormone.^[48] Contemporary understanding of these core structures has advanced beyond early 20th-century empirical observations through computational modeling, such as molecular docking and virtual screening, which reveal precise interactions between the pharmacophore and receptor binding pockets to guide selective agonist design. Recent cryo-EM structures (as of 2023) of α1A-adrenergic receptor complexes with agonists like epinephrine have revealed detailed interactions in the binding pocket, aiding selective ligand design.^[49] Additionally, GRK-biased β-adrenergic agonists developed in 2025 show promise for diabetes treatment with altered SAR.^[50]^[51]^[52]

Substituent Effects on Activity

Substituent modifications to the core phenylethanolamine structure of adrenergic agonists significantly influence their receptor selectivity, potency, and duration of action, guiding the design of agents tailored for specific therapeutic needs. For instance, increasing the bulk of the N-substituent shifts selectivity from alpha to beta receptors; the N-tert-butyl group in terbutaline enhances beta-2 selectivity by sterically hindering alpha receptor binding while maintaining potent beta-2 agonism, resulting in EC50 values around 1-10 nM for beta-2 mediated bronchodilation.^[53]^[23] Similarly, removal of the phenolic hydroxyl group at the para position reduces affinity for alpha receptors, promoting alpha selectivity in compounds like metaraminol, where this modification lowers beta activity and focuses vasoconstrictive effects.^[54] Ring substitutions on the phenyl moiety further modulate potency and receptor preference. The 3,4-dihydroxy (catechol) configuration is optimal for alpha receptor potency, as seen in norepinephrine, where it facilitates hydrogen bonding for high-affinity binding (EC50 ~ 0.1-1 μM at alpha-1), but it also confers broad alpha/beta activity.^[23]^[54] In contrast, replacing the catechol with a resorcinol (3,5-dihydroxy) ring in terbutaline improves beta-2 selectivity and potency, shifting EC50 for beta-2 activation to sub-nanomolar levels while reducing alpha affinity by over 100-fold.^[53] These SAR trends highlight how ortho/para hydroxyl positioning balances potency (e.g., 3,4-diOH yielding 10-50 fold higher alpha potency than mono-substituted analogs) against metabolic stability.^[23] To extend duration, alpha-carbon substitutions resist monoamine oxidase (MAO) degradation; the alpha-methyl group in metaraminol sterically blocks MAO access, prolonging the duration of action to 20-60 minutes compared to norepinephrine's ~2 minutes, due to resistance to MAO degradation and tissue storage, while preserving alpha-1 potency for pressor effects.^[55]^[56] This modification reduces overall agonist potency (e.g., EC50 ~0.06 μM at alpha-1A compared to norepinephrine's ~0.002 μM in some assays) but enhances oral bioavailability and sustained action.^[57]^[54] Quantitative structure-activity relationship (QSAR) analyses, including Hansch-type models, correlate lipophilicity (logP) with adrenergic activity, revealing parabolic dependencies where optimal logP values (~1.5-2.5) maximize potency by balancing membrane permeability and receptor binding. For alpha-adrenergic agonists, logP positively influences binding affinity (r > 0.9 in some datasets), with higher lipophilicity enhancing potency up to a cutoff beyond which solubility decreases activity.^[58] Recent advancements incorporate fluorinated substituents to refine beta-2 selectivity for asthma therapy. In conformationally restricted analogs, fluoroalkyl groups (e.g., 2-fluoroethyl) at the amine side chain boost beta-2 potency (EC50 ~0.3 nM for beta-arrestin recruitment) and selectivity (>1000-fold over beta-1), minimizing cardiac side effects while providing sustained bronchodilation.^[59] These modifications improve pharmacokinetic profiles, enabling once-daily dosing in asthma management.^[59]

Neurotransmitter Handling

Uptake Mechanisms

The norepinephrine transporter (NET), encoded by the SLC6A2 gene, is a plasma membrane protein that mediates the sodium- and chloride-dependent reuptake of norepinephrine from the synaptic cleft into presynaptic noradrenergic neurons, thereby terminating its postsynaptic signaling.^[60] This secondary active transport process relies on the sodium gradient established by the Na+/K+-ATPase, with a stoichiometry of approximately 1 norepinephrine : 1 Na+ : 1 Cl-, facilitating efficient clearance of extracellular catecholamines.^[61] Following reuptake into the neuronal cytoplasm, the vesicular monoamine transporter 2 (VMAT2) sequesters norepinephrine from the cytosol into synaptic vesicles through a proton antiport mechanism, exchanging intravesicular protons for cytosolic monoamines driven by the vesicular H+-ATPase-generated pH gradient.^[62] VMAT2, an integral membrane protein of the SLC18 family, ensures storage of norepinephrine in a protected form, preventing cytoplasmic degradation by monoamine oxidase.^[63] The kinetics of NET-mediated uptake follow Michaelis-Menten parameters, with a typical Km value for norepinephrine ranging from 0.1 to 1.6 μM, indicating moderate affinity that allows rapid response to synaptic norepinephrine fluctuations without saturation under physiological conditions.^[64] Inhibition of NET by tricyclic antidepressants, such as desipramine and nortriptyline, blocks reuptake and prolongs norepinephrine's synaptic availability, contributing to their therapeutic effects in mood disorders by enhancing noradrenergic transmission.^[65] These agents bind competitively to NET with high affinity (Ki values around 0.3-3 nM), mimicking the action of indirect adrenergic agonists that disrupt uptake to amplify signaling.^[66] Physiological regulation of norepinephrine uptake involves presynaptic alpha-2 adrenergic autoreceptors, which, upon activation by extracellular norepinephrine, suppress NET activity at resting sympathetic firing rates, providing negative feedback to fine-tune reuptake and prevent excessive depletion of synaptic transmitter.^[67]

Storage and Release Processes

In adrenergic neurons, catecholamines such as norepinephrine are synthesized in the neuronal cytosol and subsequently sequestered into synaptic vesicles by the vesicular monoamine transporter 2 (VMAT2), a proton antiporter that utilizes the acidic pH gradient across the vesicular membrane to actively concentrate these neurotransmitters up to 10,000-fold inside the vesicles.^[68]^[69] This vesicular storage, analogous to chromaffin granules in adrenal chromaffin cells, shields the catecholamines from enzymatic degradation by cytosolic monoamine oxidase (MAO), thereby preserving the neurotransmitter pool for regulated release and preventing the formation of toxic metabolites.^[70]^[71] The release of stored norepinephrine occurs through calcium-dependent exocytosis triggered by action potentials arriving at presynaptic terminals. Depolarization opens voltage-gated calcium channels, leading to a rapid influx of Ca²⁺ ions that bind to sensor proteins like synaptotagmin on the vesicular membrane, promoting SNARE complex-mediated fusion of vesicles with the plasma membrane and the quantal discharge of norepinephrine in discrete packets corresponding to individual vesicle contents.^[72]^[73] This quantal release ensures precise signaling at adrenergic synapses, with each quantum representing the coordinated efflux from a single vesicle.^[74] Regulation of norepinephrine release involves presynaptic autoreceptors that provide feedback control. Activation of α₂-adrenergic autoreceptors by released norepinephrine couples to Gᵢ/o proteins, inhibiting adenylyl cyclase and reducing cAMP levels, which in turn suppresses voltage-gated Ca²⁺ channel activity and vesicle priming to curtail further release and prevent synaptic overload.^[75] Conversely, presynaptic β-adrenergic receptors, activated by circulating epinephrine or local norepinephrine, couple to Gₛ proteins to stimulate adenylyl cyclase, elevating cAMP and enhancing release probability through phosphorylation of ion channels and fusion proteins.^[76]^[77] Chronic administration of indirect agonists, such as amphetamine, disrupts this storage-release cycle by reversing VMAT2 function, causing non-quantal leakage of catecholamines from vesicles into the cytosol where they are vulnerable to MAO degradation, ultimately leading to vesicular depletion and exhaustion of neuronal stores.^[78]^[79] Advances in 21st-century imaging techniques, including fast-scan cyclic voltammetry and genetically encoded fluorescent sensors, have elucidated the sub-millisecond dynamics of norepinephrine exocytosis, revealing spatiotemporal patterns of release at varicosities and its modulation by presynaptic regulators.^[80]^[81]

Clinical and Therapeutic Aspects

Therapeutic Indications

Adrenergic agonists are employed in the management of various cardiovascular conditions, particularly through alpha-1 receptor stimulation to address hypotension in scenarios such as septic or cardiogenic shock, where they help restore vascular tone and blood pressure.^[1] Beta-1 receptor agonists support cardiac function in heart failure and cardiogenic shock by enhancing myocardial contractility and output.^[1] Alpha-2 receptor agonists contribute to blood pressure control in hypertension, including gestational cases, by modulating sympathetic outflow.^[82] In respiratory disorders, beta-2 receptor agonists are indicated for bronchodilation in asthma and chronic obstructive pulmonary disease (COPD), alleviating airflow obstruction and improving lung function, as supported by meta-analyses confirming their efficacy in reducing exacerbations.^[1]^[83] Ophthalmic applications include the use of alpha-2 receptor agonists in glaucoma to reduce intraocular pressure by decreasing aqueous humor production and enhancing uveoscleral outflow, serving as monotherapy or adjunctive therapy.^[84]^[85] Other indications encompass the treatment of anaphylaxis with non-selective agonists to counteract severe allergic reactions through systemic effects on multiple receptors.^[1] Experimental applications of beta-3 receptor agonists target obesity by promoting thermogenesis and energy expenditure, though clinical translation remains limited.^[86] Epinephrine, a key non-selective adrenergic agonist, is included on the World Health Organization's Model List of Essential Medicines for managing anaphylaxis and cardiac emergencies, underscoring its foundational role.^[87] The clinical utility of adrenergic agonists traces back to the 1940s, when they were first integrated into shock treatments to stabilize hemodynamics during critical illnesses, evolving into evidence-based standards informed by subsequent meta-analyses contrasting their benefits with antagonists like beta-blockers in conditions such as heart failure.^[1]^[88]

Common Examples and Administration

Adrenergic agonists are classified by their receptor selectivity, with common examples spanning alpha, beta, and mixed subtypes, each administered via routes tailored to achieve localized or systemic effects. Phenylephrine, a selective alpha-1 agonist, is frequently used for hypotension and nasal congestion. For hypotensive states such as those occurring during anesthesia or septic shock, it is administered intravenously as a bolus of 50 to 100 mcg or via continuous infusion at 0.1 to 1.5 mcg/kg/min after appropriate dilution.^[22] Intranasally, phenylephrine (0.125% to 1% solution) provides vasoconstriction to relieve congestion, applied as 2 to 3 sprays per nostril every 4 hours, not exceeding 6 doses in 24 hours. Note that while intranasal phenylephrine remains effective, the U.S. Food and Drug Administration (FDA) proposed in November 2024 to remove oral phenylephrine from over-the-counter nasal decongestants due to lack of demonstrated efficacy.^[22]^[89]^[90] Beta agonists include short- and long-acting variants, with administration often prioritizing inhalation for respiratory conditions to minimize systemic exposure. Albuterol, a short-acting beta-2 selective agonist, is the cornerstone for acute asthma management, delivered via metered-dose inhaler with 2 inhalations (approximately 180 mcg) every 4 to 6 hours as needed for bronchospasm relief or prevention.^[91] For cardiogenic shock, dobutamine, a beta-1 predominant agonist, is given intravenously starting at 2.5 to 5 mcg/kg/min, titrated up to 20 mcg/kg/min to enhance cardiac output without excessive vasoconstriction.^[1] Mixed agonists like ephedrine combine alpha and beta effects, making them suitable for hypotension where both vasopressor and inotropic support are needed. It is administered intravenously as a 5 to 10 mg bolus for acute perioperative hypotension or intramuscularly at 25 to 50 mg for prolonged effect; oral dosing, such as 30 to 50 mg prophylactically, may also be used prior to procedures like spinal anesthesia.^[31]^[92] A contemporary beta-3 selective example is mirabegron, approved for overactive bladder symptoms including urgency and incontinence, taken orally at an initial 25 mg daily dose, which may be increased to 50 mg if tolerated, with or without food.^[93] Routes of administration vary by agonist subtype and therapeutic goal: inhalers and nebulizers deliver beta-2 agents like albuterol locally to the lungs for rapid bronchodilation, while intravenous infusions provide systemic control for alpha and mixed agents in critical settings like shock.^[94] Pharmacovigilance efforts have shaped usage, notably the FDA's 2000 request to withdraw phenylpropanolamine (PPA), a mixed alpha/beta agonist once common in decongestants and appetite suppressants, due to its association with increased risk of hemorrhagic stroke—a cardiovascular event—particularly in women using it for weight control.^[95]

Safety and Adverse Effects

Side Effects Profile

Adrenergic agonists elicit a range of predictable adverse reactions primarily due to their stimulation of specific receptor subtypes, with effects varying by selectivity and dosage. These side effects are often dose-dependent and more pronounced in vulnerable populations, such as the elderly or those with preexisting cardiac conditions, where heightened sensitivity to cardiovascular changes increases the risk of complications.^[1]^[96] Alpha-1 adrenergic agonists commonly cause hypertension through vasoconstriction of vascular smooth muscle, leading to elevated blood pressure and potential reflex bradycardia as a compensatory response.^[8] In topical applications, such as nasal decongestants, they may induce nasal dryness by reducing mucosal blood flow.^[8] These effects are particularly concerning in patients with congestive heart failure or renal impairment, where increased afterload and reduced perfusion can exacerbate underlying conditions.^[8] Beta-1 adrenergic agonists primarily affect the heart, resulting in tachycardia, palpitations, and arrhythmias due to enhanced myocardial contractility and rate.^[1] Tremors may also occur, reflecting central nervous system stimulation, though less prominently than with beta-2 agents.^[1] These cardiac effects are dose-dependent, with high doses (e.g., above 20 mcg/kg/min for dobutamine) posing risks of dangerous tachyarrhythmias, especially in elderly patients or those with preexisting arrhythmias.^[1] Beta-2 adrenergic agonists frequently lead to hypokalemia via intracellular potassium shifts and hyperglycemia through stimulation of hepatic glycogenolysis.^[1]^[97] Tremors are a common systemic effect, with clinical trials reporting incidences of 10-20% in users of inhaled beta-2 agonists like sibenadet or salmeterol.^[98] Earlier post-2010 meta-analyses highlighted potential increased risks of severe asthma events with long-acting beta-2 agonists, including a net excess of 6.3 events per 1000 patient-years overall, with higher rates in children and potential for asthma-related mortality when used without concomitant corticosteroids.^[99] However, subsequent large-scale studies, including a 2018 combined analysis of four trials involving over 30,000 patients, and FDA reviews, found no significant increase in serious asthma-related events with inhaled corticosteroid (ICS)/LABA combination therapy compared to ICS alone. As of 2025, the Global Initiative for Asthma (GINA) guidelines recommend ICS/LABA combinations, including single maintenance and reliever therapy (SMART), as safe and preferred options for moderate persistent asthma, while strongly contraindicating LABA monotherapy.^[100]^[101] These risks are amplified in cardiac patients, where beta-2 stimulation may precipitate myocardial infarction or heart failure exacerbation.^[96]

Toxicity and Management

Adrenergic agonists, depending on their receptor specificity, can produce distinct patterns of toxicity in overdose scenarios. Direct alpha-1 agonists, such as phenylephrine, primarily cause severe hypertension due to intense vasoconstriction, often accompanied by reflex bradycardia and potential cardiac arrhythmias.^[22] In contrast, beta agonists like albuterol lead to tachyarrhythmias, hypokalemia, hyperglycemia, and lactic acidosis from excessive stimulation of cardiac and metabolic pathways.^[102] Indirect-acting agonists, including amphetamines, induce a sympathomimetic toxidrome characterized by hypertension, tachycardia, hyperthermia, agitation, and seizures, with risks of rhabdomyolysis and serotonin syndrome in severe cases.^[103] Management of acute overdose emphasizes supportive care and targeted antagonists. For alpha-mediated hypertension, intravenous phentolamine (1-5 mg bolus, titrated) serves as a competitive alpha-blocker to reverse vasoconstriction, while benzodiazepines (e.g., lorazepam 1-2 mg IV) address central nervous system effects like agitation or seizures across all types.^[104] Beta-blockers, such as propranolol (0.5-1 mg IV, cautiously), may be used for beta-induced tachyarrhythmias but require monitoring to avoid unopposed alpha stimulation in mixed cases.^[105] Airway protection, cooling for hyperthermia, and electrolyte correction are essential; activated charcoal aids decontamination if ingestion occurred within 1-2 hours.^[103] Withdrawal from chronic adrenergic agonist use can precipitate rebound effects. For alpha-1 agonists like midodrine used in orthostatic hypotension, abrupt discontinuation may lead to worsening hypotension due to sudden loss of vascular tone, managed with gradual tapering and supportive measures such as fluids.^[106] This contrasts with the rebound hypertension commonly seen upon withdrawal from alpha-2 agonists like clonidine.^[107] Prolonged exposure to adrenergic agonists contributes to chronic toxicity through cardiovascular remodeling, where sustained beta stimulation activates protein kinase A and CaMKII, promoting cardiomyocyte apoptosis, hypertrophy, and fibrosis.^[108] This leads to progressive heart failure, as evidenced in models of isoproterenol infusion mimicking chronic sympathetic overdrive.^[109] Recent toxicology data from the 2020s highlight emerging risks from designer stimulants like synthetic cathinones, which act as indirect adrenergic agonists by enhancing catecholamine release. These compounds frequently cause seizures (up to 5.5% in adolescent exposures) and sympathomimetic toxidrome, often compounded by co-ingestions, necessitating enhanced surveillance and benzodiazepine protocols in pediatric and adult cases.^[110]

References

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Adrenergic Drugs - StatPearls - NCBI Bookshelf
Adrenergic drugs are a broad class of medications that bind to adrenergic receptors throughout the body.
[2]
Adrenergic Agonists | Basic Concepts in Pharmacology
In other words, these compounds mimic the effects of norepinephrine or epinephrine. These drugs are sometimes referred to as adrenomimetics or sympathomimetics.Missing: definition | Show results with:definition
[3]
How Do Adrenergic Agonists Work? - Uses, Side Effects, Drug Names
May 5, 2021 · Adrenergic agonists are drugs that work by mimicking the functioning of the sympathetic nervous system—the part of the nervous system that ...
[4]
A STUDY OF THE ADRENOTROPIC RECEPTORS
Alpha- and beta-adrenergic receptors: Ahlquist's landmark hypothesis of a single mediator with two receptors ... Adrenergic Receptors: Classification ...
[5]
Adrenoceptors | Introduction
Adrenoceptors (AR) are a group of nine 7-transmembrane receptors comprising 3 main types, α1, α2 and β, each with 3 subtypes that mediate the central and ...
[6]
Biochemistry, G Protein Coupled Receptors - StatPearls - NCBI - NIH
G proteins have three subunits (α,β, and γ). ... GPCRs are widely expressed in human cells and tissues and cross-talk with other signaling pathways, such as ...
[7]
α1-Adrenergic Receptor Subtypes | Circulation Research
α 1 ARs are activated by the catecholamines, norepinephrine and epinephrine. They are intrinsic membrane glycoproteins and are members of the GPCR superfamily.
[8]
Alpha-1 Receptor Agonists - StatPearls - NCBI Bookshelf - NIH
Jun 5, 2023 · Adrenergic receptors are G-protein-coupled receptors (GPCR) that play a central role in the sympathetic nervous system. The alpha-1 ...
[9]
https://pubmed.ncbi.nlm.nih.gov/11454900/
[10]
Physiology, Catecholamines - StatPearls - NCBI Bookshelf - NIH
Dec 11, 2024 · α-adrenergic receptors include α1- and α2-adrenergic receptors. These receptors are GPCRs that work with different types of G proteins. α1- ...
[11]
Structural insights into ligand recognition, activation, and signaling ...
Mar 4, 2022 · The α2A adrenergic receptor (α2AAR) is a G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor that mediates important ...
[12]
Beta 1 Receptors - StatPearls - NCBI Bookshelf - NIH
Beta-1 receptors, along with beta-2, alpha-1, and alpha-2 receptors, are adrenergic receptors primarily responsible for signaling in the sympathetic nervousIntroduction · Issues of Concern · Clinical Significance · Other Issues
[13]
Beta2 Receptor Agonists and Antagonists - StatPearls - NCBI - NIH
Beta-adrenergic receptors are transmembrane glycoprotein structures that elicit a response inside the cell when interacting with catecholamines. They belong to ...
[14]
Targeting β3-Adrenergic Receptors in the Heart: Selective Agonism ...
Of note, after the Gi signaling pathway activation, the β3AR is able to give rise to NO through both eNOS and neuronal NOS (nNOS) located on the sarcoplasmic ...<|control11|><|separator|>
[15]
GPCR Signaling Regulation: The Role of GRKs and Arrestins - NIH
Feb 19, 2019 · Here we focus on the mechanisms of GRK- and arrestin-mediated regulation of GPCR signaling, which includes homologous desensitization and redirection of ...
[16]
https://doi.org/10.1126/science.283.5402.655
[17]
Beta-2 Adrenergic Agonists - LiverTox - NCBI Bookshelf - NIH
Sep 11, 2017 · Direct agonists directly interact with the adrenergic receptors, whereas indirect agonists typically stimulate the release of endogenous ...Missing: definition | Show results with:definition
[18]
Adrenaline/Epinephrine Hunters: Past, Present, and Future at 1900
In August 5, 1900 the Japanese industrial chemist Takamine and his young associate Uenaka settled in New York, succeeded to crystallize the adrenal extract by a ...
[19]
Epinephrine analogues - PubMed
Tyramine was the first epinephrine analogue to be introduced into medicine, in the early 1900s. It was followed by ephedrine and pseudoephedrine in the 1920s.
[20]
Agonist binding by the β2-adrenergic receptor - PubMed Central - NIH
The orthosteric binding site of β2-AR, which is the site of action of endogenous catecholamines, is highly conserved (Ring et al. 2013; Swaminath et al. 2005).
[21]
Distinct binding conformations of epinephrine with α- and β ... - Nature
Sep 2, 2024 · Agonists targeting α2-adrenergic receptors (ARs) are used to treat diverse conditions, including hypertension, ...
[22]
Phenylephrine - StatPearls - NCBI Bookshelf - NIH
Oct 30, 2023 · Phenylephrine primarily acts as an alpha-1 adrenergic receptor agonist and exhibits minimal to no beta-adrenergic activity.Continuing Education Activity · Indications · Mechanism of Action · Adverse Effects
[23]
Structure Activity Relationship - Adrenergic Drugs - Pharmacy 180
STRUCTURAL-ACTIVITY RELATIONSHIP. Many of the sympathomimetic drugs contain β-phenyl ethylamine as parent structure.
[24]
Isoproterenol - StatPearls - NCBI Bookshelf
Isoproterenol is a beta-1 and beta-2 adrenergic receptor agonist resulting in the following: Increased heart rate. Increased heart contractility. Relaxation of ...
[25]
Pharmacology of Drugs Used as Stimulants - Wiley Online Library
Aug 15, 2021 · Amphetamine causes release of amounts of NE unrelated to nerve activity, whereas cocaine acts not to release neurotransmitter, but to prevent ...
[26]
Amphetamine redistributes dopamine from synaptic vesicles to the ...
May 1, 1995 · These experiments indicate that amphetamine acts at the vesicular level where it redistributes dopamine to the cytosol, promoting reverse ...
[27]
VMAT2 knockout mice: Heterozygotes display reduced ... - PNAS
Amphetamines dissipate proton gradients across the membranes of synaptic vesicles, disrupt VMAT2 function, enhance cytoplasmic monoamine concentrations, and ...Vmat2 Knockout Mice... · Materials And Methods · Results And Discussion
[28]
Cocaine Acts as an Apparent Competitive Inhibitor at the Outward ...
Dec 15, 1998 · The norepinephrine transporter (NET) mediates uptake of synaptic norepinephrine (NE) into NE neurons. It also transports structurally similar ...
[29]
interactions of sympathomimetic drugs and
The adrenergic nerve blocking drug bretylium inhibits the nicotinic action of acetylcholine but potentiates the action of tyramine (Hukovic, 1960). However ...Missing: research | Show results with:research
[30]
Tachyphylaxis to the stimulant actions of the indirectly acting ...
2. Following four 2 min exposures to a given dose of tyramine, phenylethylamine, or d-amphetamine, the response had decreased by 65–75%. The ...
[31]
Ephedrine - StatPearls - NCBI Bookshelf - NIH
Mechanism of Action Absorption: Oral ephedrine attains peak plasma concentration at 1.8 hours and has a bioavailability of 88%. Metabolism: Ephedrine is ...Missing: mixed | Show results with:mixed
[32]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092956/
[33]
Ephedrine | C10H15NO | CID 9294 - PubChem - NIH
The mechanism of action of ephedrine is as an Adrenergic alpha-Agonist, and Adrenergic beta-Agonist. The physiologic effect of ephedrine is by means of ...
[34]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173670/
[35]
Hemodynamic impact of ephedrine on hypotension during general ...
Aug 22, 2023 · Ephedrine is a mixed α- and β-agonist vasopressor that is frequently used for the correction of hypotension during general anesthesia.
[36]
Effect of infused L-threo-3,4-dihydroxyphenylserine on adrenergic ...
L-threo-3,4-dihydroxyphenylserine (DOPS), an immediate precursor amino acid of (-)-norepinephrine, was used as a pharmacological tool to investigate the ...
[37]
Levodopa (L-Dopa) - StatPearls - NCBI Bookshelf - NIH
Apr 17, 2023 · Levodopa is the precursor to dopamine. Most commonly, clinicians use levodopa as a dopamine replacement agent for the treatment of Parkinson disease.
[38]
Timeline of History of Hypertension Treatment - PMC
Introduction of thiazide diuretics in late 50s made some headway in successful treatment of hypertension and ambitious multicenter VA co-operative study (phase ...
[39]
Methyldopa - StatPearls - NCBI Bookshelf
Alpha-methyldopa is converted to methyl norepinephrine centrally to decrease the adrenergic outflow by alpha-2 agonistic action from the central nervous system, ...
[40]
New centrally acting antihypertensive drugs related to methyldopa ...
SUMMARY It has been well established that the antihypertensive drugs clonidine and methyldopa lower blood pressure by acting on postsynaptic a2-adrenergic ...
[41]
Prospects for Droxidopa in Neurogenic Orthostatic Hypotension - PMC
Droxidopa, a synthetic precursor of norepinephrine, was approved for the treatment of nOH; however, the efficacy of the drug in long-term trials was unclear.
[42]
Dipivefrin: current concepts - PubMed - NIH
Dipivefrin (dipivalyl epinephrine or DPE) is an epinephrine pro-drug produced by the addition of two pivalic acid groups to the parent compound. This ...
[43]
Adrenergic Drugs - Chemistry LibreTexts
Jul 4, 2022 · The three main catacholamines (chatecol is ortho-dihydroxybenzene) are epinephrine EP, norepinephrine NE, and dopamine DA. A host of ...
[44]
Structure-Function of α1-Adrenergic Receptors - PubMed Central - NIH
Through chemical modifications of the catecholamine core structure, the need was established for a protonated amine, a β-hydroxyl on a chiral center, and an ...
[45]
Cryo-EM structure of the β3-adrenergic receptor reveals the ...
Aug 5, 2021 · β3AR agonists have the basic pharmacophore 2-amino-1-phenylethanol, but with variations that affect their selectivity, as in other selective ...
[46]
Pharmacophore-guided Virtual Screening to Identify New β 3 ...
Dec 28, 2021 · This moiety is derived from the catecholamine structure of both the endogenous agonists adrenaline (epinephrine) and noradrenaline ( ...
[47]
Albuterol: Uses, Interactions, Mechanism of Action | DrugBank Online
It is 29 times more selective for beta2 receptors than beta1 receptors giving it higher specificity for pulmonary beta receptors versus beta1-adrenergic ...
[48]
Conformation Guides Molecular Efficacy in Docking Screens of ...
Mar 13, 2013 · A prospective, large library virtual screen against an activated β2-adrenergic receptor (β2AR) structure returned potent agonists to the exclusion of inverse- ...Figure 2 · Figure 3 · Figure 4
[49]
The Discovery of Novel α2a Adrenergic Receptor Agonists Only ...
Jun 30, 2024 · To obtain novel and potent α 2A -AR agonists, we performed virtual screening for human α 2A -AR and α 2B -AR to find α 2A -AR agonists with higher selectivity.
[50]
SAR of Sympathomimetic Agents: Direct Acting: Dobutamine ...
The butyl group of higher education in salbutamol (or albuterol) makes you more selective in β -₂ receptors. • The drug is marketed as a racemic compound mainly ...
[51]
(PDF) DRUGS ACTING ON AUTONOMIC NERVOUS SYSTEM
May 21, 2023 · Substitution of alkyl groups (methyl or ethyl) at alpha carbon, decreases the metabolism by MAO. And produces longer duration of action ...<|separator|>
[52]
Metaraminol • LITFL • CCC
Jul 18, 2025 · Methyl group substituent on the alpha carbon of the ethylamine side chain: relative resistance to MAO metabolism, resulting in a longer ...
[53]
6: Adrenergic Agonists - Pocket Dentistry
Jan 5, 2015 · Adrenergic agents are also referred to as sympathomimetic drugs because they mimic the effects caused by stimulation of the sympathetic nervous ...
[54]
QSPR analysis of some agonists and antagonists of α-adrenergic ...
Chromatographic and lipophilicity data. The values of the logarithm of partition coefficient, log P, were derived from the paper by Timmermans et al. (1984), ...Missing: Hansch | Show results with:Hansch
[55]
WO2019112913A1 - Beta-2 selective adrenergic receptor agonists
The subject beta-2 selective adrenergic receptor agonist compounds may serve as bronchiodilators and find use in the treatment of a variety of ...<|control11|><|separator|>
[56]
Entry - *163970 - SOLUTE CARRIER FAMILY 6 ... - OMIM
The SLC6A2 gene encodes a norepinephrine (noradrenaline) transporter, which is responsible for reuptake of norepinephrine into presynaptic nerve terminals.
[57]
Norepinephrine Transporter - an overview | ScienceDirect Topics
The norepinephrine transporter (NET) is defined as a sodium-dependent transporter that terminates the action of norepinephrine by reuptaking it into ...Introduction to Norepinephrine... · Molecular Structure...
[58]
The ins and outs of vesicular monoamine transporters - PMC
Yaffe et al. review structure-guided studies that have provided insight into the mechanism of proton-monoamine antiport by VMATs.
[59]
Transport and inhibition mechanism for VMAT2-mediated synaptic ...
Jan 2, 2024 · Powered by the cytosol-directed proton gradient, VMAT2 opens its cytosolic gate (state 1) and prepares for monoamine entry (state 2). Substrate ...
[60]
Human norepinephrine transporter kinetics using rotating ... - PubMed
The initial rate of norepinephrine uptake was saturable, with Vmax and KM of 197 +/- 17 amol min-1 cell-1 and 1.64 +/- 0.46 microM, respectively. The RDE ...
[61]
Norepinephrine transporter inhibitors and their therapeutic potential
The NET thus serves as the primary mechanism for the inactivation of noradrenergic signaling. Some potent and selective or mixed NET inhibitors (e.g., ...
[62]
Tricyclic Antidepressants: Evidence for an Intraneuronal Site of Action
Desipramine, a tricyclic antidepressant drug, almost completely prevents the accumulation of tritiated norepinephrine by sympathetic neurons of the rat ...
[63]
Storage and Release of Catecholamines - Basic Neurochemistry
The expressed protein, referred to as vesicular membrane transporter 2 (VMAT2), has a high affinity for reserpine, which blocks vesicular uptake in vivo [10].
[64]
Vesicular Monoamine Transporters: Structure-Function ...
Vesicular monoamine transporters (VMAT) are responsible for the uptake of cytosolic monoamines into synaptic vesicles in monoaminergic neurons.Missing: MAO | Show results with:MAO
[65]
Vesicular Transport Regulates Monoamine Storage and Release ...
Exposure to 10 mM D-amphetamine for 30 min induces dopamine release from the midbrain cultures of VMAT22/2 mice (Figure 7A), indicating that VMAT2 is not ...
[66]
Intricacies of the Molecular Machinery of Catecholamine ...
After synthesis, dopamine and epinephrine are actively transported from the cytosol into chromaffin storage vesicles by vesicular monoamine transporters (VMAT1 ...Missing: MAO | Show results with:MAO
[67]
Mechanisms of Neurotransmitter Release (Section 1, Chapter 5 ...
An action potential in the presynaptic cell produces an influx of Ca2+which promotes the exocytosis of synaptic vesicles from the presynaptic terminal.Missing: norepinephrine adrenergic
[68]
Exocytosis of norepinephrine at axon varicosities and neuronal cell ...
Apr 3, 2007 · Norepinephrine secretion from central neurons was widely assumed to occur by exocytosis, but the essential characteristics of this process ...<|separator|>
[69]
Diverse Effects of Noradrenaline and Adrenaline on the Quantal ...
Dec 15, 2019 · Quantal release became more asynchronous under noradrenaline, as evidenced by a greater dispersion of real synaptic delays; in contrast ...
[70]
Physiology, Noradrenergic Synapse - StatPearls - NCBI Bookshelf
Presynaptic noradrenergic terminals contain alpha-2 autoreceptors which prevent further release of norepinephrine.
[71]
Presynaptic enhancement of excitatory synaptic transmission by ...
These results suggest that activation of presynaptic beta-adrenergic receptors enhances synaptic transmission in area CA1 via activation of cAMP-dependent ...
[72]
Norepinephrine: A Neuromodulator That Boosts the Function of ...
NE, through β-adrenergic receptor activation, facilitates transmission of action potential trains by suppressing Ca2+ activated K+ channels (SK) and its after- ...
[73]
Regulation of the Dopamine and Vesicular Monoamine Transporters
Methamphetamine, Methylphenidate, and Dopaminergic Agonists. AMPH and related amphetamines disrupt VMAT2 transport of DA into synaptic vesicles through at least ...Missing: exhaustion | Show results with:exhaustion
[74]
[PDF] AMPHETAMINE-INDUCED DOPAMINERGIC TOXICITY - RUcore
Long-term dopaminergic depletion has been observed in monkeys, guinea pigs, rats, and mice following repeated amphetamine exposure. Depletions have been.<|separator|>
[75]
Designing a norepinephrine optical tracer for imaging individual ...
Jul 19, 2018 · Cell-based reporters reveal in vivo dynamics of dopamine and norepinephrine release ... Amphetamine paradoxically augments exocytotic dopamine ...
[76]
Quantifying neurotransmitter secretion at single-vesicle resolution ...
Jan 18, 2021 · Using amperometry, the sub-millisecond dynamics of exocytosis can be monitored and the modulation of exocytosis due to drug treatment or ...
[77]
Alpha-2 Adrenergic Receptor Agonists: A Review of Current Clinical ...
The α-2 adrenergic receptor agonists have been used for decades to treat common medical conditions such as hypertension; attention-deficit/hyperactivity ...
[78]
Beta-2 adrenergic agonists: Focus on safety and benefits versus risks
Multiple prospective clinical trials and meta-analyses have demonstrated that the combination of a LABA and an ICS confers proven clinical benefits which appear ...
[79]
Glaucoma: Medications - American Academy of Ophthalmology
Nov 6, 2015 · More commonly used glaucoma drugs in this class are the selective alpha‑2 agonists, which reduce IOP by suppressing aqueous production and ...
[80]
Update on the role of alpha-agonists in glaucoma management
Alpha-adrenergic receptor agonists are used either as monotherapy, as second-line therapy, or in fixed combination with beta-blockers.
[81]
Beta 3-adrenoceptor agonists as anti-diabetic and anti-obesity drugs ...
Beta(3)-AR agonists directed at the human receptor are showing promising results in their ability to increase energy expenditure in humans following a single ...
[82]
Epinephrine - eEML - Electronic Essential Medicines List
It has multiple therapeutic uses including management of severe allergic reactions (anaphylaxis), and management of life-threatening emergencies such as cardiac ...
[83]
https://mayoclinic.elsevierpure.com/en/publications/beta-2-adrenergic-agonists-focus-on-safety-and-benefits-versus-ri
[84]
EQUATE NASAL- phenylephrine hydrochloride spray - DailyMed - NIH
adults and children 12 years and over: 2 or 3 sprays in each nostril not more often than every 4 hours - • children under 12 years: ask a doctor - • Use ...<|separator|>
[85]
[PDF] PROAIR HFA (albuterol sulfate) INHALATION AEROSOL
For oral inhalation only. • Treatment or prevention of bronchospasm in adults and children 4 years of age and older: 2 inhalations every 4 to 6 hours.
[86]
[PDF] EMERPHED (ephedrine - accessdata.fda.gov
The recommended dosages for the treatment of clinically important hypotension in the setting of anesthesia is an initial dose of 5 mg to 10 mg administered by ...
[87]
Mirabegron - StatPearls - NCBI Bookshelf
Aug 28, 2023 · Mirabegron is used to treat urgency, urge urinary incontinence, and increased urinary frequency found in the overactive bladder.
[88]
Beta2-Agonists - StatPearls - NCBI Bookshelf - NIH
Beta-2 adrenergic receptor agonists are a class of medications used in the frontline management and treatment of bronchial asthma and COPD.
[89]
Phenylpropanolamine (PPA) Information Page - FDA
Although the risk of hemorrhagic stroke is very low, FDA recommends that consumers not use any products that contain PPA. FDA's Nonprescription Drugs Advisory ...Missing: cardiovascular | Show results with:cardiovascular
[90]
Cardiovascular safety of beta(2)-adrenoceptor agonist use in ...
Results: Case-control studies have shown that beta(2)-adrenoceptor agonist use is associated with an increased risk of myocardial infarction, congestive heart ...
[91]
[PDF] 208294Orig1s000 - accessdata.fda.gov
Apr 25, 2016 · Beta2-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential ...<|separator|>
[92]
Long-term Use of Viozan (Sibenadet HCl) in Patients With Chronic ...
Sibenadet therapy was generally well tolerated, with the only notable differences seen in the incidence of tremor and taste of treatment (16.9% vs. 4.1% and 14 ...
[93]
Age and Risks of FDA-Approved Long-Acting β 2 - AAP Publications
Nov 1, 2011 · The first trial involved 25 180 persons older than 12 years (6.4% adolescents) and found a threefold increase in the asthma mortality rate with ...
[94]
Albuterol - StatPearls - NCBI Bookshelf
Jan 10, 2024 · A recommended dosage for tablet and syrup formulations is 2 to 4 mg every 6 to 8 hours, with caution not to exceed 32 mg in a day. The extended- ...Continuing Education Activity · Indications · Administration · Adverse Effects
[95]
Amphetamine Toxicity - StatPearls - NCBI Bookshelf - NIH
May 6, 2024 · Symptoms of amphetamine toxicity span a spectrum, encompassing tachycardia, hypertension, impulsivity, aggression, serotonin syndrome, psychosis, and seizures.
[96]
PHENYLEPHRINE | Poisoning & Drug Overdose, 7e - AccessMedicine
If extravasation occurs, immediately infiltrate the affected area with phentolamine, 5–10 mg in 10–15 mL of normal saline (children: 0.1-0.2 mg/kg; maximum, 10 ...
[97]
Propranolol treatment of albuterol poisoning in two asthmatic patients
Both were treated successfully with IV propranolol. Neither patient developed bronchospasm. The toxicity of albuterol overdoses and its treatment are discussed.Missing: management | Show results with:management
[98]
Withdrawal reactions following cessation of central alpha-adrenergic ...
SUMMARY Interruption of long-term treatment with a2-adrenergic receptor agonists may be associated with reversal of their hemodynamic effects, clinical and ...
[99]
Clonidine withdrawal. Mechanism and frequency of rebound ...
After sudden cessation of clonidine (900 microgram daily) almost all of the patients showed an excessive increase of the heart rate and blood pressure.
[100]
Cardiotoxic and Cardioprotective Features of Chronic β-adrenergic ...
Persistently activated β-adrenergic system induces chronic loss of contractile heart cells (cardiomyocytes) via apoptosis. PKA, CaMKII and EPAC are activated ...
[101]
Chronic β-Adrenergic Stimulation Induces Myocardial ...
Chronic activation of the adrenergic nervous system (ANS) in heart failure (HF) results in detrimental myocardial effects, including cardiac myocyte injury and ...
[102]
Clinical and Public Health Challenge of Handling Synthetic ...
Feb 8, 2025 · Results: Five studies demonstrate that synthetic cathinones frequently cause seizures, sympathomimetic toxidrome (tachycardia, hypertension), ...Missing: 2020s | Show results with:2020s