Adrenergic System direct acting agonists 2023.pdf

Adrenergic System DIRECT ACTING AGONISTS José O. Colón Sáez, PhD. FARM-7225 OBJECTIVES • Learn the steps involved in adrenergic neurotransmission. • Know the organ sympathomimetics receptors involved. effects of and the • Understand for Direct sympathomimetics the: ✓ Mechanism of action ✓...

Adrenergic System DIRECT ACTING AGONISTS José O. Colón Sáez, PhD. FARM-7225 OBJECTIVES • Learn the steps involved in adrenergic neurotransmission. • Know the organ sympathomimetics receptors involved. effects of and the • Understand for Direct sympathomimetics the: ✓ Mechanism of action ✓ Pharmacodynamics ✓ Therapeutic ✓ Pharmacokinetics ✓ Adverse applications effects ADRENERGIC AGONISTS Sympathomimetics mimic the action of activation of the sympathetic ANS. noafectani sintesisniliberacion WE pendiendodelas enzimaspresentesseraietneurotransmisorproducido 6090 dela ne es recicada ADRENERGIC NEUROTRANSMISSION • Tyrosine Hydroxylase ✓ Tyrosine → DOPA Neurotransmission in adrenergic neurons involves six sequential steps: • Decarboxylase ✓ DOPA → Dopamine • Transported into vesicles (VMAT). • Dopamine hydroxylase ✓Dopamine → NE • Adrenergic Receptors • COMT and MAO • Reuptake (NET) Rate Limiting Step SYMPATHOMIMETIC DRUGS • Direct-acting sympathomimetic drugs act directly on one or more of the adrenergic receptors. • Indirect-acting drugs ↑ the availability of NE or Epi to stimulate adrenergic receptors. 1. Releasing or displacing NE from sympathetic terminals. 2. By blocking the transport of NE into sympathetic neurons. 3. By blocking the metabolizing enzymes, monoamine oxidase (MAO) or catechol-O- methyltransferase (COMT). • Mixed acting sympathomimetic drugs indirectly release NE and directly activate receptors. Cardiovascular System (b1): responsable r en elritmocardiaco ✓Positive chronotropic effect. ✓Positive inotropic effect. Vascular Smooth Muscle (a1 & b2): ✓Vasoconstriction. ✓Vasodilation. Respiratory Tract (b2): ✓Bronchodilation. Urinary Tract (a1 & b3): ✓Relaxes bladder ✓Constrict sphincter vejiga la relaja GI Tract (a1 & b2): ✓↓ GI motility ✓Constrict sphincter Glands (M3): ✓Stimulates secretion (sweat glands). Kidney (b1): ✓↑ renin secretion Adipocytes (b3): ✓↑ lipolysis. ACTIONS OF SYMPATHOMIMETICS 1. Excitatory action on: ✓ Certain • Blood vessels supplying skin, kidney, and mucous membranes. ✓ Gland cells (sweat glands). ✓ Cardiac • 2. types of smooth muscle muscle. ↑ heart rate and force of contraction. Inhibitory action on: ✓ Certain • types of smooth muscle. Wall of the gut, the bronchial tree and in blood vessels supplying skeletal muscle. ACTIONS OF SYMPATHOMIMETICS 3. Metabolic actions: rate of glycogenolysis (↑ glucagon release) in liver and muscle and liberation of free fatty acids from adipose tissue (lipolysis). ✓↑ ✓ ↓ Secretion 4. of insulin, ↑ renin and pituitary hormones. CNS: ✓ Respiratory stimulation. ✓↑ Wakefulness and psychomotor activity. ✓↓ Appetite. ALPHA 1 AND 2 RECEPTORS: α-adrenoceptors: weak response to the synthetic agonist isoproterenol; responsive to the naturally occurring catecholamines. Epinephrine ≥ Norepinephrine >> Isoproterenol • α1 (Gq) ✓Vascular s.muscle: Vasoconstriction ✓GI and bladder sphincters: Constriction • α2 (Gi)(Auto-/hetero-receptor) ✓Presynaptic: Suppression of release of norepinephrine by negative feedback. ✓Inhibition of insulin. BETA RECEPTORS: b-adrenoreceptors: Strong response to isoproterenol, less sensitive to Epi and NE. Isoproterenol > Epinephrine > Norepinephrine • b1: ✓ Heart: ↑ heart rate and force of contraction. ✓ Kidney: ↑ renin secretion. • b2: ✓ smooth muscle • Vasodilation. • Bronchodilation. ✓ Induction • b3: of glucagon. Vascular smooth muscle ✓ Adipocytes: Lypolisis. ✓ Bladder: relaxation. CATECHOLAMINES • Sympathomimetic amines that contain the 3,4-dihydroxybenzene group: (epinephrine, norepinephrine, isoproterenol, and dopamine) are called catecholamines. • Catecholamine share the following properties: ✓High potency. ✓Rapid inactivation. Catechol ✓Poor CNS penetration. • Compounds lacking the catechol hydroxyl groups have longer half-lives, because they are not inactivated by COMT. PHYSIOLOGIC AND PHARMACOLOGIC EFFECTS: Endogenous Cathecholamines • Endogenous catecholamines: Dopamine, Epinephrine and Norepinephrine. ✓Agonists at both a- and b -adrenoceptors. • The overall effect of each catecholamine is complex and depends on: ✓The concentration of the agent on tissue. ✓Density and proportion of a- and b-adrenoceptors. ✓Reflex homeostatic adjustments of the organism. • Catecholamines have a brief duration of action, because they are rapidly inactivated in the intestinal mucosa and in the liver before reaching the systemic circulation. PHYSIOLOGIC AND PHARMACOLOGIC EFFECTS: Endogenous Cathecholamines pseconsideraquenotieneafinid port α receptors: Epinephrine ≥ Norepinephrine >> Isoproterenol β receptors: Isoproterenol > Epinephrine > Norepinephrine. seactivaetectobaroreceptor yaritmocardiaco mayormente • The s.muscle of blood vessels that supply skeletal muscles has both b2 and a1 receptors. ✓b2 causes vasodilation ✓a1 causes vasoconstriction vasoconstrican activate fan've's's nonayafinidad aporioannonay vasoconstriction ag • The threshold concentration for activation of b2 receptors by epinephrine is lower than that for α1 receptors. ✓ Physiological concentrations of Epi cause vasodilation. Final response depends on the: concentration of the drug, proportion of a and b receptors and homeostatic reflex. EPINEPHRINE Epinephrine is synthesized in the adrenal medulla and released, along with small quantities of norepinephrine, into the bloodstream. • Agonist at both α- and β-adrenoceptors (all). ✓Low concentrations (SC or slow IV infusion); predominantly β1 and β2. ✓High concentration; α1 > β2. efectovasopresor • One of the most potent vasopressor drugs known. • Very potent vasoconstrictor and cardiac stimulant. ✓↓ Cardiac efficiency (work done relative to O2 consumption). EPINEPHRINE ADME • Not effective orally. ✓Liver is rich in both COMT and MAO. • Absorption from subcutaneous tissues occurs slowly. ✓Local vasoconstriction. • Absorption is more rapid after intramuscular injection. tienecomo asiad rdem ✓Emergencies, it may be necessary to administer IV.riesgo la ototae vasoconstriction corpora • When nebulized and inhaled, the actions of the drug largely are restricted to the respiratory tract. EPINEPHRINE ACTIONS • Cardiovascular: ✓+ inotropic (b1). ✓+ chronotropic (b1). ✓↑ cardiac oxygen consumption. • Respiratory: powerful bronchodilation ✓Direct action on bronchial s.muscle (b2). • Metabolic Processes: ✓Hyperglycemia: • ↑ glycogenolysis (b2; liver and muscle). • ↑ release of glucagon (b2). • ↓ release of insulin (α2). ✓Lipolysis: initiates lipolysis (b3). EPINEPHRINE ACTIONS • Eye: Mydriasis (a1) ✓Lowers intraocular pressure. • ↓ production of aqueous humor (vasoconstriction). • Skeletal muscle: ↓ plasma K+. ✓↑ K+ uptake into skeletal muscle (b2). • GI: s.muscle is relaxed by epinephrine (↓motility); constrict sphincter. • Bladder: relaxes the detrusor muscle of the bladder (b3) and constrict the sphincter muscles (α1). EPINEPHRINE Therapeutic Applications: • Cardiac arrest: hypotensive emergency. • Anaphylactic shock: Drug of choice to reverse serious hypersensitivity reactions. ✓IM- (EpiPen® Auvi-Q™). • Bronchospasms: Acute asthmatic attack and anaphylaxis. • Anesthetics: anesthesia. ↑ duration of local ✓Vasoconstriction ↓ systemic absorption of local anesthetics and ↑ duration of action. EPINEPHRINE Therapeutic Applications: • Glaucoma: In ophthalmology, may be used topically to ↓ intraocular pressure in open-angle glaucoma. • Hyperkalemia: a common complication during massive blood transfusion and in trauma patients. ✓ Cause a fall in plasma K+, largely due to stimulation of K+ uptake into skeletal muscle (b2). EPINEPHRINE Adverse Effects: • Large doses or rapid IV injection may result in: vasoconstriccion grande provoca ✓ Cerebral pressure). hemorrhage (sharp rise in blood ✓ Ventricular ✓ Angina arrhythmias. (patients with coronary artery disease). • Contraindicated in patients who are receiving non-selective b-blockers. ✓Unopposed actions on vascular α1 receptors may lead to severe hypertension and cerebral hemorrhage. NOREPINEPHRINE α receptors: Epi ≥ NE >> Iso β receptors: Iso > Epi ≥ NE • Agonist at α1 and β1; little effect at β2. ✓ Systemic administration ↑ blood pressure (α1). • Blood vessels of skeletal muscle constrict rather than dilate. ✓ In most cases heart rate is decreased. • ↑ HR is overcome by reflex vagal activity in response to ↑BP. • Can cause severe hypertension. unadosisseverevasodilatation aning delvasosanguine ✓ Unlike epinephrine, small doses of NE do not cause vasodilation or lower blood pressure (Careful monitoring). ✓ ↓blood flow to organs such as kidney and intestines. NOREPINEPHRINE • Can cause necrosis at the site of injection. ✓Impaired circulation. ✓Relieved by infiltrating the area with phentolamine. a a receptores antagonist revertirefectos seatlirapara • Metabolic effects like epinephrine. ✓Observed only when large doses are given because NE is not as effective a "hormone" as epinephrine. • Therapeutic use: NE emergency treatment of replacement. bitartrate (Levophed) shock, after volume ✓IV in hypotensive crisis and cardiac arrest. noviewer NOREPINEPHRINE Droxidopa: pro-drug; converted to NE by DOPA-decarboxylase. • FDA-approved for the treatment of orthostatic hypotension (neurogenic or autonomic dysfunction). ✓Cross the BBB (AA transporter). DOPAMINE precursorcatecolaminas Activates D1-D5 Dopamine receptors and α- and β-adrenergic receptors. • Prominent CNS neurotransmitter; systemic administration has few CNS effects because it does not readily cross the blood–brain barrier. • Substrate for both MAO & COMT; ineffective orally. • Activates one or more subtypes of catecholamine receptor in peripheral tissues, and the predominant effect is dependent on the local concentration of the compound. DOPAMINE a a vasocons provoca envasossanguineous hay Ydisminugeproduction ovina a a aumenta vasodilatationperiferal aproductionorina estimulacioncardiaco a 50 3 receptores dopaminergicos provoca DOPAMINE EFFECTS Effects of Dopamine are dose dependent. • Low-dose: Acts on D1 dopaminergic receptors. niveloptimo ✓Vasodilation of renal, mesenteric, and coronary vasculature. • ↑ renal blood flow and urine output. • Intermediate-dose: Acts on D1 and b1 receptors. niveloptimo ✓↑ HR and cardiac contractility. • High-dose: a1-adrenergic effects predominate. nosonlosefectosdeseadosparaaplicacionesclinicas ✓↑BP ✓↑ Risk of arrhythmias. DOPAMINE Therapeutic Applications • Shock (cardiogenic or septic): low cardiac output accompanied by compromised renal function and/or severe congestive heart failure. ✓↓urine flow, tachycardia, or the development of arrhythmias may be indications to slow or terminate the infusion. Fenoldopam: agonist for D1 peripheral dopamine receptors, is a rapidly acting vasodilator used for control of severe hypertension (malignant hypertension with end organ damage).soloprovoca ten presionsanguinea α-ADRENERGIC AGONISTS • The major clinical effects of activation of aadrenergic receptors is in vascular smooth muscle • Limited clinical utility: ✓Hypotension • Orthostatic • Shock • α1-selective adrenergic agonists: ✓↑ peripheral vascular resistance. ✓ Cause bradycardia through activation of reflex vagal responses. α 1-SELECTIVE ADRENERGIC AGONISTS seproboqueadosis Phenylephrine: midriatico • Shock: IV treatment of hypotension. descongetionantenasa otenoesefectivopara descongentionartenasal • Vasoconstrictor in regional analgesia. • Mydriatic in ophthalmic procedures and treatment of open-angle glaucoma. • Topically administered α1-agonists are used to constrict vascular smooth muscle in the symptomatic relief of nasal congestion and ophthalmic hyperemia. α1-SELECTIVE ADRENERGIC AGONISTS checkpppasado Metaraminol: IV, IM, SC actuademaneramixta naumentareleaseENE • Direct effects (vascular a1), indirectly ↑ NE release. • Treatment of hypotensive states specially in spinal anesthesia and surgical procedures. Midodrine: oral nopasaBBB provocaefectosperiferales • Pro-drug: active metabolite: desglymidodrine. • Treatment of orthostatic hypotension due to impaired autonomic nervous system function. ✓↑ BP → arterial and venous smooth muscle contraction. ✓A complication is supine hypertension. • Avoid dosing within 4 hours of bedtime. α 2- SELECTIVE ADRENERGIC AGONIST α2-Selective adrenergic agonists are used primarily for the treatment of hypertension. • Surprising efficacy as antihypertensive agents. ✓ Blood vessels contain postsynaptic α2 receptors, activation results in vasoconstriction. activation of α2 receptors in the cardiovascular centers of the CNS (↓ outflow of sympathetic nervous system). ✓ ↓BP→ • α2- selective adrenergic agonist inhibits release of NE in presynaptic terminal. • In addition, α2 agonists ↓ intraocular pressure. ✓ ↓the production of aqueous humor. α 2- SELECTIVE ADRENERGIC AGONIST Clonidine • Well, absorbed orally. ✓Bioavailability ≈ 100%. • Developed as a vasoconstricting nasal decongestant. ✓During clinical trials found to cause hypotension, sedation, and bradycardia. • Lowers BP even if applied topically to the eye. • IV infusion causes an acute rise in blood pressure (activation of postsynaptic α2 receptors). ✓Not seen with oral administration. α 2- SELECTIVE ADRENERGIC AGONIST • Peak concentration in plasma and hypotensive effect 1-3 hours after an oral dose. Elimination t1/2 12 hrs. • Transdermal delivery patch permits continuous administration, alternative to oral therapy. ✓Released at a constant rate for a week. ✓↓ incidence of adverse effects. • Avoids the high concentrations that occur with oral administration. ✓About 15-20% of patients develop contact dermatitis. ✓Transdermal administration reduces the incidence of menopausal hot flashes. α 2- SELECTIVE ADRENERGIC AGONIST Therapeutic Applications: hypertension, preparing addicted subjects for withdrawal (opioids, alcohol, and nicotine). • Off-label disorder. use in attention-deficit/hyperactivity ✓Regulation of NE release in the CNS. nosesabecomofuncionaparaADHD • Diagnosis of hypertension or pheochromocytoma. cancermedala adrenal produceNEyEp asistema enca ✓Patients with hypertension ↓ plasma NE concentration. ✓No suppression seen in pheochromocytoma. view α 2- SELECTIVE ADRENERGIC AGONIST Adverse effects: sedation (≈50%). Xerostomia, bradycardia and • Therapy should be gradually tapered off when discontinuing therapy to avoid rebound effect. ✓Withdrawal reactions follow abrupt discontinuation of longterm therapy with clonidine in some hypertensive patients. Apraclonidine and Brimonidine: derivatives of clonidine that retain the ability to ↓ intraocular pressure with little effect on systemic blood pressure. α 2- SELECTIVE ADRENERGIC AGONIST Apraclonidine: used topically to ↓ intraocular pressure (glaucoma or not); do not cross to CNS. hayefectoscardiacos no • Minimal effects on CV parameters. ✓More useful than clonidine for ophthalmic therapy. ✓α2 receptor–mediated ↓ in the formation of aqueous humor. • Adjunctive therapy in glaucoma patients whose intraocular pressure is not well controlled by other agents (b-blockers or parasympathomimetics ???). α 2- SELECTIVE ADRENERGIC AGONIST Brimonidine: crosses the BBB, can menosefectos produce hypotension and sedation.cardiacos • Lower CNS effects than clonidine. • As with all a2 agonists, this drug should be used with caution in patients with cardiovascular disease. Guanfacine: more selective for α2 than clonidine. • A sustained-release form has been FDA-approved for treatment of ADHD in children aged 6-17 years. • Similar efficacy for the treatment of hypertension and adverse effects, less withdrawal syndrome. α 2- SELECTIVE ADRENERGIC AGONIST sede carboxila Methyldopa: pro-drug to α-methylNE. carveen eecito plasma una delaspocasutilizadospa • Centrally acting antihypertensive agent.tratarmujeres embarazadas ✓Contraindicated in active hepatic disease. ✓Can be associated with autoimmune hemolytic anemia, is not a first-line agent in the treatment of hypertension. • Has proven safer than other antihypertensive agents in pregnancy; drug of choice for the treatment of hypertension during pregnancy. α 2- SELECTIVE ADRENERGIC AGONIST Tizanidine: centrally acting α2 agonist. utilizadaparaes pasnosmuscle • ↓ muscle tone and frequency of muscle spasms without reducing strength (@ doses that cause little change in BP). ✓Used for spasticity due to neurological disorders, and in painful muscle spasms of spinal origin. • Multiple sclerosis • ALS • Adverse Events: ✓Liver damage (↑ liver enzymes). ✓Xerostomia. ✓Sedation. ✓Hypotension (Caution with orthostatic hypotension). α 2- SELECTIVE ADRENERGIC AGONIST Dexmedetomidine: centrally acting α2 agonist. • Used for sedation under intensive care and during anesthesia. ✓↓ sympathetic response to surgery. ✓↓ opioid requirement for pain control. • No respiratory depression. Agitation associated with bipolar disorder and schizophrenia MIXED-ACTING SYMPATHOMIMETIC Ephedrine: Agonist at both a and b receptors; in addition, ↑ release of NE from sympathetic neurons. drogamixta • No catechol moiety, effective after oral administration (t1/2≈3-6 hrs). • Stimulates heart rate and cardiac output and variably ↑ peripheral resistance (↑ BP). ✓↓ Urine outflow ✓Cause bronchodilation. MIXED-ACTING SYMPATHOMIMETIC Potent CNS stimulant. Ephedrine (má huáng) used in traditional Chinese medicine, since the Han dynasty (206BC–220AD) as an anti-asthmatic and stimulant. • In 2004, the FDA prohibited the sale of dietary supplements containing ephedrine or ephedra. ✓Extensively promoted weight control and boosting sports performance and energy. • Linked to significant adverse events (heart attack and stroke). ✓The Combat Methamphetamine Epidemic Act of 2005 regulates the sale of ephedrine, phenylpropanolamine, and pseudoephedrine, can be used as precursors in the illicit manufacture of amphetamine and methamphetamine. MIXED-ACTING SYMPATHOMIMETIC Phenylephrine & Pseudoephedrine: Stereoisomer of ephedrine, used in most oral preparations for the relief of nasal congestion. • Available without a prescription in a variety of solid and liquid dosage forms. b-ADRENERGIC RECEPTOR AGONISTS ISOPROTERENOL α receptors: Epi ≥ NE >> Iso β receptors: Iso > Epi ≥ NE. Metabolized by COMT, poor substrate for MAO. • Synthetic catecholamine potent stimulation of both b1- and b2-adrenergic receptors (non-selective). • Cardiovascular: intense stimulation of the heart. ✓ Stimulation of b1-adrenergic receptors: ↑ HR and the force of contraction, ↑ cardiac output. ✓ Lowers peripheral vascular resistance (↓BP, b2). ISOPROTERENOL • Pulmonary: rapidly alleviates an acute asthma attack when inhaled. ✓Stimulation of b2-adrenergic receptors: relaxation of vascular, bronchial, and GI smooth muscle. ✓Inhibit antigen-induced release of histamine. • Metabolic Processes: ↑ blood sugar and lipolysis. • Therapeutic Applications: ✓Asthma: (high incidence of cardiac side effects). ✓Emergency stimulation of the heart (bradycardia or heart block). DOBUTAMINE • Two stereoisomers (racemic mixture): ✓(-) isomer acts as an a1-agonist and a weak b1-agonist. ✓(+)isomer acts as an a1-antagonist and a potent b1-agonist. • The observed clinical effect is that of a selective b1-agonist. Therapeutic Applications: short-term treatment of cardiac decompensation after cardiac surgery, in congestive heart failure or acute myocardial infarction. May ↑ the size of a myocardial infarct (↑ myocardial O2 demand). b2-ADRENERGIC RECEPTOR AGONISTS • Useful in the treatment of bronchoconstriction: asthma or chronic obstructive pulmonary disease (COPD). Relaxation Contraction β2-SELECTIVE AGONISTS Most important effects are relaxation of bronchial smooth muscle and ↓ airway resistance. • Adverse effects are caused of b1 receptors in the heart. by stimulation affinity for b2 receptors with b1receptors have been developed. ✓ Preferential • compared Selectivity is relative, not absolute, and is lost at high concentrations. ✓ ≈40% of the b receptors in the human heart are b2 receptors. tienen la capacidaddeafectar By • Patients with underlying coronary artery disease or pre-existing arrhythmias are at greater risk. β2-SELECTIVE AGONISTS • Aerosolizing inhalers facilitate selective stimulation of b2receptors in the target tissue. ✓Results in very low systemic drug concentrations. • b2- agonists also suppress the release of leukotrienes and histamine from mast cells in lung tissue. ✓Airway inflammation is also directly involved in airway hyper-responsiveness. • Long-acting b2-agonists are used concomitantly with anti-inflammatories in the treatment of asthma. ASTHMA • Chronic Inflammatory disease of the airways (airflow obstruction and bronchospasm). • In 2017, >25 million americans have asthma. Each day 10 americans die from asthma (3,564/year) • Diagnose using the methacholine challenge. ↑ concentration → airway narrowing. ASTHMA SHORT ACTING β2-SELECTIVE AGONISTS Metaproterenol: for long-term treatment of COPD, asthma, and acute bronchospasm. • Aerosol for absorbed). inhalation, nebulizer, oral (40% ✓Resistant to methylation by COMT. • Fast acting within minutes of inhalation and persist for several hours (3-4 hrs). • Less selective than albuterol or terbutaline, more prone to cause cardiac stimulation. SHORT ACTING β2-SELECTIVE AGONISTS Albuterol: Inhalation or oral administration. manengement destatusasmatico ✓ Inhalation produces bronchodilation within 15 minutes and persist for 3-4 hours. ✓ Orally has the potential to delay preterm labor. ✓ Prevention ✓ Status evitaconstracciondelutero of exercise-induced bronchospasm. Asthmaticus. Levalbuterol: R-enantiomer of albuterol (racemic drug); similar pharmacokinetics. • Has fewer side effects than albuterol. SHORT ACTING β2-SELECTIVE AGONISTS farmacologicomentesimilara albuterol Pirbuterol: available in a activated meter-dose inhaler. breath- Terbutaline: Effective orally, subcutaneously, or by inhalation (not marketed for inhalation in the U.S.). ✓Effects are observed rapidly after inhalation or parenteral administration and persist for 3-6 hrs. • Delayed onset following oral administration (1-2 hrs). • Used for long-term treatment of obstructive airway diseases, acute bronchospasm, and in the emergency treatment of status asthmaticus (IV). ✓Used off label to treat preterm labor. MANAGEMENT OF STATUS ASTHMATICUS LONG ACTING β2-SELECTIVE AGONISTS Salmeterol • Onset of action is slow. ✓Not suitable as monotherapy or for acute attacks. • Highly lipophilic, long duration of action (>12 hrs). • 50-fold > selectivity for b2 receptors than albuterol. • • Provides symptomatic relief and improves lung function and quality of life in patients with COPD. ✓As effective as ipratropium (effects are additive). LONG ACTING β2-SELECTIVE AGONISTS • Salmeterol and formoterol are the agents of choice for nocturnal asthma in patients who remain symptomatic despite anti-inflammatory agents. ✓Patients with moderate or severe persistent asthma, benefit from the use of long-acting b-agonists together with an inhaled corticosteroid. Formoterol: rapid bronchodilation. Last 12 hrs. • FDA-approved for asthma, bronchospasm, prophylaxis of exercise-induced bronchospasm, and chronic obstructive pulmonary disease (COPD). LONG ACTING β2-SELECTIVE AGONISTS Arformoterol: the (R,R) enantiomer of formoterol, has twice the potency of racemic formoterol. • FDA-approved for the long-term treatment of bronchoconstriction in patients with COPD, including chronic bronchitis and emphysema. . VERY LONG ACTING β2-SELECTIVE AGONISTS Indacaterol: Once daily dosing with a fast onset (5 min) and longer duration of action than salmeterol (24 hrs). Olodaterol: used alone or in in combination with tiotropium bromide. Vilanterol: approved for use in combination with fluticasone. Vilanterol is available in Europe in combination with umeclidinium. ADVERSE EFFECTS β2 AGONISTS Patients with underlying cardiovascular disease are particularly at risk for significant reactions. • Tachycardia (b1 on heart, b2 on vasculature). • Tremor- tolerance develops (b2 in skeletal muscle). • ↑Glucose and free fatty acids levels. • ↓K • Adverse effects can be greatly ↓ in patients with lung disease by administering the drug by inhalation rather than orally or parenterally. β3-SELECTIVE AGONISTS Mirabegron & Vibegron: β3 adrenergic receptor agonist approved for use against incontinence. • Side effects include ↑ blood pressure, ↑ incidence of urinary tract infection, and headache. • Moderate CYP2D6 inhibitor.