Sympathomimetic drugs Natalia M. Crespo Colón MS4 09/29/23 Introduction ● Sympathomimetic drugs: enhance the actions of endogenous catecholamines of the SNS. ● Classification A. Direct sympathomimetic drugs ❏ B. Stimulate adrenergic and dopaminergic receptors directly Indirect sympathomimetic drugs ❏ ↑ synaptic activity of endogenous catecholamines by ↑ presynaptic release or inhibiting reuptake C. Mixed-acting Overview of Sympathetic Nervous System Direct sympathomimetics ➔ Alpha-adrenergic agonists ➔ Beta-adrenergic agonists ➔ Dopaminergic agonists Phenylephrine ● Brand name: Neo-synephrine hydrochloride ● MOA: Selective ɑ-1 agonist (ɑ1 ﹥ɑ2). ● ○ Potent vasoconstrictor; ↑ systolic and diastolic pressure and PVR; lowers HR ○ Reduces nasal congestion. Indications: ○ Hypotension (Surgical setting- anesthetics); Rhinitis (obstructed Eustachian tubes); nasal decongestant (reduce hyperemia and mucosal edema); Allergic conjunctivitis, Open-angle glaucoma ● Contraindications: Hypersensitivity; MAO inhibitor use w/in 14 days (metabolized by monoamine oxidase A), urinary retention ● Adverse effects: Hypertension, decreased renal perfusion and reduced urine output, decreased tissue perfusion resulting in necrosis and/or lactic acidosis. Midodrine ● Brand name: ProAmatine, Orvaten ● MOA: ɑ-1 agonist; prodrug converted to an active metabolite, desglymidodrine. ○ ● Contraction of both arterial and venous vasculature→ increase in vascular tone and elevation of BP Indications: ○ Autonomic dysfunction ○ Symptomatic orthostatic hypotension ● Contraindications: severe organic heart disease, acute renal disease, pheochromocytoma or thyrotoxicosis. ● Adverse effects: worsening of supine hypertension, paresthesia, pruritus, urinary retention, urinary frequency Norepinephrine ● Brand name: Levophed, Levarterenol ● MOA: Acts on both ɑ1 and ɑ2 adrenergic receptors to cause peripheral vasoconstriction and ↑ BP ○ CO is unchanged or ↓, and ↑ TPR ○ ɑ1﹥ɑ2 ﹥ β1 ■ Doses less than 2 mcg/min β1 can predominate increasing CO ● Indications: Hypotension secondary to distributive shock; sepsis that does not respond to fluid resuscitation. ● Contraindications: Peripheral vascular thrombosis (except for lifesaving procedures) ● Adverse effects: severe hypertension, arrhythmias Epinephrine ● One of the most potent vasopressor drugs known ● Brand name: Epipen, Adrenaline, Allerject, Anapen ● MOA: potent stimulant of both ɑ and β adrenergic receptors. ○ β > ɑ at low doses; at high doses the ɑ effect is predominant ○ Cardiovascular: Positive inotropic and chronotropic action (↑ strength of ventricular contraction, ↑ HR) ■ Pulse rate at first accelerate, may be slowed by compensatory vagal discharge (baroreceptor reflex) ○ Respiratory: Bronchodilation ○ Hyperglycemia (↑glycogenolysis in liver, increases release glucagon and inhibit secretion of insulin) Epinephrine ● MOA ○ Minimizes the vasodilation and increased vascular permeability that occurs during anaphylaxis. Raises BP at high doses, HR, CO ○ β﹥ɑ (at high doses the effect of ɑ is predominant) ○ Dales vasomotor reversal: If it is administered after giving ɑ blockers, only fall in blood pressure is seen. ** ● Indications: Anaphylactic shock, bronchospasm, cardiac arrest, to prolong the actions of local anesthetics, bleeding peptic ulcers during upper endoscopy ● Contraindications: Hyperthyroidism, Diabetes, in patients receiving nonselective β receptor antagonists because its unopposed actions on vascular ɑ1 receptors may lead to severe hypertension and cerebral hemorrhage. ** ● Adverse effects: Anxiety, fear, tension, headache, tremor; cerebral hemorrhage; cardiac arrhythmias; pulmonary edema Beta adrenergic agonists Drug Brand MOA Indications Contraindications Adverse effect Albuterol Proventil, Ventolin Short-acting, selective β2 agonist Acute exacerbation of asthma, COPD, prevention of bronchospasm Hypersensitivity Tremor Insomnia Salmeterol Advair, Serevent, Airduo Long-acting β2 agonist causes relaxation of smooth muscle, bronchodilation and increased airflow. Prophylaxis in chronic asthma, COPD maintenance Nocturnal asthma Headache Beta adrenergic agonists Drug Brand MOA Indications Contraindications Adverse effect Formoterol Perforomist Long-acting selective β2 agonist Long-term maintenance tx of bronchoconstriction in COPD patients Asthma tx w/o inhaled corticosteroid Viral infection Bronchitis Bronchial smooth muscle relaxation Prophylaxis of exercise-induced bronchospasm Prolonged tocolysis (﹥72 hr) Tremor, nervousness, dizziness, headache Nocturnal asthma Terbutaline Berthaire, Brethine, Bricanyl Β2-selective bronchodilator Acute bronchospasm Preterm labor Dobutamine ● Brand name: Dobutrex ● MOA: selective β1 agonist increase myocardial contractility and stroke volume, increasing cardiac output. ○ β1﹥β2 ● Indications: ADHF w cardiogenic shock, cardiac stress testing ● Contraindications: Idiopathic hypertrophic subaortic stenosis ● Adverse effects: Tachyarrhythmias, hypertension, eosinophilic esophagitis Isoproterenol ● Brand name: Isuprel ● MOA: potent nonselective β1 & β2 agonist ○ Relaxation of GI, bronchial, and uterine smooth muscle ○ Cardiovascular: ↓ PVR. **Diastolic pressure falls. Systolic blood pressure may remain unchanged or rise, although mean arterial pressure typically falls. **Cardiac output is ↑ because of the positive inotropic and chronotropic effects. ● Indications: Electrophysiologic evaluation of tachyarrhythmias, bradycardia, heart block Cardiac arrest, shock, bronchospasm during anesthesia ● Contraindications: Digitalis intoxication, angina pectoris, preexisting cardiac arrhythmias ● Adverse effects: Tachycardia, flushing, hypertension, dysrhythmias; may cause thyroid storm in patients with hyperthyroidism; may worsen ischemia Dopamine ● Brand name: Intropin ● MOA: D1=D2 > β> ɑ ○ Low dose (0.5-2 mcg/min) → mainly dopaminergic receptors→ renal and mesenteric vasodilation ○ Intermediate dose (2-10 mcg/min) → β1-adrenergic and dopaminergic receptors → cardiac stimulation and renal vasodilation ○ Higher doses → ɑ adrenergic receptors → vasoconstriction and ↑ BP ● Indications: Hypotension, Cardiogenic shock, unstable bradycardia ● Contraindications: Adrenal gland dysfunction, ventricular arrhythmias and tachycardia ● Adverse effects: May cause peripheral ischemia in patients w hx of occlusive vascular disease, arrhythmias. Fenoldopam ● Brand name: Corlopam ● MOA: D1 agonist ○ Rapid-acting vasodilator (coronary, peripheral, renal, and splanchnic) ○ ↓ BP, ↑ HR and cardiac output; ↓ PVR and ↑ renal blood flow, natriuresis and diuresis ● Indications: Postoperative hypertension, hypertensive crisis. ● Contraindications: None ● Adverse effects: Dose-related tachycardia, hypotension, flushing, headache ○ Hypokalemia has been observed after ﹤6 hrs of indusion Indirect sympathomimetics Amphetamines ● Brand name: Adderall, Concerta, Dexedrine ● MOA: indirect general agonist, reuptake inhibitor, releases catecholamines ○ CNS stimulant, ↑ the amounts of dopamine, norepinephrine, and serotonin in the synaptic cleft ● Indications: ADHD and narcolepsy ● Contraindications: Hypersensitivity, during or w/n 14 days of MAOIs therapy. Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate-to-severe hypertension; patients with hx of drug abuse. ● Adverse effects: May exacerbate symptoms of pre-existing psychotic disorder, aggressive behavior, decreased appetite, infections, abdominal pain, headache, insomnia, abdominal pain. Cocaine ● Cocaine has only received FDA approval for adult nasal mucosal surgery anesthesia. ● MOA: indirect general agonist and reuptake inhibitor of dopamine ○ Principal action on mucosa is anesthesia and vasoconstriction ○ Topical: produces anesthesia by blocking sodium channel and interfering with action potential propagation. ○ If significant systemic absorption occurs → ɑ and β1 adrenoceptor stimulation results in ↑ HR, systemic arterial pressure, and myocardial contractility. ● Indications: Local anesthesia ● Contraindications: Hypersensitivity, elderly patients with hx of hypertension or cardiovascular disease, pregnancy ● Adverse effects: intense agitation, convulsions, hypertension, rhythm disturbance, coronary insufficiency, hyperthermia, rhabdomyolysis, renal impairment. Ephedrine ● (akovaz, Bronkaid, Corphedra) ● MOA: ○ Direct effect: activates ɑ and β adrenergic receptors. ○ Indirect effect: inhibits norepinephrine reuptake and ↑ the release of norepinephrine ● Indications: Anesthesia-induced hypotension, allergy relief, asthma, bronchoconstriction, nasal congestion (pseudoephedrine) ● Contraindications: Acute hypertension or tachycardia ● Adverse effects: Nause, vomiting, tachycardia, palpitations, ventricular tachyarrhythmias, reactive hypertension, bradycardia, dizziness, postpartum hypertension and stroke Questions Bibliography Horowitz, A. J., Frey, D., Denault, D., & Smith, T. (2023, July 21). Sympathomimetics - StatPearls - NCBI Bookshelf. National Library of Medicine NCBI. https://www.ncbi.nlm.nih.gov/books/NBK546597/ Le, T., Bhushan, V., Qiu, C., Chalise, A., Kaparaliotis, P., Coleman, C., & Kallianos, K. (2023). Pharmacology- Autonomic drugs. In First aid for the USMLE step 1 2023 (p. 241). essay, McGraw Hill. Sympathomimetic drugs. Next.amboss.com. (2023, January 12). https://next.amboss.com/us/article/tN0X1g?q=sympathomimetic%2Bdrugs#Zaee1137cefa7d573a3 108c85c6ee68c7 Westfall T.C., & Macarthur H, & Westfall D.P. (2017). Adrenergic agonists and antagonists. Brunton L.L., & Hilal-Dandan R, & Knollmann B.C.(Eds.), Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e. McGraw Hill. https://bibliodig.uag.mx:2091/content.aspx?bookid=2189&sectionid=167890123 Overview Adrenergic receptors Alpha Alpha-1 receptor: significant vasoconstriction, GI sphincter contraction, bladder sphincter contraction- urinary retention, mydriasis, increase glycogenolysis Alpha-2 receptor: ↓ norepinephrine release and synthesis, ↓ insulin release, ↓ lipolysis, ↓ aqueous humor production, ↑ platelet aggregation Beta Beta-1 receptor: cardiac excitation (↑ HR, ↑ conduction velocity, ↑ force of contraction), ↑ renin release Beta-2 receptor: relaxation of smooth muscle (vasodilation, bronchodilation, relaxation of uterus, bladder relaxation), ↑contractility, ↑glycogenolysis, ↑ insulin release. Beta-3 receptor: bladder relaxation, ↑ lipolysis, thermogenesis Dopaminergic receptors: renal, splanchnic, coronary, cerebral vascular beds; vasodilation A second subtype of dopamine receptors causes vasoconstriction by inducing norepinephrine release. 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