Sympathomimetic Agents

Educational Objectives

The goal of this program is to improve use of drugs that mimic the sympathetic nervous system in clinical practice. After hearing and assimilating this program, the clinician will be better able to:

1. Differentiate between nonselective direct-acting drugs and selective direct-acting drugs (SDADs).
2. Explain the cardiac effects of epinephrine.
3. List SDADs and their mechanisms of action.
4. Compare effects of amphetamine with effects of methamphetamine.
5. Relate the structure of ephedrine to that of methamphetamine.

Summary

Catecholamines: sympathomimetic backbone; composed of catechol and amine; dopamine is the simplest catecholamine and adding substituents to its structure conveys specific pharmacologic properties; they have the highest potency at adrenoceptors (AR); a catecholamine backbone is necessary for the molecule to be a substrate for catechol-O-methyltransferase (COMT), one of the primary enzymes metabolizing catecholamines; compounds lacking the catechol backbone are not substrates of COMT, and typically have a longer duration of action; the 2 hydroxyl groups in the catechol backbone also make the compounds more polar, and they penetrate less easily into the central nervous system (CNS); monoamine oxidase (MAO) is another enzyme important in the metabolism of biogenic amines but if a substituent is added to the backbone, the drug ceases to be a substrate for MAO and has a longer duration of action; this modification enables the drug to displace norepinephrine from storage granules, increasing the indirect sympathomimetic activity; if there are 2 hydroxyl groups at the number 3 and 5 positions, the compound is resistant to metabolism by COMT and becomes much more selective for the beta 2 receptor; adding substituents to the nitrogen atom generally increases specificity for beta ARs

Sympathomimetic drugs: these are divided into direct-acting drugs that act as agonists for ARs and indirect acting drugs that act via multiple mechanisms; some drugs have both direct and indirect effects; classification — nonselective direct-acting drugs (NDADs; eg, epinephrine [EP], isoproterenol, norepinephrine); selective direct-acting drugs (SDADs; eg, phenylephrine, terbutaline) for specific AR subtypes; indirect-acting drugs (IADs), including those that increase neurotransmitter release (eg, tyramine, amphetamine), those that inhibit neurotransmitter re-uptake (eg, cocaine), those that inhibit MAO (eg, antidepressants), or those that inhibit COMT (eg, drugs for Parkinson disease)

Nonselective Direct-acting Drugs

Epinephrine: this activates all ARs; it is released from the adrenal medulla and circulates throughout the body to affect cells with ARs, functioning as a hormone; beta ARs are activated by lower concentrations of EP compared with alpha ARs

Cardiac effect: low concentration activates only beta 1 (b1) and beta 2 (b2) ARs, thereby decreasing blood pressure (BP) via b2 AR-mediated vasodilation and increasing the heart rate (HR) from b1 AR-mediated chronotropy and reflex increase in HR mediated by the barostatic reflex; high concentration activates alpha 1 (a1) ARs and causes an increase in BP as the a1 effect overwhelms the b2 effect on the vasculature; when the BP is high from EP, the HR remains high as the b1 chronotropic effect overwhelms the parasympathetic efferent limb of barostatic reflex

Effect on skeletal muscles: during exercise or with “flight or fight” response, increased oxygen and glucose use results in local vasodilation that overwhelms the vasoconstricted effect of EP; highly active muscles experience a significant increase in blood flow while less intricate tissues and organs receive less blood flow; blood vessels in brain and heart have few alpha ARs, so blood flow is preserved

Clinical use: used for its effects on the cardiovascular system and the bronchi; given by injection in a high dose as part of the advanced cardiac life support protocol during a cardiac arrest; it is given by subcutaneous injection to treat life-threatening allergic reactions that manifest as severe bronchoconstriction and hypotension; it is mixed with local anesthetics to prolong duration and decrease toxicity by producing local vasoconstriction and decreased local blood flow, decreasing uptake into blood vessels; it is used to increase cardiac contraction, HR, and BP in cardiogenic shock manifested as low perfusion because of inadequate cardiac pump activity

Norepinephrine: activates a1, alpha 2 (a2), b1, and beta 3 (b3) ARs; it is the neurotransmitter released at most sympathetic synapses; because it lacks effect on b2 AR activity, it does not dilate blood vessels or bronchi; when given intravenously (IV), there is vasoconstriction in most vascular beds, leading to increased BP and a concurrent decrease in HR because of the barostatic reflex and because it is not as potent as EP at b1 ARs; it is used to treat hypotension caused by vasodilation, such as in septic shock manifested as low perfusion caused by a bacterial toxin

Isoproterenol: this stimulates b1 and b2 ARs with no activity at alpha ARs; its selectivity achieved by replacing methyl group on the nitrogen atom in EP with isopropyl group; when given via IV administration, it produces b2 AR-mediated vasodilation and b1 AR- and reflex-mediated tachycardia; the systolic BP increases because of the increase in cardiac output while diastolic BP decreases because of vasodilation, with mean BP unchanged or slightly decreased; this was previously used to increase HR as a temporizing measure while awaiting placement of a cardiac pacemaker; it was also used via inhalation in asthma but is no longer used in this way because of associated tachycardia

Dopamine: at low concentrations, this selectively activates dopamine b1 receptors in the kidney, causing vasodilation in renal blood vessels and an increase in glomerular filtration rate and sodium excretion; at moderate concentrations, it stimulates b1 ARs, and at high levels it stimulates a1 ARs; it is most commonly used to treat low cardiac output associated with compromised renal function, such as with severe congestive heart failure; it is also used to treat septic shock

Selective Direct-acting Drugs

Phenylephrine: it is relatively selective for a1 ARs, producing vasoconstriction in most vascular beds and increasing BP accompanied by reflex bradycardia; it is derived from EP by removing the 4 hydroxy groups from the benzene ring; it is not a substrate for COMT and has a longer duration of action than EP; it is commonly used to treat hypotension in cases of hypovolemic shock following trauma while administering fluid to restore circulating volume, and is used in septic shock to overcome vasodilation caused by bacterial toxins; it is used to treat sympathetic blockade observed with spinal or epidural anesthesia and drug-induced vasodilation observed when administering a bolus of propofol; it is used topically in the nose to vasoconstrict blood vessels to decrease swelling and secretions in hay fever and in the eye to produce mydriasis to facilitate retina examination

Oxymetazoline: selective for a1 ARs; used only topically as a vasoconstrictor in the nose or eye; it is longer lasting than phenylephrine; if used for several days, rebound vascular congestion occurs when it is stopped

Clonidine: this is a selective a2 AR agonist; it activates presynaptic a2 ARs primarily in the CNS to decrease sympathetic outflow from the CNS, reducing BP and HR; the magnitude of BP reduction is greater in individuals with hypertension than in normotensive individuals; when given via IV route, there is a transient increase in BP caused by vasoconstriction mediated by a2 ARs in some vascular beds, and is not observed when administered orally; it is used orally for treatment of hypertension; it is used to treat intractable cancer pain by continuous infusion into epidural space via an implanted pump; the mechanism by which an a2 AR agonist decreases transmission of pain impulses in the spinal cord is not well understood; it often causes sedation when first administered and tolerance develops in 2 to 3 wk; it may cause xerostomia and impotence in men

Dobutamine: the minus isomer is an a1 AR agonist and the plus isomer is a nonspecific beta AR agonist and a1 AR antagonist; in most patients, little overall effect on vascular tone is seen, because the vasoconstricting effects of minus isomer balance the vasodilating effects of the a1 AR antagonism and the b2 AR agonism of the plus isomer; it has a greater effect on cardiac contractility than on HR; it is used to increase cardiac output in heart failure

Terbutaline: this is a b2 AR agonist given orally or by IV route to prevent or treat bronchospasm; at high doses, beta selectivity is lost and it may cause tachycardia; it can be used to try to arrest premature labor by activating b2 ARs in the uterus that mediate uterine muscular relaxation

Albuterol: this is a b2 AR agonist given orally or by inhalation to prevent or treat bronchospasm; at high doses, it loses b2 selectivity and may cause tachycardia; it is the most commonly used b2 AR agonist for management of bronchospasm in persons with asthma or chronic obstructive pulmonary disease (COPD); it is inhaled every 4 hr

Salmeterol: this is more selective for b2 ARs and longer acting (12 hr) vs albuterol (4 hr); it is associated with an increase in the incidence of asthma-related deaths but the reason is unknown; it should be used only in patients with COPD

Mirabegron: this is the only selective b3 AR agonist used in clinical medicine; it causes relaxation of bladder detrusor muscle; it is used to treat symptoms of overactive bladder, including urinary urgency and frequency; this should be avoided in persons with bladder outlet obstruction

Indirect-acting Drugs

Amphetamine: this acts via stimulating release of norepinephrine, dopamine, and serotonin from storage vesicles in the presynaptic nerve terminal; peripheral effects are dose dependent, with small doses activating primarily beta ARs; larger doses activate alpha and beta ARs; in tissues in which there are opposing activities mediated by alpha and beta ARs, eg, blood vessels, the dose dependency of effects is not important clinically, because the clinical doses are large enough to activate alpha ARs, leading to an increase in HR mediated by b1 ARs and an increase in BP caused by b1 AR-mediated ionotropic receptors and a1 AR-mediated vasoconstriction

CNS effects: these are dose dependent in terms of the neurotransmitters affected; lower doses cause the release of norepinephrine and dopamine and higher doses cause the release of serotonin; it causes activation of a1, a2, b1, and b2 ARs; effects are difficult to predict based solely upon receptor actions; by virtue of increasing a2 AR activity, it decreases sympathetic outflow from the CNS; for eg, clonidine causes sedation and decreases anesthetic requirements and these effects are overwhelmed by a1 AR stimulation that increases arousal and anesthetic requirements; this is one of the most potent drugs in causing increased alertness and wakefulness; it is 10 to 20 times more potent vs caffeine; it typically increases ability to concentrate and increases mood; it increases motor and speech activities

Effect on sleep: it delays onset of fatigue, quality of task performance increases and a short-term requirement for sleep may be decreased; prolonged use results in prolonged need for sleep once the effects have dissipated; stopping after long-term use causes disordered sleep for months

Effect on pulmonary function: it increases ventilatory drive via an effect on ventilatory centers in the medulla, resulting in increased ventilatory rate and tidal volume; this is most noticeable in individuals with drug-induced ventilatory depression

Effect on behavior: it is used to treat attention-deficit/hyperactivity disorder (ADHD) at a relatively low dose; lower doses selectively affect neurons projecting to brain regions important in behavior and cognition, most notably the prefrontal cortex

Methamphetamine: this causes neurotransmitter release and decreases neurotransmitter reuptake, especially dopamine; it has greater selectivity for the CNS compared with amphetamine, making it more potent and more likely to lead to misuse and dependence; it is a nonselective inhibitor of MAO; long-term use at high doses is associated with more severe adverse effects vs amphetamine, including damage to dopaminergic neurons that may result in psychosis and/or Parkinson disease, cardiomyopathy, and premature loss of teeth; this is the most likely to lead to abuse amongst stimulants; withdrawal syndrome in someone with long-term misuse is not life threatening, but can include depression, hypersomnia, anhedonia, and transient psychosis (in some cases this does not remit)

Methylphenidate: this contains the structure of methamphetamine within its own structure and shares its mechanism of action; it has greater lipid solubility vs amphetamine or methamphetamine, so it has a greater ratio of CNS to peripheral effects

IAD and anesthetic: animal studies suggest that IAD may reverse the general anesthetic state, although these experiments have not been replicated in humans; patients who have recently misused a stimulant may require larger doses of general anesthetic drugs to maintain the general anesthetic state

Tyramine: this is taken into norepinephrine-containing synaptic vesicles and causes release of norepinephrine, giving it the same receptor actions (a1, a2, and b1 ARs) as norepinephrine; it is not used therapeutically, but is present in many foods, eg, aged and “smelly” cheeses, pickled or aged fish or meat, fermented soy products, fermented cabbage foods, caviar, tap beer, vermouth, red wine; it undergoes nearly 100% first-pass metabolism, catalyzed by MAO in the gut wall and liver; nonselective MAO inhibitors may result in inadequate metabolism of the drug, and individuals using this must refrain from consuming foods rich in tyramine, because it can cause a dangerous elevation in BP because of unmetabolized tyramine reaching the systemic circulation

Drugs with Mixed Direct and Indirect Sympathomimetic Effects

Ephedrine: this has direct effects like EP, but because it is not a catechol, it is less potent; it also has indirect effects like amphetamine; its structure is the same as methamphetamine, but with the addition of a hydroxyl group added to the beta carbon, resulting in lower potency in the CNS; it is not metabolized by MAO or COMT, giving it a relatively longer duration of action; it is effective when given orally; it is marketed as a single isomer that is obtained from the “ma huang” plant; this has been used in traditional Chinese medicine; in United States, it is classified as a food item and its sale is governed by the Dietary Supplement Health and Education Act of 1994; its use as a dietary supplement has been associated with numerous cases of stroke and myocardial infarction, and is the only dietary supplement that has been successfully banned by the Food and Drug Administration in the US but remains a constituent of herbal products; it was previously used as a bronchodilator but has been replaced by more selective medications at the b2 AR; it is most commonly used to increase BP during general or regional anesthesia; it is typically given by intermittent IV bolus injection because of its short duration

Pseudoephedrine: this is an isomer of ephedrine in which the alpha effects predominate; it is used as an over-the-counter (OTC) decongestant; its sale is often regulated at the local level because it can be used to make methamphetamine; some OTC cold and allergy preparations have replaced pseudoephedrine with phenylephrine; but this does not make sense pharmacologically, because phenylephrine has essentially no oral bioavailability

Readings

Abbruscato TJ, Trippier PC. DARK classics in chemical neuroscience: methamphetamine. ACS Chem Neurosci. 2018;9:2373-2378; doi: 10.1021/acschemneuro.8b00123; Deeks ED. Mirabegron: A review in overactive bladder syndrome. Drugs. 2018;78:833-844; doi: 10.1007/s40265-018-0924-4; Goldstein DS. Catecholamines 101. Clin Auton Res. 2010;20:331-352; doi: 10.1007/s10286-010-0065-7; Goldstein DS et al. Relationship between plasma norepinephrine and sympathetic neural activity. Hypertension. 1983;5:552-559; doi: 10.1161/01.hyp.5.4.552; Heal DJ et al. Amphetamine, past and present--a pharmacological and clinical perspective. J Psychopharmacol. 2013;27:479-496; doi: 10.1177/0269881113482532; Larson S et al. Effect of phenylephrine on cerebral oxygen saturation and cardiac output in adults when used to treat intraoperative hypotension: A systematic review. JBI Evid Synth. 2021;19:34-58; doi: 10.11124/JBISRIR-D-19-00352; Stohs SJ et al. p-Synephrine, ephedrine, p-octopamine and m-synephrine: comparative mechanistic, physiological and pharmacological properties. Phytother Res. 2020;34:1838-1846; doi: 10.1002/ptr.6649; Szymanski MW, Singh DP. Isoproterenol. StatPearls Publishing. 2021 May 1; Yasaei R, Saadabadi A. Clonidine. StatPearls Publishing. 2021 Aug 6; Zhong JQ, Dorian P. Epinephrine and vasopressin during cardiopulmonary resuscitation. Resuscitation. 2005;66:263-269; doi: 10.1016/j.resuscitation.2005.02.014.

Disclosures

In adherence to ACCME Standards for Commercial Support, Audio Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, members of the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Dershwitz was recorded exclusively for Audio Digest using virtual teleconference software, in compliance with social-distancing guidelines during the COVID-19 pandemic. Audio Digest thanks Dr. Dershwitz for his cooperation in the production of this program.

CME/CE INFO

Accreditation:

Lecture ID:

AN634001

Qualifies for:

Clinical Pharmacology

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.