the endocrine gland situated on top of each kidney, which produces and releases epinephrine (also known as adrenaline) to stimulate functions of the sympathetic autonomic nervous system (SANS).
related to the actions of epinephrine (adrenaline); sometimes used to designate actions and responses to the sympathetic autonomic nervous system.
a neuron carrying nerve impulses to the central nervous system (brain and spinal cord) from the periphery (other parts of the body).
Autonomic nervous system
the system of nerves that controls automatic bodily actions, such as the functions of glandular tissues, the heart and smooth muscle, and involuntary movements and body functions (including secretions, pulse, and blood pressure).
an elongated protrusion of the neuron that conducts impulses away from the cell.
characterization of substances, such as epinephrine and norepinephrine, that exert their effect in the sympathetic autonomic nervous system and agents that are chemically similar to these substances.
related to the actions of the neurotransmitter acetylcholine. Cholinergic effects include slowed heart rate, increased secretion, and increased activity of the gastrointestinal tract.
cells or tissues that perform their functions in response to a stimulus (such as a nerve impulse); sometimes called target organs. Those receiving stimulation from the nervous system are designated by the term neuroeffector.
a neuron carrying nerve impulses toward an effector organ.
the release of substances (hormones) synthesized by glands directly into the bloodstream to circulate throughout the body. (Contrasts with paracrine secretion, in which substances are released to act locally on nearby tissues.)
refers to an agent synthesized or produced within the organism.
the release of glandular products to ducts or tracts that lead directly to the outside of the body. Examples are sweat and tears.
refers to an agent introduced to an organism from an outside source, even if the same as substances also produced or synthesized endogenously.
a mass of neuron bodies (nerves). Plural = ganglia.
physiologic equilibrium required for life processes and maintained by several systems and biologic mechanisms.
the function of supplying an organ or tissue with nerves. (“Innervate” means to supply an organ or tissue with nerves.)
a nerve cell.
chemical compounds produced by the body (“endogenous”) that relay, amplify, and/or modulate signal transmission between two neurons or between neurons and other cells.
pertaining to autonomic functions mainly governing body systems at rest, including glandular secretions, tone and contractility of smooth muscle, and slowing the heart rate.
the process of production and release of chemical compounds from a tissue (gland). The secreted product has a function, as opposed to an excreted waste.
pertaining to autonomic functions related to stress situations, often called the fight or flight response. This includes suppressing glandular secretions, reducing tone and contractility of smooth muscle, and increasing the heart rate.
the space between the axon terminal of a neuron and the dendrite body of another neuron where a functional connection between them occurs.
rapid heart rate that exceeds 100 beats per minute in adults.
the state of tension of tissues or organs in the body.
After completing this chapter, you should be able to
Define the autonomic nervous system (ANS) and its divisions, the parasympathetic and sympathetic autonomic nervous systems (PANS and SANS, respectively).
Outline the anatomy, physiology, and functions of the ANS, PANS, and SANS.
Describe the targets/sites of action of endogenous neurotransmitters and of exogenous drugs that act on the ANS,
Review the classification and mechanisms of action of drugs acting on the ANS.
List therapeutic applications of the primary drug classes acting on the ANS.
State the brand and generic names of representative therapeutic agents acting on the ANS, together with their routes of administration, side effects, and potential drug interactions.
The nervous system is the most complex system in the human body. It has two main anatomical and functional divisions: the central nervous system (CNS), discussed in Chapter 5, and the peripheral nervous system (PNS). The PNS is divided into two subsystems: the somatic and autonomic nervous systems. The somatic nervous system involves voluntary movement such as walking or talking. It is discussed in more detail in Chapter 12. The autonomic nervous system (ANS) is the major involuntary, unconscious, automatic portion of the PNS. For example, the ANS keeps the heart beating. The heart doesn’t need to be “told” by the conscious mind to continue beating, it just does so. Other examples of the ANS at work include regulation of blood pressure, saliva secretion, sweating, gastrointestinal motility, and bronchial air exchange. The ANS relies on neurotransmitters acting on certain receptors to cause its effects on body systems.1 See Figure 4-1 for a graphical representation of the relationships between the divisions of the nervous system. Knowledge of the anatomy and physiology, neurotransmitter synthesis and release, signal termination, receptor characteristics, and functional integration of the ANS is important to an understanding of how many drugs act on many systems and organs of the body.
ANATOMY AND PHYSIOLOGY
The ANS has two functional divisions: the sympathetic autonomic nervous system (SANS) and the parasympathetic autonomic nervous system (PANS). These two divisions have opposite effects and serve to keep the body in a balanced state called homeostasis. The PANS is involved in conserving body processes such as digestion and resting (causing decreased heart rate and increased secretions). The SANS contributes to the provision of energy and stamina in emergency situations such as fighting or escape from danger (sometimes called the fight or flight reactions). For example, both the SANS and PANS stimulate muscles in the eye to change pupil size. The SANS increases pupil size (mydriasis), resulting in better far-range vision for emergency situations or night/low light conditions. The PANS decreases pupil size (miosis), which produces better shortrange vision for reading or viewing fine details.1
All body systems are affected by ANS neurons, but not all organs have both PANS and SANS innervation. Innervation is described as the distribution of nerve fibers to a specific body system or organ. The overall response of an organ to ANS stimulation will equal the sum of influences from both PANS and SANS fibers. This means that if more SANS nerves are activated in a specific organ, then the SANS actions will predominate there. Sensory nerves (afferent neurons) communicate the happenings in the periphery (outside the CNS) back to the brain through the spinal cord. This communication allows the appropriate ANS actions to occur in a given situation. These responses are also integrated with the somatic nervous system so appropriate voluntary movements can occur. Figure 4-2 is an anatomical representation of the ANS. The variety of effects of the ANS on effector organs in the human body is summarized in Table 4-1.
A nerve cell is called a neuron. It has the ability to carry impulses and is much like an electrical wire in which a signal can be transmitted. Innervation in the ANS is composed of two neurons: a preganglionicefferent neuron, with a body in the CNS and an axon extending to a ganglion; and a postganglionic neuron, with a cell body in a ganglion (mass of several neuron bodies) and the axon extending to an effector organ. Neurons communicate with one another across a connection called a synapse. A ganglion contains several synapses, and all ganglia are located between the spinal cord and the effector organ. Figure 4-3 shows the parts of the nerve cell and its connections. Axons and synapses are discussed in more detail in Chapter 5. The adrenal gland is innervated only by sympathetic neurons. The adrenal medulla acts as a sympathetic ganglion, but its primary function is the release of epinephrine into the systemic circulation (endocrine secretion).
Mr. Rosario is 78 years old and has just had a hip replacement. He is being admitted to a rehabilitation facility for intensive physical therapy. The “med rec” pharmacy technician compiled a list of the medications Mr. Rosario had been taking prior to surgery for the pharmacist to review. This includes prescriptions for an albuterol inhaler for occasional wheezing and lisinopril for hypertension. When asked about over-the-counter drugs, Mr. Rosario reported that he has mild allergies, and frequently self-treats with oral phenylephrine and diphenhydramine products.
Neurotransmitters are chemical compounds synthesized and stored in neurons, which allow nerve cells to communicate with each other. A neurotransmitter can produce either an excitatory or an inhibitory response. An excitatory response causes action at the effector site; an inhibitory response stops or slows an action. Additional information about neurotransmitters and receptors can be found in Chapter 5.
In the ANS, there are three main neurotransmitters involved in conduction and signaling: acetylcholine (Ach), epinephrine (Epi), and norepinephrine (NE).1 Ach is released by all presynaptic (preganglionic) nerve terminals in both the PANS and SANS and activates the adrenal medulla. The major difference between the PANS and SANS, besides anatomy, is the neurotransmitter released by postganglionic neurons. PANS postganglionic neurons release Ach to activate effector organs or tissues. The PANS is designated as a cholinergic system because this neurotransmitter is the final messenger acting on organs and tissues. The SANS postganglionic neurons release NE to activate organs and tissues. Table 4-2 lists the ANS neurons and their corresponding neurotransmitters. Epi is also a messenger for the activation of organs and tissues innervated by the SANS. NE and Epi are sometimes known as noradrenaline and adrenaline, respectively. This is the reason for the designation of the SANS as the adrenergic system.
Neurotransmitters in the Autonomic Nervous System 1
The interaction between a neurotransmitter and its receptor is specific and depends on the chemical structure of both. Neurotransmission, however, is not continuous. There are two ways the action of a neurotransmitter is stopped. The first is through “reuptake”—transport of the neurotransmitter back into the neuron by special pumps on the presynaptic neuron. The other mechanism by which neurotransmission is ended is through degradation or breakdown of the neurotransmitter by enzymes. Cholinergic neurons have a mechanism of degradation in which the enzyme acetylcholinesterase (AchE) hydrolyzes Ach to form acetic acid and choline. Both of these inactive metabolites can be recycled by the cell to produce new Ach or to maintain other processes. AchE is present near the receptor and prevents overactivation of the PANS.
Adrenergic neurons terminate the action of NE by utilizing both mechanisms. NE reuptake is accomplished by a specific NE transporter (NET) present in the neuronal membrane. NE that undergoes reuptake can be recycled for future use or metabolized by enzymatic degradation. One mechanism of NE degradation utilizes the enzyme monoamine oxidase (MAO), which is present inside the nerve cell. Another degradative enzyme is catechol-O-methyltransferase (COMT). The overall processes of reuptake and degradation contribute to a decrease in adrenergic activity in the SANS.2
Ach binds to two types of receptors: nicotinic and muscarinic (or cholinergic) receptors. These designations were made based on the chemicals (nicotine and muscarine) that were first used to demonstrate the presence of these receptors and to study them. Nicotinic receptors are present on all the preganglionic neurons in both the PANS and SANS, while muscarinic receptors are present on organs only for the PANS. There are several different subtypes of muscarinic receptors, each with its own location and function.
Receptors for NE and Epi are present in effector organs and tissues innervated by the SANS, and they are designated adrenergic receptors. There are three main classes of adrenergic receptors: α1 (alpha one), β1 (beta one), and β2 (beta two), which are located in different organs and tissues and can produce different actions. Another type of adrenergic receptors is the α2 (alpha two) type; these receptors are located in the presynaptic membrane terminals, and they control or inhibit NE release.
PHARMACOLOGICAL INTERVENTION AT THE AUTONOMIC NERVOUS SYSTEM
The use of medications to activate or inhibit any specific division of the ANS is designated as pharmacological intervention. The ANS acts as a regulator of body functions, and a balance of the activities of the PANS and SANS is required to maintain homeostasis. Pathological disorders can arise from excessive activation or inhibition of either the PANS or SANS and pharmacological interventions can increase or decrease activity by different mechanisms of action. A variety of ANS chemicals and functions can be targets for pharmacological intervention.
As discussed earlier, Ach is the primary mediator of PANS activity. There are two mechanisms by which the actions of Ach can be mimicked by medications (increasing PANS activity). One mechanism is that the medication can look like (chemically resemble) Ach and bind its receptor. Another mechanism of increasing PANS activity is by blocking the degradation of Ach, allowing more of it to be present for a longer time (so increasing its action). In both cases direct- or indirect-acting drugs are designated cholinergic agents (also known as cholinomimetic or parasympathomimetic agents).
Ach is the simplest choline derivative, so the easiest way to increase PANS activity would be to administer Ach. However, when administered by conventional routes such as orally or intravenously, Ach is very unstable and not bioavailable. As such, more stable esters can be administered to mimic the effects of Ach and to activate the PANS.
The cholines that are active in the body are known as esters, a term used to describe a particular type of chemical molecule.
Bethanechol is a choline ester drug. It binds selectively to the muscarinic cholinergic receptor (found only in the PANS) without affecting nicotinic receptors (present in both SANS and PANS), making it selective for the PANS. Its effects on body organs can be predicted from the PANS Effect column in Table 4-1. Bethanechol is administered orally and is used to treat urinary retention (by its action on bladder muscle tone). It is administered three to four times per day and is contraindicated in patients with asthma, epilepsy, or a bladder or gastrointestinal blockage. Common adverse effects are also predictable from its cholinergic activity and include miosis, increased tear production (exocrine gland secretion), and diarrhea (increased GI motility).
Another choline ester is carbachol (Miostat), which is used as an intraocular instillation in cataract surgery. Carbachol activates the pupillary sphincter and the ciliary muscles (which cause pupil contraction) to obtain miosis during surgery and decrease intraocular pressure afterward. Because they decrease intraocular pressure, carbachol and other choline esters were once a mainstay of glaucoma treatment (see Chapter 34), but they are used infrequently at this time because more specific therapies with fewer toxicities are available.3 When administered in the eye, there are limited adverse effects since the action is local and only a small amount of the medication is absorbed into the body. However, when choline esters are administered orally, adverse effects include increased sweating, diarrhea, and runny nose.
This group includes agents that act by binding and inhibiting the enzyme AchE, which degrades Ach, thereby indirectly increasing the concentration of Ach in the synapses. As a result, they activate both nicotinic (found in PANS and SANS) and muscarinic (PANS-only) receptors. They can be subdivided into three categories: very long acting (organophosphates), intermediate acting (carbamates or alkaloids), and short acting (edrophonium). Very-long-acting agents include malathion (Ovide) and echothiophate. Malathion is a pesticide and has no clinical use as a cholinergic agent (although it is available as a scalp lotion for the treatment of head lice). Echothiophate, which reduces intraocular pressure, is used as a last-line option in the treatment of glaucoma.
Intermediate-acting agents include physostigmine, neostigmine, and pyridostigmine. Physostigmine was once used as an eye drop for glaucoma, but now is only indicated for use as an antidote administered intravenously for anticholinergic toxicity. It has a fairly short half-life of 1–2 hours, so repeated doses (every 30–60 minutes) may be necessary if anticholinergic symptoms return. Physostigmine is preferred over neostigmine and pyridostigmine for anticholinergic toxicity due to its high lipid (fat) solubility, which allows the medication to cross the blood–brain-barrier (BBB). Adverse effects from physostigmine are similar to those of the previous agents that act on the PANS. Neostigmine is used in the reversal of neuromuscular blockade used in surgery.
Patients who intentionally or accidentally ingest overdoses of medications with potent anticholinergic properties may receive physostigmine in the emergency room. Administration is by intravenous push, but the administration rate should not exceed 1 mg/min to avoid potential cholinergic toxicity if too much is administered too quickly. Whenever it is used, atropine (an anticholinergic agent) should be readily available to reverse any excess effects caused by physostigmine administration.4
Myasthenia gravis is an autoimmune disorder in which antibodies reduce available Ach receptors, inhibiting the actions of Ach and resulting in muscle weakness because of decreased Ach stimulation. While immunotherapy is the primary treatment, pyridostigmine is used to treat myasthenia gravis symptoms, overcoming, to a certain extent, the decreased stimulation by increasing the amount of Ach available. This medication is very similar to physostigmine in its actions and adverse effects, except that pyridostigmine has a longer half-life (8 hours).5
Other AchE inhibitors include donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne ER), which are used to prevent the progression of Alzheimer disease. They are orally bioavailable and are highly lipid soluble, resulting in enhanced penetration through the BBB. These medications are discussed in more depth in Chapter 6.
Edrophonium is the shortest-acting (15 minutes) AchE inhibitor and is not orally bioavailable. It has little clinical application other than for the diagnosis of myasthenia gravis. (Its short action makes it useless in treating myasthenia gravis; the longer-acting agents mentioned above are used instead.) Drugs with cholinergic activity (both direct and indirect) are used in a variety of ways. Medication Table 4-1 lists some representative agents from this class (Medication Tables are located at the end of the chapter).
Adverse or Toxic Reactions
Adverse reactions associated with the administration of cholinergic agents are essentially extensions of their pharmacologic effects. The adverse or toxic effects are described by the acronym BAD SLUDGE. They are summarized in Table 4-3. Large doses can result in neuromuscular paralysis and CNS effects and can ultimately lead to death.
Cholinergic Adverse Effects
Parasympathetic Autonomic Nervous System (PANS) Effect
Decreased heart rate
(non-PANS effect related to central nervous system arousal with excess acetylcholine [Ach])
(non-PANS effect related to central nervous system arousal with excess Ach)
The treatment of intoxication with AchE inhibitors, such as pesticides (like malathion), includes a combination of pralidoxime (Protopam) and atropine. Pralidoxime reactivates the AchE enzyme, and atropine blocks the muscarinic effects of the excess of Ach.
Contraindications for cholinergic agents include asthma, gastrointestinal or urinary obstruction, cardiac disease, or peptic ulcer disease. These conditions may be either caused or exacerbated by increasing cholinergic activity.
PANS inhibition refers to the blockade of cholinergic (acetylcholine-mediated) conduction, and the agents that do this are termed anticholinergic. They prevent the activity of Ach primarily at the postganglionic nerve endings. Some of the agents block cholinergic signaling by interfering with the synthesis and release of Ach. Botulinum toxins are proteins produced by the bacteria Clostridium botulinum that are extremely neurotoxic (poisonous at the nerve level). This bacterium is responsible for causing botulism, which some patients may get from eating improperly stored food. Botulinum toxins inhibit the release of Ach from vesicles; the lack of Ach causes paralysis in skeletal muscle. While botulinum toxins are not classified as anticholinergic medications, they do have various clinical uses, such as for blepharospasm (eyelid muscle spasm), cervical dystonia (muscle tone impairment), and for cosmetic procedures (“Botox”).
Even small doses of botulinum toxin can be fatal, but the doses used clinically are miniscule and are carefully placed to avoid systemic absorption and distribution.
In contrast to botulinum toxins, anticholinergic agents currently used systemically cause blockade or antagonism of Ach at its receptors, resulting in decreased stimulation of the PANS. Most anticholinergic medications are competitive inhibitors (antagonists) at the muscarinic (PANS) receptor, meaning they interact with receptors normally stimulated by Ach, preventing that stimulation. Anticholinergic agents can be divided into two groups: antimuscarinic and antinicotinic. Antinicotinic medications have little therapeutic use, except as neuromuscular blockers. Medications such as pancuronium, vecuronium, and atracurium bind to cholinergic receptors and are used to produce skeletal muscle blockade resulting in paralysis pre- and perioperatively to assist in anesthesia. These actions are detailed in Chapter 12.
Because cholinergic innervation and muscarinic receptors are so widespread throughout the body, drugs that block activity at these sites (antimuscarinics/anticholinergics) are used in the treatment of a variety of conditions. Some clinical applications of antimuscarinic drugs are shown in Medication Table 4-2. Medication Table 4-3 lists a representative group of anticholinergic agents and their clinical applications.
Atropine is the prototype antimuscarinic agent. It is a natural alkaloid extracted from the plant Atropa belladonna. Atropine is relatively fat soluble and readily crosses cell membranes, including the BBB, resulting in central nervous system activity in addition to its PANS actions. The drug is well absorbed when taken orally. It is eliminated by liver metabolism and renal excretion and the half-life is approximately 2 hours. The duration of action of oral doses is 4–8 hours, longer in the eye, where the effects can last for 72 hours or more. As an eye drop, atropine is used to dilate the pupil (by interfering with the miosis caused by PANS stimulation) and paralyze the accommodating effects of the eye to aid in performing eye examinations. Other anticholinergic eye drops for eye examinations are covered in Chapter 34.
Parenteral atropine has long been used to reduce airway secretions during surgery. Atropine is also administered in patients who are in cardiac arrest and have severe bradycardia, although the most recent guidelines state that atropine is no longer a first-line option. Scopolamine (Transderm Scop) is an alkaloid substance derived from the same plant as atropine. It represents the standard therapy for prevention of motion sickness in the form of a transdermal patch. This patch is applied behind the ear every 3 days and is usually the treatment of choice for prolonged sea voyages.
Patients who are admitted to a hospice facility may be given scopolamine patches to reduce drooling and respiratory secretions at the end of life.
Benztropine (Cogentin) and trihexyphenidyl are antimuscarinic agents that are active in the CNS. They are representative of anticholinergic agents used to treat symptoms of Parkinson disease (PD) and similar symptoms caused by some CNS drugs. They work by combating the overactivity of cholinergic neurons that results from the low activity of CNS dopamine in patients with PD. Anticholinergics can result in decreasing the movement symptoms associated with PD. (See Chapter 6 for more on the use of these agents in PD treatment.)
Ipratropium (Atrovent) is an agent used to reduce bronchoconstriction in asthma and chronic obstructive pulmonary disease (COPD). It is administered directly to the respiratory tract either through a metered dose inhaler or by a nebulizer. Because inhaled ipratropium is poorly absorbed from the lungs, most of its action is confined to the bronchi, which prevents antimuscarinic side effects in other parts of the body. It is less likely to cause cardiac arrhythmias in patients sensitive to adrenergic drugs. The use of anticholinergics in respiratory disease is discussed at length in Chapter 19.
Methscopolamine (Pamine) and similar agents were once commonly used in the treatment of gastrointestinal disorders due to their ability to block Ach-stimulated gastric secretion. Since they are not as effective as newer medications such as histamine2 receptors or proton pump blockers (discussed in Chapter 21), they are no longer indicated for these conditions.
Methscopolamine, oxybutynin (Ditropan), tolterodine (Detrol), darifenacin, solifenacin (Vesicare), and trospium are agents that can be used to reduce urgency in mild cystitis (inflammation of the urinary bladder), to reduce bladder spasms following urologic surgery, or to treat an overactive bladder. Newer agents in this class, such as tolterodine, darifenacin, solifenacin, and trospium are more specific for muscarinic receptors in the bladder, resulting in fewer systemic and CNS adverse effects. Drugs with anticholinergic activity that are useful in treating bladder conditions are listed in Medication Table 4-4.
Parasympathetic Autonomous Nervous System (PANS) Effect Antagonized
“Hot as Hades”
Increased body temperature/decreased sweating
Exocrine gland secretion
“Dry as a bone”
Dry mouth and dry mucous membranes
Exocrine gland secretion
“Red as a beet”
Tachycardia with skin flushing
Heart rate lowering
“Blind as a bat”
Ocular muscle tone
“Mad as a hatter”
Agitation, confusion, hallucinations
(Non-PANS effect related to actions of acetylcholine in central nervous system)
The pharmacist mentions that agents with anticholinergic side effects are not recommended for use in older adult patients. Which of Mr. Rosario’s medications will probably be changed or discontinued because of this?
The adverse reactions that can result from anticholinergic agents are extensions of their pharmacological effects. These can include xerostomia (dry mouth due to a lack of saliva), blurred vision, photophobia (excessive sensitivity to light producing eye pain or discomfort during light exposure), confusion, reflex tachycardia, decreased sweating, urinary retention, and constipation. Fever is caused by decreased sweating, which can result in hyperpyrexia (severely increased body temperature) that is potentially lethal in infants. A popular list of anticholinergic reactions is included in Table 4-4. Many drugs used primarily for actions other than those in the autonomic nervous system also have some anticholinergic activity that can cause unwanted side effects. This is particularly true of older antihistamines.6
Contraindications for the antimuscarinic drugs include narrow angle glaucoma (because these drugs can increase intraocular pressure), benign prostatic hyperplasia (potential worsening of urinary retention), and intestinal or mechanical obstruction of the GI or urinary tract. They are used with caution in patients who have cardiovascular disease due to the increased risk of tachycardia and in patients who have irritable bowel syndrome.
Medications with anticholinergic effects are generally to be avoided in older adults because their effects on vision, urination, and the cardiovascular system are more likely to be problematic in this population.
The important endogenous messengers in the SANS include NE and Epi. NE is the primary neurotransmitter released at nerve terminals of the SANS. Epi is released from the adrenal medulla into the bloodstream to act at adrenergic receptors throughout the body. NE, Epi, dopamine (DA), and some adrenergic drugs such as isoproterenol, belong to the chemical class of catecholamines.
Drugs that activate the SANS are designated adrenergic drugs or sympathomimetics. These drugs are classified according to their mechanism of action, as either direct-acting or indirect-acting adrenergic medications. Direct-acting adrenergic agents bind to and have activity on the adrenergic receptors of the SANS. Indirect-acting adrenergic agents are drugs that cause the release of NE or block the termination of NE signaling. They are subdivided as releasers, reuptake inhibitors, and enzyme inhibitors. Mixed-acting agents act by both mechanisms to directly activate adrenergic receptors and to increase NE concentrations at synapses.
Endogenous NE and Epi are rapidly metabolized by MAO and COMT. As a result, NE and Epi are inactive when orally administered. Synthetic catecholamines and synthetic noncatecholamine sympathomimetics are resistant to MAO and COMT, and some have activity when administered orally.
Adrenergic receptors are distributed differentially on various effector organs and tissues and have been classified in two types: α (alpha) and β (beta) (see Medication Table 4-5). Additionally, there are two subtypes of each, known as α1, α2, β1, and β2. When discussing the pharmacologic effects of adrenergic drugs, it is important to note the proportion of activity at α or β receptors and the subclasses of receptors involved. For example, Epi is active at both α and β receptors, while NE is active primarily at α receptors but also at β1 receptors in the heart. Several newer drugs are very selective, acting primarily on α or β subclasses of receptors. The more selective an agent’s activity is, the narrower its spectrum of actions and side effects will be. Table 4-5 summarizes the actions of the SANS on the human body. An agent such as Epi, which is active on all four subclasses of receptors, can be expected to stimulate SANS receptors throughout the body when administered systemically. In contrast, a drug such as dobutamine, which is only active at β1 receptors, specifically increases the heart rate and force of contraction of the heart. This mechanism explains its use as an emergency drug to treat cardiac arrest.
Adrenergic Receptors, Distribution in the Body, and Effects of Their Activation
All SANS-innervated Tissues
All in List
Vascular smooth muscle
Pupillary dilator muscle
Pilomotor smooth muscle
Adrenergic nerve terminals
Inhibits NE release
Rate and force of contraction
Vascular smooth muscle
Glycogenolysis (increases blood sugar by releasing it from storage)
Adrenergic or sympathomimetic medications are available to treat pathologies in which any type of SANS stimulation is required. Examples of drugs with clinical applications are detailed in Medication Table 4-5.
What type of autonomic action does albuterol have that makes it effective for wheezing?
Epinephrine (Epi) is the endogenous agent released from the adrenal medulla (and also known as adrenaline) in emergency situations. Epi can act at all four subclasses of adrenergic receptors. Epi is clinically indicated in cases of anaphylactic shock (a widespread and very serious allergic reaction) by intramuscular (IM) or intravenous (IV) administration. It is also administered IV to produce vasoconstriction (narrowing of the blood vessels), increase blood pressure and the force of contraction of the heart, and induce bronchodilation. Other clinical applications of Epi include asthmatic crises and in combination with local anesthetics to prolong their duration of action. Epi is quickly metabolized in the tissues by both monoamine oxidase and catechol-O-methyltransferase, so it has a short duration of action. It does not reach the CNS and its potential toxicity is an extension of its pharmacological activities, causing adverse effects such as cardiac arrhythmia, excessive vasoconstriction, hypertension, and pulmonary edema.
What ANS effects does phenylephrine have? Why might an oral product containing this drug be contraindicated for Mr. Rosario?
Phenylephrine (Neo Synephrine), oxymetazoline, naphazoline, and similar agents are primarily α1 agonists that produce vasoconstriction and are used clinically to reduce nasal congestion or to treat conjunctivitis. These agents are primarily used locally as eye or nasal drops or nasal sprays. Side effects are extensions of their pharmacological effects if the drugs reach the systemic circulation. The vasoconstriction produced by these agents can lead to increases in blood pressure, but since they normally act locally at the site where they are administered, this is rarely an issue.
Phenylephrine can be used intravenously to increase blood pressure and heart rate in patients who are in a critical care setting.
Clonidine (Catapres) and guanfacine are typical α2 agonists. They are used to lower blood pressure and can act in the CNS. Clonidine is available in tablet form and as a patch, which is applied once weekly. If stopped abruptly clonidine can cause reflex hypertension, which may be quite severe. More information about its use as an antihypertensive is available in Chapter 15. The CNS actions of these agents are useful in treating attention deficit hyperactivity disorder (ADHD—see Chapter 7).
Isoproterenol (Isuprel) is a nonselective β agonist with activity at both β1 and β2 receptor types. It is poorly absorbed when administered orally and is usually administered intravenously to treat heart block and cardiac arrest. It was previously used to treat asthma, but its activity at β1 receptors produced many unwanted side effects, so that it has been supplanted by specific β2 agonists. Dobutamine is a more specific β1 agonist with important activities on the heart. This agent is used clinically to treat cardiac decompensation and heart failure, as well as some types of shock. It increases cardiac output and blood flow to tissues. Dopamine is also useful in cardiac patients but doesn’t have the selectivity that dobutamine does for the heart.
Different doses of dopamine are used in different clinical situations. Lower doses (2–5 mcg/kg/min) are used for a diuretic effect on the kidney and to increase kidney blood flow. This action is accomplished because of dopamine’s action on the D1 receptor present in the kidney. Medium doses (5–10 mcg/kg/min) are used to stimulate the heart’s β1 receptors leading to increased blood pressure and cardiac output for patients who are in shock. High doses (10–20 mcg/kg/min) are used to cause systemic vasoconstriction and further increase blood pressure by activation of α1 receptors.
Salmeterol (Serevent), albuterol (Ventolin, Proventil), levalbuterol (Xopenex), and other specific β2 agonists (considered in detail in Chapter 19) have primary actions on the bronchi, with few effects on the heart, making them the drugs of choice to treat asthma. These agents are absorbed orally, but they are used in the form of inhalers or nebulizers to reduce systemic adverse effects, including tachycardia and CNS stimulation.
Amphetamines (Adderall), methylphenidate (Ritalin or Concerta), dexmethylphenidate (Focalin), and lisdexamfetamine (Vyvanse) are agents that can cross the BBB and, while they have little or no effect on the SANS, they induce the release of the neurotransmitters NE and DA in the brain. These agents have a spectrum of stimulant effects, beginning with increasing alertness and reducing fatigue. Higher doses can produce anorexia, euphoria, and insomnia. They are used clinically to treat ADHD in both children and adults. Toxicity and adverse effects are extensions of their pharmacological effects and include nervousness, insomnia, decreased appetite, and, rarely, paranoia and convulsions.
Ephedrine and pseudoephedrine (Sudafed) are mixed-acting agents that can act directly on adrenergic receptors and may also induce NE release. Pseudoephedrine is less able to penetrate the BBB and therefore has fewer CNS effects. Pseudoephedrine, which alleviates nasal congestion, is used clinically to treat common colds and allergies and is available over the counter. Ephedrine is administered intravenously in emergency situations, and is also available in combination with guaifenesin, in an oral tablet for asthma relief. The adverse effects of pseudoephedrine include increased blood pressure, tachycardia, and excitability. Misuse or overdoses of these agents produce CNS stimulation, insomnia, anxiety, and psychotic episodes.
Ephedrine or pseudoephedrine can be used as a precursor in the illicit manufacture of methamphetamine. Federal law limits quantities sold and requires that even nonprescription dosage forms of these drugs be kept “behind the counter.” Some state laws are even more restrictive.
Indirect Reuptake Inhibitors
Cocaine is a natural agent with a mechanism of action combining the inhibition of reuptake transporters of NE in the body and DA in the CNS. Cocaine crosses the BBB and increases the concentration and signaling of NE and DA in the synapses there but can also cause increased blood pressure and tachycardia by peripheral effects on the ANS, as well as produce local anesthesia. One clinical application for cocaine is as an anesthetic in facial surgery. In addition, antidepressants are inhibitors of the NE reuptake transporter and act by increasing both concentration and signaling of NE as well as those of other neurotransmitters in the brain. See Chapter 7 for more information on antidepressants.
Monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT) inhibitors such as selegiline and entacapone prevent the enzyme-mediated degradation of NE, dopamine, and chemically similar neurotransmitters. These agents are used to treat Parkinson disease and for their antidepressant actions, and their side effects are mostly a result of stimulation of the SANS by the excess (undegraded) NE. See Chapters 6 and 7 for more information on COMT and MAO inhibitors.
Adrenergic antagonists (blocking agents) are drugs that decrease or prevent the stimulation of SANS receptors. Some adrenergic antagonists can cause blockade at all types of adrenergic receptors, while others are specific and act at one type or subtype. α- and β-blocking drugs are considered separately because they exhibit markedly different pharmacological effects. Representative adrenergic antagonists are listed in Medication Table 4-6.
Alpha-Adrenergic Blocking Agents
Nonspecific α Blockers
Agents of this type have affinity for both α1- and α2-adrenergic receptors. They attach to the receptors without stimulating them and competitively block the physiological effects of both NE and Epi at these sites. The most important effect of nonselective alpha blockers on the cardiovascular system is reduced blood pressure. They do not produce direct cardiac effects but may produce a reflex tachycardia.
Phentolamine is a nonselective, competitive, and reversible blocking agent that binds to both α1- and α2-adrenergic receptors, preventing the binding of NE and Epi at those spots. Phentolamine (OraVerse) has a duration action of about 2–4 hours when taken orally and 20–40 minutes when administered parenterally. Phentolamine is used to treat hypertension associated with pheochromocytoma (a tumor of the adrenal medulla that secretes excessive Epi and NE), and to prevent the effects of norepinephrine extravasation, as well as to reverse the effects of some oral anesthesia. Another medication used in the treatment of hypertension due to pheochromocytoma is phenoxybenzamine. Phenoxybenzamine has a longer duration of action than phentolamine since the binding of phenoxybenzamine to α receptors is irreversible.
Prazosin (Minipress), terazosin, and doxazosin (Cardura) are very selective, reversible α1 blockers that have little or no effect on the other SANS receptors. Their duration of action is about 8–10 hours. They have clinical applications in the management of hypertension and prevention of urinary retention in men with benign prostatic hyperplasia. These medications cause much less tachycardia than nonselective α blockers but do cause orthostatic hypotension. For more information on the use of these drugs for hypertension see Chapter 15, and for benign prostatic hyperplasia see Chapter 11.
Yohimbine has affinity for α2-adrenergic receptors, where it acts as a competitive antagonist; however, it also has affinity for serotonin and DA receptors. This drug had been used clinically to treat male impotence and sexual dysfunction caused by antidepressants, but it has been replaced by newer, non-SANS agents with fewer and less intense side effects. Yohimbine has significant side effects, such as anxiety, hypertension, tachycardia, insomnia, hallucinations, and skin flushing. It has a narrow therapeutic index; overdoses can be harmful and dangerous. While it no longer has FDA-approved indications, it is a component of some OTC herbal supplements containing yohimbe derivatives.
Beta-Adrenergic Blocking Agents
These drugs, commonly called beta blockers, competitively block β receptors in the SANS. As mentioned above, β-receptor activation results in vasodilation, bronchodilation, and tachycardia; therefore, β blockers antagonize these effects, producing lower heart rates and bronchoconstriction. The primary applications of these agents are the treatment of cardiovascular pathologies such as hypertension, angina pectoris, arrhythmia prophylaxis after myocardial infarction, and congestive heart failure. Pheochromocytoma is sometimes treated with combined α and β blockers, especially if the tumor is producing large amounts of both Epi and NE. Some of these agents are used in the form of eye drops to treat glaucoma.7 The toxicities of these agents are extensions of the β blockade and can include bradycardia, atrioventricular blockade, and arrhythmia. Some of these agents, such as propranolol, metoprolol, pindolol, timolol, and labetalol can cross the BBB and result in sedation, fatigue, and sleep alterations. Patients with asthma or other reactive airway diseases may have worsening of their condition unless a selective β1 blocker is used, but β blocker use is generally cautioned in these patients.
These agents have effects on the heart and cardiovascular system (β1 receptors) and on the bronchi (β2 receptors). More information on these medications can be found in the chapters covering the conditions they are used to treat. Carteolol, levobunolol, and metipranolol are nonselective β blockers administered as eye drops in the treatment of glaucoma, and they work by decreasing aqueous humor production.3 Nadolol (Corgard), propranolol (Inderal), and timolol are all used to treat hypertension or other cardiovascular conditions. Carvedilol (Coreg) and labetalol are antagonists at both β receptors and at α1 receptors and are also used to treat high blood pressure.
These agents have more antagonist effects on the actions of the SANS in the heart and blood vessels, and little action in the lungs. This specificity results in fewer side effects and a lower risk of exacerbating asthma symptoms. Medications in the class include atenolol (Tenormin), metoprolol (Lopressor), and others. These agents are all used to treat high blood pressure and prevent heart failure; more information on them can be found in Chapters 15 and 16.
The autonomic nervous system (ANS) is the part of the nervous system that is responsible for the coordination and regulation of body functions. The ANS has two functional divisions, the parasympathetic autonomic nervous system (PANS) and the sympathetic autonomic nervous system (SANS), which have opposing functions but work in a coordinated manner to maintain homeostasis. The ANS functions by rapid transmission of nerve impulses through innervations that terminate at organs or tissues releasing a neurotransmitter. The effector cells respond to the release of neurotransmitters, which activate specific receptors. Pathological disorders or diseases can arise from excessive activation or inhibition of either division of the ANS. Medications used to treat these disorders act at the level of the neurotransmitters and receptors, working to balance the functions of the ANS.
The author wishes to acknowledge and thank Raymond A. Lorenz, PharmD, BCPP, Alejandro Pino-Figueroa, PhD, Mark Böhlke, PhD, Timothy J. Maher, PhD, Karen A. Newell, MMSc, PA-C, and Elizabeth P. Rothschild, MMSc, PA-C, contributors to this chapter in the first edition of this book.
WestfallTC, MacarthurH, WestfallDP.Neurotransmission: The autonomic and somatic motor nervous systems. In: BruntonLL, Hilal-DandanR, KnollmannBC., eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw-Hill; 2017.
WestfallTC, MacarthurH, WestfallDP.Neurotransmission: The autonomic and somatic motor nervous systems. In: BruntonLL, Hilal-DandanR, KnollmannBC., eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw-Hill; 2017.)| false
AmatoAA.Myasthenia gravis and other diseases of the neuromuscular junction. In: JamesonJ, FauciAS, KasperDL, et al., eds. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw-Hill; 2018.
AmatoAA.Myasthenia gravis and other diseases of the neuromuscular junction. In: JamesonJ, FauciAS, KasperDL, et al., eds. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw-Hill; 2018.)| false
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SkidgelRA.Histamine, bradykinin, and their antagonists. In: BruntonLL, Hilal-DandanR, KnollmannBC., eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw-Hill; 2017.)| false
Oral or SL: 0.125–0.25 mg q 4 hr or as needed; oral, timed release: 0.375–0.75 mg q 12 hr; IM, IV, SUBQ: 0.25–0.5 mg given 5–10 min prior to procedure
Oral: peptic ulcers, irritable bowel, neurogenic bladder/bowel; injection: preoperative to reduce secretions and block cardiac vagal inhibitory reflexes; to improve radiologic visibility of the kidneys
Antimuscarinic: blockade of muscarinic receptors limits bladder contractions, reducing the symptoms of bladder irritability/overactivity (urge incontinence, urgency and frequency)
Oral: tablet, extended release
7.5–15 mg once daily
Used in the management of symptoms of bladder overactivity; tablet should be taken with liquid and swallowed whole
Fesoterodine (fes oh TER oh deen)
Converted in the body to a competitive Ach antagonist at muscarinic receptors
Oral: tablet, extended release
4 mg once daily; may be increased to 8 mg once daily
Treatment of patients with an overactive bladder with symptoms of urinary frequency, urgency, or urge incontinence; do not crush
Flavoxate (fla VOX ate)
Synthetic antispasmodic with a direct relaxant effect on smooth muscles, providing symptomatic relief for a variety of smooth muscle spasms, especially urinary tract
100–200 mg 3–4 times/day
Should be taken with water on an empty stomach; may cause CNS depression
Oxybutynin (ox i BYOO ti nin)
Ditropan XL, Gelnique, Oxytrol
Inhibits action of Ach on bladder muscle and acts as a direct antispasmodic; increases bladder capacity, decreases uninhibited contractions, and delays desire to void—therefore, decreases urgency and frequency