The two groups of drugs that affect the parasympathetic nervous system are the (1) cholinergic agonists (parasympathomimetics) and the (2) anticholinergics (parasympatholytics). The Unit V opener offers a discussion and comparison of the parasympathetic nervous system (parasympathomimetics and parasympatholytics) and the sympathetic nervous system.

Cholinergic Agonists

Drugs that stimulate the parasympathetic nervous system are called cholinergic agonists, or parasympathomimetics, because they mimic the parasympathetic neurotransmitter acetylcholine. Cholinergic agonists are also called cholinomimetics or cholinergic stimulants. Acetylcholine (ACh) is the neurotransmitter located at the ganglions and the parasympathetic terminal nerve endings. It innervates cholinergic receptors in organs, tissues, and glands. The two types of cholinergic receptors are (1) muscarinic receptors, which stimulate smooth muscle and slow the heart rate; and (2) nicotinic receptors (neuromuscular), which affect the skeletal muscles. Many cholinergic agonists are nonselective because they can affect both the muscarinic and nicotinic receptors. However, there are selective cholinergic agonists for the muscarinic receptors that do not affect the nicotinic receptors. Figure 19-1 illustrates the effects of parasympathetic or cholinergic stimulation.

FIGURE 19-1 Parasympathetic responses. Stimulation of the parasympathetic nervous system or use of parasympathomimetic drugs will cause the pupils to constrict, bronchioles to constrict and bronchial secretions to increase, heart rate to decrease, blood vessels to dilate, peristalsis and gastric secretions to increase, the bladder muscle to contract, and salivary glands to increase salivation.

There are direct-acting cholinergic agonists and indirect-acting cholinergic agonists. Direct-acting cholinergic agonists act on receptors to activate a tissue response (Figure 19-2, A). Indirect-acting cholinergic agonists inhibit the action of the enzyme cholinesterase (ChE) (acetylcholinesterase) by forming a chemical complex, thus permitting acetylcholine to persist and attach to the receptor (Figure 19-2, B). Drugs that inhibit cholinesterase are called cholinesterase inhibitors, acetylcholinesterase (AChE) inhibitors, or anticholinesterases. Cholinesterase may destroy acetylcholine before it reaches the receptor or after it has attached to the site. By inhibiting or destroying the enzyme cholinesterase, more acetylcholine is available to stimulate the receptor and remain in contact with it longer.

FIGURE 19-2 A, Direct-acting parasympathomimetic (cholinergic agonist). Cholinergic agonists resemble acetylcholine and act directly on the receptor. B, Indirect-acting parasympathomimetic (cholinesterase inhibitor). Cholinesterase inhibitors inactivate the enzyme acetylcholinesterase (cholinesterase), thus permitting acetylcholine to react to the receptor. *ACh,* Acetylcholine; *AChE,* acetylcholinesterase or cholinesterase; D, cholinergic agonist; *DD,* cholinesterase inhibitor (anticholinesterase).

Cholinesterase inhibitors (anticholinesterases) can be separated into reversible inhibitors and irreversible inhibitors. The reversible inhibitors bind the enzyme cholinesterase for several minutes to hours, and the irreversible inhibitors bind the enzyme permanently. The resulting effects vary with how long the cholinesterase is bound.

The major responses of cholinergic agonists are to stimulate bladder and gastrointestinal (GI) tone, constrict the pupils of the eyes (miosis), and increase neuromuscular transmission. Other effects of cholinergic agonists include decreased heart rate and blood pressure and increased salivary, GI, and bronchial glandular secretions. Table 19-1 lists the functions of direct- and indirect-acting cholinergic agonists.

TABLE 19-1

EFFECTS OF CHOLINERGIC AGONISTS

BODY TISSUE	RESPONSE
Cardiovascular*	Decreases heart rate, lowers blood pressure because of vasodilation, and slows conduction of atrioventricular node.
Gastrointestinal^†	Increases tone and motility of smooth muscle of stomach and intestine. Increases peristalsis and relaxes sphincter muscles.
Genitourinary	Contracts muscles of the urinary bladder, increases tone of ureters, and relaxes bladder’s sphincter muscles. Stimulates urination.
Ocular^†	Increases pupillary constriction, or miosis (pupil becomes smaller) and increases accommodation (flattening or thickening of eye lens for distant or near vision).
Glandular*	Increases salivation, perspiration, and tears.
Bronchial (lung)*	Stimulates bronchial smooth muscle contraction and increases bronchial secretions.
Striated muscle^†	Increases neuromuscular transmission and maintains muscle strength and tone.

*Tissue responses to large doses of cholinergic agonists.

^†Major tissue responses to normal doses of cholinergic agonists.

Direct-Acting Cholinergic Agonists

Many drugs classified as direct-acting cholinergic agonists are primarily selective to the muscarinic receptors but are nonspecific because the muscarinic receptors are located in the smooth muscle of the GI and genitourinary tracts, glands, and heart. Bethanechol chloride (Urecholine), a direct-acting cholinergic agonist, acts on the muscarinic (cholinergic) receptor and is used primarily to increase micturition (urination) in the treatment of urinary retention and neurogenic bladder. Metoclopramide HCl (Reglan) is a direct-acting cholinergic agonist that is usually prescribed to treat gastroesophageal reflux disease (GERD). Metoclopramide accelerates gastric emptying time. Prototype Drug Chart 19-1 details the pharmacologic behavior of bethanechol, which is a classic cholinergic agonist.

Prototype Drug Chart 19-1

Bethanechol Chloride

Drug Class	Dosage
Cholinergic: parasympathomimetic Trade Names: Urecholine Pregnancy Category: C	A: PO: 10-50 mg t.i.d./q.i.d.; max: 200 mg/d
Contraindications	Drug-Lab-Food Interactions
Contraindicated: Intestinal or urinary tract obstruction, severe bradycardia, hypotension, COPD, asthma, peptic ulcer, parkinsonism.	Drug: Decreases bethanechol effect with antidysrhythmics (e.g., procainamide); ganglionic blocking agents (e.g., mecamylamine) cause significant hypotension and false test results (amylase, lipase); atropine counteracts bethanechol action Lab: Increases AST, bilirubin, amylase, lipase
Pharmacokinetics	Pharmacodynamics
Absorption: PO: Poorly absorbed Distribution: PB: UK Metabolism: : UK Excretion: In urine	PO: Onset: 0.5-1.5 h Peak: 1-2 h Duration: 4-6 h
Therapeutic Effects/Uses
To treat urinary retention
Mode of Action: Stimulates the cholinergic (muscarinic) receptors; promotes contraction of the bladder; increases GI secretions and peristalsis, pupillary constriction, and bronchoconstriction
Side Effects	Adverse Reactions
Nausea, vomiting, diarrhea, abdominal cramps, salivation, sweating, flushing, frequent urination, blurred vision, miosis	Orthostatic hypotension, bradycardia, muscle weakness Life-threatening: Acute asthma attack, heart block, circulatory collapse, cardiac arrest

A, Adult; AST, aspartate aminotransferase; b.i.d., two times a day; COPD, chronic obstructive pulmonary disease; d, day; GI, gastrointestinal; h, hour; IM, intramuscular; IV, intravenous; min, minute; PB, protein-binding; PO, by mouth; PRN, as needed; q.i.d., four times a day; subQ, subcutaneous; , half-life; t.i.d., three times a day; UK, unknown.

Pharmacokinetics

Bethanechol chloride (Urecholine) is poorly absorbed from the GI tract. The percentage of protein-binding and the half-life are unknown. The drug is most likely excreted in the urine.

Pharmacodynamics

The principal use of bethanechol is to promote micturition by stimulating the muscarinic cholinergic receptors in the detrusor muscle to contract the bladder and produce urine output. The patient voids approximately 30 minutes to 1.5 hours after taking an oral dose of bethanechol because of the increased tone of the detrusor muscle. Bethanechol also increases peristalsis in the GI tract. The drug should be taken on an empty stomach. It should not be administered by injection.

Side Effects and Adverse Reactions

Mild to severe side effects of most muscarinic agonists such as bethanechol include hypotension, bradycardia, blurred vision, excessive salivation, increased gastric acid secretion, abdominal cramps, diarrhea, bronchoconstriction, and, in some cases, cardiac dysrhythmias. This group of agents should be prescribed cautiously for patients with low blood pressure and heart rates. Muscarinic agonists are contraindicated for patients with intestinal or urinary tract obstruction, severe bradycardia, and for those with active asthma.

Direct-Acting Cholinergics: Eye

Pilocarpine is a direct-acting cholinergic agonist that constricts the pupils of the eyes, thus opening the canal of Schlemm to promote drainage of aqueous humor (fluid). This drug is used to treat glaucoma by relieving fluid (intraocular) pressure in the eye and to promote miosis in eye surgery and examinations. An oral form of pilocarpine is used to relieve xerostomia (dry mouth). Pilocarpine also acts on the nicotinic receptor, as does carbachol. Both agents are discussed in more detail in Chapter 49.

Indirect-Acting Cholinergic Agonists

The indirect-acting cholinergic agonists do not act on receptors; instead they inhibit or inactivate the enzyme cholinesterase, permitting acetylcholine to accumulate at the receptor sites (see Figure 19-2, B). This action gives them the name cholinesterase (ChE) inhibitors, acetylcholinesterase (AChE) inhibitors, or anticholinesterases, of which there are two types: reversible and irreversible.

Nursing Process

Patient-Centered Collaborative Care

Cholinergic Agonist, Direct Acting: Bethanechol (Urecholine)

Assessment

Assess baseline vital signs for future comparison.

Assess urine output (should be >1500 mL/d).

Obtain patient history of health problems such as peptic ulcer, urinary obstruction, or asthma. Cholinergic agonists can aggravate symptoms of these conditions.

Nursing Diagnoses

Impaired urinary elimination related to urinary retention

Anxiety related to wheezing

Risk for impaired skin integrity related to rash

Ineffective breathing pattern related to excess mucous secretions in lungs

Planning

Patient will have increased bladder tone after taking cholinergic agonists.

Nursing Interventions

Monitor patient’s vital signs. Heart rate and blood pressure decrease when large doses of cholinergics are taken. Orthostatic hypotension is a side effect of a cholinergic agonist such as bethanechol.

Record fluid intake and output. Decreased urinary output should be reported because it may be related to urinary obstruction.

Give cholinergic agonists 1 hour before or 2 hours after meals. If patient complains of gastric pain, the drug may be given with meals.

Check serum amylase, lipase, aspartate aminotransferase, and bilirubin levels. These laboratory values may increase slightly when taking cholinergic agonists.

Observe patient for side effects such as gastric pain or cramping, diarrhea, increased salivary or bronchial secretions, bradycardia, and orthostatic hypotension.

Auscultate breath sounds for rales (cracking sounds from fluid congestion in lungs) or rhonchi (rough sounds resulting from mucous secretions in lungs). Cholinergic agonists can increase bronchial secretions.

Have IV atropine sulfate (0.6 mg to 1.2 mg) available as an antidote for cholinergic overdose. Early signs of overdosing include flushing, salivation, sweating, nausea, and abdominal cramps.

Increase bathing frequency and linen change when needed. Diaphoresis (excessive perspiration) may occur.

Monitor for possible cholinergic crisis (overdose) including symptoms of muscular weakness and increased salivation.

Patient Teaching

Teach patient to take the cholinergic agonist as prescribed. Compliance with the drug regimen is essential.

Direct patient to report severe side effects, such as profound dizziness or a decrease in heart rate below 60 beats/min.

Teach patient to arise from a lying position slowly to avoid dizziness. This is most likely a result of orthostatic hypotension.

Encourage patient to maintain effective oral hygiene if excess salivation occurs.

Advise patient to report any difficulty in breathing as a result of respiratory distress.

Cultural Considerations

Use both hands to show respect when offering a prescription, instructions, or pamphlets to Asians and Pacific Islanders.

Recognize the importance of including women in decision making and disseminating health information. The extended family structure is important for teaching health strategies and providing support.

Evaluation

Determine the effectiveness of the cholinergic agonist or anticholinesterase drug.

Evaluate the stability of patient’s vital signs, and note the presence of side effects or adverse reactions.

The function of the enzyme cholinesterase is to break down into choline and acetic acid. A small amount of cholinesterase can break down a large amount of acetylcholine in a short period. A cholinesterase inhibitor drug binds with cholinesterase, allowing acetylcholine to activate the muscarinic and nicotinic cholinergic receptors. This action permits skeletal muscle stimulation, which increases the force of muscular contraction. Because of this action, cholinesterase inhibitors are useful to increase muscle tone for patients with myasthenia gravis (a neuromuscular disorder). By increasing acetylcholine, additional effects occur, such as increase in GI motility, bradycardia, miosis, bronchial constriction, and increased micturition.

The primary use of reversible cholinesterase inhibitors is to treat myasthenia gravis; another use is to treat Alzheimer’s disease. The primary clinical indication for irreversible cholinesterase inhibitors is glaucoma.

Reversible Cholinesterase Inhibitors

Reversible cholinesterase inhibitors are used (1) to produce pupillary constriction in the treatment of glaucoma and (2) to increase muscle strength in patients with myasthenia gravis. Drug effects persist for several hours. Drugs used to increase muscular strength in myasthenia gravis include neostigmine (Prostigmin [short-acting]), pyridostigmine bromide (Mestinon [moderate-acting]), ambenonium chloride (Mytelase [long-acting]), and edrophonium chloride (Tensilon [short-acting for diagnostic purposes]). These drugs are discussed in more detail in Chapter 24. A reversible anticholinesterase drug is physostigmine (Antilirium) or ophthalmic form (Isopto Eserine). Physostigmine is used as an antidote for atropine to reverse anticholinergic toxicity. Ophthalmic agents are further discussed in Chapter 49.

Side Effects

Caution for reversible cholinesterase inhibitors is required for patients who have bradycardia, asthma, peptic ulcers, or hyperthyroidism. Cholinesterase inhibitors are contraindicated for patients with intestinal or urinary obstruction.

Irreversible Cholinesterase Inhibitors

Irreversible cholinesterase inhibitors are potent agents because of their long-lasting effect. The enzyme cholinesterase must be regenerated before the drug effect diminishes—a process that may take days or weeks. These drugs are used to produce pupillary constriction.

Table 19-2 lists examples of cholinergic drugs and their standard dosages and common uses.

TABLE 19-2

CHOLINERGIC AGONISTS

GENERIC (BRAND)	ROUTE AND DOSAGE	USES AND CONSIDERATIONS
Direct-Acting Cholinergic Agonists
bethanechol Cl (Urecholine)	See Prototype Drug Chart 19-1.
metoclopramide HCl (Reglan)	A: PO: 5-10 mg q8h PRN	For GERD, gastroparesis, and nausea. Central dopamine receptor antagonist. Increases gastric emptying time. Pregnancy category: B; PB: 30%; : 2.5-6 h
carbachol (Miostat)	Ophthalmic: 0.75%-3%, 1-2 gtt, 3 daily	To reduce IOP, miosis. See Chapter 49.
pilocarpine HCl (Pilocar)	Ophthalmic: 0.5%-4%, 1 gt	To reduce IOP, miosis. See Chapter 49.
Cholinesterase Inhibitor
donepezil HCl (Aricept); rivastigmine (Exelon)	See Chapter 23, Table 23-6.
*Indirect-Acting Cholinergics or Cholinesterase Inhibitors for the Eye*
demecarium bromide (Humorsol)	0.125%-0.25%, 1 gt q12-48h	To reduce IOP in glaucoma; long-acting miotic. See Chapter 49.
echothiophate iodide (Phospholine Iodide)	0.03%-0.25%, 1 gt daily or b.i.d.	To reduce IOP; long-acting miotic. See Chapter 49.
isoflurophate (Floropryl)	0.25%, ointment q8-72h	To treat glaucoma. Apply to the conjunctival sac. See Chapter 49.
Reversible Cholinesterase Inhibitors: Myasthenia Gravis
ambenonium Cl (Mytelase)	A: PO: 2.5-5 mg t.i.d./q.i.d.; dose may be increased; maint: 50-75 mg t.i.d./q.i.d.	To increase muscle strength in myasthenia gravis; long-acting. May be used with glucocorticoids. Pregnancy category: C; PB: UK; : UK
edrophonium Cl (Tensilon)	A: IV: 2 mg; then 8 mg if no response IM: 10 mg; may repeat with 2 mg in 30 min C: <34 kg: IV: 1 mg; repeat in 30-45 sec if no response; max: 5 mg C: >34 kg: IV: 2 mg; repeat with 1 mg if no response; max: 10 mg	To diagnose myasthenia gravis; very short-acting. Pregnancy category: C; PB: UK; : 1.2-2 h
neostigmine methylsulfate (Prostigmin)	A: 15 mg t.i.d.; gradually increase to maintenance dose of 150 mg; max: 375 mg/d A: IM/IV: 0.5-2.5 mg q1-3h; max: 10 mg/d C: IM/IV: 0.01-0.04 mg/kg q2-4h	To increase muscle strength in myasthenia gravis; short-acting. Used also to prevent or treat postoperative urinary retention. Pregnancy category: C; PB: 15%-25%; : 1-1.5 h
physostigmine salicylate (Antilirium); (Isopto Eserine Salicylate-ophthalmic form)	A: IV/IM: 0.5-2 mg/dose, repeat q10-30min PRN; C: IV: 0.02 mg/kg/dose, repeat q5-10 min PRN; max: 2 mg total A: 0.25% to 0.5%, 1-2 gtt daily or q.i.d.; max: 8 gtt/d	To reverse anticholinergic toxicity and to reduce IOP, miosis; short-acting. Pregnancy category: C; PB: UK; : 15-40 min
pyridostigmine bromide (Mestinon)	A: PO: 60-120 mg t.i.d./q.i.d.; maint: 600 mg/d in 3-4 divided doses; SR: 180-540 mg daily or b.i.d. IM/IV: 2 mg q2-3h C: PO: 7 mg/kg/d in 5-6 divided doses	To increase muscle strength in myasthenia gravis. Prevents destruction of the neurotransmitter acetylcholine. Pregnancy category: C; PB: 10%; : 3-4 h
Antidote for Irreversible and Reversible Cholinesterase Inhibitors
pralidoxime Cl (Protopam)	A: IV: 1-2 g in 100 mL of saline solution infused over 15-30 min; follow with 250 mg q5min PRN	To treat overdose of a cholinesterase inhibitor for myasthenia gravis and to treat overdose of organophosphate pesticides that cause muscle paralysis. Pregnancy category: C; PB: UK; : 1-2.7 h