Cholinergic Drugs
Objectives
When you reach the end of this chapter, you will be able to do the following:
Drug Profiles
Key Terms
Acetylcholine The neurotransmitter responsible for transmission of nerve impulses to effector cells in the parasympathetic nervous system. (p. 325)
Acetylcholinesterase The enzyme responsible for the breakdown of acetylcholine (also referred to simply as cholinesterase). (p. 325)
Alzheimer’s disease A disease of the brain that is characterized by progressive mental deterioration manifested by confusion, disorientation, and loss of memory, ability to calculate, and visual-spatial orientation. (p. 327)
Atony A lack of normal muscle tone (p. 326)
Cholinergic crisis Severe muscle weakness and respiratory paralysis due to excessive acetylcholine; often seen in patients with myasthenia gravis as an adverse effect of drugs used to treat the disorder (p. 327)
Cholinergic receptor A nerve receptor that is stimulated by acetylcholine. (p. 325)
Miosis The contraction of the pupil. (p. 326)
Muscarinic receptors Cholinergic receptors that are located postsynaptically in the effector organs such as smooth muscle, cardiac muscle, and glands supplied by parasympathetic fibers. (p. 325)
Nicotinic receptors Cholinergic receptors located in the ganglia (where presynaptic and postsynaptic nerve fibers meet) of both the parasympathetic nervous system and the sympathetic nervous system; so named because they can be stimulated by the alkaloid nicotine. (p. 325)
Parasympathomimetics Drugs that mimic the parasympathetic nervous system; also referred to as cholinergic agonist drugs. (p. 325)
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Anatomy, Physiology, and Pathophysiology Overview
Cholinergic drugs, cholinergic agonists, and parasympathomimetics are all terms that refer to the class of drugs that stimulate the parasympathetic nervous system.
Parasympathetic Nervous System
The parasympathetic nervous system (PNS) is the branch of the autonomic nervous system with functions opposite those of the sympathetic nervous system (Figure 20-1). Acetylcholine is the neurotransmitter responsible for the transmission of nerve impulses to effector cells in the parasympathetic nervous system. A cholinergic receptor is a receptor that binds acetylcholine and mediates its actions. There are two types of cholinergic receptors, as determined by their location and their action. Nicotinic receptors are located in the ganglia of both the parasympathetic nervous system and sympathetic nervous system. They are called nicotinic because they can also be stimulated by nicotine. The other type of cholinergic receptor is the muscarinic receptor. Muscarinic receptors are located postsynaptically in the effector organs (i.e., smooth muscle, cardiac muscle, and glands) supplied by the parasympathetic fibers. They are called muscarinic because they are stimulated by the alkaloid muscarine, a substance isolated from mushrooms. Figure 20-2 shows how the nicotinic and muscarinic receptors are arranged in the parasympathetic nervous system.
Pharmacology Overview
Cholinergic Drugs
Cholinergic drugs, also known as cholinergic agonists or parasympathomimetics, mimic the effects of acetylcholine. These drugs can stimulate cholinergic receptors either directly or indirectly. Direct-acting cholinergic agonists bind directly to cholinergic receptors and activate them. Indirect-acting cholinergic agonists stimulate the postsynaptic release of acetylcholine at the receptor site. This then allows acetylcholine to bind to and stimulate the receptor. Indirect-acting cholinergic drugs (also known as cholinesterase inhibitors) work by inhibiting the action of acetylcholinesterase, the enzyme responsible for breaking down acetylcholine. Acetylcholinesterase is also referred to as cholinesterase. There are two categories of cholinesterase inhibitors: reversible inhibitors and irreversible inhibitors. Reversible cholinesterase inhibitors bind to cholinesterase for a short period of time, whereas irreversible cholinesterase inhibitors have a long duration of activity, and the body must generate new cholinesterase enzymes to override the effects of the irreversible drugs. Box 20-1 lists the direct- and indirect-acting cholinergics.
Mechanism of Action and Drug Effects
When acetylcholine directly binds to its receptor, stimulation occurs. Once binding takes place on the membranes of an effector cell (cell of the target tissue or organ), the permeability of the cell changes, and calcium and sodium are permitted to flow into the cell. This then depolarizes the cell membrane and stimulates the effector organ.
The effects of direct- and indirect-acting cholinergic drugs are seen when the parasympathetic nervous system is stimulated. There are many mnemonics to aid in remembering these effects. One is to think of the parasympathetic nervous system as the “rest and digest” system, in contrast to the “flight or fight” sympathetic nervous system.
Cholinergic drugs are used primarily for their effects on the gastrointestinal tract, bladder, and eye. These drugs stimulate the intestine and bladder, which results in increased gastric secretions, gastrointestinal (GI) motility, and urinary frequency. They also stimulate constriction of the pupil, termed miosis. This helps decrease intraocular pressure. In addition, cholinergic drugs cause increased salivation and sweating. Cardiovascular effects include reduced heart rate and vasodilation. Pulmonary effects include causing the bronchi of the lungs to constrict and the airways to narrow.
At recommended dosages, cholinergic drugs primarily affect the muscarinic receptors, but at high dosages the nicotinic receptors can also be stimulated. The desired effects come from muscarinic receptor stimulation; many of the undesirable adverse effects are due to nicotinic receptor stimulation. The various effects of the cholinergic drugs are listed in Table 20-1 according to the receptors stimulated.
TABLE 20-1
CHOLINERGIC AGONISTS: DRUG EFFECTS
| Response to Stimulation | ||
| BODY TISSUE/ORGAN | MUSCARINIC | NICOTINIC |
| Bronchi (lung) | Increased secretions, constriction | None |
| Cardiovascular | ||
| Blood vessels | Dilation | Constriction |
| Heart rate | Slowed | Increased |
| Blood pressure | Decreased | Increased |
| Eye | Miosis (pupil constriction), decreased accommodation | Miosis (pupil constriction), decreased accommodation |
| Gastrointestinal | ||
| Tone | Increased | Increased |
| Motility | Increased | Increased |
| Sphincters | Relaxed | None |
| Genitourinary | ||
| Tone | Increased | Increased |
| Motility | Increased | Increased |
| Sphincter | Relaxed | Relaxed |
| Glandular secretions | Increased intestinal, lacrimal, salivary, and sweat gland secretion | — |
| Skeletal muscle | — | Increased contraction |
Indications
Direct-Acting Drugs
Direct-acting drugs, such as carbachol, pilocarpine, and echothiophate, are used topically to reduce intraocular pressure in patients with glaucoma or in those undergoing ocular surgery (see Chapter 57). They are poorly absorbed orally, which limits their use mostly to topical application. One exception is the direct-acting cholinergic drug bethanechol, which is administered orally. Bethanechol affects the detrusor muscle of the urinary bladder and also the smooth muscle of the GI tract. It causes increased bladder and GI tract tone and motility, which increases the movement of contents through these areas. It also causes the sphincters in the bladder and the GI tract to relax, allowing them to empty. Bethanechol is also used to treat atony of the bladder and GI tract. Atony can occur after a surgical procedure. The direct-acting drug, cevimeline, is used to treat excessively dry mouth (xerostomia) resulting from a disorder known as Sjögren’s syndrome. Oral pilocarpine can also be used for this purpose. Another direct-acting cholinergic is succinylcholine, which is used as a neuromuscular blocker in general anesthesia (see Chapter 11).
Indirect-Acting Drugs
Indirect-acting drugs work by increasing acetylcholine concentrations at the receptor sites, which leads to stimulation of the effector cells. Indirect-acting drugs cause skeletal muscle contraction and are used for the diagnosis and treatment of myasthenia gravis. Their ability to inhibit acetylcholinesterase also makes them useful for the reversal of neuromuscular blockade produced either by neuromuscular blocking drugs or by anticholinergic poisoning. For this reason, the indirect-acting drug physostigmine is considered the antidote for anticholinergic poisoning as well as poisoning by irreversible cholinesterase inhibitors such as the organophosphates and carbonates, common classes of insecticides.
Indirect-acting drugs are also used to treat Alzheimer’s disease, which is a neurologic disorder in which patients have decreased levels of acetylcholine. In the treatment of Alzheimer’s disease, cholinergic drugs increase concentrations of acetylcholine in the brain by inhibiting cholinesterase. This increase in acetylcholine levels helps to enhance and maintain memory and learning capabilities. There are three cholinesterase inhibitors used to treat Alzheimer’s disease, including donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon); all are indirect-acting cholinergic drugs. Although their therapeutic efficacy is often limited (it has been reported that only 15% to 30% of patients treated actually see benefits), these drugs may enhance a patient’s mental status enough to cause a noticeable, if temporary, improvement in the quality of life for patients as well as caregivers and family members. The most commonly used of these medications at this time is donepezil. Patient response to these drugs is highly variable. For this reason, failure to respond to maximally titrated dosages of one of these drugs does not necessarily rule out an attempt at therapy with another drug in this same class. Memantine (Namenda) is also used to treat Alzheimer’s disease, but it is not a cholinesterase inhibitor. For dosage information on all of these drugs, see the table on p. 328.
Contraindications
Contraindications to the use of cholinergic drugs include known drug allergy, GI or genitourinary (GU) tract obstruction, bradycardia, defects in cardiac impulse conduction, hyperthyroidism, epilepsy, hypotension, or chronic obstructive pulmonary disease. Parkinson’s disease (see Chapter 15) is listed as a precaution to these drugs; however, rivastigmine (Exelon) is used in patients with Parkinson’s disease who also have dementia.
Adverse Effects
The primary adverse effects of cholinergic drugs are the consequence of overstimulation of the parasympathetic nervous system. They are extensions of the cholinergic reactions that affect many body functions. The major effects are listed by body system in Table 20-2. The effects on the cardiovascular system are complex and may include syncope, hypotension with reflex tachycardia, hypertension, or bradycardia, depending on if the muscarinic or nicotinic receptors are stimulated.
TABLE 20-2
CHOLINERGIC AGONISTS: ADVERSE EFFECTS
| BODY SYSTEM | ADVERSE EFFECTS |
| Cardiovascular | Bradycardia or tachycardia, hypotension or hypertension, syncope, conduction abnormalities (atrioventricular block and cardiac arrest) |
| Central nervous | Headache, dizziness, convulsions, ataxia |
| Gastrointestinal | Abdominal cramps, increased secretions, nausea, vomiting, diarrhea |
| Respiratory | Increased bronchial secretions, bronchospasm |
| Other | Lacrimation, sweating, salivation, miosis |
Toxicity and Management of Overdose
There is little systemic absorption of the topically administered drugs and therefore little systemic toxicity. When administered locally in the eye, they can cause temporary ocular changes such as transient blurring and dimming of vision. Systemic toxicity with topically applied cholinergics is seen most commonly when longer-acting drugs are given repeatedly over a long period. This can result in overstimulation of the parasympathetic nervous system and all the attendant responses. Treatment is generally symptomatic and supportive, and the administration of a reversal drug (e.g., atropine) is rarely required.
The likelihood of toxicity is greater for cholinergics that are given orally or intravenously. The most severe consequence of an overdose of a cholinergic drug is a cholinergic crisis. Symptoms include circulatory collapse, hypotension, bloody diarrhea, shock, and cardiac arrest. Early signs include abdominal cramps, salivation, flushing of the skin, nausea, and vomiting. Transient syncope, transient complete heart block, dyspnea, and orthostatic hypotension may also occur. These can be reversed promptly by the administration of atropine, a cholinergic antagonist. Severe cardiovascular reactions or bronchoconstriction may be alleviated by epinephrine, an adrenergic agonist. One way of remembering the effects of cholinergic poisoning is to use the acronym SLUDGE, which stands for salivation, lacrimation, urinary incontinence, diarrhea, GI cramps, and emesis.
Interactions
Anticholinergics (such as atropine), antihistamines, and sympathomimetics may antagonize cholinergic drugs and lead to a reduced response to them. Other cholinergic drugs may have additive effects.
Dosages
For the recommended dosages of the cholinergic drugs, see the Dosages table on p. 328.
Drug Profiles
♦ bethanechol
Bethanechol (Urecholine) is a direct-acting cholinergic agonist. It is used in the treatment of acute postoperative and postpartum nonobstructive urinary retention and for the management of urinary retention associated with neurogenic atony of the bladder. It has also been used to prevent and treat bladder dysfunction induced by phenothiazine and tricyclic antidepressants (see Chapter 16). In addition, it is used in the treatment of postoperative GI atony and gastric retention, chronic refractory heartburn, as well as in diagnostic testing for infantile cystic fibrosis. Bethanechol is available orally and subcutaneously. Contraindications include known drug allergy, hyperthyroidism, peptic ulcer, active bronchial asthma, cardiac disease or coronary artery disease, epilepsy, and Parkinsonism. The drug is to be avoided in patients in whom the strength or integrity of the GI tract or bladder wall is questionable or with conditions
DOSAGES
Selected Cholinergic Agonist Drugs
| DRUG (PREGNANCY CATEGORY) | PHARMACOLOGIC CLASS | USUAL DOSAGE RANGE | INDICATIONS/USES |
| ♦ bethanechol (Urecholine) (C) | Muscarinic (direct-acting) | Adult PO: 10-50 mg tid-qid (usually start with 5-10 mg, repeating hourly until urination, max 50 mg/cycle) | Postoperative and postpartum functional urinary retention |
| ♦ donepezil (Aricept) (C) | Anticholinesterase (indirect-acting) | Adult PO: 5-10 mg/day as a single dose | Alzheimer’s dementia |
| ♦ memantine (Namenda) (B) | NMDA-receptor antagonist | Adult only PO: Initial dose is 5 mg/day; titrate by 5 mg/wk up to a target dose of 10 mg/bid (20 mg/day). Maximum dose in renal impairment is 10 mg/day. | Alzheimer’s dementia |
| physostigmine (Antilirium) (C) | Anticholinesterase (indirect-acting) | Pediatric IM/IV: 0.01-0.03 mg/kg repeated at 5-10 min intervals until desired effect or 2 mg is reached Adult IM/IV; 0.5-2 mg repeated q20 min if needed | Reversal of anticholinergic drug effects and tricyclic antidepressant overdose |
| ♦ pyridostigmine (Mestinon) (C) | Anticholinesterase (indirect-acting) | Adult PO: 600 mg/day in divided doses IV: 0.1-0.25 mg/kg | Myasthenia gravis Antidote for neuromuscular blocker toxicity |
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