Cholinoceptor Blockers & Cholinesterase Regenerators: Introduction
The cholinoceptor antagonists are readily grouped into subclasses on the basis of their spectrum of action (ie, whether they block muscarinic or nicotinic receptors). These drugs are pharmacologic antagonists. A special subgroup, the cholinesterase regenerators, are not receptor blockers but rather are chemical antagonists of organophosphate cholinesterase inhibitors.
High-Yield Terms to Learn
Anticholinergic A drug that blocks muscarinic or nicotinic receptors, but commonly used to mean antimuscarinic Antimuscarinic A drug that blocks muscarinic but not nicotinic receptors Atropine feverHyperthermia induced by antimuscarinic drugs; caused mainly by inhibition of sweating Atropine flush Marked cutaneous vasodilation of the arms and upper torso and head by antimuscarinic drugs; mechanism unknown Cholinesterase regenerator A chemical antagonist that binds the phosphorus of organophosphates and displaces acetylcholinesterase Cycloplegia Paralysis of accommodation; inability to focus on close objects Depolarizing blockade Flaccid skeletal muscle paralysis caused by persistent depolarization of the neuromuscular end plate Miotic A drug that constricts the pupil Mydriatic A drug that dilates the pupil Nondepolarizing blockade Flaccid skeletal muscle paralysis caused by blockade of the nicotinic receptor and prevention of end plate depolarization Parasympatholytic, parasympathoplegic A drug that reduces the effects of parasympathetic nerve stimulation, usually by blockade of the muscarinic receptors of autonomic effector tissues
Muscarinic Antagonists
Classification and Pharmacokinetics
Classification of the Muscarinic Antagonists
Muscarinic antagonists can be subdivided according to their selectivity for specific M receptors or their lack of such selectivity. Although the division of muscarinic receptors into subgroups is well documented (Chapters 6 and 7), only 2 receptor-selective M1 antagonists have reached clinical trials (eg, pirenzepine, telenzepine). However, as noted later, several agents in use in the United States are somewhat selective for the M3 subtype. Most of the drugs in general use in the United States are relatively nonspecific. The muscarinic blockers can also be subdivided on the basis of their primary clinical target organs (central nervous system [CNS], eye, bronchi, or gastrointestinal and genitourinary tracts). Drugs used for their effects on the CNS or the eye must be sufficiently lipid-soluble to cross lipid barriers. A major determinant of this property is the presence or absence of a permanently charged (quaternary) amine group in the drug molecule. This is because charged molecules are more polar and therefore less likely to penetrate a lipid barrier such as the blood-brain barrier or the cornea of the eye.
Pharmacokinetics of Atropine
Atropine is the prototypical nonselective muscarinic blocker. This alkaloid is found in Atropa belladonna and many other plants. Because it is a tertiary amine, atropine is relatively lipid-soluble and readily crosses membrane barriers. The drug is well distributed into the CNS and other organs and is eliminated partially by metabolism in the liver and partially unchanged in the urine. The elimination half-life is approximately 2 h, and the duration of action of normal doses is 4-8 h except in the eye, where effects last for 72 h or longer.
Pharmacokinetics of Other Muscarinic Blockers
In ophthalmology, topical activity (the ability to enter the eye after conjunctival administration) and duration of action are important in determining the usefulness of several antimuscarinic drugs (see Clinical Uses). Similar ability to cross lipid barriers is essential for the agents used in parkinsonism. In contrast, the drugs used for their antisecretory or antispastic actions in the gut, bladder, and bronchi are often selected for minimum CNS activity; these drugs may incorporate quaternary amine groups to limit penetration through the blood-brain barrier.
Mechanism of Action
The muscarinic blocking agents act like competitive (surmountable) pharmacologic antagonists; their blocking effects can be overcome by increased concentrations of muscarinic agonists.
Effects
The peripheral actions of muscarinic blockers are mostly predictable effects derived from cholinoceptor blockade (Table 8-1). These include the ocular, gastrointestinal, genitourinary, and secretory effects. The CNS effects are less predictable. CNS effects seen at therapeutic concentrations include sedation, reduction of motion sickness, and, as previously noted, reduction of some of the signs of parkinsonism. Cardiovascular effects at therapeutic doses include an initial slowing of heart rate caused by central or presynaptic vagal effects followed by the tachycardia and decreased atrioventricular conduction time that would be predicted from peripheral vagal blockade. It has been claimed that the M1-selective agents (not currently available in the United States) are somewhat selective for the gastrointestinal tract.
TABLE 8-1 Effects of muscarinic blocking drugs.
Organ Effect Mechanism CNS Sedation, anti-motion sickness action, antiparkinson action, amnesia, delirium Block of muscarinic receptors, several subtypes Eye Cycloplegia, mydriasis Block of M3 receptors
Bronchi Bronchodilation, especially if constricted Block of M3 receptors
Gastrointestinal tract Relaxation, slowed peristalsis, reduced salivation Block of M1, M3 receptors
Genitourinary tract Relaxation of bladder wall, urinary retention Block of M3 and possibly M1 receptors
Heart Initial bradycardia, especially at low doses, then tachycardia Tachycardia from block of M2 receptors in the sinoatrial node
Blood vessels Block of muscarinic vasodilation; not manifest unless a muscarinic agonist is present Block of M3 receptors on endothelium of vessels
Glands Marked reduction of salivation; moderate reduction of lacrimation, sweating; less reduction of gastric secretion Block of M1, M3 receptors
Skeletal muscle None
Clinical Uses
The muscarinic blockers have several useful therapeutic applications in the CNS, eye, bronchi, gut, and urinary bladder. These uses are listed in the Drug Summary table at the end of this chapter.
CNS
Scopolamine is standard therapy for motion sickness; it is one of the most effective agents available for this condition. A transdermal patch formulation is available. Benztropine, biperiden, and trihexyphenidyl are representative of several antimuscarinic agents used in parkinsonism. Although not as effective as levodopa (see Chapter 28), these agents may be useful as adjuncts or when patients become unresponsive to levodopa. Benztropine is sometimes used parenterally to treat acute dystonias caused by antipsychotic medications.
Eye
Antimuscarinic drugs are used to cause mydriasis, as indicated by the origin of the name belladonna ("beautiful lady") from the ancient cosmetic use of extracts of the Atropa belladonna plant to dilate the pupils. They also cause cycloplegia and paralyze accommodation. In descending order of duration of action, these drugs are atropine (>72 h), homatropine (24 h), cyclopentolate (2-12 h), and tropicamide (0.5-4 h). These agents are all well absorbed from the conjunctival sac into the eye.
Bronchi
Parenteral atropine has long been used to reduce airway secretions during general anesthesia. Ipratropium is a quaternary antimuscarinic agent used by inhalation to promote bronchodilation in asthma and chronic obstructive pulmonary disease (COPD). Although not as efficacious as 
agonists, ipra-tropium is less likely to cause tachycardia and cardiac arrhythmias in sensitive patients. It has very few antimuscarinic effects outside the lungs because it is poorly absorbed and rapidly metabolized. Tiotropium is a newer analog with a longer duration of action.
Gut
Atropine, methscopolamine, and propantheline were used in the past to reduce acid secretion in acid-peptic disease, but are now obsolete for this indication because they are not as effective as H2 blockers (Chapter 16) and proton pump inhibitors (Chapter 59), and they cause far more frequent and severe adverse effects. The M1-selective inhibitor pirenzepine is available in Europe for the treatment of peptic ulcer. Muscarinic blockers can also be used to reduce cramping and hypermotility in transient diarrheas, but drugs such as diphenoxylate and loperamide (Chapter 31) are more effective.
Bladder
Oxybutynin, tolterodine, or similar agents may be used to reduce urgency in mild cystitis and to reduce bladder spasms after urologic surgery. Tolterodine, darifenacin, solifenacin, and fesoterodine are promoted for the treatment of stress incontinence.
Toxicity
A traditional mnemonic for atropine toxicity is "Dry as a bone, red as a beet, mad as a hatter." This description reflects both predictable antimuscarinic effects and some unpredictable actions.
Predictable Toxicities
Antimuscarinic actions lead to several important and potentially dangerous effects. Blockade of thermoregulatory sweating may result in hyperthermia or "atropine fever." This is the most dangerous effect of the antimuscarinic drugs in children and is potentially lethal in infants. Atropine toxicity is described as feeling "dry as a bone" because sweating, salivation, and lacrimation are all significantly reduced or stopped. Moderate tachycardia is common, and severe tachycardia or arrhythmias are common with large overdoses. In the elderly, important additional targets of toxicity include the eye (acute angle-closure glaucoma may occur) and the bladder (urinary retention is possible, especially in men with prostatic hyperplasia). Constipation and blurred vision are common adverse effects in all age groups.
Other Toxicities
Toxicities not predictable from peripheral autonomic actions include the following.
CNS Effects
CNS toxicity includes sedation, amnesia, and delirium or hallucinations ("mad as a hatter"); convulsions may also occur. Central muscarinic receptors are probably involved. Other drug groups with antimuscarinic effects, for example, tricyclic antidepressants, may cause hallucinations or delirium in the elderly, who are especially susceptible to antimuscarinic toxicity.
Cardiovascular Effects
At very high doses, intraventricular conduction may be blocked; this action is probably not mediated by muscarinic blockade and is difficult to treat. Dilation of the cutaneous vessels of the arms, head, neck, and trunk also occurs at these doses; the resulting "atropine flush" ("red as a beet") may be diagnostic of overdose with these drugs. The mechanism is unknown.
Contraindications
The antimuscarinic agents should be used cautiously in infants because of the danger of hyperthermia. The drugs are relatively contraindicated in persons with glaucoma, especially the closed-angle form, and in men with prostatic hyperplasia.
Skill Keeper: Drug Ionization
(See Chapter 1)
The pKa of atropine is 9.7. What fraction of atropine (an amine) is in the lipid-soluble form in urine of pH 7.7? The Skill Keeper Answer appears at the end of the chapter.
Nicotinic Antagonists
Classification
Nicotinic receptor antagonists are divided into ganglion-blocking drugs and neuromuscular-blocking drugs.
Ganglion-Blocking Drugs
Blockers of ganglionic nicotinic receptors act like competitive pharmacologic antagonists, although there is evidence that some also block the pore of the nicotinic channel itself. These drugs were the first successful agents for the treatment of hypertension. Hexamethonium (C6, a prototype), mecamylamine, and several other ganglion blockers were extensively used for this disease. Unfortunately, the adverse effects of ganglion blockade in hypertension are so severe (both sympathetic and parasympathetic divisions are blocked) that patients were unable to tolerate them for long periods (Table 8-2). Trimethaphan was the ganglion blocker most recently used in clinical practice, but it too has been almost abandoned. It is poorly lipid-soluble, inactive orally, and has a short half-life. It was used intravenously to treat severe accelerated hypertension (malignant hypertension) and to produce controlled hypotension.
TABLE 8-2 Effects of ganglion-blocking drugs.
Organ Effects CNS Antinicotinic action may include reduction of nicotine craving and amelioration of Tourette's syndrome (mecamylamine only) Eye Moderate mydriasis and cycloplegia Bronchi Little effect; asthmatics may note some bronchodilation Gastrointestinal tract Marked reduction of motility, constipation may be severe Genitourinary tract Reduced contractility of the bladder;impairment of erection (parasympathetic block) and ejaculation (sympathetic block) Heart Moderate tachycardia and reduction in force and cardiac output at rest; block of exercise-induced increases Vessels Reduction in arteriolar and venous tone, dose-dependent reduction in blood pressure; orthostatic hypotension usually marked Glands Reductions in salivation, lacrimation, sweating, and gastric secretion Skeletal muscle No significant effect
Recent interest has focused on nicotinic receptors in the CNS and their relation to nicotine addiction and to Tourette's syndrome. Paradoxically, nicotine (in the form of nicotine gum or patches), varenicline (a partial agonist given by mouth), and mecamylamine, a nicotinic ganglion blocker that enters the CNS, have all been shown to have some benefit in smoking cessation.
Because ganglion blockers interrupt sympathetic control of venous tone, they cause marked venous pooling; postural hypotension is a major manifestation of this effect. Other toxicities of ganglion-blocking drugs include dry mouth, blurred vision, constipation, and severe sexual dysfunction (Table 8-2). As a result, ganglion blockers are rarely used.
Neuromuscular-Blocking Drugs
Neuromuscular-blocking drugs are important for producing complete skeletal muscle relaxation in surgery; new ones are introduced regularly. They are discussed in greater detail in Chapter 27.
Nondepolarizing Group
Tubocurarine is a prototype. It produces a competitive block at the end plate nicotinic receptor, causing flaccid paralysis that lasts 30-60 minutes (longer if large doses have been given). Pancuronium, atracurium, vecuronium, and several newer drugs are shorter-acting, nondepolarizing blockers.
Depolarizing Group
Although these drugs are nicotinic agonists, not antagonists, they also cause flaccid paralysis. Succinylcholine , the only member of this group used in the United States, produces fasciculations during induction of paralysis; patients may complain of muscle pain after its use. The drug is hydrolyzed by butyrylcholinesterase (also known as plasma cholinesterase or pseudocholinesterase) and has a half-life of a few minutes in persons with normal plasma cholinesterase. Approximately 1 in 2500 persons produces a genetically determined form of abnormal cholinesterase that does not metabolize succinylcholine effectively. The drug's duration of action is grossly prolonged in such persons.
Toxicity
The toxicity of neuromuscular blockers is discussed in Chapter 27.
Cholinesterase Regenerators
Pralidoxime is the prototype cholinesterase regenerator. These agents are not receptor antagonists but belong to a class of chemical antagonists. These molecules contain an oxime group, which has an extremely high affinity for the phosphorus atom in organophosphate insecticides. Because the affinity of the oxime group for phosphorus exceeds the affinity of the enzyme-active site for phosphorus, these agents are able to bind the inhibitor and displace the enzyme (if aging has not occurred). The active enzyme is thus regenerated. Pralidoxime, the oxime currently available in the United States, may be used to treat patients exposed to insecticides, such as parathion, or to nerve gases.
Skill Keeper Answer: Drug Ionization
(See Chapter 1)
The pKa of atropine is 9.7. According to the Henderson-Hasselbalch equation,
Log (protonated/unprotonated) = pKa - pH
Log (P/U) = 9.7 - 7.7
Log (P/U) = 2
P/U = antilog (2)
= 100/1
Therefore, about 99% of the drug is in the protonated form, 1% in the unprotonated form. Since atropine is a weak base, it is the unprotonated form that is lipid soluble. Therefore, about 1% of the atropine in the urine is lipid soluble.
Checklist
When you complete this chapter, you should be able to:
Describe the effects of atropine on the major organ systems (CNS, eye, heart, vessels, bronchi, gut, genitourinary tract, exocrine glands, skeletal muscle).
List the signs, symptoms, and treatment of atropine overdose.
List the major clinical indications and contraindications for the use of muscarinic antagonists.
Describe the effects of the ganglion-blocking nicotinic antagonists.
List one antimuscarinic agent promoted for each of the following uses: to produce mydriasis and cycloplegia; to treat parkinsonism, asthma, bladder spasm, and the muscarinic toxicity of insecticides.
Describe the mechanism of action and clinical use of pralidoxime.
Drug Summary Table: Cholinoceptor Blockers & Cholinesterase Regenerators
Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions Antimuscarinic, nonselective Atropine Competitive pharmacologic antagonist at all M receptors Mydriatic, cycloplegic; antidote for cholinesterase inhibitor toxicity Lipid-soluble Duration: 2-4 h except in eye: 
72 h All parasympatholytic effects plus sedation, delirium, hyperthermia, flushing Benztropine, others: Antiparkinsonism; oral and parenteral Dicyclomine, glycopyrrolate: Oral, parenteral for gastrointestinal applications Homatropine, cyclopentolate, tropicamide: Topical ophthalmic use to produce mydriasis, cycloplegia Ipratropium, tiotropium: Inhaled for asthma, chronic obstructive pulmonary disease Oxybutynin: Oral, transdermal, promoted for urinary urgency, incontinence Scopolamine: Anti-motion sickness via transdermal patch Trospium: Oral, for urinary urgency Antimuscarinic, selective Darifenacin, fesoterodine, solifenacin, tolterodine Like atropine, but modest selectivity for M3 receptors
Urinary urgency, incontinence Oral Duration: 12-24 h Excessive parasympatholytic effects Pirenzepine, telenzepine Significant M1 selectivity
Peptic disease (not available in USA) Oral Excessive parasympatholytic effects Antinicotinic ganglion blockers Hexamethonium Selective block of NN receptors
Obsolete; was used for hypertension Oral, parenteral Block of all autonomic effects Trimethaphan: IV only, short-acting; was used for hypertensive emergencies and controlled hypotension Mecamylamine: Oral, enters CNS; investigational use for smoking cessation Antinicotinic neuromuscular blockers See Chapter 27 Regenerator Pralidoxime Chemical antagonist of organophosphates Organophosphate poisoning Parenteral Muscle weakness