The cholinergic antagonists (also called cholinergic blockers, parasympatholytics, or anticholinergic drugs) bind to cholinoceptors, but they do not trigger the usual receptor-mediated intracellular effects. The most useful of these agents selectively block muscarinic receptors of the parasympathetic nerves. The effects of parasympathetic innervation are, thus, interrupted, and the actions of sympathetic stimulation are left unopposed.
A second group of drugs, the ganglionic blockers, show a preference for the nicotinic receptors of the sympathetic and parasympathetic ganglia. Clinically, they are the least important of the anticholinergic drugs. A third family of compounds, the neuromuscular-blocking agents, interfere with transmission of efferent impulses to skeletal muscles. These agents are used as skeletal muscle relaxant adjuvants in anesthesia during surgery, intubation, and various orthopedic procedures. Figure 5.1 summarizes the cholinergic antagonists discussed in this chapter.
Figure 5.1.Summary of cholinergic antagonists.
Commonly known as antimuscarinics, these agents (for example, atropine and scopolamine) block muscarinic receptors (Figure 5.2), causing inhibition of all muscarinic functions. In addition, these drugs block the few exceptional sympathetic neurons that are cholinergic, such as those innervating salivary and sweat glands. In contrast to the cholinergic agonists, which have limited usefulness therapeutically, the cholinergic blockers are beneficial in a variety of clinical situations. Because they do not block nicotinic receptors, the antimuscarinic drugs have little or no action at skeletal neuromuscular junctions (NMJs) or autonomic ganglia. [Note: A number of antihistaminic and antidepressant drugs also have antimuscarinic activity.]
Figure 5.2.Sites of actions of cholinergic antagonists.
Atropine [A-troe-peen] is a tertiary amine belladonna alkaloid with a high affinity for muscarinic receptors. It binds competitively and prevents acetylcholine (ACh) from binding to those sites (Figure 5.3). Atropine acts both centrally and peripherally. Its general actions last about 4 hours, except when placed topically in the eye, where the action may last for days. Neuroeffector organs have varying sensitivity to atropine. The greatest inhibitory effects are on bronchial tissue and the secretion of sweat and saliva (Figure 5.4).
Figure 5.3.Competition of atropine and scopolamine with acetylcholine for the muscarinic receptor.
Figure 5.4.Dose-dependent effects of atropine.
Atropine blocks all cholinergic activity on the eye, resulting in persistent mydriasis (dilation of the pupil, see Figure 4.6), unresponsiveness to light, and cycloplegia (inability to focus for near vision). In patients with narrow-angle glaucoma, intraocular pressure may rise dangerously. Shorter-acting agents, such as the antimuscarinic tropicamide, or an ?-adrenergic drug, such as phenylephrine, are generally favored for producing mydriasis in ophthalmic examinations.
b. Gastrointestinal (GI)
Atropine (as the active isomer, l-hyoscyamine) can be used as an antispasmodic to reduce activity of the GI tract. Atropine and scopolamine (which is discussed below) are probably the most potent drugs available that produce this effect. Although gastric motility is reduced, hydrochloric acid production is not significantly affected. Thus, the drug is not effective in promoting healing of peptic ulcer. [Note: Pirenzepine (see Muscarinic agonists and antagonists), an M1-muscarinic antagonist, does reduce gastric acid secretion at doses that do not antagonize other systems.] In addition, doses of atropine that reduce spasms also reduce saliva secretion, ocular accommodation, and micturition (urination). These effects decrease patient compliance with the use of these medications.
c. Urinary system
Atropine-like drugs are also used to reduce hypermotility states of the urinary bladder. It is still occasionally used in enuresis (involuntary voiding of urine) among children, but ?-adrenergic agonists with fewer side effects may be more effective.
Atropine produces divergent effects on the cardiovascular system, depending on the dose (Figure 5.4). At low doses, the predominant effect is a decreased cardiac rate (bradycardia). Originally thought to be due to central activation of vagal efferent outflow, the effect is now known to result from blockade of the M1 receptors on the inhibitory prejunctional (or presynaptic) neurons, thus permitting increased ACh release. With higher doses of atropine, the M2 receptors on the sinoatrial node are blocked, and the cardiac rate increases modestly. This generally requires at least 1 mg of atropine, which is a higher dose than ordinarily given. Arterial blood pressure is unaffected, but, at toxic levels, atropine will dilate the cutaneous vasculature.
Atropine blocks the salivary glands, producing a drying effect on the oral mucous membranes (xerostomia). The salivary glands are exquisitely sensitive to atropine. Sweat and lacrimal glands are similarly affected. [Note: Inhibition of secretions by sweat glands can cause elevated body temperature, which can be dangerous in children and the elderly.]
2. Therapeutic uses
In the eye, topical atropine exerts both mydriatic and cycloplegic effects, and it permits the measurement of refractive errors without interference by the accommodative capacity of the eye. [Note: Phenylephrine or similar ?-adrenergic drugs are preferred for pupillary dilation if cycloplegia is not required]. Shorter-acting antimuscarinics (cyclopentolate and tropicamide) have largely replaced atropine due to the prolonged mydriasis observed with atropine (7–14 days versus 6–24 hours with other agents). Atropine may induce an acute attack of eye pain due to sudden increases in eye pressure in individuals with narrow-angle glaucoma.
Atropine (as the active isomer, l-hyoscyamine) is used as an antispasmodic agent to relax the GI tract and bladder.
c. Antidote for cholinergic agonists
Atropine is used for the treatment of overdoses of cholinesterase inhibitor insecticides and some types of mushroom poisoning (certain mushrooms contain cholinergic substances that block cholinesterases). Massive doses of the antagonist may be required over a long period of time to counteract the poisons. The ability of atropine to enter the central nervous system (CNS) is of particular importance. The drug also blocks the effects of excess ACh resulting from acetylcholinesterase (AChE) inhibitors such as physostigmine.
The drug is sometimes used as an antisecretory agent to block secretions in the upper and lower respiratory tracts prior to surgery.
Atropine is readily absorbed, partially metabolized by the liver, and eliminated primarily in urine. It has a half-life of about 4 hours.
4. Adverse effects
Depending on the dose, atropine may cause dry mouth, blurred vision, “sandy eyes,” tachycardia, urinary retention, and constipation. Effects on the CNS include restlessness, confusion, hallucinations, and delirium, which may progress to depression, collapse of the circulatory and respiratory systems, and death. Low doses of cholinesterase inhibitors, such as physostigmine, may be used to overcome atropine toxicity.
In older individuals, the use of atropine to induce mydriasis and cycloplegia is considered to be too risky, because it may exacerbate an attack of glaucoma due to an increase in intraocular pressure in someone with a latent condition. It may also induce troublesome urinary retention in this population. Atropine may be dangerous in children, because they are sensitive to its effects, particularly to the rapid increases in body temperature that it may elicit.
Scopolamine [skoe-POL-a-meen], another tertiary amine plant alkaloid, produces peripheral effects similar to those of atropine. However, scopolamine has greater action on the CNS (unlike with atropine, CNS effects are observed at therapeutic doses) and a longer duration of action in comparison to those of atropine. It has some special actions as indicated below.
Scopolamine is one of the most effective anti–motion sickness drugs available (Figure 5.5). Scopolamine also has the unusual effect of blocking short-term memory. In contrast to atropine, scopolamine produces sedation, but at higher doses it can produce excitement instead. Scopolamine may produce euphoria and is susceptible to abuse.
Figure 5.5.Scopolamine is an effective anti–motion sickness agent.
2. Therapeutic uses
Although similar to atropine, therapeutic use of scopolamine is limited to prevention of motion sickness (for which it is particularly effective) and to blocking short-term memory. [Note: As with all such drugs used for motion sickness, it is much more effective prophylactically than for treating motion sickness once it occurs. The amnesic action of scopolamine makes it an important adjunct drug in anesthetic procedures.]
3. Pharmacokinetics and adverse effects
These aspects are similar to those of atropine.
C. Ipratropium and tiotropium
Inhaled ipratropium [i-pra-TROE-pee-um] and inhaled tiotropium [ty-oh-TROPE-ee-um] are quaternary derivatives of atropine. These agents are approved as bronchodilators for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), both chronic bronchitis and emphysema. These agents are also pending approval for treating asthma in patients who are unable to take adrenergic agonists.
Because of their positive charges, these drugs do not enter the systemic circulation or the CNS, isolating their effects to the pulmonary system. Tiotropium is administered once daily, a major advantage over ipratropium, which requires dosing up to four times daily. Both are delivered via inhalation. Important characteristics of the muscarinic antagonists are summarized in Figures 5.6 and 5.7.
Figure 5.6.Adverse effects commonly observed with cholinergic antagonists.
Figure 5.7.Summary of cholinergic antagonists.
*Contraindicated in narrow-angle glaucoma. GI = gastrointestinal; COPD = chronic obstructive pulmonary disease.
D. Tropicamide and cyclopentolate
These agents are used similarly to atropine as ophthalmic solutions for mydriasis and cycloplegia. Their duration of action is shorter than that of atropine. Tropicamide produces mydriasis for 6 hours, and cyclopentolate for 24 hours.
E. Benztropine and trihexyphenidyl
These agents are centrally acting antimuscarinic agents that have been used for many years in the treatment of Parkinson disease. With the advent of other drugs (for example, levodopa/carbidopa), they have been largely replaced. However, benztropine and trihexyphenidyl are useful as adjuncts with other antiparkinsonian agents to treat all types of parkinsonian syndromes, including antipsychotic-induced extrapyramidal symptoms. These drugs may be helpful in geriatric patients who cannot tolerate stimulants.
F. Darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, and trospium chloride
These synthetic atropine-like drugs are used to treat overactive urinary bladder disease. By blocking muscarinic receptors in the bladder, intra-vesicular pressure is lowered, bladder capacity is increased, and the frequency of bladder contractions is reduced. Side effects of these agents include dry mouth, constipation, and blurred vision, which limit tolerability of these agents if used continually. Oxybutynin is available as a transdermal system (topical patch), which is better tolerated because it causes less dry mouth than do oral formulations, and is more widely accepted with greater patient acceptance. The overall efficacies of these antimuscarinic drugs are similar.
Ganglionic blockers specifically act on the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia. Some also block the ion channels of the autonomic ganglia. These drugs show no selectivity toward the parasympathetic or sympathetic ganglia and are not effective as neuromuscular antagonists. Thus, these drugs block the entire output of the autonomic nervous system at the nicotinic receptor. Except for nicotine, the other drugs mentioned in this category are nondepolarizing, competitive antagonists. The responses of the nondepolarizing blockers are complex, and nearly all the physiological responses to these agents can be predicted by knowledge of the predominant tone of a given organ system.
For example, the predominant tone in the arterioles is sympathetic. In the presence of a nondepolarizing blocker, this system is affected the most, leading to vasodilation. The parasympathetic nervous system is the predominant tone in many organ systems (see Enteric neurons). Thus, the presence of a ganglionic blocker will also produce atony of the bladder and GI tract, cycloplegia, xerostomia, and tachycardia. Therefore, ganglionic blockade is rarely used therapeutically, but often serves as a tool in experimental pharmacology.
A component of cigarette smoke, nicotine [NIK-oh-teen] is a poison with many undesirable actions. It is without therapeutic benefit and is deleterious to health. Depending on the dose, nicotine depolarizes autonomic ganglia, resulting first in stimulation and then in paralysis of all ganglia. The stimulatory effects are complex and result from increased release of neurotransmitter (Figure 5.8), due to effects on both sympathetic and parasympathetic ganglia. For example, enhanced release of dopamine and norepinephrine may be associated with pleasure as well as appetite suppression, the latter of which may contribute to lower body weight.
The overall response of a physiological system is a summation of the stimulatory and inhibitory effects of nicotine. These include increased blood pressure and cardiac rate (due to release of transmitter from adrenergic terminals and from the adrenal medulla) and increased peristalsis and secretions. At higher doses, the blood pressure falls because of ganglionic blockade, and activity in both the GI tract and bladder musculature ceases. (See Nicotine for a full discussion of nicotine.)
Figure 5.8.Neurochemical effects of nicotine.
GABA = ?-Aminobutyric acid.
Mecamylamine [mek-a-MILL-a-meen] produces a competitive nicotinic blockade of the ganglia. Mecamylamine has been supplanted by superior agents with fewer side effects.