Section 2: Scientific Principles
Part C: Other Drugs Commonly Used in Anesthesia
Chapter 14: The Autonomic Nervous System

Cholinergic Drugs

Overview of Mechanisms of Action

The cholinergic drugs act by mimicking, amplifying, or inhibiting the effects of ACh. Cholinergic drugs do not behave exactly as does ACh: their drug action is more specific, affecting fewer sites than ACh, and their duration of action is generally longer than that of ACh.

Unlike adrenergic pharmacology, in which the clinician can select from a wide choice of drugs, there is a relative paucity of drugs that influence parasympathetic function. In general, drugs that affect the parasympathetic system act in one of four ways:

  1. As an agonist, stimulating cholinergic receptors.

  2. As an antagonist, blocking or inhibiting the actions mediated by the cholinergic receptor.

  3. Blocking or stimulating receptors on autonomic ganglia.

  4. Inhibiting the metabolism of ACh, thus increasing and prolonging the effect of ACh.

There are currently no effective clinically used drugs that act through mechanisms affecting synthesis of ACh (e.g., by inhibiting choline acetyltransferase) or by causing indirect release of ACh (as tyramine, ephedrine, and amphetamine may release NE). Hemicholinium does interfere with choline uptake and could deplete ACh stores, but it is not used clinically. Adenosine may inhibit the release of ACh by decreasing the affinity of binding sites for calcium ions; aminoglycoside antibiotics may compete with calcium for membrane calcium channels, as does magnesium ion. Exocytotic release of ACh is inhibited by botulinum toxin; this toxin is sometimes given by local injection to treat strabismus and blepharospasm. In a full-blown botulism poisoning syndrome, fatalities may result from muscle weakness and respiratory failure.

Agonists

Cholinergic agonists have limited therapeutic use because of their detrimental effects. ACh, as a result of its diffuse, nonselective actions and rapid hydrolysis by both acetylcholinesterase and butyrylcholinesterase, has had almost no therapeutic use other than as an intraocular medication for transient constriction of the pupil during ophthalmic surgery.

Cholinergic agonists in clinical use have been derived from ACh, but they resist hydrolysis by cholinesterase, permitting a useful duration of action. The different systemic effects of the cholinergic agonists are more quantitative than qualitative, but some limited organ selectivity is useful therapeutically, as is seen with the synthetic choline esters bethanechol and carbachol. Methacholine and bethanechol are primarily muscarinic agonists; carbachol has significant nicotinic and muscarinic effects. The simple maneuver of adding a methyl group to the b-position of the choline in ACh produces methacholine, which is almost purely muscarinic and is almost totally resistant to hydrolysis by either of the cholinesterases. An IV infusion of methacholine causes hypotension and bradycardia; a small SQ dose causes a more transient hypotension with a reflex increase in heart rate. The sole current use of methacholine (Provocholine) is as a provocative agent in diagnosing hyperreactive airways, making positive use of the deleterious bronchoconstrictive effect of muscarinic agonists. It is administered only by inhalation; serious side effects including gastrointestinal symptoms, chest pain, hypotension, loss of consciousness, and complete heart block have occurred when the drug is given orally or parenterally. Excessive bronchoconstrictive response should be treated by an inhaled b-agonist; coexisting beta blockade is considered a contraindication to the use of methacholine.

The carbamate derivative of methacholine, bethanecol (Urecholine), is occasionally used postoperatively to reinstitute peristaltic activity in the gut or to force the extrusion of urine from an atonic bladder. It is administered SQ or orally to avoid effects in other organ systems.

Carbachol is used topically or intraocularly to constrict the pupil, for long-term treatment of wide-angle glaucoma. When used topically, it is often better tolerated than the ophthalmic anticholinesterase agents, and it may be effective in patients resistant to pilocarpine and physostigmine. The rapid pupillary constriction is due to the combination of ganglionic block and muscarinic effects. Another natural alkaloid, pilocarpine, was used to treat glaucoma until the advent of more modern drugs.

Muscarinic Antagonists

Muscarinic antagonists are the active ingredients in some common plants used since antiquity for both medicinal and poisonous effects. It has been suggested that atropine poisoning figures in the American classic, The Scarlet Letter.401  Despite their age, muscarinic antagonists still represent important drugs in anesthesia and critical care (Fig. 14–22).

Click thumbnail to see full size image
FIGURE 14–22 Structural formulas of the clinically useful antimuscarinic drugs.

Muscarinic antagonists compete with neurally released ACh for access to muscarinic cholinoceptors and block its effects. They also antagonize the actions of muscarinic agonists at noninnervated, muscarinic cholinoceptors. Presynaptic muscarinic receptors on the adrenergic nerve terminal may inhibit NE release. Hence, muscarinic antagonists may enhance sympathetic activity. With the exception of quaternary ammonium compounds that do not readily cross the blood-brain barrier and so have few CNS actions, there is no significant specificity of action among these drugs; they block all muscarinic effects with equal efficacy, although some quantitative differences in effect may be seen (Table 14–13). Research has revealed several subtypes of muscarinic receptors, and agonists and antagonists have been synthesized that bind preferentially to one or another. None of these selective agents is yet available commercially, but this is a rapidly developing area of research, and there will soon be drugs that selectively act on one site or another, such as the heart, bronchial system, smooth muscle, gastric mucosa, or some particular area of the CNS.

TABLE 14–13. Muscarinic Anticholinergic Drugs

Historically, these drugs were used in peptic ulcer disease, various forms of “spastic bowel syndrome,” upper respiratory illness, and asthma. However, with the availability of the specific histamine (H2 ) drug cimetidine for peptic ulcer disease and inhaled b-agonists and steroids for asthma, these uses have markedly decreased. Historically, atropine was one of the important drugs used to treat bronchospasm, but it was displaced with the introduction of b2 -agonist drugs that did not cause drying of secretions or diminished ciliary motility. Topical use of atropine analogues in ophthalmologic practice to dilate the pupil is still common.

The addition of a muscarinic anticholinergic drug to anesthetic premedication to decrease secretions and to prevent harmful vagal reflexes was mandatory in the era of ether anesthesia, but it is no longer necessary with modern inhalational agents. Scopolamine combined with an opiate, usually morphine, is still used by cardiac anesthesiologists to sedate a patient while minimizing cardiorespiratory effects. Routine preoperative use of these drugs as antisialogogues continues in some pediatric and otorhinolaryngologic cases.

Atropine is a tertiary structure that easily crosses the blood-brain barrier (see Fig. 14–22). CNS effects have been seen with the relatively large doses (1–2 mg) given to block the muscarinic side effects of the anticholinesterase drugs used for reversal or neuromuscular blockade reversal (Ch. 12). In contrast, one of the synthetic antimuscarinic drugs, glycopyrrolate (Robinul), does not cross the blood-brain barrier and has gained popularity for this use. In addition, glycopyrrolate has a longer duration of action than does atropine.

Scopolamine, which resembles the others of this class in peripheral actions, has pronounced CNS effects. It is the active ingredient in most over-the-counter preparations sold as soporifics, and it is effective in preventing motion sickness. The patch preparation of scopolamine can be used prophylactically for motion sickness and postoperative nausea and vomiting, but like oral and parenteral forms, it may be associated with eye, bladder, skin and psychologic side effects. 402, 403 

The development of ipratropium (Atrovent) reestablished antimuscarinic drugs as an important therapeutic approach in asthma and bronchospastic disorders. 404  Although ipratropium is structurally similar to atropine and has essentially the same effects when administered parenterally, an important difference is that ipratropium is a quarternary ammonium compound. Thus, it is very poorly absorbed when delivered via inhalation and essentially has few extrapulmonary effects even when given in extremely large doses by this route. Ninety percent of inhaled drug is swallowed, but only 1 percent of the total dose is absorbed systemically.

When administered to normal volunteers, ipratropium provides almost complete protection against bronchospasm induced by a variety of provocative agents. However, in asthmatic patients, results are more variable. The bronchospastic effects of some agents, such as methacholine or sulfur dioxide, are completely blocked, whereas there is little effect on leukotriene-induced bronchoconstriction. Further, there is considerable variability among patients. The onset of bronchodilation is slow, and the maximal effect is less than that seen with b-agonists. Unlike atropine, ipratropium has no negative effect on ciliary clearance. In general, more therapeutic effect from antimuscarinics, including ipra-tropium, is seen in patients with chronic obstructive pulmonary disease than in asthmatic patients. 404, 405  Ipra-tropium is supplied as a metered-dose inhaler supplying 18 mg per puff. Dosage is two puffs orally four times a day. Maximum bronchodilation occurs in 30 to 90 minutes, but the duration may be 4 hours. 405 

The toxic effects of the muscarinic antagonists are due to the blockade of muscarinic cholinoceptors in the periphery and the CNS. The peripheral effects (e.g., dry mouth) may be irritating, but not life-threatening, in healthy adults. However, children are more dependent than adults on sweating for thermoregulation and easily become dangerously hyperthermic. Moreover, older individuals may not be able to tolerate the cardiac, ocular, or urinary effects of muscarinic blockade.

The CNS effects are the usual cause of death or injury. Increasing doses of atropine or scopolamine cause greater distortions of mentation, progressing from thought disorders to hallucinations, delusions, delirium, and severe psychoses. These effects are reversible, but the mental dysfunction can persist for weeks. Left alone, the intoxicated individual will die of starvation, dehydration, and/or trauma. However, recovery will be complete if the individual receives appropriate supportive and protective care until the drug is eliminated. Volunteers have received more than 500 mg of atropine, more than 1,000 times the usual dose, and, although they have been disabled for weeks, they have recovered fully.

Small doses of atropine (0.05 mg) can evoke bradycardia, a finding that has led some clinicians to increase the dose in children. It was thought that a CNS effect of atropine could be responsible, but the time course, as well as the fact that it occurred in vagotomized animals, cast doubt on this mechanism. Whether this paradoxic bradycardia is a central or peripheral effect, or both, and the role of muscarinic subtypes, are still subjects of debate. 406 

Atropine and scopolamine toxicity have been treated for decades by the use of the naturally occurring alkaloid physostigmine (Antilirium), which is an anticholinesterase that penetrates the blood-brain barrier. 407  Consequently, the use of this drug in doses of 1 to 2 mg IV to treat the postoperative CNS effects of IV atropine or scopalamine has been successful. Physostigmine may also reverse the CNS effects of other compounds with anticholinergic activity, including the tricyclic antidepressants, several major tranquilizers, and antihistamine drugs. 408  Physostigmine may antagonize the sedative effects of the benzodiazepines as well, but the specific benzodiazepine antagonist, flumazenil (Romazicon), will undoubtedly supplant physostigmine for this use. 409, 410  Physostigmine must be administered with care because of its potentially lethal nicotinic effects, which are not prevented by the muscarinic antagonists, and because its half-life rarely matches that of the intoxicant.

Cholinesterase Inhibitors

Anticholinesterase drugs provide the most commonly used means of producing sustained systemic cholinergic agonism. These drugs are used to reverse neuromuscular blockade, to treat myasthenia gravis, and to treat certain tachyarrhythmias.

The first anticholinesterase agent available was physostigmine (see earlier). There are currently three chemical classes of compounds used as cholinesterase inhibitors: carbamates, organophosphates, and quaternary ammonium alcohols. Neostigmine was first used as a gastrointestinal tract stimulant and later as a treatment for myasthenia gravis.

Physostigmine, neostigmine, and pyridostigmine are carbamates, whereas edrophonium is a quaternary ammonium alcohol. The cholinesterase enzyme is inhibited so long as the esteratic site is bound to an acetate, carbamate, or phosphate. Carbamate and phosphate bonds are much more resistant to attack by hydroxyl groups than are acetate bonds. The acetylated form lasts for only microseconds, whereas the carbamylated form lasts for 15 to 20 minutes. Organophosphates include diisopropylfluorophosphate, parathion, malathion, soman, sarin, VX, and a variety of other compounds used as insecticides. Although the toxicity of the organophosphate insecticides is primarily related to their anticholinesterase activity, the mechanism of this effect is different from the clinically used anticholinesterase drugs. The organophosphates produce an irreversible enzyme inhibition and have CNS effects as well. 411  Consequently, treatment of organophosphate insecticide poisoning relies on chemical compounds capable of displacing the insecticides from the enzyme and therefore of reactivating the cholinesterase activity. The best-documented of these chemicals is pralidoxime (2-PAM). Physostigmine and most of the organophosphates are not quaternary ammonium compounds and have major effects on cholinergic functions in the CNS.

Edrophonium is unique in that it lacks an acetate, carbamate, or a phosphate group. It acts because the positive charge of the nitrogen is attracted strongly by the anionic site and physically blocks the esteratic site. Thus, the edrophonium molecule is postulated to be held in place only by an ionic bond. The duration of inhibition provided by each molecule is short (e.g. milliseconds), but because they are not changed in the reaction, the molecules can hop onto and off the enzyme repeatedly and consequently render the enzyme unavailable to ACh.

Aside from reversal of neuromuscular blockade, there are few other therapeutic uses of these compounds. Because these compounds can increase the effect and duration of neurally released ACh, they are useful in situations in which such release is deficient, such as myasthenia gravis. Further, anticholinesterase drugs are occasionally used to stimulate intestinal function and topically in the eye as a miotic. An irreversible organophosphate anticholinesterase that is used clinically is echothiophate iodide (Phospholine), which is available as topical drops for the treatment of glaucoma. Its major advantage over other topical agents is its prolonged duration of action. Because this chemical also inactivates plasma cholinesterase, it may prolong the action of succinylcholine. Although prudence dictates discontinuation of echothiophate for 1 week prior to surgery, there are numerous case reports of successful anesthesia performed under emergency conditions.