Introduction

Anticholinergic drugs are commonly used in veterinary anesthesia to treat and/or prevent anesthetic and preanesthetic bradycardia, decrease airway and salivary secretions, dilate the pupil, block vagally mediated reflexes (viscerovagal, oculocardiac, and Branham), and block the effects of parasympathomimetic drugs. Historically, inhalant anesthetics such as diethyl ether produced profound parasympathetic effects that resulted in hypersalivation and bradycardia. As such, anticholinergics were consistently used preoperatively to counteract these unwanted adverse effects. Modern inhalant anesthetics have lesser effects on the autonomic nervous system, making the indiscriminate use of anticholinergic drugs less popular. The administration of an anticholinergic drug as part of a patient’s premedication should be based on a thorough knowledge of the drug’s benefits and risks, taking into account the drugs to be co‐administered, the patient’s species, age, and disease status, and the procedure being performed.

History

Plants such as deadly nightshade (Atropa belladonna) (Fig. 20.1), henbane (Hyoscyamus niger), mandrake (Mandragora officinalis), and Datura species contain naturally occurring tropane alkaloids (atropine, hyoscyamine, and scopolamine) in concentrations that are potentially toxic to most species. For example, ingesting 3–5 nightshade berries may prove lethal to a person. Despite this risk, extracts from these plants have been used since ancient times for their anesthetic, mydriatic, antidiarrheal, and analgesic properties. In the 1830s, atropine was isolated from deadly nightshade, and in the 1880s hyoscine was isolated from henbane. These breakthroughs paved the way for a clearer understanding of how the autonomic nervous system functions and the eventual discovery of the neurotransmitter acetylcholine [1,2]. The anticholinergic preparations used in modern veterinary anesthesia have a relatively high margin of safety by comparison.

General pharmacology

Modern anticholinergics exert their effects by competitively antagonizing acetylcholine at postganglionic muscarinic cholinergic receptors in the parasympathetic nervous system. This has led some to prefer the use of the term antimuscarinics to differentiate the drugs that only act as antagonists at muscarinic receptors from some naturally occurring compounds that can non‐specifically antagonize both muscarinic and nicotinic acetylcholine receptors. Muscarinic receptors have five subtypes, classified as M₁–M₅, based on the order in which they were cloned [3]. Intracellular signaling by activation of the different subtypes occurs via coupling to multiple G‐proteins, with single receptor subtypes being capable of activating more than one G‐protein in the same cell [4]. The muscarinic receptors can be placed into two groups based on the primary G‐protein to which they couple: M₁, M₃, and M₅ couple with G_q/11‐type proteins and have an excitatory action. M₂ and M₄ couple with G_i/o‐type proteins which are inhibitory. There is also evidence that M₁, M₂, and M₃ receptors can cause actions via non‐G‐protein mechanisms, such as protein kinase [5]. In addition to being able to activate different G‐proteins, the muscarinic receptor subtypes show a tissue‐specific anatomic distribution, and physiologic response (Table 20.1) [6–10].

Atropine and glycopyrrolate, the anticholinergics most commonly used in veterinary anesthesia, are relatively unselective in their binding to muscarinic receptor subtypes. Different tissue types, however, appear to have different responses to clinically administered doses of these drugs (Table 20.2) [11]. Receptors in salivary, cardiac, and bronchial tissues are more sensitive than those in the urinary and gastrointestinal tracts.

Anticholinergic effects in the heart are mediated by pre‐ and postsynaptic M₂ receptors located in the sinoatrial and atrioventricular nodes and also in the atrial myocardium. Systemic anticholinergic drug administration typically leads to an increase in sinus rate, acceleration of atrioventricular nodal conduction, and increased atrial contractility. The increase in heart rate may result in tachycardia and tachydysrhythmias, which may be unwanted, particularly if these changes result in decreased cardiac output (CO) or significantly increased myocardial oxygen consumption. Routine use of anticholinergics should be avoided in patients with hypertrophic or restrictive forms of cardiomyopathy.

Sometimes, worsening of bradycardia may occur immediately following anticholinergic administration. This paradoxical effect has been postulated to be due to more rapid blockade of presynaptic M₁ receptors that inhibit the negative feedback mechanism, resulting in a transient increase in acetylcholine release and further slowing of the heart rate [12]. When this occurs in the clinical setting, waiting a few minutes or repeating the dose of anticholinergic administered will typically induce blockade of postsynaptic M₂ receptors, resulting in the desired increase in heart rate.

Bronchodilation and reduced airway secretions via M₂ and M₃ receptor antagonism can decrease airway resistance and the likelihood of airway obstruction, but can contribute to hypoventilation and, theoretically, decreased arterial oxygen tension as a result of increased anatomic deadspace. This is unlikely to be clinically relevant when a patient is breathing 100% oxygen. Additionally, in many species, the viscosity of the airway secretions increases as the volume is decreased following anticholinergic administration, potentially offsetting any benefit with respect to reducing airway secretions.

In the eye, cholinergic fibers originating from cranial nerve III innervate the circular muscles (sphincter pupillae) of the iris that control pupil diameter, and also the ciliary muscle that controls the shape of the lens, facilitating accommodation. Topical application of anticholinergic drugs to the cornea blocks the action of acetylcholine at both of these sites and results in mydriasis and cycloplegia. This has been well documented for atropine in numerous species, including sheep, goats, cats, and horses [13–17], and for glycopyrrolate in rabbits [18]. Topical application of anticholinergic drugs has also been shown to acutely increase intraocular pressure (IOP) caused by drainage angle closure in cats [15], but not in sheep and horses [13,17]. These mixed findings have led some to suggest that this route of administration should be avoided in patients with pre‐existing elevations of IOP or those predisposed to developing angle‐closure glaucoma.

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