Chapter 11: Agents Acting at the Neuromuscular Junction and Autonomic Ganglia

History. The electrical organs from the aquatic species of Electrophorus and Torpedo provide rich sources of nicotinic receptor. The electrical organ is derived embryologically from myoid tissue; however, in contrast to vertebrate skeletal muscle, in which motor end plates occupy 0.1% or less of the cell surface, up to 40% of the surface of the electric organ's membrane is excitable and contains cholinergic receptors. The discovery of seemingly irreversible antagonism of neuromuscular transmission by α-toxins from venoms of the krait, Bungarus multicinctus, or varieties of the cobra, Naja naja, offered suitable markers for identification of the receptor. The α-toxins are peptides of ~7 kDa. Radioisotope-labeled toxins were used in 1970 to assay the isolated cholinergic receptor in vitro (Changeux and Edelstein, 1998). The α-toxins have extremely high affinities and slow rates of dissociation from the receptor, yet the interaction is non-covalent. In situ and in vitro, their behavior resembles that expected for a high-affinity antagonist. Since cholinergic neurotransmission mediates motor activity in marine vertebrates and mammals, a large number of peptide, terpinoid, and alkaloid toxins that block the nicotinic receptors have evolved to enhance predation or protect plant and animal species from predation (Taylor et al., 2007).

Purification of the receptor from Torpedo ultimately led to isolation of complementary DNAs for each of the subunits. These cDNAs, in turn, permitted the cloning of genes encoding the multiple receptor subunits from mammalian neurons and muscle (Numa et al., 1983). By simultaneously expressing various permutations of the genes that encode the individual subunits in cellular systems and then measuring binding and the electrophysiological events that result from activation by agonists, researchers have been able to correlate functional properties with details of primary structures of the receptor subtypes (Changeux and Edelstein, 2005; Karlin, 2002; Sine et al., 2008).

Nicotinic Receptor Structure. The nicotinic receptor of the electrical organ and vertebrate skeletal muscle is a pentamer composed of four distinct subunits (α, β, γ, and δ) in the stoichiometric ratio of 2:1:1:1, respectively. In mature, innervated muscle end plates, the γ subunit is replaced by ∊, a closely related subunit. The individual subunits arose from a common primordial gene and are ~ 40% identical in their amino acid sequences.

The nicotinic receptor became the prototype for other pentameric ligand-gated ion channels, which include the receptors for the inhibitory amino acids (γ-aminobutyric acid and glycine; Chapter 14) and certain serotonin (5-HT₃) receptors (Chapter 13). Each of the subunits in the pentameric receptor has a molecular mass of 40-60 kDa. In each subunit, the amino-terminal ~210 residues constitute a large extracellular domain. This is followed by four transmembrane-spanning (TM) domains; the region between TM3 and TM4 forms most of the cytoplasmic component (Figure 11–1).

The five subunits are arranged around a pseudo-axis of symmetry to circumscribe a channel (Changeux and Edelstein, 1998; Karlin, 2002; Unwin, 2005). The resulting receptor is an asymmetrical molecule (16 × 8 nm) of 290 kDa, with the bulk of the non-membrane-spanning domain on the extracellular surface. The receptor is present at high densities (10,000/μm²) in junctional areas (i.e., the motor end plate in skeletal muscle and the ventral surface of the electrical organ). The regular packing of receptors in these membranes has facilitated electron microscopic image reconstruction of the molecular structure (Figure 11–2). Agonist-binding sites are found at the subunit interfaces; in muscle, only two of the five subunit interfaces, αγ and αδ, have evolved to bind ligands (Figure 11-2D). Both of the subunits forming the subunit interface contribute to ligand specificity. The binding of agonists and reversible competitive antagonists involves overlapping surfaces on the receptor and is mutually exclusive.

Measurements of membrane conductance demonstrate that rates of ion translocation are sufficiently rapid (5 × 10⁷ ions per second) to require ion translocation through an open channel rather than by a rotating carrier. Moreover, agonist-mediated changes in ion permeability (typically an inward movement of Na⁺, and secondarily, of Ca²⁺) occur through a cation channel intrinsic to the receptor structure. The TM2 regions of the five subunits form the internal perimeter of the channel. The agonist-binding site is intimately coupled with an ion channel; in the muscle receptor, simultaneous binding of two agonist molecules results in a rapid conformational change that opens the channel. Both the binding and gating response show positive cooperativity. Details on the kinetics of channel opening have emerged from electrophysiological patch-clamp techniques that distinguish the individual opening and closing events of a single receptor (Sakmann, 1992).

An ACh-binding protein homologous to only the extracellular domain of the nicotinic receptor has been identified in fresh- and saltwater snails and characterized structurally and pharmacologically (Brejc et al., 2001). This protein assembles as a homomeric pentamer and binds nicotinic receptor ligands with selectivity similar to neuronal nicotinic ACh receptors; its crystal structure reveals an atomic organization expected of the nicotinic receptor. Moreover, fusion of the ACh-binding protein and the transmembrane spans of the receptor yields a functional protein that exhibits the channel gating and changes in state expected of the receptor (Bouzat et al., 2004). This binding protein serves as both a structural and functional surrogate of the receptor and has provided a detailed understanding of the determinants governing ligand specificity of the nicotinic receptor.

Neuronal Nicotinic Receptor Composition. Cloning by sequence homology identified the genes encoding the vertebrate nicotinic receptor. Neuronal nicotinic receptors found in ganglia and the CNS also exist as pentamers of one, two, or more types of subunits. A single subunit of the α-type sequence (denoted as α1) is found in abundance in muscle, along with β, δ, and γ or ∊. At least eight subtypes of α (α2 through α9) and three of the non-α type (designated as β2 through β4) are found in neuronal tissues (Figure 11–2). Studies of neuronal receptor subunit abundance and associations in brain and the periphery have enabled investigators to identify subunit combinations that confer function. Although not all permutations of α and β subunits lead to functional receptors, the diversity in subunit composition is large and exceeds the capacity of ligands to distinguish subtypes on the basis of their selectivity. For example, the α3/β4 and α3/β2 subtypes are prevalent in peripheral ganglia, whereas the α4/β2 subtype is most prevalent in brain. The subtypes α2 through α6 and β2 through β4 associate as heteromeric pentamers composed of two or three distinct subtypes, whereas α7 through α9 often are seen as homomeric associations. Distinctive selectivities of the receptor subtypes for Na⁺ and Ca²⁺ suggest that certain subtypes may possess functions other than rapid trans-synaptic signaling.

History, Sources, and Chemistry. Curare is a generic term for various South American arrow poisons. The drug has been used for centuries by Indians along the Amazon and Orinoco Rivers for immobilizing and paralyzing wild animals used for food; death results from paralysis of skeletal muscles. The preparation of curare was long shrouded in mystery and was entrusted only to tribal witch doctors. Soon after the discovery of the American continent, European explorers and botanists became interested in curare, and late in the 16th century, samples of the native preparations were brought to Europe. Following the pioneering work of the scientist/explorer von Humboldt in 1805, the botanical sources of curare became the object of much field research. The curares from eastern Amazonia come from Strychnos species; these and other South American species of Strychnos contain chiefly quaternary neuromuscular-blocking alkaloids. The Asiatic, African, and Australian species nearly all contain tertiary strychnine-like alkaloids.

The modern clinical use of curare apparently dates from 1932, when West employed highly purified fractions in patients with tetanus and spastic disorders. Research on curare was accelerated greatly by the work of Gill, who, after prolonged and intimate study of the native methods of preparing curare, brought to the U.S. a sufficient amount of the authentic drug to permit chemical and pharmacological investigations. Griffith and Johnson reported the first trial of curare for promoting muscular relaxation in general anesthesia in 1942. Details of the fascinating history of curare and the chemical identification of the curare alkaloids are presented in previous editions of this book.

King established the essential structure of tubocurarine in 1935 (Figure 11–3). A synthetic derivative, metocurine (formerly called dimethyl tubocurarine), contains three additional methyl groups and possesses two to three times the potency of tubocurarine in human beings. The most potent curare alkaloids are the toxiferines, obtained from Strychnos toxifera. A semisynthetic derivative, alcuronium chloride (N,N′-diallylnortoxiferinium dichloride), was widely used clinically in Europe and elsewhere. The seeds of the trees and shrubs of the genus Erythrina, widely distributed in tropical and subtropical areas, contain erythroidines that possess curare-like activity. Gallamine is one of a series of synthetic substitutes for curare described by Bovet and co-workers in 1949.

Early structure-activity studies led to the development of the polymethylene bis-trimethyl-ammonium series (referred to as the methonium compounds). The most potent of these agents at the neuromuscular junction was the compound with 10 carbon atoms between the quaternary nitrogens: decamethonium (C10) (Figure 11–3). The compound with 6 carbon atoms in the chain, hexamethonium (C6), was found to be essentially devoid of neuromuscular blocking activity but particularly effective as a ganglionic blocking agent (see following discussion).

Structure-Activity Relationships. Several structural features distinguish competitive and depolarizing neuromuscular blocking agents. The competitive agents (e.g., tubocurarine, the benzylisoquinolines, the ammonio steroids, and the asymmetric mixed-onium chlorofumarates) are relatively bulky, rigid molecules, whereas the depolarizing agents (e.g., decamethonium [no longer marketed in the U.S. and succinylcholine) generally have more flexible structures that enable free bond rotations (Figure 11–3). While the distance between quaternary groups in the flexible depolarizing agents can vary up to the limit of the maximal bond distance (1.45 nm for decamethonium), the distance for the rigid competitive blockers is typically 1.0 ± 0.1 nm. l-Tubocurarine is considerably less potent than d-tubocurarine, perhaps because the d-isomer has all the hydrophilic groups localized uniquely to one surface.

The steps involved in ACh release by the nerve action potential, the development of miniature end-plate potentials (MEPPs), their summation to form a postjunctional end-plate potential (EPP), the triggering of the muscle action potential, and contraction are described in Chapter 8. Biophysical studies with patch electrodes reveal that the fundamental event elicited by ACh or other agonists is an "all or none" opening of the individual receptor channels, which gives rise to a square wave pulse with an average open-channel conductance of 20-30 picosiemens (pS) and a duration that is exponentially distributed around a time of ~1 ms. The duration of channel opening is far more dependent on the nature of the agonist than is the magnitude of the open-channel conductance (Sakmann, 1992).

Increasing concentrations of the competitive antagonist tubocurarine progressively diminish the amplitude of the excitatory postjunctional EPP. The amplitude of this potential may fall to below 70% of its initial value before it is insufficient to initiate the propagated muscle action potential; this provides a safety factor in neuromuscular transmission. Analysis of the antagonism of tubocurarine on single-channel events shows that, as expected for a competitive antagonist, tubocurarine reduces the frequency of channel-opening events but does not affect the conductance or duration of opening for a single channel (Katz and Miledi, 1978). At higher concentrations, curare and other competitive antagonists block the channel directly in a fashion that is noncompetitive with agonists and dependent on membrane potential (Colquhoun et al., 1979).

The decay time of the MEPP is similar to the average lifetime of channel opening (1-2 ms). MEPPs are a consequence of the spontaneous release of one or more quanta of ACh (~10⁵ molecules); individual molecules of ACh in the synapse have only a transient opportunity to activate the receptor and do not rebind successively to receptors to activate multiple channels before being hydrolyzed by acetylcholinesterase (AChE). The concentration of unbound ACh in the synapse from nerve-released ACh diminishes more rapidly than does the decay of the EPP (or current). In the presence of anti-cholinesterase drugs, the EPP is prolonged up to 25-30 ms, which is indicative of the rebinding of transmitter to neighboring receptors before hydrolysis by AChE or diffusion from the synapse.

Simultaneous binding by two agonist molecules at the respective αγ and αδ subunit interfaces of the receptor is required for activation. Activation shows positive cooperativity and thus occurs over a narrow range of concentrations (Changeux and Edelstein, 1998; Sine and Claudio, 1991). Although two molecules of competitive antagonist or snake α-toxin can bind to each receptor molecule at the agonist sites, the binding of one molecule of antagonist to each receptor is sufficient to render it nonfunctional (Taylor et al., 1983).

In other animal species and occasionally in humans, depolarizing agents produce a blockade that has unique features, some of which combine those of the depolarizing and the competitive agents; this type of action is termed a dual mechanism. In such cases, the depolarizing agent initially produces characteristic fasciculations and potentiation of the maximal twitch, followed by the rapid onset of neuromuscular block. This phase I block is potentiated by anticholinesterase agents (e.g., ambenonium, edrophonium, neostigmine, pyridostigmine, donepezil, galantamine, rivastigmine, and tacrine): Inhibition of ACh degradation results in additional depolarizing agent, in this case endogenous ACh, at the neuromuscular junction. Following the onset of blockade, there is a poorly sustained response to tetanic stimulation of the motor nerve, intensification of the block by tubocurarine, and lack of potentiation by anti-cholinesterase agents. The dual action of the depolarizing blocking agents is also seen in intracellular recordings of membrane potential; when agonist is applied continuously, the initial depolarization is followed by a gradual repolarization, which in many respects resembles receptor desensitization.

Under clinical conditions, with increasing concentrations of succinylcholine and over time, the block may convert slowly from a depolarizing phase I block to a non-depolarizing, phase II block (Durant and Katz, 1982). The pattern of neuromuscular blockade produced by depolarizing drugs in anesthetized patients appears to depend, in part, on the anesthetic; fluorinated hydrocarbons may be more apt to predispose the motor end plate to non-depolarization blockade after prolonged use of succinylcholine (Fogdall and Miller, 1975). While the response to peripheral stimulation during phase II block resembles that of the competitive agents, reversal of phase II block by administration of anti-cholinesterase agents (e.g., with neostigmine) is difficult to predict and should be undertaken with much caution. The characteristics of phase I and phase II blocks are shown in Table 11–1.

Although the observed fasciculations also may be a consequence of stimulation of the prejunctional nerve terminal by the depolarizing agent, giving rise to stimulation of the motor unit in an antidromic fashion, the primary site of action of both competitive and depolarizing blocking agents is the post-junctional membrane. Presynaptic actions of the competitive agents may become significant on repetitive high-frequency stimulation because pre-junctional nicotinic receptors may be involved in the mobilization of ACh for release from the nerve terminal (Bowman et al., 1990; Van der Kloot and Molgo, 1994).

Many drugs and toxins block neuromuscular transmission by other mechanisms, such as interference with the synthesis or release of ACh (Chapter 8), but most of these agents are not employed clinically for this purpose. One exception is botulinum toxin, which has been administered locally into muscles of the orbit in the management of ocular blepharospasm and strabismus and has been used to control other muscle spasms and to facilitate facial muscle relaxation (Chapters 8 and 64). This toxin also has been injected into the lower esophageal sphincter to treat achalasia (Chapter 47). The sites of action and interrelationship of several agents that serve as pharmacological tools are shown in Figure 11–4.

Sequence and Characteristics of Paralysis. When an appropriate dose of a competitive blocking agent is injected intravenously in human beings, motor weakness progresses to a total flaccid paralysis. Small, rapidly moving muscles such as those of the eyes, jaw, and larynx relax before those of the limbs and trunk. Ultimately, the intercostal muscles and finally the diaphragm are paralyzed, and respiration then ceases. Recovery of muscles usually occurs in the reverse order to that of their paralysis, and thus the diaphragm ordinarily is the first muscle to regain function (Feldman and Fauvel, 1994; Viby-Mogensen, 2005).

After a single intravenous dose of 10-30 mg of succinylcholine, muscle fasciculations, particularly over the chest and abdomen, occur briefly; then relaxation occurs within 1 minute, becomes maximal within 2 minutes, and generally disappears within 5 minutes. Transient apnea usually occurs at the time of maximal effect. Muscle relaxation of longer duration is achieved by continuous intravenous infusion. After infusion is discontinued, the effects of the drug usually disappear rapidly because of its efficient hydrolysis by plasma and hepatic butyrylcholinesterase. Muscle soreness may follow the administration of succinylcholine. Small prior doses of competitive blocking agents have been employed to minimize fasciculations and muscle pain caused by succinylcholine, but this procedure is controversial because it increases the requirement for the depolarizing drug.

During prolonged depolarization, muscle cells may lose significant quantities of K⁺ and gain Na⁺, Cl^–, and Ca²⁺. In patients with extensive injury to soft tissues, the efflux of K⁺ following continued administration of succinylcholine can be life-threatening. The life-threatening complications of succinylcholine-induced hyperkalemia are discussed later, but it is important to stress that there are many conditions for which succinylcholine administration is contraindicated or should be undertaken with great caution. The change in the nature of the blockade produced by succinylcholine (from phase I to phase II) presents an additional complication with long-term infusions.

When long-acting competitive blocking agents such as d-tubocurarine and pancuronium are administered, blockade may diminish after 30 minutes owing to redistribution of the drug, yet residual blockade and plasma levels of the drug persist. Subsequent doses show diminished redistribution. Long-acting agents may accumulate with multiple doses.

The ammonio steroids contain ester groups that are hydrolyzed in the liver. Typically, the metabolites have about one-half the activity of the parent compound and contribute to the total relaxation profile. Ammonio steroids of intermediate duration of action, such as vecuronium and rocuronium (Table 11–2), are cleared more rapidly by the liver than is pancuronium. The more rapid decay of neuromuscular blockade with compounds of intermediate duration argues for sequential dosing of these agents rather than administering a single dose of a long-duration neuromuscular blocking agent. There is a modified γ-cyclodextrin available as an investigational chelating agent specific for rocuronium and vecuronium (see "Reversal of Effects by Chelation Therapy" later in the chapter).

Atracurium is converted to less active metabolites by plasma esterases and spontaneous Hofmann elimination (Figure 11–3). Cisatracurium is also subject to this spontaneous degradation. Because of these alternative routes of metabolism, atracurium and cisatracurium do not exhibit an increased t_1/2 in patients with impaired renal function and therefore are good choices in this setting (Hunter, 1994; Naguib and Lien, 2005).

The extremely brief duration of action of succinylcholine is due largely to its rapid hydrolysis by the butyrylcholinesterase synthesized by the liver and found in the plasma. Among the occasional patients who exhibit prolonged apnea following the administration of succinylcholine or mivacurium, most have an atypical plasma cholinesterase or a deficiency of the enzyme owing to allelic variations (Pantuck, 1993; Primo-Parmo et al., 1996), hepatic or renal disease, or a nutritional disturbance; however, in some, the enzymatic activity in plasma is normal (Whittaker, 1986).

Gantacurium is degraded by two chemical mechanisms, a rapid cysteine adduction and a slower hydrolysis of the ester bond adjacent to the chlorine. Both processes are purely chemical and hence not dependent on enzymatic activities. The adduction process has a t_1/2 of 1-2 minutes and is likely the basis for the ultrashort duration of action of gantacurium. Administration of exogenous cysteine, which may have excitotoxic side effects, can accelerate the antagonism of gantacurium-induced neuromuscular blockade (Naguib and Brull, 2009).

Two characteristics are useful in distinguishing side effects and pharmacokinetic behavior of neuromuscular blocking agents. The first relates to the duration of drug action: These agents are categorized as long-, intermediate-, or short-acting. The persistent blockade and difficulty in complete reversal after surgery with d-tubocurarine, metocurine, doxacurium, and pancuronium led to the development of vecuronium (norcuron, others) and atracurium (tracrium, others), agents of intermediate duration; cisatracurium (nimbex) is one of ten isomers of atracurium with three times its potency. This was followed by the development of a short-acting agent, mivacurium (not available in the U.S.). Often, the long-acting agents are the more potent, requiring the use of low concentrations (Table 11–3). The necessity of administering potent agents in low concentrations delays their onset. Rocuronium (zemuron, others) is an agent of intermediate duration but of rapid onset and lower potency. Its rapid onset allows its use as an alternative to succinylcholine in rapid-induction anesthesia and in relaxing the laryngeal and jaw muscles to facilitate tracheal intubation (Bevan, 1994; Naguib and Lien, 2005). Gantacurium, a mixed-onium chlorofumarate, recently completed phase 2 clinical trials and is the first in a new class of ultra-short acting, competitive neuromuscular blocking agents designed to replace succinylcholine in rapid-induction anesthesia (Naguib and Brull, 2009; Savarese, 2006).

The second useful classification is derived from the chemical nature of the agents and includes the natural alkaloids or their congeners, the ammonio steroids, the benzylisoquinolines, and the asymmetric mixed-onium chlorofumarates (Table 11–2, Figure 11–3). The natural alkaloid d-tubocurarine and the semisynthetic alkaloid alcuronium are not approved for use in the U.S. Apart from a shorter duration of action, newer agents exhibit greatly diminished frequency of side effects, chief of which are ganglionic blockade, block of vagal responses, and histamine release. The prototypical ammonio steroid, pancuronium, induces virtually no histamine release; however, it blocks muscarinic receptors, and this antagonism is manifested primarily in vagal blockade and tachycardia. Tachycardia is eliminated in the newer ammonio steroids, vecuronium and rocuronium.

The benzylisoquinolines appear to be devoid of vagolytic and ganglionic blocking actions but show a slight propensity to cause histamine release. The unusual metabolism of the prototype compound atracurium and its congener mivacurium confers special indications for use of these compounds. For example, atracurium's disappearance from the body depends on hydrolysis of the ester moiety by plasma esterases and by a spontaneous or Hofmann degradation (cleavage of the N-alkyl portion in the benzylisoquinoline). Hence two routes for degradation are available, both of which remain functional in renal failure. Mivacurium is extremely sensitive to catalysis by cholinesterase or other plasma hydrolases, accounting for its short duration of action.

Side effects are not yet fully characterized for gantacurium, but transient adverse cardiovascular effects suggestive of histamine release have been observed at doses over three times the ED₉₅.

Measurement of Neuromuscular Blockade in Humans. Assessment of neuromuscular block usually is performed by stimulation of the ulnar nerve. Responses are monitored from compound action potentials or muscle tension developed in the adductor pollicis (thumb) muscle. Responses to repetitive or tetanic stimuli are most useful for evaluation of blockade of transmission because individual measurements of twitch tension must be related to control values obtained prior to the administration of drugs. Thus, stimulus schedules such as the "train of four" and the "double burst" or responses to tetanic stimulation are preferred procedures (Drenck et al., 1989; Waud and Waud, 1972). Rates of onset of blockade and recovery are more rapid in the airway musculature (jaw, larynx, and diaphragm) than in the thumb. Hence, tracheal intubation can be performed before onset of complete block at the adductor pollicis, whereas partial recovery of function of this muscle allows sufficient recovery of respiration for extubation (Naguib and Lien, 2005). Differences in rates of onset of blockade, recovery from blockade, and intrinsic sensitivity between the stimulated muscle and those of the larynx, abdomen, and diaphragm should be considered.

Preventing Trauma During Electroshock Therapy. Electroconvulsive therapy (ECT) of psychiatric disorders occasionally is complicated by trauma to the patient; the seizures induced may cause dislocations or fractures. Inasmuch as the muscular component of the convulsion is not essential for benefit from the procedure, neuromuscular blocking agents, usually succinylcholine, and a short-acting barbiturate, usually methohexital or thiopental, are employed. The combination of the blocking drug, the anesthetic agent, and postictal depression usually results in respiratory depression or temporary apnea. An endotracheal tube and oxygen always should be available. An oropharyngeal airway should be inserted as soon as the jaw muscles relax (after the seizure) and provision made to prevent aspiration of mucus and saliva. A cuff may be applied to one extremity to prevent the effects of the drug in that limb; evidence of an effective electroshock is provided by contraction of the group of protected muscles. After the procedure, ventilation with oxygen by mask should be continued until adequate breathing resumes (Stensrud, 2005). These agents are also used in capital punishment by electrocution. Although a convulsive response is blocked, ethical concerns have been raised because all motor function is blocked.

The anaerobic bacterium Clostridium botulinum produces a family of toxins targeted to presynaptic proteins that block the release of ACh (Chapter 8). Onabotulinum toxin A (botox), abobotulinum toxin A (dysport), and rimabotulinum toxin B (myobloc), by blocking ACh release, produce flaccid paralysis of skeletal muscle and diminished activity of parasympathetic and sympathetic cholinergic synapses. Inhibition lasts from several weeks to 3 to 4 months, and restoration of function requires nerve sprouting. Immunoresistance is uncommon but may develop with continued use (Davis and Barnes, 2000). Originally approved for the treatment of the ocular conditions of strabismus and blepharospasm and for hemifacial spasms, botulinum toxin has been used to treat spasms and dystonias such as adductor spasmodic dysphonia, oromandibular dystonia, cervical dystonia, and spasms associated with the lower esophageal sphincter and anal fissures. Its dermatological uses include treatment of hyperhidrosis of the palms and axillae that is resistant to topical and iontophoretic remedies and removal of facial lines associated with excessive nerve stimulation and muscle activity. Treatment involves local intramuscular or intradermal injections (Boni et al., 2000; Flynn, 2006). Botox treatments also have become a popular cosmetic procedure for those seeking a wrinkle-free face. Like the bloom of youth, the reduction of wrinkles is temporary; unlike the bloom of youth, the effect of Botox can be renewed by re-administration. The FDA has issued a safety alert, warning of respiratory paralysis from unexpected spread of the toxin from the site of injection (Chapter 65).

Dantrolene (dantrium, others) inhibits Ca²⁺ release from the sarcoplasmic reticulum of skeletal muscle by limiting the capacity of Ca²⁺ and calmodulin to activate RYR-1 (Fruen et al., 1997). RYR-1 and the L-type Ca²⁺ channel are juxtaposed to associate at a triadic junction formed between the T-tubule and the sarcoplasmic reticulum. The L-type channel with its T-tubular location serves as the voltage sensor receiving the depolarizing activation signal. The intimate coupling of the two proteins at the triad, along with a host of modulatory proteins in the two organelles and the surrounding cytoplasm, regulates the release of and response to Ca²⁺ (Lehmann-Horn and Jurkat-Rott, 1999). Because of its efficacy in managing an acute attack of malignant hyperthermia (described under "Toxicology"), dantrolene has been used experimentally in the treatment of muscle rigidity and hyperthermia in neuroleptic malignant syndrome (NMS). NMS is a life-threatening complication of treatment with both typical and atypical antipsychotic drugs (Chapter 16) characterized by fever, severe muscle rigidity, mental status change, and dysautonomia. Administration of 1-2.5 mg/kg dantrolene in severe NMS cases, concurrent with immediate discontinuation of antipsychotic therapy, usually results in rapid reversal of hyperthermia and rigidity (Strawn et al., 2007). Dantrolene is also used in treatment of spasticity and hyperreflexia. With its peripheral action, it causes a generalized weakness. Thus, its use should be reserved to non-ambulatory patients with severe spasticity. Hepatotoxicity has been reported with continued use, requiring liver function tests (Kita and Goodkin, 2000).

Several agents, many of limited efficacy, have been used to treat spasticity involving the α-motor neuron with the objective of increasing functional capacity and relieving discomfort. Agents that act in the CNS at either higher centers or the spinal cord to block spasms are considered in Chapter 22. These include baclofen (lioresal, others), the benzodiazepines, tizanidine (zanaflex, others), and cyclobenzaprine (flexaril, others). A number of other agents used as muscle relaxants seem to rely on sedative properties and blockade of nociceptive pathways; this group includes carisoprodol (which is metabolized to meprobamate; soma, others); metaxalone (skelaxin); methocarbamol (robaxin, others); and orphenadrine (norflex, others). Tetrabenazine (xenazine) is available for treatment of the chorea associated with Huntington's disease; the drug is a VMAT2 inhibitor that depletes vesicular stores of dopamine in the CNS (Chapters 8 and 22).

Many inhalational anesthetics exert a stabilizing effect on the postjunctional membrane and therefore potentiate the activity of competitive blocking agents. Consequently, when such blocking drugs are used for muscle relaxation as adjuncts to these anesthetics, their doses should be reduced. The rank of order of potentiation is desflurane > sevoflurane > isoflurane > halothane > nitrous oxide-barbiturate-opioid or propofol anesthesia (Naguib and Lien, 2005).

Aminoglycoside antibiotics produce neuromuscular blockade by inhibiting ACh release from the preganglionic terminal (through competition with Ca²⁺) and to a lesser extent by noncompetitively blocking the receptor. The blockade is antagonized by Ca²⁺ salts but only inconsistently by anti-ChE agents (Chapter 54). The tetracyclines also can produce neuromuscular blockade, possibly by chelation of Ca²⁺. Additional antibiotics that have neuromuscular blocking action, through both presynaptic and postsynaptic actions, include polymyxin B, colistin, clindamycin, and lincomycin (Pollard, 1994). Ca²⁺ channel blockers enhance neuromuscular blockade produced by both competitive and depolarizing antagonists. It is not clear whether this is a result of a diminution of Ca²⁺-dependent release of transmitter from the nerve ending or is a postsynaptic action. When neuromuscular blocking agents are administered to patients receiving these agents, dose adjustments should be considered; if recovery of spontaneous respiration is delayed, Ca²⁺ salts may facilitate recovery.

Miscellaneous drugs that may have significant interactions with either competitive or depolarizing neuromuscular blocking agents include trimethaphan (no longer marketed in the U.S.), lithium, opioid analgesics, procaine, lidocaine, quinidine, phenelzine, carbamazemine, phenytoin, propranolol, dantrolene, azathioprine, tamoxifen, magnesium salts, corticosteroids, digitalis glycosides, chloroquine, catecholamines, and diuretics (Naguib and Lien, 2005; Pollard, 1994).

The depolarizing agents can release K⁺ rapidly from intracellular sites; this may be a factor in production of the prolonged apnea in patients who receive these drugs while in electrolyte imbalance. Succinylcholine-induced hyperkalemia is a life-threatening complication of that drug (Yentis, 1990). For example, such alterations in the distribution of K⁺ are of particular concern in patients with congestive heart failure who are receiving digoxin or diuretics. For the same reason, caution should be used or depolarizing blocking agents should be avoided in patients with extensive soft-tissue trauma or burns. A higher dose of a competitive blocking agent often is indicated in these patients. In addition, succinylcholine administration is contraindicated or should be given with great caution in patients with nontraumatic rhabdomyolysis, ocular lacerations, spinal cord injuries with paraplegia or quadriplegia, or muscular dystrophies. Succinylcholine no longer is indicated for children ≤8 years of age unless emergency intubation or securing an airway is necessary. Hyperkalemia, rhabdomyolysis, and cardiac arrest have been reported. A subclinical dystrophy is frequently associated with these adverse responses. Neonates may also have an enhanced sensitivity to competitive neuromuscular blocking agents.

Malignant Hyperthermia. Malignant hyperthermia is a potentially life-threatening event triggered by the administration of certain anesthetics and neuromuscular blocking agents. The clinical features include contracture, rigidity, and heat production from skeletal muscle resulting in severe hyperthermia (increases of up to 1°C/5 min), accelerated muscle metabolism, metabolic acidosis, and tachycardia. Uncontrolled release of Ca²⁺ from the sarcoplasmic reticulum of skeletal muscle is the initiating event. Although the halogenated hydrocarbon anesthetics (e.g., halothane, isoflurane, and sevoflurane) and succinylcholine alone have been reported to precipitate the response, most of the incidents arise from the combination of depolarizing blocking agent and anesthetic. Susceptibility to malignant hyperthermia, an autosomal dominant trait, is associated with certain congenital myopathies such as central core disease. In the majority of cases, however, no clinical signs are visible in the absence of anesthetic intervention.

Determination of susceptibility is made with an in vitro contracture test on a fresh biopsy of skeletal muscle, where contractures in the presence of halothane and caffeine are measured. In over 50% of affected families, a linkage is found between the phenotype as measured by the contracture test and a mutation in the gene encoding the skeletal muscle ryanodine receptor (RYR-1). Over 30 mutations in a region of the gene that encodes the cytoplasmic face of the receptor have been described. Other loci have been identified on the L-type Ca²⁺ channel (voltage-gated dihydropyridine receptor) and on other associated proteins or channel subunits. The large number of mutations in the RYR-1 gene, combined with genetic and metabolic heterogeneity of the condition, have precluded reliable genotypic determination of susceptibility to malignant hyperthermia (Rosenberg et al., 2007).

Treatment entails intravenous administration of dantrolene (dantrium, others), which blocks Ca²⁺ release from the sarcoplasmic reticulum of skeletal muscle (see "Control of Muscle Spasms and Rigidity" earlier in the chapter). Rapid cooling, inhalation of 100% oxygen, and control of acidosis should be considered adjunct therapy in malignant hyperthermia. Declining fatality rates for malignant hyperthermia relate to anesthesiologists' awareness of the condition and the efficacy of dantrolene.

Patients with central core disease, so named because of the presence of myofibrillar cores seen on biopsy of slow-twitch muscle fibers, show muscle weakness in infancy and delayed motor development. These individuals are highly susceptible to malignant hyperthermia with the combination of an anesthetic and a depolarizing neuromuscular blocker. Central core disease has five allelic variants of RYR-1 in common with malignant hyperthermia. Patients with other muscle syndromes or dystonias also have an increased frequency of contracture and hyperthermia in the anesthesia setting. Succinylcholine in susceptible individuals also induces trismus-masseter spasm, an increase in jaw muscle tone, which may complicate endotracheal tube insertion and airway management (van der Spek et al., 1990). This condition has been correlated with a mutation in the gene encoding the α subunit of the voltage-sensitive Na⁺ channel (Vita et al., 1995). This increase in jaw muscle tone can be an early sign of the onset of malignant hyperthermia, and when observed along with rigidity in other muscles, is a signal that anesthesia should be halted and treatment of malignant hyperthermia begun (Gronert et al., 2005).

Respiratory Paralysis. Treatment of respiratory paralysis arising from an adverse reaction or overdose of a neuromuscular blocking agent should be by positive-pressure artificial respiration with oxygen and maintenance of a patent airway until recovery of normal respiration is ensured. With the competitive blocking agents, this may be hastened by the administration of neostigmine methylsulfate (0.5-2 mg IV) or edrophonium (10 mg IV, repeated as required up to a total of 40 mg) (Watkins, 1994).

Interventional Strategies for Other Toxic Effects. Neostigmine effectively antagonizes only the skeletal muscular blocking action of the competitive blocking agents and may aggravate such side effects as hypotension or induce bronchospasm. In such circumstances, sympathomimetic amines may be given to support the blood pressure. Atropine or glycopyrrolate is administered to counteract muscarinic stimulation. Antihistamines are definitely beneficial to counteract the responses that follow the release of histamine, particularly when administered before the neuromuscular blocking agent.

Reversal of Effects by Chelation Therapy. There is now an investigational chelating agent specific for rocuronium and vecuronium, sugammadex (bridion), a modified γ-cyclodextrin. Administration of sugammadex at doses >2 mg/kg is able to reverse neuromuscular blockade from rocuronium within 3 minutes. The majority of sugammadex and its complex with rocuronium is eliminated in the urine. In patients with impaired renal function, sugammadex clearance is markedly reduced and this agent should be avoided. Theoretically, neuromuscular blockade can reoccur if rocuronium or vecuronium become displaced from the sugammadex complex, necessitating careful monitoring and repeat dosing if necessary. Sugammadex is approved for clinical use in Europe but not yet in the U.S. (Naguib and Brull, 2009). Side effects include dysgeusia and rare self-limiting hypersensitivity.

An action potential is generated in the postganglionic neuron when the initial EPSP attains a critical amplitude. In mammalian sympathetic ganglia in vivo, it is common for multiple synapses to be activated before transmission is effective. Unlike the neuromuscular junction, discrete end plates with focal localization of receptors do not exist in ganglia; rather, the dendrites and nerve cell bodies contain the receptors. Iontophoretic application of ACh to the ganglion results in a depolarization with a latency < 1 ms; this decays over a period of 10-50 ms (Ascher et al., 1979). Measurements of single-channel conductances indicate that the characteristics of nicotinic-receptor channels of the ganglia and the neuromuscular junction are quite similar.

The secondary events that follow the initial depolarization (IPSP; slow EPSP; late, slow EPSP) are insensitive to hexamethonium or other N_n antagonists. The IPSP is unaffected by the classical nicotinic-receptor blocking agents. Electrophysiological and neurochemical evidence suggests that catecholamines participate in the generation of the IPSP. Dopamine and norepinephrine cause hyperpolarization of ganglia; however, in some ganglia IPSPs are mediated by M₂ muscarinic receptors (Chapter 9). Since the IPSP is sensitive in most systems to blockade by both atropine and α adrenergic receptor antagonists, ACh that is released at the preganglionic terminal may act on catecholamine-containing interneurons to stimulate the release of dopamine or norepinephrine; the catecholamine in turn produces hyperpolarization (an IPSP) of ganglion cells. Histochemical studies indicate that dopamine- or norepinephrine-containing small, intensely fluorescent (SIF) cells and adrenergic nerve terminals are present in ganglia. Details of the functional linkage between the SIF cells and the electrogenic mechanism of the IPSP remain to be resolved (Prud'homme et al., 1999; Slavikova et al., 2003).

The slow EPSP is generated by ACh activation of M₁ (G_q-coupled) muscarinic receptors and is blocked by atropine or antagonists that are selective for M₁ muscarinic receptors (Chapter 9). The slow EPSP has a longer latency and greater duration (10-30 seconds) than the initial EPSP. Slow EPSPs result from decreased K⁺ conductance, the M current that regulates the sensitivity of the cell to repetitive fast-depolarizing events (Adams et al., 1982). In contrast, the late slow EPSP lasts for several minutes and is mediated by peptides released from presynaptic nerve endings or interneurons in specific ganglia, as discussed in the next section. The peptides and ACh may be co-released at the presynaptic nerve terminals; the relative stability of the peptides in the ganglion extends its sphere of influence to postsynaptic sites beyond those in the immediate proximity of the nerve ending.

The secondary synaptic events modulate the initial EPSP. The importance of the secondary pathways and the nature of the modulating transmitters appear to differ among individual ganglia and between parasympathetic and sympathetic ganglia. A variety of peptides, including gonadotropin-releasing hormone, substance P, angiotensin, calcitonin gene–related peptide, vasoactive intestinal polypeptide, neuropeptide Y, and enkephalins, have been identified in ganglia by immunofluorescence. They appear localized to particular cell bodies, nerve fibers, or SIF cells, are released on nerve stimulation, and are presumed to mediate the late slow EPSP (Elfvin et al., 1993). Other neurotransmitter substances, such as 5-hydroxytryptamine and γ-aminobutyric acid, are known to modify ganglionic transmission. Precise details of their modulatory actions are not understood, but they appear to be most closely associated with the late slow EPSP and inhibition of the M current in various ganglia. Conventional ganglionic blocking agents can inhibit ganglionic transmission completely; the same cannot be said for muscarinic antagonists or α adrenergic receptor agonists (Volle, 1980).

History. Two natural alkaloids, nicotine and lobeline, exhibit peripheral actions by stimulating autonomic ganglia. Nicotine (Figure 11–6) was first isolated from leaves of tobacco, Nicotiana tabacum, by Posselt and Reiman in 1828; Orfila initiated the first pharmacological studies of the alkaloid in 1843. Langley and Dickinson painted the superior cervical ganglion of rabbits with nicotine and demonstrated that its site of action was the ganglion rather than the preganglionic or postganglionic nerve fiber. Lobeline, from Lobelia inflata, has many of the same actions as nicotine but is less potent.

Other ganglionic stimulants include tetramethylammonium (TMA) and 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) (Figure 11–6). Stimulation of ganglia by TMA or DMPP differs from that produced by nicotine in that the initial stimulation is not followed by a dominant blocking action. DMPP is about three times more potent and slightly more ganglion-selective than nicotine. Although parasympathomimetic drugs stimulate ganglia, their effects usually are obscured by stimulation of other neuroeffector sites. McN-A-343 represents an exception: in certain tissues its primary action appears to occur at muscarinic M₁ receptors in ganglia.

Peripheral Nervous System. The major action of nicotine consists initially of transient stimulation and subsequently of a more persistent depression of all autonomic ganglia. Small doses of nicotine stimulate the ganglion cells directly and may facilitate impulse transmission. Following larger doses, the initial stimulation is followed very quickly by a blockade of transmission. Whereas stimulation of the ganglion cells coincides with their depolarization, depression of transmission by adequate doses of nicotine occurs both during the depolarization and after it has subsided. Nicotine also possesses a biphasic action on the adrenal medulla: small doses evoke the discharge of catecholamines; larger doses prevent their release in response to splanchnic nerve stimulation.

The effects of high doses of nicotine on the neuromuscular junction are similar to those on ganglia. However, with the exception of avian and denervated mammalian muscle, the stimulant phase is obscured largely by the rapidly developing paralysis. In the latter stage, nicotine also produces neuromuscular blockade by receptor desensitization. At lower concentrations, such as those typically achieved by recreational tobacco use (~200 nM), nicotine's effects reflect its higher affinity for a neuronal nicotinic receptor (α4β2) than for the neuromuscular junction receptor (α1β1γδ), as explained in molecular detail by Xiu and associates (2009). This high affinity, coupled with the ability of nicotine to cross the blood-brain barrier, allows nicotine to selectively activate neuronal receptors without causing intolerable contractions or paralysis of skeletal muscle.

Nicotine, like ACh, stimulates a number of sensory receptors. These include mechanoreceptors that respond to stretch or pressure of the skin, mesentery, tongue, lung, and stomach; chemoreceptors of the carotid body; thermal receptors of the skin and tongue; and pain receptors. Prior administration of hexamethonium prevents stimulation of the sensory receptors by nicotine but has little, if any, effect on the activation of sensory receptors by physiological stimuli.

Central Nervous System. Nicotine markedly stimulates the CNS. Low doses produce weak analgesia; with higher doses, tremors leading to convulsions at toxic doses are evident. The excitation of respiration is a prominent action of nicotine; although large doses act directly on the medulla oblongata, smaller doses augment respiration reflexly by excitation of the chemoreceptors of the carotid and aortic bodies. Stimulation of the CNS with large doses is followed by depression, and death results from failure of respiration owing to both central paralysis and peripheral blockade of the diaphragm and intercostal muscles that facilitate respiration.

Nicotine induces vomiting by both central and peripheral actions. The central component of the vomiting response is due to stimulation of the emetic chemoreceptor trigger zone in the area postrema of the medulla oblongata. In addition, nicotine activates vagal and spinal afferent nerves that form the sensory input of the reflex pathways involved in the act of vomiting. Studies in isolated higher centers of the brain and spinal cord reveal that the primary sites of action of nicotine in the CNS are prejunctional, causing the release of other transmitters. Accordingly, the stimulatory and pleasure–reward actions of nicotine appear to result from release of excitatory amino acids, dopamine, and other biogenic amines from various CNS centers (MacDermott et al., 1999). Release of excitatory amino acids may account for much of nicotine's stimulatory action.

Chronic exposure to nicotine in several systems causes a marked increase in the density or number of nicotinic receptors, possibly contributing to tolerance and dependence. Nicotine acts as an intracellular molecular chaperone to promote the assembly of receptor subunits by inducing an active conformation in the nascent subunits that assemble more efficiently. Chronic low dose exposure to nicotine also significantly increases the t_1/2 of receptors on the cell surface (Kuryatov et al., 2005; Lester et al., 2009).

Cardiovascular System. When administered intravenously to dogs, nicotine characteristically produces an increase in heart rate and blood pressure. The latter is usually more sustained. In general, the cardiovascular responses to nicotine are due to stimulation of sympathetic ganglia and the adrenal medulla, together with the discharge of catecholamines from sympathetic nerve endings. Contributing to the sympathomimetic response to nicotine is the activation of chemoreceptors of the aortic and carotid bodies, which reflexly results in vasoconstriction, tachycardia, and elevated blood pressure.

GI Tract. The combined activation of parasympathetic ganglia and cholinergic nerve endings by nicotine results in increased tone and motor activity of the bowel. Nausea, vomiting, and occasionally diarrhea are observed following systemic absorption of nicotine in an individual who has not been exposed to nicotine previously.

Exocrine Glands. Nicotine causes an initial stimulation of salivary and bronchial secretions that is followed by inhibition.

Absorption, Distribution, and Elimination. Nicotine is readily absorbed from the respiratory tract, buccal membranes, and skin. Severe poisoning has resulted from percutaneous absorption. As a relatively strong base, nicotine has limited absorption from the stomach. Intestinal absorption is far more efficient. Nicotine in chewing tobacco, because it is absorbed more slowly than inhaled nicotine, has a longer duration of effect. The average cigarette contains 6-11 mg nicotine and delivers ~1-3 mg nicotine systemically to the smoker; bioavailability can increase as much as 3-fold with the intensity of puffing and technique of the smoker (Benowitz, 1998).

Approximately 80-90% of nicotine is altered in the body, mainly in the liver but also in the kidney and lung. Cotinine is the major metabolite, with nicotine-1′-N-oxide and 3-hydroxycotinine and conjugated metabolites found in lesser quantities (Benowitz, 1998). The profile of metabolites and the rate of metabolism appear to be similar in smokers and nonsmokers. The t_1/2 of nicotine following inhalation or parenteral administration is ~2 hours. Nicotine and its metabolites are eliminated rapidly by the kidney. The rate of urinary excretion of nicotine diminishes when the urine is alkaline. Nicotine also is excreted in the milk of lactating women who smoke; the milk of heavy smokers may contain 0.5 mg/L.

Acute Nicotine Poisoning. Poisoning from nicotine may occur from accidental ingestion of nicotine-containing insecticide sprays or in children from ingestion of tobacco products. The acutely fatal dose of nicotine for an adult is probably ~ 60 mg. Smoking tobacco usually contains 1-2% nicotine. Apparently, the gastric absorption of nicotine from tobacco taken by mouth is delayed because of slowed gastric emptying, so vomiting caused by the central effect of the initially absorbed fraction may remove much of the tobacco remaining in the GI tract.

The onset of symptoms of acute, severe nicotine poisoning is rapid; they include nausea, salivation, abdominal pain, vomiting, diarrhea, cold sweat, headache, dizziness, disturbed hearing and vision, mental confusion, and marked weakness. Faintness and prostration ensue; the blood pressure falls; breathing is difficult; the pulse is weak, rapid, and irregular; and collapse may be followed by terminal convulsions. Death may result within a few minutes from respiratory failure.

Therapy. Vomiting may be induced, or gastric lavage should be performed. Alkaline solutions should be avoided. A slurry of activated charcoal is then passed through the tube and left in the stomach. Respiratory assistance and treatment of shock may be necessary.

Smoking Cessation. Two goals of the pharmacotherapy of smoking cessation are the reduction of the craving for nicotine and inhibition of the reinforcing effects of nicotine. Myriad approaches and drug regimens are used, including nicotine replacement, bupropion (Chapter 15), and nicotinic ACh receptor agonists (Chapters 15 and 24 and the review by Frishman, 2009). Nicotine dependence is likely mediated, at least in part, by subtypes of the neuronal nicotinic acetylcholine receptor (N_n). The mesolimbic α₄β₂ subtype of N_n and α₄β₂-stimulated release of dopamine seem to play major roles in nicotine dependence. Thus, one aim of drug development in this area is discovery of an agent that will stimulate α₄β₂-mediated DA release sufficiently to reduce craving during periods of abstinence from smoking yet occupy the α₄β₂ N_n receptor sufficiently to inhibit nicotine reinforcement during smoking (Rollema et al., 2007).

Varenicline (chantix) has been recently introduced as an aid to smoking cessation. The drug interacts with nicotinic ACh receptors. In model systems, varenicline is a partial agonist at α₄β₂ receptors and a full agonist at the α₇ subtype, with weak activity toward α₃β₂- and α₆-containing receptors (Mihalak et al., 2006). The drug is effective clinically; however, it is not benign: Based on post-marketing studies, the FDA has issued a warning about mood and behavioral changes associated with its use (Frishman, 2009).

Nicotine itself is available in several dosage forms to help achieve abstinence from tobacco use. Efficacy results primarily from preventing a withdrawal or abstinence syndrome. Nicotine is marketed for over-the-counter use as a gum or lozenge (nicotine polacrilex, nicorette, commit, thrive, others), transdermal patch (nicoderm, habitrol, others), a nasal spray (nicotrol), or a vapor inhaler (nicotrol). The gum and transdermal systems are used most widely, and the objective is to obtain a sustained plasma nicotine concentration lower than venous blood concentrations after smoking. Arterial blood concentrations immediately following inhalation can be as much as 10-fold higher than venous concentrations. The efficacy of these dosage forms in producing abstinence from smoking is enhanced when linked to counseling and motivational therapy (Benowitz, 1999; Fant et al., 1999; Frishman, 2009).

History and Structure-Activity Relationship. Although Marshall first described the "nicotine-paralyzing" action of tetraethylammonium (TEA) on ganglia in 1913, TEA was largely overlooked until the effects of the ion on the cardiovascular system and autonomic ganglia were analyzed. The prototypical ganglionic blocking drug in this series, hexamethonium (C6), has a bridge of six methylene groups between the two quaternary nitrogen atoms (Figure 11–7). It has minimal neuromuscular and muscarinic blocking activities. Triethylsulfoniums (e.g., trimethaphan), like the quaternary and bis-quaternary ammonium ions, possess ganglionic blocking actions (Figure 11–7). Mecamylamine, a secondary amine, is currently licensed as an orphan drug for Tourette's syndrome.

Pharmacological Properties. Nearly all the physiological alterations observed after the administration of ganglionic blocking agents can be anticipated with reasonable accuracy by a careful inspection of Figure 8–1 and Table 8–1, and by knowing which division of the autonomic nervous system exercises dominant control of various organs (Table 11–5). For example, blockade of sympathetic ganglia interrupts adrenergic control of arterioles and results in vasodilation, improved peripheral blood flow in some vascular beds, and a fall in blood pressure. Generalized ganglionic blockade also may result in atony of the bladder and GI tract, cycloplegia, xerostomia, diminished perspiration, and by abolishing circulatory reflex pathways, postural hypotension. These changes represent the generally undesirable features of ganglionic blockade that severely limit the therapeutic efficacy of ganglionic blocking agents.

Cardiovascular System. Existing sympathetic tone is critical in determining the degree to which blood pressure is lowered by ganglionic blockade; thus, blood pressure may be decreased only minimally in recumbent normotensive subjects but may fall markedly in sitting or standing subjects. Postural hypotension was a major limitation in ambulatory patients receiving ganglionic blocking drugs.

Changes in heart rate following ganglionic blockade depend largely on existing vagal tone. In humans, mild tachycardia usually accompanies the hypotension, a sign that indicates fairly complete ganglionic blockade. However, a decrease may occur if the heart rate is high initially.

Cardiac output often is reduced by ganglionic blocking drugs in patients with normal cardiac function, as a consequence of diminished venous return resulting from venous dilation and peripheral pooling of blood. In patients with cardiac failure, ganglionic blockade frequently results in increased cardiac output owing to a reduction in peripheral resistance. In hypertensive subjects, cardiac output, stroke volume, and left ventricular work are diminished.

Although total systemic vascular resistance is decreased in patients who receive ganglionic blocking agents, changes in blood flow and vascular resistance of individual vascular beds are variable. Reduction of cerebral blood flow is small unless mean systemic blood pressure falls below 50-60 mm Hg. Skeletal muscle blood flow is unaltered, but splanchnic and renal blood flow decrease following the administration of a ganglionic blocking agent.

Absorption, Distribution, and Elimination. The absorption of quaternary ammonium and sulfonium compounds from the enteric tract is incomplete and unpredictable. This is due both to the limited ability of these ionized substances to penetrate cell membranes and to the depression of propulsive movements of the small intestine and gastric emptying. Although the absorption of mecamylamine is less erratic, a danger exists of reduced bowel activity leading to frank paralytic ileus.

After absorption, the quaternary ammonium- and sulfonium-blocking agents are confined primarily to the extracellular space and are excreted mostly unchanged by the kidney. Mecamylamine concentrates in the liver and kidney and is excreted slowly in an unchanged form.

Untoward Responses and Severe Reactions. Among the milder untoward responses observed are visual disturbances, dry mouth, conjunctival suffusion, urinary hesitancy, decreased potency, subjective chilliness, moderate constipation, occasional diarrhea, abdominal discomfort, anorexia, heartburn, nausea, eructation, and bitter taste and the signs and symptoms of syncope caused by postural hypotension. More severe reactions include marked hypotension, constipation, syncope, paralytic ileus, urinary retention, and cycloplegia.