The nicotinic acetylcholine (ACh) receptor mediates neurotransmission postsynaptically at the neuromuscular junction and peripheral autonomic ganglia; in the CNS, it largely controls release of neurotransmitters from presynaptic sites. The receptor is called the nicotinic acetylcholine receptor because both the alkaloid nicotine and the neurotransmitter ACh can stimulate the receptor. Distinct subtypes of nicotinic receptors exist at the neuromuscular junction and the ganglia.
THE NICOTINIC ACETYLCHOLINE RECEPTOR
The binding of ACh to the nicotinic ACh receptor initiates an endplate potential (EPP) in muscle or an excitatory postsynaptic potential (EPSP) in peripheral ganglia (see Chapter 8). The nicotinic receptor is the prototype for other pentameric ligand-gated ion channels, which include the receptors for the inhibitory amino acids (γ-aminobutyric acid [GABA] and glycine; see Chapter 14) and serotonin (the 5HT3 receptor) (Figure 11–1).
Figure 11–1 Subunit organization of pentameric ligand-gated ion channels and the ACh binding protein. For each receptor, the amino terminal region of ~210 amino acids is found at the extracellular surface. It is then followed by 4 hydrophobic regions that span the membrane (TM1-TM4), leaving the small carboxyl terminus on the extracellular surface. The TM2 region is α-helical, and TM2 regions from each subunit of the pentameric receptor line the internal pore of the receptor. Two disulfide loops at positions 128-142 and 192-193 are found in the α-subunit of the nicotinic receptor. The 128-142 motif is conserved in the family of pentameric receptors; the vicinal cysteines at 192-193 occur only in α-subunits of the nicotinic receptor and in the ACh binding protein.
NICOTINIC RECEPTOR STRUCTURE. Nicotinic receptors of vertebrate skeletal muscle (Nm) are pentamers composed of 4 distinct subunits (α, β, γ, and δ) in the stoichiometric ratio of 2:1:1:1. In mature, innervated muscle endplates, the γ subunit is replaced by ε, a closely related subunit. The individual subunits are ~40% identical in their amino acid sequences. The 5 subunits of the nicotinic acetylcholine receptor are arranged around a pseudo-axis of symmetry to circumscribe a channel. Agonist-binding sites occur at the subunit interfaces; in muscle, only 2 of the 5 subunit interfaces, αγ and αδ, bind ligands (Figure 11–2). Both of the subunits forming the subunit interface contribute to ligand specificity.
Figure 11–2 Subunit arrangement and molecular structure of the nicotinic acetylcholine receptor. A. Longitudinal view of receptor schematic with the m subunit removed. The remaining subunits, 2 copies of α, 1 of β, and 1 of δ, are shown to surround an internal channel with an outer vestibule and its constriction located deep in the membrane bilayer region. Spans of α-helices with slightly bowed structures form the perimeter of the channel and come from the TM2 region of the linear sequence (Figure 11–1). ACh binding sites, indicated by red arrows, occur at the αγ and αδ (not visible) interfaces. B.Nicotinic receptor subunit arrangement, with examples of subunit assembly. Agonist binding sites (red circles) occur at α subunit-containing interfaces. A total of 17 functional receptor isoforms have been observed in vivo, with different ligand specificity, relative Ca2+/Na+ permeability, and physiological function as determined by their subunit composition. The only isoform found at the neuromuscular junction is that shown here. There are 16 neuronal receptor isoforms found at autonomic ganglia and in the CNS, homo- and hetero-pentamers of α (α2-α10) and β (β2-β4) subunits.
Neuronal nicotinic (Nn) receptors found in ganglia and the CNS also exist as pentamers of 1 or more types of subunits. Subunit types α2 through α10 and β2 through β4 are found in neuronal tissues (seeFigure 11–2). 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.
NEUROMUSCULAR BLOCKING AGENTS
Modern-day neuromuscular blocking agents fall generally into 2 classes, depolarizing and competitive/nondepolarizing. At present, only a single depolarizing agent, succinylcholine (ANECTINE, QUELICIN), is in general clinical use; multiple competitive or nondepolarizing agents are available (see Table 11–2).
Classification of Neuromuscular Blocking Agents
See the 12th edition of the parent text for the history, sources, and chemistry of curare, the prototypical South American arrow poison and neuromuscular blocking agent, the action of which was described by Claude Bernard in the 1850s. The 12th edition also shows the structures of the various classes of depolarizing and competitive neuromuscular blockers in Figure 11–3.
Figure 11–3 A pharmacologist’s view of the motor end plate. The structures of the motor end plate (left side of figure) facilitate the series of physiological events leading from nerve action potential (AP) to skeletal muscle contraction (center column). Pharmacological agents can modify neurotransmission and excitation-contraction coupling at myriad sites (righthand column). enhancement; blockade; depolarization and phase II block.
SKELETAL MUSCLE. Competitive antagonists bind the nicotinic ACh receptor of the motor endplate and thereby competitively block the binding of ACh. The depolarizing agents, such as succinylcholine, depolarize the membrane by opening channels in the same manner as ACh. However, they persist longer at the neuromuscular junction primarily because of their resistance to AChE. The depolarization is thus longer lasting, resulting in a brief period of repetitive excitation that may elicit transient and repetitive muscle excitation (fasciculations), followed by block of neuromuscular transmission and flaccid paralysis (called phase I block).
The block arises because, after an initial opening, peri-junctional Na+ channels close and will not reopen until the endplate is repolarized. At this point, neural release of ACh results in the binding of ACh to receptors on an already depolarized endplate. These closed perijunctional channels keep the depolarization signal from affecting downstream channels and effectively shield the rest of the muscle from activity at the motor endplate. The characteristics of depolarization and competitive blockade are contrasted in Table 11–3.
Dosing Ranges for Neuromuscular Blocking Agents
Under clinical conditions, with increasing concentrations of succinylcholine and over time, the block may convert slowly from a depolarizing phase I block to a nondepolarizing, phase II block. While the response to peripheral stimulation during phase II block resembles that of the competitive agents, reversal of phase II block by administration of anticholinesterase (anti-ChE) 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.
Clinical Responses and Monitoring of Phase I and Phase II Neuromuscular Blockade by Succinylcholine Infusion
Sequence and Characteristics of Paralysis. Following intravenous injection of an appropriate dose of a competitive blocking agent, 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.
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 min, becomes maximal within 2 min, and generally disappears within 5 min. 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.
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. 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.
CNS. Tubocurarine and other quaternary neuromuscular blocking agents are virtually devoid of central effects following ordinary clinical doses because of their inability to penetrate the blood-brain barrier.
AUTONOMIC GANGLIA AND MUSCARINIC SITES. Neuromuscular blocking agents show variable potencies in producing ganglionic blockade. Ganglionic blockade by tubocurarine and other stabilizing drugs is reversed or antagonized by anti-ChE agents.
Clinical doses of tubocurarine produce partial blockade both at autonomic ganglia and at the adrenal medulla, which results in a fall in blood pressure and tachycardia. Pancuronium shows less ganglionic blockade at common clinical doses. Atracurium, vecuronium, doxacurium, pipecuronium, mivacurium, and rocuronium are even more selective. The maintenance of cardiovascular reflex responses usually is desired during anesthesia. Pancuronium has a vagolytic action, presumably from blockade of muscarinic receptors, which leads to tachycardia.
Of the depolarizing agents, succinylcholine at doses producing neuromuscular relaxation rarely causes effects attributable to ganglionic blockade. However, cardiovascular effects are sometimes observed, probably owing to the successive stimulation of vagal ganglia (manifested by bradycardia) and sympathetic ganglia (resulting in hypertension and tachycardia).
MAST CELLS AND HISTAMINE RELEASE. Tubocurarine produces typical histamine-like wheals when injected intracutaneously or intraarterially in humans, and some clinical responses to neuromuscular blocking agents (e.g., bronchospasm, hypotension, excessive bronchial and salivary secretion) appear to be caused by the release of histamine. Succinylcholine, mivacurium, and atracurium also cause histamine release, but to a lesser extent unless administered rapidly. The ammonio steroids, pancuronium, vecuronium, pipecuronium, and rocuronium, have even less tendency to release histamine after intradermal or systemic injection. Histamine release typically is a direct action of the muscle relaxant on the mast cell rather than IgE-mediated anaphylaxis.
ABSORPTION, DISTRIBUTION, AND ELIMINATION
Quaternary ammonium neuromuscular blocking agents are very poorly absorbed from the GI tract. Absorption is quite adequate from intramuscular sites. Rapid onset is achieved with intravenous administration. The more potent agents must be given in lower concentrations, and diffusional requirements slow their rate of onset.
When long-acting competitive blocking agents such as D-tubocurarine and pancuronium are administered, blockade may diminish after 30 min 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.
Atracurium is converted to less active metabolites by plasma esterases and spontaneous Hofmann elimination. Cisatracurium is also subject to this spontaneous degradation. Because of these alternative routes of metabolism, atracurium and cisatracurium do not exhibit an increased t1/2 in patients with impaired renal function and therefore are good choices in this setting.
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, hepatic or renal disease, or a nutritional disturbance; however, in some, the enzymatic activity in plasma is normal.
Gantacurium is degraded by 2 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 t1/2 of 1-2 min 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.
CHOICE OF AGENT
Therapeutic selection of a neuromuscular blocking agent should be based on achieving a pharmacokinetic profile consistent with the duration of the interventional procedure and minimizing cardiovascular compromise or other side effects, with attention to drug-specific modes of elimination in patients with renal or hepatic failure (see Table 11–2).
Two characteristics are useful in distinguishing side effects and pharmacokinetic behavior of neuromuscular blocking agents:
• Duration of drug action. These agents are categorized as long-, intermediate-, or short-acting agents. 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.
• The chemical nature of the agents (Table 11–2). 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 2 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 3 times the ED95.
Muscle Relaxation. The main clinical use of the neuromuscular blocking agents is as an adjuvant in surgical anesthesia to obtain relaxation of skeletal muscle, particularly of the abdominal wall, to facilitate operative manipulations. With muscle relaxation no longer dependent on the depth of general anesthesia, a much lighter level of anesthesia suffices. Thus, the risk of respiratory and cardiovascular depression is minimized, and postanesthetic recovery is shortened. Neuromuscular blocking agents of short duration often are used to facilitate endotracheal intubation and have been used to facilitate laryngoscopy, bronchoscopy, and esophagoscopy in combination with a general anesthetic agent. Neuromuscular blocking agents are administered parenterally, nearly always intravenously.
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. 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.
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.
Control of Muscle Spasms and Rigidity. Botulinum toxins and dantrolene act peripherally to reduce muscle contraction; a variety of other agents act centrally to reduce skeletal muscle tone and spasm. 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 3-4 months, and restoration of function requires nerve sprouting.
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, and spasms associated with the lower esophageal sphincter and anal fissures. 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 readministration. The FDA has issued a safety alert, warning of respiratory paralysis from unexpected spread of the toxin from the site of injection (uses are described in 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 RYR1. 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). 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 nonambulatory patients with severe spasticity. Hepatotoxicity has been reported with continued use, requiring liver function tests.
Synergisms and Antagonisms. The comparison of interactions between competitive and depolarizing neuromuscular blocking agents is instructive (Table 11–4) and a good test of one’s understanding of the drugs’ actions. In addition, many other drugs affect transmission at the neuromuscular junction, and thus can affect the choice and dosage of neuromuscular blocking agent used.
Comparison of Competitive (D-Tubocurarine) and Depolarizing (Decamethonium) Blocking Agents
Because the anti-ChE agents neostigmine, pyridostigmine, and edrophonium preserve endogenous ACh and also act directly on the neuromuscular junction, they have been used in the treatment of overdosage with competitive blocking agents. Similarly, on completion of the surgical procedure, many anesthesiologists employ neostigmine or edrophonium to reverse and decrease the duration of competitive neuromuscular blockade. A muscarinic antagonist (atropine or glycopyrrolate) is used concomitantly to prevent stimulation of muscarinic receptors and thereby to avoid slowing of the heart rate. Anti-ChE agents will not reverse depolarizing neuromuscular blockade and, in fact, can enhance it.
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.
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 (see 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. Ca2+ channel blockers enhance neuromuscular blockade produced by both competitive and depolarizing antagonists. When neuromuscular blocking agents are administered to patients receiving these agents, dose adjustments should be considered.
Miscellaneous drugs that may have significant interactions with either competitive or depolarizing neuromuscular blocking agents include trimethaphan, lithium, opioid analgesics, procaine, lidocaine, quinidine, phenelzine, carbamazepine, phenytoin, propranolol, dantrolene, azathioprine, tamoxifen, magnesium salts, corticosteroids, digitalis glycosides, chloroquine, catecholamines, and diuretics.
The important untoward responses of the neuromuscular blocking agents include prolonged apnea, cardiovascular collapse, those resulting from histamine release, and rarely, anaphylaxis. Related factors may include alterations in body temperature; electrolyte imbalance, particularly of K+; low plasma butyrylcholinesterase levels, resulting in a reduction in the rate of destruction of succinylcholine; the presence of latent myasthenia gravis or of malignant disease such as small cell carcinoma of the lung with Eaton-Lambert myasthenic syndrome; reduced blood flow to skeletal muscles, causing delayed removal of the blocking drugs; and decreased elimination of the muscle relaxants secondary to hepatic dysfunction (cisatracurium, rocuronium, vecuronium) or reduced renal function (pancuronium). Great care should be taken when administering neuromuscular blockers to dehydrated or severely ill patients. Depolarizing agents can cause rapid release of K+ 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.
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.
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% O2, and control of acidosis should be considered adjunct therapy in malignant hyperthermia.
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).
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. Sugammadex (BRIDION), a modified γ-cyclodextrin, is a chelating agent specific for rocuronium and vecuronium. Sugammadex at doses >2 mg/kg is able to reverse neuromuscular blockade from rocuronium within 3 min. In patients with impaired renal function, sugammadex clearance is markedly reduced and this agent should be avoided. Sugammadex is approved for clinical use in Europe but not yet in the U.S. Side effects include dysgeusia and rare hypersensitivity.
Neurotransmission in autonomic ganglia involves release of ACh and the rapid depolarization of postsynaptic membranes via the activation of neuronal nicotinic (Nn) receptors by ACh. Intracellular recordings from postganglionic neurons indicate that at least 4 different changes in postsynaptic membrane potential can be elicited by stimulation of the preganglionic nerve (Figure 11–4):
Figure 11–4 Postsynaptic potentials recorded from an autonomic postganglionic nerve cell body after stimulation of the preganglionic nerve fiber. The preganglionic nerve releases ACh onto postganglionic cells. The initial EPSP results from the inward Na+ current (and perhaps Ca2+ current) through the nicotinic receptor channel. If the EPSP is of sufficient magnitude, it triggers an action potential spike, which is followed by a slow IPSP, a slow EPSP, and a late, slow EPSP. The slow IPSP and slow EPSP are not seen in all ganglia. The electrical events subsequent to the initial EPSP are thought to modulate the probability that a subsequent EPSP will reach the threshold for triggering a spike. Other interneurons, such as catecholamine-containing, small intensely fluorescent (SIF) cells, and axon terminals from sensory, afferent neurons also release transmitters and that may influence the slow potentials of the postganglionic neuron. There are cholinergic, peptidergic, adrenergic, and amino acid receptors on the dendrites and soma of the postganglionic neuron and the interneurons. The preganglionic fiber releases ACh and peptides; the interneurons store and release catecholamines, amino acids, and peptides; the sensory afferent nerve terminals release peptides. The initial EPSP is mediated through nicotinic (Nn) receptors, the slow IPSP and EPSP through M2 and M1 muscarinic receptors, and the late, slow EPSP through various peptidergic receptors.
• An initial excitatory postsynaptic potential (EPSP, via nicotinic receptors) that may result in an action potential
• An inhibitory postsynaptic potential (IPSP) mediated by M2 muscarinic receptors
• A secondary slow EPSP mediated by M1 muscarinic receptors
• A late, slow EPSP mediated by myriad peptides
There are multiple nicotinic receptor subunits (e.g., α3, α5, α7, β2, and β4) in ganglia, with α3 and α2 being most abundant. The ganglionic nicotinic ACh receptors are sensitive to classical blocking agents such as hexamethonium and trimethaphan.
An action potential is generated in the postganglionic neuron when the initial EPSP attains a critical amplitude. Unlike the neuromuscular junction, discrete endplates with focal localization of receptors do not exist in ganglia; rather, the dendrites and nerve cell bodies contain the receptors. The characteristics of nicotinic-receptor channels of the ganglia and the neuromuscular junction are quite similar.
The events that follow the initial depolarization (IPSP; slow EPSP; late, slow EPSP) are insensitive to hexamethonium or other Nn antagonists. 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. The slow EPSP is generated by ACh activation of M1 (Gq-coupled) muscarinic receptors and is blocked by atropine and M1-selective antagonists (see Chapter 9).
Secondary synaptic events modulate the initial EPSP. 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. Other neurotransmitter substances (e.g., 5HT and GABA) can modify ganglionic transmission.
Drugs that stimulate cholinergic receptor sites on autonomic ganglia have been essential for analyzing the mechanism of ganglionic function; however, these ganglionic agonists have very limited therapeutic use. They can be grouped into 2 categories. The first group consists of drugs with nicotinic specificity, including nicotine, lobeline, tetramethylammonium (TEA), and dimethylphenylpiperazinium (DMPP). Nicotine’s excitatory effects on ganglia are rapid in onset, are blocked by ganglionic nicotinic-receptor antagonists, and mimic the initial EPSP. The second group consists of muscarinic receptor agonists such as muscarine, McN-A-343, and methacholine (see Chapter 9); their excitatory effects on ganglia are delayed in onset, blocked by atropine-like drugs, and mimic the slow EPSP.
Nicotine is of considerable medical significance because of its toxicity, presence in tobacco, and propensity for conferring a dependence on its users. The chronic effects of nicotine and the untoward effects of the chronic use of tobacco are considered in Chapter 24.
PHARMACOLOGICAL ACTIONS. In addition to the actions of nicotine on a variety of neuroeffector and chemosensitive sites, the alkaloid can both stimulate and desensitize receptors. The ultimate response of any 1 system represents the summation of stimulatory and inhibitory effects of nicotine. Nicotine can increase heart rate by excitation of sympathetic ganglia or by paralysis of parasympathetic cardiac ganglia, and it can slow heart rate by paralysis of sympathetic or stimulation of parasympathetic cardiac ganglia. The effects of the drug on the chemoreceptors of the carotid and aortic bodies and on regions of the CNS also can influence heart rate, as can the compensatory baroreceptor reflexes resulting from changes in blood pressure caused by nicotine. Finally, nicotine elicits a discharge of epinephrine from the adrenal medulla, which accelerates heart rate and raises blood pressure.
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 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, the stimulant phase is obscured largely by the rapidly developing paralysis. In the latter stage, nicotine also produces neuromuscular blockade by receptor desensitization.
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.
CNS. 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: large doses act directly on the medulla oblongata, whereas 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 primary sites of action of nicotine in the CNS are prejunctional, causing the release of other transmitters. 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. 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.
Cardiovascular System. 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.
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. The t1/2 of nicotine following inhalation or parenteral administration is ~2 h. 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 n60 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 (see Chapter 15), and nicotinic ACh receptor agonists (see Chapters 15 and 24).
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 α4 β2 receptors and a full agonist at the α7 subtype, with weak activity toward α3 β2- and α6-containing receptors. The drug is effective clinically; however, it is not benign: the FDA has issued a warning about mood and behavioral changes associated with its use.
Nicotine itself is available in several dosage forms to help achieve abstinence from tobacco use. 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 efficacy of these dosage forms in producing abstinence from smoking is enhanced when linked to counseling and motivational therapy.
GANGLIONIC BLOCKING DRUGS
There are 2 categories of agents that block ganglionic nicotinic receptors. The prototype of the first group, nicotine, initially stimulates the ganglia by an ACh-like action and then blocks them by causing a persistent depolarization. Compounds in the second category (e.g., trimethaphan and hexamethonium) impair transmission. Trimethaphan acts by competition with ACh, analogous to the mechanism of action of curare at the neuromuscular junction. Hexamethonium appears to block the channel after it opens; this action shortens the duration of current flow because the open channel either becomes occluded or closes. Thus the initial EPSP is blocked, and ganglionic transmission is inhibited. The diverse chemicals that block autonomic ganglia without first causing stimulation are:
Ganglionic blocking agents were the first effective therapy for the treatment of hypertension. However, due to the role of ganglionic transmission in both sympathetic and parasympathetic neurotransmission, the antihypertensive action of ganglionic blocking agents was accompanied by numerous undesirable side effects. Mecamylamine, a secondary amine, is currently licensed as an orphan drug for Tourette 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.
Usual Predominance of Sympathetic or Parasympathetic Tone at Various Effector Sites, and Consequences of Autonomic Ganglionic Blockade
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 limits the use of ganglionic blockers in ambulatory patients.
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.
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, reduced bowel activity and paralytic ileus are a danger. 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.