With long-acting competitive blocking agents (e.g., D-tubocurarine, pancuronium), 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 metabo-lites have about half the activity of the parent compound and contribute to the total relaxation pro-file. Ammonio steroids of intermediate duration of action (e.g., vecuronium, rocuronium; see Table 9–1) are cleared more rapidly by the liver than is pancuronium. The more rapid decay of neu-romuscular 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 degra-dation. Because of these alternative routes of metabolism, atracurium does not exhibit an increased t1/2in patients with impaired renal function and therefore is the agent of choice in this setting.
Mivacurium shows an even greater susceptibility to butyrylcholinesterases, and thus has the short-est duration among nondepolarizing blockers. The extremely brief duration of action of succinyl-choline also is due largely to its rapid hydrolysis by the butyrylsuccinyl-cholinesterase of liver and plasma.
Among the occasional patients who exhibit prolonged apnea following the administration of suc-cinylcholine or mivacurium, most (but not all) have atypical or deficient plasma cholinesterase, hepatic or renal disease, or a nutritional disturbance.
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In addition to its use in managing an acute attack of malignant hyperthermia (see above), dantrolene has been used in the treatment of spasticity and hyperreflexia. Dantrolene causes a gen-eralized weakness; thus, its use should be restricted to nonambulatory patients with severe spastic-ity. Hepatotoxicity has been reported with continued use, requiring liver function tests.
GANGLIONIC NEUROTRANSMISSION
Neurotransmission in autonomic ganglia is a more complex process than that described by a single neurotransmitter–receptor system, with at least 4 distinct changes in membrane potential elicited by stimulation of the preganglionic nerve. The primary event involves a rapid depolarization of post-synaptic sites by ACh. An action potential is generated in the postganglionic neuron when the ini-tial EPSP attains sufficient amplitude; in mammalian sympathetic ganglia in vivo, effective transmission likely requires activation at multiple synapses. The EPSP is followed by a slow inhibitory postsynaptic potential (IPSP), a slow EPSP, and a late, slow EPSP; slow IPSP and slow EPSP are not seen in all ganglia. The initial EPSP is mediated through nicotinic (N) receptors, the slow IPSP and EPSP through M2and M1muscarinic receptors, and the late, slow EPSP through var-ious peptidergic receptors in response to peptides released from presynaptic nerve endings or interneurons in specific ganglia (see Chapter 7). The slow EPSPs result from decreased K+ con-ductance (the M current, which regulates the sensitivity of the cell to repetitive fast-depolarizing events). The IPSP is unaffected by nicotinic receptor antagonists but is generally sensitive to block-ade by both atropine and a adrenergic receptor antagonists; apparently, ACh released at the pre-ganglionic terminal acts on catecholamine-containing interneurons to stimulate the release of dopamine (DA) or norepinephrine (NE); the catecholamine, in turn, produces hyperpolarization (an IPSP) of ganglion cells. Small, intensely fluorescent (SIF) cells containing DA and NE and adren-ergic nerve terminals are present in ganglia and presumably participate in IPSP generation (see Figure 9–5 in the 11th edition of the parent text).
The relative importance of secondary pathways and the identity of modulating transmitters differ amongst individual ganglia and between parasympathetic and sympathetic ganglia. Myriad pep-tides (gonadotropin-releasing hormone, substance P, angiotensin, calcitonin gene-related peptide [CGRP], vasoactive intestinal polypeptide, neuropeptide Y, and enkephalins), are present in gan-glia and are presumed to mediate the late slow EPSP. Other neurotransmitters, such as 5-HT and GABA, are known to modify ganglionic transmission. Precise details of their modulatory actions are not understood; they are most closely associated with the late slow EPSP and inhibition of the M current. Secondary transmitters (and their antagonists) only modulate the initial EPSP. By con-trast, conventional ganglionic blocking agents can inhibit ganglionic transmission completely.
Drugs that stimulate cholinergic receptor sites on autonomic ganglia can be grouped into two categories. The first group consists of drugs with nicotinic specificity, including nicotine itself.
Their excitatory effects on ganglia are rapid in onset, are blocked by ganglionic nicotinic receptor antagonists, and mimic the initial EPSP. The second group is composed of agents such as mus-carine, McN-A-343, and methacholine. Their excitatory effects on ganglia are delayed in onset, blocked by atropine-like drugs, and mimic the slow EPSP.
Ganglionic blocking agents acting on the nicotinic receptor may be classified into two groups.
The first group includes drugs that initially stimulate the ganglia by an ACh-like action and then block them because of a persistent depolarization (e.g., nicotine); prolonged application of nicotine results in desensitization of the cholinergic receptor site and continued blockade. Drugs in the second group of blockers, of which hexamethonium and trimethaphan are prototypes, impair trans-mission either by competing with ACh for ganglionic nicotinic receptor sites (trimethaphan) or by blocking the channel after it opens (hexamethonium). Regardless of the mechanism, the initial EPSP is blocked, and ganglionic transmission is inhibited.
GANGLIONIC STIMULATING DRUGS
Nicotine and several other compounds stimulate ganglionic nicotinic receptors (Figure 9–4).
Nicotine
Nicotine is medically and socially significant because of its presence in tobacco, its toxicity, and its propensity to cause dependence in its users. The chronic effects of nicotine and the untoward effects of the chronic use of tobacco are considered in Chapter 23. Nicotine is one of the few natural liquid alkaloids. It is a colorless, volatile base (pKa= 8.5) that turns brown and acquires the odor of tobacco on exposure to air.
PHARMACOLOGICAL ACTIONS
The complex and often unpredictable changes that occur in the body after administration of nico-tine are due not only to its actions on a variety of neuroeffector and chemosensitive sites but also to the fact that the alkaloid can stimulate and desensitize receptors. The ultimate response of any one system represents the summation of stimulatory and inhibitory effects of nicotine. For example, the drug can increase heart rate by excitation of sympathetic or paralysis of parasympathetic car-diac ganglia, or it can slow heart rate by paralysis of sympathetic or stimulation of parasympathetic cardiac ganglia. In addition, the effects of the drug on the chemoreceptors of the carotid and aortic bodies and on brain centers influence heart rate, as do the cardiovascular compensatory 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 followed by a more persist-ent depression of all autonomic ganglia. Small doses of nicotine stimulate the ganglion cells directly and may facilitate impulse transmission. When larger doses of the drug are applied, the initial stimulation is followed very quickly by a blockade of transmission. Nicotine also possesses a biphasic action on the adrenal medulla; small doses evoke the discharge of catecholamines, and larger doses prevent their release in response to splanchnic nerve stimulation.
The effects of nicotine on the neuromuscular junction are similar to those on ganglia. How-ever, 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, will stimulate a number of sensory receptors. These include mechanore-ceptors 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 promi-nent 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.
FIGURE 9–4 Ganglionic stimulants.
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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 muscles of 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. Accordingly, the stimulatory and pleasure–reward actions of nicotine appear to result from release of excita-tory amino acids, DA, and other biogenic amines from various CNS centers. Release of excitaexcita-tory amino acids may account for much of nicotine’s stimulatory action. Chronic exposure to nicotine increases the density or number of nicotinic receptors.
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. Also contributing to the sympathomimetic response to nicotine is the activation of chemoreceptors of the aortic and carotid bodies, which reflexly results in vasoconstriction, tachy-cardia, and elevated blood pressure.
Gastrointestinal 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 diar-rhea 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, FATE, AND EXCRETION
Nicotine is readily absorbed from the respiratory tract, buccal membranes, and skin. Severe poison-ing has resulted from percutaneous absorption. Bepoison-ing a relatively strong base, its absorption from the stomach is limited. 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 ciga-rette contains 6–11 mg nicotine and delivers about 1–3 mg nicotine systemically to the smoker;
bioavailability can increase as much as threefold with intensity of puffing and technique of the smoker.
Nicotine is available in several dosage forms to help achieve abstinence from tobacco use.
Efficacy results primarily from preventing a withdrawal or abstinence syndrome. Nicotine may be administered orally as a gum (nicotine polacrilex, NICORETTE), transdermal patch (NICODERM,
HABITROL, others), a nasal spray (NICOTROL NS), and a vapor inhaler (NICOTROL INHALER). The first two are used most widely, and the objective is to obtain a sustained plasma nicotine concentra-tion lower than venous blood concentraconcentra-tions after smoking (arterial blood concentraconcentra-tions imme-diately following inhalation can be as much as tenfold higher than venous concentrations). The efficacy of these dosage forms in producing abstinence from smoking is enhanced when linked to counseling and motivational therapy (see Chapter 23).
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 profile of metabolites and the rate of metabolism appear to be similar in smokers and nonsmokers. The t1/2of nicotine following inhalation or par-enteral 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 of the base. Smoking tobacco usually contains 1–2% nicotine. Appar-ently, 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: nausea, salivation, abdom-inal pain, vomiting, diarrhea, cold sweat, headache, dizziness, disturbed hearing and vision, mental confusion, and marked weakness. Faintness and prostration ensue; the blood pressure falls; breath-ing 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.
FIGURE 9–5 Ganglionic blocking agents.
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.
Other Ganglionic Stimulants
Stimulation of ganglia by tetramethylammonium (TMA) or 1,1-dimethyl-4-phenylpiperazinium iodide (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 is an exception; it can stimulate muscarinic M1receptors in ganglia.
GANGLIONIC BLOCKING DRUGS
A chemically diverse group of compounds blocks autonomic ganglia without causing prior stim-ulation (Figure 9–5).
PHARMACOLOGICAL PROPERTIES
Most of the physiological alterations observed after the administration of ganglionic blocking agents can be anticipated by a careful inspection of Figure 6–1 and by knowing which division of the auto-nomic nervous system exercises dominant control of various organs (Table 9–4). For example, blockade of sympathetic ganglia interrupts adrenergic control of arterioles and results in vasodila-tion, 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, cyclo-plegia, xerostomia, diminished perspiration, and postural hypotension (via abolition of circulatory reflex pathways); these changes are the generally undesirable effects that 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 nor-motensive subjects but may fall markedly in sitting or standing subjects. Postural hypotension limits use of ganglionic blockers in ambulatory patients.
Changes in heart rate following ganglionic blockade depend largely on existing vagal tone.
Mild tachycardia usually accompanies the hypotension, a sign that indicates fairly complete
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ganglionic blockade. However, a decrease may occur if the heart rate is high initially. In patients with normal cardiac function, these drugs may reduce cardiac output as a consequence of dimin-ished 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 ganglionic blockade decreases total systemic vascular resistance, changes in blood flow and vascular resistance of individual vascular beds vary: reduction of cerebral blood flow is small unless mean systemic blood pressure falls below 50–60 mm Hg; skeletal muscle blood flow is unaltered; splanchnic and renal blood flow decrease.
ABSORPTION, FATE, AND EXCRETION
Absorption of quaternary ammonium and sulfonium compounds from the GI tract is incomplete and unpredictable, due to the limited ability of these ionized substances to penetrate cell mem-branes and depression of propulsive movements of the small intestine and gastric emptying.
Absorption of mecamylamine is less erratic, but reduced bowel activity and paralytic ileus are a danger. After absorption, the quaternary ammonium- and sulfonium-blocking agents are con-fined 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
Milder untoward responses 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.
FORMULATIONS AND THERAPEUTIC USES
Only mecamylamine (INVERSINE) is currently available in the U.S. Ganglionic blocking agents have been supplanted by superior agents for the treatment of chronic hypertension (see Chapter 32), acute hypertensive crises and the production of controlled hypotension (e.g., reduction in blood pressure during surgery to minimize hemorrhage in the operative field).
For a complete Bibliographical listing see Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th ed., or Goodman & Gilman Online at www.accessmedicine.com.
Table 9–4
Usual Predominance of Sympathetic or Parasympathetic Tone at Various Effector Sites, and Consequences of Autonomic Ganglionic Blockade
Site Predominant Tone Effect of Ganglionic Blockade
Arterioles Sympathetic (adrenergic) Vasodilation; increased peripheral blood flow; hypotension
Veins Sympathetic (adrenergic) Dilation: peripheral pooling
of blood; decreased venous return; decreased cardiac output
Heart Parasympathetic (cholinergic) Tachycardia
Iris Parasympathetic (cholinergic) Mydriasis
Ciliary muscle Parasympathetic (cholinergic) Loss of visual accommodation Gastrointestinal tract Parasympathetic (cholinergic) Reduced tone and motility;
constipation; decreased gastric and pancreatic secretions Urinary bladder Parasympathetic (cholinergic) Urinary retention Salivary glands Parasympathetic (cholinergic) Xerostomia Sweat glands Sympathetic (cholinergic) Anhidrosis
Genital tract Sympathetic and parasympathetic Decreased stimulation
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