CHAPTER 10 Drugs Affecting Nicotinic Receptors*
Early in the sixteenth century, Spanish explorers of the New World encountered a plant extract used by South American natives to poison the tips of their hunting arrows. This extract, known as curare, was brought back to Europe, and its lethal action was quickly found to depend on muscular paralysis. Further understanding of the actions of curare did not occur for many years.
In 1856, Bernard reported that the site of action of curare was the junction between nerve and muscle. He found that although curare blocked neuromuscular transmission, it did not impede conduction of impulses along the motor nerve or contraction of a directly stimulated muscle. The active substance used by Bernard in his studies, d-tubocurarine, was subsequently purified, and in 1942 it was administered for the first time to a patient undergoing surgery for appendicitis to relax the abdominal musculature. Drugs that block neuromuscular transmission have since found widespread acceptance for their ability to produce muscular flaccidity and are frequently administered as adjuncts to general anesthesia during surgery.
In 1889, Langley showed that nicotine could “paralyze” transmission at autonomic ganglia, and in 1905 he showed that nicotine could stimulate muscle when applied to the motor end plate and that curare could block this effect. These findings led to the adoption of the term nicotinic to refer to the receptors present at autonomic ganglia and the neuromuscular junction.
The discovery of curare4 led to developments in two different directions: to drugs that affect transmission at nicotinic cholinergic receptors and to drugs that interfere with the mechanisms of skeletal muscle contraction. These two topics are the subjects of this chapter.
Nicotinic receptors (see Chapter 1) play a crucial role in the transmission of autonomic impulses across the ganglionic synapse. As described in Chapter 5, acetylcholine (ACh) is the primary neurotransmitter at sympathetic and parasympathetic ganglia, where it is released by preganglionic neurons and stimulates postganglionic neurons by activating nicotinic NN receptors. Although it is sometimes convenient to think of autonomic ganglia as simple relay stations between the central nervous system (CNS) and effector tissues, the existence of other receptors and neurotransmitters within the ganglia indicates that some modulation of the primary nervous inputs may occur. It is also evident that transmission is not the same in sympathetic and parasympathetic ganglia even though NN receptors are the primary receptors in both cases.
Various pharmacologic and electrophysiologic studies on sympathetic ganglia have led to models of ganglionic transmission that involve at least four classes of receptors: cholinergic nicotinic, cholinergic muscarinic, α-adrenergic, and peptidergic.8 Muscarinic and peptidergic receptors mediate slow and late slow excitatory postsynaptic potentials, which seem to facilitate the transmission of high-frequency impulses through the primary nicotinic receptor pathway. Catecholamine-containing (dopamine or norepinephrine) interneurons have been proposed for sympathetic ganglia12 but are not found in parasympathetic ganglia.21 As shown in Figure 10-1, these interneurons may be stimulated by preganglionic muscarinic activity to release catecholamines that hyperpolarize the postganglionic neuron, producing an inhibitory postsynaptic potential. These secondary events of ganglionic transmission only modulate the primary depolarization, by making it more or less likely to occur. Conventional NN receptor antagonists can inhibit ganglionic transmission completely, but muscarinic antagonists, α-adrenergic antagonists, and peptidergic antagonists cannot do so.
FIGURE 10-1 Synaptic connections in the mammalian superior cervical ganglion. The principal pathway involves nicotinic receptor transmission (NN) sensitive to conventional ganglionic blocking drugs. Muscarinic receptors (M1 and M2), sensitive to atropine blockade, support and inhibit depolarization of the postganglionic neuron. As shown, a catecholamine-containing interneuron may participate in causing inhibition. Corelease of peptides such as gonadotropin-releasing hormone (GRH) produces long-lasting facilitation of transmission. α, α-Adrenergic receptor; ACH, acetylcholine; D, dopamine; NE, norepinephrine; P, peptidergic receptor.
There are two important facts in ganglionic transmission. First, the autonomic ganglia contain neuronal components that are not protected by a structure analogous to the blood-brain barrier, which means that they are affected by many drugs and chemicals that never gain access to central synapses. Second, ACh is the primary transmitter of the ganglionic synapse, and any drug that interferes with the synthesis, release, or inactivation of ACh or with its interaction with the NN receptor has the capacity to interfere with ganglionic transmission.
Nicotine, as indicated in Chapter 8, is the principal psychoactive ingredient in tobacco products. As a selective depolarizing drug at nicotinic receptors, this alkaloid stimulates transmission at autonomic ganglia and at nicotinic synapses in the CNS. It also activates various sensory fibers equipped with nicotinic receptors, including mechanoreceptors in the lung, skin, mesentery, and tongue; nociceptive nerve endings; and chemoreceptors in the carotid body and aortic arch. Stimulation of nicotinic receptors in skeletal muscle is easily shown in the laboratory, but it is not evident normally in humans because initial stimulation is soon followed by inhibition at these nicotinic sites. Nicotine has a dual effect on ganglionic transmission—initial stimulation and subsequent depression (see later).
An important feature of nicotinic receptors is their tendency to become desensitized (i.e., unresponsive) on continuous exposure to agonists or depolarizing antagonists (e.g., succinylcholine, as described later). The actions of nicotine are highly time and concentration dependent, and complex patterns of stimulation and depression are observed. The heart rate may be increased by stimulation of sympathetic ganglia and the adrenal medulla or by inhibition of vagal transmission in the heart, or both. Conversely, blockade of sympathetic transmission to the heart and stimulation of parasympathetic transmission can cause bradycardia. The heart rate may also be affected by central influences and by actions at peripheral sensory sites.
Generally, usual amounts of nicotine absorbed during cigarette smoking cause mild cardiovascular stimulation, increased gastrointestinal activity, and CNS stimulation accompanied in regular users by a feeling of well-being and decreased irritability. With long-term use, tolerance and physical dependence occur. The addictive nature of nicotine is thought to result from its action on the reward pathway—the circuitry in the brain that regulates feelings of pleasure and euphoria.
Acute overdose of nicotine causes nausea and vomiting, abdominal pain, dizziness and confusion, and muscular weakness. If untreated, death may ensue from cardiopulmonary collapse. Nevertheless, the primary health issues regarding nicotine stem from the chronic use of tobacco products. An increased incidence of cancer and cardiovascular and pulmonary disease has been well documented.20 In dentistry, tobacco use has been linked to oropharyngeal carcinoma, leukoplakia, acute and chronic periodontal disease, delayed wound healing, halitosis, and tooth staining.5
The only therapeutic use of nicotine is as an adjunct in tobacco cessation programs. Nicotine is administered in multiple forms (Table 10-1) to maintain pharmacologic concentrations of the alkaloid and to prevent tobacco cessation from triggering an acute withdrawal syndrome, which includes irritability, anxiety, sleep disturbances, and cognitive impairment. It also dissociates the self-administration of nicotine from the social, tactile, and oral and olfactory components of tobacco smoking, weakening the psychological link between satisfaction of the nicotine craving and the physical actions of tobacco use. The nicotine dose is reduced in a stepwise fashion over several months, during which time the patient ideally receives continued counseling and motivational assistance to remain abstinent.
Because of the deleterious effects of smoking and smokeless tobacco on oral health, the dentist is encouraged to participate actively in helping patients quit tobacco use.5 Such participation may include—in addition to prescribing a nicotine product—procedures to promote fresh breath and tooth bleaching to remove tobacco stains from teeth, which may provide additional positive psychological feedback to encourage abstinence from tobacco use.
Tetramethylammonium and dimethylphenylpiperazinium are also ganglionic stimulants. They differ from nicotine primarily in the fact that the stimulation is not followed by pronounced ganglionic depolarization blockade. Dimethylphenylpiperazinium is about three times more potent and slightly more ganglion-selective than nicotine.
Between 1895 and 1926, numerous compounds having the generic structure shown in Figure 10-2 and termed methonium compounds were synthesized. In 1915, Burn and Dale described the ganglionic blocking action of tetraethylammonium. In the 1940s, an entire series of diiodide and dibromide derivatives of these methonium compounds were synthesized; in 1946, Acheson and Moe published a systematic and extensive pharmacologic study of tetraethylammonium. Interest in these drugs arose because they could be used as pharmacologic tools for exploring various aspects of autonomic pharmacology and because, at least at first, they offered the promise of being useful therapeutic agents in the treatment of hypertension, peptic ulcers, and other diseases that seemed to have an autonomic component and that had not yet yielded to therapeutic measures then available.
The discussion in this section is restricted to the pharmacology of the competitive and noncompetitive nondepolarizing blocking agents because clinically used ganglionic blockers belong to these two groups. Nicotine has been discussed previously regarding its ganglionic stimulating properties and its use in tobacco cessation programs.
All the ganglionic blocking drugs, regardless of their structure or their mechanism of action, have the same basic pharmacology, although many of them have additional actions at sites other than ganglionic receptors. An ideal ganglionic blocking agent would be a compound that interferes only with ganglionic transmission, blocks without previous excitation, and does not influence the release of transmitter. Hexamethonium is a prototype agent that meets these criteria.
The pharmacology of the ganglionic blocking drugs is predictable because all parasympathetic and sympathetic ganglia are blocked by most of the available agents. Ganglia are not equally sensitive to the blocking drugs, however, and some effects are easier to block than others. The effects of ganglionic agents are profoundly influenced by the background tone; that is, the effect of blocking a ganglion is proportional to the rate of nerve transmission through that ganglion at any given time. If vascular tone is high, as it would be in a standing individual, the ganglionic blocking agents would produce a profound decrease in blood pressure, much greater than they would in a recumbent individual, in whom vascular tone would be lower. Finally, as is shown in Table 10-2, because these drugs block sympathetic and parasympathetic actions, the direction and magnitude of their effects are related to which autonomic division provides the dominant baseline control for a given organ.
|SITE||PREDOMINANT TONE||EFFECT OF GANGLIONIC BLOCKADE|
|Arterioles||Sympathetic (adrenergic)||Vasodilation, increased peripheral blood flow, hypotension|
|Veins||Sympathetic (adrenergic)||Vasodilation, peripheral pooling of blood, decreased venous return, decreased cardiac output|
|Ciliary muscle||Parasympathetic (cholinergic)||Cycloplegia|
|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|
From Taylor P: Agents acting at the neuromuscular junction and autonomic ganglia. In Brunton LL, Lazo JS, Parker KL, editors: Goodman & Gilman’s the pharmacological basis of therapeutics, ed 11, New York, 2006, McGraw-Hill.
Parasympathetic neurons play a dominant role in the regulation of pupillary diameter and activity in the ciliary muscle. Blockade of autonomic ganglia leads to partial, but not maximal, dilation of the pupil and to paralysis of accommodation.
Ganglionic blocking drugs cause a decrease in blood pressure that depends on posture. Normotensive recumbent subjects show the least change; the most prominent alteration in blood pressure occurs in sitting or standing subjects because vascular reflexes play an important role in the maintenance of blood pressure in these circumstances. The blood pressure may decrease by 35%. Changes in heart rate depend on the existing vagal tone, but generally cardiac rate increases slightly in humans. Cardiac output tends to decrease, mainly because of poor venous return and pooling of blood in the extremities. Localized blood flow alterations depend on the location of the vascular bed. In the skin, there is an increase in blood flow that manifests as an increase in surface temperature and a pinkness of the skin. The effects on coronary, pulmonary, muscle, renal, cerebral, and splanchnic circulation are inconsistent because, although vascular resistance may decrease in some of these organs, the reduced cardiac output may not permit a concomitant increase in blood flow.
The volume and acidity of gastric secretions that occur spontaneously are strongly inhibited by the ganglionic blocking agents, but there is little effect on secretion induced by histamine. Vagal stimulation is inhibited, and marked inhibition of motility occurs throughout the gastrointestinal tract, leading to paralytic ileus and causing constipation. Sympathetically maintained sphincter tone is also lost, and so the constipation may alternate with diarrhea.
The parasympathetic component of the efferent arm of the spinal reflex normally responsible for micturition is blocked. As a result, distention of the bladder does not trigger the voiding response, and urinary retention develops because of incomplete bladder emptying.
In therapeutic doses, the cationic blocking drugs, including hexamethonium and its congeners, do not gain ready access to the CNS, and they usually have no direct CNS effects. Mecamylamine and other secondary and tertiary amine blocking agents have been reported to produce such effects as tremor, choreiform movements, mental aberrations, and convulsions.
For ganglionic blocking agents, the question of absorption, fate, and excretion is an academic one because only one drug, mecamylamine, is available in an oral formulation and it is seldom used because of its numerous side effects. Trimethaphan has been administered by intravenous drip; it has a rapid onset and short duration of action.
Because of their multiple side effects, ganglionic blockers are rarely used. For most patients these effects are intolerable except for acute use in recumbent patients. Trimethaphan was used in the past as an adjunct during anesthesia to produce controlled hypotension and in hypertensive emergencies.
As is true of other autonomic drugs, toxicity from the ganglionic blocking agents is an extension of their known pharmacologic effects. Some of these effects, such as xerostomia, blurring of vision, and constipation, are annoying but bearable. Other side effects, such as orthostatic hypotension, urinary retention, and sexual impotence, present more significant problems. More severely, the ganglionic blocking agents can produce peripheral circulatory collapse with cerebral and coronary insufficiency, paralytic ileus, and complete urinary retention. The toxic liabilities of the drugs are the major reason for their abandonment in the treatment of hypertension.
Nervous control of skeletal muscle contraction is mediated by ACh. In response to a motor neuron action potential, ACh is released from the terminal region of the nerve fiber. The transmitter diffuses across the junctional cleft and binds with the nicotinic NM receptor on the postjunctional membrane (end plate) of the muscle fiber. As with other nicotinic receptors the NM receptor has two binding sites for cationic ligands, and the binding of two molecules of ACh to the receptor brings about an increase in the cation permeability of the end plate membrane and a consequent depolarization (excitatory end plate potential) of the junctional region of the muscle fiber. Under normal conditions, the depolarization is sufficient to trigger an action potential in the electrically excitable muscle fiber membrane, and muscular contraction follows.10 Figure 10-3 shows the physiologic events that occur in a nerve, neuromuscular junction, and skeletal muscle that lead to contraction of muscle and indicates points along the pathway at which drugs can block these events.
Neuromuscular blocking drugs interfere with the ability of ACh to evoke end plate depolarization at the nicotinic NM receptor. They are generally separated into two groups according to whether the agents themselves bring about end plate depolarization in the course of their action. The depolarizing and the nondepolarizing blocking agents differ in the mechanisms through which they produce neuromuscular blockade (discussed subsequently).
Nondepolarizing, or competitive, neuromuscular blocking drugs include tubocurarine (d-tubocurarine) and several other benzylisoquinolines (e.g., atracurium, cisatracurium, and mivacurium); aminosteroids such as pancuronium, rocuronium, and vecuronium; and a few unrelated drugs.19 Tubocurarine, rocuronium, and vecuronium are monoquaternary amines with a second nitrogen that is partially ionized at physiologic pH; the other clinically available drugs are bisquaternary compounds. Commonly, these drugs incorporate two cationic nitrogen sites into a rigid molecular structure (Figure 10-4). The rank order of potency at the NM receptor correlates highly with the clinical dose needed to produce 50% twitch depression of the adductor muscle of the thumb (adductor pollicis).
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