10: Drugs Affecting Nicotinic Receptors

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.


Ganglionic Transmission

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.

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.

Ganglionic Stimulating Drugs


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.

Ganglionic Blockers

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.

Pharmacologic effects

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.

TABLE 10-2 Usual Predominance of Sympathetic or Parasympathetic Tone at Various Effector Sites, with Consequent Effects of Autonomic 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
Heart Parasympathetic (cholinergic) Tachycardia
Iris Parasympathetic (cholinergic) Mydriasis
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.


Neuromuscular Junction Blockers

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 agents

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).

Jan 5, 2015 | Posted by in General Dentistry | Comments Off on 10: Drugs Affecting Nicotinic Receptors
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