Chapter: Modern Pharmacology with Clinical Applications: Ganglionic Blocking Drugs and Nicotine

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Ganglionic Stimulants

A variety of agents, including nicotine, lobeline, and di-methylphenyl piperazinium (DMPP), can stimulate gan-glionic nicotinic receptors. Although these drugs have lit-tle or no therapeutic use, they offer considerable interest for several reasons.

GANGLIONIC STIMULANTS

A variety of agents, including nicotine, lobeline, and di-methylphenyl piperazinium (DMPP), can stimulate gan-glionic nicotinic receptors. Although these drugs have lit-tle or no therapeutic use, they offer considerable interest for several reasons. First, drugs such as nicotine that both stimulate and block ganglionic receptors have proved valuable as an aid in identifying and localizing postgan-glionic fibers. Second, nicotine’s use as a potent insecti-cide and rodenticide and its presence in tobacco smoke have endowed it with considerable toxicological interest.

Mechanism of Ganglionic Stimulation

Nicotine, lobeline, trimethylammonium, and DMPP stimulate all autonomic ganglia by simple combination with ganglionic nicotinic receptors on the postsynaptic membrane. This leads to membrane depolarization, an influx of sodium and calcium ions, and the generation of a fast EPSP. These agents produce general stimulation of autonomic ganglia and a complex pattern of mixed sympathetic and parasympathetic responses.

In addition to autonomic ganglia, nicotinic receptors are found in a variety of organs, and their stimulation will produce quite different results in these different tissues. Activation of nicotinic receptors on the plasma mem-brane of the cells of the adrenal medulla leads to the exo-cytotic release of epinephrine and norepinephrine; stimu-lation of nicotinic receptors at the neuromuscular junction results in the contraction of skeletal muscle .

Stimulation of nicotinic receptors in adren-ergic nerve terminals leads to the release of norepineph-rine; and activation of nicotinic chemoreceptors in the aortic arch and carotid bodies causes nausea and vomit-ing. Nicotinic receptors in the central nervous system me-diate a complex range of excitatory and inhibitory effects.

Mechanism of Ganglionic Blockade

Large doses of nicotine produce a prolonged blockade of ganglionic nicotinic receptors. Unlike the blockade of ganglionic transmission produced by most ganglionic blocking agents, that is, a nondepolarizing competitive antagonism, the blockade produced by nicotine consists of two phases. Phase 1 can be described as persistent de-polarization of the ganglion cell. The initial application of nicotine to the ganglion cells depolarizes the cell, which initiates an action potential. After a few seconds, however, this discharge stops and transmission is blocked. At this time, antidromic stimuli fail to induce an action potential. In fact, during this phase, the ganglia fail to respond to the administration of any ganglionic stimulant, regardless of the type of receptor it activates. The main reason for the loss of electrical or receptor-mediated excitability during a period of maintained de-polarization is that the voltage-sensitive sodium channel is inactivated and no longer opens in response to a brief depolarizing stimulus. During the latter part of phase 1, all ganglionic stimulants that are not nicotinic, such as histamine, angiotensin, bradykinin, and serotonin, be-come effective.

Phase 1 is followed by a postdepolarization phase (phase 2) during which only the actions of nicotinic re-ceptor agonists are blocked. This phase takes place after nicotine has acted for several minutes. At this time, the cell partially repolarizes, and its electrical excitability returns. The main factor responsible for phase 2 block appears to be desensitization of the receptor to ACh, which causes transmission failure.

Pharmacological Actions of Nicotine

Nicotine is present in varying amounts in all forms of tobacco smoke. Following its absorption from the lungs, the blood nicotine levels are sufficient to cause stimula-tion but not blockade of nicotinic receptors. In addition to stimulating receptors on autonomic ganglia, all other nicotinic receptors mentioned earlier can be activated. Thus, tobacco smoking stimulates the cardiovascular, respiratory, and nervous systems.

Cardiovascular System

The effects of nicotine on the cardiovascular system mimic those seen after activation of the sympathoad-renal system, and they are principally the result of a re-lease of epinephrine and norepinephrine from the adre-nal medulla and adrenergic nerve terminals. These effects include a positive inotropic and chronotropic ef-fect on the myocardium as well as an increase in cardiac output. In addition, both systolic and diastolic blood pressures are increased secondary to stimulation of the sympathoadrenal system. These effects are the end re-sult of a summation of adrenergic and cholinergic stim-ulation.

Respiratory System

Low doses of nicotine stimulate respiration through acti-vation of chemoreceptors in the aortic arch and carotid bodies, while high doses directly stimulate the respiratory centers. In toxic doses, nicotine depresses respiration by inhibiting the respiratory centers in the brainstem and by a complex action at the receptors at the neuromuscular junction of the respiratory muscles. At these neuromus-cular receptors, nicotine appears to occupy the receptors, and the end plate is depolarized.After this, the muscle ac-commodates and relaxes. These central and peripheral effects paralyze the respiratory muscles.

 Central Nervous System

The actions of nicotine on the central nervous system are the result of a composite of stimulatory and depres-sant effects. These can include tremors, convulsions, res-piratory stimulation or depression, and release of antid-iuretic hormone from the pituitary. Nausea and emesis are frequently observed after the initial use of nicotine in the form of tobacco smoke. However, tolerance to these effects rapidly develops. This is in contrast to the effects of nicotine on the cardiovascular system, where tolerance develops much more slowly.

Other Systems

Additional effects of nicotine include an increase in gas-tric acid secretion and an increase in the tone and motil-ity of the gastrointestinal tract. These effects are pro-duced because of the predominance of cholinergic input to these effector systems.

Absorption, Distribution, and Excretion of Nicotine

Nicotine is well absorbed from the mucous membranes in the oral cavity, gastrointestinal tract, and respiratory system. If tobacco smoke is held in the mouth for 2 sec-onds, 66 to 77% of the nicotine in the smoke will be ab-sorbed across the oral mucosa. If tobacco smoke is in-haled, approximately 90 to 98% of the nicotine will be absorbed. Nicotine is distributed throughout the body, readily crossing the blood-brain and placental barriers. The liver, kidney, and lung metabolize approximately 80 to 90% of the alkaloid. The kidney rapidly eliminates nicotine and its metabolites.

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