Ganglionic Transmission Whether sympathetic or parasympa- thetic, all efferent visceromotor nerves are made up of two serially connected neurons. The point of contact (synapse) between the first and second neurons occurs mainly in ganglia; therefore, the first neuron is referred to as pregan- glionic and efferents of the second as postganglionic. Electrical excitation (action poten- tial) of the first neuron causes the re- lease of acetylcholine (ACh) within the ganglia. ACh stimulates receptors locat- ed on the subsynaptic membrane of the second neuron. Activation of these re- ceptors causes the nonspecific cation channel to open. The resulting influx of Na + leads to a membrane depolariza- tion. If a sufficient number of receptors is activated simultaneously, a threshold potential is reached at which the mem- brane undergoes rapid depolarization in the form of a propagated action poten- tial. Normally, not all preganglionic im- pulses elicit a propagated response in the second neuron. The ganglionic syn- apse acts like a frequency filter (A). The effect of ACh elicited at receptors on the ganglionic neuronal membrane can be imitated by nicotine; i.e., it involves nic- otinic cholinoceptors. Ganglionic action of nicotine. If a small dose of nicotine is given, the gan- glionic cholinoceptors are activated. The membrane depolarizes partially, but fails to reach the firing threshold. How- ever, at this point an amount of re- leased ACh smaller than that normally required will be sufficient to elicit a propagated action potential. At a low concentration, nicotine acts as a gan- glionic stimulant; it alters the filter function of the ganglionic synapse, al- lowing action potential frequency in the second neuron to approach that of the first (B). At higher concentrations, nico- tine acts to block ganglionic transmis- sion. Simultaneous activation of many nicotinic cholinoceptors depolarizes the ganglionic cell membrane to such an ex- tent that generation of action potentials is no longer possible, even in the face of an intensive and synchronized release of ACh (C). Although nicotine mimics the ac- tion of ACh at the receptors, it cannot duplicate the time course of intrasynap- tic agonist concentration required for appropriate high-frequency ganglionic activation. The concentration of nico- tine in the synaptic cleft can neither build up as rapidly as that of ACh re- leased from nerve terminals nor can nicotine be eliminated from the synap- tic cleft as quickly as ACh. The ganglionic effects of ACh can be blocked by tetraethylammonium, hexa- methonium, and other substances (gan- glionic blockers). None of these has in- trinsic activity, that is, they fail to stim- ulate ganglia even at low concentration; some of them (e.g., hexamethonium) actually block the cholinoceptor-linked ion channel, but others (mecamyla- mine, trimethaphan) are typical recep- tor antagonists. Certain sympathetic preganglionic neurons project without interruption to the chromaffin cells of the adrenal me- dulla. The latter are embryologic homo- logues of ganglionic sympathocytes. Ex- citation of preganglionic fibers leads to release of ACh in the adrenal medulla, whose chromaffin cells then respond with a release of epinephrine into the blood (D). Small doses of nicotine, by in- ducing a partial depolarization of adre- nomedullary cells, are effective in liber- ating epinephrine (pp. 110, 112). 108 Nicotine Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotine 109 D. Adrenal medulla: epinephrine release by nicotine A. Ganglionic transmission: normal state B. Ganglionic transmission: excitation by nicotine C. Ganglionic transmission: blockade by nicotine -70 mV -55 mV -30 mV First neuron Preganglionic Second neuron postganglionic Acetylcholine Impulse frequency Persistent depolarization Ganglionic activation Depolarization Ganglionic blockade Low concentration High concentration Adrenal medulla Epinephrine Excitation Nicotine Nicotine Nicotine Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Effects of Nicotine on Body Functions At a low concentration, the tobacco al- kaloid nicotine acts as a ganglionic stim- ulant by causing a partial depolarization via activation of ganglionic cholinocep- tors (p. 108). A similar action is evident at diverse other neural sites, considered below in more detail. Autonomic ganglia. Ganglionic stimulation occurs in both the sympa- thetic and parasympathetic divisions of the autonomic nervous system. Para- sympathetic activation results in in- creased production of gastric juice (smoking ban in peptic ulcer) and en- hanced bowel motility (“laxative” effect of the first morning cigarette: defeca- tion; diarrhea in the novice). Although stimulation of parasym- pathetic cardioinhibitory neurons would tend to lower heart rate, this re- sponse is overridden by the simultane- ous stimulation of sympathetic cardio- accelerant neurons and the adrenal me- dulla. Stimulation of sympathetic nerves resulting in release of norepi- nephrine gives rise to vasoconstriction; peripheral resistance rises. Adrenal medulla. On the one hand, release of epinephrine elicits cardiovas- cular effects, such as increases in heart rate und peripheral vascular resistance. On the other, it evokes metabolic re- sponses, such as glycogenolysis and li- polysis, that generate energy-rich sub- strates. The sensation of hunger is sup- pressed. The metabolic state corre- sponds to that associated with physical exercise – “silent stress”. Baroreceptors. Partial depolariza- tion of baroreceptors enables activation of the reflex to occur at a relatively smaller rise in blood pressure, leading to decreased sympathetic vasoconstric- tor activity. Neurohypophysis. Release of vaso- pressin (antidiuretic hormone) results in lowered urinary output (p. 164). Levels of vasopressin necessary for va- soconstriction will rarely be produced by nicotine. Carotid body. Sensitivity to arterial pCO 2 increases; increased afferent input augments respiratory rate and depth. Receptors for pressure, tempera- ture, and pain. Sensitivity to the corre- sponding stimuli is enhanced. Area postrema. Sensitization of chemoceptors leads to excitation of the medullary emetic center. At low concentration, nicotine is al- so able to augment the excitability of the motor endplate. This effect can be manifested in heavy smokers in the form of muscle cramps (calf muscula- ture) and soreness. The central nervous actions of nico- tine are thought to be mediated largely by presynaptic receptors that facilitate transmitter release from excitatory aminoacidergic (glutamatergic) nerve terminals in the cerebral cortex. Nico- tine increases vigilance and the ability to concentrate. The effect reflects an en- hanced readiness to perceive external stimuli (attentiveness) and to respond to them. The multiplicity of its effects makes nicotine ill-suited for therapeutic use. 110 Nicotine Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotine 111 A.Effects of nicotine in the body Antidiuretic effect Vigilance Respiratory rate Sensitivity Partial depolarization of sensory nerve endings of mechano- and nociceptors Partial depolarization in carotid body and other ganglia Release of vasopressin Partial depolarization of chemoreceptors in area postrema Partial depolarization of baroreceptors Epinephrine release Emetic center Emesis Partial depolarization of autonomic ganglia Para- sympathetic activity Sympathetic activity Darmtätigkeit Herzfrequenz Vasoconstriction Blood pressure Defecation, diarrhea Blood glucose and free fatty acids Glycogenolysis, lipolysis, “silent stress” Bowel motilityVasoconstriction Nicotine Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Consequences of Tobacco Smoking The dried and cured leaves of the night- shade plant Nicotiana tabacum are known as tobacco. Tobacco is mostly smoked, less frequently chewed or tak- en as dry snuff. Combustion of tobacco generates approx. 4000 chemical com- pounds in detectable quantities. The xenobiotic burden on the smoker de- pends on a range of parameters, includ- ing tobacco quality, presence of a filter, rate and temperature of combustion, depth of inhalation, and duration of breath holding. Tobacco contains 0.2–5 % nicotine. In tobacco smoke, nicotine is present as a constituent of small tar particles. It is rapidly absorbed through bronchi and lung alveoli, and is detectable in the brain only 8 s after the first inhalation. Smoking of a single cigarette yields peak plasma levels in the range of 25–50 ng/mL. The effects described on p. 110 become evident. When intake stops, nicotine concentration in plasma shows an initial rapid fall, reflecting distribu- tion into tissues, and a terminal elimi- nation phase with a half-life of 2 h. Nic- otine is degraded by oxidation. The enhanced risk of vascular dis- ease (coronary stenosis, myocardial in- farction, and central and peripheral is- chemic disorders, such as stroke and intermittent claudication) is likely to be a consequence of chronic exposure to nicotine. Endothelial impairment and hence dysfunction has been proven to result from smoking, and nicotine is under discussion as a factor favoring the progression of arteriosclerosis. By releasing epinephrine, it elevates plas- ma levels of glucose and free fatty acids in the absence of an immediate physio- logical need for these energy-rich me- tabolites. Furthermore, it promotes platelet aggregability, lowers fibrinolyt- ic activity of blood, and enhances coag- ulability. The health risks of tobacco smoking are, however, attributable not only to nicotine, but also to various other ingre- dients of tobacco smoke, some of which possess demonstrable carcinogenic properties. Dust particles inhaled in tobacco smoke, together with bronchial mucus, must be removed from the airways by the ciliated epithelium. Ciliary activity, however, is depressed by tobacco smoke; mucociliary transport is impair- ed. This depression favors bacterial in- fection and contributes to the chronic bronchitis associated with regular smoking. Chronic injury to the bronchi- al mucosa could be an important causa- tive factor in increasing the risk in smokers of death from bronchial carci- noma. Statistical surveys provide an im- pressive correlation between the num- ber of cigarettes smoked a day and the risk of death from coronary disease or lung cancer. Statistics also show that, on cessation of smoking, the increased risk of death from coronary infarction or other cardiovascular disease declines over 5–10 years almost to the level of non-smokers. Similarly, the risk of de- veloping bronchial carcinoma is re- duced. Abrupt cessation of regular smok- ing is not associated with severe physi- cal withdrawal symptoms. In general, subjects complain of increased nervous- ness, lack of concentration, and weight gain. 112 Nicotine Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotine 113 A. Sequelae of tobacco smoking Nitrosamines, acrolein, polycyclic hydrocarbons e. g., benzopyrene heavy metals Sum of noxious stimuli "Tar" Nicotiana tabacum Nicotine Number of cigarettes per day 5 4 3 2 Platelet aggregation Epinephrine Coronary disease Annual deaths/1000 people Bronchial carcinoma Annual cases/1000 people Inhibition of mucociliary transport Years Months Chronic bronchitis BronchitisFree fatty acids Fibrinolytic activity –40–20–100 >40 >4015-401–140 Ex-smoker Duration of exposure Damage to bronchial epithelium Damage to vascular endothelium Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Biogenic Amines — Actions and Pharmacological Implications Dopamine A. As the precursor of nore- pinephrine and epinephrine (p. 184), dopamine is found in sympathetic (adre- nergic) neurons and adrenomedullary cells. In the CNS, dopamine itself serves as a neuromediator and is implicated in neostriatal motor programming (p. 188), the elicitation of emesis at the level of the area postrema (p. 330), and inhibi- tion of prolactin release from the anteri- or pituitary (p. 242). Dopamine receptors are coupled to G- proteins and exist as different subtypes. D 1 -receptors (comprising subtypes D 1 and D 5 ) and D 2 -receptors (comprising subtypes D 2 , D 3 , and D 4 ). The aforemen- tioned actions are mediated mainly by D 2 receptors. When given by infusion, dopamine causes dilation of renal and splanchnic arteries. This effect is mediat- ed by D 1 receptors and is utilized in the treatment of cardiovascular shock and hypertensive emergencies by infusion of dopamine and fenoldopam, respective- ly. At higher doses, ! 1 -adrenoceptors and, finally, "-receptors are activated, as evidenced by cardiac stimulation and vasoconstriction, respectively. Dopamine is not to be confused with do- butamine which stimulates "- and !-ad- renoceptors but not dopamine receptors (p. 62). Dopamine-mimetics. Administra- tion of the precursor L-dopa promotes endogenous synthesis of dopamine (in- dication: parkinsonian syndrome, p. 188). The ergolides, bromocriptine, pergolide, and lisuride, are ligands at D- receptors whose therapeutic effects are probably due to stimulation of D 2 recep- tors (indications: parkinsonism, sup- pression of lactation, infertility, acrome- galy, p. 242). Typical adverse effects of these substances are nausea and vomit- ing. As indirect dopamine-mimetics, (+)- amphetamine and ritaline augment do- pamine release. Inhibition of the enzymes involved in dopamine degradation, catechol- amine-oxygen-methyl-transferase (COMT) and monoamineoxidase (MAO), is another means to increase actual available dopamine concentration (COMT-inhibitors, p. 188), MAO B -inhibi- tors, p. 88, 188). Dopamine antagonist activity is the hallmark of classical neuroleptics. The antihypertensive agents, reserpine (ob- solete) and "-methyldopa, deplete neu- ronal stores of the amine. A common ad- verse effect of dopamine antagonists or depletors is parkinsonism. Histamine (B). Histamine is stored in basophils and tissue mast cells. It plays a role in inflammatory and allergic reactions (p. 72, 326) and produces bronchoconstriction, increased intesti- nal peristalsis, and dilation and in- creased permeability of small blood ves- sels. In the gastric mucosa, it is released from enterochromaffin-like cells and stimulates acid secretion by the parietal cells. In the CNS, it acts as a neuromod- ulator. Two receptor subtypes (G-pro- tein-coupled), H 1 and H 2 , are of thera- peutic importance; both mediate vascu- lar responses. Prejunctional H 3 recep- tors exist in brain and the periphery. Antagonists. Most of the so-called H 1 -antihistamines also block other re- ceptors, including M-cholinoceptors and D-receptors. H 1 -antihistamines are used for the symptomatic relief of allergies (e.g., bamipine, chlorpheniramine, cle- mastine, dimethindene, mebhydroline pheniramine); as antiemetics (mecli- zine, dimenhydrinate, p. 330), as over- the-counter hypnotics (e.g., diphenhy- dramine, p. 222). Promethazine repre- sents the transition to the neuroleptic phenothiazines (p. 236). Unwanted ef- fects of most H 1 -antihistamines are las- situde (impaired driving skills) and atro- pine-like reactions (e.g., dry mouth, con- stipation). At the usual therapeutic dos- es, astemizole, cetrizine, fexofenadine, and loratidine are practically devoid of sedative and anticholinergic effects. H 2 - antihistamines (cimetidine, ranitidine, famotidine, nizatidine) inhibit gastric acid secretion, and thus are useful in the treatment of peptic ulcers. 114 Biogenic Amines Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Biogenic Amines 115 A. Dopamine actions as influenced by drugs “H 1 -Antihistamines” ChlorpromazineDiphenhydramine DopamineAcetylcholine mACh-Receptor Dopamine receptors Sedation, hypnotic, antiemetic action H 2 -ReceptorsH 1 -Receptors H 2 -Antagonists e.g., ranitidine H 1 -Antagonists e.g., fexofenadine Histamine D 2 -Agonists e.g., bromocriptine Dopamin Receptors Dopamine Dopaminergic neuron Striatum (extrapyramidal motor function) Area postrema (emesis) Adenohypophysis (prolactin secretion ) D 1 Bronchoconstriction HCl Parietal cell Vasodilation permeabilityBowel peristalsis D 2 -Antagonists e.g., metoclopramide D 1 /D 2 -Antagonists Neuroleptics D 2 Inhibition of synthesis and formation of false transmitter: Methyldopa Destruction of storage vesicles: Reserpine Increase in dopamine synthesis L-Dopa B. Histamine actions as influenced by drugs D 1 -Agonists e.g., fenoldopam Blood flow Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Inhibitors of histamine release: One of the effects of the so-called mast cell stabilizers cromoglycate (cromolyn) and nedocromil is to decrease the re- lease of histamine from mast cells (p. 72, 326). Both agents are applied topi- cally. Release of mast cell mediators can also be inhibited by some H 1 antihista- mines, e.g., oxatomide and ketotifen, which are used systemically. Serotonin Occurrence. Serotonin (5-hydroxytrypt- amine, 5-HT) is synthesized from L- tryptophan in enterochromaffin cells of the intestinal mucosa. 5-HT-synthesiz- ing neurons occur in the enteric nerve plexus and the CNS, where the amine fulfills a neuromediator function. Blood platelets are unable to synthesize 5HT, but are capable of taking up, storing, and releasing it. Serotonin receptors. Based on bio- chemical and pharmacological criteria, seven receptor classes can be distin- guished. Of major pharmacotherapeutic importance are those designated 5-HT 1 , 5-HT 2 , 5-HT 4 , and 5-HT 7 , all of which are G-protein-coupled, whereas the 5-HT 3 subtype represents a ligand-gated non- selective cation channel. Serotonin actions. The cardiovascu- lar effects of 5-HT are complex, because multiple, in part opposing, effects are exerted via the different receptor sub- types. Thus, 5-HT 2A and 5-HT 7 receptors on vascular smooth muscle cells medi- ate direct vasoconstriction and vasodi- lation, respectively. Vasodilation and lowering of blood pressure can also oc- cur by several indirect mechanisms: 5- HT 1A receptors mediate sympathoinhi- bition (Ǟ decrease in neurogenic vaso- constrictor tonus) both centrally and peripherally; 5-HT 2B receptors on vas- cular endothelium promote release of vasorelaxant mediators (NO, p. 120; prostacyclin, p. 196) 5-HT released from platelets plays a role in thrombogenesis, hemostasis, and the pathogenesis of preeclamptic hypertension. Ketanserin is an antagonist at 5- HT 2A receptors and produces antihyper- tensive effects, as well as inhibition of thrombocyte aggregation. Whether 5- HT antagonism accounts for its antihy- pertensive effect remains questionable, because ketanserin also blocks !-adren- oceptors. Sumatriptan and other triptans are antimigraine drugs that possess agonist activity at 5-HT 1 receptors of the B, D and F subtypes and may thereby allevi- ate this type of headache (p. 322). Gastrointestinal tract. Serotonin released from myenteric neurons or en- terochromaffin cells acts on 5-HT 3 and 5-HT 4 receptors to enhance bowel mo- tility and enteral fluid secretion. Cisa- pride is a prokinetic agent that pro- motes propulsive motor activity in the stomach and in small and large intes- tines. It is used in motility disorders. Its mechanism of action is unclear, but stimulation of 5HT 4 receptors may be important. Central Nervous System. Serotoni- nergic neurons play a part in various brain functions, as evidenced by the ef- fects of drugs likely to interfere with se- rotonin. Fluoxetine is an antidepressant that, by blocking re-uptake, inhibits in- activation of released serotonin. Its ac- tivity spectrum includes significant psy- chomotor stimulation, depression of ap- petite, and anxiolysis. Buspirone also has anxiolytic properties thought to be me- diated by central presynaptic 5-HT 1A re- ceptors. Ondansetron, an antagonist at the 5-HT 3 receptor, possesses striking effectiveness against cytotoxic drug-in- duced emesis, evident both at the start of and during cytostatic therapy. Trop- isetron and granisetron produce analo- gous effects. Psychedelics (LSD) and other psy- chotomimetics such as mescaline and psilocybin can induce states of altered awareness, or induce hallucinations and anxiety, probably mediated by 5-HT 2A receptors. Overactivity of these recep- tors may also play a role in the genesis of negative symptoms in schizophrenia (p. 238) and sleep disturbances. 116 Biogenic Amines Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Biogenic Amines 117 A. Serotonin receptors and actions LSD Lysergic acid diethylamide Psychedelic 5-HT 1D 5-HT 3 5-HT 1A 5-HT 2A Serotoninergic neuron Ondansetron Antiemetic Buspirone Anxiolytic Fluoxetine 5-HT- reuptake inhibitor Antidepressant Sumatriptan Antimigraine Propulsive motility Entero- chrom- affin cell Cisapride Prokinetic 5-HT 2B Platelets Constriction Endothelium- mediated Dilation 5-HT 2 5-HT 4 Hallucination Emesis Blood vessel Intestine 5-Hydroxy-tryptamine Serotonin Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. . medulla Epinephrine Excitation Nicotine Nicotine Nicotine Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Effects. 112). 108 Nicotine Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotine 109 D.