Color Atlas of Pharmacology (Part 10): Nicotine

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Color Atlas of Pharmacology (Part 10): Nicotine

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Nicotine is no longer possible, even in the face of an intensive and synchronized release of ACh (C). Although nicotine mimics the action of ACh at the receptors, it cannot duplicate the time course of intrasynaptic agonist concentration required for appropriate high-frequency ganglionic activation. The concentration of nicotine in the synaptic cleft can neither build up as rapidly as that of ACh released from nerve terminals nor can nicotine be eliminated from the synaptic cleft as quickly as ACh. The ganglionic effects of ACh can be blocked by tetraethylammonium, hexamethonium, and other substances (ganglionic blockers). None of these has intrinsic...

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108 Nicotine Ganglionic Transmission is no longer possible, even in the face of an intensive and synchronized release Whether sympathetic or parasympa- of ACh (C). thetic, all efferent visceromotor nerves Although nicotine mimics the ac- are made up of two serially connected tion of ACh at the receptors, it cannot neurons. The point of contact (synapse) duplicate the time course of intrasynap- between the first and second neurons tic agonist concentration required for occurs mainly in ganglia; therefore, the appropriate high-frequency ganglionic first neuron is referred to as pregan- activation. The concentration of nico- glionic and efferents of the second as tine in the synaptic cleft can neither postganglionic. build up as rapidly as that of ACh re- Electrical excitation (action poten- leased from nerve terminals nor can tial) of the first neuron causes the re- nicotine be eliminated from the synap- lease of acetylcholine (ACh) within the tic cleft as quickly as ACh. ganglia. ACh stimulates receptors locat- The ganglionic effects of ACh can be ed on the subsynaptic membrane of the blocked by tetraethylammonium, hexa- second neuron. Activation of these re- methonium, and other substances (gan- ceptors causes the nonspecific cation glionic blockers). None of these has in- channel to open. The resulting influx of trinsic activity, that is, they fail to stim- Na+ leads to a membrane depolariza- ulate ganglia even at low concentration; tion. If a sufficient number of receptors some of them (e.g., hexamethonium) is activated simultaneously, a threshold actually block the cholinoceptor-linked potential is reached at which the mem- ion channel, but others (mecamyla- brane undergoes rapid depolarization in mine, trimethaphan) are typical recep- the form of a propagated action poten- tor antagonists. tial. Normally, not all preganglionic im- Certain sympathetic preganglionic pulses elicit a propagated response in neurons project without interruption to the second neuron. The ganglionic syn- the chromaffin cells of the adrenal me- apse acts like a frequency filter (A). The dulla. The latter are embryologic homo- effect of ACh elicited at receptors on the logues of ganglionic sympathocytes. Ex- ganglionic neuronal membrane can be citation of preganglionic fibers leads to imitated by nicotine; i.e., it involves nic- release of ACh in the adrenal medulla, otinic cholinoceptors. whose chromaffin cells then respond Ganglionic action of nicotine. If a with a release of epinephrine into the small dose of nicotine is given, the gan- blood (D). Small doses of nicotine, by in- glionic cholinoceptors are activated. The ducing a partial depolarization of adre- membrane depolarizes partially, but nomedullary cells, are effective in liber- fails to reach the firing threshold. How- ating epinephrine (pp. 110, 112). 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 Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Nicotine 109 First neuron Preganglionic Second neuron postganglionic -70 mV Acetylcholine Impulse frequency A. Ganglionic transmission: normal state -55 mV Persistent depolarization Low concentration Ganglionic activation Nicotine B. Ganglionic transmission: excitation by nicotine -30 mV Depolarization High concentration Ganglionic blockade Nicotine C. Ganglionic transmission: blockade by nicotine Adrenal medulla Nicotine Excitation Epinephrine D. Adrenal medulla: epinephrine release by nicotine Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
110 Nicotine Effects of Nicotine on Body Functions Carotid body. Sensitivity to arterial pCO2 increases; increased afferent input At a low concentration, the tobacco al- augments respiratory rate and depth. kaloid nicotine acts as a ganglionic stim- Receptors for pressure, tempera- ulant by causing a partial depolarization ture, and pain. Sensitivity to the corre- via activation of ganglionic cholinocep- sponding stimuli is enhanced. tors (p. 108). A similar action is evident Area postrema. Sensitization of at diverse other neural sites, considered chemoceptors leads to excitation of the below in more detail. medullary emetic center. Autonomic ganglia. Ganglionic At low concentration, nicotine is al- stimulation occurs in both the sympa- so able to augment the excitability of thetic and parasympathetic divisions of the motor endplate. This effect can be the autonomic nervous system. Para- manifested in heavy smokers in the sympathetic activation results in in- form of muscle cramps (calf muscula- creased production of gastric juice ture) and soreness. (smoking ban in peptic ulcer) and en- The central nervous actions of nico- hanced bowel motility (“laxative” effect tine are thought to be mediated largely of the first morning cigarette: defeca- by presynaptic receptors that facilitate tion; diarrhea in the novice). transmitter release from excitatory Although stimulation of parasym- aminoacidergic (glutamatergic) nerve pathetic cardioinhibitory neurons terminals in the cerebral cortex. Nico- would tend to lower heart rate, this re- tine increases vigilance and the ability sponse is overridden by the simultane- to concentrate. The effect reflects an en- ous stimulation of sympathetic cardio- hanced readiness to perceive external accelerant neurons and the adrenal me- stimuli (attentiveness) and to respond dulla. Stimulation of sympathetic to them. nerves resulting in release of norepi- The multiplicity of its effects makes nephrine gives rise to vasoconstriction; nicotine ill-suited for therapeutic use. 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. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Nicotine 111 Vigilance Antidiuretic Respiratory rate Sensitivity effect Partial Partial depolarization Release of depolarization in vasopressin of sensory nerve carotid body and endings of mechano- other ganglia and nociceptors Nicotine Partial depolarization of Partial chemoreceptors depolarization in area postrema of baroreceptors Epinephrine Emetic center release Partial depolarization Emesis of autonomic ganglia Sympathetic Para- activity sympathetic activity Vasoconstriction Vasoconstriction Herzfrequenz Darmtätigkeit Bowel motility Blood pressure Defecation, diarrhea Glycogenolysis, Blood glucose lipolysis, and “silent stress” free fatty acids A.Effects of nicotine in the body Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
112 Nicotine Consequences of Tobacco Smoking possess demonstrable carcinogenic properties. The dried and cured leaves of the night- Dust particles inhaled in tobacco shade plant Nicotiana tabacum are smoke, together with bronchial mucus, known as tobacco. Tobacco is mostly must be removed from the airways by smoked, less frequently chewed or tak- the ciliated epithelium. Ciliary activity, en as dry snuff. Combustion of tobacco however, is depressed by tobacco generates approx. 4000 chemical com- smoke; mucociliary transport is impair- pounds in detectable quantities. The ed. This depression favors bacterial in- xenobiotic burden on the smoker de- fection and contributes to the chronic pends on a range of parameters, includ- bronchitis associated with regular ing tobacco quality, presence of a filter, smoking. Chronic injury to the bronchi- rate and temperature of combustion, al mucosa could be an important causa- depth of inhalation, and duration of tive factor in increasing the risk in breath holding. smokers of death from bronchial carci- Tobacco contains 0.2–5 % nicotine. noma. In tobacco smoke, nicotine is present as Statistical surveys provide an im- a constituent of small tar particles. It is pressive correlation between the num- rapidly absorbed through bronchi and ber of cigarettes smoked a day and the lung alveoli, and is detectable in the risk of death from coronary disease or brain only 8 s after the first inhalation. lung cancer. Statistics also show that, on Smoking of a single cigarette yields peak cessation of smoking, the increased risk plasma levels in the range of 25–50 of death from coronary infarction or ng/mL. The effects described on p. 110 other cardiovascular disease declines become evident. When intake stops, over 5–10 years almost to the level of nicotine concentration in plasma shows non-smokers. Similarly, the risk of de- an initial rapid fall, reflecting distribu- veloping bronchial carcinoma is re- tion into tissues, and a terminal elimi- duced. nation phase with a half-life of 2 h. Nic- Abrupt cessation of regular smok- otine is degraded by oxidation. ing is not associated with severe physi- The enhanced risk of vascular dis- cal withdrawal symptoms. In general, ease (coronary stenosis, myocardial in- subjects complain of increased nervous- farction, and central and peripheral is- ness, lack of concentration, and weight chemic disorders, such as stroke and gain. 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 Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Nicotine 113 Nicotine Nicotiana tabacum "Tar" Nitrosamines, acrolein, polycyclic hydrocarbons e. g., benzopyrene heavy metals Sum of noxious stimuli Platelet Damage to Damage to Inhibition of aggregation vascular bronchial mucociliary endothelium epithelium transport Duration of Fibrinolytic Epinephrine Years exposure Months activity Free Chronic Bronchitis fatty acids bronchitis Coronary disease Bronchial carcinoma Annual deaths/1000 people Annual cases/1000 people 5 4 3 Ex-smoker 2 0 –10 –20 –40 >40 0 1–14 15-40 >40 Number of cigarettes per day A. Sequelae of tobacco smoking Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
114 Biogenic Amines Biogenic Amines — Actions and (COMT) and monoamineoxidase (MAO), Pharmacological Implications is another means to increase actual available dopamine concentration Dopamine A. As the precursor of nore- (COMT-inhibitors, p. 188), MAOB-inhibi- pinephrine and epinephrine (p. 184), tors, p. 88, 188). dopamine is found in sympathetic (adre- Dopamine antagonist activity is the nergic) neurons and adrenomedullary hallmark of classical neuroleptics. The cells. In the CNS, dopamine itself serves antihypertensive agents, reserpine (ob- as a neuromediator and is implicated in solete) and "-methyldopa, deplete neu- neostriatal motor programming (p. 188), ronal stores of the amine. A common ad- the elicitation of emesis at the level of verse effect of dopamine antagonists or the area postrema (p. 330), and inhibi- depletors is parkinsonism. tion of prolactin release from the anteri- Histamine (B). Histamine is stored or pituitary (p. 242). in basophils and tissue mast cells. It Dopamine receptors are coupled to G- plays a role in inflammatory and allergic proteins and exist as different subtypes. reactions (p. 72, 326) and produces D1-receptors (comprising subtypes D1 bronchoconstriction, increased intesti- and D5) and D2-receptors (comprising nal peristalsis, and dilation and in- subtypes D2, D3, and D4). The aforemen- creased permeability of small blood ves- tioned actions are mediated mainly by sels. In the gastric mucosa, it is released D2 receptors. When given by infusion, from enterochromaffin-like cells and dopamine causes dilation of renal and stimulates acid secretion by the parietal splanchnic arteries. This effect is mediat- cells. In the CNS, it acts as a neuromod- ed by D1 receptors and is utilized in the ulator. Two receptor subtypes (G-pro- treatment of cardiovascular shock and tein-coupled), H1 and H2, are of thera- hypertensive emergencies by infusion of peutic importance; both mediate vascu- dopamine and fenoldopam, respective- lar responses. Prejunctional H3 recep- ly. At higher doses, !1-adrenoceptors tors exist in brain and the periphery. and, finally, "-receptors are activated, as Antagonists. Most of the so-called evidenced by cardiac stimulation and H1-antihistamines also block other re- vasoconstriction, respectively. ceptors, including M-cholinoceptors and Dopamine is not to be confused with do- D-receptors. H1-antihistamines are used butamine which stimulates "- and !-ad- for the symptomatic relief of allergies renoceptors but not dopamine receptors (e.g., bamipine, chlorpheniramine, cle- (p. 62). mastine, dimethindene, mebhydroline Dopamine-mimetics. Administra- pheniramine); as antiemetics (mecli- tion of the precursor L-dopa promotes zine, dimenhydrinate, p. 330), as over- endogenous synthesis of dopamine (in- the-counter hypnotics (e.g., diphenhy- dication: parkinsonian syndrome, dramine, p. 222). Promethazine repre- p. 188). The ergolides, bromocriptine, sents the transition to the neuroleptic pergolide, and lisuride, are ligands at D- phenothiazines (p. 236). Unwanted ef- receptors whose therapeutic effects are fects of most H1-antihistamines are las- probably due to stimulation of D2 recep- situde (impaired driving skills) and atro- tors (indications: parkinsonism, sup- pine-like reactions (e.g., dry mouth, con- pression of lactation, infertility, acrome- stipation). At the usual therapeutic dos- galy, p. 242). Typical adverse effects of es, astemizole, cetrizine, fexofenadine, these substances are nausea and vomit- and loratidine are practically devoid of ing. As indirect dopamine-mimetics, (+)- sedative and anticholinergic effects. H2- amphetamine and ritaline augment do- antihistamines (cimetidine, ranitidine, pamine release. famotidine, nizatidine) inhibit gastric Inhibition of the enzymes involved acid secretion, and thus are useful in the in dopamine degradation, catechol- treatment of peptic ulcers. amine-oxygen-methyl-transferase Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Biogenic Amines 115 Increase in dopamine synthesis Dopaminergic neuron L-Dopa Inhibition of synthesis and formation of false transmitter: Methyldopa Destruction of storage vesicles: Reserpine Dopamin D2-Agonists e.g., bromocriptine D1/D2-Antagonists D2-Antagonists Neuroleptics e.g., metoclopramide D1 D2 Receptors Striatum (extrapyramidal motor function) Area postrema (emesis) Dopamine Adenohypophysis (prolactin secretion ) D1-Agonists Blood e.g., fenoldopam flow A. Dopamine actions as influenced by drugs H1-Antagonists H2-Antagonists e.g., fexofenadine e.g., ranitidine Histamine H1-Receptors H2-Receptors Vasodilation HCl Bronchoconstriction Bowel peristalsis permeability “H1-Antihistamines” Diphenhydramine Chlorpromazine Parietal cell Acetylcholine Dopamine Sedation, hypnotic, antiemetic action mACh-Receptor Dopamine receptors B. Histamine actions as influenced by drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
116 Biogenic Amines Inhibitors of histamine release: One Ketanserin is an antagonist at 5- of the effects of the so-called mast cell HT2A receptors and produces antihyper- stabilizers cromoglycate (cromolyn) tensive effects, as well as inhibition of and nedocromil is to decrease the re- thrombocyte aggregation. Whether 5- lease of histamine from mast cells (p. HT antagonism accounts for its antihy- 72, 326). Both agents are applied topi- pertensive effect remains questionable, cally. Release of mast cell mediators can because ketanserin also blocks !-adren- also be inhibited by some H1 antihista- oceptors. mines, e.g., oxatomide and ketotifen, Sumatriptan and other triptans are which are used systemically. antimigraine drugs that possess agonist activity at 5-HT1 receptors of the B, D Serotonin and F subtypes and may thereby allevi- Occurrence. Serotonin (5-hydroxytrypt- ate this type of headache (p. 322). amine, 5-HT) is synthesized from L- Gastrointestinal tract. Serotonin tryptophan in enterochromaffin cells of released from myenteric neurons or en- the intestinal mucosa. 5-HT-synthesiz- terochromaffin cells acts on 5-HT3 and ing neurons occur in the enteric nerve 5-HT4 receptors to enhance bowel mo- plexus and the CNS, where the amine tility and enteral fluid secretion. Cisa- fulfills a neuromediator function. Blood pride is a prokinetic agent that pro- platelets are unable to synthesize 5HT, motes propulsive motor activity in the but are capable of taking up, storing, stomach and in small and large intes- and releasing it. tines. It is used in motility disorders. Its Serotonin receptors. Based on bio- mechanism of action is unclear, but chemical and pharmacological criteria, stimulation of 5HT4 receptors may be seven receptor classes can be distin- important. guished. Of major pharmacotherapeutic Central Nervous System. Serotoni- importance are those designated 5-HT1, nergic neurons play a part in various 5-HT2, 5-HT4, and 5-HT7, all of which are brain functions, as evidenced by the ef- G-protein-coupled, whereas the 5-HT3 fects of drugs likely to interfere with se- subtype represents a ligand-gated non- rotonin. Fluoxetine is an antidepressant selective cation channel. that, by blocking re-uptake, inhibits in- Serotonin actions. The cardiovascu- activation of released serotonin. Its ac- lar effects of 5-HT are complex, because tivity spectrum includes significant psy- multiple, in part opposing, effects are chomotor stimulation, depression of ap- exerted via the different receptor sub- petite, and anxiolysis. Buspirone also has types. Thus, 5-HT2A and 5-HT7 receptors anxiolytic properties thought to be me- on vascular smooth muscle cells medi- diated by central presynaptic 5-HT1A re- ate direct vasoconstriction and vasodi- ceptors. Ondansetron, an antagonist at lation, respectively. Vasodilation and the 5-HT3 receptor, possesses striking lowering of blood pressure can also oc- effectiveness against cytotoxic drug-in- cur by several indirect mechanisms: 5- duced emesis, evident both at the start HT1A receptors mediate sympathoinhi- of and during cytostatic therapy. Trop- bition ( decrease in neurogenic vaso- isetron and granisetron produce analo- constrictor tonus) both centrally and gous effects. peripherally; 5-HT2B receptors on vas- Psychedelics (LSD) and other psy- cular endothelium promote release of chotomimetics such as mescaline and vasorelaxant mediators (NO, p. 120; psilocybin can induce states of altered prostacyclin, p. 196) 5-HT released from awareness, or induce hallucinations and platelets plays a role in thrombogenesis, anxiety, probably mediated by 5-HT2A hemostasis, and the pathogenesis of receptors. Overactivity of these recep- preeclamptic hypertension. tors may also play a role in the genesis of negative symptoms in schizophrenia (p. 238) and sleep disturbances. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Biogenic Amines 117 Serotoninergic neuron LSD Buspirone Lysergic acid diethylamide Psychedelic 5-HT1A Anxiolytic 5-HT2A Hallucination Ondansetron Antiemetic 5-HT3 Fluoxetine 5-HT- reuptake inhibitor Antidepressant Emesis 5-HT1D Sumatriptan Antimigraine 5-Hydroxy-tryptamine Cisapride Prokinetic Serotonin Blood vessel Intestine Endothelium- mediated Dilation 5-HT2B 5-HT4 Constriction Platelets Propulsive motility 5-HT2 Entero- chrom- affin cell A. Serotonin receptors and actions Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.

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