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Glycogenolysis, lipolysis, "silent stress"

Blood glucose and free fatty acids

A.Effects of nicotine in the body

Consequences of Tobacco Smoking

The dried and cured leaves of the nightshade plant Nicotiana tabacum are known as tobacco. Tobacco is mostly smoked, less frequently chewed or taken as dry snuff. Combustion of tobacco generates approx. 4000 chemical compounds in detectable quantities. The xenobiotic burden on the smoker depends on a range of parameters, including 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 distribution into tissues, and a terminal elimination phase with a half-life of 2 h. Nicotine is degraded by oxidation.

The enhanced risk of vascular disease (coronary stenosis, myocardial infarction, 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 plasma levels of glucose and free fatty acids in the absence of an immediate physiological need for these energy-rich metabolites. Furthermore, it promotes platelet aggregability, lowers fibrinolyt-ic activity of blood, and enhances coagulability.

The health risks of tobacco smoking are, however, attributable not only to nicotine, but also to various other ingredients of tobacco smoke, some of which Lullmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.

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 impaired. This depression favors bacterial infection and contributes to the chronic bronchitis associated with regular smoking. Chronic injury to the bronchial mucosa could be an important causative factor in increasing the risk in smokers of death from bronchial carcinoma.

Statistical surveys provide an impressive correlation between the number 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 developing bronchial carcinoma is reduced.

Abrupt cessation of regular smoking is not associated with severe physical withdrawal symptoms. In general, subjects complain of increased nervousness, lack of concentration, and weight gain.

Physical Effects Smoking
A. Sequelae of tobacco smoking

Biogenic Amines — Actions and Pharmacological Implications

Dopamine A. As the precursor of norepinephrine and epinephrine (p. 184), dopamine is found in sympathetic (adrenergic) 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 inhibition of prolactin release from the anterior pituitary (p. 242).

Dopamine receptors are coupled to G-proteins and exist as different subtypes. D1-receptors (comprising subtypes D1 and D5) and D2-receptors (comprising subtypes D2, D3, and D4). The aforementioned actions are mediated mainly by D2 receptors. When given by infusion, dopamine causes dilation of renal and splanchnic arteries. This effect is mediated by D1 receptors and is utilized in the treatment of cardiovascular shock and hypertensive emergencies by infusion of dopamine and fenoldopam, respectively. At higher doses, Pi-adrenoceptors and, finally, a-receptors are activated, as evidenced by cardiac stimulation and vasoconstriction, respectively. Dopamine is not to be confused with do-butamine which stimulates a- and p-ad-renoceptors but not dopamine receptors (p. 62).

Dopamine-mimetics. Administration of the precursor L-dopa promotes endogenous synthesis of dopamine (indication: parkinsonian syndrome, p. 188). The ergolides, bromocriptine, pergolide, and lisuride, are ligands at D-receptors whose therapeutic effects are probably due to stimulation of D2 receptors (indications: parkinsonism, suppression of lactation, infertility, acromegaly, p. 242). Typical adverse effects of these substances are nausea and vomiting. 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), MAOe-inhibi-tors, p. 88, 188).

Dopamine antagonist activity is the hallmark of classical neuroleptics. The antihypertensive agents, reserpine (obsolete) and a-methyldopa, deplete neuronal stores of the amine. A common adverse 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 intestinal peristalsis, and dilation and increased permeability of small blood vessels. 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), H1 and H2, are of therapeutic importance; both mediate vascular responses. Prejunctional H3 receptors exist in brain and the periphery.

Antagonists. Most of the so-called Hi-antihistamines also block other receptors, including M-cholinoceptors and D-receptors. H1-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 represents the transition to the neuroleptic phenothiazines (p. 236). Unwanted effects of most H1-antihistamines are lassitude (impaired driving skills) and atro-pine-like reactions (e.g., dry mouth, constipation). At the usual therapeutic doses, astemizole, cetrizine, fexofenadine, and loratidine are practically devoid of sedative and anticholinergic effects. H2-antihistamines (cimetidine, ranitidine, famotidine, nizatidine) inhibit gastric acid secretion, and thus are useful in the treatment of peptic ulcers.

Dopamine Actions
A. Dopamine actions as influenced by drugs
Anticholinergic Effects

Inhibitors of histamine release: One of the effects of the so-called mast cell stabilizers cromoglycate (cromolyn) and nedocromil is to decrease the release of histamine from mast cells (p. 72, 326). Both agents are applied topically. Release of mast cell mediators can also be inhibited by some H1 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 biochemical and pharmacological criteria, seven receptor classes can be distinguished. Of major pharmacotherapeutic importance are those designated 5-HT1, 5-HT2, 5-HT4, and 5-HT7, all of which are G-protein-coupled, whereas the 5-HT3 subtype represents a ligand-gated non-selective cation channel.

Serotonin actions. The cardiovascular effects of 5-HT are complex, because multiple, in part opposing, effects are exerted via the different receptor subtypes. Thus, 5-HT2A and 5-HT7 receptors on vascular smooth muscle cells mediate direct vasoconstriction and vasodi-lation, respectively. Vasodilation and lowering of blood pressure can also occur by several indirect mechanisms: 5-HT1A receptors mediate sympathoinhi-bition (^ decrease in neurogenic vasoconstrictor tonus) both centrally and peripherally; 5-HT2B receptors on vascular 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-HT2A receptors and produces antihypertensive effects, as well as inhibition of thrombocyte aggregation. Whether 5-HT antagonism accounts for its antihy-pertensive effect remains questionable, because ketanserin also blocks a-adren-oceptors.

Sumatriptan and other triptans are antimigraine drugs that possess agonist activity at 5-HT1 receptors of the B, D and F subtypes and may thereby alleviate this type of headache (p. 322).

Gastrointestinal tract. Serotonin released from myenteric neurons or en-terochromaffin cells acts on 5-HT3 and 5-HT4 receptors to enhance bowel motility and enteral fluid secretion. Cisapride is a prokinetic agent that promotes propulsive motor activity in the stomach and in small and large intestines. It is used in motility disorders. Its mechanism of action is unclear, but stimulation of 5HT4 receptors may be important.

Central Nervous System. Serotoni-nergic neurons play a part in various brain functions, as evidenced by the effects of drugs likely to interfere with serotonin. Fluoxetine is an antidepressant that, by blocking re-uptake, inhibits in-activation of released serotonin. Its activity spectrum includes significant psychomotor stimulation, depression of appetite, and anxiolysis. Buspirone also has anxiolytic properties thought to be mediated by central presynaptic 5-HT1A receptors. Ondansetron, an antagonist at the 5-HT3 receptor, possesses striking effectiveness against cytotoxic drug-induced emesis, evident both at the start of and during cytostatic therapy. Trop-isetron and granisetron produce analogous 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-HT2A receptors. Overactivity of these receptors may also play a role in the genesis of negative symptoms in schizophrenia

Serotoninergic neuron

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