- •Preface to the 3rd edition
- •General Pharmacology
- •Systems Pharmacology
- •Therapy of Selected Diseases
- •Subject Index
- •Abbreviations
- •General Pharmacology
- •History of Pharmacology
- •Drug and Active Principle
- •The Aims of Isolating Active Principles
- •European Plants as Sources of Effective Medicines
- •Drug Development
- •Congeneric Drugs and Name Diversity
- •Oral Dosage Forms
- •Drug Administration by Inhalation
- •Dermatological Agents
- •From Application to Distribution in the Body
- •Potential Targets of Drug Action
- •External Barriers of the Body
- •Blood–Tissue Barriers
- •Membrane Permeation
- •Binding to Plasma Proteins
- •The Liver as an Excretory Organ
- •Biotransformation of Drugs
- •Drug Metabolism by Cytochrome P450
- •The Kidney as an Excretory Organ
- •Presystemic Elimination
- •Drug Concentration in the Body as a Function of Time—First Order (Exponential) Rate Processes
- •Time Course of Drug Concentration in Plasma
- •Time Course of Drug Plasma Levels during Repeated Dosing (A)
- •Time Course of Drug Plasma Levels during Irregular Intake (B)
- •Accumulation: Dose, Dose Interval, and Plasma Level Fluctuation (A)
- •Dose–Response Relationship
- •Concentration–Effect Curves (B)
- •Concentration–Binding Curves
- •Types of Binding Forces
- •Agonists—Antagonists
- •Other Forms of Antagonism
- •Enantioselectivity of Drug Action
- •Receptor Types
- •Undesirable Drug Effects, Side Effects
- •Drug Allergy
- •Cutaneous Reactions
- •Drug Toxicity in Pregnancy and Lactation
- •Pharmacogenetics
- •Placebo (A)
- •Systems Pharmacology
- •Sympathetic Nervous System
- •Structure of the Sympathetic Nervous System
- •Adrenergic Synapse
- •Adrenoceptor Subtypes and Catecholamine Actions
- •Smooth Muscle Effects
- •Cardiostimulation
- •Metabolic Effects
- •Structure–Activity Relationships of Sympathomimetics
- •Indirect Sympathomimetics
- •Types of
- •Antiadrenergics
- •Parasympathetic Nervous System
- •Cholinergic Synapse
- •Parasympathomimetics
- •Parasympatholytics
- •Actions of Nicotine
- •Localization of Nicotinic ACh Receptors
- •Effects of Nicotine on Body Function
- •Aids for Smoking Cessation
- •Consequences of Tobacco Smoking
- •Dopamine
- •Histamine Effects and Their Pharmacological Properties
- •Serotonin
- •Vasodilators—Overview
- •Organic Nitrates
- •Calcium Antagonists
- •ACE Inhibitors
- •Drugs Used to Influence Smooth Muscle Organs
- •Cardiac Drugs
- •Cardiac Glycosides
- •Antiarrhythmic Drugs
- •Iron Compounds
- •Prophylaxis and Therapy of Thromboses
- •Possibilities for Interference (B)
- •Heparin (A)
- •Hirudin and Derivatives (B)
- •Fibrinolytics
- •Intra-arterial Thrombus Formation (A)
- •Formation, Activation, and Aggregation of Platelets (B)
- •Inhibitors of Platelet Aggregation (A)
- •Presystemic Effect of ASA
- •Plasma Volume Expanders
- •Lipid-lowering Agents
- •Diuretics—An Overview
- •NaCl Reabsorption in the Kidney (A)
- •Aquaporins (AQP)
- •Osmotic Diuretics (B)
- •Diuretics of the Sulfonamide Type
- •Potassium-sparing Diuretics (A)
- •Vasopressin and Derivatives (B)
- •Drugs for Gastric and Duodenal Ulcers
- •Laxatives
- •Antidiarrheal Agents
- •Drugs Affecting Motor Function
- •Muscle Relaxants
- •Nondepolarizing Muscle Relaxants
- •Depolarizing Muscle Relaxants
- •Antiparkinsonian Drugs
- •Antiepileptics
- •Pain Mechanisms and Pathways
- •Eicosanoids
- •Antipyretic Analgesics
- •Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
- •Cyclooxygenase (COX) Inhibitors
- •Local Anesthetics
- •Opioid Analgesics—Morphine Type
- •General Anesthesia and General Anesthetic Drugs
- •Inhalational Anesthetics
- •Injectable Anesthetics
- •Sedatives, Hypnotics
- •Benzodiazepines
- •Pharmacokinetics of Benzodiazepines
- •Therapy of Depressive Illness
- •Mania
- •Therapy of Schizophrenia
- •Psychotomimetics (Psychedelics, Hallucinogens)
- •Hypothalamic and Hypophyseal Hormones
- •Thyroid Hormone Therapy
- •Glucocorticoid Therapy
- •Follicular Growth and Ovulation, Estrogen and Progestin Production
- •Oral Contraceptives
- •Antiestrogen and Antiprogestin Active Principles
- •Aromatase Inhibitors
- •Insulin Formulations
- •Treatment of Insulin-dependent Diabetes Mellitus
- •Treatment of Maturity-Onset (Type II) Diabetes Mellitus
- •Oral Antidiabetics
- •Drugs for Maintaining Calcium Homeostasis
- •Drugs for Treating Bacterial Infections
- •Inhibitors of Cell Wall Synthesis
- •Inhibitors of Tetrahydrofolate Synthesis
- •Inhibitors of DNA Function
- •Inhibitors of Protein Synthesis
- •Drugs for Treating Mycobacterial Infections
- •Drugs Used in the Treatment of Fungal Infections
- •Chemotherapy of Viral Infections
- •Drugs for the Treatment of AIDS
- •Drugs for Treating Endoparasitic and Ectoparasitic Infestations
- •Antimalarials
- •Other Tropical Diseases
- •Chemotherapy of Malignant Tumors
- •Targeting of Antineoplastic Drug Action (A)
- •Mechanisms of Resistance to Cytostatics (B)
- •Inhibition of Immune Responses
- •Antidotes and Treatment of Poisonings
- •Therapy of Selected Diseases
- •Hypertension
- •Angina Pectoris
- •Antianginal Drugs
- •Acute Coronary Syndrome— Myocardial Infarction
- •Congestive Heart Failure
- •Hypotension
- •Gout
- •Obesity—Sequelae and Therapeutic Approaches
- •Osteoporosis
- •Rheumatoid Arthritis
- •Migraine
- •Common Cold
- •Bronchial Asthma
- •Emesis
- •Alcohol Abuse
- •Local Treatment of Glaucoma
- •Further Reading
- •Further Reading
- •Picture Credits
- •Drug Indexes
112 Nicotine
Actions of Nicotine
Acetylcholine (ACh) is a mediator in the ganglia of the sympathetic and parasympathetic divisions of the autonomic nervous system. Here, ACh receptors are considered that are activated by nicotine (nicotinic receptors; NAChR, p.102) and that play a leading part in fast ganglionic neurotransmission. These receptors represent ligand-gated ion channels with a structure and mode of operation as described on p.64. Opening of the ion pore induces Na+ influx followed by membrane depolarization and excitation of the cell. NAChR tend to desensitize rapidly; that is, during prolonged occupation by an agonist the ion pore closes spontaneously and cannot reopen until the agonist detaches itself.
enjoyment of its central stimulant action. Nicotine activates the brain’s reward system, thereby promoting dependence. Regular intake leads to habituation, which is advantageous in some respects (e.g., stimulation of the area postrema, p.342). In habituated subjects, cessation of nicotine intake results in mainly psychological withdrawal symptoms (increased nervousness, lack of concentration). Prevention of these is an additional important incentive for continuing nicotine intake. Peripheral effects caused by stimulation of autonomic ganglia may be perceived as useful (“laxative” effect of the first morning cigarette). Sympathoactivation without corresponding physical exertion (“silent stress”) may in the long term lead to grave cardiovascular damage (p.114).
Localization of Nicotinic ACh Receptors
Autonomic nervous system (A, middle). In analogy to autonomic ganglia, NAChR are found also on epinephrine-releasing cells of the adrenal medulla, which are innervated by spinal first neurons. At all these synapses, thereceptorislocatedpostsynapticallyinthe somatodendritic region of the gangliocyte.
Motor end plate. Here the ACh receptors are of the motor type (p.182).
Central nervous system (CNS; A, top). NAChR are involved in various functions. They have a predominantly presynaptic location and promote transmitter release from innervated axon terminals by means of depolarization. Together with ganglionic NAChR they belong to the neuronal type, which differs from the motor type in terms of the composition of its five subunits.
Effects of Nicotine on Body Function
Nicotine served as an experimental tool for the classification of acetylcholine receptors. As a tobacco alkaloid, nicotine is employed daily by a vast part of the human race for the
Aids for Smoking Cessation
Administration of nicotine by means of skin patch, chewing gum, or nasal spray is intended to eliminate craving for cigarette smoking. Breaking of the habit is to be achieved by stepwise reduction of the nicotine dose. Initially this may happen; however, the long-term relapse rate is disappointingly high.
Bupropion (amfebutamon) shows structural similarity with amphetamine (p.329) and inhibits neuronal reuptake of dopamine and norepinephrine. It is supposed to aid smokers in “kicking the habit,” possibly because it evokes CNS effects resembling those of nicotine. The high relapse rate after termination of the drug and substantial side effects put its therapeutic value in doubt.
Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
Actions of Nicotine |
113 |
A. Effects of nicotine in body |
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Attentiveness |
Stimulation |
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Avoidance of withdrawal |
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of reward system |
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symptoms: |
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Vigilance |
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Irritability, impatience |
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Ability to concentrate |
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Difficulty concentrating |
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Dependence |
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Dysphoria |
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Excitation of |
Release of |
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Release of vasopressin |
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area postrema |
transmitters |
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Nausea, vomiting |
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Mainly presynaptic |
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Postsynaptic |
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receptors |
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receptors of |
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motor end plate |
Sensitization of |
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receptors for pressure, |
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N |
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temperature and |
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pain sensation |
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CH |
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N |
Nicotine |
3 |
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Postsynaptic |
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receptors of |
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autonomic |
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Adrenal |
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gangliocytes and |
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medulla |
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adrenal medullary |
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cells |
Norepinephrine |
Epinephrine |
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Acetylcholine |
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Vasoconstriction |
Glycogenolysis |
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Bowel peristalsis |
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Heart rate |
Lipolysis |
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Defecation |
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Blood pressure |
“Silent stress” |
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Diarrhea |
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Neuro- |
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Presynaptic receptors |
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transmitters |
Postsynaptic receptors |
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Nicotine |
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Nicotine |
Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
114 Nicotine
Consequences of Tobacco Smoking
The dried and cured leaves of the nightshade plant Nicotianatabacumare known as tobacco. Tobacco is mostly smoked, less frequently chewed or taken as dry snuff. Combustion of tobacco generates ~ 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. The amount of nicotine absorbed during smoking depends on the nicotine content, the size of membrane area exposed to tobacco smoke (N.B.: inhalation), and the pH of the absorbing surface. It is rapidly absorbed through bronchi and lung alveoli when present in free base form. However, protonation of the pyrrolidine nitrogen renders the corresponding part of the molecule hydrophilic and absorption is impeded. To maximize the yield of nicotine, tobaccos of some manufacturers are made alkaline. Smoking of a single cigarette produces peak plasma levels in the range of 25–50 ng/ml. The effects described on p.113 become evident. When intake stops, nicotine concentration in plasma shows an initial rapid fall, due to distribution into tissues, and a terminal elimination phase with a half-life of 2 hours. Nicotine is degraded by oxidation.
The enhanced risk of vascular disease (coronary stenosis, myocardial infarction, and central and peripheral ischemic disorders, such as stroke and intermittent claudication) is likely to be a consequence of chronic exposure to nicotine. At the least, nicotine is under discussion as a factor favoring the progression of atherosclerosis. 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. Further-
more, it promotes platelet aggregability, lowers fibrinolytic 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 these promote formation of thrombogenic plaques; others possess demonstrable carcinogenic properties (e.g., the tobacco-specific nitrosoketone).
Dust particles inhaled in tobacco smoke, together with bronchial mucus, must be removed by the ciliated epithelium from the airways. However, ciliary activity is depressed by tobacco smoke and mucociliary transport is impaired. This favors bacterial infection and contributes to the chronic bronchitis associated with regular smoking (smoker’s cough). 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 numbers of cigarettes smoked per day and the risk of death from coronary disease or lung cancer. On the other hand, 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 nonsmokers. Similarly, the risk of developing bronchial carcinoma is reduced.
An association with tobacco use has also been established for cancers of the larynx, pharynx, esophagus, stomach, pancreas, kidney, and bladder.
Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
Consequences of Tobacco Smoking |
115 |
A. Sequelae of tobacco smoking |
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+ |
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N |
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H |
CH3 |
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N |
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-H+ |
+H+ |
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N |
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N |
CH3 |
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Nicotine free base |
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Nicotiana |
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tabacum |
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“Tar” |
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Nitrosamines, |
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acrolein, |
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polycyclic |
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hydrocarbons, e.g., |
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benzopyrene |
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heavy metals |
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Sum of noxious |
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stimuli |
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Platelet |
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Damage to |
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Damage to |
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Inhibition of |
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aggregation |
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vascular |
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bronchial |
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mucociliary |
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endothelium |
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epithelium |
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transport |
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Fibrinolytic |
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Epinephrine |
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Years |
Duration |
Months |
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of |
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activity |
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exposure |
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Free |
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Chronic |
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Bronchitis |
fatty acids |
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bronchitis |
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Coronary disease |
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Bronchial carcinoma |
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Annual deaths/1000 people |
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Annual cases/1000 people |
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5 |
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4 |
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3 |
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Ex-smoker |
2 |
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1 |
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0 |
–10 |
–20 |
–40 |
>40 |
0 |
–15 |
–40 |
>40 |
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Number of cigarettes per day |
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Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.