chapter12- nicotine and caffeine

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Chapter 12: Nicotine and Caffeine General information and learning issues: In chapter 11, we have learned those stimulants like cocaine, amphetamine, and methamphetamine, which are relatively limited because they are illegal except for limited medical purposes. In this chapter, we are continuing to introduce more stimulant drugs that are legally consumed; The most commonly used stimulant (and the most widely consumed drug) in the world are nicotine and caffeine, that are found in cigarettes, coffee, tea, soft drinks, chocolate, and drugs, including pain relievers, diet pills, and cold and allergy medications; In this chapter, we are discussing the properties of these two substances, their mechanisms of action, and their potential for abuse. Caffeine is addictive. People who consume it regularly develop a tolerance for it; ractice and significance of learning issues: Caffeine causes physical dependence, producing withdrawal symptoms including anxiety, headaches, and fatigue when its use is discontinued; People who stop using caffeine also experience a craving for it - psychological dependence; tine is consumed in smoking, which has well been suggested to be closely associat ancer; Nicotine withdrawal symptoms include anxiety, irritability, insomnia, depression, headaches, mood swings, difficulty concentrating, and changes in appetite. 1

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Page 1: Chapter12- Nicotine and Caffeine

Chapter 12: Nicotine and Caffeine General information and learning issues:

In chapter 11, we have learned those stimulants like cocaine, amphetamine, and methamphetamine, which are relatively limited because they are illegal except for limited medical purposes. In this chapter, we are continuing to introduce more stimulant drugs that are legally consumed;

The most commonly used stimulant (and the most widely consumed drug) in the world are nicotine and caffeine, that are found in cigarettes, coffee, tea, soft drinks, chocolate, and drugs, including pain relievers, diet pills, and cold and allergy medications;

In this chapter, we are discussing the properties of these two substances, their mechanisms of action, and their potential for abuse.

Caffeine is addictive. People who consume it regularly develop a tolerance for it;

Practice and significance of learning issues:

Caffeine causes physical dependence, producing withdrawal symptoms including anxiety, headaches, and fatigue when its use is discontinued;

People who stop using caffeine also experience a craving for it - psychological dependence;

Nicotine is consumed in smoking, which has well been suggested to be closely associated withlung cancer;

Nicotine withdrawal symptoms include anxiety, irritability, insomnia, depression, headaches, mood swings, difficulty concentrating, and changes in appetite.

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Nicotine

Nicotine is an alkaloid found in tobacco leaves; Nicotine was first isolated from the tobacco plant in 1828 by German chemists Posselt & Reimann, who considered it a poison. Its chemical empirical formula was described by Melsens in 1843, its structure was discovered by Garry Pinner in 1893, and it was first synthesized by A. Pictet and Crepieux in 1904 – history of finding. What we are concerned is about its action as a stimulant in mammals and is the main factor responsible for the dependence-forming properties of tobacco smoking – reinforcing properties. According to the American Heart Association, the nicotine addiction has historically been one of the hardest addictions to break. The pharmacological and behavioral characteristics that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine – Smokers are actually the nicotine dependent!

Nicotine forms salts with acids that are usually solid and water soluble, which easily penetrates the skin – features of pharmacokinetics;

Free base nicotine will burn at a temperature below its boiling point, and its vapors will combust at 35 °C in air despite a low vapor pressure. Because of this, most of the nicotine is burned when a cigarette is smoked - features of pharmacokinetics;

The amount of nicotine inhaled with tobacco smoke is a fraction of the amount contained in the tobacco leaves – pharmacological actions of nicotine;

Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major (70-80%) metabolite is cotinine. 2

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Nicotine (continued)

The typical cigarette contains between 6-11 mg of nicotine, although no more than 1-3 mg actually reaches the bloodstream of the smoker. The amount of available nicotine depends mainly on features of the smoker's behavior such as the number of puffs and the length of each puff; It enters the smoker's lungs mainly on tiny particles called tar, a complex mixture of hydrocarbons that are known to be carcinogenic. Tar is an important contributor to the taste and smell of cigarette smoke, and along with nicotine, these sensory qualities contribute significantly to the reinforcing effects of smoking; A typical smoker takes about 10 total puffs on a cigarette at intervals of approximately 30-60 s. Each puff delivers a small burst of nicotine to the brain. If the person smokes 30 cigarettes per day, 10 puffs per cigarette yields 300 separate “hits" of nicotine each day;

The nicotine first reaches the brain in about 7 s, which is approximately twice as fast as when the drug is administered IV. Thus smoking a cigarette is the quickest and most efficient method of delivering nicotine to the brain, where the drug produces its reinforcing effects; The rapid transit of nicotine to the brain is thought to powerfully reinforce smoking behavior. Moreover, the rapidly repeated, puff-by-puff drug delivery that occurs during smoking permits the user unmatched control over both the pattern of intake and the dose; Levels of nicotine in the arterial blood circulation following smoking are important index of reflecting how much of the drug is reaching the brain; Arterial nicotine rises more rapidly and reaches a much greater peak than the concentration in venous blood;

Within a few min, the arterial concentration falls to the same level as the venous concentration.

Features of pharmacokinetics and its contribution to withdrawal and dependence 3

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Nicotine (continued) Although the elimination (drug clearance) half-life of nicotine varies among individuals (related at least partially to differences in the level of CYP2A6), it is typically around 2 h. This requires that the user smoke repeatedly over the day to avoid withdrawal symptoms due to falling blood nicotine levels (a sustained level of nicotine is needed to avoid withdrawal responses); Frequent smoking leads to ever increasing peak levels of nicotine across the day, since each dose builds on the re’sidual nicotine left over from that day's previous cigarettes. However, this does not cause greater and greater effects, because of tolerance that has also developed over the same time period; Mild nicotine withdrawal emerges during the overnight period while the smoker is sleeping, yet at the same time the nicotine tolerance built up over the previous day partially dissipates;

Because of these two processes, the individual awakens the next morning with a strong craving for a cigarette but also may experience the strongest or best response that he will have all day.

Mechanisms of Nicotine Action (pharmacology): Nicotine works mainly by activating nicotinic cholinergic receptors (nAChRs), one of the two basic subtypes of acetylcholine (ACh) receptor; nAChRs are ionotropic receptors comprising five separate protein subunits with only α- and β- (α4X2,β2x3) in the CNS/PNS, and that these subunits are somehow different from those found on muscle cells (αx2,β,γ,δ; see Chapter 6);

In the brain, two α- and three β-subunits are thought to be a high-affinity nAChR. However, several different varieties of each subunit are present in the brain;

Despite the fact that all of these receptors are considered nicotinic because of their basic structure and function, some of them bind nicotine with a much higher affinity than others;

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Nicotine (continued)

High-affinity nAChRs are found in many parts of the CNS, including the cerebral cortex, thalamus, striatum, hippocampus, and monoamine-containing nuclei such as the substantia nigra, ventral tegmental area (VTA) , locus coeruleus, and the raphe nuclei;

Peripherally, such receptors are found in the ganglia of the autonomic (parasympathetic and sympathetic) nervous system;

The high-affinity nAChRs are commonly thought to possess two α- and three β-subunits, and within this general category the most common type of receptor contains a mixture of α4- and β2-subunits;

When nicotine binds to a nicotinic receptor, it opens a channel that allows sodium (Na+) ions to flow into the cell across the plasma membrane. This depolarizes the cell membrane, leading to a fast excitatory response by the cell;

Some nAChRs also allow significantly a mounts of Ca2+ to enter the cell, thereby stimulating Ca2+-dependent second messenger functions;

Some nAChRs are located presynaptically, that is, on nerve terminals. At this location, the receptors function by enhancing neurotransmitter release from the terminal;

High doses of nicotine lead to a persistent activation of nicotinic receptors and a continuous depolarization of the postsynaptic cell;

This causes a depolarization block, and the cell cannot fire again until the nicotine is removed. Thus, a high dose of nicotine exerts a biphasic effect that begins with stimulation of nicotinic cholinergic functions but then turns to a nicotinic receptor blockade. This biphasic action accounts for the features of nicotine poisoning.

Behavioral and Physiological Effects Nicotine elicits different mood changes in smokers compared to nonsmokers:

The mood-altering effects of nicotine depend on whether the subject is an abstinent smoker or a nonsmoker.

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Nicotine (enhanced recognition) In temporarily abstinent smokers (regular or established) , administration of pure nicotine usually increases calmness and relaxation. This effect is likely due to relief from nicotine withdrawal symptoms;

Administration of nicotine to abstinent smokers also leads to enhanced performance on various cognitive tasks, particularly those involving attentional demands;

Nicotine enhances cognitive function:

ACh plays an important role in certainaspects of cognitive functioning. Although this is mediated in large part by the muscarinic cholinergic receptors, nicotinic receptors could also be involved;

If you either smoke now or have ever smoked in the past, you may recall having experienced some of these same effects when you tried your first cigarette.

Abstinent smokers given nicotine show enhanced performance on many kinds of cognitive tasks, particularly those involving attentional demands. Much of this enhancement appears to be due to alleviation of withdrawal-related deficits;

There is some indication that nicotine has positive effects on cognitive performance even in nonsmokers;

Nicotine injection decreased reaction times of both smokers and non-smokers in a task requiring sustained visual attention.

Cognitive enhancement by nicotine is also indicated by the drug's effects on electroencephalogram (EEG) activity.

In contrast, nicotine given to nonsmokers more often elicits feelings of tension, arousal, lightheadedness or dizziness, and sometimes nausea;

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Nicotine (enahnced recognition)

Nicotine enhances working memory (short-term, requires to make a correct response quickly) of rats in the radial arm maze (see Fig. 4.19)

Rats received an acute injection of either nicotine (0.2 mg/kg) or placebo and then were tested for their performance in the radial arm maze. The nicotine-treated animals showed better working memory as indicated by a greater number of arm entries before they committed their first error (going into a previously entered arm).

Using a mutant mouse strain that lacks the β2-receptor subunit, the involvement of particular nicotinic receptor subtypes on the behavioral and physiological effects of nicotine is studied.

Wild-type (genetically normal) mice showed enhanced retention of a one-trial passive avoidance task when given a low dose of nicotine immediately after the learning trial (one-time only). However, nicotine had absolutely no effect on memory in the β2 knockout mice;

Since the β2-subunitis most commonly found along with α4, this finding raises the possibility that α4β2, receptors may be critical for the memory-enhancing

effects of nicotine.Compared to vehicle treatment, nicotine produced increased retention in the wild-type mice as indicated by greater latency to enter the dark compartment. No such effect was observed in the mutant (β2-subunit knockout) mice.

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Nicotine (reinforcing properties) Nicotine's reinforcing effects are mediated by activation of the mesolimbic dopamine system: The mesolimbic dopamine (DA) pathway from the VTA to the nucleus accumbens (NA) plays a key role in nicotine's reinforcing effects (reward response); High-affinity nicotinic receptors, when activated, located in the VTA stimulate the firing of dopaminergic neurons, which causes increased DA release in the NA; Nicotine-induced activation of DA neurons in VTA and subtantia nigra is evident by way of directly inhaling cigarette smoke;

Activation of midbrain dopamine neuron by tobacco smoke

Rats were connected to an artificial respirator through which tobacco smoke (TS) could be delivered. Smoke containing approximately 100 μg of nicotine was inhaled several times for 2 minutes during each trial (shaded area). Firing rates of a representative neuron in the VTA (A) and another neuron in the substantia nigra (B) are shown by the amplitude of the rate histogram. Tobacco smoke caused a substantial increase in VTA neuronal firing that returned to baseline within a few minutes. A smaller but still noticeable effect also occurred for cells in the substantia nigra. Note that prior intravenous (lV) infusion of the selective nicotinic receptor antagonist mecamylamine (lower right-hand part of each graph) completely blocked the effects of tobacco smoke on dopaminergic neuron firing, demonstrating that these effects are mediated by nicotinic cholinergic receptors.

Lesioning the dopaminergic innervation of nucleus accumbens with 6-OHDA significantly attenuated nicotine self-administration;

Several subtypes of nicotinic receptors are probably involved in the activation of DA neurons and the elicitation of behavioral reinforcement;

Among these may be receptors that contain the β2-subunit, since β2 knockout mice show little self-administration of nicotine.

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Nicotine (physiological effects)

Nicotine produces a wide range of physiological effects:

Nicotinic receptors are abundantly expressed in autonomic ganglia. Consequently, nicotine can activate elements of both the sympathetic and parasympathetic systems to cause a wide spectrum of physiological manifestation;

Activation of the adrenal glands and sympathetic ganglia leads to symptoms of physiological arousal such as tachycardia (increased heart rate) and elevated blood pressure. This mild physiological arousal is thought to contribute to the reinforcing features of smoking;

The same effects could increase the smoker's risk for cardiovascular disease and cerebrovascular accidents (strokes), particularly if the smoker has high blood pressure to begin with;

1. The action of nicotine on parasympathetic ganglia increases hydrochloric acid secretion in the stomach, which exacerbates or contributes to the formation of stomach ulcers;

2. There is also increased muscle contraction in the bowel, which sometimes leads to chronic diarrhea that is especially harmful to individuals vulnerable to colitis, a chronic irritability of the colon;3. One consequence that many cigarette smokers find desirable is the constraining effect of nicotine on body weight, who weighs an average of 8-10 pounds less than gender- and age-matched nonsmokers, and quitting smoking usually results in weight gain. This effect of nicotine has been attributed to an increase in metabolic rate combined with appetite suppression.

Nicotine is a toxic substance that can be fatal at high doses:

But what would you believe? Would you recommend smoking for weigh control?

Nicotine is a toxic substance that can cause dangerous symptoms such as nausea, salivation,abdominal pain, vomiting and diarrhea, confusion, and weakness;

If a sufficient dose has been ingested, death may occur from respiratory failure;

Treatment involves an attempt to remove the nicotine from the victim's stomach (if the nicotine has been swallowed), administration of artificial respiration, and dealing with drug-induced shock.

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Chronic Nicotine (tolerance) Chronic exposure to nicotine induces tolerance and dependence: Repeated exposure to nicotine can lead to tolerance and, in some cases, sensitization. If it develops a long-term exposure, the chronic tolerance occurs. It is only present in smokers and others who use tobacco frequently; Laboratory studies have found that many effects of nicotine administration are attenuated (tolerance) in smokers compared to non-smokers; Subcutaneous injection of a high dose of nicotine elicited an aversive reaction consisting of at least some symptoms of mild nicotine toxicity (nausea, dizziness, sweating, headache, palpitations, stomachache, or clammy hands) in nonsmokers, but no such reaction in smoker (tolerance);

Nicotine dependence in smokers can be seen by either stopping chronic administration of nicotine (such as 1-2 weeks’ infusion of nicotine) or giving a nicotinic receptor antagonist, like mecamylamine, in the dependent animals (dependence); Typical nicotine withdrawal symptoms include gasps, shakes or tremors, teeth chatter, ptosis (drooping eyelids), reduced locomotor activity, and increased startle reactivity; Current evidence suggests that the nicotine abstinence syndrome is mediated by a combination of central (that is, within the brain) and peripheral (outside of the brain) nicotinic receptors. The peripheralreceptors might be those located within autonomic ganglia, whereas the central component of nicotine withdrawal may involve receptors in the VTA; Nicotinic receptors in the VTA play a significant role in nicotine withdrawal and that this role at least partially involves changes in the NA’s DA release, because DA release in the NA is inhibited during mecamylamine precipitated nicotine withdrawal, and withdrawal symptoms can be elicited by injecting mecamylamine directly into the VTA of nicotine-dependent rats (but not known further mechanisms).

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Chronic nicotine (smoking)

Cigarette Smoking

Yearly per capita cigarette consumption in the US from 1900 to 1998 for individuals 18 years of age or older

How many smokers during nearly 100 yrs? Who are they?

Approximately 30% of the population age 12 years or older is tobacco users;

Tobacco use varies significantly by age, with the highest incidence in the 18-to-25-year age range;

Males are generally more likely to smoke than females, although it can be seen from the figure that this gender difference is not present within the l2-to-17 -year age group;

Across different ethnic groups, the highest rate of smoking occurs in Native Americans, followed by whites, Hispanics and African Americans, and then Asians;

The prevalence of cigarette smoking is inversely related to level of education. For individuals 18 years or older, about 14% of college graduates are smokers, compared to 32% of high school graduates and 35% of people without a high school diploma.

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Chronic nicotine (smoking)

Cigarette smokers progress through a series of stages in their smoking behavior:

Most smokers pick up the habit during adolescence. There are many theories about why teenagers take up smoking - start;

Some of the hypothesized reasons include establishing feelings of independence and maturity (by defying parental wishes or societal norms), improving self-image and enhancing social acceptance (assuming that one's friends are already smokers), counteracting stress and/or boredom, and simple curiosity - reasons;

Moreover, young people tend to emphasize the positive elements of smoking while disregarding or denying the negative aspects, including the health consequences - reasons;

Most investigators agree that smokers pass through several different stages on their way to eventual nicotine dependence - development;

Generally, there can be movement in both directions along the continuum from occasional to regular smoking;

However, unless an individual is actively attempting to quit, stage changes are usually toward heavier cigarette use.

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Chronic nicotine (smoking) Why do smokers smoke? Smoking and stress: Based on the reports by the smokers that smoking causes relaxation, alleviation of stress, and increased ability to concentrate, which hypothesizes a nicotine resource model. That is the nicotine obtained through smoking has the beneficial effects of increasing mood control and enhancing concentration; However, accumulated evidence favors an alternative model, the deprivation reversal model, which argues that the positive effects experienced when smoking actually constitute the alleviation of withdrawal effects such as irritability, anxiety, and poor concentration (passive). These are still debated; The role of nicotine in smoking (one of the most critical factors causing addiction/dependence):

1. Delivery of nicotine is obviously one of the key factors in smoking;

2. Smoking behavior itself. Cigarettes devoid of nicotine (for example, lettuce-based cigarettes) havenever been commercially successful; 3. It is well established that smoking intensity is increased when smokers of regular cigarettes switch to a brand that is low in nicotine and tar. This change in smoking behavior increases nicotine yields well beyond those specified by the Federal Trade Commission (FTC), which are based on standardized smoking by a machine;

4. Withdrawal from regular tobacco use leads to significant abstinence symptoms that are thought to result primarily from removal of nicotine from the person's system; 5. For habitual smokers who meet the criteria for nicotine dependence, even a brief abstinence of a few hours leads to craving and a growing urge to smoke. These feelings correlate with a drop in nicotine levels in the individual's bloodstream. The much longer abstinence that occurs when people try to quit smoking leads to a more complex abstinence syndrome characterized not only by tobacco craving but also by irritability, impatience, restlessness, anxiety, insomnia, difficulty concentrating, and hunger and weight gain; Will and how long, if yes, the abstinent symptoms last?

The next figure presents time course analysis of tobacco withdrawal symptoms and the effects of nicotine replacement therapy from one study that examined the time course of withdrawal symptoms as well as the ability of nicotine gum to prevent such symptoms.

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Chronic nicotine (smoking)Regular smokers who wanted to quit smoking were randomly assigned to either a nicotine gum or placebo gum group. symptom ratings were obtained before the beginning of treatment (baseline, BL) and then again 1 and 4 weeks later. The figure illustrates data for those subjects who were abstinent at the 4-week test point compared to those who failed to quit (Nonquiters) during the study.

1. Most abstinence symptoms were still present at 1 week post cessation, but the average levels of most symptoms were at or near baseline at 4 weeks;

3. Placebo data suggest that the abstinence syndrome from tobacco is relatively short-lasting. Most of these symptoms are due to nicotine dependence;

2. However, it is found that about 20-25% of the subjects still reported significant symptoms at the 4-week time point. Nicotine gum clearly prevented almost all of the withdrawal symptoms except for hunger and weight gain;

4. However, the fact is more complicated according to other studies, even with the nicotine gum, more than 2/3 of the subjects were back smoking at a 6-month follow-up test despite lacking the typical withdrawal symptoms;

5. These and other experimental results indicate that the nicotine-induced abstinence syndrome is not the only reason that most regular smokers find it so difficult to quit their habit. 14

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Chronic nicotine (smoking)

The role of other factors in smoking: Although withdrawal symptoms (critically due to nicotine) undoubtedly play an important role in maintaining the smoking habit in dependent smokers, other factors also contribute to this habit; One factor is the sensory aspects of smoking, namely the taste and smell of cigarette smoke; Assuming 30 cigarettes per day and 10 puffs per cigarette, a 10-year smoker has had over 1 million "learning trials" in which a mouthful of cigarette smoke was paired with one of those bursts of nicotine; For these reasons, it is likely that the sensory aspects of smoking help maintain this behavior under conditions where direct nicotine reinforcement is minimal due to receptor desensitization (not sure yet desensitized due to chronic?); One additional factor is a pharmacologically unrelated to nicotine. Brain imaging studies using positron emission tomography (PET) found a large reduction in the activities of both monoamine oxidase A (MAO-A) and MAO-B in smokers compared to nonsmokers (see the figure); This effect is not produced by administration of pure nicotine (nicotine-like drug is given, not smoking) and therefore must be caused by other substances present in cigarette smoke; MAO inhibition seems to require repeated cigarette use, since it is not found after the smoking of a single cigarette (acute);

Since MAO is an enzyme that plays a critical role in metabolizing DA, it is possible that smoking not only causes DA release (acute) but also slows its breakdown (chronic);

The MAO-B in both brain and peripheral organs is decreased in smokers. As these organs are exposed to catecholamines (CA) via the circulation as well as from sympathetic nerve endings, a deficiency in MAO-B could result in adverse consequences due to augmented CA activity throughout the body.

It is interesting that some individuals, called chippers, can smoke small numbers of cigarettes regularly without becoming dependent; Chippers do develop tolerance but might not be dependence, however, which demonstrates a separation between the processes underlying nicotine tolerance and dependence.

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Chronic nicotine (smoking) Smoking is a major cause of illness and premature death: It has been estimated that one-third to one-half of smokers die prematurely due to their exposure to tobacco; Cigarette smoking increases the risk for many life-threatening illnesses, including several kinds of cancer as well as cardiovascular disease. Smoking can also lead to other respiratory diseases such as emphysema and chronic bronchitis;

Smokers are at increased risk for heart attack, stroke, and atherosclerosis;

Pregnant smokers in particular should try to stop or at least cut back on their smoking habit. Smoking during pregnancy is the leading cause of low birth weight, which delays the infant's development and puts him at risk for other complications;

The deleterious (harmful) effects of smoking stem from a combination of factors, including tar, carbon monoxide gas that is produced by the burning of tobacco, and possibly also nicotine;

Tar contains a number of identified carcinogens, and the strong association between cigarette smoking and lung cancer has been known for well over 30 years.

Behavioral and pharmocologicaI strategies are used to treat tobacco dependence:

Surveys indicate that 70-75% of current smokers in the US would like to quit smoking, and about 40-45% of daily smokers actually attempt to quit each year. However, the success rate is very low due to addiction to nicotine is so powerful;

A variety of behavioral and pharmacological approaches for treating tobacco dependence are available, but it is important to recognize that the success rate of any treatment approach is influenced by numerous variables, such as the duration of smoking behavior and number of cigarettes smoked daily, the intensity of the abstinence syndrome, the motivation to quit, whether or not the smoker lives and/or works in a smoking environment, and so on;

Even if a given therapeutic program claims a high success rate for its clients, such claims are meaningless unless there is careful follow-up for months and years to ascertain long term abstinence.

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Chronic nicotine (treatment)

Behavioral interventions:

Strategies for directed toward discouraging young people from beginning tobacco use or giving it up if it is already habitually used: o Anti-smoking appeals;o Mandated health warnings on cigarette packages by the Surgeon General;o Levying of high taxes on tobacco products;

However, these may not prevent people from starting to use these products, but it does reduce the amount of use.

o Various self-help programs involving books or manuals are used by smokers; o Individual or group counseling programs provided by health professionals, particularly those that provide social support and/or coping-skills training to their clients.

Pharmacological interventions:

The most common pharmacological intervention for smoking cessation is nicotine replacement. This approach is based on several premises:o The difficulty associated with smoking cessation is significantly related to nicotine withdrawal symptoms;o Blocking (or at least reducing) these symptoms by maintaining a certain circulating level of nicotine can assist in terminating smoking;

o There are safer ways for individuals to obtain nicotine than by smoking. Nicotine replacement was first accomplished by formulating a special nicotine-containing chewing gum (nicotine polacrilex). This has the advantage that nicotine can be absorbed by the buccal mucosa (mucous membranes lining the mouth) rather than the gastrointestinal tract, where absorption is minimal and there is substantial first-pass metabolism in the liver;

This was later followed by the transdermal nicotine patch (Nicoderm, Habitrol, Nicotrol), nicotine nasal spray (Nicotrol NS), nicotine inhaler (Nicotrol Inhaler), and nicotine lozenges (Commit Lozenges);

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Chronic nicotine (treatment) Below lists some of the advantages and disadvantages of each nicotine delivery vehicle:

Two other points should also be noted with respect to nicotine replacement therapy:

First, combination treatments such as nicotine gum plus the patch or the nicotine inhaler plus the patch may be more effective than either treatment alone in helping some smokers quit their habit;

Second, a number of studies have shown that success rates are increased when behavioral or psychosocial (supportive) therapy is provided along with nicotine replacement;

Given the complex nature of nicotine addiction and the smoking habit, it should not be surprising that a combined therapeutic approach gives the smoker the best chance of quitting.

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Chronic nicotine (treatment) In addition to nicotine replacement therapy, bupropion, an unusual antidepressant medication thought to act by inhibiting DA and norepinephrine reuptake, is reported to reduce cravings and were able to quit smoking without additional therapeutic intervention;

Formal studies confirmed the efficacy of bupropion, and the drug is now available for smoking cessation in the form of a sustained-release preparation, which shows that sustained release bupropion is as effective as the nicotine patch in reducing nicotine withdrawal symptoms in newly abstinent smokers. However, the combination of bupropion and the patch did not reduce symptoms below the level achieved with either treatment alone;

Efficacy of bupropion treatment in reducing symptoms of smoking withdrawal

Subjects were enrolled in a smoking cessation program in which they received bupropion alone, nicotine patch alone, bupropion plus nicotine patch, or placebo. The intensity of withdrawal symptoms was rated and compared to baseline (pretreatment) scores for the first 6 days after quitting (A), and then at weekly intervals for a total of 9 weeks (B). All treatment groups showed reduced withdrawalsymptoms compared to the placebo group.

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Caffeine

The major source of caffeine is coffee beans, which are the seeds of the plant Coffea arabica; Tea leaves contain significant amounts of both caffeine and a related compound called theophylline;

While you are drinking a cup of coffee or tea, you are consuming caffeine at least partly for its pharmacological properties as a stimulant;

The typical caffeine content of various foodstuffs and over-the-counter drugs is shown in Table;

Basic Pharmacology of Caffeine

Caffeine is normally consumed orally through the beverages in which it is present. Under this condition, it is virtually completely absorbed from the gastrointestinal tract within 30-60 min;

Caffeine absorption begins in the stomach but takes place mainly within the small intestine. The plasma half-life of caffeine varies substantially from one person to another, but the average value is about 4 hours;

Consequently, people who drink coffee repeatedly over the course of a day experience gradually rising plasma caffeine concentrations.

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Caffeine (continued)

Most of this caffeine is then cleared from the circulation during sleep;

The rate of plasma clearance is stimulated by smoking and reduced when smoking is terminated;

The resulting increase in plasma caffeine levels could contribute to cigarette withdrawal symptoms in heavy coffee drinkers, particularly since caffeine is anxiogenic (anxiety provoking) at high dose, because it seems that high level of caffeine in the blood evokes more smoking to clear more caffeine; Caffeine is converted to a variety of metabolites by the liver. These metabolites account for almost all caffeine excretion, as only 1-2% of an administered dose is excreted unchanged; In humans, approximately 95% of caffeine metabolites are eliminated through the urine, 2- 5% through the feces, and the remainder through other bodily fluids such as saliva.

Behavioral and Physiological Effects

Acute subjective and behavioral effects of caffeine depend on dose and prior exposure:

Animal studies show that, at low doses, caffeine has stimulant effects as shown by increased locomotor activity. At high doses, this effect is reversed and animals actually show reduced activity;

People ingest caffeine mostly for its stimulating and fatigue-reducing effects. At high doses of caffeine, humans do not show behavioral depression like rodents but rather experience feelings of tension and anxiety. Moreover, caffeine does more than just increase our arousal;

Humans receiving low or intermediate doses of caffeine report a variety of positive subjective effects, including feelings of well-being, enhanced energy or vigor, increased alertness and ability to concentrate, self-confidence, increased work motivation, and enhanced sociability;

Following figure shows the results of one such study in which college students were tested on a variety of mood and performance measures, given a beverage containing either 40 mg of caffeine or no drug (decaffeinated placebo), and then tested a second time;

Compared to placebo, caffeine administration significantly increased alertness, reduced tension, anddecreased reaction times on a focused attention task.

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Caffeine (continued)

Some of caffeine's subjective effects may be related to its peripheral physiological actions;

These include increased blood pressure and respiration rate, enhanced water excretion (diuresis), and stimulation of catecholamine, particularly epinephrine release;

There is growing concern that even though the influence of caffeine on blood pressure is generally small, chronic caffeine use may represent a risk factor for heart disease or stroke, particularly in individuals who are especially sensitive to the drug's cardiovascular effects;

Therapeutic uses of caffeine:

Caffeine is a constituent of several over-the-counter analgesic agents. It is suggested that caffeine is mildly effective in the treatment of (nonmigraine) headache either alone or acting synergistically with aspirin or acetaminophen (the active ingredient in Tylenol);

The most important clinical use of caffeine is in the treatment of newborn infants who show apneic episodes (periodic cessation of breathing). Caffeine can be lifesaving in these babies by regularizing their breathing.

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Caffeine (continued) Regular caffeine use leads to tolerance and dependence:Studies show that regular caffeine use does lead to tolerance and dependence; For those of you who are regular caffeine users, perhaps you have occasionally been forced to miss your morning cup of coffee or tea. You might experience at least a few psychological and/or physical symptoms, including headache and lethargy or fatigue. If so, then you are dependent on caffeine;

However, this common drug dependence is harmless except in a small percentage of individuals who have extremely high levels of caffeine intake; Caffeine withdrawal symptoms and resulting craving may be experienced. The figures show withdrawal symptoms if caffeine is withheld for a prolonged period of time, and these may last a few days but then dissipate.

Time course of caffeine withdrawal in regular usersDuring the first phase of the study (left panel), subjects were maintained on 100 mg of caffeine daily in capsule form while abstaining from all dietary sources of caffeine. During the second phase (middle panel), placebo capsules were substituted for caffeine without the knowledge of the subjects. In the third phase (right panel), caffeine administration was reinstated. Caffeine withdrawal symptoms rapidly appeared during abstinence; however, the symptoms gradually disappeared over the course of several days.

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Caffeinism is caused due to chronic ingestion of excessive amounts of caffeine, which is characterized by restlessness, nervousness, insomnia, and physiological disturbances including tachycardia (increased heart rate) and gastrointestinal upset. Chronic caffeine consumption may be a risk factor for certain physiological disorders.

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Caffeine (continued)

Mechanisms of Action It is clear that caffeine does not directly influence catecholamine systems in the manner of the psychomotor stimulants amphetamine and cocaine, but how else might it work?1. When the biochemistry of the second messenger cyclic adenosine monophosphate (cAMP) was first beings studied, investigators discovered that caffeine and theophylline are inhibitors of cAMP phosphodiesterase, the enzyme that breaks down cAMP (increase in cAMP?);

a. This led to the theory that the behavioral activation produced by caffeine or theophylline was caused by a buildup of brain cAMP concentrations. b. Such activation can occur at brain caffeine concentrations, but are insufficient to inhibit phosphodiesterase (in other words, other evidence does not seem to verify caffeine-induced activation of cAMP is done by inhibition of phosphodiesterase) !!!???

c. In addition, phosphodiesterase inhibitors that differ in their chemical structure from caffeine or theophylline are actually behavioral depressants rather than stimulants!!!???

2. Several other cellular actions of caffeine have been identified, including blockade of GABAA receptors, stimulation of Ca2+ release within cells, and blockade of A1 and A2 receptors for a substance called adenosine. Figure on right illustrates idealized concentration-response functions for the various cellular effects of caffeine;

a. The levels of caffeine associated with one or a few cups of coffee, only the adenosine receptor blockade would come into play.b. The other effects require much higher doses, even into the toxic range associated with caffeinism.

24 It is generally believe that relief from withdrawal is a major factor in chronic coffee drinking, but the caffeinism’s dependence is not as severe as seen in other drugs. Thus, it has been less attention.

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Caffeine (continued) Adenosine and its receptors: Adenosine in the brain seems to serve a neurotransmitter-like function. It can be released into the brain extracellular fluid, where it acts on several different types of identified and specific adenosine receptors in nerve cell membranes (A1, A2A, A2B, and A3);

Caffeine most potently blocks the A1 and A2A receptor subtypes, which are therefore thought to mediate most of the behavioral effects of caffeine in laboratory animals;

It is not yet very clear whether adenosine plays a role in feelings of drowsiness or sleepiness in humans. If it does, then one can see how that first cup of coffee in the morning helps shake off the lingering sleepiness of the previous night, or how a mid-afternoon coffee break brings workers back to an alert state during a post-lunch period of drowsiness, or how that late-night cup of coffee keeps you awake unless you are already tolerant to caffeine.

25

There is now overwhelming evidence that blockade of adenosine receptors underlies caffeine-induced behavioral stimulation – caffeine might have a blocking effect on adenosine receptors;

Adenosine binds to adenosine receptors, which causes drowsiness (a sleepy feeling) by slowing down neuronal activity. Extracellular adenosine levels in the basal forebrain are significantly elevated during prolonged wakefulness, indicating this substance is responsible for the drowsiness that occurs following a period of sleep deprivation – long-term wakefulness is a trigger for getting sleep;

To a nerve cell, caffeine looks like adenosine that binds to the adenosine receptor. However, it does not slow down the cell's activity like adenosine would, because it blocks the receptors. As a result, the cell can no longer identify adenosine because caffeine is taking up all the receptors. Accordingly, the neurons are not slowing down because of the adenosine's effect, Instead, they are “speeding up” due to the receptors are bound by caffeine;