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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 with lung cancer;
Nicotine withdrawal symptoms include anxiety, irritability, insomnia, depression, headaches, mood swings, difficulty concentrating, and changes in appetite.
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.
Nicotine (continued)
Features of pharmacokinetics and its contribution to withdrawal and dependence
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.
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 residual 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.
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 - and three -subunits, and within this general category the most common type of receptor contains a mixture of 4- and 2-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.
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 g 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 righthand 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 2-subunit, since 2 knockout mice show little selfadministration of nicotine.
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Yearly per capita cigarette consumption in the US from 1900 to 1998 for individuals 18 years of age or older 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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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; 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; 3. Placebo data suggest that the abstinence syndrome from tobacco is relatively shortlasting. Most of these symptoms are due to nicotine dependence; 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.
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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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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 withdrawal symptoms compared to the placebo group.
Caffeine
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 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;
The typical caffeine content of various foodstuffs and over-the-counter drugs is shown in Table;
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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.
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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-thecounter 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.
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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.
Caffeine (continued)
It is generally believe that relief from withdrawal is a major factor in chronic coffee drinking, but the caffeinisms dependence is not as severe as seen in other drugs. Thus, it has been less attention.
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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.
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);
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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; There is now overwhelming evidence that blockade of adenosine receptors underlies caffeineinduced behavioral stimulation caffeine might have a blocking effect on adenosine receptors; 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; 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.