Action and mechanism - [ANTI-TOBACCO], [GANGLIOPLEGIC]. Nicotine is an agonist of nicotinic cholinergic receptors, located primarily in the autonomic ganglia, adrenal medulla, neuromuscular junction, and central nervous system. Nicotines effects on the body are multiple and varied, and depend on the dose administered and the individuals autonomic tone. Nicotine is also responsible for tobacco dependence in smokers, possibly through two mechanisms. At low doses, it appears to have a stimulating effect on the cortex through the locus ceruleus, increasing cognitive function and alertness. At higher doses, it appears to produce a reward effect originating in the limbic system. Abrupt cessation of tobacco use after a prolonged period of use results in a characteristic withdrawal syndrome, which includes symptoms such as dysphoria, insomnia, irritability, anger, anxiety, difficulty concentrating, agitation, bradycardia, and increased appetite with weight gain. Nicotine craving is also noted. Nicotine delivered through patches or gum has similar effects to those delivered through tobacco, and provides those who wish to quit smoking with enough nicotine to reduce the onset of withdrawal symptoms. The nicotine dose is gradually reduced until the body can do without it. Pharmacokinetics Oral, transdermal, nasal: - Absorption: * Chewing gum: Chewing gum releases the drug evenly during chewing. The released nicotine is absorbed very rapidly. Some is ingested in saliva, but its bioavailability is very low, as it is partially inactivated in the stomach and intestines and undergoes a strong first-pass effect in the liver. Nicotine is barely released from chewing gum if swallowed. Nicotine release is highly variable (45-90% at 20-30 minutes) and depends on the intensity and length of chewing. After chewing a 2 mg piece of gum, a Cmax of 6.4 ng/ml is obtained after 25-30 minutes. These levels are 2-5 times lower than those obtained after smoking a cigarette. - Distribution: It is poorly bound to plasma proteins (5%). Its intravenous dose is approximately 2–3 l/kg. Nicotine crosses the blood-brain and placental barriers. It is excreted in milk. - Metabolism: Nicotine is extensively metabolized in the liver, and to a lesser extent in the lungs and kidneys, very rapidly, giving rise to more than 20 metabolites, which are less active than the original molecule. The main metabolite is cotinine, which appears in plasma concentrations 10 times higher than nicotine. - Elimination: Nicotine is eliminated by hepatic metabolism and subsequent urinary excretion of metabolites. Up to 10% of the dose is recovered unchanged in urine, although if the urinary pH is below 5, up to 30% can be recovered. The half-life of nicotine when administered artificially is 1-3 hours, compared to 15-20 hours for nicotine from tobacco. Cl is approximately 70 l/h. Pharmacokinetics in special situations: - Elderly: In healthy elderly patients, there is a slight decrease in nicotine clearance, but this does not justify dosage adjustment. - Renal insufficiency: In patients with renal insufficiency, an increase in plasma nicotine levels is observed depending on the degree of renal function. - Hepatic impairment: The pharmacokinetics of nicotine are not affected in patients with mild hepatic impairment (Child-Pugh score of 5), while Cl is decreased in cirrhotic patients with moderate hepatic impairment (Child-Pugh score of 7). Indications - [TOBACCO DEPENDENCE]. Adjuvant treatment in smoking cessation programs, with the aim of alleviating the symptoms of nicotine withdrawal syndrome. Although these products mimic the effects of tobacco, they should never be used as tobacco substitutes. Posology - Adults, oral: * Chewing gum: The characteristics of chewing gum as a pharmaceutical form are such that they can lead to different individual blood nicotine levels. Therefore, dosing frequency should be adjusted according to individual requirements within the established maximum limit. The dose will depend on the dependence and the number of cigarettes smoked. It is recommended to start with 2 mg chewing gum, administering one chewing gum when the patient feels the urge to smoke. If administering 15 chewing gums is insufficient or if the patient smokes more than 20 cigarettes per day, single doses of 4 mg should be administered. The daily dose is usually between 8 and 12 pieces of gum, up to a maximum of 25 pieces. During the initial withdrawal phase, it is recommended not to exceed 15 pieces of gum per day. The duration of treatment also varies, although it should be continued for at least 3 months. After this period, the user should gradually reduce the number of chewing gums per day. Abrupt discontinuation of chewing gum is not advisable, as the patient may relapse. Once the patient has reduced the dose to 1 or 2 chewing gums per day, treatment can be discontinued. 2 mg gum may not be sufficient for patients with severe or very severe dependence, such as patients who smoke more than 20 cigarettes per day or who have previously failed to quit smoking with nicotine replacement therapy. - Children: Safety and efficacy in children and adolescents under 18 years of age have not been evaluated. Treatment duration: Use of this product for periods exceeding 6 months is not recommended, although certain patients may require longer treatment periods. Rules for correct administration The patient should stop smoking completely during nicotine treatment, due to the risk of adverse reactions due to higher plasma nicotine levels. Combining patches with gum or lozenges is not recommended. Simultaneous consumption of acidic beverages such as coffee or soft drinks can reduce the release of nicotine from gum or lozenges. It is recommended to avoid consuming these beverages for 15 minutes before administering nicotine. - Gum: Chew the gum gently and slowly, waiting several seconds between chews, as chewing too quickly can cause rapid absorption of nicotine, causing adverse reactions. Continue chewing until the flavor becomes intense or a tingling sensation is felt. The gum should then be placed between the gum and the wall of the mouth. When the flavor diminishes, the gum should be chewed again. This routine should be repeated for 30 minutes. Contraindications - Hypersensitivity to any component of the medication. - Non-smokers or occasional smokers. Precautions - [RENAL INFECTION]. Nicotine and its metabolites are eliminated in urine, so a decrease in renal function could lead to their accumulation. Because the metabolites are also active, adverse reactions may occur. No significant differences in the incidence of adverse reactions have been described in patients with mild or moderate renal impairment (CLcr between 30-90 ml/minute), but close monitoring of these patients is recommended. Safety and efficacy have not been evaluated in patients with severe renal impairment (CLcr less than 30 ml/minute), so its use is not recommended (See Contraindications). - [LIVER FAILURE]. Nicotine is extensively metabolized in the liver, so accumulation of nicotine may occur in patients with liver failure. Extreme caution is recommended in patients with mild or moderate liver failure, and patients should be monitored for adverse reactions. Safety and efficacy have not been evaluated in patients with severe liver failure; therefore, its use is not recommended (see Contraindications). - [HEART DISEASE]. Nicotine has cardiac stimulant and vasoconstrictor effects, and may therefore worsen cardiovascular conditions. Occasional cases of cardiovascular adverse reactions with nicotine have been reported. However, oral or transdermal administration of nicotine does not appear to be associated with a particularly significant risk of cardiovascular disease. Patients with heart disease should be advised to stop smoking, preferably without nicotine replacement therapy. However, if this is not possible, it is recommended to adequately assess the need for treatment, studying the benefits and risks, and to exercise extreme caution in patients with [HEART FAILURE], [ISCHEMIC HEART DISEASE] such as recent [ACUTE MYOCARDIAL INFARCTION] or [ANGINA PECTORIS], [CARDIAC ARRHYTHMIA], [STROKE] and vasospastic diseases such as [THROMBOANGEITIS OBLITERANS], [PRINZMETALS ANGINA] or [RAYNAUDS DISEASE]. Likewise, special caution is recommended in patients with [ARTERIAL HYPERTENSION], since nicotine could increase blood pressure. If the patient experiences a worsening of any of these symptoms, it is advisable to discontinue treatment (See Contraindications). - [PHEOCHROMOCYTOMA], [HYPERTHYROIDISM], or any condition that may be worsened by catecholamines, such as [TYPE 1 DIABETES MELLITUS]. Nicotine stimulates the production and release of catecholamines in the adrenal medulla. This may lead to a worsening of symptoms such as pheochromocytoma, hyperthyroidism, or diabetes. In general, the administration of nicotine presents fewer risks than continued smoking, but it is recommended that the benefit-risk ratio be assessed beforehand in these patients. - [PEPTIC ULCER] and other inflammatory processes of the stomach, such as [GASTRITIS]. Nicotine delays the healing of gastroduodenal ulcers, so it is recommended to use it in these patients only if the benefits outweigh the possible risks. - Dependence. Any nicotine preparation presents a risk of causing dependence, although due to the lower plasma levels achieved, it is less likely than with tobacco alone. However, abrupt discontinuation of treatment can lead to a withdrawal syndrome similar to that experienced when quitting smoking. For this reason, it is recommended to gradually discontinue nicotine administration and not discontinue treatment until it is relatively certain that withdrawal syndrome will not occur. - [HYPERSENSITIVITY REACTIONS]. Caution in patients susceptible to developing [ANGIOEDEMA] or [URTICARIA]. - Inflammations of the upper digestive tract, such as [ESOPHAGITIS] or [PHARYNGITIS]. Nicotine may exacerbate these conditions. - Patients with dentures or any chewing disorder may have trouble chewing gum, so other forms of administration such as patches are recommended. Warnings on excipients: - This medicinal product contains sodium salts. For the exact sodium content, please refer to the composition. Oral and parenteral dosage forms with sodium levels greater than 1 mmol (23 mg)/maximum daily dose should be used with caution in patients on or following a low-sodium diet. Warnings on excipients: - Because it contains butyl hydroxytoluene as an excipient, it may produce local skin reactions, such as contact dermatitis, or irritation of the eyes or mucous membranes. Patient Advice - It is advisable to reduce the dose progressively to avoid a relapse. - Nicotine-based preparations can cause dependence. - It is advisable to notify your doctor of any symptoms of overdose such as nausea, vomiting, diarrhea, dizziness, weakness, or palpitations. - If chest pain occurs, it is recommended to discontinue treatment and consult a doctor. - Do not smoke during treatment, nor combine chewing gum or tablets with patches. - If nicotine is administered to breastfeeding women, it should be done at least two hours before breastfeeding the child. - Treatment periods longer than 6 months are not recommended. - The medication should not be left where it can be misused, tampered with, or ingested by children, as it can cause severe toxicity that can even be fatal. - Gum should be chewed slowly to avoid absorbing nicotine too quickly. - Treatment should be discontinued if oral problems, persistent indigestion, or severe sore throat occur. - Before chewing gum, it is recommended to wait at least 15 minutes if you have previously consumed coffee or other acidic beverages. - It is recommended not to administer more than 25 pieces of gum per day, and no more than 15 pieces of gum at the beginning of treatment. - Professional advice may be sufficient to help smokers quit. - The duration of treatment and the required dosage depend on the persons dependency, although treatment of at least 3 months is usually required. - It is recommended to evaluate the benefit-risk ratio in patients with cardiovascular problems before starting treatment. Interactions Tobacco smoke appears to act as an enzyme-inducing agent, probably due to the polycyclic aromatic hydrocarbons in the smoke, generated during the partial combustion of plant fiber, and perhaps due to nicotine. By inducing metabolism, primarily the cytochrome P450 isoenzyme CYP1A2, a decrease in pharmacological effects may occur. Similarly, when smoking is stopped, plasma concentrations of drugs metabolized by this route may increase, leading to the occasional appearance of toxic effects. It may therefore be necessary to readjust the dosage of drugs such as oral anticoagulants, benzodiazepines that are metabolized in the liver, caffeine, chlorpromazine, dextropropoxyphene, estrogens, phenacetin, phenazone, flecainide, fluphenazine, haloperidol, imipramine, lidocaine, olanzapine, pentazocine, ritonavir or theophylline. Other reported effects of smoking include reduced diuretic response to furosemide, modification of the pharmacological effect of propranolol, and altered response rates in ulcer healing with H2 antagonists. In diabetic smokers, there is a possibility of a decreased antidiabetic effect of insulin, probably due to increased levels of catecholamines, which oppose the hypoglycemic action, and the difficulty in subcutaneous insulin absorption due to peripheral vasoconstriction. Smokers typically require a 15-30% higher dose to control their blood glucose levels. When smoking is stopped, a reduction in insulin dose is usually necessary. These enzyme-inducing effects have not been observed when nicotine is administered in the form of smoking cessation preparations, so a dosage adjustment of these drugs may be necessary. Nicotine may interact with the following drugs: - Adrenergic agonists and antagonists. Nicotine stimulates adrenal production of cortisol and catecholamines, which can modify the effects of adrenergic drugs. Similarly, the administration of a vasoconstrictor drug, such as an adrenergic agonist, or a vasodilator, such as a beta-blocker, can alter the transdermal absorption of nicotine. - Bupropion. The efficacy and safety of combining bupropion with nicotine have not been studied. In fact, the use of nicotine was an exclusion criterion in the first clinical trials conducted with bupropion. The manufacturers of this drug have reported a possible increased risk of hypertension, with a 6.1% increase compared to 2.5% with bupropion alone. However, limited clinical data indicate that combining bupropion with nicotine patches may achieve better smoking cessation results. If the decision is made to combine nicotine patches with bupropion tablets, weekly blood pressure monitoring is recommended, given the risk of hypertensive crisis. Pregnancy FDA Category D. In studies with monkeys, administration of a 2 mg/kg intravenous bolus of nicotine resulted in fetal acidosis, hypoxia, hypercapnia, and hypotension. Uterine blood flow was reduced by 30% with an infusion of 0.1 µg/kg/minute. Smoking during the last trimester of pregnancy can cause fetal harm, such as growth retardation, risk of spontaneous abortion, and increased perinatal mortality, although its teratogenic potential has not been clearly established. It has been shown that tobacco can also reduce fetal respiratory movements. These effects have also been observed with nicotine gum. Therefore, pregnant women should be advised to completely quit smoking before the third trimester. Due to the inherent risk associated with nicotine replacement therapy, it is recommended that educational and behavioral programs be used before starting this treatment. However, highly dependent pregnant women may need to resort to nicotine replacement therapy. This therapy poses fewer risks than smoking, as the plasma nicotine concentrations achieved are lower and there is no exposure to polycyclic hydrocarbons and carbon monoxide. Smoking cessation, with or without nicotine replacement therapy, should not be undertaken individually by the patient, but rather as part of a medically supervised smoking cessation program. In the third trimester, nicotine has hemodynamic effects, such as changes in fetal heart rate, that can affect the fetus near delivery. Therefore, after the sixth month of pregnancy, nicotine should only be used by pregnant smokers who have not been able to quit smoking in the third trimester, and always under medical supervision. Lactation Nicotine and its metabolites are excreted in breast milk for up to two hours after the last cigarette. Levels in breast milk are 2.9 times higher than those in plasma. It should be noted that the amount of nicotine present in breast milk is lower in users of nicotine-containing medications than in smokers. Nicotine can be absorbed orally by infants to a greater extent than in adults, due to the immaturity of hepatic metabolic mechanisms and the resulting reduction in the first-pass effect. Breastfeeding patients should be advised not to smoke or use nicotine to quit smoking. However, in highly dependent patients who have not been able to quit smoking, the risk to the infant of using nicotine should be assessed and compared with that of tobacco exposure. If you are on replacement therapy, it is recommended to use only the chewing gum or tablets and administer them after breastfeeding. At least two more hours should pass before resuming breastfeeding. A pregnant woman should never begin a nicotine-intensive smoking cessation program without consulting her doctor. Children The safety and efficacy of nicotine preparations in children under 18 years of age have not been evaluated, so their use is not recommended. However, because of the potential benefits of smoking cessation and based on the established efficacy of nicotine replacement therapy in adults, some experts recommend that such therapy could be considered for nicotine-dependent adolescents. Nicotine doses well tolerated by adult smokers during treatment can cause symptoms of severe and even fatal intoxication in young children. Patients should be warned that nicotine preparations should be handled carefully and not stored or disposed of in a way that could be accidentally used or consumed by children. Seniors No specific pharmacokinetic studies have been conducted in the elderly, but adverse effects and relapse rates in patients over 60 years of age are similar to those in younger patients. However, heart disease is more common in these patients, and a slightly increased incidence of asthenia, body aches, and dizziness has been reported. Adverse reactions This medication may cause adverse reactions related to the pharmacological effects of nicotine or the withdrawal effects associated with smoking cessation. Certain reported symptoms, such as depression, irritability, nervousness, restlessness, moodiness, anxiety, drowsiness, loss of concentration, insomnia, and sleep disturbances, may be related to the withdrawal symptoms associated with smoking cessation. The most common adverse reactions to the patches are those at the application site, including transient rash, itching, burning sensation, tingling, numbness, swelling, pain, and hives. Most of these topical reactions are minor and resolve promptly upon patch removal. Pain or heaviness in the extremities or surrounding area where the patch is applied (e.g., the chest) has been reported. Hypersensitivity reactions, including contact dermatitis and allergic reactions, have been reported. In the event of severe or persistent local reactions at the application site (e.g., severe erythema, pruritus, or edema) or generalized skin reactions (e.g., urticaria or generalized rash), patients should discontinue use of the patch and consult a physician. The dose of this medication should be reduced or discontinued if there is a clinically significant increase in cardiovascular or other effects attributed to nicotine. The most characteristic adverse reactions are: - Digestive: It is normal (20-40%) for [DYSPEPSIA], [NAUSEA], [VOMITING] or [GASTRIC HYPERACIDITY] to appear. Less frequent is the appearance of [DRY MOUTH], [ANOREXIA], [DIARRHEA], [CONSTIPATION], [ABDOMINAL PAIN], [FLATULENCE] or [HICCUPATIONS]. Chewing gum can also cause [hypersalivation], symptoms of inflammation of the oral cavity, such as [stomatitis], [glossitis], [periodontitis], [pharyngitis], [esophagitis] and pain in the jaw muscles, due to its high viscosity. These adverse reactions appear at the beginning of treatment, and can be reduced with correct administration of chewing gum. - Neurological/psychological. [DIZZINESS] (3-9%), [HEADACHE] (17-29%), [INSOMNIA] (3-23%), [REDUCED CONCENTRATION] (1-3%) and [IRRITABILITY] are common (1-25%). More rarely (<1%), [EUPHORIA], [DROWSY], [CONFUSION], [DEPRESSION], [PARESTHESIA] and [SEIZURES] have been reported. [DEPENDENCE] syndrome may occur if withdrawal is abrupt or premature. - Cardiovascular. Cases of [ARTERIAL HYPERTENSION] and [EDEMA] have been reported. Occasionally (1-0.1%) [PALPITATIONS] may occur, and more rarely (<0.1%) [CARDIAC ARRHYTHMIA]. Some cases of [ACUTE MYOCARDIAL INFARCTION], [ATRIAL FIBRILLATION] and [STROKE] have been reported in patients treated with nicotine patches. However, a causal relationship with nicotine could not be established. - Respiratory. Some cases of [COUGH] (3-9%), chest congestion and [DYSPNEA] have been reported. Nicotine administered nasally may cause local irritation such as [NASAL CONGESTION], [SNEEZING], mucosal irritation, [PHARYNGITIS], [SINUSITIS], [EPISTAXIS], [CONJUNCTIVITIS], [TASTE DISORDERS] and [SMELL DISORDERS]. These effects occur very frequently (94%) at the beginning of treatment but are reduced with continued use. - Allergic/dermatological. Nicotine may cause [HYPERSENSITIVITY REACTIONS], with itching and erythema, and even [ANGIOEDEMA]. Patches have caused local reactions in certain individuals, including [ERYTHEMA] (14-17%), which disappeared within 24 hours, localized edema (3-4%), [PRURITUS], burning sensation at the application site (35-47%), [CONTACT DERMATITIS] (2-3%), and [VASCULITIS]. In the event of serious adverse reactions, such as [DERMATITIS] (1-7%) or generalized dermatological reactions such as erythema or severe lesions, it is recommended to discontinue treatment. Topical corticosteroids and/or oral antihistamines have been shown to be effective in reversing these symptoms. - Musculoskeletal. The patches have occasionally caused [MYALGIA] and [MUSCLE PAIN] (3-9%). - General. Some cases of [CHEST PAIN], [ASTHENIA], back pain or [EXCESSIVE SWEATING] have been reported. Overdose Symptoms: Nicotine is a highly toxic substance, and doses of 0.6–0.9 mg/kg can be lethal in humans. However, there is considerable interindividual variability, as chronic smokers can tolerate higher doses than children and nonsmokers due to the development of tolerance. In children, a small dose of nicotine can be dangerous and lead to severe and even fatal symptoms. Therefore, it is recommended that these medications be kept out of the reach of children and that if poisoning is suspected, a doctor be consulted immediately. Despite nicotines high toxicity, very little data is available on nicotine poisoning. Poisoning can occur if multiple pieces of gum are chewed at once, multiple lozenges are sucked, multiple patches are applied, or if these devices are combined with each other or with tobacco. If nicotine is ingested, the risk of overdose is low, as it is released slowly in small amounts and inactivated by a first-pass effect. Furthermore, vomiting usually occurs quickly, which prevents nicotine absorption. In general, nicotine poisoning causes the same symptoms as excessive tobacco use. However, it should be noted that tobacco smoke contains other toxic substances such as tar and carbon monoxide. General symptoms of poisoning include nausea, vomiting, diarrhea, abdominal pain, headache, nervousness, irritability, insomnia, dizziness, rapid heartbeat and palpitations, high or low blood pressure, QT interval prolongation, pallor, muscle weakness, sweating, excessive salivation, burning sensation in the throat, visual and hearing disturbances, and dyspnea. In the most severe cases, lethargy, circulatory collapse, seizures, coma, and death from central or peripheral respiratory paralysis or, occasionally, heart failure may occur. Treatment: - Oral forms: There is no specific antidote for nicotine. Nicotine administration should be discontinued immediately, and traditional measures to promote elimination should be instituted. If the patient has not vomited previously and is conscious, the stomach should be emptied quickly by inducing vomiting with syrup of ipecac. In comatose patients with seizures or loss of reflexes, gastric lavage with a large-bore tube is recommended. A suspension of activated charcoal should then be administered. Administration of a saline or sorbitol laxative may also be helpful to speed up intestinal transit. An attempt will be made to keep the individual in a suitable position and warm, to maintain normal body temperature. Symptoms of poisoning should be treated symptomatically. Seizures and excitability can be treated with benzodiazepines, while tachycardia may require a beta-blocker. Bradycardia responds to atropine. Hypotension and vascular collapse should be treated intensively with intravenous fluids or other effective measures. If necessary, in case of respiratory paralysis, artificial respiration will be instituted.