ACTION AND MECHANISM [ANTI-SMOKING], [GANGLIOPLEGIC]. Nicotine is an agonist of nicotinic cholinergic receptors, located primarily in the autonomic ganglia, adrenal medulla, neuromuscular junction, and central nervous system. The effects of nicotine on the body are numerous and varied, depending on the administered dose 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 via the locus coeruleus, increasing cognitive function and alertness. At higher doses, it seems to produce a reward effect originating in the limbic system. Abrupt cessation of tobacco use after a prolonged period leads to 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 cravings are also common. Administering nicotine via patches or gum produces effects similar to those obtained from tobacco, providing those wishing to quit smoking with enough nicotine to reduce withdrawal symptoms. The nicotine dose is gradually reduced until the body can function without it. 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 slight increase in the incidence of fatigue, body aches, and dizziness has been reported. PATIENT ADVICE - It is advisable to reduce the doses gradually, to avoid a relapse. - Nicotine-based preparations can cause dependence. - It is advisable to notify the doctor of any overdose symptoms such as nausea, vomiting, diarrhea, dizziness, weakness or palpitations. - If chest pain occurs, it is recommended to stop treatment and see a doctor. - Smoking should not be done during treatment, nor should chewing gum or tablets be combined 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, handled or ingested by children, as it can produce severe toxicity that can be fatal. CONTRAINDICATIONS - Hypersensitivity to any component of the medication. - Non-smokers or occasional smokers. PREGNANCY FDA Pregnancy Category D. In monkey studies, intravenous bolus administration of 2 mg/kg 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 miscarriage, and increased perinatal mortality, although its teratogenic potential has not been clearly established. Tobacco has also been shown to reduce fetal respiratory movements. These effects have also been observed with nicotine gum. Therefore, pregnant women should be advised to completely stop smoking before the third trimester of pregnancy. Due to the inherent risks associated with nicotine replacement therapy, it is recommended that educational and behavioral programs be used before initiating this treatment. However, in highly dependent pregnant women, nicotine replacement therapy may be necessary. This therapy presents fewer risks than smoking, as the plasma concentrations of nicotine achieved are lower, and there is no exposure to polycyclic aromatic 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, which can affect the fetus near delivery. Therefore, after the sixth month of pregnancy, nicotine should only be used in pregnant smokers who have not been able to quit smoking in the third trimester, and always under medical supervision. PHARMACOKINETICS Oral, transdermal, nasal routes: - Absorption: * Chewing gum: Chewing gum releases the drug uniformly during chewing. The released nicotine is absorbed very rapidly. Some is ingested with saliva, but it has very low bioavailability, as it is partially inactivated in the stomach and intestines and undergoes extensive first-pass hepatic metabolism. Nicotine is barely released from chewing gum if it is swallowed. Nicotine release is highly variable (45-90% at 20-30 minutes) and depends on the intensity and duration of chewing. After administration of 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 binds poorly to plasma proteins (5%). Its Vd when administered intravenously is approximately 2-3 L/kg. Nicotine crosses the blood-brain barrier and the placenta. It is excreted in breast milk. - Metabolism: Nicotine is extensively metabolized in the liver, and to a lesser extent in the lungs and kidneys, very rapidly, resulting in 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 the 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. The Cl is approximately 70 L/hour. 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 impairment: In patients with renal impairment, 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 the 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 relieving the symptoms of nicotine withdrawal syndrome. Although these products mimic the effects of tobacco, they should never be used as substitutes for tobacco. INTERACTIONS Tobacco smoke appears to act as an enzyme inducer, likely due to the polycyclic aromatic hydrocarbons in the smoke, generated during the partial combustion of plant fiber, and perhaps to nicotine. By inducing metabolism, primarily of the cytochrome P450 isoenzyme CYP1A2, a decrease in the pharmacological effects of drugs can occur. Similarly, when smoking is discontinued, plasma concentrations of drugs metabolized via this pathway can increase, which may occasionally lead to toxic effects. It may therefore be necessary to readjust the dosage of drugs such as oral anticoagulants, benzodiazepines 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 a 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 decrease in the antidiabetic effect of insulin, probably due to increased levels of catecholamines, which oppose the hypoglycemic action, and to impaired subcutaneous absorption of insulin due to peripheral vasoconstriction. Patients who smoke often require a 15-30% higher dose to control their blood glucose levels. When smoking is stopped, a reduction in the 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 the adrenal production of cortisol and catecholamines, so it may 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, may alter the transdermal absorption of nicotine. - Bupropion. The efficacy and safety of the combination of bupropion with nicotine have not been studied. In fact, nicotine use was an exclusion criterion in the first clinical trials conducted with bupropion. The manufacturers of this drug have described a possible increased risk of hypertension, with a rate of 6.1% compared to 2.5% for bupropion alone. However, limited clinical data indicate that combining bupropion with nicotine patches may lead to better smoking cessation outcomes. If nicotine patches are combined with bupropion tablets, weekly blood pressure monitoring is recommended due to the risk of hypertensive crisis. 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 women using nicotine replacement therapy than in smokers. Nicotine can be absorbed orally by infants to a greater extent than in adults due to the immaturity of their hepatic metabolic mechanisms and the consequent reduction of the first-pass effect. Breastfeeding mothers should be advised not to smoke or use nicotine to quit. However, in patients with severe nicotine dependence who have not been able to quit smoking, the risk to the infant from nicotine use should be assessed and compared to the risk of exposure to tobacco smoke. If nicotine replacement therapy is used, it is recommended to use only gum or lozenges, and to administer them after breastfeeding. At least two more hours should pass before breastfeeding the child again. A pregnant woman should never start a nicotine smoking cessation program without consulting a doctor. CHILDREN The safety and efficacy of nicotine preparations in individuals under 18 years of age have not been evaluated, and therefore 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 in adolescents dependent on nicotine. Doses of nicotine well tolerated by adult smokers during treatment can cause symptoms of severe and even fatal poisoning in young children. Patients should be advised that nicotine preparations must be handled with care and not stored or disposed of in a way that children could accidentally use or ingest them. GUIDELINES FOR PROPER ADMINISTRATION The patient must stop smoking completely during nicotine therapy due to the risk of adverse reactions to nicotine from the increased plasma nicotine levels. Combining patches with gum or lozenges is not recommended. POSOLOGY - Adults, oral: PRECAUTIONS - [RENAL IMPAIRMENT]. Nicotine and its metabolites are eliminated in the urine, so decreased renal function could lead to their accumulation. Because the metabolites are also active, adverse reactions could occur. No significant differences in the incidence of adverse reactions have been described in patients with mild or moderate renal impairment (creatinine clearance between 30-90 ml/minute), but close monitoring of these patients is recommended. In patients with severe renal impairment (creatinine clearance less than 30 ml/minute), safety and efficacy have not been evaluated, so its use is not recommended (See Contraindications). - [HEPATIC IMPAIRMENT]. Nicotine is extensively metabolized in the liver, so accumulation could occur in cases of hepatic impairment. Extreme caution is advised in patients with mild or moderate hepatic impairment, monitoring for the possible appearance of adverse reactions. Safety and efficacy have not been evaluated in patients with severe hepatic impairment; therefore, its use is not recommended (See Contraindications). [HEART DISEASE]. Nicotine has cardiac stimulant and vasoconstrictor effects, and therefore may worsen cardiovascular conditions. Occasionally, cases of cardiovascular adverse reactions with nicotine have been reported. However, oral or transdermal nicotine administration does not appear to be associated with a particularly significant risk of cardiovascular events. Patients with heart disease should be advised to quit smoking, if possible, without nicotine replacement therapy. However, if this is not possible, it is recommended to carefully assess the need for treatment, weighing 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 thromboangiitis obliterans, Prinzmetals angina, or Raynauds disease. Likewise, special caution is advised in patients with high blood pressure, as nicotine may increase blood pressure. If the patient experiences a worsening of any of these symptoms, it is advisable to discontinue treatment (see Contraindications). Other contraindications include pheochromocytoma, hyperthyroidism, or any condition that may be exacerbated by catecholamines, such as type 1 diabetes mellitus. Nicotine stimulates the production and release of catecholamines in the adrenal medulla. This can lead to a worsening of symptoms such as those associated with pheochromocytoma, hyperthyroidism, or diabetes. In general, nicotine administration presents fewer risks than continued smoking, but it is recommended to assess the benefit-risk ratio beforehand in these patients. Nicotine delays the healing of gastroduodenal ulcers and other inflammatory processes of the stomach, such as gastritis. Therefore, its use in these patients is recommended only if the benefits outweigh the potential risks. Dependence: Any nicotine preparation carries a risk of dependence, although due to the lower plasma levels achieved, it is less likely than with tobacco itself. However, abrupt withdrawal 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 to stop treatment until there is reasonable certainty that a withdrawal syndrome will not occur. - [HYPERSENSITIVITY REACTIONS]. Caution is advised in patients susceptible to developing [ANGIOEDEMA] or [URTICARIA]. - Inflammation of the upper digestive tract, such as [ESOPHAGITIS] or [PHARYNGITIS]. Nicotine may exacerbate these conditions. - Patients with dentures or any chewing impairment may have difficulty chewing gum; therefore, it is recommended to use other forms of administration such as patches. PRECAUTIONS RELATING TO EXCIPIENTS - Because it contains butylhydroxytoluene as an excipient, it may produce local skin reactions, such as contact dermatitis, or irritation of the eyes or mucous membranes. ADVERSE REACTIONS This medicine may cause adverse reactions related to the pharmacological effects of nicotine or to withdrawal effects associated with quitting smoking. Certain reported symptoms such as depression, irritability, nervousness, restlessness, mood swings, anxiety, drowsiness, impaired concentration, insomnia, and sleep disturbances may be related to withdrawal symptoms associated with quitting smoking. The most common adverse reactions to the patches occur at the application site, including transient rash, itching, burning, tingling, numbness, swelling, pain, and hives. Most of these topical reactions are minor and resolve quickly upon removal of the patch. Pain or a feeling of heaviness in the limbs or in the area around where the patch is applied (e.g., on the chest) has been reported. Hypersensitivity reactions, including contact dermatitis and allergic reactions, have also 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 patches and consult a doctor. The dose of this medication should be reduced or discontinued if there is a clinically significant increase in cardiovascular effects or other effects attributed to nicotine. The most characteristic adverse reactions are: - Digestive: It is normal (20-40%) to experience dyspepsia, nausea, vomiting, or gastric hyperacidity. Less frequent are the appearance of dry mouth, anorexia, diarrhea, constipation, abdominal pain, flatulence, or hiccups. Chewing gum can also produce hypersalivation, symptoms of oral cavity inflammation such as stomatitis, glossitis, periodontitis, pharyngitis, esophagitis, and jaw muscle pain due to its high viscosity. These adverse reactions appear at the beginning of treatment and can be reduced with proper administration of the gum. Neurological/psychological: It is common (1-25%) to experience dizziness (3-9%), headache (17-29%), insomnia (3-23%), decreased concentration (1-3%), and irritability. In rarer cases (<1%), euphoria, drowsiness, confusion, depression, paresthesia, and seizures have been reported. Dependence syndrome may occur if withdrawal is abrupt or premature. Cardiovascular: Cases of hypertension and edema have been reported. Palpitations may occur occasionally (1-0.1%), 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, dysgeusia, and parosmia. These effects occur very frequently (94%) at the start of treatment but decrease with continued use. Allergic/dermatological reactions: Nicotine may cause hypersensitivity reactions, with pruritus and erythema, and even angioedema. The patches have caused local reactions in some individuals, such as erythema (14-17%), which resolved within 24 hours, localized edema (3-4%), pruritus, a burning sensation at the application site (35-47%), contact dermatitis (2-3%), and vasculitis. In case of severe adverse reactions, such as dermatitis (1-7%) or generalized dermatological reactions such as erythema or severe lesions, it is recommended to discontinue treatment. The administration of topical corticosteroids and/or oral antihistamines has been shown to be effective in reversing these symptoms. Musculoskeletal: The patches have occasionally caused myalgia and musculoskeletal pain (3-9%). General: Some cases of precordial 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 significant interindividual variability, as chronic smokers can tolerate higher doses than children and non-smokers due to the development of tolerance. In children, even 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 a doctor be consulted immediately if poisoning is suspected. Despite the high toxicity of nicotine, very little data is available on nicotine poisoning. Poisoning can occur if several pieces of gum are chewed at once, several lozenges are sucked, several 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 is inactivated by a first-pass effect. In addition, vomiting usually occurs rapidly, preventing the absorption of nicotine. In general, nicotine poisoning produces 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, tachycardia and palpitations, hypertension or hypotension, QT interval prolongation, paleness, muscle weakness, sweating, excessive salivation, burning in the throat, visual and auditory disturbances, and dyspnea. In more 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 elimination measures should be implemented. If the patient has not vomited previously and is conscious, gastric emptying should be performed promptly by inducing vomiting with ipecac syrup. In comatose patients with seizures or loss of reflexes, gastric lavage with a large-bore tube is recommended. An activated charcoal suspension should then be administered. Administration of a saline or sorbitol laxative may also be helpful to accelerate intestinal transit. The individual should be kept in a comfortable 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 by administering intravenous fluids or other effective measures. If necessary, in cases of respiratory paralysis, artificial respiration should be initiated. COMPOSITION NICOTINE: 2 MILLIGRAMS - POLACRILEX BUTYL HYDROXYTOLUENE (E-321) (EXCIPIENT: 0 SODIUM SALTS (EXCIPIENT): 11.5 MILLIGRAMS SORBITOL (E-420) (EXCIPIENT): 200 MILLIGRAMS