AGENTS ACTING N-CHOLINERGIC RECEPTORS. NICOTINE TOXICOLOGY (Benzohexonium, Pirilenum, Hygronium, Pentaminum, Tubocurarini chloridum, Pipecuronii bromide (Arduanum, Mellictinum, Dithylinum)
Agents acting N-cholinergic receptors. Nicotine toxicology
Agents acting n-cholinergic receptors.
Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae), predominantly in tobacco, and in lower quantities in tomato, potato, eggplant (aubergine), and green pepper.
Site Predominant Tone Most Common Effect of Nicotine
Arterioles Sympathetic Vasoconstriction, hypertension
Veins Sympathetic Vasoconstriction, increased venous return
Heart Parasympathetic Tachycardia
GI Tract Parasympathetic Increased motility and secretions
Effects of Nicotine on the CNS
There is only anecdotal evidence about abuse or addiction with nicotine gum or nicotine patches.
Lobeline is a natural alkaloid found in “Indian tobacco” (Lobelia inflata), “Devil’s tobacco” (Lobelia tupa), “cardinal flower” (Lobelia cardinalis), “great lobelia” (Lobelia siphilitica), and Hippobroma longiflora. In its pure form it is a white amorphous powder which is freely soluble in water.
Lobeline has been used as a smoking cessation aid,[1][2][3] and may have application in the treatment of other drug addictions such as addiction to amphetamines,[4][5] cocaine[6] or alcohol.[7]
Lobeline has multiple mechanisms of action, acting as a VMAT2 ligand,[8][9][10] which stimulates dopamine release to a moderate extent when administered alone, but reduces the dopamine release caused by methamphetamine.[11][12] It also inhibits the reuptake of dopamine and serotonin,[13] and acts as a mixed agonist–antagonist at nicotinic acetylcholine receptors [14][15] to which it binds at the subunit interfaces of the extracellular domain. [16] and an antagonist at μ-opioid receptors.[17]
LOBELIN (Lobelinum).
Alkaloid contained in the plant Lobelia inflata, herewith. kolokolchikovyh (Campanulaceae). Optically active. Rasemat lobelina receive synthetic means.
In clinical practice using lobelina hydrochloride (Lobelini hydrochloridum).
l-1- benzoilmetil-6- Methyl 2 – (2-hydroxy yl) – piperidine hydrochloride.
Synonyms : Lobesil, Antisol, Atmulatin, Bantron, Lobatox, Lobeline, Lobelinum hydrochloricum, Lobesilum, Lobeton, Lobidan and others.
The white crystalline powder bitter taste, and odourless. It is soluble in water (1:100), is soluble in alcohol (1:10).
Provides specific stimulation of the nerve of the vegetative nervous system and karotidnye klubochki (see also Ganglioblokiruyuschie drugs), accompanied by the excitation of respiratory and other centres suffering brain.
Stirring while wandering psyche, lobelin is slowing heartbeat and lowering blood pressure. Later, blood pressure may rise slightly from narrowing vessels due to the drug to excite sympathetic nerve, and adrenal glands. In high doses lobelin brings emetic center, is deeply respiratory depression, convulsions toniko- klonicheskie, stopping the heart.
With the ability to bring a breath lobelin was suggested as a means for analepticheskogo with reflex stops breathing (mainly by inhalation of irritating substances, carbon monoxide poisoning, etc.).
Recently, a respiratory stimulant is rarely used. In reducing or stopping breathing, developing as a result of progressive depletion of the respiratory center, a lobelina not shown.
Applied intravenously, intramuscularly less.
Adults enter for 0,003-0,005 grams (0,3-0,5 ml 1% solution), children depending on the age of 0,001-0,003 grams (0,1-0,3 ml 1% solution). Intravenous introduction of a more efficient manner.
Intravenous lobelin enter slowly (1 ml for 1-2 min). Rapid introduction is sometimes temporary stops breathing (patients), and develop side effects of the cardiovascular system (aetiology, violation conductivity).
The maximum dose for adults : in the non-off 0,005 g, 0.01 g daily; In muscle-off 0.01 grams daily 0.02 g.
The drug is not suitable for organic expressed Cardiovascular diseases.
Lobelin and others similar to it on the substance of gangliostimuliruyuschie (tsitizin, Anabasine) found in recent years as aids to smoking cessation.
Tablets containing at 0,002 g (2 mg) lobelina hydrochloride, produced for this purpose entitled “Lobesil (Tabulettae” Lobesilum “). They covered shell (atsetilftaliltsellyulozoy) that the flow of drugs through the stomach intact and rapid release in the gut.
After taking into smoking cessation pill to 1 4-5 times a day for 7-10 days. Subsequent to receiving tablets continue 2-4 weeks with a gradual decrease its frequency. When relapse rate can be repeated.
Application pills lobelinom, tsitizinom and anabizinom contraindicated in acute gastric ulcer and duodenal ulcer, organic diseases, cardiovascular system.
Treatment must be carried out under the supervision of a doctor.
In overdose possible side effects : weakness, irritability, dizziness, nausea, vomiting.
Method of issuance : 1% solution in capsules and liquid pumps for 1 ml; Pill (lobesil) to 0,002 grams (2 mg).
Storage : List A.
The most common side effects of cholinergic antagonists
Nicotine is a potent parasympathomimetic alkaloid found in the nightshade family of plants (Solanaceae). It acts as a nicotinic acetylcholine receptor agonist. It is made in the roots and accumulates in the leaves of the plants. It constitutes approximately 0.6–3.0% of the dry weight of tobacco[1] and is present in the range of 2–7 µg/kg of various edible plants.[2] It functions as an antiherbivore chemical; therefore, nicotine was widely used as an insecticide in the past[3][4][5] and nicotine analogs such as imidacloprid are currently widely used.
In smaller doses (an average cigarette yields about 1 mg of absorbed nicotine), the substance acts as a stimulant in mammals, while high amounts (30–60 mg[6]) can be fatal.[7] This stimulant effect is likely a major contributing factor to the dependence-forming properties of tobacco smoking. According to the American Heart Association, nicotine addiction has historically been one of the hardest addictions to break, while the pharmacological and behavioral characteristics that determine tobacco addiction are similar to those determining addiction to heroin and cocaine. The nicotine content of popular American-brand cigarettes has slowly increased over the years, and one study found that there was an average increase of 1.78% per year between the years of 1998 and 2005. This was found for all major market categories of cigarettes.[8]
Research in 2011 has found that nicotine inhibits chromatin-modifying enzymes (class I and II histone deacetylases) which increases the ability of cocaine to cause an addiction.[9]
History and name
Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after the French ambassador in Portugal, Jean Nicot de Villemain, who sent tobacco and seeds to Paris in 1560, and who promoted their medicinal use. The tobacco and seeds were brought to ambassador Nicot from Brazil by Luis de Gois, a Portuguese colonist in São Paulo. Nicotine was first isolated from the tobacco plant in 1828 by physician Wilhelm Heinrich Posselt and chemist Karl Ludwig Reimann of Germany, who considered it a poison.[10][11] Its chemical empirical formula was described by Melsens in 1843,[12] its structure was discovered by Adolf Pinner and Richard Wolffenstein in 1893,[13][clarificatioeeded] and it was first synthesized by Amé Pictet and A. Rotschy in 1904.[14]
Historical use of nicotine as an insecticide
Tobacco was introduced to Europe in 1559, and by the late 17th century, it was used not only for smoking but also as an insecticide. After World War II, over 2,500 tons of nicotine insecticide (waste from the tobacco industry) were used worldwide, but by the 1980s the use of nicotine insecticide had declined below 200 tons. This was due to the availability of other insecticides that are cheaper and less harmful to mammals.[4]
Currently, nicotine is a permitted pesticide for organic farming because it is derived from a botanical source. Nicotine sulfate sold for use as a pesticide is labeled “DANGER,” indicating that it is highly toxic.[5] However, in 2008, the EPA received a request to cancel the registration of the last nicotine pesticide registered in the United States.[15] This request was granted, and after 1 January 2014, this pesticide will not be available for sale.[16]
Chemistry
Nicotine is a hygroscopic, oily liquid that is miscible with water in its base form. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water soluble, for example nicotine sulfate which, being a solid, is easier to handle in its use as an insecticide. (For retail use it is sold as solution in water ready for spraying.)[5] Its flash point is 95°C and its auto-ignition temperature is 244°C.[17]
Optical activity
Nicotine is optically active, having two enantiomeric forms. The naturally occurring form of nicotine is levorotatory with a specific rotation of [α]D = –166.4° ((−)-nicotine). The dextrorotatory form, (+)-nicotine is physiologically less active than (–)-nicotine. (−)-nicotine is more toxic than (+)-nicotine.[18] The salts of (+)-nicotine are usually dextrorotatory.
Biosynthesis
The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that compose nicotine. Metabolic studies show that the pyridine ring of nicotine is derived from niacin (nicotinic acid) while the pyrrolidone is derived from N-methyl-Δ1-pyrrollidium cation.[19][20] Biosynthesis of the two component structures proceeds via two independent syntheses, the NAD pathway for niacin and the tropane pathway for N-methyl-Δ1-pyrrollidium cation.
The NAD pathway in the genus nicotiana begins with the oxidation of aspartic acid into α-imino succinate by aspartate oxidase (AO). This is followed by a condensation with glyceraldehyde-3-phosphate and a cyclization catalyzed by quinolinate synthase (QS) to give quinolinic acid. Quinolinic acid then reacts with phosphoriboxyl pyrophosphate catalyzed by quinolinic acid phosphoribosyl transferase (QPT) to form niacin mononucleotide (NaMN). The reactioow proceeds via the NAD salvage cycle to produce niacin via the conversion of nicotinamide by the enzyme nicotinamidase.
The N-methyl-Δ1-pyrrollidium cation used in the synthesis of nicotine is an intermediate in the synthesis of tropane-derived alkaloids. Biosynthesis begins with decarboxylation of ornithine by ornithine decarboxylase (ODC) to produce putrescine. Putrescine is then converted into N-methyl putrescine via methylation by SAM catalyzed by putrescine N-methyltransferase (PMT). N-methylputrescine then undergoes deamination into 4-methylaminobutanal by the N-methylputrescine oxidase (MPO) enzyme, 4-methylaminobutanal then spontaneously cyclize into N-methyl-Δ1-pyrrollidium cation.
The final step in the synthesis of nicotine is the coupling between N-methyl-Δ1-pyrrollidium cation and niacin. Although studies conclude some form of coupling between the two component structures, the definite process and mechanism remains undetermined. The current agreed theory involves the conversion of niacin into 2,5-dihydropyridine through 3,6-dihydronicotinic acid. The 2,5-dihydropyridine intermediate would then react with N-methyl-Δ1-pyrrollidium cation to form enantiomerically pure (–)-nicotine.[21]
Pharmacokinetics
Side effects of nicotine.[22]
As nicotine enters the body, it is distributed quickly through the bloodstream and crosses the blood–brain barrier reaching the brain within 10–20 seconds after inhalation.[23] The elimination half-life of nicotine in the body is around two hours.[24]
The amount of nicotine absorbed by the body from smoking depends on many factors, including the types of tobacco, whether the smoke is inhaled, and whether a filter is used. For chewing tobacco, dipping tobacco, snus and snuff, which are held in the mouth between the lip and gum, or taken in the nose, the amount released into the body tends to be much greater than smoked tobacco.[clarificatioeeded] Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine.
Other primary metabolites include nicotine N’-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide.[25] Under some conditions, other substances may be formed such as myosmine.[26]
Glucuronidation and oxidative metabolism of nicotine to cotinine are both inhibited by menthol, an additive to mentholated cigarettes, thus increasing the half-life of nicotine in vivo.[27]
Detection of use
Medical detection
Nicotine can be quantified in blood, plasma, or urine to confirm a diagnosis of poisoning or to facilitate a medicolegal death investigation. Urinary or salivary cotinine concentrations are frequently measured for the purposes of pre-employment and health insurance medical screening programs. Careful interpretation of results is important, since passive exposure to cigarette smoke can result in significant accumulation of nicotine, followed by the appearance of its metabolites in various body fluids.[28][29] Nicotine use is not regulated in competitive sports programs, yet the drug has been shown to have a significant beneficial effect on athletic endurance in subjects who have not used nicotine before.[30]
Pharmacodynamics
Nicotine acts on the nicotinic acetylcholine receptors, specifically the ganglion type nicotinic receptor and one CNS nicotinic receptor. The former is present in the adrenal medulla and elsewhere, while the latter is present in the central nervous system (CNS). In small concentrations, nicotine increases the activity of these receptors. Nicotine also has effects on a variety of other neurotransmitters through less direct mechanisms.
Effect of nicotine on dopaminergic neurons.
By binding to nicotinic acetylcholine receptors, nicotine increases the levels of several neurotransmitters – acting as a sort of “volume control”. It is thought that increased levels of dopamine in the reward circuits of the brain are responsible for the apparent euphoria and relaxation, and addiction caused by nicotine consumption. Nicotine has a higher affinity for acetylcholine receptors in the brain than those in skeletal muscle
, though at toxic doses it can induce contractions and respiratory paralysis.[31] Nicotine’s selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.[32]
Tobacco smoke contains anabasine, anatabine, and nornicotine. It also contains the monoamine oxidase inhibitors harman and norharman.[33] These beta-carboline compounds significantly decrease MAO activity in smokers.[33][34] MAO enzymes break down monoaminergic neurotransmitters such as dopamine, norepinephrine, and serotonin. It is thought that the powerful interaction between the MAOIs and the nicotine is responsible for most of the addictive properties of tobacco smoking.[35] The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats.[36]
Chronic nicotine exposure via tobacco smoking up-regulates alpha4beta2* nAChR in cerebellum and brainstem regions[37][38] but not habenulopeduncular structures.[39] Alpha4beta2 and alpha6beta2 receptors, present in the ventral tegmental area, play a crucial role in mediating the reinforcement effects of nicotine.[40]
In the sympathetic nervous system
Nicotine also activates the sympathetic nervous system,[41] acting via splanchnic nerves to the adrenal medulla, stimulates the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts oicotinic acetylcholine receptors, causing the release of epinephrine (and noradrenaline) into the bloodstream. Nicotine also has an affinity for melanin-containing tissues due to its precursor function in melanin synthesis or due to the irreversible binding of melanin and nicotine. This has been suggested to underlie the increased nicotine dependence and lower smoking cessation rates in darker pigmented individuals. However, further research is warranted before a definite conclusive link can be inferred.[42]
Effect of nicotine on chromaffin cells.
By binding to ganglion type nicotinic receptors in the adrenal medulla nicotine increases flow of adrenaline (epinephrine), a stimulating hormone and neurotransmitter. By binding to the receptors, it causes cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and thus the release of epinephrine (and norepinephrine) into the bloodstream. The release of epinephrine (adrenaline) causes an increase in heart rate, blood pressure and respiration, as well as higher blood glucose levels.[43]
Nicotine is the natural product of tobacco, having a half-life of 1 to 2 hours. Cotinine is an active metabolite of nicotine that remains in the blood for 18 to 20 hours, making it easier to analyze due to its longer half-life.[44]
Psychoactive effects
Further information: Psychoactive drug
Nicotine’s mood-altering effects are different by report: in particular it is both a stimulant and a relaxant.[45] First causing a release of glucose from the liver and epinephrine (adrenaline) from the adrenal medulla, it causes stimulation. Users report feelings of relaxation, sharpness, calmness, and alertness.[46] Like any stimulant, it may very rarely cause the often uncomfortable neuropsychiatric effect of akathisia. By reducing the appetite and raising the metabolism, some smokers may lose weight as a consequence.[47][48]
When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds and immediately stimulates the release of many chemical messengers such as acetylcholine, norepinephrine, epinephrine, vasopressin, histamine, arginine, serotonin, dopamine, autocrine agents, and beta-endorphin.[49] This release of neurotransmitters and hormones is responsible for most of nicotine’s effects. Nicotine appears to enhance concentration[50] and memory due to the increase of acetylcholine. It also appears to enhance alertness due to the increases of acetylcholine and norepinephrine. Arousal is increased by the increase of norepinephrine. Pain is reduced by the increases of acetylcholine and beta-endorphin. Anxiety is reduced by the increase of beta-endorphin. Nicotine also extends the duration of positive effects of dopamine[51] and increases sensitivity in brain reward systems.[52] Most cigarettes (in the smoke inhaled) contain 1 to 3 milligrams of nicotine.[53]
Research suggests that, when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine.[54] This stimulates nerve transmission. When they wish to relax, they take deep puffs, which produce a high level of blood nicotine, which depresses the passage of nerve impulses, producing a mild sedative effect. At low doses, nicotine potently enhances the actions of norepinephrine and dopamine in the brain, causing a drug effect typical of those of psychostimulants. At higher doses, nicotine enhances the effect of serotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use.
Technically, nicotine is not significantly addictive, as nicotine administered alone does not produce significant reinforcing properties.[55] However, after coadministration with an MAOI, such as those found in tobacco, nicotine produces significant behavioral sensitization, a measure of addiction potential. This is similar in effect to amphetamine.[35]
A 21 mg patch applied to the left arm. The Cochrane Collaboration finds that NRT increases a quitter’s chance of success by 50 to 70%.[56] But in 1990, researchers found that 93% of users returned to smoking within six months.[57]
Nicotine gum, usually in 2-mg or 4-mg doses, and nicotine patches
are available, as well as smokeless tobacco, nicotine lozenges and electronic cigarettes.
Side effects
Nicotine increases blood pressure and heart rate in humans.[58] Nicotine can stimulate abnormal proliferation of vascular endothelial cells, similar to that seen in atherosclerosis.[59] Nicotine induces potentially atherogenic genes in human coronary artery endothelial cells.[60] Nicotine could cause microvascular injury through its action oicotinic acetylcholine receptors (nAChRs),[61] but other mechanisms are also likely at play.
A study on rats showed that nicotine exposure abolishes the beneficial and protective effects of estrogen on the hippocampus,[62] an estrogen-sensitive region of the brain involved in memory formation and retention.
Dependence and withdrawal
See also: Smoking cessation
Modern research shows that nicotine acts on the brain to produce a number of effects. Specifically, research examining its addictive nature has been found to show that nicotine activates the mesolimbic pathway (“reward system”) – the circuitry within the brain that regulates feelings of pleasure and euphoria.[63]
Dopamine is one of the key neurotransmitters actively involved in the brain. Research shows that by increasing the levels of dopamine within the reward circuits in the brain, nicotine acts as a chemical with intense addictive qualities. In many studies it has been shown to be more addictive than cocaine and heroin.[64][65][66] Like other physically addictive drugs, nicotine withdrawal causes downregulation of the production of dopamine and other stimulatory neurotransmitters as the brain attempts to compensate for artificial stimulation. As dopamine regulates the sensitivity of nicotinic acetylcholine receptors decreases. To compensate for this compensatory mechanism, the brain in turn upregulates the number of receptors, convoluting its regulatory effects with compensatory mechanisms meant to counteract other compensatory mechanisms. An example is the increase in norepinephrine, one of the successors to dopamine, which inhibit reuptake of the glutamate receptors,[67] in charge of memory and cognition. The net effect is an increase in reward pathway sensitivity, the opposite of other addictive drugs such as cocaine and heroin, which reduce reward pathway sensitivity.[52] This neuronal brain alteration can persist for months after administration ceases.
A study found that nicotine exposure in adolescent mice retards the growth of the dopamine system, thus increasing the risk of substance abuse during adolescence.[68]
Some have been able to restart their natural dopamine production and bypass months or years of depression caused by nicotine withdrawal by using a combination of two over-the-counter supplements: 5-HTP (5-Hydroxytryptophan also known as oxitriptan) and L-Tyrosine (para-hydroxyphenylalanine). Studies of the combination have been conducted only on general depression[69] and no one has yet measured the effects specifically oicotine withdrawal-related depression. However, anecdotal evidence suggests that the combination can be effective. In addition to being a natural and low-cost alternative to prescription anti-depressants, this protocol also has the benefit of being short-term in that the treatment is only necessary for a few months after nicotine abatement. Certain side effects, especially negative drug interactions, have been found with 5-HTP, so this treatment should not be undertaken in combination with any prescription medication or without specific approval from a doctor.
A model of a nicotine molecule
Because of the severe addictions and the harmful effects of smoking, vaccination protocols have been developed. The principle operates under the premise that if an antibody is attached to a nicotine molecule, it will be prevented from diffusing through the capillaries, thus making it less likely that it ever affects the brain by binding to nicotinic acetylcholine receptors.
These include attaching the nicotine molecule as a hapten to a protein carrier such as Keyhole limpet hemocyanin or a safe modified bacterial toxin to elicit an active immune response. Often it is added with bovine serum albumin.
Additionally, because of concerns with the unique immune systems of individuals being liable to produce antibodies against endogenous hormones and over the counter drugs, monoclonal antibodies have been developed for short term passive immune protection. They have half-lives varying from hours to weeks. Their half-lives depend on their ability to resist degradation from pinocytosis by epithelial cells.[70]
Toxicology
The LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 30–60 mg (0.5–1.0 mg/kg) can be a lethal dosage for adult humans.[6][71] Nicotine therefore has a high toxicity in comparison to many other alkaloids such as cocaine, which has an LD50 of 95.1 mg/kg when administered to mice. It is unlikely that a person would overdose on nicotine through smoking alone, although overdose can occur through combined use of nicotine patches or nicotine gum and cigarettes at the same time.[7] Spilling a high concentration of nicotine onto the skin can cause intoxication or even death, since nicotine readily passes into the bloodstream following dermal contact.[72]
Historically, nicotine has not been regarded as a carcinogen and the IARC has not evaluated nicotine in its standalone form or assigned it to an official carcinogen group. While no epidemiological evidence supports that nicotine alone acts as a carcinogen in the formation of human cancer (on the contrary, a mechanism of urinary excretion of nicotine metabolites was identified as the link between smoking and bladder cancer [73]), research over the last decade has identified nicotine’s carcinogenic potential in animal models and cell culture.[74][75] Nicotine has beeoted to directly cause cancer through a number of different mechanisms such as the activation of MAP Kinases.[76] Indirectly, nicotine increases cholinergic signalling (and adrenergic signalling in the case of colon cancer[77]), thereby impeding apoptosis (programmed cell death), promoting tumor growth, and activating growth factors and cellular mitogenic factors such as 5-LOX, and EGF. Nicotine also promotes cancer growth by stimulating angiogenesis and neovascularization.[78][79] In one study, nicotine administered to mice with tumors caused increases in tumor size (twofold increase), metastasis (nine-fold increase), and tumor recurrence (threefold increase).[80]
The teratogenic properties of nicotine has been investigated. According to a study of ca. 77,000 pregnant women in Denmark[citatioeeded], women who used nicotine gum and patches during the early stages of pregnancy were found to face an increased risk of having babies with birth defects. The study showed that women who used nicotine-replacement therapy in the first 12 weeks of pregnancy had a 60% greater risk of having babies with birth defects compared to women who were non-smokers.
Tobacco use among pregnant women has also been correlated to increased frequency of ADHD. Children born to mothers who used tobacco were two and a half times more likely to be diagnosed with ADHD.[81] Froelich estimated that “exposure to higher levels of lead and prenatal tobacco each accounted for 500,000 additional cases of ADHD in U.S. children”.[82]
Effective April 1, 1990, the Office of Environmental Health Hazard Assessment (OEHHA) of the California Environmental Protection Agency added nicotine to the list of chemicals known to cause developmental toxicity.[83]
Therapeutic uses
The primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with the damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, electronic/substitute cigarettes or nasal sprays in an effort to wean them off their dependence.
However, in a few situations, smoking has been observed to be of therapeutic value. These are often referred to as “Smoker’s Paradoxes“.[84] Although in most cases the actual mechanism is understood only poorly or not at all, it is generally believed that the principal beneficial action is due to the nicotine administered, and that administration of nicotine without smoking may be as beneficial as smoking, without the higher risk to health due to tar and other ingredients found in tobacco.
For instance, studies suggest that smokers require less frequent repeated revascularization after percutaneous coronary intervention (PCI).[84] Risk of ulcerative colitis has been frequently shown to be reduced by smokers on a dose-dependent basis; the effect is eliminated if the individual stops smoking.[85][86] Smoking also appears to interfere with development of Kaposi’s sarcoma in patients with HIV.[87][88]
Nicotine reduces the chance of preeclampsia,[89] and atopic disorders such as allergic asthma.[90][dubious ] A plausible mechanism of action in these cases may be nicotine acting as an anti-inflammatory agent, and interfering with the inflammation-related disease process, as nicotine has vasoconstrictive effects.[91]
Tobacco smoke has been shown to contain compounds capable of inhibiting monoamine oxidase, which is responsible for the degradation of dopamine in the human brain. When dopamine is broken down by MAO-B, neurotoxic by-products are formed, possibly contributing to Parkinson’s and Alzheimers disease.[92]
Many such papers regarding Alzheimer’s disease[93] and Parkinson’s Disease[94] have been published. While tobacco smoking is associated with an increased risk of Alzheimer’s disease,[95] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer’s disease.[96] Nicotine has been shown to delay the onset of Parkinson’s disease in studies involving monkeys and humans.[97][98][99] A study has shown a protective effect of nicotine itself oeurons due to nicotine activation of α7-nAChR and the PI3K/Akt pathway which inhibits apoptosis-inducing factor release and mitochondrial translocation, cytochrome c release and caspase 3 activation.[100]
Studies have indicated that nicotine can be used to help adults suffering from autosomal dominant nocturnal frontal lobe epilepsy. The same areas that cause seizures in that form of epilepsy are responsible for processing nicotine in the brain.[101]
Studies suggest a correlation between smoking and schizophrenia, with estimates near 75% for the proportion of schizophrenic patients who smoke. Although the nature of this association remains unclear, it has been argued that the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine.[102][103] Other research found that mildly dependent users got some benefit from nicotine, but not those who were highly dependent.[104]
Research at Duke University Medical Center found that nicotine may improve the symptoms of depression.[105] Nicotine appears to improve ADHD symptoms. Some studies have focused on benefits of nicotine therapy in adults with ADHD.[106]
While acute/initial nicotine intake causes activation of nicotine receptors, chronic low doses of nicotine use leads to desensitisation of nicotine receptors (due to the development of tolerance) and results in an antidepressant effect, with research showing low dose nicotine patches being an effective treatment of major depressive disorder ion-smokers.[107]
Nicotine (in the form of chewing gum or a transdermal patch) has been explored as an experimental treatment for OCD. Small studies show some success, even in otherwise treatment-refractory cases.[108][109][110]
The relationship between smoking and inflammatory bowel disease has been firmly established, but remains a source of confusion among both patients and doctors. It is negatively associated with ulcerative colitis but positively associated with Crohn’s disease. In addition, it has opposite influences on the clinical course of the two conditions with benefit in ulcerative colitis but a detrimental effect in Crohn’s disease.[111][112]
Site Predominant Tone Most Common Effect of Nicotine
Arterioles Sympathetic Vasoconstriction, hypertension
Veins Sympathetic Vasoconstriction, increased venous return
Heart Parasympathetic Tachycardia
GI Tract Parasympathetic Increased motility and secretions
Effects of Nicotine on the CNS
Cellular Events following Cholinergic Receptor Activation
§ Membrane Depolarization leading to muscle contraction
§ Nicotinic (muscle) receptor’s cation ion channel opening
§ Depolarization: postsynaptic cell activation
§ Nicotinic (muscle) receptor’s cation ion channel opening
One class of blocker produces a depolarization block: Nicotine could produce this effect.
For essential hypertension, ganglionic blockers have been replaced by better drugs.
|
vasodilatation; increased peripheral blood flow; hypotension |
||
|
dilatation; blood pooling; decreased venous return; decreased cardiac output |
||
|
reduced tone and motility; constipation; decreased secretions |
||
The majority of the drugs used to reduce the effects of acetylcholine inhibit specifically certain types of acetylcholine receptors and can be named cholinolytic or cholinergic antagonists. Others inhibit acetylcholine release at the synaptic level.
PHARMACOLOGY OF NEUROMUSCULAR TRANSMISSION
I. Introduction and History
II. Pharmacology of Competitive Neuromuscular blockers
1. d-tubocurarine, metocurine, pancuronium
a. Long lasting duration of blockade
2. Vecuronium, atracurium, rocuronium
B. Actions on skeletal muscles:
1. Almost all contain a quaternary nitrogen therefore they do not cross the blood brain barrier.
D. Effects on Autonomic Ganglia
E. Effects on Histamine release
F. Drug Interactions with Competitive Neuromuscular Blockers
1. Tubocurarine and metocurine, pancuronium are excreted primarily by the kidneys.
3. Vecuronium and Rocuronium are metabolized by the liver.
4. Because of their ionized structures, they are poorly absorbed orally, and are given i.v.
3. Bronchospasm and increased secretions due to histamine release.
III. Pharmacology of Depolarizing Neuromuscular Blockers
A. Mechanisms of action and effects on skeletal muscle
a. Phase 1 blockade is potentiated by anticholinesterases and antagonized by competitive blockers.
a. Phase 2 blockade is antagonized by anticholinesterases, and potentiated by competitive blockers.
1. Both compounds contain quaternary nitrogens and therefore do not cross the BBB.
C. Effects on autonomic ganglia are relatively rare.
D. Histamine is released by succinylcholine, but not by decamethonium.
3. Phase 1 block potentiated by anticholinesterases and antagonized by competitive blockers.
4. Phase 2 block antagonized by anticholinesterases and potentiated by competitive blockers.
2. Decamethonium is excreted directly by the kidney.
3. Because of their ionized structure, they are poorly absorbed orally, and are given i.v.
IV. Therapeutic Uses of Neuromuscular Blockers
A. Mainly as adjuvants to surgical anesthesia to cause muscle relaxation.
B. In orthopedics to facilitate correction of dislocations and alignment of fractures.
C. To facilitate endotracheal intubation
D. To prevent trauma in electroconvulsive shock therapy
E. In treatment of severe cases of tetanus
I. Ganglionic Neurotransmission
B. Other ganglionic stimulants
I. Ganglionic Neurotransmission
A. The primary event at autonomic ganglia is the rapid depolarization of postsynaptic Nn receptors by ACh. The duration of this event is on the order of milliseconds. This effect is blocked by hexamethonium.
B. The next event seen is the development of an IPSP which also lasts only milliseconds. The IPSP is blocked by both atropine, and by alpha adrenergic blockers. This evidence suggests that a preganglionic cholinergic nerve terminal in the ganglion acts on M2 receptors to activate a catecholaminergic interneuron (probably containing dopamine) which then synapses on the postganglionic neuron.
C. The next event is the development of the late EPSP. This event lasts on the order of 30-60 seconds. It is blocked by atropine and appears to be due to the activation of M1 receptors.
D. Finally one sees the late slow EPSP, which persists for several minutes. This appears to be due to the action of multiple peptides including VIP, SP, NPY, Enkephalin, etc.
E. It should be emphasized that the secondary events of ganglionic transmission modulate the primary depolarization, by making it more or less likely to occur. This is so because these secondary events either facilitate or inhibit the processes of spatial and temporal summation of subthreshold depolarizing stimuli. The relative importance of secondary pathways and receptors also appear to differ between different parasympathetic and sympathetic ganglia. Remember that conventional Nn receptor antagonists can inhibit ganglionic transmission completely, but muscarinic antagonists, alpha adrenergic antagonists, and peptidergic antagonists caot do so.
II. Ganglionic Stimulating Drugs
A. Nicotine is an alkaloid isolated from the leaves of tobacco, Nicotiana tabacum in 1828. Its pharmacological actions are complex and often unpredictable because 1) its effects are on both sympathetic and parasympathetic ganglia, and 2) because stimulation is frequently followed by depolarization blockade. The drug also can stimulate and desensitize receptors. The ultimate response of any one system thus represents the summation of several different and opposing effects of nicotine. For example, heart rate can be increased by excitation of sympathetic or inhibition of parasympathetic ganglia. Conversely, heart rate can be decreased by excitation of parasympathetic or inhibition of sympathetic ganglia. Nicotine also 1) stimulates release of Epi from the adrenal medulla, 2) excites cardiorespiratory reflexes by a direct effect on the chemoreceptors of the carotid and aortic bodies, 3) excites cardiovascular responses secondary to evoked blood pressure changes mediated by baroreceptors, and 4) stimulates and blocks CNS cholinergic pathways in the medulla influencing heart rate.
1. In autonomic ganglia,the major action of nicotine consists initially in transient stimulation and subsequently in a more persistent depression. In larger doses, stimulation is followed very rapidly by blockade of transmission.
2. Nicotine also stimulates the nicotinic receptors of muscle (Nm), and this is followed rapidly by depolarization blockade.
3. Nicotine stimulates sensory receptors including mechanoreceptors, thermoreceptors, and pain receptors.
4. In the CNS, nicotine can cause tremors which proceed to convulsions as the dose is increased. Excitation of respiration which is a prominent effect seen after nicotine is due to both activation of medullary sites, and activation of chemoreceptors of carotid body. Stimulation is followed by depression and death occurs from respiratory paralysis of both central origin and due to paralysis of muscles of respiration. Another CNS effect of nicotine is stimulation of the area postrema ie the chemoreceptor trigger zone to induce vomiting.
5. Nicotine is readily absorbed from the respiratory tract, oral membranes, and skin. Since nicotine is a strong base it is highly ionized in the stomach and hence poorly absorbed from the stomach. It is metabolized primarily in the liver, but also in the lung and kidney. Both nicotine and its metabolites are rapidly excreted by the kidney. Nicotine is excreted in the milk of lactating mothers who smoke.
6. Poisoning occurs from exposure to insecticides containing nicotine, or in children by accidental ingestion of tobacco products. Death may result within a few minutes from respiratory failure. For therapy, vomiting should be induced with syrup of ipecac, or gastric lavage performed. Activated charcoal is then passed into the stomach to bind free nicotine.
B. Other ganglionic stimulants
1. Tetramethyl ammonium (TMA) and dimethylphenyl piperazinium (DMPP) are also ganglionic stimulants. They differ from nicotine primarily in the fact that stimulation is not followed by ganglionic depolarization blockade.
III. Ganglionic blocking drugs
Ganglionic Blockers
Ganglionic blockers specifically act on the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia. Some also block the ion channels of the autonomic ganglia. These drugs show no selectivity toward the parasympathetic or sympathetic ganglia and are not effective as neuromuscular antagonists. Thus, these drugs block the entire output of the autonomic nervous system at the nicotinic receptor. Except for nicotine, the other drugs mentioned in this category are nondepolarizing, competitive antagonists. The responses observed are complex and unpredictable, making it impossible to achieve selective actions. Therefore, ganglionic blockade is rarely used therapeutically. However, ganglionic blockers often serve as tools in experimental pharmacology.
|
|
A. The available ganglionic blockers in the U.S.A. are trimethaphan and mecamylamine. They are competitive antagonists. Trimethaphan has a positive charge, while mecamylamine does not, therefore trimethaphan is given intravenously and acts peripherally, while mecamylamine can be given orally, but crosses the blood-brain barrier. Trimethaphan is rapidly excreted in unchanged form by the kidney. Mecamylamine is excreted by kidney much more slowly. Other ganglionic blockers that you may hear about include hexamethonium and pentolinium, but they are no longer in clinical use in the U.S.
B. Pharmacological properties of ganglionic blockers can often be predicted by knowing which division of the ANS exerts dominant control of various organs ie
SITE PREDOMINANT TONE EFFECT OF GANGLIONIC BLOCKADE
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Salivary Gland Parasympathetic Xerostomia (reduced secretions) |
History Curare is a plant alkaloid and has been used for centuries by South American Indians to kill wild animals to eat. Curare was first used in humans in 1932 for the treatment of tetanus and spasticity. Ten years later, Griffith and Johnson discovered that curare gave adequate muscle relaxation for surgery without using excessive amounts of general anesthetics. Although succinylcholine was available for many years, it was only recognized as having neuromuscular blocking properties in 1949.Several synthetic neuromuscular blockers have been developed and utilized over the last 50 years including gallamine and pancuronium. Newer synthetic competitive blocking agents with differing durations of action, metabolism, elimination, and side effects have been marketed in the last 15 years.
Mechanism of Action: There are two classes of neuromuscular blockers, depolarizing and nondepolarizing neuromuscular blockers. Tubocurare is a competitive antagonist of acetylcholine, a nondepolarizing agent. Tubocurare binds to the nicotinic cholinergic receptor and prevents acetylcholine from stimulating motor nerves, resulting in muscle paralysis. Other nondepolarizing agents are pancuronium, pipecuronium, doxacurium, vecuronium, atracurium, rocuronium, and gallamine.
Succinylcholine is a depolarizing agent with a different mechanism of action. It binds to the acetylcholine receptor and stimulates depolarization causing initial excitation followed by block of neurotransmission and muscle paralysis.
Distinguishing Features: Succinylcholine and mivacurium are short-acting, with effects lasting 10 to 20 minutes. Intermediate-acting agents, atracurium and vecuronium, have effects for 30 to 60 minutes. The long-acting agents, tubocurarine, metocurine, pancuronium, doxacurium, and pipecuronium, have effects lasting 60 to 90 minutes.
The nondepolarizing neuromuscular blockers can cause cardiovascular changes and histamine release to varying degrees. Disadvantages of pancuronium and gallamine include increases in heart rate and blood pressure. Vecuronium, doxacurium, pipecuronium, and atracurium cause minimal hemodynamic effects and may be preferred in patients with compromised cardiovascular status. In asthmatic patients, agents that do not cause histamine release are preferred, including vecuronium, pancuronium, doxacurium, and pipecuronium.
Atracurium is unique among the nondepolarizing agents. It is broken down in the plasma by Hofmann elimination and ester hydrolysis. Metabolites of the drug have little activity. Therefore, atracurium may be the drug of choice in patients with severe renal and/or hepatic dysfunction.
Adverse Reactions: Side effects include hypotension secondary to histamine release is seen with tubocurarine and atracurium. Tachycardia is more common with pancuronium and gallamine. Prolonged paralysis (1 week) after long term administration of pancuronium or vecuronium has been reported. This problem may be enhanced by other conditions such as age, electrolyte imbalance, and renal or hepatic failure. In asthmatic patients treated with steroids and neuromuscular blockers while on mechanical ventilation have experienced an acute myopathy lasting days to weeks. Phlebitis and pain is reported with peripheral intravenous administration of atracurium and vecuronium, respectively. Inhalation anesthetics potentiate the side effects of the nondepolarizing agents. Patients with myasthenia gravis are very sensitive to these agents and small doses should be used. Succinylcholine has a different side-effect profile. It can cause tachycardia or bradycardia, hyperkalemia, and potentiate arrhythmias
Hexamethonium is a depolarising ganglionic blocker,[1] a nicotinic nACh (NN) receptor antagonist that acts in autonomic ganglia by binding mostly in or on the NN receptor, and not the acetylcholine binding site itself. It does not have any effect on the muscarinic acetylcholine receptors (mAChR) located on target organs of the parasympathetic nervous system but acts as antagonist at the nicotinic acetylcholine receptors located in sympathetic and parasympathetic ganglia (NN).[2]
Pharmacology
It can act on receptors at pre-ganglionic sites in both the sympathetic and parasympathetic nervous systems, which are both regulated by nicotinic ligand-gated ionotropic acetylcholine receptors. Postganglionic sympathetic systems are usually regulated by norepinephrine (noradrenaline) (adrenergic receptors), whereas parasympathetic systems are acetylcholine-based, and instead rely on muscarinic receptors (some post-ganglionic sympathetic neurons, such as those stimulating sweat glands, release acetylcholine).
The organ system and adverse effects of ganglion blockers are due to the parasympathetic and sympathetic stimuli blockage at preganglionic sites. Side-effects include combined sympatholytic (e.g., orthostatic hypotension and sexual dysfunction) and parasympatholytic (e.g., constipation, urinary retention, glaucoma, blurry vision, decreased lacrimal gland secretion, dry mouth (xerostomia)) effects.
Uses
It was formerly used to treat disorders, such as chronic hypertension, of the peripheral nervous system, which is innervated only by the sympathetic nervous system. The non-specificity of this treatment led to discontinuing its use.[3]
The use of inhaled hexamethonium, an unapproved drug, in a normal volunteer during a medical study is believed to have caused or contributed to her death[4][5] in light of the presence of abnormal “ground glass opacities” on her chest X-ray.
Tubocurarine (also known as D-tubocurarine or DTC) is a skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation. Unlike a number of other related skeletal muscle relaxants, it is now rarely considered clinically to facilitate endotracheal intubation.
Tubocurarine is classified as a long-duration,[1] antagonist for Nicotinic acetylcholine receptor.[2] It is the active agent of curare.
Currently, tubocurarine is rarely used as an adjunct for clinical anesthesia because safer alternatives, such as cisatracurium and rocuronium, are available.
History
Tubocurare is a naturally occurring mono-quaternary alkaloid obtained from the bark of the South American plant Chondrodendron tomentosum, a climbing vine known to the European world since the Spanish conquest of South America. Curare had been used as a source of arrow poison by South Americaatives to hunt animals, and they were able to eat the animals’ contaminated flesh subsequently without any untoward effects, because tubocurarine cannot easily cross mucous membranes. Tubocurarine is thus effective only if given parenterally, as demonstrated by Bernard, who also showed the site of its action was at the neuromuscular junction.[3] Virchow and Munter confirmed the paralyzing action was limited to voluntary and not involuntary muscles.[4] Thus, a conscious individual administered this agent will be unable to move any voluntary muscles, including the diaphragm: a large enough dose will therefore result in death from respiratory failure unless artificial ventilation is initiated.
The word “curare” comes from the South American Indiaame for the arrow poison, ourare. Presumably, the initial syllable was pronounced with a heavy glottal stroke. Tubocurarine is so-called because the plant samples containing the curare were stored and shipped to Europe in tubes. Likewise, curare stored in calabash containers was called calabash curare.
Structurally, tubocurarine is a benzylisoquinoline derivative. For many years, its structure, when first elucidated in 1948,[5] was wrongly thought to be bis-quaternary: in other words, it was thought to be an N,N-dimethylated alkaloid. In 1970, the correct structure was finally established,[6] showing one of the two nitrogens to be tertiary, actually a mono–N-methylated alkaloid.
Griffith and Johnson are credited with pioneering the formal clinical introduction of tubocurarine as an adjunct to anesthetic practice on 23 January 1942, at the Montreal Homeopathic Hospital.[7] In this sense, tubocurarine is the prototypical adjunctive neuromuscular blocking agent. However, others before Griffith and Johnson had attempted use of tubocurare in several situations:[8][9][10] some under controlled study conditions[11][12] while others not quite controlled and remained unpublished.[13] Regardless, all in all some ~30,000 patients had been given tubocurare by 1941, although it was Griffith and Johnson’s 1942 publication[7] that provided the impetus to the standard use of neuromuscular blocking agents in clinical anesthestic practice – a revolution that rapidly metamorphosized into the standard practice of “balanced” anesthesia: the triad of barbiturate hypnosis, light inhalational anesthesia and muscle relaxation.[14] The technique as described by Gray and Halton was widely known as the “Liverpool technique”,[14] and became the standard anesthetic technique in England in the 1950s and 1960s for patients of all ages and physical status. Present clinical anesthetic practice still employs the central principle of balanced anesthesia though with some differences to accommodate subsequent technological advances and introductions of new and better gaseous anesthetic, hypnotic and neuromuscular blocking agents, and tracheal intubation, as well as monitoring techniques that were nonexistent in the day of Gray and Halton: pulse oximetry, capnography, peripheral nerve stimulation, noninvasive blood pressure monitoring, etc.
Biosynthesis
Tubocurarine biosynthesis involves a radical coupling of two enantiomeric tetrahydrobenzylisoquinolines, more specifically, the two enantiomers of N-methyl-coclaurine. (R) and (S)-N-methyl-coclaurine come from a Mannich-like reaction between dopamine and 4-hydroxyphenyl-acetaldehyde, facilitated by norcoclaurine synthase (NCS). Both dopamine and 4-hydroxyphenylacetyladehyde originate from L-tyrosine. The biosynthetic pathway is described in more detail in the figures. Methylation of the amine and hydroxyl substituents are facilitated by S-adenosyl methionine (SAM).[15]
Clinical pharmacology and pharmacokinetics
Tubocurarine has a time of onset of 300 seconds or more (which is relatively slow among neuromuscular-blocking drugs), and has a duration of action of 60 to 120 minutes (which is relatively long time).[16]
It also causes histamine release,[17] now a recognized hallmark of the tetrahydroisioquinolinium class of neuromuscular blocking agents. The amount of histamine release in some instances following tubocurarine administration is such that it is contraindicated in asthmatics and patients with allergies.[citatioeeded] However, the main disadvantage in the use of tubocurarine is its significant ganglion-blocking effect,[18] that manifests as hypotension,[19] in many patients; this constitutes a relative contraindication to its use in patients with myocardial ischaemia.
Because of the shortcomings of tubocurare, much research effort was undertaken soon after its clinical introduction to find a suitable replacement. The efforts unleashed a multitude of compounds borne from structure-activity relations developed from the tubocurare molecule. Some key compounds that have seen clinical use are identified in the muscle relaxants template box below. Of the many tried as replacements, only a few enjoyed as much popularity as tubocurarine: pancuronium, vecuronium, rocuronium, atracurium, and cisatracurium. Succinylcholine is a widely used paralytic drug which acts by activating, instead of blocking, the ACh receptor.
The potassium channel blocker tetraethylammonium (TEA) has been shown to reverse the effects of tubocurarine. It is thought to do so by increasing ACh release, which counteracts the antagonistic effects of tubocurarine on the ACh receptor.
Ditilin (dithylinum)
DITILIN (Dithylinum). b-Dimetilaminoetilovogo amber acid ester diyodmetilat.
Synonyms : Suxamethonii iodidum, Suxamethonium iodide.
Similar dihloridy and dibromidy issued under the title : Listenon [name drug (suksametoniya chloride) firm Hafslund Nycomed Pharma AG] Miorelaksin, A nectin e revidil In Moscow, locaine Se, Se locurin, hlorsuccilin S, S ura with holin, uracit S, S uralest, Diacetylcholine, L er tosuccin (YU )), Lysthenon, M y o-Relaxin, Ra ntolax, Quelicin with hloride, Scoline, Succinylcholini with hloridum, Sucostrin, Su ha methonii with hloridum, Suxinyl, Syncuror and others.
White melkokristallichesky powder. The easily soluble in water, very little of alcohol.
On chemical structure of molecules can ditilina rassmatrivatsya as renewed molecule acetylcholine [diatsetilholin). He is the representative depolyarizuyuschih muscle. When intravenously violates a neuro-muscular stimulation and causes skeletal muscle relaxation.
Ditilin psevdoholinesterazoy collapses and falls into choline and amber acid. The drug has a quick and short term action; The cumulative effect is not. For a long muscle to the reintroduction of the drug. Quick offensive impact and subsequent rapid restoration of muscle tone allows a controlled and managed by the relaxation of muscles.
The main indication for use ditilina (listenona) are tracheal intubations, endoscopic procedures (bronchial and ezofagoskopiya, tsistoskopiya etc.), short-term transactions (overlay seams at the abdominal wall, lumbar fractures, etc.). With appropriate dose and the re-introduction ditilin (listenon) can be used for longer operations, but for a long relaxing muscles normally apply antidepolyarizuyuschie muscle, which give prior tracheal intubations in the face ditilina. The drug can also be used to remove convulsing with tetanus.
Enter ditilin intravenously. For heavy and full relaxation skeletal and respiratory muscles during an operation to impose drug dose of 1, 5, 2 mg / kg. For a long muscles relax during the entire operation can be administered medication fraktsionno after 5 to 7 minutes on the 0.5-1 mg / kg. Repeated dose ditilina operate more continuously.
Complications in the application ditilina usually no. However, it should be borne in mind that in some cases there may be increased sensitivity to ditilinu the long oppression of breath, which may be related to genetically caused violations education cholinesterase. The reason for acting drug may also gipokaliemiya.
Ditilin can be applied to different types of narcosis (ether, nitrous oxide, Halothane, barbiturates). In all cases, the introduction ditilina in high doses is permitted only after the patient for artificial respiration (controlled). When using low doses can be maintained independently breath. However, in those cases you have all devices tank.
Neostigmine and other anticholinesterase substances are not antagonists against depolyarizuyuschego of ditilina Conversely, inhibiting cholinesterase activity, they lengthened and strengthened it.
When complications arising from the use ditilina (prolonged respiratory depression) have resorted to artificial respiration, and blood transfusions if necessary, thereby contained in cholinesterase.
It should be borne in mind that in high doses can cause ditilin “double block” after depolyarizuyuschego of developing antidepolyarizuyuschy effect. So, if after the last injection ditilina muscle relaxation of long-term (over 25-30 min) and respiration is not fully restored resort with intravenous prozerina or galantamina (see), after the introduction of atropine (0.5 -0.7 ml 0.1% solution).
One possible complication in the application ditilina are muscular pain caused by 10 to 12 h after injection of preparation. Introduction of 1 min before ditilina 3 – 4 mg d-tubokurarina 10 or 15 mg diplatsina almost completely prevents fibrillyarnye car and the subsequent muscle pain.
Ditilin contraindications infants and glaucoma (possibly boost inner pressure).
With caution should be used when heavy ditilin liver diseases, anemia, cachexia, pregnancy (product passes through the placental barrier).
Pharmacological properties ditilina to use it in patients with myasthenia.
Solutions should not be confused with solutions ditilina barbiturates (sludge), and blood (hydrolysis occurs).
Method of issuance : 2% solution in ampoules for 5 or 10 ml pack of 10 vials.
Listenon issued on 5 ml ampoules containing 0.1 g suksametoniya hydrochloride.
Storage : List A. In the dark spot (in the refrigerator) at a temperature of +2′ C to 8 C (point is not permitted).
Nicotine poisoning can be fatal in extreme cases, but most of the time, if nicotine poisoning is treated quickly a person should have no long-term effects. Nicotine is a poison in and of itself, and when someone overdoses oicotine (typically a child consuming nicotine gum or patches) serious harmful reactions can occur as a result. While most common in children, nicotine poisoning can occur in anyone who consumes nicotine in large amounts. Learn the signs and symptoms of nicotine poisoning and what you should do if nicotine poisoning is suspected.
Nicotine is of course found in tobacco products, such as chew, cigarettes, gum, patches, and tobacco leaves. Some insecticides also contaiicotine. While a typical smoker will not usually get nicotine poisoning (unless they eat a whole can of chew in one consumption), children often fall victim by getting ahold of those nicotine patches and gum. And nicotine poisoning can occur in anyone who consumes it, so it’s important to know the signs and symptoms of nicotine poisoning.
Warning signs and symptoms of nicotine poisoning include nausea, dizziness, vomiting, rapid heart rate that quickly falls, high blood pressure that rapidly drops, abdominal cramping, rapid breathing or lack of breathing, confusion, burning sensation in the mouth, convulsions, muscle twitching, agitation or restlessness, coma, weakness or fainting, or even drooling. While some people who consume high levels of nicotine experience many of these lesser symptoms of nicotine poisoning, the more serious symptoms can lead to seizures or even death.
Wheicotine poisoning is suspected, it’s important to seek medical care right away. Do not make the victim vomit up the poison unless directed to do so by a medical professional. If the nicotine is on the skin, wash the area with cold water for 15 minutes.
If you can, supply the age, weight, what was swallowed or inhaled, how much was consumed, and the type of nicotine (patch, gum, cigarette, etc). Emergency care will typically involve using activated charcoal to absorb and eliminate the nicotine poisoning in the body, or the use of a tube via the nose or mouth to flush out the stomach (gastric lavage) of the toxin. If you suspect nicotine poisoning, get emergency care right away, as nicotine poisoning can be fatal.
Tobacco smoking is the practice of burning tobacco and inhaling the smoke (consisting of particle and gaseous phases). (A more broad definition may include simply taking tobacco smoke into the mouth, and then releasing it, as is done with tobacco pipes and cigars). The practice may have begun as early as 5000-3000 BC.[1] Tobacco was introduced to Eurasia in the late 17th century where it followed common trade routes. The practice encountered criticism from its first import into the Western world onwards, but embedded itself in certain strata of a number of societies before becoming widespread upon the introduction of automated cigarette-rolling apparatus.[2][3]
German scientists identified a link between smoking and lung cancer in the late 1920s, leading to the first anti-smoking campaign in modern history, albeit one truncated by the collapse of the Third Reich at the end of the Second World War.[4] In 1950, British researchers demonstrated a clear relationship between smoking and cancer.[5] Evidence continued to mount in the 1980s, which prompted political action against the practice. Rates of consumption since 1965 in the developed world have either peaked or declined.[6] However, they continue to climb in the developing world.[7]
Smoking is the most common method of consuming tobacco, and tobacco is the most common substance smoked. The agricultural product is often mixed with additives[8] and then combusted. The resulting smoke is then inhaled and the active substances absorbed through the alveoli in the lungs.[9] Combustion was traditionally enhanced by addition of potassium or other nitrates. Elimination of these would result in a fire safe cigarette, This subject has never been addressed by the cigarette manufacturers. substances trigger chemical reactions ierve endings, which heighten heart rate, alertness,[10] and reaction time.[11] Dopamine and endorphins are released, which are often associated with pleasure.[12] As of 2008 to 2010, tobacco is used by about 3 billion people (about 49% of men and 11% of women) with about 80% of this usage in the form of smoking.[13] The gender gap tends to be less pronounced in lower age groups.[14][15]
Many smokers begin during adolescence or early adulthood. During the early stages, a combination of perceived pleasure acting as positive reinforcement and desire to respond to social peer pressure may offset the unpleasant symptoms of initial use, which typically include nausea and interrupted sleep patterns. After an individual has smoked for some years, the avoidance of withdrawal symptoms and negative reinforcement become the key motivations to continue.
In a study done by Jennifer O’ Loughlin and her colleagues for seventh grade students were studied, with their first smoking experience.[16] They found out that the most common factors leading students to smoke is cigarette advertisements. Smoking by parents, siblings and friends also encourage students to smoke.[16]
Health
Main article: Health effects of tobacco
Cigarette smoking is the leading cause of preventable death and a major public health concern.[82]
Common adverse effects of tobacco smoking. The more common effects are in bold face.[83]
Tobacco use leads most commonly to diseases affecting the heart and lungs, with smoking being a major risk factor for heart attacks, strokes, chronic obstructive pulmonary disease (COPD), emphysema, and cancer (particularly lung cancer, cancers of the larynx and mouth, esophageal cancer and pancreatic cancer). Cigarette smoking increases the risk of Crohn’s disease as well as the severity of the course of the disease.[84] It is also the number one cause of bladder cancer. The smoke from tobacco elicits carcinogenic effects on the tissues of the body that are exposed to the smoke.[85]
Tobacco smoke can combine with other carcinogens present within the environment in order to produce elevated degrees of lung cancer.
Cigarette smoking has also been associated with sarcopenia, the age-related loss of muscle mass and strength.[86]
The World Health Organization estimate that tobacco caused 5.4 million deaths in 2004[87] and 100 million deaths over the course of the 20th century.[88] Similarly, the United States Centers for Disease Control and Prevention describes tobacco use as “the single most important preventable risk to human health in developed countries and an important cause of premature death worldwide.”[89]
Lung cancer occurs at non-smokers in 3.4 cases per 100 000 population. At people smoking 0.5 packs of cigarettes a day this figure rises to 51.4 per 100 000, 1-2 packs – up to 143.9 per 100 000 and if the intensity of smoking is over 2 packs a day – up to 217.3 per 100,000 population.[citation needed] Tobacco smoke can combine with other carcinogens present within the environment in order to produce elevated degrees of lung cancer.[90]
Rates of smoking have generally levelled-off or declined in the developed world. Smoking rates in the United States have dropped by half from 1965 to 2006 falling from 42% to 20.8% in adults.[91] In the developing world, tobacco consumption is rising by 3.4% per year.[92]
Second-hand smoke presents a very real health risk, to which six hundred thousand deaths were attributed in 2004.[93]
Effects of Secondhand Smoke
By now, it’s become very clear that smoking is bad for your health. The government, American Lung Association, and a variety of other health organizations have launched campaign after campaign to illustrate the grim repercussions (from lung cancer to heart disease) of lighting up and to encourage Americans to kick the habit.
What may be less obvious is the effect smoking has on those who are exposed to it secondhand. That exposure can be significant, especially for those who live or work with a smoker. In reality, most of the smoke from a burning cigarette doesn’t get sucked down into a smoker’s lungs — it escapes into the air, where it can be inhaled by anyone unfortunate enough to be nearby.
Recommended Related to Smoking Cessation
Note: Separate PDQ summaries on Oral Cancer Screening; Lip and Oral Cavity Cancer Treatment; and Cigarette Smoking: Health Risks and How to Quit are also available. Who is at Risk? People who use tobacco in any of the commonly available forms (cigarettes, cigars, pipes, and smokeless tobacco) or have high alcohol intake are at elevated risk of oral cancer; and they are at particularly high risk if they use both tobacco and alcohol. People who chew betel quid (whether mixed with tobacco…
In an effort to protect the health of nonsmokers, many states have passed laws outlawing smoking in public places such as restaurants, bars, airplanes, and offices. Yet there are still many people who can’t escape secondhand smoke, especially the children of smokers, who regularly breathe in the toxic fumes from their parents’ cigarettes and cigars. Even smokers who try to be careful about where they light up may not be doing a good enough job of protecting those around them.
What Is Secondhand Smoke?
When you breathe in smoke that comes from the end of a lit cigarette, cigar, or pipe (sidestream smoke) or that is exhaled by a smoker (mainstream smoke), you’re inhaling almost the same amount of chemicals as the smoker breathes in. Tobacco smoke contains more than 4,000 different chemical compounds, more than 50 of which are known to cause cancer. These are just a few of the chemicals that float into your lungs when you are exposed to secondhand smoke:
- Hydrogen cyanide — a highly poisonous gas used in chemical weapons and pest control
- Benzene — a component of gasoline
- Formaldehyde — a chemical used to embalm corpses
- Carbon monoxide — a poisonous gas found in car exhaust
A 2006 surgeon general’s report confirmed that secondhand smoking (also called involuntary or passive smoking) can kill, and it concluded that there is no amount of exposure to secondhand smoke that is safe. The more secondhand smoke you breathe in, the more your health risks increase.
Here are a few statistics on the effects of secondhand smoke exposure:
- 126 millioonsmoking Americans are exposed to secondhand smoke at home and work.
- Secondhand smoke exposure causes nearly 50,000 deaths in adult nonsmokers in the U.S. each year.
- Nonsmokers increase their risk of developing lung cancer by 20% to 30% and heart disease by 25% to 30% when they are exposed to secondhand smoke.
- About 3,000 deaths from lung disease ionsmokers each year are caused by secondhand smoke exposure.
- An estimated 46,000 nonsmokers who live with smokers die each year from heart disease.
- Between 150,000 and 300,000 children under the age of 18 months get respiratory infections (such as pneumonia and bronchitis) from secondhand smoke; 7,500 to 15,000 of them must be hospitalized.
- More than 40% of children who visit the emergency room for severe asthma attacks live with smokers.
Secondhand smoke can have a number of serious health effects oonsmokers, particularly cancer and heart disease.
Cancer
Cancer is probably the most discussed health repercussion of smoking, and it’s also a significant problem with secondhand smoke exposure. Lung cancer may be the most talked about effect of secondhand smoke exposure, but the risks of breast cancer, cervical cancer, and other types of cancer are also thought to be higher.
Heart Disease
Breathing in secondhand smoke is bad for your heart, and research shows that it takes as little as 10 minutes for the smoke to start causing damage. Smoke exposure makes your blood platelets stickier, raises the level of artery-clogging LDL “bad” cholesterol, and damages the lining of your blood vessels. Eventually, these changes can make you more likely to develop a blockage that leads to a heart attack or stroke. Researchers have found that women who have been exposed to secondhand smoke face a 69% higher risk of heart disease and a 56% higher risk of stroke than those who haven’t been exposed.
Children and Secondhand Smoke
Children are particularly vulnerable to the effects of secondhand smoke because their bodies are still growing and they breathe at a faster rate than adults.
All of these conditions have been attributed to secondhand smoke exposure in children:
- Sudden infant death syndrome (SIDS)
- Increased number of respiratory infections (such as bronchitis and pneumonia)
- More severe and frequent asthma attacks
- Ear infections
- Chronic cough
Smoking during pregnancy is especially dangerous to the developing baby. It has been linked to premature delivery, low birth weight, SIDS, mental retardation, learning problems, and attention deficit hyperactivity disorder (ADHD). The more cigarettes a mother-to-be smokes, the greater the danger to her unborn baby.
How to Avoid Secondhand Smoke
The best way to lower your risk of all these conditions is to avoid smoking, and to convince those around you who smoke to quit. Anyone who does smoke should do so outside, as far away from nonsmokers as possible.
The home is probably the most important place to keep smoke-free, especially when children live there. An estimated 21 million children live in homes where a resident or visitor regularly smokes, and more than half of all American kids have detectable levels of cotinine (the breakdown product of nicotine) in their blood. Keeping kids (and adults) far away from smoke can help reduce their risks of developing respiratory infections, severe asthma, cancer, and many other dangerous health conditions.
1. http://www.youtube.com/watch?v=797WAV3kZhQ&playnext=1&list=PL83879046C561EB07&index=5
2. http://www.youtube.com/watch?v=fPzjU6YRsf4&feature=related
3. http://www.youtube.com/watch?v=TaAvhG2SInM&playnext=1&list=PLE304A951086EE624&index=50
4. http://www.apchute.com/moa.htm
