BPH3024 NEUROPHARMACOLOGY

NICOTINENUR SUMAIYYAH LAWSON BINTI ABDULLAHBACHELOR IN BIOMEDICINE SCIENCES

What is nicotine?

Nicotine is a nitrogen-containing chemical that is an alkaloid. It is made by several types of plants including the tobacco plant. Nicotine can also be produced synthetically.

Nicotine is obtained from the tobacco plant , Nicotiana tabacum. This plant comes from the nightshade family which has other members for example red peppers, eggplant, tomatoes and potatoes.

What is nicotine?

Nicotine is a potent parasympathomimetic which accumulates in the leaves of the Nicotiana tabacum plant.

Nicotine constitutes approximately 0.6–3.0% of the dry weight of tobacco and is present in the range of 2–7 µg/kg of various edible plants. It functions as an antiherbivore being a potent neurotoxin with particular specificity to insects.

Nicotine's molecular formula is C10H14N2.

History about nicotine

Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after Jean Nicot, French ambassador in Portugal, who sent tobacco and seeds from Brazil to Paris in 1560 and promoted their medicinal use.

Nicotine was first isolated from the tobacco plant in 1828 by German chemists Posselt & Reimann.

Its chemical empirical formula was described by Melsens in 1843, and it was first synthesized by A. Pictet and Crepieux in 1893.

French scientist that first found nicotineNicolas Louis Vauquelin was an inventor and scientist from France. He discovered nicotine in 1828

Chemistry in the nicotine

Nicotine is a hygroscopic, oily liquid that is miscible with water in its base form. It forms salts with acids that are usually solid and water soluble.

Nicotine easily penetrates the skin. Free base nicotine will burn at a temperature below its

boiling point, and its vapors will combust at 95 °F in air. Most of the nicotine is burned when a cigarette is smoked;

however, enough is inhaled to provide the desired effects.

Structure of nicotine

What are receptors of nicotine ?

The nicotinic cholinergic receptor consists of five subunits. The brain expresses nine α subunits (α2 through α10) and three β subunits (β2 through β4). The most abundant receptors are α4β2, α3β4, and α7, the latter of which are homomeric. 

The α4β2 is the principal mediator of nicotine dependence. In mice, disruption of the β2 subunit gene eliminates the behavioural effects of nicotine; reinserting the gene into the ventral tegmental area restores behavioural responses to nicotine.

What are receptors of nicotine ?

The α4 subunit is an important determinant of sensitivity to nicotine. 

A mutation affecting a single nucleotide in the receptor gene increases the hypersensitivity to the effects of nicotine.The presence of α5 subunit combined with α4β2 increases calcium conductance seven times; α5 gene variants also alter nicotine responsiveness in cultured human cells. 

NICOTINIC RECEPTORS

These receptors are found in the central nervous system (CNS), peripheral nervous systems (PNS) and skeletal muscles. They are ligand-gated ion channels with binding sites for acetylcholine and other molecules.

The nicotinic receptors are made up by different subunits which determine the quaternary structure of the receptor, those subunits are α subunits (α1−α10), β subunits (β1−β4), one δ subunits, one γ subunit and one ε subunit.

LOCATION of receptors of nicotine

Pharmacology OF nicotine

As nicotine enters the body, it is distributed quickly through the bloodstream and can cross the blood-brain barrier.

On average, it takes about seven seconds for the substance to reach the brain when inhaled.

The half life of nicotine in the body is around two hours. Nicotine is metabolized in the liver by cytochrome P450

enzymes. A major metabolite is cotinine.

PharmacologICAL effectS OF nicotine

Mainly mediated through release of catecholamines (adrenaline and noradrenaline).

Increase in systolic and diastolic blood pressure, heart rate, force of myocardial contraction, myocardial oxygen consumption, coronary artery blood flow, myocardial excitability and peripheral vasoconstriction.

It also increases serum concentrations of glucose, cortisol, free fatty acids, antidiuretic hormone and increases platelet aggregation

What are actionS of nicotine?

When nicotine binds to the receptors it stabilizes the open state of the ion channel allowing influx of cations such as potassium, calcium and sodium ions.

This binding stimulates the receptors to produce the clinical effects of nicotine.

Nicotine agonists

A nicotinic agonist is a drug that mimics the action of  Acetylcholine (ACh) at nicotinic acetylcholine receptors, named for the affinity for nicotine.

Examples of nicotinic agonists are nicotine, acetylcholine choline, epibatidine, lobeline, varenicline and cytisine.

Nicotine antagonists

A nicotinic antagonist is a type of anticholinergic drug that inhibits the action of acetylcholine at nicotinic acetylcholine receptors. These compounds are mainly used for peripheral muscle paralysis in surgery. For example tubocurarine.

Some centrally acting compounds such as bupropion, mecamylamine and 18 methoxycoronaridine block nicotinic acetylcholine receptors in the brain.

MECHANISM OF ACTION OF NICOTINE agonists and antagonists

MECHANISMS, RECEPTORS AND USES OF NICOTINE antagonists

What ARE the effectS OF nicotine?

Nicotine promotes cancer growth by stimulating angiogenesis and neovascularisaton.

Nicotine increases cholinergic signaling (and adrenergic signaling in the case of colon cancer), thereby impeding apoptosis (programmed cell death), promoting tumor growth, and activating growth factors and cellular mitogenic factors .

Nicotine increases blood pressure and heart rate. Nicotine can also induce potentially atherogenic genes in human coronary artery endothelial cells. Microvascular injury can result through its action on nicotinic acetylcholine receptors.

What ARE the effectS OF nicotine?

Nicotine increases blood pressure and heart rate. Nicotine can also induce potentially atherogenic genes in human coronary artery endothelial cells. Microvascular injury can result through its action on nicotinic acetylcholine receptors.

Nicotine appears to have significant performance enhancing effects, particularly in fine motor skills, attention, and memory.

Studies suggest a correlation between smoking and schizophrenia , with estimates near 75% for the proportion of schizophrenic patients who smoke.

SIDE EFFECTS OF NICOTINE

What ARE the effectS OF nicotine?

  Nicotine also has been shown to have significant

deleterious effects on brain development, including alterations in brain metabolism and neurotransmitter systems and abnormal brain development.

By causing a release of glucose from the liver and adrenaline from the adrenal medulla, it causes stimulation.

What ARE the effectS OF nicotine?

Nicotine appears to enhance concentration and memory due to the increase of acetylcholine. It also appears to enhance alertness due to the increases of acetylcholine and norepinephrine. 

Nicotine also extends the duration of positive effects of dopamine and increases sensitivity in brain reward systems.

Pain is reduced by the increases of acetylcholine and beta-endorphin. 

LOCATION OF SITES OF NICOTINIC RECEPTORS

NICOTINE ADDICTION

The criteria to diagnose nicotine addiction include any 3 of the following within a 1-year time span: Tolerance to nicotine with decreased effect and increasing dose

to obtain same effect Withdrawal symptoms after cessation Smoking more than usual Persistent desire to smoke despite efforts to decrease intake Extensive time spent smoking Postponing work, social, or recreational events in order to

smoke Continuing to smoke despite health hazards

Treating nicotine addiction

Mode of Action : Substitute source of nicotine to achieve and sustain tobacco abstinence

Using :Nicorette chewing gumNicorette inhalerNiquitin patchNiquitin lozenges

NICOTINE ADDICTION AND ABUSE

Most smokers use tobacco regularly because they are addicted to nicotine. Addiction is characterized by compulsive drug seeking and abuse, even in the face of negative health consequences.

Most smokers identify tobacco use as harmful and express a desire to reduce or stop using it, and nearly 35 million of them want to quit each year. Unfortunately, more than 85 percent of those who try to quit on their own relapse, most within a week.

NICOTINE ADDICTION AND ABUSE

Of primary importance to its addictive nature are findings that nicotine activates reward pathways—the brain circuitry that regulates feelings of pleasure.

A key brain chemical involved in mediating the desire to consume drugs is the neurotransmitter dopamine, and research has shown that nicotine increases levels of dopamine in the reward circuit.

ADVERSE REACTIONS OF NICOTINE DEPENDENCE TREATMENT

Nausea, vomiting, dyspepsia, upper abdominal pain, diarrhea, dry mouth, constipation, hiccups, stomatitis, flatulence, oral discomfort, headache, dizziness, tremor, sleep disturbances

e.g. insomnia and abnormal dreams, nervousness, palpitations, pharyngitis, cough, pharyngolaryngeal pain, dyspnea, increased sweating, arthralgia, myalgia, chest pain ,pain in the limb, asthenia, fatigue

NICOTINE WITHDRAWAL

Nicotine withdrawal is classified as a nicotine-induced disorder.

Symptoms include difficulty concentrating, nervousness, headaches, weight  gain due to increased appetite, decreased heart rate,  insomnia, irritability, and depression. These symptoms peak in the first few days but eventually disappear within a month. For some people, however, symptoms may persist for months.

NICOTINE WITHDRAWAL

Many behavioral factors can also affect the severity of withdrawal symptoms.

For some people, the feel, smell, and sight of a cigarette and the ritual of obtaining, handling, lighting, and smoking the cigarette are all associated with the pleasurable effects of smoking and can make withdrawal or craving worse.

TREATING NICOTINE WTHDRAWAL

Nicotine replacement therapies such as gum, patches, and inhalers may help alleviate the pharmacological aspects of withdrawal; however, cravings often persist.

Behavioral therapies can help smokers identify environmental triggers of craving so they can employ strategies to prevent or circumvent these symptoms and urges.

CONCLUSION

Nicotine is a potent parasympathomimetic present in cigarettes and tobacco.

Nicotine binds to and stimulates nicotinic receptors of acetylcholine causing nicotinic effects. These effects are addictive and detrimental to the body.

Withdrawal from nicotine use causes withdrawal symptoms that can be treated with nicotine replacement therapy or behavioral therapy.

references

Benowitz N.L., 1986 Clinical Pharmacology of Nicotine Annual Review of Medicine 37 (1): 21

Lande R.G. , Dunayevich E 2014 Nicotine Addiction Clinical Presentation Medscape emedicine.medscape.com

Levin E.D., McClernon F.J., Rezvani A.H., 2006 Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization Psychopharmacology Vol 184 Issue 3-4: pg 523 -539

Petersdorf, Adams, Braunwald, Isselbacher, Martin, Wilson Harrison’s Principles of Internal Medicine 10 th Edition pg 1032-1303

references

http://www.medicalnewstoday.com/articles/240820.php

http://www.researchgate.net/post/Nicotinic_Receptors_Nicotine_addiction

Thank you