Synthesis:

Nicotine, a plant defense alkaloid, is a pale yellow to dark brown liquid with a slight, fishy odor when warm.  Biologically, production of nicotine requires nicotinic acid (aka vitamin B3 or niacin) and an N-methyl-pyrrolinium cation, which is derived from ornithine (a non-protein amino acid derived from Krebs cycle intermediates) (1). (Figure 1)

 
In Nicotiana sylvestris (Figure 2), nicotine production is induced by jasmonic acid signals in response to leaf damage (2, 3, 12).  Synthesis occurs in the roots, followed by transport throughout the plant.  By using jasmonic acid as a chemical signal, the defense becomes inducible.  Induced plants have about 6% of their total nitrogen content locked up in nicotine (3,12), and synthesis also diverts fixed carbon out of the TCA cycle (a-ketoglutarate is an ornithine precursor).

Nicotine is isolated from tobacco by a variety of methods, many of which can be found at the US Patent Office.  Some of the most recent include supercritical CO2 extraction, where carbon dioxide is compressed to a supercritical state (between a liquid and a gas) under high pressure, thus becoming a non-polar solvent.  When the extraction is done, the CO2 evaporates leaving behind nicotine.

Mode of Action:

Although nicotine is approved by the FDA as an insecticide.  Its effectiveness is similar to that of organophosphorous compounds, and it is one of the few poisons that bugs have not evolved resistance to (5).  However, our exposure to nicotine is usually from cigarette smoke.  Whether used as an insecticide or drug, the mode of action is the same.  Nicotine inhibits the function of acetylcholine receptors located at the neuromuscular junctions.  In general terms, it causes stimulation of the ganglions in low doses but causes blockade at higher concentrations.  The nicotinic acetylcholine receptors (named for their interaction with nicotine, and not to be confused with the muscarinic acetylcholine receptor) are 270kD proteins with 4 subunits located in the CNS (Figure 3).  Under normal conditions, a change in calcium ion concentration releases acetylcholine from storage vesicles.  Acetylcholine then crosses the synaptic cleft and binds to the alpha subunit of the nicotinic receptor causing a conformational changes which opens an ion channel, allowing the passage of cations.  This depolarizes the postsynaptic membrane initiating an action potential in the adjacent membrane, and thus a signal is transmitted.  (Figure 4)   Nicotine stimulates, then blocks the acetylcholine receptor, locking the ion channels in the open position and impairing signaling ability (7, Lippincott).

Figure 4: ÏCell-cell communication at the synapse (a) is mediated by neurotransmitters such as acetylcholine, produced from choline by cholineacetyltransferase.  The arrival of an action potential the synaptic knob (b) opens Ca2+ channels in the presynaptic membrane.  Influx of Ca2+ induces the fusion of acetylcholine containing vesicles with the plasma membrane and release of acetylcholine into the synaptic cleft (c).  Binding of acetylcholine to receptors in the postsynaptic membrane opens Na+ channels (d).  The influx of Na+ depolarizes the postsynaptic membrane, generating a new action potential.Ó  (7)  Nicotine locks this ion channel in the ÏopenÓ conformation (click to enlarge)

Nicotine is highly lipophillic and can pass through dermal tissue as well as the blood-brain barrier (5, Lippincott).  Accidental exposure to nicotine through pesticide is a real threat.  Severe exposure causes nausea, headache, dizziness, abdominal craps, and vomiting.  An anecdotal reference to a florist who sat on a chair covered with spilled nicotine and ended up in the hospital is discussed in Gieger paper.  The man lost consciousness on the way to the hospital and became semi comatose, making a recovery only after 24 hours.

In a 1989 scandal resulting from the investigation of health officials in Maricopa County, Arizona, it was discovered that nicotine had been used for a number of years as an animal tranquilizer (8).  This use is not approved by the FDA, but apparently is effective.  These Arizonians  had been making dilutions of the pesticide and using it to fill animal control darts.  The results of the investigation lead to restructuring of the Rabies Animal Control Center staffing, and a search for alternative tranquilizer medications.  This example again shows the potency of nicotine.

Uses:

 
Other than use in small doses to help people quit smoking, nicotine has no therapeutic value (14), unless you consider  pesticidal activity to be therapeutic (for exogenous applications!).  Unfortunately, humans have a long history of adapting plant defense alkaloids to recreational drug habits.  Perhaps it is our acute awareness of death which drives us to such distractions.  In any case, alkaloids are big business for Big Tobacco.

Low doses of nicotine, like those obtained from self administration through cigarettes (6-8mg (14), facilitates relaxation and causes mild euphoria.  Additionally it can improve attention as well as problem-solving skills.  It takes about 19 seconds for nicotine to reach the brain after it is absorbed into the blood stream (9).  Where it causes changes in many types of neurological chemicals. Dopamine levels increase, causing pleasure enhancement.  Acetylcholine and norepinephrine levels rise (to compensate for nicotine's disabling of the receptors) facilitating performance and memory ability.  At higher doses, significant increases in growth hormone has also been observed.  Anxiety and tension is soothed by elevated endorphins and weight gain thwarted by appetite reduction (9).  In cigarettes, there is also an unknown component (possibly the carcinogenic benzopyrenes) which increases the rate of metabolism of other drugs (14).  Nicotine also causes vasoconstriction (not so great for someone with angina!).

Most health problems associated with nicotine are actually caused by the carrier: cigarettes.  Inhalation of scalding, partially oxidized plant debris is bound to cause problems.  Incomplete combustion results in polycyclic aromatic hydrocarbons (like benzopyrenes) which are carcinogenic.  Tar coating of the lungs also leads to reduced lung efficiency and major tissue damage.  And don't forget about cytochrome oxidase-inhibiting carbon monoxide!

Nicotine itself causes dependency partially due to the body's increased production of acetylcholine receptors over long-term nicotine exposure.  In fact, the body becomes tolerant to the toxic effects of nicotine within a few days after exposure (14).  Withdrawal is associated with headache, constipation, insomnia, depression, inability to concentrate and anxiety (9, 14).  Notice some of these are the reverse of the services nicotine provides.

At the molecular level, some studies have indicated nicotine impairs cells ability to repair DNA damage (10).  Results vary depending on cell type; whether the cell is terminally differentiated or actively replicating.  In the Kozlovskis-Wade paper, it was found that Ïpharmacologically relevantÓ concentrations of nicotine (about 50 µm) enhances DNA degradation and stimulates DNA repair in adult myocytes (heart cells).  It was unclear whether this was caused directly by stimulation of nucleases or indirectly by interference with poly ADP-ribose polymerase binding to DNA.  This interfering activity would cause an increase in possibility for mutations, some of which could no doubt lead to cancer, tumors, etc., especially when coupled with the carcinogens found in cigarette smoke.

The benefits of smoking cessation are numerous:

Figure 5: Advantages of Kicking the Habit, from the Merk Manual ONLINE

It can be surmised that nicotine, due to its highly addictive and somewhat beneficial qualities, is merely a tool of the Tobacco industry to ensure a strong market for their products.  According to the FDA, tobacco companies have had the technology for over 30 years to remove nicotine from cigarettes (13).  But then, who would smoke?

Overcoming nicotine addiction is not an easy task, although the best way to quit is a combination of medication (patch, gum, etc.) and behavioral modification (14).

Now, if you happen to be sitting in the green house and find you have accidentally been poisoned with nicotine insecticide, there are a few things you can do.  If oral ingestion was the culprit, Yahoo! Health online suggests emesis, while the Toxnet database at the NIH says you should keep it down.  Both resources concede that activated charcoal could be helpful.  However, emesis and charcoal won't help much for dermal exposure.  In this case, Toxnet advises to wash the affected area with soapy water.  While 4-6mg can cause nausea, 40-60mg is a lethal dose.  Approaching this exposure level, seizures could occur, for which IV administration of Diazepam (benzodiazepine) is prescribed.  Atropine may also be used to correct heart rate.  For oral exposure use of antacids should be avoided, as nicotine is more readily absorbed in an alkaline environment.  The Yahoo! site cheerfully predicts that "If the patient survives the first 4 hours, complete recovery is very likely."
 

Web Links:

From the Merk Manual, for information on smoking cessation.
For a good laugh, or perhaps small reality check into the opined mind of the uneducated masses, check out In Defense of Smokers
The Quit Net is a web site devoted to helping smokers quit smoking
To learn more about nicotine and other insecticides, visit An Introduction to Insecticides (6).
Health info at Yahoo! Health is only topically informative...
Toxnet (Toxicology Data Network) from the National Institute for Health has a huge searchable database

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