As key component of the vapor inhaled by consumers of electronic cigarettes, nicotine has raised controversy because of its alleged addictive potential and toxic effects. Therefore, I will briefly summarize the chemistry, pharmacology and toxicology of nicotine in the first post of this blog. Some important issues, such as toxicology or addiction/dependence will be discussed in detail later.
Chemistry and occurrence
Pure nicotine is a colorless fluid with a boiling point of 247 °C. It is well soluble in water and non-polar solvents. The alkaloid is found in the Solanaceae family of plants, particularly in Nicotiana tabacum, the tobacco plant, which contains up to 3 % of nicotine (per dry weight). Various edible plants, such as potatoes, tomatoes and fungi, contain nicotine in the range of several µg/kg of dry weight. These trace amounts of nicotine are negligible and irrelevant.
The nicotine molecule contains two basic nitrogen atoms, resulting in the overlapping occurrence of three different species at different pH values (pKa values of 3.12 and 8.02). The following main species are present at the following ranges of pH values:
(i) pH < 3.0: fully protonated (two bound H+ ions; not relevant to the biology of nicotine containing products)
(ii) pH 4-8: one bound H+ ion (also referred to as “bound” nicotine)
(iii) pH >8: fully deprotonated (also referred to as “unbound” nicotine)
Despite some claims of the occurrence of specific nicotine transport proteins in cell membranes, passive diffusion is considered as the main route of nicotine resorption. Since the protonated forms, i.e. species (i) and (ii) above, cannot cross cell membranes, the fraction of resorbed nicotine and/or the speed of uptake may be determined by pH, with high pH values shifting the equilibrium towards fully deprotonated (unbound) nicotine that is resorbed by passive diffusion along its concentration gradient. The precisely adjusted pH of 7.4 results in a defined equilibrium between species (ii) and (iii) inside cells. Thus there are no “different nicotins” in the body (as sometimes claimed).
Upon oral intake of nicotine, resorption in the intestine is followed by extensive hepatic metabolism (“first pass effect”), such that only about 20% of the initial amount of nicotine show up in the bloodstream, while 80% is metabolized to biologically inactive compounds. In technical language, one would say that the oral bioavailability of nicotine is 20%. Hepatic metabolism through the first pass effect is circumvented in the course of other routes of administration, i.e. intravenous, inhalative, or dermal.
Mechanism of action
The pharmacological effects of nicotine are mediated by stimulation of nicotinic acetylcholine receptors, pentameric proteins that function as ligand-gated Na+ channels. Binding of the neurotransmitter acetylcholine elicits a conformational change resulting in a flow of Na+ ions down their electrochemical gradient into the cell. This inward current of positive charges leads to depolarization of the cell membrane and initiation of an action potential.
The five subunits of nicotinic receptors are members of a multigene family, the combination of which results in a large number of receptor subtypes with distinct tissue distribution and variable properties. Nicotine is an agonist of the receptors in vegetative ganglia and in the brain, but does not bind to the receptors in the neuromuscular junction. It also has poor binding affinity to nicotinic receptors expressed in chromaffin cells of the adrenal gland, possibly explaining the lack of compelling evidence for significantly increased catecholamine plasma levels of smokers.
Stimulation of nicotinic receptors in sympathetic ganglia provokes a moderate increase in heart rate and systolic blood pressure (through increased cardiac output) and, possibly, peripheral vasoconstriction. These effects are mild and well tolerated. It should be noted that virtually all of the detrimental effects ascribed to smoking (e.g. increased risk of cancer, myocardial infarction and stroke) are not caused by nicotine but toxic compounds generated in the course of tobacco combustion.
The effects of nicotine in the central nervous system are complex and not well understood. There is substantial evidence that stimulation of nicotinic receptors in the brain improves cognitive performance, awareness and memory. Thus, synthetic nicotinic receptor agonists are potentially interesting drugs for the treatment of cognitive impairment and Alzheimer’s Disease.
Nicotine may be addictive by causing release of dopamine in the nucleus accumbens, a component of the reward center of the brain that is essentially involved in reinforcing effects which stimulate drug-taking behavior. However, this issue is controversial due to frequent confusion of (well established) tobacco dependence with nicotine dependence.
In normal use nicotine containing products are not toxic. Slight overdosing is readily recognized as dizziness, nausea and headache, prompting users to stop or reduce nicotine intake. Continued consumption of high nicotine doses would result in poisoning evident as severe diarrhea and vomiting, effects which significantly decrease the amount of systemically available nicotine. Therefore, fatal cases of nicotine poisoning are extremely rare and will not occur upon inhalation of – or dermal contact with – nicotine containing products.
Note that nicotine is not a neurotoxin in the classical sense as frequently claimed. Nicotine modulates the function of neurons by mimicking the effects of an endogenous neurotransmitter (acetylcholine), while neurotoxins have detrimental effects on neuronal function, mostly by targeting ion channels, leading to disruption of vital signal transduction pathways. At abnormally high concentrations of nicotine, permanent depolarization of cell membranes may cause inactivation of voltage-dependent Na+ channels, but this effect is not observed in normal use of nicotine containing products.