The Pharmacology of Nicotine
Photo: Richard Villalon
The fascinating workings of a widely misunderstood chemical
By Grant Churchill
In this article, I will describe the pharmacology of nicotine. I will guide you along nicotine’s journey, starting with how it gets into a person, explain what it does once inside by interacting with specific receptors and finally, how it is inactivated and leaves.
Due to its chemical properties, nicotine can exist in two forms, depending on acidity, which controls its ability to be absorbed and, in turn, the effectiveness of delivery by different routes of administration. For example, certain forms of smoked tobacco must be inhaled to absorb nicotine, such as cigarettes, whereas others, such as cigar and pipe tobacco, are not inhaled but nicotine is still absorbed.
It might be useful for the reader to know where I’m coming from in writing this article. I’ve got a professional interest in how drugs work as I do research and teach in this area and find the pharmacology of nicotine fascinating and convey this to medical students. I’ve also got a personal interest as both my parents smoked and died from cancer. So, I wonder if vapes were available 40 years ago, would my parents still be alive? And now, should I be concerned that my adult son is vaping?
Routes and Rates
I’ll now describe in more detail how nicotine gets into the body and then the brain. This depends on the fascinating interplay between the route of administration and the chemical formulation, for example, free base or salt of nicotine. Regarding the route of administration, one can have an intuitive and qualitative understanding by considering the number of barriers and distance from the site of application to the brain.
When inhaled, nicotine has a short journey with few barriers as it is absorbed into the oxygenated arterial blood and goes from the heart to the brain within 10 seconds.
When swallowed, nicotine has a much longer journey with several barriers as it has to make its way through the stomach on to the small intestine before it can be absorbed into the bloodstream. Then it is in the deoxygenated venous blood that goes to the liver, then through veins to the heart, then through the lungs, where it finally meets the starting point for the inhaled nicotine. Importantly, the liver acts as a paper shredder for drugs and metabolizes them before they are delivered to the rest of the body.
When applied by a patch, the skin provides an additional barrier before nicotine can enter the bloodstream. Surprisingly, an intravenous injection of nicotine results in a slower route to the brain than inhalation.
For the intuitive understanding of the routes and rates, one can think about the physiological role of each system. The job of the lungs is to absorb large amounts of oxygen and quickly deliver it to the brain, the importance of which is driven home by considering that consciousness is lost within tens of seconds if inhibited. In contrast, the job of the gastrointestinal tract is to absorb food for energy, which is not needed at the pace of oxygen. Moreover, the job of the liver has evolved to protect us from the remarkably diverse and potentially harmful chemicals we consume in our diets, and in this regard, a drug is just another nonfood or non-nutrient to be inactivated and removed.
The uptake of nicotine can be more precisely studied quantitatively by monitoring nicotine in the blood and graphing this over time. This reveals an initial increase, a peak and then a tapering off, and numbers can be put to the time and concentration at the peak and the area under the curve. The hit comes from a combination of the speed of the peak and the maximum concentration, and the craving comes from when the concentration falls below a critical activity threshold. The different routes of administration show characteristic concentration over time profiles, with inhaled nicotine showing a fast peak within minutes whereas a patch-delivered nicotine shows a slow increase, taking an hour to peak. This has implications in the user experience and the success of nicotine-replacement therapies for tobacco harm reduction. The rate of decrease in nicotine concentration is similar for all routes of administration due to the same elimination mechanisms: a combination of metabolism by the liver and excretion by the kidney into the urine.
Crossing Barriers
The chemical formulation of nicotine as a salt or free base has a major impact on its uptake into the body as only the latter gets in. The chemical basis of this can be understood by considering a vinaigrette, which forms two layers, with the oil floating on a layer of vinegar and table salt (sodium chloride) dissolving only in the vinegar. This demonstrates that molecules can be watery or oily and only mix with their own kind, as summed up by the adage that oil and water don’t mix. Bringing this back to biology, the barriers to uptake of nicotine are cells that form layers like brick walls to separate the contents of our gastrointestinal tract from blood and blood from the organs. The cell’s barrier is its surface membrane called a bilayer, which is an inside out soap bubble with a watery surface and an oily interior forming the barrier. A water-loving nicotine salt cannot cross the oily interior whereas the oily free base of nicotine easily crosses.
The ability of nicotine free base to easily cross cell membranes is the mechanistic explanation of why nicotine can be absorbed from pipe and cigar smoke held in the mouth whereas cigarette smoke must be inhaled. The processing of the tobacco alters the chemical composition and acidity, resulting in cigarette flue-cured tobacco being acidic with nicotine salt whereas air-cured pipe tobacco is alkaline with nicotine free base. For a fuller explanation, we must again consider how chemistry interacts with biology. Smoke from acidic tobacco (nicotine salt) is less harsh and irritating and can be inhaled deeply into the lungs, where the large surface area (approximately the size of a tennis court) compensates for the inability of the salt to cross membranes.
Nicotine is always present in both forms, and the acidity controls the relative amounts of salt to free base with only a tenth of a percent in cigarette smoke being the free base compared to 50 percent in pipe smoke.
The trade-offs between the amount of nicotine that is bioavailable and how deeply it can be inhaled to take advantage of the large surface area of the lungs can also explain the nicotine salt craze in vapes. Nicotine salt formed by adding benzoic acid leads to a “smooth” taste, enabling deep inhalation of higher concentrations of nicotine.
How it Works Inside
Now that nicotine is in the body, I’ll describe its effects and how it is active. Nicotine affects cognition, body function and mood. The effects of nicotine on cognition relate to attention and memory and it has been suggested to be a “work” drug as opposed to what most of society would think of as a recreational or “fun” drug. The effects of nicotine on body function mostly relate to heart rate and blood pressure. The effects of nicotine on mood are relaxation and euphoria, arguably two of its major effects as nicotine stimulates a reward pathway in our brains the causes one brain region to stimulate other regions involved in emotion by releasing the neurotransmitter dopamine. Neurotransmitters are chemical messengers that enable communication between the brain cells termed neurons. Very generally, dopamine signals reward or the anticipation of reward—think sex, drugs and rock ’n’ roll, and these days, smartphones—which leads to pleasure and risk of dependence. Nicotine itself acts by mimicking the neurotransmitter acetylcholine, which is involved in learning, memory and attention, which fits with its subjective effects mentioned above.
Remarkably, all the diverse actions of nicotine arise from it acting on the same pharmacological target: the nicotinic acetylcholine receptor. This receptor spans the surface membrane of a cell and acts as a gated pore that allows ions such as sodium to flow through and trigger a wave of voltage change that sweeps from one end of the cell to the other. The binding of acetylcholine, or nicotine, results in opening and turning on the signal—but with prolonged presence, the gate on the pore jams shut in what is termed “desensitization.”
So, nicotine has time-dependent effects: Over a period of minutes, the nicotinic acetylcholine receptors open and release dopamine, but after several hours in the presence of nicotine, many of the receptors desensitize, dopamine levels fall, and more nicotine is required to return to the higher level of dopamine. Over a period of weeks, the neuron responds by increasing the number of nicotinic acetylcholine receptors, but most are desensitized, and if nicotine is no longer present, dopamine levels fall, giving rise to physiological withdrawal and addiction. Addiction at the molecular level is related to the structure of the nicotinic acetylcholine receptor, which is made up of five cylindrical subunits arranged side by side in a circle to form the pore. Each subunit is given a Greek letter designation, and in a mouse model, addiction relates to the presence or absence of the beta subunit.
Chemical Inactivation
The pharmacological effects of nicotine wear off with time, not from the above desensitization mechanisms but through chemical inactivation and excretion. Nicotine in the blood has a half-life, the time for a given concentration to be reduced by half, of about two hours. Nicotine declines over time through processes common to all drugs in which the underlying principle is to convert a drug from an oily compound to one that is watery. Water is watery due to it being composed of hydrogen and oxygen, therefore introducing oxygen into nicotine makes it watery.
This chemical transformation occurs in the liver by the enzyme (a molecular machine) cytochrome P450, which forms the major metabolite cotinine. As cotinine has a half-life of about a day, it can be used to examine past nicotine exposure, often by health insurance companies. Cytochrome P450 is a family of enzymes, and different forms are more or less active in converting nicotine to cotinine; the specific form varies between individuals, and certain forms are more frequent in a given ethnic group. For example, a less active form of the enzyme is more prevalent in individuals with Black or Asian heritage. Cotinine or its metabolites are finally removed from the body through the action of the kidneys and excreted into the urine. Again, the effect of acidity on nicotine can be employed by acidifying the urine to increase the fraction of salt, which cannot be reabsorbed back by the body, which thereby increases nicotine excretion.
Addressing Misunderstandings
Lastly, there are many controversies surrounding nicotine based on misunderstanding, half-truths and myths. The major health consequences of smoking are due to chemicals other than nicotine produced during combustion of tobacco, so other methods of nicotine delivery provide for tobacco harm reduction. For example, the relative health harms are such that vaping is a method for smoking cessation endorsed by the National Health Service in the U.K. and promoted as such by the government based on the best current scientific evidence.
Nicotine was used as a pesticide and can be toxic, but as Paracelsus famously stated, the dose makes the poison; any chemical can be toxic, including seemingly innocuous water, or an exceptionally toxic substance such as Botox can be used safely at a lowered concentration. Nicotine may have bona fide therapeutic use beyond smoking cessation in Alzheimer’s disease, Parkinson’s disease, schizophrenia and obesity. Intriguing evidence has been published regarding all these disorders, but the studies were small, leading to equivocal results.
Larger studies are needed, but the demonization of the tobacco industry for past wrongs is tainting and hampering the ability of scientists and physicians to obtain funding and conduct large, definitive trials. Given that psychedelic drugs, which were made illegal and vilified in the 1960s, are experiencing a renaissance to treat depression and post-traumatic stress disorder, there is hope that nicotine can be separated from smoked tobacco and used or not based on the evidence.
