Saturday, 20 July 2013

Varenicline

Varenicline (CHANTIX, CHAMPIX) is the name of a popular, and, according to a few clinical trials, most of which were funded by Pfizer -- the pharmaceutical company sponsoring the development and profiting from the sales of the drug, an effective smoking cessation aid (i.e. a drug designed to help people quit smoking).1

A more impartial source (albeit since the bulk of the clinical trial data they would have analysed would be from Pfizer-funded trials it is impossible to say that it would get unbiased results), the Cochrane collaboration (which performs statistical analysis of available clinical trial data) demonstrated that it was more effective than a placebo and that it was more effective than the smoking cessation aid bupropion (WELLBUTRIN, ZYBAN), and while statistical significance wasn't reached there was a trend in this meta-analysis (statistical analysis) that favoured varenicline over nicotine replacement therapy (NRT; this is where attempts are made to replace the nicotine a smoker would normally get by smoking they get via less dangerous and less addicting ways like nicotine patches and gum). What this means is that the data we have comparing varenicline with NRT isn't strong enough to rule out the possibility of a coincidence occurring in the trials comparing the efficacy of NRT with that of varenicline that so happened to favour varenicline over NRT2

It works by serving as a partial agonist at the α4β2 subtype of nicotinic acetylcholine receptors (nAChR). To explain what this means I need to teach you a little bit about the nicotinic acetylcholine receptors.

nAChRs are receptors that are found throughout the central and peripheral nervous systems (explained in the sentence after next). The term acetylcholine refers to the fact that these receptors are activated by the body-synthesised neurotransmitter (chemical messenger between the electrically-signalling cells of the peripheral and central nervous systems), acetylcholine, which the body synthesises from choline – a member of the B group of essential vitamins.

In the central nervous system (CNS; brain and spinal cord) nAChRs are found in a number of places, particularly in the regions of the brain involved in reward (like where the rewarding, or pleasurable, effects of recreational drugs originate), wakefulness, sensory perception, memory, learning and mood. In the peripheral nervous system (PNS; the nerves we all use to sense pain, pressure, temperature, etc. and to control our voluntary and involuntary movements) they regulate muscular activity, both voluntary and involuntary, as is exemplified by the fact that the muscle relaxants often used to prevent twitching/shivering during surgeries and also in the lethal injection to stop breathing work by blocking certain peripheral nAChRs. Some nAChRs are also found on the vagus nerve (a nerve that goes directly from the brain down through much of the torso) where they appear to regulate immune function.3,4

Another fact about the nAChRs is that they are made out of subunits, which you could think of as the building blocks the receptor. These subunits are designated a Greek letter (e.g. α) and a number (e.g. 4), e.g. one subunit is called the α4 subunit based on this. Each receptor must contain a total of exactly five subunits in order for it to be functional (i.e. for it to actually work); for α4β2 nAChRs there are 2 α4 and 3 β2 subunits found in each receptor.

Varenicline binds to the α4β2 nAChRs and activates them, but it does so less “fully” or strongly than acetylcholine does, and this is why we call it a partial agonist at this receptor. α4β2 nAChRs are expressed solely in the CNS where they regulate the release of neurotransmitters including those involved in reward and hence the euphoric effects of many drugs (e.g. dopamine and β-endorphin would be examples of such neurotransmitters) and it is via this action that α4β2 nAChRs, when activated, produce euphoric (or rewarding) effects. It is believed that it is via these receptors that nicotine produces much of its rewarding and hence addictive effects.5 Varenicline, by serving as a partial agonist, it is able to antagonise (block or prevent) the increase in nAChR activity triggered by nicotine because it binds to the same site on the α4β2 nAChRs as nicotine hence preventing nicotine from binding to said site and hence preventing it from inducing many of its effects, including the rewarding effects it produces that leads to addiction. Simultaneously, via its ability to “partially” activate the α4β2 nAChRs it is able to reduce nicotine cravings by mimicking nicotine’s effects on dopamine and β-endorphin release, just to a lesser extent. Hence it is able to both block the rewarding effects of nicotine while simultaneously reducing cravings, and perhaps other symptoms characteristic of nicotine withdrawal.


For the past few years questions have been raised regarding the safety of varenicline, amidst reports of suicidal ideation (thinking about suicide) and cardiovascular (pertaining to the heart and blood vessels; e.g. myocardial infarctions [heart attacks]) adverse effects in patients receiving varenicline as a smoking cessation aid. The risks of both these types of adverse effects appears to be quite small, with mostly just those with pre-existing psychiatric or cardiovascular conditions, respectively, afflicted by such adverse effects.6 Despite these reports that varenicline can cause suicidality (even though depression does not strike me as a particularly unusual problem for people that by definition are trying to kick such an addictive habit) there is some evidence from tests on mice that suggests that it might have antidepressant effects, likewise, in mice, it was also found to potentiate the antidepressant effects of the popular, Therapeutic Goods Administration (TGA)-approved antidepressant, sertraline (ZOLOFT).7

Varenicline also serves as a full agonist at the α7 subtype of nAChRs, i.e. it activates the receptor to the same extent as acetylcholine, and since the α7 nAChRs appears to be heavily involved in memory and learning it may have some positive effects on the aforementioned functions. Varenicline also activates the 5-HT3 receptor,8 which might be responsible for its high propensity for causing nausea (approximately 50% of patients treated with varenicline experience nausea).6

References

  1. Jorenby DE, Hays J, Rigotti NA, et al. Efficacy of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: A randomized controlled trial. JAMA [Internet]. 2006 Jul 5 [cited 2013 Jul 21];296(1):56–63. Available from: http://dx.doi.org/10.1001/jama.296.1.56
  2. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database of Systematic Reviews [Internet]. John Wiley & Sons, Ltd; 2013 [cited 2013 Jul 21]. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006103.pub6/abstract
  3. De Jonge WJ, Ulloa L. The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation. Br J Pharmacol [Internet]. 2007 Aug [cited 2013 Jul 21];151(7):915–29. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042938/
  4. Van der Zanden EP, Snoek SA, Heinsbroek SE, Stanisor OI, Verseijden C, Boeckxstaens GE, et al. Vagus Nerve Activity Augments Intestinal Macrophage Phagocytosis via Nicotinic Acetylcholine Receptor α4β2. Gastroenterology [Internet]. 2009 Sep [cited 2013 Jul 21];137(3):1029–1039.e4. Available from: http://www.gastrojournal.org/article/S0016-5085(09)00737-9/abstract?referrer=http://www.ncbi.nlm.nih.gov/pubmed/19427310
  5. Albuquerque EX, Pereira EFR, Alkondon M, Rogers SW. Mammalian Nicotinic Acetylcholine Receptors: From Structure to Function. Physiol Rev [Internet]. 2009 Jan 1 [cited 2013 Jul 21];89(1):73–120. Available from: http://physrev.physiology.org/content/89/1/73.full.pdf
  6. Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Jul 21]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  7. Rollema H, Guanowsky V, Mineur YS, Shrikhande A, Coe JW, Seymour PA, et al. Varenicline has antidepressant-like activity in the forced swim test and augments sertraline’s effect. European Journal of Pharmacology [Internet]. 2009 Mar 1 [cited 2013 Jul 21];605(1–3):114–6. Available from: http://www.sciencedirect.com/science/article/pii/S0014299909000302
  8. Lummis SCR, Thompson AJ, Bencherif M, Lester HA. Varenicline Is a Potent Agonist of the Human 5-Hydroxytryptamine3 Receptor. J Pharmacol Exp Ther [Internet]. 2011 Oct [cited 2013 Jul 21];339(1):125–31. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186289/pdf/zpt125.pdf

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