Transcribed by Charles Buchanan Date of the Lecture: 10/22/14 [General Pathology] [Lecture] – [Nicotine Addiction] by Dr. Spielman [Slide 1] – [Nicotine Addiction] [Dr. Spielman]– Is this the normal attendance pattern? Sorry? Oh. Ok. This is about normal. Wow. So everybody is familiar. Let me ask you, how many of you are smokers? We’re going to do some counseling in a minute. Anyone smoked in their life? I’m not talking about the illegal stuff. I’m talking about the- I’m talking about the regular cigarettes. Ok? When did you stop smoking? [Student]— Oh, about 2 months ago. [Dr. Spielman]— Alright. [Student]— It was more of a social thing. ~class applauds~ [Dr. Spielman]— Good. Good job. Now , if you’re not entirely convinced that you did the right thing, after I’m done with you, you will see what the mess- what is it in cigarettes that we don’t really appreciate. The kind of damage that they bring. [Slide 2] – [Major Points of the Lecture] [Dr. Spielman]– So this is about- the lecture major points that we’re going to talk about. We’re going to talk about the mechanism of nicotine and where does it work and why. Why is it so difficult to actually get rid of the smoking habit? Then, we’re going to talk about the addiction itself. We’ll talk about short-term and long-term effects of nicotine. In terms of smoking. We’ll talk about the ingredients that are in cigarettes. And you will be horrified to find out what can a small cigarette have. The 4,000 ingredients. 4,000 ingredients. Some in the paper. Some in the tobacco. Some in the fumes that- essentially, once it’s burned it is modified compounds that you inhale.All this. I’m not going to list 4,000 compounds, I made 10 of them. Most of them are well known carcinogens. Some of them, you’re using when you are renovating your house. So, it will be- and then of course, we’ll talk about health consequences. So, um. [Slide 2a] – [How many of you smoke?] [Dr. Spielman]— I don’t know if you have your clicker with you. And I’ll try to actually bring this up. Maybe a show of hand. That might be easier. How many of you smoke? And obviously, I did ask. Nobody smoking. How many did. Well I do have, so its 1,2,3,4,5. I smoked big time. It started in the dissection room. And, um, age 18. I was top of the world. What can be- what can go wrong? And by the time I got to 25, I made a decision. Actually , my father who smoked and died of lung cancer asked me not to smoke and I did not follow up on that. I promised him and I broke my promise. And then, one Christmas, I said I owe this to my father. And that was 1975, December 27. Never had a cigarette in my mouth. Cold turkey. From that day on. ~applause~ So, now 2 months. Do you know how long it takes for your lung to replace all its cells that you have damaged during your smoking?Ok? Do you know how much time you need actually- how long have you stopped smoking? Yes. [Student] —10 years? [Dr. Spielman] — Do you think your lungs have been replaced? [Student]— Uh, if they have, I must have been asleep 1
Transcribed by Charles Buchanan Date of the Lecture: 10/22/14
[General Pathology] [Lecture] – [ Nicotine Addiction ] by Dr. Spielman
[Slide 1] – [Nicotine Addiction][Dr. Spielman] – Is this the normal attendance pattern? Sorry? Oh. Ok. This is about normal.Wow. So everybody is familiar. Let me ask you, how many of you are smokers? We’re going todo some counseling in a minute. Anyone smoked in their life? I’m not talking about the illegalstuff. I’m talking about the- I’m talking about the regular cigarettes. Ok? When did you stopsmoking?
[Student] — Oh, about 2 months ago.
[Dr. Spielman] — Alright.
[Student] — It was more of a social thing.~class applauds~
[Dr. Spielman] — Good. Good job. Now, if you’re not entirely convinced that you did the right
thing, after I’m done with you, you will see what the mess- what is it in cigarettes that we don’treally appreciate. The kind of damage that they bring.
[Slide 2] – [Major Points of the Lecture][Dr. Spielman] – So this is about- the lecture major points that we’re going to talk about. We’regoing to talk about the mechanism of nicotine and where does it work and why. Why is it sodifcult to actually get rid of the smoking habit? Then, we’re going to talk about the addictionitself. We’ll talk about short-term and long-term effects of nicotine. In terms of smoking. We’lltalk about the ingredients that are in cigarettes. And you will be horried to nd out what can asmall cigarette have. The 4,000 ingredients. 4,000 ingredients. Some in the paper. Some in thetobacco. Some in the fumes that- essentially, once it’s burned it is modied compounds thatyou inhale. All this. I’m not going to list 4,000 compounds, I made 10 of them. Most of them are
well known carcinogens. Some of them, you’re using when you are renovating your house. So, itwill be- and then of course, we’ll talk about health consequences. So, um.
[Slide 2a] – [How many of you smoke?][Dr. Spielman] — I don’t know if you have your clicker with you. And I’ll try to actually bringthis up. Maybe a show of hand. That might be easier. How many of you smoke? And obviously, Idid ask. Nobody smoking. How many did. Well I do have, so its 1,2,3,4,5. I smoked big time. Itstarted in the dissection room. And, um, age 18. I was top of the world. What can be- what can gowrong? And by the time I got to 25, I made a decision. Actually, my father who smoked and diedof lung cancer asked me not to smoke and I did not follow up on that. I promised him and I brokemy promise. And then, one Christmas, I said I owe this to my father. And that was 1975,December 27. Never had a cigarette in my mouth. Cold turkey. From that day on. ~applause~ So,
now 2 months. Do you know how long it takes for your lung to replace all its cells that youhave damaged during your smoking? Ok? Do you know how much time you need actually-how long have you stopped smoking? Yes.[Student] — 10 years?
[Dr. Spielman] — Do you think your lungs have been replaced?
[Student] — Uh, if they have, I must have been asleep
Transcribed by Charles Buchanan Date of the Lecture: 10/22/14
[Dr. Spielman] — Actually, they haven’t. It takes 15 years for the lung parenchyma tocompletely replace itself. So you wouldn’t have the same exact- any ingredients that you havedamaged with smoke. So you have 14 years and 10 months. So, and again. The purpose of thiswas I was hoping that we could actually see some effect. But since nobody smoked in this group-or no body smokes, it essentially is useless. In past experience, I would show the hand, you know“how many of you have smoked?” and by the end of the lecture, I would ask “now, how many ofyou would like to quit.” And you’d see a few souls that essentially have been saved by this lecturewhich means that we have gotten through.
[Slide 2b] – [ What does nicotine bind to in the body? ][Dr. Spielman] — So, can you guess, what does nicotine bind to in the body? How many of youthink #1, the hemoglobin receptor? How many of you think the acetylcholine muscarinicreceptor? So we have 3,4,5,6,7. How many think that the other type of acetylcholine receptor?Ok, so we have double dipping for some. Good. How many think that it’s both types ofacetylcholine receptor. Ok. Uh. Smoke receptor? Never smoked I don’t know. So the answer isthe other type. It’s not all acetylcholine receptors. And it’s very important because it’s kind of
confusing and thats the reason why I put it out there. Acetylcholine and nicotine are only tied inone receptor. And it happens to be a receptor that mediates acetylcholine which is sensitive tonicotine. But it has nothing to do with the other acetylcholine receptor that is called amuscarinic receptor. And it is a different type of receptor. It doesn’t have a nicotine binding siteso get this out of your system. It is only a nicotine acetylcholine receptor. But, that receptor isall over the place. And you will see how much effect it has on you when you smoke becausethat’s the binding site. So that’s the correct answer. The other type.
[Slide 2b] – [ What is the most addictive component of a cigarette? ]—[Dr. Spielman] – Um. Most addictive part of nicotine- of the cigarette. And you have 1-8. Tar,ammonia, nicotine, aromatic amines, polonium 210, carbon monoxide, hydrogen benzene and thecigarette butt. So, anyone can call out which number is this? It’s obviously nicotine . It has
nothing to do with the ust- the rest. We will talk about Polonium 210. Some of you may haveeven seen an interesting video about this but that's the answer. It’s nicotine is makes it obviously-and that’s why the lecture title.
[Slide 2c] – [ If my patient is a smoker, my role as a dentist is? ]—[Dr. Spielman] – So, I’m going to skip this because B/C is correct. Because you can prescribe asmoke prevention program. You are not limited in terms of scope of practice. In fact, we expectyou to educate your patients to stop smoking.(Answer: B/C: I can prescribe a smoke prevention program. I can refer the patient to aprofessional )
[Slide 3] – [ Why do I need to know this? ] —
[Dr. Spielman] – So why do you need to know about this? First because it’s addictive . Becausethere are millions of products sold in the U.S . Because 1/3 of the adult population smokes .1/3. Think about this. That’s approximately- there are 6 trillion cigarettes in the world. Do youknow how much is 6 trillion cigarettes? If you were to take a pack of cigarettes, put it on top ofthis- 6 trillion cigarettes would go around the world-the equator 226,000 times. 226,000 times.That’s how many cigarettes are still sold in the world today. That’s a lot. Now the U.S. populationis relatively reduced in the number of smokers. And New York is particularly- do you know whatpercentage of New York population smokes?
Transcribed by Charles Buchanan Date of the Lecture: 10/22/14
[Student] — 40%?
[Dr. Spielman] – Oh no, no, no, no. We are actually very good. You know, you walk into somerestaurants in the south of the country and you would have people smoke in a restaurant or in abar. New York has banned all over the place. We are around 12% , nationally is 23% and 17%for women. And it’s coming down. But this is an amazing achievement. 12% is still too muchbut- Um, this is the number, 75 million people die worldwide and this is the single mostpreventable death.
[Slide 4] – [Nicotine][Dr. Spielman] – 1 in 8 seconds. Think about it. A person dies just by the end of me stating thissentence. Because of smoking. So what is nicotine ? It’s really a natural alkaloid which byitself, it doesn’t have a smell . It is brown, colorless, (on the slide it says colorless that turnsbrown on exposure to air , etc.) it’s volatile . And acquires the odor of tobacco only onexposure to air . But if you think about this. If it’s in the bottle, it does not smell. You startsmelling, then it becomes odorous in the air- it oxidizes and changes it’s color. Interestingly, it
was brought, originally, from Brazil to the French ambassador in Portugal whose name wasNicol. That’s where the nicotine comes from. It’s the name of the French ambassador to Portugalwho received it from Brazil as a gift. And it became, in the 1500s- 1600s, so it became quitefashionable at the time. And it wasn’t cigarettes- they were snuffs, and they were chewing. And ofcourse, the goodies that occurred with oral cancer and cigarettes for the past 600 years essentially.Or 500 years. It’s just terrible how much effect it had.
[Slide 5] – [Where Does Nicotine Act?][Dr. Spielman] – So this is the image of the receptor. I mentioned to you that the receptor isreally the nicotinic acetylcholine receptor . And you may or may not remember, I covered thistopic actually in Cell Biology last year, talking about the various subunits. It has 5 subunits ,really. And you can see these colors- 2 of them yellow meaning 2 alpha subunits are the same .
And then there is a beta gamma and delta subunit . You can see this, sort of a superimposedimage- it’s in the membrane . And it’s really an iron channel . And it’s primarily a sodiumchannel. What does sodium do? Depolarize the cell. So wherever this receptor exists, it usuallycan be on muscle, it could be on nerve. It has- when acetylcholine is released, it binds to thisreceptor, opens it up and allows sodium to enter the cell and depolarize whatever is the nexttarget. It happens that this receptor also has a binding site for nicotine that makes it active. Just like acetylcholine does. So you need acetylcholine and you need nicotine. Nicotine byitself is not going to be sufcient. But what it does is when nicotine is not enough, then thisreceptor starts to fail. It’s not releasing, it’s not depolarizing. It becomes- if nicotine becomesthe activator, the receptor starts to essentially becomes less sensitive to it over time, themore nicotine becomes available. So that’s part of the process of becoming desensitized andtherefore becoming addicted to it. Because as you will see, nicotine and acetylcholine and the
response is just a local response. What happens next is the reward system that the brainpicks up. So overtime you get this depolarization caused by acetylcholine and nicotine, thebrain releases this reward system, the dopamine. And that’s really where the addictionoccurs. Because as you will see, the reward system is- for everything from food to enjoyment tosex. Everything is tied to the dopamine receptor and that reward system requires constantreinforcement. And when you don’t get the reinforcement, you keep on adding more of theinitial stimulus to get to that point. That’s the basic mechanism of addiction. Good morning,Billy. So, where does the receptor localize? Well, the nicotinic acetylcholine receptor has
Transcribed by Charles Buchanan Date of the Lecture: 10/22/14
multiple versions. And you can just imagine just how many alpha subunits there may be. Howmany beta versions. Imagine if you could bind them in different types. Because, as I said, thereare 2 alphas, and there are beta, gamma, and delta subunits . Imagine if you had differentversions of each. And each combination can generate a different iron channel with differentproperties. It is still a sodium channel. They may be located in different places of the body. But they all create a different version. And that’s important, as it turns out, in thepathogenesis of the disease- of the addiction and apparently of cancer. I’ll show you a recentstudy that looked at specic subtypes of acetylcholine subunit composition as being the key tocancer. And they are essentially promoted in the presence of nicotine. So there’s far more to itthan just the biological effect and the addiction. So there are 17 types, 17 different types ofacetylcholine receptor.
[Slide 6] – [N-AChR locations and composition][Dr. Spielman] – And here is a pre and postsynaptic terminus showing in different color. So whatyou see here, this in purple, that’s one type of acetylcholine receptor made up of alpha, beta,gamma delta subunits, and then the blue is a different kind of acetylcholine receptor. And then thepurple here is a different color. So what it really tells you is that the postsynaptic area, thepresynaptic area or the presynaptic terminus may have different composition. Andtherefore, the effect of nicotine on those receptors is different based on the composition ofthe acetylcholine receptor. There are alpha-2 to alpha-10, beta-2 to beta-4 and there may begamma and delta subunit variants of these that make up the 17 different types ofacetylcholine receptors.
[Slide 7] – [Sympathetic/Parasympathetic Involvement of Nicotine][Dr. Spielman] – Take a look at this map of the entire human body. If you just look at the nervoussystem. The autonomous nervous system- the sympathetic and parasympathetic system. Wheredo you think acetylcholine and nicotinic acetylcholine receptors would be found in thismap? Sorry?
[Student] — Parasympathetic
[Dr. Spielman] – There is both parasympathetic and sympathetic. One side is parasympathetic,the other side is sympathetic. Look at these. Preganglionic cholinergic- thats what really is theside that we’re looking at. So anywhere you see this purple, you would nd nicotinicacetylcholine receptors with different compositions with different biological effects. You knowthat when someone smokes, they have all kinds of effects. First, you feel smart, you feelcondent, you feel alert, you can study, you can drink a coffee. You can do anything. And then astime goes by, other effects start to appear. There is short term, long term. All of these effects arereally the way nicotine reaches the various nicotinic receptors . That’s really what it is. Sowhere they are? The entire parasympathetic division which is right here-all of these would be
affected by nicotine. And you can look at it- from heart, to lungs, to stomach, to bladder, topancreas, to ureter, colon- everything is affected. And of course, there are some of these adrenalmedulla. You see, every purple line that you see is the parasympathetic nervous system. So I justwanted to impress upon you that this is not just the lungs or the brains. It is everywhere nicotinicacetylcholine receptors are and acetylcholine is released as a neurotransmitter.
[Slide 8] – [Location of the NAChR at the motor end plate]
Transcribed by Charles Buchanan Date of the Lecture: 10/22/14
[Dr. Spielman] – So this is another location. Very common, just to give you a sense. When youlook at a motor plate, all these- this is a magnied version of the invaginations between a motornerve that releases acetylcholine and a high magnication view, where the acetylcholine isbeing released and then they bind to this sodium channel. Once they bind, they open it up,Na runs in and depolarizes the muscle. Now, in the case of the muscle, you know you needCa in addition to Na— but Na is the initial impulse- and it is mediated. So, all this machofeeling when you smoke and you feel your muscles so good, and you are strong- this is becausethat acetylcholine receptor releases-or accepts the acetylcholine and nicotine makes it depolarize.
[Slide 9] – [Is cancer triggered by altered signaling of nicotinic acetylcholinereceptors?][Dr. Spielman] – Um. So this is what I was talking about. It’s a recent study, 2009 in NatureReviews. And it’s talking about the modication of certain types of acetylcholine receptors to avery specic type. And that type is made up of alpha-7 and an acetylcholine receptor or analpha-4 beta-2. Now, you know what is alpha. It’s a different type of alpha subunit out of tendifferent version and there are 2-4 beta versions. When you have this particular combination,apparently makes far more- the chance of developing a cancer is far more realistic. In otherwords, nicotine converts the composition of expression of specic type of acetylcholinereceptors. So, nicotine binds to it. Nicotine essentially activates and sodium runs through. Itmakes the cells start to express different type of acetylcholine receptor that leads to a farhigher chance for a person to develop cancer. This is, apparently, new development. And Ithink that it’s interesting to see because in the past, we did not know that nicotine can actuallyalter the expression of different types of acetylcholine receptors. This is a relatively new nding.
[Slide 10] – [ Effects of nicotine ][Dr. Spielman] – So what are the effects. Well, short term - obviously, you increaseneurotransmitter release . That’s what it does. Primary dopamine . And we’ll talk about this, asthe primary reward system. But long term, and here’s the kicker, the acetylcholine receptor
becomes desensitized. It means that it requires more acetylcholine to make that ion channelactive. And how do you make more acetylcholine? You induce more nicotine in order torelease more acetylcholine and activate that ion channel. So the more you need or crave forthis, the more you smoke. And that’s really one aspect- the desensitization of the receptor. So,I’ll give you an example of desensitization because it’s a process where cells make them selvesrefractory to stimulation. It’s usually a protective mechanism. For instance, you would have apiece of chocolate and eat it. And it’s wonderful and it’s sweet. And then you you would have apiece of cookie, right after chocolate. And that what you feel is, the cookie actually would besweet but not as sweet. Now you take a piece of bread, and you eat it and you cleanse the palate.You take a little bit of water and you wash it out. And now you take the cookie and it’s sweetagain. Far more sweeter than it used to be after the chocolate. So, what really happened is that thesweet receptor becomes desensitized for a period of time. And that desensitization makes it
refractory to the cookie to be perceived as sweet. In the case of the nicotinic acetylcholinereceptor, we are talking bout a different timeline, but it’s the same process. The timeline ismonths rather than minutes. What happens is, you put acetylcholine into the- to access thesereceptors in the presence of nicotine, they actually depolarize. But as time passes, this receptorbecomes less and less sensitive to the amount of nicotine and acetylcholine that used todepolarize it. You would need far more to reach a threshold, now it’s going to release thesame amount of sodium and depolarize the post synaptic cell. So you need- essentially you
Transcribed by Charles Buchanan Date of the Lecture: 10/22/14
are craving for far more response. And the response is not just a depolarization. It’s reallythe release of dopamine. So, that’s the basis of the long-term desensitization.
[Slide 10a] – [Nicotine and Brain Chemistry] - SKIP
[Slide 11] – [Nicotine and Brain Chemistry][Dr. Spielman] – So let me show you this. The nicotine and the brain chemistry. And I want youto think about this reward system not for smoking. Many of you cannot imagine what it’s likesmoking. But I can say that you probably can imagine, say, eating a piece of cake . That’s awonderful thing. It works through the same exact reward system . So you take a piece of cake
and your brain goes haywire. It starts releasing dopamine . And what it does, is activates thisreward system called the ventral tegmental area. That’s the reward system- for cookies, forchocolate, for cake, for cigarettes, for sex, for drugs- it’s the same reward system. And suddenly,the ventral tegmental area starts pushing out dopamine. Big chunks of dopamine and hasconnections. Unique connections. Now, the reward system is not just the ventral tegmentalarea. There are at least 4 areas that have to be involved. The rst is the amygdala. It’s theemotional center. Now, you know when you eat something really good, good food. You smellsomething. Your amygdala is being activated. You eat the chocolate, your amygdala is beingactivated. It is the emotional center that not only connects via the rewards system, but it becomesnow, in part of your network. It needs to be activated over and over. And so, your emotions, youliking this becomes entrenched in this network. The second major area of dopamine is thenucleus accumbens. Now, the nucleus accumbens is a motor coordination center. So, it allowsyou to hold a cigarette or take a fork and aim at that cake. That motor coordination requirespreparation, requires thinking, requires planning. And that comes from the prefrontalcortex which is another area that is dopamine linked. So planning to buy a pack of cigarettes.Opening it up, requires you to have a motor coordination as well as just planning. Just thinkingabout a cake, looking at it and aiming at it with a fork, that’s a planning process. That comes fromthe prefrontal cortex. It’s far more complex than just gobbling something up. But you can see howthree key areas- the amygdala the nucleus accumbens and the prefrontal cortex become lit up bydopamine that comes from the ventral tegmental area. And what good is all this if you can’t
Transcribed by Charles Buchanan Date of the Lecture: 10/22/14
remember it or associate it with good company. So now comes the hippocampus. And thehippocampus is where the memory is stored. It is the area- so if you are smoking and you’repart of a bunch of friends and you’re sitting in the bar and it’s wonderful- all that is part of yourhippocampal memory. And this is the reward map that you are essentially coming up each time.Now think about how much craving you have with all this. Because overtime you go into that bar,you will have an association lit up and say “I used to have my friends here, and it’s wonderful. Ihave all these great emotion. I need to light up.” Or you smell something that is part of youremotional memory and say ~whiff~ “Ugh, I remember this odor. It was a cigarette that I used tosmoke.” And the truth is, when I smoked, there was one particular cigarette. It was a Britishtobacco called Rutmans. It was white with blue beautiful lines. It was an amazing tobacco. I canstill smell it. 39 years ago. And I stopped smoking. That was the last cigarette. 39 years later, Istill smell that odor and it’s a pleasant odor. Someone else smokes now, obviously it’s a differentexperience, but that memory is so embedded because it’s a conditioned memory. It’s theamygdala that essentially brings a- you see odor, it’s one of the oldest and most powerful longterm memory. And it is something that you can use for associating positive or negative things. It’snot just odor. It works with anything. Kind of a personal story, my son was born. Actually, mywife was pregnant, uh, 36 years ago. And I was listening to a record by the Fleetwood Mac. How
many of you heard about the Fleetwood Mac? So 1976, they issued this record called Rumors
-amazing record. And I was listening to it all day long and my wife had morning sickness. And sheassociated the morning sickness with Fleetwood Mac. She could not listen, I was actually on theway back from Vermont 2 weeks ago, and I was listening to Fleetwood Mac, and she has no ideawhat group that is. And she said “that’s that group” and she has morning sickness till todaybecause of that auditory associated version, same works with memory that is formed by smellingsomething. Emotions are very important, and that’s the crux of addiction. The addiction isthat you essentially want that reward system if it’s a positive reinforcement. If it’s negative,obviously, you’re going to avoid it anytime you’re getting it. So it works both ways. So, I needyou to remember this pathway because it is something that is the crux of addiction.
[Slide 12] – [Nicotine Addiction][Dr. Spielman] – So why is the addiction actually taking place? It’s because the nicotinicacetylcholine receptors become desensitized and you need more and more to get the samereward. That’s the essence. Yes.
[Student] — Is there like a plateau on that like how much you need?
[Dr. Spielman] – Well, there is obviously the biological effect that too much is going to make youpuke. But, it is really certain. It goes up to the point that you’re probably going to smoke 3 packsa day, as my father used to do for 40 years, yeah. And he ended up with lung cancer. It is- there isa plateau but initially it can escalate very fast. So how does these cells cope with it? Theyessentially express a larger number of receptors so they don’t become more sensitive, they
just express a larger number. So if you have X amount of acetylcholine to go around, they justdistribute over a lot of receptors. So this is one where you’re expressing. You stop smoking, thatmeans there’s a down regulation of these receptors. Uh, it will lead, clearly to a larger level ofdopamine and therefore craving and reward system. So this remodeling of the brain circuit thatnormally reward the behavior are obviously far more active. You can see how all of these centersnow become intertwined and it’s almost a permanent network created. The problem is if youstop. Then there are, what is called a withdrawal syndrome. And that means that the bodyhas built in a system that you truly crave and you cannot stop unless you suffer. So what is
Transcribed by Charles Buchanan Date of the Lecture: 10/22/14
the system? The withdrawal system actually, it’s what is called the CRF (corticotropinreleasing factor system). This is the extra hypothalamic corticotropin releasing factor or CRPsystem. So this is relatively new. It’s a brain circuit that is being activated and makes youliterally sick upon withdrawal. Now, one idea is what if you could, somehow, block thecorticotropin releasing factor system. If you could block that, then the withdrawal system wouldbe diminished and therefore stop smoking would be far easier. And this is one of the targets thatthey are looking at in order to gure out can you use this as a system.
[Slide 14] – [Health Effects of Nicotine and Smoking][Dr. Spielman] – So what are the health effects of smoking?
[Slide 15] – [Chronic Exposure to Nicotine Leads to…][Dr. Spielman] – Well I don’t need to tell you how terrible it is. And all of these effects, and I’mnot going to go through these- it has clearly, the biological effect, it affects those receptorsthroughout the entire human body that have acetylcholine receptors. And chronic exposure,reduction of the receptor sensitivity, over expression of these receptors and therefore anover expression of the effect on those tissues is what you can see including blood pressureincreases, damage to the endothelium, damage to the bronchiae.
One of the things that yousee is that, normally the cilia on the bronchi have the ability to beat. Usually, they can clearup a trachea or bronchi 2-4mm a minute. So if you have a trachea, let’s say its 10 cm long,within a few hours, you should be able to clean up any particle or particulate material that isessentially is in the bronchi. Well, the cilia slow down in smokers. And, so, you end up with allthis mucus accumulating. If you know anyone that is a smoker, you will hear that their voice isnot clear and they have this accumulation. That’s the reason. The cilia really do not workproperly.
[Slide 15] – [Addiction and Genetics][Dr. Spielman] – Umm. This is another interesting discovery that was published in NatureGenetics in 2008 that showed that a particular variant of the acetylcholine receptor- nicotinic
acetylcholine receptor- has a high correlation with people that are born with it and have ahigher level of addiction (among Europeans in the CHRNA5 - Nicotinic ACH receptorsubunit, chr. 15, variation). Now, that’s not to take away the onus on people that are smokingand obviously would like to quit. But there are people who are more prone to that type ofaddiction because they express this variant. And so there is this higher correlation of peoplewho have addiction and present with that particular variant. And therefore have lung cancer.
[Slide 16] – [Nicotine Withdrawal][Dr. Spielman] – So these are the symptoms that you will see in individuals who smoke.Difculty concentrating, dysphoria, restlessness, heart rate deceases, appetite gain/loss andso on.
[Slide 17] – [Tobacco contains…][Dr. Spielman] – Nicotine contains- in cigarettes, it’s fairly high. So, why don’t we simply justgive people nicotine? Well, that’s the whole idea of nicotine patch, nicotine chewing gum - ofessentially trying to compensate. Or smokeless. This new electronic cigarette. How many of youhave seen these electronic cigarettes ? Ok? Any of you have tried? Ok. Do you think it’s good?Do you think it’s bad? You think that it’s not, not harmful. I mean, you’ve just eliminated
Transcribed by Charles Buchanan Date of the Lecture: 10/22/14
everything from the paper. The answer is, actually, it’s bad. It is not- I don’t think that we haveall the answers. But it is clear that if you have a controlled substance, such as nicotine, that youcan just smoke without any kind of control and amount, you will have biological effects. But now,we see that the ora, the bacterial oras in the oral cavity, might be shifting. So you canactually end up with the same type of problems that smokers have. So there’s somethingabout the smoke that affects the ora. Not necessarily the carcinogens by themselves. But,stay tuned because I believe that the data are going to show that these are actually harmful. Iwouldn’t just run in and say “nally we can smoke and there is no consequences.” I don’t thinkthat we know about the consequences. We actually know that nicotine absorption is dependenton a couple of factors. And that is- alkaline pH . If any of you have monitored this discussionthat the tobacco industry had when they had to have the settlements, and you may not have beenat that age to monitor it. But you need to know that the industry has denied that they havemanipulated their cigarettes. And that’s actually not true. What they have done is that they addedammonia to the nicotine and that made it far easier to absorb and therefore far easier tomake people addicted. So it’s really adding ammonia - simple idea - just add high pH, peoplehave a higher dose of nicotine. They feel good. Who cares? A little ammonia? It’s not going tohurt. That was the thinking in 1957. Because when the settlements- billions of dollars were at
stake. They started to talk about “well, let’s see the literature. Did you know or you didn’t?” Itturns out that in the 1950s, they had secret memos that said “we should add ammonia because thatwill make people smoke more.” Simple as that. Now, this has, actually, implications becausechewing nicotine gum with acidic soft drinks. So your patient comes and says “oh, I’mchewing the nicotine because I want to quit” but they also have a Coke. Is that a coke or a coffee?Anyone with a coke? It’s not good for you. So, not only because it’s acidic. Because the acidicpH modies the way that you’re absorbing the nicotine . So you want your patient to quit. Yougive them chewing gum, but that patient keeps on drinking the Pepsi or Coke or whatever it is.The acidity of that drink makes it inaccessible- the nicotine doesn’t absorb. So think twice, infact, if you prescribe and you will prescribe, make sure you mention “don’t have anything acidic.Don’t drink Coke or any kind of acidic soft drink with that chewing gum because you’re going toassume a certain level of nicotine and that will not be it. It makes it ineffective.”
You generate a certain level of nicotine in the blood and that nicotine is really degraded withoxidation. So if you have nicotine and it’s out in the air, it will degrade with the oxidation. So youneed to protect it if you actually want to reach a certain level in the blood. Chewing gum has to beprotected, or any of the products that you are trying to deliver. A patch would have to beprotected.And the half life is 2 hours. So these are important characteristics. If you really care about howmuch nicotine this patient gets.
[Slide 18] – [Nicotine concentrations in blood…][Dr. Spielman] – This is to show you that when somebody smokes, the level of nicotine in theblood shoots up very fast. In fact, within 10 seconds of taking a sip or taking a breath of a
cigarette, it will hit your brain. So nicotine- it will be through your lungs, it will reach yourbrain in 10 seconds. So that peak level comes down very fast. So when you prescribe a patch or achewing gum, you’re really looking at a different timeframe of delivery. The nicotine does not getto the brain. You can see, actually, the curve. The chewing is a slight- and these are minutes-chewing goes up and stays on, nicotine gum doesn’t reach the chewing tobacco. Of course, thechewing tobacco has all kinds of other side effects- oral cancer. Oral snuff goes up. So chewingtobacco and oral snuff are very similar. Nicotine gum reaches about half of the chewingtobacco and the patch has a very long- this is a slow releasing process- to give you a different
Transcribed by Charles Buchanan Date of the Lecture: 10/22/14
pattern. And that’s the reason why the patch and the nicotine gum can be combined becausethey deliver at different times. Ok, keep in mind. Now, nicotine patch has nothing to do withthe soft drink. And that could be one of the questions on the exam. Could you give an acidicsoft drink with your nicotine patch? Of course. It has nothing to do with - it’s the oral cavityand the acidity that has to coexist with the nicotine, with the chewing gum that makes itineffective. So, think. That actually was one of the questions last year.
[Slide 19] – [Ingredients in Cigarettes][Dr. Spielman] – So, what are the ingredients in cigarettes? Let’s think about this. I’m notlisting 4000 but you can see that there is cyanhydric acid used by the Germans in concentrationcamps to gas. You’re smoking it. Naphthalene . It’s a moth repellent. Urethane . You use it topaint or varnish stuff. Carbon monoxide , some people use it to commit suicide. Naphtylamine -a carcinogen. Dibenzacridine. Polonium 210 , gonna talk a bit about Polonium 210 because it’s aradioactive material. How on earth does Polonium get into cigarettes? Well, look at all this andget horried, because this is just the cream of the crop. The other 4000 or 3990 are still as nastyas this.
[Slide 20] – [Radioactive Smoke][Dr. Spielman] – So this is an article, 2011 in Scientic American that essentially describes, inlaymen's terms, how cigarettes got their Polonium.
[Slide 21] – [Polonium 210 and Smoking][Dr. Spielman] – And, any of you know who this gentleman is?
[Student] — Russian spy.
[Dr. Spielman] – Russian spy! Very good. What’s his name? Victor Litvinenko. Very good. So
this is the guy after he was poisoned with Polonium 210 by the Russian KGB. He knew toomuch, he spoke too much and so his old friends brought him to a fancy restaurant- bar in London.And while he was out in the bathroom, they dripped a few drops of liquid Polonium 210 into histea. He drank it and then months later, he looked like on the picture to your right. So how can aKGB agent walk into a bar in London and just simply drop Polonium 210 into tea. Couldn’t thisbe dangerous. Wouldn’t someone pick it up with a Geiger counter? Well, if you remember yourphysics, there are alpha particles, there are beta particles and there are gamma particles. Thishappened to be an alpha. And alpha particles are very short. You could literally- it’s a shortdistance- you could literally take a piece of paper, wrap it around and protect it. And there’sno radiation. If you’re careful enough, and obviously they were, you could carry it in an aeroight to London and then drop it into- this guys was dead and they silenced him. So Lugevoywho was the killer, is back in Russia. He’s a member of the parliament and he has immunity. So
he was never prosecuted by London. So what is this- why is this important? Because it broughtthe 210- Polonium 210 in our forefront. And that same nasty stuff is in cigarettes. So how does itget?
[Slide 21] – [Radiation and Smoking][Dr. Spielman] – Well, it turns out that the source of polonium in the smoke is actuallyRadium. It comes from 226 - this is obviously a radiation from the cosmos and it degrades
Transcribed by Charles Buchanan Date of the Lecture: 10/22/14
into Radon 222/220 . It’s absorbed into apatite rocks then were used as fertilizers andtobacco leaves have a very specic afnity for Polonium 210. So, for the past 50 years, thetobacco industry was making tobacco out of this fertilized leaves with a high level of Polonium.And everybody who was smoking U.S. made cigarettes was inhaling alpha particles. So howbad it is? Well if you smoke a pack and a half everyday- how many did you smoke?[Student] — It depends on what I was doing. Between 1 and 10.[Dr. Spielman] – Well 1 1/2 pack a day = 1 chest X-ray. I’m going to let it sink in. Becauseyou’re essentially allowed to do 1 chest x-ray a year. That’s safe. With 1 pack and a half, youessentially get 365 chest x-rays. It is an enormous amount of radiation. And the alpha particleis so shortened- so when you smoke it, it gets into your lungs and there’s nothing to protectit. No paper to wrap it. Your lung sacs, essentially, are coated by this tar that is deposited withPolonium 210 and essentially irradiates everything around it. So no wonder that after X numberof years, you get lung cancer. So, that’s really the story of Polonium 210.
[Slide 23] – [Radiation and smoking][Dr. Spielman] – And just to give you a couple of numbers so you can compare it. Tobaccogrown in the U.S. has 0.5 picoCurie. Tobacco grown in India has 0.09. They don’t use the
same fertilizer and we may have switched but this is still lingering. So, it is an enormous amountof burden. Cigarettes, again, we said essentially get 1.7 pico curie on a peak basis.
[Slide 24] – [Radiation Dose Comparisons from Common Life Activities][Dr. Spielman] – So these are some of the commonly some of the doses. You know, you y toCalifornia, you will have a radiation, caustic radiation of 6 rad. This is what it is. Chest X-rayis 6. Abdominal x-ray is 100. Annual average background radiation dose is , you sit outside,this is what you’re allowed, this is what you get. The abdominal CT scan is 1000. This is whatan annual limit is. And 2 packs of cigarettes is 83, but this is on a daily basis. On a yearlybasis, multiply this by 365. So obviously, cumulatively over 25 years, this is the dose. 752,000rads. Enormous. So if any of you ever thought about smoking, I hope you stop because this isclearly- lethal dose exposed is 450,000. So it is an enormous amount. It’s a huge burden.
[Slide 24a] – [ What receptor does nicotine bind to? ]
[Dr. Spielman] – So, that’s pretty much it. I just wanted to get some. (no kind of conclusion tothat sentence) How many of you think- what’s the correct answer. Which is the answer to thereceptor? It’s the number 3. Nicotinic acetylcholine receptor.
Transcribed by Charles Buchanan Date of the Lecture: 10/22/14
[Slide 24b] – [ What is the most addictive component of a cigarette? ]
[Dr. Spielman] – Again, this is probably. Which is the most. None of the above. You need to pay
attention. Because nicotine is not there.
[Slide 24b] – [ Chewing nicotine gum and drinking sweet carbonated soda is notrecommended because? ]
[Dr. Spielman] –And this is about nicotine and sweet drinking. This is actually a lot of thinking.chewing nicotine gum and drinking sweet carbonated soda is not recommended because nicotineand sugar are incompatible. Absorption of nicotine is inhibited by acidic pH. Nicotine and carbondioxide react to form nicotine monoxide. Chewing gum and drinking carbonated soda is bad foryour teeth or sweet soda activates Polonium? Yes, it is 2. So it is obvious. (Absorption ofnicotine in the oral cavity is inhibited in acidic pH)
[Slide 24c] – [How many of you smoke?][Dr. Spielman] – And make sure that you remember that it has nothing to do with the patch. It isonly the chewing gum. So, since nobody is smoking, I don’t think that I can save anyones soul.But I’m hoping that you have some relatives who may actually smoke and you will tell the story.
Transcribed by Charles Buchanan Date of the Lecture: 10/22/14
[Dr. Spielman] –And that’s basically it. The summary is on this slide. You need to rememberthat nicotine is addictive. It works on the N-acetylcholine receptor. It’s due todesensitization and increased receptor expression and dopamine release. And thewithdrawal activates the CRF system and you will need only one bad ingredient. Not 4,000.That’s just the bonus. Single smoking is the single most preventable item- health risk.
[Slide 26] – [References][Dr. Spielman] – And that’s it, you have these 2 links. And these are actually fascinating. TheKhan Academy. I will send it to the class so you can actually look at 8 minute videos on howsmoking and addiction works. It has the same kind of dopamine. I used the drawings from theKhan Academy because they are so good and so exquisite. Questions. Yes?
[Student] — You said the fertilizer is the source of radon? Are other things grown in thisfertilizer? Or is it just tobacco?
[Dr. Spielman] – No apparently tobacco leaves have a very unique way of accumulating so ithas not been found in other vegetables or food.
[Student] — So the radon is coming from the fertilizer but the leaves—
[Dr. Spielman] — The leaves actually amplify that response. Yes, that’s correct.
[Student] — So the study thats shown, the alpha 7 beta 4 receptors— they're amplied bynicotine? Do they show that the receptors are…were suppressed in the lungs? Because those arethe organs-
[Dr. Spielman] — They are essentially expressed in a number of- I think that the point is that thelungs have a double-whammy. So you have these receptors plus the intake. That’s the rst line of
defense. So by itself, the receptors would be expressed in other parts of the body as well. Thankyou. Oh, sorry, Pedram.
[Student] — Do you think the second had smoking has as much effect?
[Dr. Spielman] — Unfortunately, it does. Because you’re not really as exposed. Normally you’renot reacting. It is, if you live with someone who is smoking, second hand smoking is almost asbad. It’s not entirely, but it’s almost as bad. Thank you, guys.
