drug shortness of breath

dr. paul merritt: ok, sowe're going to continue lecture number six on nicotine. we just talked about caffeine. and now we'll talkabout nicotine, which is of course, anotherlegal, yet commonly used psychoactive substance. well, we'll firsttalk a little bit about nicotine epidemiology,a little bit about the history of nicotine, talk about itspharmacokinetics, its mechanism

of action, talk abouttoxicity and dependence, and then talk someabout smoking cessation and potential treatmentfor nicotine dependence. we'll finally wrap upwith a brief discussion on e-cigarette useand harm prevention. so let's start by talkingabout nicotine epidemiology. it's one of the three mostwidely used psychoactive drugs. it's the most preventablecause of disease and premature deathacross the world.

current use in the unitedstates fell from 50% in 1965 to 25% in 1998. we're now about under 10%. the average starting agefor people is declining. 9 out of 10 people areaddicted by age 21. so that's the biggestproblem we have is dealing with the age at whichwe have onset of nicotine use. but you can seefrom the top graph from the cdc-- lung cancer,coronary heart disease,

chronic pulmonary disease arethe major health side effects from tobacco use. taking a look at thehistory of nicotine, no society that hasever adopted tobacco use has ever given it up. once it's introduced,people become addicted. and they constantly use it. it's the only drug of abusethat is native to the americas. tobacco was used as atwo-pronged tube used

by natives of centralamerica to take snuff, used from paraguay to quebec. it's widely speculated thattobacco has been cultivated in the americas since 6000 bc. it was given to columbus whenhe landed at san salvador on october of 1492. and here on outis where we start to get the spread of tobaccouse throughout europe. so it was introducedby jean nicot

who was first sent tobacco seedsfrom portugal to paris in 1550. and he actively promotedits medicinal use. ironically, he claimedthat lung ailments could be cured by tobacco. within a decade of nicot'sseeds' arrival in france, the plant had made its way toengland, and quickly thereafter to virginia and othernew world locales. nicotine was firstisolated in 1828. and its molecular formulawas established in 1843.

in 1903, nicotine was firstsuccessfully synthesized by a swiss professorof chemistry in geneva. so pretty rapid introductionto the old world of europe, spreads quicklyto the new world. and of course, i don't haveto tell you the massive role that tobacco play in thedevelopment of the united states, the southern unitedstates, the slave trade, and of course, the civil war. tobacco was a substantialagricultural product

in the south really upuntil about the turn of the 21st century when wefinally start to get reductions in tobacco use,farmers getting paid to switch crops to tryto get fewer cigarettes available on the market. so how does nicotine work? well, nicotine was, again,separated out from tobacco. about 1 out of 4,000compounds released by the burning of tobacco.

it's a colorless,volatile liquids. it's an alkaloid. it's not well absorbedfrom the digestive tract. although a number of childrenpoison themselves each year from eating tobacco fromexposure to pesticides. so one of the biggest problemsassociated with tobacco is its pesticide applications. the amount of nicotinedelivered really depends on how thecigarette is smoked

and what kind of cigaretteis actually smoked. this is one of thebiggest problems with trying to replacenicotine in people who smoke. because it's a veryritualized, very specific dose. nicotine has a verynarrow point at which it is pleasant to smoke. too much and you get nauseousand dizzy very quickly. too little and it doesn'tsatisfy your craving. nicotine is metabolized bythe hepatic enzyme cytochrome

p286, which may be inhabitedby some ssri antidepressants. so you want to be verycareful by combining nicotine with antidepressants. if you look at theoverall nicotine yield, you can see nicotine yieldshave gone up over the years, and so are actuallymore and more addictive. if you look atmentholated cigarettes, they have higherlevels of nicotine. and there is some evidence thatmenthol combines with nicotine

to alter itspharmacokinetic properties. and in fact, mentholcigarettes have been developedspecifically to appeal towards certainethnic groups tastes. and there is some evidence oftargeting those ethnic groups. so nicotine can be absorbed fromevery site on or in the body. cigarettes are made fromflue-cured tobacco, which makes it an acidic smokethat reduces absorption from the mouth.

so nicotine must beinhaled from the lungs where it's ph has noeffect on absorption. nicotine is suspendedin cigarette smoke in the form of minuteparticles or tars and is quickly absorbed intothe bloodstream from the lungs. pipe and cigartobacco are air-cured. and this makes an alkalinesmoke so that nicotine can be absorbed fromthe mouth and does not need to be inhaled.

that's the biggest differencebetween cigarettes and pipe and cigar tobacco iscigarettes are inhaled, pipe and cigar tobacco are not. nicotine is quicklyand thoroughly distributed in the bodyto the brain, placenta, and all bodily fluidsincluding breast milk. the liver metabolizes about80% to 90% of nicotine before it's excretedby the kidneys. elimination half-life isapproximately two hours.

the major metabolite ofnicotine is cotinine. and this is one of thebases for testing to see if somebody has been smoking. oftentimes, insurancecompanies who will offer lowerrates for nonsmokers will verify that througha urinary cotinine test. for smokers, carbonmonoxide is also detectable in theirbreath for hours after their last cigarette.

in fact, i've conductedresearch on nicotine withdrawal. and we use a carbonmonoxide breathalyzer to detect whether or not theyhave been smoking recently. so these are avariety of components contained in a cigarette. lots of different componentsthat come out of a cigarette, including potentially arsenic,carbon monoxide, methanol, hexamine, toluene,nicotine, ammonia, lots of things that aren'tparticularly healthy for you.

how does nicotine work? well, it has anindirect activation of the sympatheticnervous system. it occupies and activates thenicotinic cholinergic sites. remember, there arenicotinic and muscarinic acetylcholine receptor sites. so it occupies and activatesthe nicotinic cholinergic sites. low doses stimulatethose receptors. high doses will actuallyblock the receptors.

high doses ofneonicotinoids are the basis of a lot of pesticides. so nicotine and pesticidesare highly related. this simulation of thereceptor causes the release of dopamine, whichmay be related to the reinforcingeffects of nicotine. also it causes the release ofacetylcholine and glutamate. nicotine has been tiedwith memory performance. it was once thoughtthat perhaps we

could provide nicotinesupplementation to older adults to improve their memory. and that has not panned out. because by the time yougive someone enough nicotine to improve their memory,they have a tendency to become dizzy and nauseous. so the question is wouldnicotine-derived drugs help dementia? well, there is limited evidencethat that has been the case.

but there is ongoingresearch to try to determine whether somesort of neonicotinoid might benefit dementia patientsby increasing acetylcholine. so nicotine attaches tonerve cells in the brain at receptors onthe cell membrane. so if you see there nicotinicacetylcholine receptors, they stimulateneurotransmission. so it's entirelypossible that you might be able to get some sortof beneficial memory effect

from some sort of neonicotinoid. through the pharmacologicaleffects of nicotine, it initially causesnausea and vomiting by stimulating thevomiting center in the brain stem and sensoryendings in the stomach. people who continuesmoking become tolerant to these effects and theyno longer notice them. it stimulates thehypothalamus to produce antidiuretic hormone, whichcan cause fluid retention.

it reduces activity comingin from the muscles, producing relaxation. this is one of the paradoxicaleffects of nicotine is it's technicallyanxiogenic, that is, it increases neural activityand should cause anxiety. but people say it relaxes them. and it seems to be due tothis muscle relaxing activity. it also increases yourheart rate, blood pressure, and contractility.

the carbon monoxide insmoke combines with oxygen better than hemoglobin. so it decreases oxygencarrying capacity and actually suffocates cells. so some majorcombination effects derived from smoking cigarettes. nicotine also constricts theblood vessels in your skin, producing cold, thin skin. it also causes yourskin to wrinkle faster.

it inhibits stomach secretionand stimulates bowel movements. so actually, in anon-tolerant person, it will function as a laxative. it may increase themetabolism of fat. this is one of the problemswith trying to get people off nicotine is oftentimesthey will gain weight and they find that intolerable,and so will go back to smoking. one big problem withpeople who smoke is it does dulltheir taste buds.

smoking slowsstomach contractions and increases blood sugar. again, nicotine may approveattention and memory. although, certainly high dosescause increases in nervousness, tremors, even causeseizures and panic attacks. so while it is associatedwith improvements in attention and memory, it'sdifficult to foresee a way in which you can dose thisright to make it a good memory enhancer.

there is a chancethat nicotine has some antidepressant effects. and there's some questionabout whether or not smokers are self-medicated totry to treat their depression. maybe some of them are. but so many people startsmoking at such a young age that it seems unlikely to me. another note under the mechanismof action is nesbitt's paradox. as i was saying earlier,there's a little bit

of a paradox in terms ofhow nicotine affects people. it causes arousal andrelease of epinephrine, which should be anxiogenic. yet most people sayit relaxes them. and this may be relevant tothe reason why people smoke. a couple of questionsabout why this might be. is it simply relieffrom withdrawal? that is, do peoplerelax because it eases their anxietyabout the fact

that they haven't been smoking? does it depend on the situation? do they get relaxation withhigh stress and stimulation with low stress? it's really unclear. but there certainly issomething situational. and certainly, smokers reportpositive subjective effects if nicotine is given bysmoking or intravenously. but nonsmokers absolutelydo not like nicotine.

so there is something tothe individual differences in people who have becometolerant to its effects. we're starting tounderstand too that there is a genetic componentto propensity for nicotine addiction. that is, thosenicotinic receptors are different incertain genotypes. and so it's somethingwe'll talk more about later on in the semester.

so why does nicotine--and why does smoking in particular--cause such damage? well, nicotine can cause acertain amount of toxicity. nicotine increases theworkload of the heart. carbon monoxide decreasesthe oxygen supply. it reduces the lungs' abilityto get oxygen, which may make the heart work even harder. it's known to increasearterial sclerosis, which is, of course, blocking of thearteries and thrombosis.

that is, it increasesthe risk for blood clots particularly in women whoare taking birth control. so if you take anoral contraceptive, smoking in combinationwith that puts you at really significantrisk for stroke. obviously one of the mostsignificant effects of smoking is lung disease. my father died of lung cancer. he was a lifetime smoker.

ash and tar are deposited inthe membranes of the lung. this reduces the action ofthe cilia and phagocytes that would normallyclean these tissues. and as a result, the lungscan get pretty gunked up. you can tell pretty clearlysomebody who smokes quite a bit based on their hacking cough. so this is what a healthy lunglooks like here on the left. in the middle is adisease lung from smoking. so there's certainlyan increased risk

of cancer of the lungs,mouth, and bladder. this is greatlyincreased by alcohol. less than 10% ofnon-smokers get lung cancer. so this really is directlyassociated with smoking. another problem or complicationassociated with smoking is reduce oxygendelivery to a fetus. it decreases fertility inboth males and females, produces smaller babies, morestill births, premature babies, and sick babies,and may increase

the risk for suddeninfant death syndrome. one thing we know is peoplecan develop tolerance to some of theeffects of nicotine as we've already discussed. and we certainly knowmany people, again, become dependent on nicotine. there's a littlebiological tolerance. smokers usually dose themselveswith very consistent amounts. withdrawal symptomsfrom nicotine

include irritability,anxiety, anger, difficulty in concentrating, restlessness,waking, and insomnia. long term nicotine use causesan alteration in gaba systems in the hippocampus. because nicotine inhibitsgaba removal of nicotine, during withdrawal causesincreased gaba activation. and we have shown becauseof this increased gaba activation duringwithdrawal, heavy smokers show marked reductions inmember performance falling

24 hours of abstinence. and this is a fairlyclear finding. we have found it in threedifferent research papers. and others have foundthe same finding throughout the literature. in one paper we found, theremaybe some sex differences in the cognitiveeffects of withdrawal. and certainly we knowthat there are differences in how men and women respond todifferent kinds of treatment.

so quitting smokingis obviously something most everyone should consider. so when you stopsmoking, your body begins to repair itselfalmost immediately. within 20 minutes, yourblood pressure returns to normal and yourheartbeat will stabilize. within eight hours, theoxygen level in your blood will increase. mucus begins to clearout of your lungs,

making it easier to breathe. within 48 hours, you'll startto get your sense of smell and taste back. your chances of heart attackwill start to decrease. within three months, youget improved circulation and immune system responses. within nine months, sinuscongestion, wheezing, shortness of breath, andphlegm production decrease. lung function improves.

within a year, you get therisk of dying of a heart attack is cut in half. five years, yourrisk of a stroke is back to that ofbeing a non-smoker. and after 10 years, your riskof lung cancer is cut in half. so lots of positive effectsfrom quitting smoking. so how do we goabout doing this? well, various therapies. low nicotine content cigarettesappear to be not a helpful way

to get people to quick smoking. they just smoke more ofthem, causing more harm. substitution or replacementof nicotine by things like nicorette gum, nicotinepatches, nasal sprays, and inhalers aredifficult. because trying to match the dosage of nicotineis very difficult. people are very expert at theirability to get the exact right of nicotine when they smoke. they inhale a certain amount.

they hold it in for acertain amount of time. they smoke the same brandof cigarettes all the time. and so they are really good atregulating their own nicotine content. and so trying to replacethat with some other way is very difficult. there are potential effortsto reduce simple craving. so some antidepressants,particularly those that involve thedopaminergic system,

are particularly effective. so bupropion which is buspar,or zyban, which is wellbutrin, have some efficacyin reducing craving. all replacement methodsare equally effective, approximately doublingthe quit rate of smokers, without any other kind of help. but 90% of smokersstop without help. deciding which is the mostrelevant factor in smoking-- pharmacologicaladdiction, there's

sensorimotor, and the cognitiveeffects of withdrawal, social factors, anddecreasing with prohibitions. so trying to figure outwhich is most relevant factor to get people to stopsmoking-- obviously, the pharmacological addictionis a big part of that. there are a lot of sensorimotorcues associated with smoking. so there is kind of thisstimulus response effect. and this seems to beparticularly salient in women. that is, they respondmuch more to smoking cues

and tend to be moresocial smokers. so that's where we startto get into social factors. decreasing smokingwith prohibitions has certainly been effective. by prohibiting smokingin public areas, one of the most effectiveways to decrease smoking is by increasing taxrates on cigarettes. in fact, we call theseso-called syntaxes. i believe it's more ofan economic externality

by recouping the cost ofsmoking through increased taxes. so factors that createthe addiction for people who smoke-- about 10% to 15%of current alcohol drinkers are considered problem drinkers. but about 85% to 90%of cigarette smokers consider themselvesaddicted to nicotine. so highly addictive. you get very rapid andfrequent reinforcement. so for every pack of cigarettes,you get 200 reinforcements.

you get rapid metabolism. so that clearance allowsfor frequent repeated use plus this rapidonset of withdrawal. these complex directpharmacological effects and social rewardsof the peer group-- although that'scertainly changed. smoking is now almostmore of a stigma than it is anything else. and smoking cansometimes be conditioned

to other activities. some people say theylike to eat and smoke, which i find perplexing. i just can't imagine eatingand smoking at the same time. but certainly, i'veseen plenty of people who are social smokers,people who just smoke at the end of the day,a lot of people who smoke a lot when they drive. and so there is this sort ofstimulus response relationship

between these effects. so other factors that createthis potential for addiction-- there's no performanceimpairment with smoking. in fact, there may be evenimprovement and alertness in reaction time forpeople who use nicotine. it used to berelatively inexpensive. i think at this point, keepinga smoking habit is probably not that far away froma cocaine habit. you don't require anyspecialized equipment.

you don't need a needleor a bong or anything. you just need a lighter. and it's readily available. any convenience store really iswhere you can find cigarettes. and of course, it'sportable and easy to store. and so all of these thingsmake it much easier for people to get at their nicotine. and of course, it'slegal for ages 18 and up. although, in california, thisjust change to 21 and up.

how do we treatnicotine dependence? well, pharmacotherapy isthe primary alternative for treatingnicotine dependence. we of course have nicotinereplacement therapy through gums, patches,even inhalers. the bupropion, which is,again, wellbutrin or zyban, is another potential treatment. and finally, we have the partialnicotinic receptor agonist varenicline, which is marketedunder the brand name chantix.

and this has beendemonstrated to be very effective in treatingnicotine dependence. unfortunately, not everyoneresponds well to varenicline. in fact, when we get totalking about pharmacogenetics and pharmacogenomics,we'll take a look at the problem ofpeople who are what we call hardenedsmokers who have a different genetic makeup whodon't respond to varenicline. in conjunction withpharmacotherapies,

some specific cognitivebehavioral therapies often work. so a specific quitdate might be set. so one of thethings we often have is no substantial social,occupational dysfunction. so that makes it easier to do. there's less need forfamily involvement. and there are effective over thecounter treatments available. varenicline is byprescription only.

but most nicotine replacementcan be taken over the counter. in terms of assessinghow dependent someone is, we can use a number ofmeasures-- number of cigarettes per day. there is the fagerstromtest of nicotine dependence, which tests a variety of issueswith nicotine dependence. if you score lessthan three, there is little to nonicotine dependence. greater than six isconsidered highly dependent.

you could also measurenicotine in cotinine levels in blood, saliva, and urine. nicotine use can bedetected within hours. cotinine reflects tobaccouse in the last seven days, and carbon monoxide breathanalysis in the last few hours nicotine replacementtherapies can be used as a first line of treatment. there are five fda-approvednicotine replacement therapies. these include patches, gums,lozenges, nasal sprays,

and inhalers. the difficulty here isin matching the dosage. we're going to talk aboute-cigarettes or vaping later. but it's a potential way toreplace one form of nicotine with another that maypotentially be less harmful. the evidence isstill out on that. but we'll talk more aboutthat here in just a moment. but you can combine nicotinereplacement therapies or you can combinenicotine replacement

therapy with bupropion. and that seems to be effective. so bupropion, again, can also beused as a first line treatment. target dose is about300 milligrams per day. start at 150 milligramsper day seven days prior to the quit date. after three or four days,you increase your dose to 300 milligrams bytaking it twice a day. side effects includejitteriness, insomnia,

and potentiallysome gi symptoms. there is the risk for seizure. definitely notsomething that should be used in anyone with anysort of eating disorder. so that's somethingto keep in mind. varenicline, or chantix,was approved in 2006. it is a unique monoamineoxidase inhibitor and is a partial agonist atthe nicotinic acetylcholine receptors.

it blocks theability of nicotine to stimulate the acetylcholinereceptors, thus blocking activation of dopamine. its elimination half-lifeis about 24 hours, which makes it almost perfectfor taking once a day. people who takevarenicline start taking it and smoke and just graduallyreduce their cigarette use. and because they're nolonger getting any reward from that cigaretteuse, it completely

disconnects the rewardfrom cigarette smoking. so dosing is usually after mealsand with a full glass of water. recommended does of chantixis one milligram twice a day following a one-weektitration as follows-- days one through three halfa milligram daily, days four through seven,half a milligram twice a day, days eight through the end,one milligram twice today. course of treatment is usually12 weeks plus another 12 weeks if they've managedto stay abstinent.

most common side effectof varenicline is nausea. but here's how itlooks out if you look at continuous abstinenceafter nine to 12 weeks. varenicline has thehighest success rate. placebo, of course, isthe lowest success rate. but some peopledo manage to stay abstinent with no helpto weeks nine through 24. again, still get the bestresults with varenicline and even out to a year later.

so much better resultsfrom varenicline. about 25% managed to obtaincontinuous abstinence if they quit with varenicline. again, just some datashowing various dosing regiments, comparingto bupropion. this is data fromthe manufacturer. so you want to always takethat with a dose of skepticism. but it doesdemonstrate efficacy. final thing i want totalk about with nicotine

is e-cigarette use. a principal componentof drug treatment is this idea of whatwe call harm reduction. and we're going to talkquite a bit about this when we get todiscussing opioids and how to potentially reducethe harm from opioid addiction. so e-cigarettes havebeen shown to be less harmful thantraditional cigarettes. but they are still more powerfulthan quitting altogether.

so some studies have shownhigh oxidative stress on lung tissue and somepotentially harmful components. the other issue withvaping is the nicotine dose is much lower. so they'll tend tohave to inhale a lot more to try to get the samedose as their cigarettes. so oftentimes,there's some concern about the high oxidative stress,and again, these potentially harmful components.

but again, if we're talkingabout relative harm, e-cigarettes are muchbetter than standard tobacco cigarettes. again, it's easier for peopleto match that nicotine dose and potentiallyreduce their nicotine usage by switching to vaping. so e-cigarettes havebeen shown to provide an appropriate nicotinereplacement therapy and can lead to total cessation.

the biggest problem currentlywith use of e-cigarettes is kids. fda just moved to regulatee-cigarettes in may requiring only salesto those over 18. most jurisdictions alreadyhave that, but not all. but as you can see,about 14% of 10th graders have been usinge-cigarettes compared to 7% of conventionalcigarettes. so we really wantto try to not have

a new generationof kids that are addicted to nicotine by vaping. so while vaping isgood for someone to transition fromtobacco to, we certainly want to keep peoplefrom starting on nicotine with vaping. well, thank you. and that's all of ourdiscussion of nicotine. i hope you found it interesting.

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