stimulants pharm
DESCRIPTION
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13. Be familiar with the pharmacokinetics and pharmacology of nicotine and with current approaches
to the treatment of smoking. KEY WORDS AND PHRASES: cocaine, norcocaine, d-amphetamine, dl-amphetamine, methamphetamine, phentermine, diethylpropion, methylphenidate, nicotine LECTURE OUTLINE: A. Cocaine 1. Introduction
Cocaine is schedule C-II. Crack is free base cocaine, a form of cocaine that can be smoked. To make crack, cocaine is
processed with ammonia or sodium bicarbonate and water, then heated to remove the hydrochloride. "Crack" refers to the crackling sound heard when the mixture is smoked (heated), presumably from the sodium bicarbonate.
2. Epidemiology
Pharmacokinetics Absorption
oral ingestion slow absorption (30-60 min) low bioavailability (30-40%; first pass effect)
snorting bioavailability limited due to constriction of
nasal mucosal vessels smoking or IV
rush occurs within 1-2 minutes Distribution
most tissue, including fetus
t = 1-1.5 hours
0 15 30 45 60time
Coc
aine
"hi
gh"
smoking/IVsnortingoral
1975 1980 1985 1990 1995 20000
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10
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NIDA, Monitoring the Future Study, 2000
Percentage of High School Seniorswho ever used cocaine or crack
Cocaine Crack
Perc
enta
ge
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oral cocaine is as effective as intranasal; peak plasma concentrations are similar; peak highs (in laboratory setting) after both routes maintained for 60 minutes (contradicts "street" reports of 15-20 minutes); cardiovascular and subjective effects are highly correlated with rapid increase in plasma levels; effects decline faster than plasma concentrations
3. Metabolism
Cocaine is metabolized to: ecgonine methyl ester by liver and plasma cholinesterases norcocaine by N-demethylation; this is an active metabolite which may in part determine
cocaine's toxicity (e.g., paranoia, convulsions, respiratory arrest); it is more potent than cocaine as a local anesthetic; it is as potent as cocaine in inhibiting norepinephrine uptake
benzoylecgonine by nonenzymatic hydrolysis; it can persist in brain for up to 10 days after cocaine injection; it constricts arteries in brain (may lead to delayed seizures and strokes)
Cocaine + ethanol lead to the formation of: cocaethylene by liver and plasma cholinesterases; it is as potent as cocaine on dopamine
uptake but much less potent on 5HT reuptake; in mice (and probably in humans) cocaethylene is 50% more potent than cocaine in causing lethality
Ethanol may also increase plasma concentration of cocaine CONCURRENT USE OF ETHANOL INCREASES THE RISK OF COCAINE-RELATED SUDDEN DEATH 18-FOLD
4. Neurochemical effects Without the presence of cocaine
dopamine is released in the synapse it interacts with its receptors it is cleared by reuptake
In presence of cocaine cocaine blocks dopamine re-uptake dopamine levels increase in the synapse cocaine blocks also norepinephrine and serotonin reuptake
5. Acute effects of cocaine euphoria increased sense of energy, enhanced mental acuity, increased self-confidence anxiety decreased appetite decreased need for sleep activation of the sympathetic system:
mydriasis tachycardia hypertension peripheral vasoconstriction
6. Signs of cocaine abuse nasal perforation madarosis (loss of eyebrows or eye lashes) cocaine tracks (injection sites)
7. Medical complications of cocaine abuse neurologic/psychiatric complications
cerebral infarction and hemorrhage seizures depression
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psychosis (paranoia-like) cardiovascular complications
myocardial ischemia arrythmias
infectious complications (due to IV administration) HIV hepatitis B, C endocarditis
8. Stimulant abstinence syndrome Crash
extreme exhaustion craving for sleep (increased REM) hyperphagia dysphoria (anxiety and depression) lasts 3-4 days
Withdrawal decreased energy (fatigue) anhedonia fluctuating drug craving (leading to binges) symptoms increase 12-96 hours after crash lasts 6-18 weeks
Extinction episodic drug craving lasts months to years
9. Cocaine overdose Symptoms
usually manifested by seizures and cardiopulmonary arrest death usually due to respiratory failure immediate death from heart failure may be due to:
direct toxic effect on heart muscle spasms and constriction of coronary arteries platelet activation
Treatment diazepam may control seizures chlorpromazine may be used for psychotic symptoms (e.g., paranoia) the use of propanolol for cardiovascular symptoms is controversial
B. Amphetamines 1. Structure-activity relationships of phenylethylamines
Amphetamine -CH3 is important for anorexia blocks MAO activity
methamphetamine N-CH3 Increases stimulant potency
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Symptoms usually manifested by seizures and cardiopulmonary arrest death usually due to respiratory failure immediate death from heart failure may be due to:
direct toxic effect on heart muscle spasms and constriction of coronary arteries platelet activation
Treatment diazepam may control seizures chlorpromazine may be used for psychotic symptoms (e.g., paranoia) the use of propanolol for cardiovascular symptoms is controversial
B. Amphetamines 1. Structure-activity relationships of phenylethylamines
Amphetamine -CH3 is important for anorexia blocks MAO activity
methamphetamine N-CH3 Increases stimulant potency
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2. Epidemiology
3. Neurochemical effects With increasing doses:
reverses vesicular and membrane uptake transporters-- releases cytoplasmic catecholamines inhibits re-uptake of catecholamines inhibits MAO releases serotonin and inhibits serotonin re-uptake
4. Methamphetamine Street names
"speed", "meth", "chalk", "ice", "crystal", "crank", "glass". Route of administration
oral smoking snorting IV injection
Methamphetamine versus cocaine Methamphetamine
Man-made Smoking produces a high that lasts 8-24 hours 50% of the drug is removed from the body in 12 hours
Cocaine Plant-derived Smoking produces a high that lasts 20-30 minutes 50% of the drug is removed from the body in 1 hour
5. Acute effects of amphetamines extreme elation wakefulness alertness enhanced self-confidence aggression talkativeness loss of appetite increased initiative increased physical activity increased respiration
1992 1994 1996 1998 2000
4,000
6,000
8,000
10,000
12,000
14,000
16,000
18,000
drug
-rela
ted
emer
genc
y de
partm
ent e
piso
des
methamphetamine amphetamine
hyperthermia increased heart rate and blood pressure
6. Medical complications of amphetamine abuse neurologic/psychiatric complications
episodes of violent behavior, paranoia, anxiety, confusion, and insomnia repetitive behavior patterns, and delusions of parasites or insects under the skin acute lead poisoning (illegal methamphetamine production uses lead acetate as a reagent) hyperthermia and convulsions
cardiovascular complications arrythmias stroke
infectious complications (due to IV administration) HIV hepatitis B, C endocardis
liver, kiney, brain damage? 7. Amphethamine withdrawal
deep depression craving, fatigue etc. (stimulant abstinence syndrome)
8. Amphetamine overdose Symptoms
restlessness tremor confusion paranoia psychosis hallucinations panic aggressiveness hypertension tachycardia, arrythmias seizures fever
Treatment safe, quiet environment ice baths anticonvulsant drugs benzodiazepines neuroleptics
9. Therapeutic uses of amphetamines Weight loss
Therapeutic targets for obesity Food intake central control
monoamines (norepinephrine, 5HT, dopamine, histamine) neuropeptides (neuropeptide Y, proopiomelanocortin, cocaine- and amphetamine-
regulated transcript, corticotropin-releasing hormone, insulin, agouti-related protein)
Food intake peripheral control leptin GI peptides (cholecystokinine, ApoA-IV) pancreatic peptides (glucagon-like peptide-1, enterostatin, amylin) nutrients
Fat absorption lipase inhibitors fatty acid transporters
Fat metabolism diacylglycerol transferase adipocyte differentiation angiogenesis apoptosis
Thermogenesis thyroid hormones 3 adrenergic agonists uncoupling proteins
Central regulation of food intake
Brain regions ventromedial hypothalami nucleus (VMN) = satiety center lateral hypothalamic nucleus (LHA) = hunger center arcuate nucleus (ARC) paraventricular nucleus (PVN) perifornical area (PFA) dorsomedial nucleus (DMN)
Neurotransmitters that suppress food intake Norepinephine
1 receptor agonists 2 receptor agonists NE releasers NE uptake blockers
5HT 5HT2c receptor agonists 5HT releasers 5HT uptake blockers
Dopamine D1 receptor agonists
Abbreviations: AM, amygdala; CC, corpus callosum; CCX, cerebral cortex; HI, hippocampus; ME, median eminence; OC, optic chiasm; SE, septum; TH, thalamus; FX, fornix; 3V, third ventricle.
peptides
Increased adiposity leads to increased leptin production in fat tissue. Leptin stimulates neurons in the arcuate nucleus of the hypothalamus that coexpress the anorexigenic hormones -melanocyte-stimulating hormone ( -MSH, a cleavage product of proopiomelanocortin [POMC]) and cocaine- and amphetamine-regulated transcript (CART). Leptin also inhibits neurons in the arcuate nucleus that coexpress the orexigenic hormones agouti-related protein and neuropeptide Y. The neurons in the arcuate nucleus project to other regions of the hypothalamus (including the paraventricular nucleus and the lateral hypothalamic areaparafornical area), where -MSH binds to its receptor, MC4R, resulting in an up-regulation of anorexigenic effectors such as corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH) and a down-regulation of orexigenic effectors such as melanin-concentrating hormone (MCH) and orexin. Agouti-related protein acts as an antagonist of MC4R.
Other anorexic agents
phentermine (Ionamin) releaser and uptake blocker of dopamine and NE schedule C-IV short-term treatment of obesity (8-12 weeks)
diethylpropion (Tenuate) schedule C-IV oral, indirect acting, nonamphetamine, sympathomimetic amine direct stimulation of the satiety center monotherapy for short-term treatment of obesity (8-12 weeks)
phendimetrazine (Plegine) schedule C-III oral, indirect acting, nonamphetamine, sympathomimetic amine direct stimulation of the satiety center monotherapy for short-term treatment of obesity (8-12 weeks)
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fenfluramine, dexflenfluramine, phenylpropanolamine and sibutramine have been discontinued in the US
Narcolepsy Modafinil (Provigil)
Attention deficit hyperactivity disorder What is ADHD?
ADHD is a childhood psychiatric disorder characterized by inattention impulsivity overactivity
neurobiology MRI studies found right prefrontal cortex, caudate nucleus and globus pallidus were
smaller than normal in boys with ADHD Genetic studies suggest that people with ADHD might have alterations in genes
encoding either the D4 dopamine receptor or the dopamine transporter In people with ADHD, the brain areas that control attention used less glucose,
indicating that they were less active (PET) ADHD treatment
methyphenidate (Ritalin) schedule CII short half-life needs to be taken 3-4 times a day catecholamine releaser extended release tablets (Concerta)
d-amphetamine (Dexedrine) schedule CII half-life 8-10 hours
d-amphetamine + dl-amphetamine (Adderall) schedule CII half-life 8-10 hours lisdexamfetamine (Vyvanse )-- prodrug metabolized to d-amphetamine
guanfacine (Intuniv) not scheduled half-life 4-6 hours norepinephrine alpha 2 agonist non-stimulant
atomoxetine (Strattera) half-life 4-6 hours norepinephrine uptake blocker non-stimulant increased risk of suicide?
C. Nicotine 1. Epidemiology In 1996 (National Household Survey on Drug Abuse)
62 million Americans were current smokers. 6.8 million used smokeless tobacco. 3,000 people under the age of 18 will start
smoking. 2. Pharmacokinetics
Absorption 0.5 M
8:00 pm
0.1 to 0.2 M
8:00 am8:00 am
Brai
n co
ncen
tratio
n
half-life 8-10 hours lisdexamfetamine (Vyvanse )-- prodrug metabolized to d-amphetamine
guanfacine (Intuniv) not scheduled half-life 4-6 hours norepinephrine alpha 2 agonist non-stimulant
atomoxetine (Strattera) half-life 4-6 hours norepinephrine uptake blocker non-stimulant increased risk of suicide?
C. Nicotine 1. Epidemiology In 1996 (National Household Survey on Drug Abuse)
62 million Americans were current smokers. 6.8 million used smokeless tobacco. 3,000 people under the age of 18 will start
smoking. 2. Pharmacokinetics
Absorption 0.5 M
8:00 pm
0.1 to 0.2 M
8:00 am8:00 am
Brai
n co
ncen
tratio
n
Lung: very rapid. The drug reaches the brain within 8 sec. GI tract: slow absorption via buccal mucosa, more efficient via intestines, but high first-pass metabolism. smokers maintain a serum concentration of about 0.1-0.2 M during the night.
Distribution In most tissue, including embryo and fetus if pregnant woman (spontaneous abortion, preterm birth, low birth weights).
Excretion Kidney.
3. Metabolism C-oxidation by cytochrome P450 (CYP2A6 genetic polymorphisms). T1/2 is about 2 hours. Metabolites: cotinine, nornicotine. Males metabolize faster than females. Eating increases nicotine metabolism ( hepatic blood flow).
4. Neurochemical Effects nicotine receptors are ion channels they are localized in the VTA nicotine binds to its receptors dopamine neurons are activated dopamine is released in the nucleus accumbens
5. Acute effects of nicotine Relaxation Reduced stress Increased vigilance Improved cognition Reduced body weight Dizziness, nausea Tachycardia, peripheral vasoconstriction
6. Medical complications of nicotine abuse Cancers
lung cancer cancers of the mouth, pharynx, larynx, esophagus, stomach, pancreas, cervix, kidney, ureter, and bladder
Lung diseases chronic bronchitis emphysema exacerbation asthma symptoms
Heart diseases stroke heart attack vascular disease aneurysm
Accidents residential fire fatalities
Role of environmental tobacco smoke secondhand smoke major source of indoor air contaminants linked to lung cancers, cardiovascular diseases, increased severity of asthma for children.
Nicotine poisoning
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accidental ingestion by children death from respiratory failure caused by paralysis.
The adverse effects of smoking during pregnancy: increased premature delivery rate decreased birth weights
7. Nicotine abstinence syndrome Irritability, impatience, hostility Anxiety Dysphoric or depressed mood Difficulty concentrating Restlessness Decreased heart rate Increased appetite or weight gain
8. Treatment of nicotine abuse More than 90 percent of the people who try to quit smoking relapse or return to smoking within 1 year, with the majority relapsing within a week. An estimated 2.5 to 5 percent succeed on their own. Pharmacological treatments can double the odds of success. Combination of pharmacological and behavioral treatments further improves the rate of success
Nicotine replacement treatments approved for use in the United States: nicotine gum (1984, OTC 96), the transdermal patch (1991, OTC 96), nasal spray (1996), and inhaler (1998) used to relieve withdrawal symptoms provide users with lower overall nicotine levels than they receive with tobacco have little abuse potential since they do not produce the pleasurable effects of tobacco products do not contain the carcinogens and gases associated with tobacco smoke. produce less severe physiological alterations than tobacco-based systems
Non-Nicotine Therapies bupropion: approved for use in the United States in 1997, an antidepressant marketed as Zyban; contains no nicotine; exact mechanism unknown, although it blocks nicotinic receptors and weakly inhibits dopamine uptake varenicline: approved for use in the United States in 2006; marketed as Chantix; contains no nicotine; partial agonist (agonist/antagonist) at nicotinic receptors
Behavioral Treatments discover high-risk relapse situations develop self-monitoring of smoking behavior establish coping responses
Cocaine Amphetamines Nicotinecocaine, amphetamines (d, racemic, L amphetamine, methamphetamine (d-methamphetamine)
Crack is freebased cocaine, mixed cocaine~HCl + H2O + na2Hco3 = crack bicarbonate + co2 + H2ococaine is usually cocaina HCl
epidemic in the 80s, newer in the 90s, more steady in the 2000 (high school students)
3-4% of high school seniors have used
it is absorbed orally, nasally, smoking, IVsmoking is quickest way (same as IV) oral is slowest
rout of administration dictates the how addictive it isthe faster = more addictivethe shorter acting drugs are federally higher rated(lower scedule level)t.5 = 1- 1.5 hours
not activeis active, but not that contribuatory
is not thought to be bioactivemay be responsible for strokes and seizureseffect are cumulative
coke + etoh has been described as being the most addictvedrug of all time: more DA > 5HT serotining regulates DA is a highly addictive drug concrrent use increases sudden death by 18 ethanol ---x metabolism of coke = raising plasma levels
Mechanismnormally: prsynaptic DA ---> diffusioncocaine ----x DA reuptake = more DAsame thing happenes @ NE and 5HT sitesbut the DA mechanism is thought to be the most importantas far as CNS, toxic, and dangerous effects of DA
Coke raises the EC [DA] in critical areas of the brain (like other addictive drugs)mainly the Nuc. AAcumbens responsible for reward (reward center)all addictive drugs have been found to raise DA in the nucleus accumbenscoke: blocks reuptakeamphetamine: releasernicotine and etoh: activate cell bodies in vent teg likeopiates: inhibit inhibitory interneurons neurons in vent teg
cocaine: euphorias, energy, arousal, sleep, dialation mydriasis, vasoconstricitonlocal anesthetic, no one uses it, but is still approved
ER: bloody nose, wont stop, hole in nasal septum = cokesnort coke: extensive vasoconstriction = ischemia/necrosis = hole in nasal septummissing eyebrows and eyelasches: smoking crack, singe eyebrows or eyelashes
IV coke: tracts bc vasoconstriction (but any IV drug)
complications: seizures, stokes, MI, paranoia (schizophrenia type) hallucination (more visual > audotory) = dfIV: HIV, hepatitis, endocarditis (not specific to cocaine) -contamination, poor hygene, reuse needles
cocain withdrawl: used to be argued that cocaine was not addicitve or withdrawlnot as bad as opiate or depressantsearly = crash (for days): symptoms is opposite to acute pharmacological actions of drug (rebound) -general withdrawl for all drugs is opposite, if you know what drug does, you know the reboundcocaine withdrawl syndrome is almost identical to amphetamine withdrawl = stimulant withdrawl syndromeare identical but time course differes -amphetamine: longer duration so withdrawl is more spread outlater = anhedonia (sex, food, fun)cravings = extremely difficult to extinguish, happen with all drugs of abuse
overdose: ER, paranoid schizohenia, cardiopulmonary arrest = medical emergence -supportive care -benzodiazapenes for seizures -antipsychotics
Sudden death phenominon: all of a sudden drops dead -coke may have toxic idiosyncratic effect on heart -ask about CPR -speculation about CAs or platelets
amphetaminesphenyl ethyl amine, put an alpha methyl group on it youget amphetamine (alpha methyl for anorexia, and MAOi)N-methyl group get meth-amphetamine which increases potency (still correct) -this is a myth, nmethyl is not more potent -it turns out N-methamphetamine and D-amphetamine are equally as potent (not true for boards)
epidemiologydependent on access an availabilitymethamphetamine is easier to synthesize2010 er visits were >150000k5 fold increase in last 10 yearsmeth is a difficult drug to treat
mechanismprimary mechanism: reverse vesicular transporters -cocaine blocks reuptaker -amphetamines reverse it first, then block it -amphetamines raise a shit ton of DA in the brain -people stop seeking pleasure in other thingsmeth is slightly more serotonergic
meth can be thought of as an extremely long acting cocaineexperiment: at first 30mins amphetamine, methamphetamine, and cocaine are indistinguishableafter 2-3 hours they can tell a differnce
like coke, you can take amphetamines in all routs, IV is common
acute effects: hyper arousal, hyperthermia is more of ann effect of amphetamineacute effects are the same as coke, but hyperthermia is more pronounced
medical complications: similar ot coke, seizures and stoke -garage: lead containing agents = lead poisoning = street drug problems
IV drugs: endocarditis, HIV, hepatitis
high doses of amphetamines may be able to destro DA neuronseventually we will see an increase in PD
withdrawl: stimulant abstence syndrome crash > withdrawl > extinction phase
shorter acting: quicker in, quicker out, more intense
OD: paraoid schizophenic state, seizure, neuroleptic, benzos maybe Ice baths
Amphetamines medicinal usesmost prevalent: weight loss, remarkable innefective, only lose 10-15lbs, gain toleracne,gain the weight back
before amphetamines were as tightly regulate there were a group of physiciansin long island diet doctors go get your drug each week (malpractice) late 70ssecratary was typing the report
possibly use for very obese motivator
2) ADHD: is effective if used properly
3) Narcolepsy: is effective but now we use medafinil
Food an appetiteabout 30 years ago we thought we knew body weight mechanismit is actually extraordinally complex
there are central mechanisms: most attention
peripheral mechanisms
fat as an organ, metabolism, and absorbtion
metabolism and thermogenesis
NE, DA, 5HT ordinary
Hypothalamus: VM, lateral, arcuate, perifornical -everyone agrees on this, but how it works....
There are many substances (peptides)
most potent stimulant for eating is NPY -no NPY antagonist???
Melanocyte stimulating hormone MSH
CART: cocaine amphetamine regulating transcript
Leptin: secreted from FAT, satiety, discovery by jeff freedmant from AMC
Gherlin: = hunger hormone, from stomach, opposite of leptin
unsuccessful drugsflouraminedexflouramine: just as toxicsebutramine: increases HTNphenylpropenalamine: fen fen cardiotoxic
now we are left with very old drugsphenterminephendimetrozinediethyproprion
all 3 are very amphetamine likeportential toxic and abuse level
2 new agentsqucimia = phenermine (stimulant) + topiramate (anticonvulsant) with some annorexic properties Newest: leurcoserin = 5HT2C agonist, cam to market, is going to be available
ADD: contraversyincidence = 2-20% problem is overdiagnosissome genetic, some MRI scansvery treatable and treatment is successfulmainstaye: methylphenolate = ridalin only 4 hour length concerta is long acting ridalinamphetamine = d-amphetaminelis-amphetamine: prodrug vyvanse = longer acting d amphetaminemost peculuare mix of 4 amphetamine salts adderall: 2di amphetamine
2 drugs: not stimulantadimoxitine: NET blockerguanfasitine: II drugs, or adjunct
Stimulant: long term addictionconclusion: is no higher incidence of substance abuse later in lifethere drugs are frequently diverted, kids can pretent to have the disorder
the abuse is not from the intendent population
Nicotinethe hardest addication to break1 pack a day = 73000 puffs a year, the chronic nature of smoking73000 self administating behaviors, physcial actions are reinforced
440000 people die a year bc of smokingthis is the single most preventable cause of death20% of adults smoke
3 government agencys and their numbers differ45million - 70 million from another
prevalancehigh school are a favoriteteenagers7-8% of 12 grader smokedecrease in adults20 years ago it was 30%
teenagers are the most resistant group to changeif they start young
very few people that start smoking after 21
brands: marlbarro is the prefered
pharmacokinetcsgets into brain in 8 secondsincreases dopaminemaintain nicotine levels in the brain,never fall to 0 even at nightchain smokers smoke in the morning
Nicotine metabolites no-nicotine: small contributions cotineine: probably inactive at low concentration but may be a sedative schizophenics (80% smoke, self medication??? not proven)
Nicotine acts via nicotine receptorsnormal agonists area AChmany subtypespentamers, most important is Nicotinic a4b2AB in the brain, Gamma in muscleother importants a3b4 a6b2, a7 in hippocampusa7 in hippocampus improves memory, pharm industry
ionotropic receptorsact on nicotine receptors in the ventral tegmental in midbrainactivate cholinergic neurons, release DA in Nuc Accumbens= responsible for addictive effects of nicotine
physical effects of nicotine
health effectslung cancer, other cancers
addiction is a disease: no matter how aweful diseases arethey are not enough to stop smokingeveryday she smokes despite an email everyday
many other hazards: accidents and fires
poisonings: if a child eats a cigarette it will kill them
Prenatal: small birth wieght, increased prematurity, more miscarrages
nothing good about drug
nicotine abstinence syndromes-does not look distressing, but is, tend to gain weight-excuse to gain weight
Rx: treatment, not as good as we hope100 motivate people, 90% fail in a yearwith Rx 75% fail in a year
Gum, inhaler, electronic, patchmethodone approach to smokingsubstitute long actinge for short acting
buproprion: = antidepressant that works (25% works)bupropion + patch 40% success
veronicoline or shantalex, a4b2 partial agonist nicotinicis effective, success rate is 44% (@ 6 months) not a year