Nicotine Replacement Therapy NRT A Clinicians Primer

1
Nicotine Replacement Therapy (NRT)-A Clinicians
Primer

• Kumar Maharaj, R.Ph, BCPP

2
Were it possible for a being who resides on our
globe to visit the inhabitants of a planet where
reason governed and to tell them that a vile weed
was in general use amongst the inhabitants of the
globe it left, which afforded no nourishment
that its use was extremely nauseous that it was
unfriendly to health and morals that its use was
attended with considerable loss of time and
property, that account would be incredible, and
the author would probably be excluded from
society for relating a story of so improbable a
natureIn no view is it possible to contemplate
the creature man in a more absurd and ridiculous
light than in his attachment to
tobacco. Benjamin Rush, Father of American
Psychiatry and Signer of the Declaration of
Independence
3
Epidemiology

• Mentally ill or addicted are 2-3 times more
  likely to be tobacco dependent than the general
  population
• Smokers with psychiatric disorders consume nearly
  50 of all cigarettes consumed in the United
  States.1-5

1) Poirier MF, Canceil O, Bayle F, et al. Prog
Neuropsychopharmacol Biol Psychiatry 2002
26529-537. 2) Breslau N, Johnson EO, Hiripi E,
Kessler R. Arch Gen Psychiatry 2001
58810-816.3) Haustein KO, Haffner S, Woodcock
BG. Int J Clin Pharmacol Ther 2002 40404-418.
4) de Leon J, Tracy J, McCann E, et al.
Schizophr Res 2002 5655-65. 5) Lasser K,
Wesley BJ, Woolhandler S, et al. JAMA 2000
2842606-2610.
4
OP EpidemiologyLasser et al. JAMA 2842606-10,
2000

• National Comorbidity Survey data collected
  1990-2.
• Included substance abuse and antisocial
  personality disorder as mental illness. Also had
  a very high prevalence of phobias anxiety
  disorders.
• By their numbers 44.3 of the cigarettes consumed
  in the US were by those with mental illness.
• That adds up to 200,000 deaths from tobacco among
  US mentally ill patients each year.

5
Prevalence of Smokers

• 1. Schizophrenia 88
• 2. Mania 70
• 3. Major depressive disorder 49
• 4. Anxiety, personality disorder, adjustment
  disorder 45-47
• 5. Controls 30 (This was almost 20 years ago)

Hughes JR, Hatukami DK, Mitchell JE. Am J
Psychiatry 143993-7, 1986
6
Overall MortalityHannerz. Pub Health
115328-37, 2001

• The life expectancy of patients with
  schizophrenia is 10 years less than the general
  population.
• Natural death accounts for 59 of the excess
  mortality.
• Age adjusted death due to pulmonary disease is
  significantly elevated for patients with
  schizophrenia.
• SMOKING IS THE LEADING CAUSE OF PREVENTABLE DEATH
  IN THE US.

7
Causes of the Excess Mortality of
SchizophreniaBrown S, Inskip, H, Barraclough Br
J Psych (2000), 212-219

• Our study suggests that most of the excess
  natural mortality of modern community samples is
  due to cigarette smoking and that helping
  patients to stop smoking should be a priority for
  doctors and health service planners

8
Nicotine and Neuropharmacology

• Given the widespread effects of tobacco and its
  withdrawal on human brain and neurotransmitter
  activity, it is perhaps not surprising that
  tobacco is associated in various ways with a
  number of mental disorders. What is perhaps more
  surprising is how often these effects continue to
  be ignored in both the clinical management and
  research into these disorders. Foulks J. The
  relationship between tobacco use and its mental
  disorders. Curr Opin Psychiatry 12303-6, 1999.

9
What Does Nicotine Do? I

• Nicotine is structurally similar to
  acetylcholine.
• Nicotinic acetylcholine receptors are widely
  distributed.
• Nicotine leads to
• Increased firing of DA neurons in
  mesocorticolimbic pathways. This leads to
  increased release of DA in the nucleus accumbens
  and prefrontal cortex.
• There is an increase in burst firing in the
  ventral tegmentum.
• DA deficiency low metabolic activity in these
  regions has been associated with negative sx
  sensory gating deficits seen in schizophrenia.

10
What Does Nicotine Do?

• Release of DA in the nucleus accumbens has been
  associated with reward.
• DA is released in this area during the
  anticipatory part of eating and sexual behaviors.
  
• This burst firing is normally under the control
  of excitatory cells from the prefrontal cortex.
• There is evidence of hypofrontality with
  schizophrenia.
• Human smokers have a 40 ? in MAO B activity.
  This reverses with discontinuation of smoking.
• Thus, we have ? DA release and ? DA metabolism.

11
Nicotine, Sensory Gating, and Atypicals

• Nicotine normalizes a deficit in auditory sensory
  gating that is seen in pts w/ schizophrenia and
  half of their first degree relatives.
• This deficit, associated with difficulty in
  censoring out extraneous information is not
  corrected by neuroleptics.
• It is corrected in atypical responders.
• Pts on CLO smoke .5 PPD less than before meds.

12
NonDA Effects of Nicotine

• Acute administration of nicotine increases 5-HT
  release.
• Chronic administration leads to a decrease in
  5-HT synthesis.
• Post-mortems with human smokers shows a decreased
  concentration of 5-HT and 5-HIAA.

13
Cigarettes are COOL

• Transported by tar droplets
• Inhaled and deposited deep into lungs
• Rapid delivery to left side of heart
• Pumped into brain and body
• Faster than injection into peripheral vein
• Onset of CNS action-seconds
• Benowitz, 1998 Henningfield et al., 1993

14
How Do Smokers Smoke

• Nicotine boost-increase in blood nicotine from
  smoking a cigarette.
• Nicotine boost determined by
• Topography-how is cigarette smoked.
• Characteristics of the cigarette.
• Level of dependence
• Gender, race, metabolism
• Reinforcement versus maintenance

15
Smoking Cessation Programs

• Few smoking cessation programs have been targeted
  toward psychiatric patients, particularly those
  with schizophrenic disorders

Haustein KO, Haffner S, Woodcock BG. Int J Clin
Pharmacol Ther 2002 40404-418.  El-Guebaly N,
Cathcart J, Currie S, et al. Psychiatr Serv
2002 531166-1170.   Hughes JR. Arch Gen
Psychiatry 2001 58817-818. Addington J, et al.
Am J Psychiatry 1998 155974-976
16
An Ideal ProgramZiedonis D. Am J Med Sci
326223-30, 2003

• MH facilities should have Nicotine Anonymous
• JCAHO should adopt a standard re tobacco
  dependence diagnosis and treatment planning.
• Initial interventions for those in the
  precontemplative stage
• Harm reduction.
• Psychoeducation with myth debunking for patients
  and families.

17
An Ideal Program IIZiedonis D. Am J Med Sci
326223-30, 2003

• Tobacco use should be included in assessment and
  treatment planning.
• Should utilize motivation-based interventions
  with the Prochaska Stage of Change model.
• Patients who are precontemplative should have
  motivational enhancement intervention.
• Tobacco should be in the patient ed curriculum.
• NRT products bupropion should on formulary.
• Integrated treatment with both NRT and
  psychosocial Rx triples quit rates.
• All things being equal, atypicals are preferred.

18
Fagerstrom Scale

• Does the patient smoke within 5 min of awakening.
• Does the patient smoke gt 25 cigarettes/day.

19
Time Course of Withdrawal Symptoms
20
Somatic Treatments

• Pharmacotherapies can be divided into
• Replacement therapy
• Antagonist therapy
• Aversion therapy
• Non-nicotine medications that mimic nicotine
  effects
• Non-medication somatic therapies include
  acupuncture and devices

21
Naltrexone

• Naltrexone 50 mg QD X 3 days versus placebo
• Subjects smoked fewer cigarettes
• Reported less satisfaction
• Lower plasma nicotine levels
• May benefit subgroups
• Wewers ME, Dhatt R, Tejwani GA Psychopharmacology
  140185-90, 1998

22
Antidepressants

• Bupropion (5)
• Doxepin (1)
• Fluoxetine (2)
• Imipramine (1)
• Moclobemide (1)

• Nortriptyline (2)
• Selegiline (1)
• Sertraline (1)
• Tryptophan (1)
• Venlafaxine (1)

23
Results

• Nortriptyline and Bupropion aid smoking cessation
• Other agents role?

24
Bupropion

• Inhibits postsynaptic uptake of dopamine
  (attention, motivation, pleasure, reward) and
  norepinephrine (alertness, energy).
• Nicotinic receptor antagonist
• Attenuates weight gain and depression
• Slemmer JE, Martin BR, Damaj MI J Pharmacol Exp
  Ther 295321-327,2000

25
Bupropion

• Quit rates versus placebo
• 6 month quit rates (18-27 vs 7-16)
• (Tonnesen P, Tonstad S, Hjalmarson A J Inter Med
  254184-192, 2003)
• Quit rates versus patch
• 12 month quit rates 30.3 vs 16.4
• (Jorenby DE, Leischow SJ, Nides MA N Enj J Med
  340685-691, 1999)

26
Side Effects

• 35-40-Insomnia
• 10 -Dry mouth
• Hypertension
• ? Seizures

27
Bupropion

• 150 mg AM for 3 days, then
• 150 mg BID
• Begin 1-2 weeks prior to quit date

28
Buproprion

• Bupropion is an effective aid to smoking
  cessation
• There is evidence from a meta-analysis of the two
  published trials of this drug that it improves 12
  month sustained abstinence rates and reduces the
  severity of withdrawal symptoms
• There is a very small but non-zero risk of
  serious adverse effects
• The risk of seizures is broadly similar to other
  antidepressants at 1 in 1000

29
Nicotine Replacement

• Relieve withdrawal symptoms.
• Allow the patient to focus on habit and
  conditioning factors.
• Receptor desensitization-reduce the reinforcing
  effects of cigarette smoking.

30
(No Transcript)
31
(No Transcript)
32
Combination NRT

• Sachs et al Short term cessation rates gt 75
  when patches were applied until nicotine levels
  matches those found when the patient was smoking.
• Sachs, DPL, Benowitz NL, Bostron AG et al. (1995)
  Percent serum replacement and success of nicotine
  patch therapy. Am Rev Resp Crit Care Med
  151(4,Part 2),A688

33
Cochrane Reviews

• Objectives To determine the effectiveness of
  different strategies.
• Outcome Measures Abstinence from smoking after
  gt 6 months.
• Cochrane Database of Systematic Reviews. 1, 2005

34
Cochrane Review
35
Results

• Tapered therapy no better than abrupt withdrawal
• 16 hour patch equivalent to 24 hour patch
• Select based on sleep disturbances

36
Results

• Odds largely independent of the intensity of
  additional support
• All trials provided some support
• Intensive support increases the likelihood of
  quitting.

37
Cardiovascular Toxicity

• Mechanisms-Cigarettes
• Induction of a hypercoagulable state.
• Increased myocardial work.
• Carbon monoxide-mediated reduced oxygen carrying
  capacity of the blood.
• Catecholamine release.

38
Cardiovascular Toxicity

• Dose-cardiovascular response relation for
  nicotine is flat.
• Implication The effects of cigarette smoking in
  conjunction with NRT are similar to those of
  cigarette smoking alone
• Benowitz NL, Gourlay SG J Am Coll Cardiol
  1997291422-31

39
What If They Are On NRT Smoke?Joseph AM.
NEJM 3351792-8, 1996 Jiminez-Ruiz.
Respiration 69452-6, 2002

• Concern about this is not supported by data.
• Joseph took a CV high risk group and put them on
  patch or PBO.
• 49 w/ active angina
• 40 w/ h/o MI
• 35 w/ h/o CABG
• No increase in CV events for the pt group
• 21 of the patients were not smoking at the end
  vs 9 of the PBO group.
• Jiminez-Ruiz severe COPD pts placed on gum.
• Most patients continued to smoke, though less.
  No adverse events attributed to nicotine. COPD
  better.

40
NRT with Cardiovascular Dx

• 5 week placebo controlled trial 14-21mg/day.
• 156 pts w CAD
• Cardiac symptoms monitored, 24h ECG
• Concomitant smoking with patch
• ECG monitoring No differences in arrhythmias or
  ST segment depression
• Working Group for the Study of Transdermal
  Nicotine in Patients with Coronary Artery Disease
  Arch Int Med 154 (1994), pp. 989-995

41
NRT with Cardiovascular Dx

• Veterans Affairs cooperative study
• 584 smokers w cardiovascular dx.
• NTP (21mg/day tapered to 7mg/day).
• Concurrent smoking.
• 49 w h/o active angina
• 40 w h/o MI
• 35 w h/o CABG
• Joseph AM. NEJM 3351792-8 1996

42
NRT with Cardiovascular Dx

• Veterans Affairs cooperative study
• Primary end points
• Death, MI, Cardiac Arrest, Admission to hospital
  for angina, arrhythmias, CHF.
• Results 5.4 Nicotine vs 7.9 Placebo
• Joseph AM. NEJM 3351792-8 1996

43
Cardiovascular Effects

• Nicotine may stimulate sympathetic neural
  pathways and cause systemic catecholamine
  release.
• Cardiovascular effects from smoking greater than
  with NRT.
• NRT plus smoking equivalent to smoking
• Benowitz NL, Gourlay SG J Am Coll Cardiol
  1997291422-31

44
Cardiovascular Effects

• Thus, caveats within the 1994 European
  Guidelines for Preventive Cardiology regarding
  the need for caution when using nicotine
  replacement therapy in patients with
  cardiovascular disease requires revision
• Balfour D, Benowitz N, Fagerstrom K, Kunze M,
  Keil U. European Heart Journal (2000) 21, 438-445

45
Cardiovascular Effects

• Murray RP, Bailey WC, Daniels K. Safety of
  nicotine polacrilex gum used by 3,094
  participants in the Lung Health Study. Chest
  1996 109438-45
• Mahmarian JJ, Moye LA, Nasser GA. Nicotine patch
  therapy in smoking cessation reduces the extent
  of exercise induced myocardial ischemia. J Am
  Coll Cardiol 1997 30125-30
• Benowitz NL, Gourlay SG Cardiovascular toxicity
  of nicotine Implications for nicotine
  replacement therapy. J Am Coll Cardiol 1997
  291422-31

46
What is the most effective NRT?

• All equally effective
• Cochrane review
• 17 success with NRT
• 10 without NRT

47
NRT Selection

• Patient preference
• Degree of nicotine dependence
• Smoking within 30 min upon awakening
• Tolerability
• NRT history

48
Potential Contraindications

• ? Pregnancy
• Post MI (2 weeks)
• Serious arrhythmias
• Serious or worsening angina pectoris

49
Nicotine Replacement Therapy (NRT)

• Nicotine replacement therapy is available in many
  different forms
• Chewing gum (2mg and 4mg)
• Transdermal patch (16 hour and 24 hour, varying
  doses)
• Nasal spray
• Oral inhaler
• Sublingual tablet/lozenge

50
NRT in Psychiatry

• Psychiatric patients appear to have more
  withdrawal symptomatology when they stop smoking
  compared to the general population (gt FTQ scores)
• Steinberg ML, Hall SM, Rustin T Psych Annals 337
  469-478, July 2003

51
Nicotine Gum

• Nicotine ingested through the GI tract is
  extensively metabolized on first pass through the
  liver
• Scheduled dosing (1 piece of 2mg gum/hour) and
  4mg gum for highly nicotine-dependent smokers is
  more effective
• Nicotine absorption from gum peaks 30min after
  initiation
• Venous nicotine levels from 2 and 4mg 1/3 and
  2/3, respectively, of the steady-state levels of
  nicotine from cigarette smoking

52
Nicotine Gum

• Nicotine via cigarettes is absorbed directly into
  the arterial circulation
• arterial levels from smoking are 5-10 times
  higher than those from the 2- and 4-mg gums
• Absorption of nicotine in the buccal mucosa is
  decreased by an acidic environment
• Patients should not use acidic beverages (e.g.,
  coffee, soda, juice) immediately before, during,
  or after nicotine gum use

53
Nicotine Gum

• Do not chew Nicorette(R) like regular gum.
• Begin by taking a few bites until a tingling or a
  peppery taste.
• As soon as the tingling starts, move gum to the
  side of mouth, between gum and cheek.
• Leave the gum there until the tingling goes away.
• Slowly start to chew again until the tingling
  returns. Move gum to the side of your mouth
  again.
• Keep repeating this cycle of slowly chewing, then
  moving the gum to the side of your mouth.
• Discard after 30 minutes or when tingling ends.

54
Side Efects

• Mouth soreness
• Hiccups
• Dyspepsia
• Jaw ache

55
Rxing

• 1-24 cigarettes/day or FTQ lt6
• Use 2mg gum (up to 24 pieces/day). May prescribe
  up to 5 boxes (540 pieces) for
• each Rx.
•  ?25 cigarettes/day or FTQ gt6
• Use 4mg gum (up to 24 pieces/day). May prescribe
  up to 5 boxes (540 pieces) for
• each Rx.
• Maximum of 6 prescription fills.

56
Nicotine Patch

• Transdermal formulations take advantage of ready
  absorption of nicotine across the skin
• Patches are applied daily each morning
• Nicotine via patches is slowly absorbed so that
  on the first day venous nicotine levels peak 6-10
  hours after administration
• Nicotine levels remain fairly steady with a
  decline from peak to trough of 25 to 40 with
  24-hour patches
• Nicotine levels are typically half those obtained
  by smoking

57
Nicotine Patch

• After 4-6 weeks patients are usually tapered to a
  middle dose (14 mg/24 hours or 10 mg/16 hours)
  and then again in 2-4 weeks to the lowest dose (7
  mg/24 hours or 5 mg/16 hours)
• Most, but not all, studies indicate abrupt
  cessation of the use of patches often causes no
  significant withdrawal, tapering may not be
  necessary
• The recommended total duration of treatment is
  usually 6-12 weeks

58
Nicotine Patch

• Combining the patch with other forms of NRT may
  be more effective than the patch alone and
  appears to be safe
• Research exists that suggests that combining
  different forms is both safe and effective

Stapleton J. BMJ 1999318289.
59
Nicotine Patch

• Apply one new patch at the same time of day every
  24 hours on a different skin site that is dry,
  clean, and hairless.
• Remove backing from patch and immediately press
  onto skin. Hold for 10 seconds.
• Wash hands after applying or removing patch.
  Throw away the patch in the enclosed disposal
  tray.
• Wear the patch for 16 or 24 hours.

60
Nicotine Patch

• Wear the patch for 24 hours if crave cigarettes
  when you wake up
• With vivid dreams or other sleep disturbances,
  remove the patch at bedtime and apply a new one
  in the morning.

61
Side Effects

• Local skin reaction
• Vivid dreams

62
Nicotine patch

• May prescribe 30 patches (30 day supply).
• Maximum of 6 prescription fills.
• Limited flexibility.
• 21mg Patch preferable.

63
Nicotine Nasal Spray

• Nicotine nasal spray is a nicotine solution in a
  nasal spray bottle
• Nasal sprays produce droplets that average about
  1 mg per administration
• More rapid rise in nicotine levels than nicotine
  gum
• Rise in nicotine levels produced by spray falls
  between nicotine gum and cigarettes
• Peak levels occur 10 minutes and venous levels
  are about 2/3 those of cigarettes
• Smokers are to use the product ad-lib up to 30
  times/day for 12 weeks, including a tapering
  period

64
Nicotine Nasal Spray

• Prime pump.
• Blow nose. Tilt head back slightly.
• Comfortably insert tip into nostril.
• Breathe through mouth.
• Spray once in each nostril-DO NOT INHALE OR SNIFF
  WHILE SPRAYING
• Wait 2-3 minutes before blowing nose.

65
Side Effects

• 94 -moderate to severe nasal irritation
• Nasal congestion
• Transient changes in smell and taste
• ? dependence

66
Nicotine Spray

• May prescribe 12 bottles per Rx.
• Maximum of 5 doses (10 sprays) per hour No more
  than 40 doses (80 sprays) per day
• Maximum of 6 prescription fills (new or refill)
  per calendar year. 

67
Nicotine Inhalers

• These are plugs of nicotine placed inside hollow
  cigarette-like rods.
• The plugs produce a nicotine vapor when warm air
  is passed through them (delivery decreases lt40
  F).
• Absorption is mostly buccal rather than
  respiratory
• Most recent versions of inhalers produce venous
  nicotine levels that rise more quickly than
  nicotine gum but less quickly than nicotine nasal
  spray
• Nicotine blood levels of about 1/3 that of
  between-cigarette levels
• The inhaler is to be used ad-lib for about 12
  weeks.

68
Nicotine Inhaler

• Inhale deeply into back of throat or puff in
  short breaths.
• Nicotine vapor is inhaled via mouth and throat.
• 20 minutes of active puffing exhausts nicotine.
• Use may be continuous or intermittent.

69
Side Effects

• 40-local irritation in mouth and throat
• 32-coughing
• 23-rhinitis

70
Nicotine Inhaler

• May prescribe up to 8 boxes (336 cartridges) each
  prescription fill.
• Maximum of 6 prescription fills per 12 months.
• Recommended dose is 6 to 16 cartridges/day.
  
• Maximum of 16 cartridges/day.
  

71
Additional Therapies

• Nicotine lozenges for buccal absorption
• Time to first cigarette (TFC) after awakening
  useful as dose indicator
• -- Less than 30 minutes, use 4-mg lozenge
• -- More than 30 minutes, use 2-mg lozenge -
  Encourage use of 9 or more lozenges daily during
  first 2 to 6 weeks, with self-disciplined
  step-down use weeks 7-9, 10-12, 13-26.
• MDD 20/day

72
Commit Lozenges

• Recommended dosage
• Weeks 1-6 1 lozenge every 1-2 hours.
• Weeks 7-9 1 lozenge every 2-4 hours.
• Weeks 10-12 1 lozenge every 4-8 hours.

73
Commit Lozenges

• Remove lozenge from blister pack.
• Place lozenge in mouth.
• Allow lozenge to slowly dissolve (20-30 minutes).
  Do not chew or swallow.
• Move lozenge from cheek to cheek.

74
Side Effects

• Mouth soreness
• Indigestion
• Sore throat
• Heartburn

75
Combination Therapy

• A Controlled Trial of Sustained-Release
  Buproprion, a Nicotine Patch, or Both for Smoking
  Cessation
• Results
• Abstinence rates at 12 months
• 15.6 percent in the placebo group
• 16.4 percent in the nicotine-patch group
• 30.3 percent in the bupropion group (Plt0.001)
• 35.5 percent in the group given bupropion and the
  nicotine patch Plt0.001).

76
Combination therapy

• 311 subjects (34.8 ) discontinued one or both
  medications
• 79 subjects stopped treatment because of adverse
  events
• 6 in the placebo group (3.8)
• 16 in the nicotine-patch group (6.6)
• 29 in the bupropion group (11.9)
• 28 in the combined-treatment group (11.4)
• The most common adverse events were insomnia and
  headache

77
Initial NRT

• The nicotine patch is recommended as the usual
  initial pharmacotherapy
• Compliance with nicotine gum is difficult
• Nicotine nasal spray has abuse potential
• Clonidine has frequent side effects
• Supplementation of nicotine patch with ad-lib use
  of nicotine gum.

78
(No Transcript)
79
Prescribing Help

• Medicaid will cover a maximum of 6 prescription
  fills (either a new script or refills on a
  script) per year, beginning on the date when the
  first nicotine replacement product is filled
• Each new prescription for nicotine replacement
  therapy can have no more than 2 refills

• C. Infantino 8/02

80
Prescribing Help

• To maximize the amount of nicotine replacement
  products that a client can receive, the maximum
  amounts that can be billed to Medicaid for each
  prescription fill are listed later
• It is also recommended Wellbutrin SR? be
  prescribed rather than Zyban?, as Zyban? follows
  the same limitations as nicotine replacement
  products per calendar year, and there are no
  limitations on Wellbutrin SR?
• Coverage of smoking cessation products through
  other insurance plans (non-medicaid) varies, and
  will have to be determined for each individual
  client

• C. Infantino 8/02

81
(No Transcript)
82
Tobacco and Psychiatric Medication Metabolism

• PAHs induce
• CYP1A2, 1A1, 2E1
• Kinetic effects of cigarette smoking
• Cigarettes are a potent inducer of the CYP1A2
  isoenzyme
• Time course
• Up to 2 weeks after starting
• Day 1 after stopping

83
Tobacco and Psychiatric Medication

• Amitriptyline
• Nortriptyline
• Imipramine
• Clomipramine
• Fluvoxamine
• Trazodone
• Fluphenazine
• Haloperidol
• Olanzapine-40
• Clozapine-30-40
• Chlorpromazine

84
Tobacco and Medication

• Drug Interactions
• Heparin
• Theophylline
• Tacrine
• Insulin
• Acetaminophen
• Warfarin
• Caffeine
• Aspirin
• Codeine
• Lidocaine
• Propranolol

85
Clozapine and Smoking

• Clozapine and demethylclozapine concentrations
  40 lower in the smokers
• Seppala NH, Leionen EV, Lehtonen ML, Kivisto KT
  Pharmacology Toxicology. 85(5)244-6, 1999 Nov.

86
Conclusions

• Thanks