Section 3

Pharmacological Interventions in Tobacco Cessation

Objectives
Participants will be able to list the 5 FDA approved pharmacological interventions for smoking cessation Participants will be able to list the dosage, contraindications, warnings and precautions of Zyban® Participants will be able to list the dosing guidelines, contraindications, warnings and precautions of Nicotine

FDA Approved Pharmaceuticals
Zyban (Bupropion SR) Nicotine Transdermal System Nicotine Gum Nicotine Nasal Spray Nicotine Inhaler

Investigational Pharmaceuticals
 Clonidine

 Nortriptyline

Zyban®
sustained-release tablets 150 mg.

Category/Action
Antidepressant; CNS; miscellaneous Marketed by GlaxoWellcome Inc. Mechanism of effect is unknown Weak blocker of neuronal uptake of serotonin and norepinephrine Weak inhibitor of neuronal reuptake of dopamine

Absorption/Metabolism/Elimina tion
Peak plasma levels reached in 3 hrs. t1/2 is 8-12 hrs. Steady state levels reached in 1.55 days Extensively metabolized by the liver Eliminated in the urine (87%) and feces (10%) Elimination of major metabolites

Clinical Studies
Two placebo-controlled, double-blind trials using non-depressed, chronic smokers One dose-response; one comparative Both showed that pharmacotherapy was significantly more effective than placebo

Indications/Usage/Dosa ge
Indicated as a first-line smoking cessation treatment. Begin while patient is still smoking. Treatment should start with one 150 mg. dose daily for 3 days. Recommended and maximum dose: 300 mg. daily in two 150 mg. doses. Continue treatment for 7-12 weeks

Contraindications, Warnings, and Precautions

Contraindications
In patients with a history of seizure disorder. In patients treated with another medication containing Bupropion (incidence of seizure is dose-dependent). In patients with a current or prior diagnosis of bulimia or anorexia nervosa. In patients treated with a monoamine oxidase inhibiter (MAOI) within the last 14 days. In patients who have a known allergy to Bupropion or it’s components

Warnings
Patients must be made aware that Zyban and Wellbutrin are the same medication. Studies in laboratory animals have indicated a potential for hepatotoxicity. There is a risk of seizure associated with bupropion (dose-dependent), even w/negative hx. Risk of seizure is r/t patient factors, clinical situations, and concomitant

Risk Factors r/t Patients
Predisposing factors, such as hx. of head trauma, prior seizure or CNS tumor. Concomitant medications that lower seizure threshold, such as antipsychotics, antidepressants, Theophylline and systemic steroids.

Risk Factors r/t Clinical Situations
Excessive use of alcohol Abrupt withdrawl from alcohol, sedatives, or benzodiazapines. Addiction to opiates, cocaine or stimulants, or use of OTC stimulants or anorectics. Diabetes, treated with insulin or oral hypoglycemics.

Precautions
Neuropsychiatric phenomena
delusions, hallucinations, psychosis, concentration disturbance, paranoia and confusion

Activation of mania in bipolar disorder patients. Altered appetite and weight Allergic reactions Pregnancy(class B); lactation Renal or hepatic impairment

Drug Interactions
Drugs metabolized by the CYP2D6 isoenzyme.
Tricyclics, SSRIs, Antipsychotics, Beta-blockers, Type 1C Antiarrhythimics

MAO inhibitors Levodopa Drugs that lower seizure threshold Nicotine Transdermal System

Adverse Reactions
Seizures Insomnia*, agitation, confusion Dry mouth* Rash Sweating Tinnitus Tremor Anorexia/wt. loss

Overdose
Limited experience in clinical trials w/bupropion SR; more w/immediate release. Symptoms: (early)-confusion, lethergy, seizure, nausea, hallucinations (late)-hypotension, muscle rigidity, stupor, coma, uncontrolled seizures, cardiac failure.

Nicotine Replacement Therapy

Category/Action
Miscellaneous; CNS Chief alkaloid in tobacco products Binds to nicotinic-cholinergic receptors at the autonomic ganglia in the adrenal medulla, at neuromuscular junctions and the brain Two positively reinforcing properties, stimulating effect and reward effect.

Action, continued
Stimulant effects (in the cerebral cortex) predominate at low doses. Reward effects (in the limbic system) predominate at high doses. Nicotine activates neurohormonal pathways, releasing acetylcholine, norepinephrine, dopamine, serotonin, vasopressin, beta-endorphin, growth hormone, and ACTH.

Action, continued
Can increase circulating cortisol and catecholamines; tolerance to this effect does not develop. Produces cardiovascular effects
peripheral vasoconstriction, tachycardia, and elevated B/P

Absorption/Metabolism/Elimina tion
Absorption varies among products (NTS doses correlate with amt. absorbed) Primary urinary metabolites are cotinine and trans-3hydroxycotinine. Major site of metabolism is the liver; also metabolized in the kidney and lung. 10% of absorbed nicotine is excreted unchanged in the urine;

Clinical Studies
Numerous studies Results show statistically significant increase in abstinence rates using all four methods of NRT, when compared to placebo at 6 weeks, 3 mos., 6 mos., and 12 mos. Adjunct group or individual counseling in addition to NRT resulted in higher success rates

Contraindications
In patients with known hypersensitivity or allergy to nicotine or it’s components In patients with recent MI , worsening angina and uncontrolled HTN

Warnings
Nicotine from any source can be toxic and addictive. The risk of using NRT in any form, should be weighed against the risk of continued smoking, and the likelihood of achieving abstinence without NRT.

Pregnancy Warning
FDA Class D Studies in pregnant animals have shown that nicotine is harmful to the fetus. Tobacco smoke has been shown to be harmful to the human fetus; single studies on nicotine have not been performed; presumption is that of harm. Breastfeeding

Safety Warning
Amounts of nicotine tolerated by adults can be harmful or fatal to children or pets. Patients should be cautioned to use safe storage and disposal techniques to prevent accidental ingestion of any form of NRT

Precautions
Smoking during NRT Allergic reactions
contact dermatitis bronchspasm

Cardiovascular or peripheral vascular disease
hx. of recent MI, serious arrhythmias, vasospastic disease, severe angina (should not be used) NTS was shown to be well tolerated in a controlled trial of patients w/CAD (no increase

Precautions continued
Renal or hepatic insufficiency Endocrine diseases
IDDM, Pheochromocytoma, hyperthyroidism

Peptic ulcer disease
nicotine delays healing

Accelerated hypertension

Drug Interactions
Smoking cessation as an indicator alone, may alter the pharmacokinetics of certain drugs.
Decrease in induction of hepatic enzymes increase in SQ insulin absorption decrease in circulating catecholamines

Prescribing provider should be made aware of smoking cessation,

Adverse Reactions
Difficult to distinguish between withdrawal symptoms and drug itself Causal relationship probable:
diarrhea, dyspepsia, dry mouth arthralgia, myalgia* abnormal dreams*, insomnia*, nervousness* sweating, skin irritation (NTS), mouth and throat irritation (inhaler, gum), nasal irritation (spray) *reported with higher

Abuse/Dependence
NTS therapy has a low abuse potential.
Slower absorption, smaller flucuations in blood levels, lower blood levels, less frequent use

Abuse has been reported with gum, inhaler and nasal spray Nasal spray has the highest abuse potential
15-20% of patients report using the spray

Overdose/Toxicity
Can occur with:
smoking while use NRT applying several NTS, ingesting cartridge from inhaler or large amounts of gum, overuse of nasal spray or ingesting contents

Signs and symptoms:
pallor, cold sweat, nausea, salivation, vomiting, abd. pain, diarrhea, HA, dizziness, disturbed hearing and vision, tremor, mental confusion,

Routes of Administration/Dosage Transdermal (patch), gum, inhaler,
nasal spray Patch and gum available OTC Nicoderm CQ® 21mg., 14mg., 7mg., Labeled mg. equal to amt. of nicotine absorbed in 24 hrs. (21mg. patch =1 ppd. Heavy smokers should cut down/switch brands prior to starting patch Weight <100 lbs. or smokes< 1/2 ppd., start on 14mg. patch

Investigational Pharmaceuticals
Clonidine
Categorized as an antihypertensive not approved by the FDA for smoking cessation Studies have shown abstinence rates twice those of placebo Second-line agent Significant side effects Cannot abruptly discontinue

Investigational Pharmaceuticals, cont.
Nortriptyline
Categorized as a tricyclic antidepressant Not approved by the FDA for use in smoking cessation Limited studies have shown abstinence rates over twice those of placebo Many side effects Second-line agent

Combination Therapy
Zyban® and Nicotine Transdermal System
Studies have shown increased abstinence rates, higher long term abstinence rates Especially successful in highly nicotinedependent, long term smokers Careful screening is necessary Treatment-emergent hypertension has been seen Patients with hx. of HTN, Consult with PCM

Conclusion
Attain competency Assess completely Consult with peers/PCM Re-assess frequently Stay informed of the latest developments Maintain competency

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