Nicotine Pharmacology - Damaj

Learning Objectives part 1

• Know the basic molecular targets of nicotine: nicotinic receptors

• Basic understanding of nicotine metabolism

• Some understanding of new tobacco/nicotine delivery forms

• Know the pharmacotherapy of smoking cessation

• Know the pharmacology of smoking cessation drugs

Evolving Nicotine Landscape?

• ENDS

  • Electron nicotine delivery systems - battery devices that heat e-liquid matrix to create aerosol

• Nicotine Pouches

  • Spitless, tobacco-free oral pouches containing synthetic nicotine or tobacco-derived nicotine salts wrapped in porous substrate

• Heated tobacco products

Chemistry of Cigarette smoke

• Gaseous Phase (CO)

  • shortness of breath

  • neonatal problems

• Particulate Phase

  • nicotine (increases CHD risks)

  • Tar (increases cancer risks)

Chemistry of cigarette smoke part 2

• Average cigarette contains about 10-15 mg of nicotine, only 1mg absorbed

• Tars are the many of 4000 chemicals in tobacco, including carcinogens

• Generally, factors that alter nicotine delivery affect delivery of tars to the same xtent

• Nearly 100% of cigarette use is filter brands

Chemistry of new nicotine products

• Lack of quality control standards

• Concern around ingredients

• No oversight or disclosure

• Propylene glycol inhalation

• Flavorings (>6000) also untested for inhalation

• Levels of nicotine vary widely- Base or salts

• Other chemicals (such as Pyrazine) may be added to boost addictive qualities

What are important receptors pertaining to Neural basis of tobacco use and Nicotine Dependence?

Alpha 2 -beta 3

Nicotine PK

• Absorption

  • Inhalation - 90-98% absorbed from respiratory tract

• Oral

  • Snuff, chewing tobacco, nicotine gum

  • Buccal absorption is pH dependent - first pass effect

• Transdermal

  • readily absorbed through skin - example nicotine patch

Nicotine PK - distribution

following inhalation, distribution is wide and quick -reaches brain in 8 seconds

• plasma levels vary according to route of administration

• Plasma half-life is around 2 hours

• Crosses placenta and can be found in breast milk

Smoking produces _____ levels of nicotine compared with NRT

much higher

NIcotine PK - Metabolism

• 80-90% is nicotine is metabolized by CYP2A6 - know this!!

• Cotinine and Nicotine-N-Oxide are major metabolites of nicotine

• Cotinine is good assessment of recent smoking (by urinalysis)

Genetic Variability in Nicotine Metabolism

• Genetic variations in CYP2A6 - can impact rate of metabolism in different ethnicities

• Asian descent typically have LOW CLEARANCE of nicotine (less cigarettes needed)

• Caucasian descent typically have HIGH CLEARANCE of nicotine (need more cigarettes often)

The natural history of smoking progression

• Initial aversive experience

• tolerance to aversive effects

• Increasing pleasurable effects

• Nicotine intake increases — withdrawal

• Social smoking

Points about nicotine dependence

• nicotine is not strongly euphorigenic

• Animals will learn to level press for IV nicotine injections, although it is a weak reinforcer

• When nicotine injections are paired with specific cue, this strongly enhances nicotine reinforcement

• Craving is very strong and plays major role in relapse

1.5 packs of cigarettes per day is how many puffs a year?

100,000 puffs!!!!

What is the nicotine titration hypothesis?

• Smokers adjust their smoking behavior to obtain a stable dose of nicotine

Nicotine tolerance definition?

• number of cigarettes increases with time and then stabilizes

• Tolerance develops to peripheral and central effects of nicotine

Nicotine withdrawal points

Withdrawal signs begin within 24 hours after cessation and peak in a day or two

• Signs: headache, inability to concentrate, irritability, sleep disturbances, anxiety, depressed mood, hunger — May persist for weeks or months

Treatment for nicotine dependence

1. NRT

   1. Gum

   2. Patch

   3. Spray

2. Varenicline (Chantix)

   1. Nicotinic partial agonist

3. Antidepressants

   1. Bupropion (Zyban)

Vaernicline points

• MOA

  • non-selective partial nicotinic agonist - when in combo with full nicotine — becomes an antagonist with little bit of nicotine activity!!! helps with reducing and coming off

  • Declined sense of satisfaction with smoking

  • Oral admin