lecture 9 - Non-Scheduled Stimulants: Caffeine & Nicotine

Caffeine Pharmacokinetics

• absorption & distribution

  • absorbed rapidly from GI tract

  • water & lipid soluble, easily distributes across body tissues

  • plasma concentrations peak ~ 2 hrs

• metabolism: liver metabolizes 90% of drug by CYP-1A enzymes

  • half-life → 4-5 hrs in most adults 

• cross tolerance effects:

  • nicotine increases CYP-1A (less sensitive to caffeine

  • SSRIs, hormonal contraceptives decreased CYP-1A (more sensitive to caffeine)

caffeine pharmacokinetics: metabolism

• 2 metabolites:

  • theophylline

  • paraxanthine

  • ^^ both are active metabolites, w/ similar effects to caffeine

  • 3rd metabolite → theobromine (inactive metabolite)

• interferes w/ adenosine body pathway → creates stimulant effect

caffeine pharmacodynamics: adenosine’s role

• adenosine: one of several purine neuromodulators that regulate biochemical energy transfer (ATP) & signal transduction (cAMP)

  • adenosince inhibits (acts as a brake on) brain arousal

  • levels build up during day to promote sleep; levels drop after a nights sleep

  • caffeine is an adenosine receptor (A2) antagonist

• adenosine receptor → metabotropic

caffeine pharmacodynamics: cortisol effects

• why early morning may be the WORST time to drink coffee

  • this is when cortisol is highest

  • ^^ give artificially high cortisol levels → can lead to stress

1. cortisol levels decrease → caffeine interferes w/ cortisol production, making you more vulnerable to stress

2. long-term tolerance increases: having caffeine in your system, while cortisol is high, leads to faster caffeine tolerance

caffeine: toxicity & caffeinism

• caffeinism → can occur w/ doses above 1,000 mg/day

  • anxiety, tremors, delusions, insomnia, diuresis, tachycardia

  • looks like anxiety disorder, but doesn’t respond to tranquilizers

  • treatment? → taper off/eliminate caffeine

• lethality → LD₅₀ = ~10,000 mg orally, equivalent to ~100 cups of coffee

  • convulsions & respiratory collapse

  • BUT potentially fatal reactions can occur at much lower doses!

• withdrawal symptoms

  • headache, fatigue, inability to concentrate, anxiety, irritability, low mood, muscle tension

  • occur 12-24 hrs. after stopping

  • symptoms last 2-3 days

nicotine pharmacokinetics: administration & metabolism

• inhalation → peak plasma levels in about 10 mins

  • ~ 1 cigarette per hour will achieve steady-state plasma levels of nicotine to avoid withdrawal

  • fatal exposure = 40-60 mg for adult, abdominal pan, womiting, decreased BP, irregular pulse, convulsions, respiratory failure

nicotine pharmacokinetics: distribution & metabolism

• nicotine quickly distributed throughout body, to brain, placenta, & all body fluids (including breast milk)

• Liver CYP-2A enzyme metabolizes 80-90% before kidney excretion

• Nicotine half-life is 2 hrs; cotinine (semi-active metabolite) half-life of 16 hrs

  • genetic differences in CYP2 enzymes affect nicotine half-life, addictive potential & cancer rates

  • ex: high enzyme activity = high cancer potential; low enzyme activity = less potential cancer

nicotine pharmacodynamics

• nicotine → full agonist at nicotine acetylcholine receptors (nACR)

  • nACRs are ionotropic, control Na+ & Ca2+ channels 

  • ex: mice w/ super-sensitive α4 subunits exhibit behaviors consistent w/ nicotine addiction but at 1/50th of the dose in typical rates

• PNS: sympathomimetic (release of adrenal gland epinephrine) & parasympathomimetic (releases skeletal muscle @ NMIs (neural muscular junction)

• stimulates ACh release (e.g., from basal forebrain)

  • also activates DA & opioid pathways (reward system)

nicotine: epidemiology

• in US → highest cause of preventable disease & death

• Cigarette use trends: 42% (1965) → 16% (2014)

  • 90% of smokers start before age 18 (avg. age = 13)

  • fortunately, cigarette smoking is declining, BUT… → (increase in E-cigarattes)

• Tolerance → develops slowly over years 

• Withdrawal symptoms → anxiety, restlessness, insomnia, irritability, difficulty concentrating, weight gain

• Estimated SUD potential:

  • tobacco (32%), opioids (23%), alcohol (15%), cannabis (9%)

  • 10-15% current alcohol drinkers are likely dependent, more like 85-990% for cigarette smokers (vapers?)

nicotine dependence: Nicotine Replacement Therapy (NRT)

• nonpharmacological approaches (psychotherapy)

  • likeliness of successful cessation increases w/ encouragement from health professional, rather than “going it alone”

• nicotine replacement therapy (NRT) → objective to replace cigarettes w/ healthier alternative, eventual total cessation 

  • gums, transdermal pathces, inhaler, lozenges, sublingal, nasal sprays (many OTC)

  • meta-analysis of NRTs showed almost 2x better quit rates @ 6mos. than controls

• electronic cigarettes (EC) → controversial; vaping might be safer than cigarettes (e.g., lack of tars), but some concern about its use as effective smoking cessation method 

nicotine dependence: pharmacological therapies

• antidepressants: bupropion (Zyban); for MDD marketed as Wellbutrin

• partial agonists @ nAChRs: varenicline (Chantix)

  • increases probability of long-term cessation 2-3x compared to placebo; more patients quit sucessfully w/ varencline than bupropion 

  • side effects: nausea & GI symptoms, increased cardiovascular risks, “psychiatric disturbances”

nicotine dependence: rTMS?

• repetitive TMS

• shown to seemingly reduce cravings

nicotine dependence: vaccine therapy

• vaccine approach: e.g., NicVAX; injection (I.M.) every 4-12 weeks; but excessive smoking will overcome antibody levels

  • antibodies bind to nicotine → can’t make it to the brain (BBB)

  • Nabi Pharmaceutical invests in NicVAX, began clinical trials

    • Phase II (2005) → 30% of responding smokers quit for at least 30 days

    • Phase III (2008) → no better than placebo; Nabi out of business

  • Selecta Biosciences (2017) → announces move from animal trials to Phase I trial using new synthetic antigen

nicotine dependence: role for psychedelic?

if they had a mystical experience → drop in smoking cravings