Nicotine – Comprehensive Study Notes

Chemical Identity & Sources

• Nicotine = 1-methyl-2-[3-pyridyl]pyrrolidine; one of several alkaloids in tobacco leaves
• Constitutes ≈ $5\%$ of dry tobacco leaf weight
• Typical U.S. cigarette: $\approx 9\,\text{mg}$ nicotine; smoker’s systemic yield ≈ $1\,\text{mg}$
• Other plant cholinomimetics historically used for ritual/hedonism: lobeline, arecoline, hyoscine, muscarine, physostigmine, pilocarpine, morphine

Historical Background

• 15th-century Columbus voyages observed indigenous American tobacco use (hedonistic, ritual, magical)
• Plant named Nicotiana tabacum after Jean Nicot (1530-1600), who promoted medicinal cultivation in Europe & introduced tobacco to Catherine de Medici
• 1988 U.S. Surgeon General: nicotine classified with alcohol, opiates, amphetamines, cocaine as addictive
• Tobacco = leading preventable cause of premature death in many societies

Basic Pharmacology of Nicotine

• Tobacco smoke mixture: carbon monoxide (CO) + thousands of particulates (tar) → taste/smell but also pathology
• Routes & kinetics (see Fig 14.1)
  • Inhalation → fastest: $25\%$ of nicotine reaches brain in $\approx 7\,\text{s}$ (twice as fast as IV)
  • Oral snuff, chewing tobacco, nicotine gum = slower absorption
• Half-life in blood: $\approx 2\,\text{h}$ (range varies)
• Metabolism: $80\text{–}90\%$ hepatic → major metabolites cotinine & nicotine-N-oxide; excreted in urine, saliva, breast milk

Reinforcing Effects & Dependence

• Human IV self-administration: dose-related euphoria similar to cocaine/morphine; saline substitution stops responding
• Secondary reinforcers: taste, smell, social cues, environmental contexts (after meals, coffee, alcohol, telephone, sports viewing)
• Animal studies (rats, dogs, primates)
  • Rats press active lever > inactive for nicotine (Fig 14.2)
  • Highest unit dose ( $0.06\,\text{mg kg}^{-1}$ ) ↓ responses → longer inter-response interval
• Plasma-level studies (Pomerleau & Pomerleau, 1992)
  • Cigarettes of differing yields produce plasma groups: low $4.5\,\text{ng ml}^{-1}$; medium $13.4\,\text{ng ml}^{-1}$; high $22.8\,\text{ng ml}^{-1}$
  • Button-press “euphoria” ↑ with dose (Fig 14.3)

Behavioral & Psychomotor Effects

• Methodological caveats: heterogeneous smoking histories, abstinence durations ( $3\,\text{h}$–$5\,\text{d}$ ), placebo issues, smoker vs nonsmoker baseline differences, withdrawal confounds
• Tasks affected:
  • Critical Flicker Fusion (CFF): nicotine ↑ threshold in abstinent smokers; less clear in nonsmokers
  • Motor (finger tapping) ↑ regardless of smoking history
  • Sustained attention (RVIP), Stroop, memory tasks: improvements mainly reverse withdrawal deficits
  • Complex tasks (simulated driving): mixed findings
• Conclusion: nicotine largely reverses withdrawal-induced deficits; absolute enhancement small & task-specific

Peripheral Physiological Effects

• Small doses stimulate autonomic ganglia > neuromuscular junctions
  • ↑ HR & BP via sympathetic ganglia + adrenal epinephrine/norepinephrine release
  • Stimulates aortic/carotid chemoreceptors → vasoconstriction, tachycardia
  • ↑ gastric HCl → ulcers; ↑ bowel motility → diarrhea/colitis risk
• High doses: prolonged depolarization → muscle weakness/paralysis

Central Nervous System Effects

• Crosses BBB rapidly; activates brain nAChRs
• Moderate doses: ↑ respiration; acts on medullary vasomotor centers; induces antidiuretic hormone release
• EEG: β-like low-voltage ( $13\text{–}30\,\text{Hz}$ ) neocortical activation + hippocampal θ ( $4\text{–}7\,\text{Hz}$ ) – correlated with arousal
• Increases cerebral glucose uptake (metabolism) similar to cocaine
• High doses: tremors, convulsions

Toxicity

• Lethal human dose ≈ $60\,\text{mg}$ (one cigar contains ≈ $2$ lethal doses but combustion destroys most nicotine)
• Pediatric ingestion: slower GI absorption (ionized in acidic stomach); vomiting via medullary trigger zone
• Nicotine insecticides → dermal absorption → respiratory paralysis, severe autonomic crisis (nausea, cold sweat, hypotension, collapse)
• Treatment: induce emesis, activated charcoal, respiratory support, shock therapy
• CO toxicity: Hb affinity ×$220$ vs O₂; COHb half-life $3\text{–}4\,\text{h}$; chronic exposure → ↑ Hb & RBCs but persistent tissue hypoxia

Mechanisms of Action (Neuropharmacology)

• nAChRs = ligand-gated ion channels (presynaptic > postsynaptic in brain)
  • Locations: VTA, nucleus accumbens, striatum, substantia nigra, cortex, hippocampus
  • Activation ↑ presynaptic $Ca^{2+}$ influx → ↑ release of ACh, DA, Glu
  • Potentiates NMDA-mediated EPSPs in hippocampus & PFC → cognitive effects
• Mesolimbic DA pathway (VTA → nucleus accumbens)
  • Systemic nicotine ↑ accumbens DA (microdialysis; Di Chiara & Imperato)
  • Antagonist (dihydro-β-erythroidine) in VTA blocks self-administration; accumbens block less effective (Corrigall et al.)
  • DA D₁ receptor blockade (SCH23390) > D₂ (spiperone) reduces nicotine self-administration

Demographics & Determinants of Smoking

• Socioeconomic status: inverse for men; complex gender interactions (women in high SES more likely to smoke)
• Occupation: blue-collar > white-collar (men); female white-collar high
• Family influences: parental & sibling smoking ↑ teen risk (both parents + sibling ×4 likelihood)
• Tobacco-farming families: kids hold favorable attitudes & higher usage
• Peer influence critical in initiation (friends smoke → early adoption)
• Subjective motives (Jaffe & Jarvik): calming, stimulation, coping with stress, habit, sensory/handling cues, withdrawal avoidance
• Arousal-matching study: performance improved when smoking matched boredom vs stress context; impaired when mismatched

Tolerance & Withdrawal

• Acute tachyphylaxis: HR increase larger after overnight abstinence vs second cigarette $30\,\text{min}$ later (Fig 14.6)
• Subjective tolerance: first cigarette → greatest arousal/sedation; effects wane across day
• Withdrawal syndrome (Hughes et al.): craving, irritability, anxiety, difficulty concentrating, restlessness, ↓ HR, dysphoria, insomnia, ↑ appetite/weight
  • Onset $\approx 24\,\text{h}$; peak $36\text{–}72\,\text{h}$; decline thereafter
  • Severity not well predicted by age, sex, cigarettes/day, nicotine yield, etc.

Chronic Health Effects

• Smoking contributes to $\approx 420{,}000$ U.S. deaths in $1990$ (≈ $20\%$ of all deaths)
• Four of top five world mortality causes: cardiovascular disease, cancers (lung, others), stroke, chronic obstructive pulmonary disease
• Lung-cancer mortality ↑ with cigarettes/day; declines with years after cessation (Fig 14.7)
• Second-hand smoke: EPA (1992) classifies as lung-cancer risk; contested by some researchers
• Economic burden (1985): $145\,\text{M}$ hospital days + $80\,\text{M}$ lost workdays → >\$65\,\text{B} (likely >\$100\,\text{B} today)

Industry & Social Context

• Advertising targets youth; e.g., Camel’s “Old Joe” recognizable to $3\text{–}6$-yr-olds
• Smokeless tobacco campaign (1974–84) ↑ sales $11\%$ annually; associated pathologies: gum recession, leukoplakia, oral cancers
• Brown & Williamson documents (1994): internal acknowledgment of nicotine addictiveness; suppression of harmful findings; use of CTR for public-relations research; attorney-client privilege to shield data
• Public health responses: warnings, taxation, smoking restrictions, fairness doctrine ads, broadcast ad ban → decline in per-capita consumption (Fig 14.5)

Treatment Strategies

• Goals: cessation + long-term abstinence
• Behavioral interventions: media campaigns, taxation, self-help literature, group programs (non-profit, HMOs, Smokenders), professional therapy (psychology, hypnosis, acupuncture)

Pharmacotherapies

• Early agents (ineffective): mecamylamine (CNS antagonist), propranolol, amphetamine, benzodiazepines
• Nicotine Gum (polacrilex)
  • Doses: $2\,\text{mg}$ or $4\,\text{mg}$; chew-park method
  • Plasma levels: $\approx 11.8$ vs $23.2\,\mu\text{g L}^{-1}$
  • Relieves irritability, anxiety, restlessness; modest craving reduction (after 1–2 wks)
  • Abstinence ~$29\%$ at $6\,\text{mo}$ (vs $19\%$ placebo); dependence risk $17\text{–}25\%$; oral/GI side-effects
• Transdermal Patches
  • Doses: $5\text{–}22\,\text{mg day}^{-1}$ (16–24 h wear) → plasma $9.4\text{–}17\,\mu\text{g L}^{-1}$
  • Criteria: ≥$20$ cigarettes/day OR first cigarette <$30\,\text{min}$ after waking OR severe past cravings
  • Better compliance; suppress craving & withdrawal; abstinence odds ×$2\text{–}3$ vs placebo; low abuse; skin irritation occasional
• Nasal Spray
  • Dose: $1\,\text{mg}$ (both nostrils); max $40\,\text{mg day}^{-1}$
  • 6-mo abstinence $32\%$ vs $12\%$ placebo (OR = $2.7$)
• Inhaler (under review)
  • $0.016\,\text{mg}$ per puff; $300$ puffs/device; 2–10 devices/day → plasma $\approx 38\%$ of smoking
  • Promising efficacy; provides handling/inhalation cues
• Combination therapy (patch + gum) shows superior withdrawal suppression
• Overall long-term success: ≈$30\%$ abstinent at $1\,\text{yr}$ with best combined modalities; continued innovation needed

Summary of Key Concepts

• Nicotine = rapid-acting, highly addictive cholinergic agonist delivered most efficiently by inhalation
• Acts on central & peripheral nAChRs; reinforces behavior via mesolimbic DA activation
• Produces acute stimulation, cognitive modulation, tolerance, and well-characterized withdrawal syndrome
• Tobacco smoke delivers additional toxins (tar, CO) → major global morbidity/mortality
• Multiple social, demographic, and marketing factors influence initiation & maintenance
• Effective cessation requires integrated behavioral support + pharmacological nicotine replacement (gum, patch, spray, inhaler)
• Despite progress, nicotine dependence remains a significant public-health challenge demanding continual research & policy action