Table of Contents
Tobacco
Physiological Pathway of Tobacco – Pharmacodynamics and Pharmacokinetics
Tobacco and its primary active substance, nicotine, exert complex effects on the human body through specific physiological pathways. These effects are understood through two key frameworks: pharmacokinetics (PK) — the absorption, distribution, metabolism, and excretion of nicotine, and pharmacodynamics (PD) — the molecular and systemic actions of nicotine and other tobacco components.
Background
Tobacco: Derived from dried or fresh leaves, consumed by smoking, chewing, snuff, or via electronic cigarettes.
Primary active compound: Nicotine — an alkaloid with potent addictive properties.
Other harmful constituents: Carbon monoxide (CO), tar, nitrosamines (NNK, NNN), heavy metals, and reactive oxidant species (ROS), all of which contribute to long-term disease and cancer risk.
Pharmacokinetics (ADME)
Absorption
Smoking: Rapid alveolar absorption; nicotine reaches peak blood levels within seconds to minutes.
Chewing tobacco/snuff: Oral mucosa absorption, slower but prolonged nicotine levels.
Nicotine patches/sublingual strips: Gradual transdermal or mucosal absorption.
Note: Nicotine is a weak base; absorption depends on pH (enhanced in alkaline environments).
Distribution
Quickly distributed via blood; crosses the blood–brain barrier within seconds.
Concentrates in the brain, lungs, kidneys, and liver.
Distribution half-life: very short, enabling rapid psychoactive effects.
Metabolism
Metabolized mainly in the liver by CYP2A6 enzyme into cotinine.
Cotinine has a longer plasma half-life (16–20 hrs) and is used as a biomarker for nicotine exposure.
Other metabolites: nicotine-N-oxide, nornicotine, etc.
Excretion
Primarily excreted through urine, also detectable in saliva, sweat, breast milk, hair, and nails.
Biomarker measurement: urinary or plasma cotinine.
Pharmacodynamics – Nicotine’s Actions
Primary Target: Nicotinic Acetylcholine Receptors (nAChRs)
Nicotine binds to nAChRs (ligand-gated ion channels).
Subtypes: α4β2 and α7 are especially important; α4β2 is key in addiction.
Binding opens channels → sodium and calcium influx → neuronal depolarization → neurotransmitter release.
Brain Effects — Reward and Dependence
Stimulates the dopaminergic reward pathway (ventral tegmental area → nucleus accumbens).
Produces euphoria, relaxation, and reinforcement.
Chronic exposure causes receptor upregulation, sensitization/desensitization, leading to tolerance and dependence.
Affects multiple neurotransmitters: dopamine, acetylcholine, glutamate, GABA, serotonin, norepinephrine.
Cardiovascular Effects
Stimulates sympathetic nervous system → increases norepinephrine and epinephrine.
Results: elevated heart rate, blood pressure, and cardiac contractility.
Long-term: contributes to atherosclerosis and cardiovascular disease (exacerbated by CO and tar).
Respiratory Effects
Direct irritation, inflammation, impaired mucociliary clearance → chronic bronchitis, COPD.
CO binds hemoglobin (carboxyhemoglobin) → reduced oxygen carrying capacity → tissue hypoxia.
Carcinogenesis
Tobacco nitrosamines and tar form DNA adducts, mutations, and genomic instability.
Increases risk of cancers: lung, oral, pharyngeal, esophageal, pancreatic, and bladder.
Immune and Inflammatory Effects
Disrupts both innate and adaptive immunity.
Increases susceptibility to infections, chronic inflammation, and tissue remodeling.
Molecular and Cellular Pathways
nAChR activation → Ca²⁺ influx → CAMK / PKA / MAPK signaling → altered gene expression.
Oxidative stress: ROS → lipid peroxidation, DNA damage, NF-κB activation → pro-inflammatory cytokines (IL-6, TNF-α).
Carcinogen activation: Nitrosamines metabolized by CYP450 → DNA adducts → mutations.
Endothelial dysfunction: Reduced nitric oxide bioavailability → impaired vascular tone → atherosclerosis.
Clinical Effects
Short-Term
Cardiovascular: tachycardia, elevated blood pressure.
CNS: alertness, improved attention, mild euphoria.
GI: nausea, vomiting (in high doses).
Long-Term
Addiction: strong physical and psychological dependence.
Respiratory disease: COPD, chronic bronchitis, emphysema.
Cardiovascular disease: coronary artery disease, stroke, peripheral vascular disease.
Cancer: lung, oral, pharyngeal, esophageal, pancreatic, bladder.
Pregnancy risks: intrauterine growth restriction, prematurity, low birth weight, neurodevelopmental impairments.
Biomarkers
Cotinine (blood/urine/saliva): gold standard for nicotine exposure.
Carboxyhemoglobin (CO-Hb): indicates recent smoking.
Pulmonary function tests, cardiac biomarkers, inflammatory markers (CRP), and genetic mutation screens may also be used.
Drug Interactions and Special Considerations
CYP2A6 polymorphisms affect nicotine metabolism speed → influence addiction severity and cessation success.
Nicotine alters metabolism of certain drugs.
Vulnerable groups: pregnant women, infants, heart disease patients, chronic illness patients.
Dependence and Withdrawal
Physiological dependence: receptor adaptation and dopamine deficiency upon cessation.
Withdrawal symptoms: craving, irritability, anxiety, insomnia, poor concentration, increased appetite/weight gain.
Behavioral cues and rituals reinforce psychological dependence.
Cessation Strategies
Behavioral therapy
Counseling, motivational interviewing, trigger management.
Pharmacotherapy
Nicotine replacement therapy (NRT): patches, gums, lozenges.
Non-nicotine medications: bupropion, varenicline.
Public health interventions
Taxation, smoking bans, education campaigns, school-based prevention.
Clinical approach
Biomarker monitoring, cardiovascular and pulmonary assessment, cancer screening.
Research and Future Directions
Precision medicine: tailoring cessation strategies based on genetic polymorphisms (e.g., CYP2A6).
Long-term effects of e-cigarettes and vaping remain under investigation.
Novel therapies: subtype-specific nAChR modulators.
Summary – Key Points
Nicotine is rapidly absorbed, crosses into the brain, and activates nAChRs, driving dopamine-mediated reward and addiction.
Pharmacokinetics: fast absorption, CYP2A6 metabolism to cotinine, urinary excretion.
Tobacco harm goes beyond nicotine — CO, tar, nitrosamines, ROS cause cardiovascular disease, COPD, and cancers.
Dependence is both physiological and behavioral; effective cessation requires integrated strategies.
Prevention and public health policies are critical in reducing the global tobacco burden.
