Nicotine and Caffeine: Biochemical and Physiological Effects

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Tobacco leaves are the primary natural source of nicotine. They were introduced to the New World in 1492 and are now cultivated globally.
Tobacco can be consumed by smoking (cigarettes, pipes), chewing (intralingual), or transdermal patches.
Nicotine content in cigarettes varies, typically delivering 8 mg per cigarette, with about 0.1-2 mg absorbed systemically.
90% of nicotine from cigarette is found in smoke stream, contains carcinogens
mainstream is absorbed by lungs while sidestream causes second-hand smoking

It acts as an agonist at nicotinic acetylcholine receptors (nAChRs) (agonist of acetylcholine) which are ligand-gated ion channels
Cholinergic neurons (where nicotinic receptors are found): cortex, cerebllum, septal nuclei, hippocampus, nucleus basalis
Nicotinic receptors: muscular (NM junction) and neuronal, TWO NICOTINE MOLECULES are needed to activate receptor
Nicotinic receptors are excitatory and allow entrance of Na+, depolarization of cell
nAChRs are composed of various subunits (5; α4β2), and their composition affects nicotine's effects and addiction potential.
Repeated stimulation can lead to desensitization (depolarization block) of these receptors.
REDUCES MAO-B activity
Up-regulation of nicotinic receptors is observed in smokers // schizophrenia

Nicotine crosses BBB in 7 seconds, Smoking delivers nicotine to the brain within seconds, making it one of the fastest routes of drug delivery.
30-60min half-life (causes users to seek ideal "sweet spot", titrate according to the effects felt)
Nicotine is rapidly absorbed through the lungs, oral mucosa, or nasal membranes, depending on the route of administration.
10% of nicotine is absorbed and passes through urine without metabolizing
90% metabolized in liver
Nicotine is metabolized primarily in the liver by the enzyme CYP2A6 to cotinine, which is used as a biomarker for nicotine exposure.
COTININE IS USED IN DRUG TESTS
LETHAL DOSE: 60mg (muscle paralysis, low arterial pressure, etc)

Nicotine stimulates the sympathetic nervous system (SYMPATOMIMETIC), increasing heart rate, blood pressure, tremors, convulsions, nausea and the release of catecholamines (norepinephrine, epinephrine)
produces biphasic effects -> activates neuron initially and then inhibits (muscular relaxation)
It can enhance alertness, attention, and reaction time, especially in habitual users.
State dependent learning: mejora el aprendizaje (cognitive enhancer)
Increases metabolism and fatty-acid oxidation
Nicotine also has reinforcing effects via the mesolimbic dopamine pathway, contributing to its addictive potential.
Chronic use leads to tolerance and dependence, with withdrawal symptoms including irritability, anxiety, and difficulty concentrating.
Chronic cigarette smoking causes erogenous pleasure in mouth, can cause ex-users to over eat to stimulate mouth
Activates dopaminergic neurons in nucleus accumbens to cause pleasure

Nicotine is toxic at high doses and can cause poisoning, especially in children
Increases stroke risk in women and heart attack
Smoking is associated with increased risk of cancer, cardiovascular disease, and low birth weight in infants.
Other toxic substances in tobacco smoke include tar (12-16mg, damages cilia in lungs, lets carcinogens accumulate) and nitrosamines, but not mecamylamine (a nicotinic antagonist used therapeutically).
- Cigarette main components:
  arsenic
  ammonia
  methanol
  methane
  acetic acid
  butane
  toluene
- Smoke of cigarette:
  CO (25ppm in blood)
  CO2
  Ammonia
  Acetone
  CNOH

Dependence is maintained by both pharmacological (nicotine's effects on the brain) and behavioral (sensory cues, habits) factors.
- speed of reaching brain
- circumstances/habits surrounding smoking
- number of doses
Nicotine replacement therapies (NRT) include patches, gum, nasal sprays, and lozenges, which help reduce withdrawal symptoms and cravings.
Pharmacotherapies such as bupropion and varenicline are also used to aid cessation.
Mecamylamine is antagonist, stops peaking of dopamine release by tobacco smoke
Quitting smoking is challenging, with high relapse rates and multiple attempts often required.

Formulation	Route	Advantages	Disadvantages
Patch	Transdermal	Steady delivery, easy to use	Slow onset, skin irritation
Gum	Oral	Flexible dosing, oral fixation	Jaw discomfort, taste
Nasal spray	Intranasal	Rapid delivery	Nasal irritation
Lozenge	Oral	Discreet, flexible dosing	GI upset

Social factors

higher education, higher socioeconomic status and occupational level ar correlated with lower nicotine use
1940 = 50% of US were smokers
younger age (18-25) and male gender present higher tobacco use
non-smokers don't initially like nicotine

Withdrawal