Lecture 10 - Smoking and Vaping

There has been a significant decrease in tobacco product use over the past 70 yrs
Primarily as a result of surgeon general reports, public education and awareness, secondhand smoke-related issues, tobacco company settlements, taxation, and alternative nicotine forms

Decrease in smokin' countered by the recent rise in use of electronic cigarettes
E-cigarettes consist of a battery-powered atomizer and heating element that vaporize (aerosolize) flavored nicotine solution
Originally developed as a smoking cessation aid, but now being used by people with no prior smoking history
Can also be used to vaporize drugs such as marijuana, meth, etc.

>8000 chemicals in cigarette smoke
~50% are formed by combustion (pyrrolysis)
~ 70 are known carcinogens
~600 are additives such as menthol (for airway numbing) and bronchodilators
Nicotine is primarily the addictive one (taking more reduces withdrawal syndromes)

Vape

E-cigarette vapor contains some similar chemicals but at much lower levels
Primary components of vape solutions are nicotine, flavorings, glycerin, and propylene glycol as humectants for vaporization and solubility

~70-90% of inhaled nicotine enters bloodstream
Nicotine starts to reach brain <10 sec after inhalation
Nicotine elimination t1/2 = ~2hr, which necessitates repeated dosing within each day to maintain desired blood levels
Pack a day smoker can smoke >7,000 cigarettes per year

~70-80% of nicotine converted to inactive metabolite cotinine (elimination t1/2 = ~15 hr) and its lasting presence makes it more useful measure of recent nicotine intake
Metabolites are primarily created in liver and excreted through kidneys
Remaining 20-30% converted to other metabolites or excreted unchanged via kidneys
Some individual have p450 variants that prolong nicotine half-life, reducing overall nicotine intake and decreasing potential toxicity (i.e., cancer)

Cognitive behavioral effects of nicotine alone are relatively benign
The most widely desired effect is a cognitive enhancement, particularly in low-attention situations
Other desired effects include relief from anxiety (anxiolysis), relief of cognitive disturbances in schizophrenia
Nicotine shows some protective effects against neurodegeneration in Alzheimers and Parkinsons diseases (might help with ADHD + Schizophrenia) by reducing oxidative stress and neuroinflammation
Neuroprotective (protects neurons from damaging and dying)^

Acetylcholine (ACh) synthesized from choline and acetyl CoA
After release, rapidly broken down into choline and acetate
Reuptake is performed by presynaptic choline (not ACh) transporter
Nicotine binds to nicotinic ACh receptor (nAChR), a pentameric (5 subunit) ligand-gated Na+/Ca2+ channel
Receptor very high affinity for nicotine, which acts as a full non-competitive agonist that is capable of activating the receptor on its own

nAChRs are comprised of 5 different subunits belonging to alpha, beta, etc, families
Specific subunits and their combinations are differently distributed throughout the brain
Nicotine does not activate all n AChRs, rather it preferentially activtaes nAChRs containing only a7 subunits (homomeric) and those containing a mixture of a4 and b2 suunits (heteromic)
Although not a target of nicotine, another class of ACh receptors is termed teh Muscarinic (m) ACh receptor [not relevant other acetycholic receptor]

nAChRs are presnet in both sympathetic and parasympathetic division of autonomic nerbouse system
- Parasympathetic activation → increased gastric acid secretion and intestial motility
- Sympathetic activiation → tachycardia, vasoconstriction
- Thus, nicotine produces mized sympathetic and parasympathetic activation

Neurons innervating skeletal muscle use ACh as their neurotransmitter at neuromuscular junctions (NMJ) within motor end plates
At normal doses, nicotine does not affect NMJs
At very high concentrations (40% w/v, >1000x that of cigarettes or e-cigarette liquid) nicotine can cause overexcitation of teh NMJ, resulting in paralysis of the diaphragm and death

VTA dopamine neurons are innervated by ACh neurons originating from other brain regions
A4b2 heteromeric nAChRs are located directly on VTA dopamine neurons, so nicotine directly ascites the reward system
A7 homomerc nAChRs are located on glutamate nerve terminas (also originating from other brain regions) that innervate VTA DA neurons, so their activation by nicotine increases glutamate release and indirectly activates teh reward pathway

After binding nicotine, nAChRs rapidly desensitize, closing the ion channel even while the drug is still bound to the receptor (acute desensitization)
Repeated use leads to chronic desensititzation, causing a compensatory nAChR up-regulation (contrary to the usual down-regulating effect of other receptor agonists)

Cerebral cortex graymatter thickness reduced in chronic smokers
Ex-smokers showed partial recovery for each year of abstinence, but projected ~25 years for full recovery
However, nicotine is not generally considered to be neurotoxic, and may even be neuroprotective

*Intended to be harm reduction strategy

Weakly blocks reuptake of NE and DA (NE/DA reuptake inhibitor, or NDRI) which increase levels of DA, partially satisfying nicotine cracifn
May also alleviate underlying anxiety and depression

Overall efficancy of smoking cesstation approaches

Best abstinence rates are found when NRTs/ pharmacoterapises AND psychosocial support, though each have ~70-90% relapse rates

10-1) The half-life of nicotine is much longer than that of its primarily

metabolite cotinine.

a) true

b) false

10-2) The smoking cessation aid varenicline (Chantix) is actually just

nicotine sold under a newer brand name.

a) true

b) false

10-3) Pyrolis_________ (one word) is a term that means the formation of new

chemicals by burning something such as the tobacco leaf.