Term
| How can NNK in nicotine cause cancer? |
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Definition
| Form of nicotine that spontaneously rearranges to release nitrosamines which are highly active compounds that form DNA adducts |
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Term
| What determines absorption of nicotine? |
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Definition
1) Aborption
- pH dependent (weak base, so well-absorbed in alkaline environment when it is de-ionized)
- pH of the lung is 7.4, allowing for a large fraction of non ionized nicotine Alveolar surface area of the lung is large Capillary system in the lung is extensive. Results in extremely high, transient blood levels of nicotine with each inhalation. |
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Term
| How is nicotine distributed in the body? |
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Definition
1) After inhalation (higher and less-prolonged than buccal absorption), non-charged nicotine is absorbed across pulmonary epithelium to enter circulation
2) Delivered to CNS (rapidly crosses BBB) |
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Term
| Why are cigars less addictive than cigarettes? |
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Definition
| Buccal absorption leads to lower serum levels and decline more slowly. Less of a spike and drop cause less mood alteration and lower potential for craving/addiction. |
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Term
| How is nicotine metabolized/excreted? |
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Definition
1) Extensively by liver and somewhat by kidney and lung
2) Metabolized to cotinine, which may or may not be active, but is not associated with CVD or addiction (may weakly bind neuronal ACh receptors)
**Protective against neurological disease**
3) Half-life of nicotine is 2h, and cotinine (18-20h half-life) is glucouronidated and excreted in urine. |
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Term
| How does nicotine exert its pharmacodynamic effects? |
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Definition
1) Bind nAChR in brain, mimicking effects of ACh (does NOT bind muscarinic AChR)
2) nAChR acts as ion channel, increasing permeability to sodium (NMJ) and calcium (CNS and ganglia)
**alpha subunit contains ACh binding site** |
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Term
| What are the peripheral parasympathetic and sympathetic effects of nAChR stimulation by nicotine? |
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Definition
Through stimulation of autonomic ganglia, both symp and parasymp pathways are stimulated.
1) NMJ (Parasympathetic effects)
- Parasympathetic contraction of bronchial muscle
2) Adrenal gland (Sympathetic effects)
- stimulates release of sympathetic neurotransmitters |
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Term
True or False:
Depending upon dose, duration of exposure and frequency of use, nicotine can produce any positive or negative effect on an organ. |
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Definition
True.
Effects depend on dominant autonomic tone, depolarizing block, reflexes to CNS to oppose stimulation and frequency of absorption. |
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Term
What are the predominant tones and effects of nicotine on each of the following organs?
1) Arterioles
2) Veins
3) Heart
4) GI tract |
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Definition
1) Sympathetic: Vasoconstriction and HTN
2) Sympathetic: Increased venous return and CO
3) Parasympathetic: Tachycardia (adrenal overrides tone)
4) Parasympathetic: Increased motility and secretion (can be over-riden by de-sensitization |
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Term
| What are the important CNS actions of nicotine? |
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Definition
1) Pre-synpatic nAChR neurons are much more common than post-synaptic.
- Example would be that pre-synaptic nAChR activation depolarizes glutamate-releasing neuron.
2) Central NAChR receptors are Ca-permeable and tend to enhance glutamatergic transmission in hippocampus (may also increase dopamine release:reward)
**NT released by nicotine include glutamate, GABA, dopamine, ACh, 5-HT and beta-endorphin |
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Term
| What is the receptor-based mechanism of nicotine addiction? |
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Definition
Activation and Desensitization
1) Sustained low-levels of nicotine shift receptors into desensitized state (higher affinity, but less ion flow)
2) Compensatory up-regulation of receptor # |
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Term
True or False:
Lung ciliary function impairment from smoking remains unchanged following cessation |
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Definition
False!
It will improve in 1-9 months
LUNG CANCER RISK WILL NOT. |
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Term
True or False:
The Relative Addictiveness score of nicotine is higher than crack cocaine and heroin. |
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Definition
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Term
| What do mutations in the dopamine pathway have to due to susceptibility to nicotine addiction? |
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Definition
Higher biological activity means reduced smoking rates and reduced dependence!
1) SLC6A3 encodes a dopamine reuptake transporter 9-repeat allele shows diminished dopamine reuptake compared to other alleles due to decreased protein expression (more dopamine remains in synapse).
2) DRD2-A2 allele higher density of dopamine receptors (more dopamine signaling).
3) DRD4-S allele shows increased dopamine affinity (heightened overall response to dopamine) |
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Term
True or False:
Majority of patients require more than 1 quit attempt, relapsing within the first 6-12 months |
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Definition
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Term
| What precautions should be taken when starting NRT therapy? |
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Definition
Watch out for in TMJ disease, pregnancy, lactation and CVD!
1) Post MI (within 2 weeks0
2) Arrhythmias
3) Worsening AP
**LOwer than continued tobacco use though!** |
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Term
| What psychotropic drugs have proven to be useful in treating nicotine addiction? |
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Definition
1) Buproprion (Zyban)- Look out for DEPRESSION
- inhibits re-uptake of NE, 5-HT and dopamine, reducing urge.
- long half life and slow steady-state achievement (give it before they stop smoking)
- GREAT option for patients with DRD2-A2 allele and SLC6A3-9 allele (also protective against addiction).
2) Varencicline tartrate (Chantix)- Nausea
- a4b2 (neuronal) partial agonist that inhibits pre-synpatic nicotine effects (blunts rewarding affects)
- Be be better than buproprion in long-term.
3) NicVAX
- Conjugates nicotine to carreir protein that elicits an immune response in bloodstream, preventing BBB crossing. |
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Term
| What population benefits most strongly from Buproprion treatment? |
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Definition
| Those with protective Dopamine processing alleles like DRD2-A2 and SLC6A3-9, that increase dopamine responsiveness. |
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