Chapter 6 Caffeine and Nicotine

Partial nicotinic agonists

-(Varenicline, cytisine, and dianicline). Partially stimulate nicotine receptor and reduce withdrawal symptoms but block access of nicotine to the receptor. Continued smoking is less satisfying. Also induces a low amount of dopamine.

Half life of caffeine, and how it is effected

-2.5-10 hours half life. -Alcohol and other medications can extend this. Cigarette smoking decreases half-life. Reduced metabolism of caffeine can increase plasma caffeine levels and contribute to cigarette withdrawal symptoms in heavy coffee drinkers (caffeine can induce or intensify anxiety disorders, such as panic disorder).

Nicotine MOA

-Affects CNS and PNS by activating acetylcholine receptors (Nicotinic receptors: Muscle receptors found on skeletal muscles and neuronal receptors through the PNS/CNS). -Neuronal nicotinic receptors: five subunits arranged around a central pore. Proteins (Alpha 2-10, Beta 2-4, serve as subunits in nACh receptors, a4 and b2 are more abundant). Nicotine is an agonist to these receptors at low doses, and an antagonist at high doses (biphasic action). After smoking a cig, these nicotinic receptors become desensitized (temporarily do not respond to nicotine or acetylcholine). During the day tolerance develops as nicotine builds up in the smoker's body, but this is lost overnight when the user is not smoking, which contributes to the powerful effect of the first cigarette of the day.

What are the adverse effects of caffeine?

-Agitation, anxiety, tremors, rapid breathing, insomnia in heavy consumption. Lethal dose is 10 grams. -Reported deaths and seizures from energy drinks.

What drugs have shown to combat smoking?

-Antidepressants bupropion and nortiptyline double chances of giving up smoking and have an acceptable rate of side effects. -SSRIs such as fluoxetine (prozac) are not effective. -Bupropion delays smoking relapse and results in less weight gain.

Nicotine doses

-Avg cigarette is 8-10mg of nicotine, 20-25% enters the bloodstream (1-2mg of nicotine per puff). -Lethal dose is 60mg. -Half-life of nicotine in a chronic smoker is about 2 hours.

Caffeine MOA

-Blocks all adenosine receptors (A1, A2A, A3, A2B)/adenosine antagonist. Positive stimulatory effects from blocking these receptors which indirectly stimulates dopaminergic activity in the prefrontal cortex. -Does not induce a release of dopamine in the nucleus accumbens. -Promote calcium release.

Cardiovascular disease risk from nicotine

-Carbon monoxide in smoke decreases amount of oxygen delivered to the heart muscle, while nicotine increases amount of work the heart must do (increasing HR/BP). -Carbon monoxide and nicotine increase chance of narrowing and clotting coronary arteries. These actions increase the risk of death from coronary heart disease in smokers.

Tolerance and dependence of caffeine

-Chronic use and discontinuation produces low-grade withdrawal symptoms (headaches, drowsiness, fatigue, negative mood, impaired intellectual/motor performance, difficulty with concentration, drug cravings). These symptoms usually begin slowly, maximize after 1-2 days, and cease within a few days; re-administration of caffeine rapidly relieves withdrawal symptoms. -4 caffeine related disorders from the DSM-5: 1) Caffeine intoxication, 2) caffeine withdrawal 3) other caffeine-induced disorders, 4) unspecified caffeine-related disorder.

Cancer and other illness risks from nicotine

-Cigarette smoke contains carcinogens which cause lung cancer. Smoking causes cancer in the mouth, voice box, and throat. Cigarette smoke causes bladder cancer, pancreatic cancer, and uterine cervix cancer. Also, cutaneous squamous cell cancer. -Smoking also increases the risk of developing insulin resistance and type 2 diabetes. -Smoking effects the visual system (increasing risk of cataract formation and the autoimmune diseases, Graces' ophthalmopathy. Also premature aging of skin.

How does caffeine affect sleep?

-Impairs duration and quality of sleep and cause repeated awakenings.

Nicotine's effect on the brain

-In the CNS, the nicotine receptors are widely distributed and may be located on the presynaptic nerve terminals of dopamine, acetylcholine, and glutamate-secreting neurons, where their activation, either directly or indirectly, facilitates the release of these and other transmitters, such as serotonin.

Effects of nicotine during pregnancy

-Increase chance for small gestational age or being born preterm/infants with low birth weight. -Reduces oxygen delivery to developing fetus causing fetal hypoxia.

Effects on the body

-Increase in BP, HR, cardiac contractility, release of epinephrine (adrenaline), increase activity of the gastrointestinal tract in the PNS. -Nicotine increases blood flow to meet increased oxygen demand of the heart muscle. -Nicotine can induce nausea and vomiting (in early stages of smoking). Reduces weight gain, stimulates the hypothalamus to release antidiuretic hormone which causes fluid retention. Decrease in muscle tone. Nicotine is also a laxative.

Effects of passive smoke

-Increase risk of lung cancer, coronary heart disease, sudden infant death syndrome, and psychiatric disorders. -Accounts for about 1 percent of deaths.

How does nicotine affect dopamine?

-Increases dopamine levels in the mesocorticolimbic reward system (VTA, NAc). -(3 potential ways) 1. Nicotine receptors on the VTA dopamine neurons directly cause dopamine to release onto the NAc. 2. Nicotine causes glutamate to be released onto VTA neurons, from glutamate neurons originating in the frontal cortex. Glutamate then sitimulates the VTA neurons to release dopamine. 3. Nicotine desensitizes nicotinic receptors on the GABA neurons in the VTA. These receptors are normally stimulated by Ach to release GABA onto VTA dopamine neurons, and GABA normally inhibits dopamine release. (When nicotine desensitizes the nicotine receptors, less GABA is released; the VTA is less inhibited and releases more dopamine).

Metabolizing nicotine

-Liver metabolizes 80-90% of nicotine, primarily by the CYP-2A6 enzyme (people w/o this enzyme or when this enzyme is inhibited have higher blood levels of nicotine and lower levels of its metabolite). -Compounds of tobacco smoke induce hepatic enzymes CYP1A1, 1A2, (possibly 2E1), which are involved in the metabolism of hormones and drugs (caffeine, estrogen, antidepressants, and psychotropic agents). Smoking may reduce levels of these medications and smoking cessation may increase blood levels, esp in moderate or heavy smokers. -Primary metabolite of nicotine is cotinine. A marker of tobacco use and exposure to environmental smoke.

Beneficial pharmacological effects of caffeine

-Moderate caffeine intake is associated with lower risk for coronary heart disease, and lower risk for stroke. Protective against Parkinson's disease and decreases risk for Alzheimer's disease. -Decreases blood flow to the brain, reducing pressure in the brain, which reduces migraines. -Improves glucose metabolism, insulin secretion, reduced risk for type 2 diabetes. -Moderate to heavy consumption can decrease risk for cancers. -Shown to decrease risk for depression.

Reproductive effects of caffeine

-Modest degree of fetal growth restriction, and in large doses may increase risk of miscarriage.

What is caffeine?

-Most widely consumed psychoactive drug. Stimulates CNS, act on kidneys producing urine, stimulate cardiac muscle, relax smooth muscle. -Occurs naturally in coffee beans, tea leaf, kola nut, cocoa bean. -Added to soft drinks, water, candies, medications.

What is adenosine?

-Neuromodulator that influences release of several neurotransmitters in the CNS. -Increase during the day and exert a sleep-inducing effect in the brain. Blocking adenosine receptors, such as with caffeine, promotes wakefulness. -Adenosine receptors stimulate GABAergic neurons of inhibitory pathways to the dopamine reward system.

Nicotine replacement therapies (Pharmacological therapies for nicotine dependence

-Nicotine replacement therapies: Nicotine-containing gum, lozengens, trandermal patches, nasal sprays, inhalers, dissolvable tobacco, mouth spray, sublingual products (snus: moist powdered tobacco sold as small mesh pouches). -E cigarettes use liquid nicotine, are cheaper, and allow for more precise nicotine control. Studies suggest ECs are safer. Although the amount of nicotine varies with ECs. -The goal is to replace smoking cigarettes as a source of the nicotine with an alternative, and slowly reduced. Gum, patches, and lozenges are over the counter, inhalers, sprays, and other medications require a prescription.

Vaccine therapy

-Once nicotine is bound to antibodies, it cannot cross the BBB, reducing the rewarding effect promoting abstinence. This does not reduce drug craving, only blocking access.

Pharmacokinetics of caffeine

-Oral administration, rapid absorption. Peak blood levels in 15-20 minutes, 99% are taken up within 45 minutes. -Soluble in water and oil (equally distributed throughout body/brain, freely crosses placenta to fetus) -Metabolized by the liver into active stimulants (theophylline and theobromine), exreted by the kidneys.

Pharmacokinetics of nicotine.

-Primary addictive substance, responsible for dependence. -Absorbed from every site in the body (lungs, nasal mucosa, skin, gastrointestinal tract). -Suspended in smoke in the form of minute particles (tars), and quickly absorbed into the bloodstream from the lungs when the smoke is inhaled.

Tolerance and dependence of nicotine

-Symptoms of withdrawal: severe cravings, irritability, anxiety, anger, difficulty in concentrating, restlessness, impatience, increased appetite, weight gain, insomnia. (Acute symptoms last for 10 days to several weeks gradually declining, weight gain and mild depression can persist for months). -Cigarette smokers in treatment for other drugs/alcohol find it harder to give up smoking. -Severity of tobacco withdrawal is not related to the dose, the duration of the habit, previous attempts at quitting, sex, age, education, alcohol and caffeine use.

What is caffeinism?

-Syndrome produced by overuse and oversdoses of caffeine. -CNS effects: Increase in anxiety, agitation, insomnia. PNS effects: Tachycardia, hypertension, cardiac arrhythmias, gastrointestinal issues. -Can produce psychosis during periods of increased stress and worsen in people with schizophrenia.

Pulmonary disease risk from nicotine

-Tar and ash inhaled from tobacco smoke are deposited on the membranes through which oxygen and carbon dioxide cross to and from the blood causing the lung to be more susceptible to infections and toxic damage. -Chronic smoking results in difficulty breathing, wheezing, chest pain, lung congestion, and increased susceptibility to infections of the respiratory tract. -Impairs ventilation and increases chance for lung damage. Reduces efficacy of the immune defense mechanisms in the lungs.

Toxicity of nicotine

-Tar in tobacco is responsible for diseases associated with long-term tobacco use.

Metabolism of caffeine

-Two major metabolites of caffeine are theophylline and paraxanthine, behave similarly to caffeine. The third metabolite mtheobromine does not. -Caffeine is metabolized by the CYP-1A2 subgroup of hepatic drug-metabolizing enzymes. -Certain SSRIs (fluoxetine and fluvoxamine) are potent inhibitors of CYP-1A2, and people taking these can exhibit unexpected toxicity to caffeine as plasma levels of caffeine rise (Caffeinism/severe anxiety reactions).

Pharmacological effects of nicotine

-Widespread throughout the brain and body. -Powerful effects on CNS and PNS, which influence the heart, respiratory and neuroendocrine function.