Caffeine & Methylxanthines PDF

Caffeine & the Methylxanthines  Sources of the Methylxanthines Coffee Caffeine: best known of methylxanthines Common sources: coffee, tea, and chocolate Coffee cultivation began in Ethiopia Types of Coffee Beans Coffea arabica: originate in Ethiopia; grown in South America; 70%...

Caffeine & the Methylxanthines  Sources of the Methylxanthines Coffee Caffeine: best known of methylxanthines Common sources: coffee, tea, and chocolate Coffee cultivation began in Ethiopia Types of Coffee Beans Coffea arabica: originate in Ethiopia; grown in South America; 70% of world coffee production Coffea canephora (robusta): grown on Java, origin of phrase “Cup of Java”; harsher taste, cheaper, twice the caffeine content Tea Camellia sinesis plant Types of tea: Green unfermented tea: cultivated in China, leaves are steamed then dried, prevents oxidization Black fermented tea: cultivated in India & Sri Lanka, tea leaves crushed, releases enzymes that oxidizes leaves, turn black Oolong semi-fermented tea: roasting stops oxidation before completed Tea Health benefits from polyphenols (prevent heart disease, inflammatory disorders, cancers) Oxidation causes black tea to lose polyphenols Oldest caffeine containing beverage; cultivated and marketed in China in 780 C.E. Chocolate Cacao tree cultivated by Aztecs, Mayans, & Incas Cacao cultivation originates in South America, bulk of production currently in West Africa Sources of Caffeine, Theophylline & Theobromine 35 mg 100 mg 100 mg 6 mg in 1 ounce Theobromine 53 mg 44 mg Theophylline 40-120mg Sources Beverages: 98% of caffeine intake Coffee 100 mg in 5 oz cup; 196 mg in 14 oz Tim Horton’s cup Tea 14 t0 65 mg caffeine in 8 fl oz cup, also contains theobromine and theophylline Chocolate 2 oz milk chocolate contains 3-20 mg caffeine Chocolate milk: 2-7 mg in 8 fl oz Other sources Guarana paste from seeds of Paullaina cupana (4.3% caffeine) – most potent natural source, S. America Cola nuts,(2-3.5% caffeine) chewing nuts is widespread habit in Western Africa, used to flavor Coca-Cola and Pepsi-Cola – not as a source of caffeine Energy Drinks: considered dietary supplement, unlike soft drinks (max 71 mg/12 oz) caffeine content not regulated by FDA; contain 50-300 mg caffeine per 8.4 oz; average daily consumption 160 mg from energy drinks Consumption Average world daily consumption per capita is 70 mg Scandinavian countries highest intake of coffee (7- 9 kg green beans per capita) Canadian: 6.3 kg Ireland and Great Britain greatest consumers of tea Pharmacokinetics Absorption Bases with very low pKa (0.5); rapid absorption from GI tract (stomach walls , small intestine) Peak blood levels after coffee within 45-75 min Distribution Crosses blood-brain and placental barriers 10 - 30% bound to plasma proteins Distributes in equal [ ] throughout the body Pharmacokinetics Metabolism and Excretion Half-life: ~ 5 hours (2.5 – 7.5 hours) Metabolized by liver; ~ 1% excreted unchanged Metabolized by Cytochrome P 450 enzymes; CYP1A2 gene codes for enzyme 1A form = rapid metabolism, 1F form = slow metabolism, greater effect, also experience adverse effects Pharmacokinetics Metabolism and Excretion Metabolic rate: Slowed by alcohol, grapefruit juice, slower in nonsmokers, women taking oral contraceptives, and pregnant women Sped up by broccoli Newborns can’t metabolize; excrete 85% unchanged; half life = 100 hours in infant; adult-like metabolism by 7-9 months of age Neurophysiological Effects Methylxanthines are Adenosine receptor blockers (A1, A2A) Neuromodulator acts presynaptically to inhibit release of NT Blocking adenosine receptors increases release of NT Reinforcing effect: block A1 receptors on DA terminals in ventral striatum, á DA release High doses block BZ receptors; 10 cups block 20% BZ receptors Neurophysiological Effects Mazziotta, C., Rotondo, J. C., Lanzillotti, C., Campione, G., Martini, F., & Tognon, M. (2022). Cancer biology and molecular genetics of A3 adenosine receptor. Oncogene, 41(3), 301–308 Effects on Non-Human Performance Unconditioned behavior á spontaneous motor activity (20-40 mg/kg); â at 80 mg/kg LD50 = 250 mg/kg [rats, mice]; due to convulsions Conditioned behavior 30 mg/kg increases food-reinforced responding suppressed by punishment with shock Effects on Body Vasodilator in the Peripheral NS Stimulates heart rate by dilating the arteries of the heart muscle (reflexive tachycardia); á blood flow and oxygen to the heart Causes skeletal muscle to strengthen and smooth muscle to relax Dilation of bronchial muscles = therapeutic use to ease breathing; theophylline has stronger effects than caffeine Reduces likelihood of fatigue in striated muscles Effects on Body Increased urination á frequency and urgency of urination, â sensation of a full bladder, á flow rate and volume Women who consumed > 450 mg/day had greater risk of urinary incontinence than those that drank < 150 mg Effects on Body Vasoconstrictor in Central NS Commonly assumed caffeine relieves headaches by constricting blood vessels Vasodilation is symptom, not cause, of migraine Adenosine levels é during a migraine – é causes vasodilation and pain Relief from caffeine is due to blocking adenosine, not vasoconstriction Caffeine in OTC medications – enhances the effectiveness of pain relievers that alleviate pain from headache Effects on Human Performance Methodological concerns When participants avoid caffeine prior to assessment, changes in performance may be due to decrease in withdrawal rather than improvement from baseline Effects on Human Performance Improves athletic performance that requires sub maximal output for long periods (X-country skiing; running, cycling) Produces insomnia [best known effect] 300 mg á latency to sleep from 18 to 66 min; â total sleep time from 475 to 350 min easily startled â acoustic arousal threshold; awakened more easily woke and - Can counteract sleep-inducing effects of pentobarbital Tolerance to sleep effects develops within a week Effects Subjective Effects quaefest increase Feelings of well-being; alertness; energy; motivation for work; self-confidence More likely to be reported by nonusers or users deprived of caffeine Occur with low doses (20 to 200 mg) Caffeine in 1-2 cups of coffee (100 to 200 mg) â fatigue and á mental alertness Caffeine in 12 - 15 cups of coffee (1.5 g) produces anxiety and tremors Self-Administration Nonhumans Not a robust reinforcer, does not support a lot of behavior  Self-Administration Humans Preference for caffeinated coffee and caffeine capsules People seek effects of caffeine to actively avoid caffeine withdrawal people Task dependent: vigilance task – prefer caffeine most aware of what & capsules beforehand, relaxation task – only 2 of 7 prefer caffeine capsules caffeine does to them Tolerance Less effect on heavy drinkers than on non-drinkers of coffee (150 to 300 mg è jitteriness, nervousness in nonusers, but alertness, contentment in users) Different effects show tolerance at different rates (cardiovascular effects fade in 2 to 5 days; á urination does not show tolerance) Tolerance due to upregulation of adenosine receptors Cross-tolerance among methylxanthines Withdrawal Headache most common; also drowsiness, fatigue, â energy, impaired concentration, á irritability, aches and muscle stiffness, â feelings of well-being Severity related to dose Begins in 12-28 hours, peaks at 20-51 hours, lasts 2 -9 days Physical dependence within 6-14 days at 600 mg/day Dependence Syndrome Dependence Low dependence potential ↳ harder to be physically depende a Harmful Effects Reproduction Consumption of > 200 mg/day retards fetal development and lowers birth weight (60-70 g for 200 mg) Bone Density Consumption of 2-3 cups per day accelerates bone loss in spine and body of postmenopausal women  Caffeine Use Disorder (not a current diagnosis) DSM V: Emerging Measures and Models 3 Criteria Persistent desire or unsuccessful efforts to reduce or control caffeine use Continued caffeine use despite it causing or important exacerbating an existing physical or psychological problem Withdrawal symptoms upon cessation or reduction of caffeine intake Given high levels of daily use, risk of overdiagnosis Harmful Effects Lethal Effects- hard to overdose Lethal dose 150-200 mg/kg of weight (70 kg X 150 mg = 10,500 mg or 10.5 g); 50- 100 cups of coffee causes ventricular fibrillation in heart, respiratory collapse and convulsions ~100 mg/kg in children – cases of accidental death from eating large quantities of caffeine containing medication ↳ easier to overdose in children Beneficial Effects Lowered risk of Type II diabetes (6 cups/day have 35% less risk than 2 cups/day) Risk is also lower in those that drink decaffeinated coffee; effect due to ingredient other than caffeine Beneficial Effects Protective effects against Parkinson’s disease in men Caffeine blocks adenosine A2A receptor and increases DA activity; alleviates motor symptoms including tremor and freezing of gait