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STIMULANTS Allen Fowler Mycheal Scott Psyc 472 1 DEFINITION Stimulants are a substance which tends to increase behavioral activity when administered Elevate Mood Increase Motor Activity Increase Alertness Decrease need for Sleep Increase the brains metabolic and neuronal activity 2 PROCESSES While all stimulants increase behavioral activity the component processes involved differ. Neurotransmitter or receptor processes Increase neurotransmitters release Block reuptake Inhibition of inhibitory neurotransmitters disinhibition 3 COMMONLY USED STIMULANTS Caffeine Nicotine Amphetamine Cocaine Ephedrine Ritalin 4 CAFFEINE AND NICOTINE Allen Fowler 5 CAFFEINE (picture courtesy Erowid web site) 6 CAFFEINE Most commonly consumed psychoactive drug in the world Average intake per person per day is between 80 to 400 milligrams Consumption of caffeine is not considered drug abuse No regulation on sale or use 7 CAFFEINE CONTENT Item Coffee (5 oz) Tea (5oz) Cocoa (5oz) Chocolate (1oz) Chocolate milk (1oz) Cola drink (12oz) OTC stimulants OTC analgesics (aspirin) OTC cold remedies Average (mg) 100 50 5 25 5 100+ 100+ 35-65 30 8 EFFECTS Caffeine elicits positive effects such as Enhanced mental alertness Sustained intellectual effort No substantial disruption of coordinated intellectual thought or motor activity Increased energy A sense of well-being Faster and clearer flow of thought Reduced fatigue Need for sleep is delayed 9 Effects Caffeine may adversely effect tasks involving Heavy doses - 1.5 grams delicate muscle coordination Accurate timing Arithmetic skills Agitation Anxiety Tremors Rapid breathing Insomnia Lethal dose – 10 grams 100 cups of coffee 100 OTC stimulant capsules 10 Effects Caffeine causes a slight stimulant action on the heart Increases the workload cardiac contractility Increases cardiac output Dilates coronary arteries More oxygen to the heart 11 Effects Caffeine constricts cerebral blood vessels Decreases blood flow by about 30% Can relieve headaches Bronchial relaxation Increased secretion of gastric acid Increased urine 12 Effects Chronic use associated with habituation and tolerance Quitting may cause withdrawal Headaches Drowsiness Fatigue Negative mood 13 Reproductive Effects Freely crosses the placenta to the fetus Consumed by estimated 75% of pregnant women Breast milk contains levels equal or higher in concentration than mothers plasma Safety still unresolved One study shows 300 mg relatively safe Another study shows 160 mg may cause growth retardation Higher doses increased intrauterine growth retardation 300mg intake even in the month before doubled the risk of spontaneous abortion Recent study shows 6-10 cups per day is associated with increased risk of spontaneous abortion Moderate consumption does not increase the risk 14 Therapeutic Uses Asthma Narcolepsy To help maintain daytime wakefulness Migraine Bronchial relaxation effects Restricts blood flow in the cerebral cortex Headache and other minor pain syndromes In conjunction with aspirin 15 Pharmacokinetics Caffeine is rapidly and completely absorbed Significant blood levels reached in 30-45 minutes Levels peak in about 2 hours Caffeine is freely and equally distributed through total body water Caffeine can be found in almost equal concentrations throughout body and brain 16 Pharmacokinetics Caffeine has 3.5 to 5 hours half life Extended half life for Elderly Pregnant women Up to ten hours Infants Decreased half life for smokers 17 Pharmacokinetics Caffeine is metabolized in the liver by the CYP1A2 subgroup of enzymes into three metabolites Theophylline Bronchial relaxation Paraxanthine Theobromine Theophylline and Paraxanthine act similar to caffeine About 10% is excreted unchanged 18 Mechanism of Action Major site of action – Adenosine receptors – Most potent at adenosine A1 and A2A Caffeine works as an antagonism agent – Blocks the adenosine receptor 19 Mechanism of Action – Adenosine is a neuromodulator Modulatory effect increasing or decreasing the rate at which neurons fire Works in conjunction with the G protein processes – Adenosine appears to exert sedative, depressant, and anticonvulsant actions Works to slow down the system Important to sleeping – Adenosinergic neurons form a diffuse system No exclusively adenosinergic pathways Adenosine stimulates GABAA inhibitory neurons 20 Mechanism of Action – Adenosine is created from the process by which the body breaks down ATP for energy ATP is used throughout the body for energy Used for high energy bursts such as exercising and running Phosphates form a high energy bond Cells break the phosphate bond to extrapolate the energy When the phosphates are pulled off the adenosine is now free to have an effect in the body 21 Mechanism of Action A1 receptors inhibit excitatory neurons – – – – Dopamine, glutamate, and ACh secreting neurons Reduces production of cAMP Slows the activity of the kinase Reduces occurrence of the action potential A2A receptors stimulate inhibitory neurons – – – – GABAA neurons Stimulates production of cAMP Increases activity of the kinase Increases occurrence of the action potential picture courtesy “The Brain a Neuroscience Primer ” 22 Mechanism of Action Adenosine A receptors 1 – Inhibit the release of dopamine and glutamate – Limit the release of acetylcholine Blockade of A receptors 1 – Modest reward – Increased vigilance and mental acuity – Creates arousal effect 23 Mechanism of Action Adenosine A2A receptors – Stimulate GABAA neurons of inhibitory pathways – Inhibit dopamine activity Blockade of A2A receptors – Increases the potency of endogenous dopamine 24 Mechanism of Action Caffeine facilitates a disinhibition process at adenosine receptor sites Caffeine removes the negative effects of adenosine from dopamine receptors increasing dopamine activity – Caffeine does not stimulate dopamine release 25 NICOTINE (picture courtesy Erowid web site) 26 NICOTINE Primary active ingredient in tobacco One of the three most widely used psychoactive drugs Caffeine Alcohol Few or no therapeutic applications Important because of widespread use and toxicity 27 Background Information Indigenous to the Americas 1492 Columbus beaches in West Indies Natives offer them tobacco as gift 1556 first plants taken to Europe 1571 believed to have curing properties for 36 different ailments 1575-1600 becomes “duty” of every man of fashion – worth its weight in silver 28 Background Information 1881 Cigarette rolling machine invented 1889 2.4 billion cigarettes produced annually in U.S. 1904 3 billion cigarettes sold in U.S. 1912 13 billion cigarettes sold in U.S. WWII through mid-1960’s smoking considered cool Now beginning to be shunned as unhealthy and unwise 29 Background Information Responsible for the deaths of 1100 Americans every day Each day 6000 American teenagers try their first cigarette 3000 children become regular smokers 1000 of these will die from smoking related disease 9 in 10 smokers become addicted before age 21 30 Background Information ½ of all people who have smoked have quit % American adults who smoke has fallen from 50 in 1965 to 25 in 1998 Smoking identified as the major preventable cause death and disability As far as 30 years ago 31 Background Information o Nicotine is only one of about 4000 compounds released by burning tobacco o Adverse cardiovascular, pulmonary, and carcinogenic effects are from the other compounds 32 Effects Nicotine exerts powerful effects on Brain Spinal cord Peripheral nervous system Heart Various other body structures 33 Effects Stimulation of the vomit center in the brain stem and sensory receptors in the stomach Nausea in early stages of smoking Tolerance develops rapidly Reduces weight gain probably by suppressing appetite 34 Effects Stimulates release of ADH (antidiuretic hormone) causing fluid retention Reduces activity of afferent nerve fibers from muscles Higher doses Reduction in muscle tone May be partially involved with relaxation effect Can induce nervousness and tremors Seizures in toxic overdose Smoking associated with increased occurrence of panic attacks and panic disorders 35 Effects In the CNS nicotine increases Psychomotor activity Cognitive functioning Sensorimotor performance Attention Memory consolidation 36 Effect Nicotine can improve performance on vigilance and rapid information processing Effects are greater for working memory rather than long term memory Nicotine exerts an antidepressant effect High smoking rates among depressed individuals may be an attempt at self medication 37 Effects Nicotine exerts a potent reinforcing action Indirect activation of midbrain dopamine neurons Greatest in early phases Diminishes over time Smoking is continued to avoid withdrawal symptoms 38 Reproductive Effects Smoking during pregnancy increases rates spontaneous abortion Stillbirth Early postpartum death Preterm deliveries Intrauterine growth retardation is increased 40% 2000 infant deaths per year attributed to smoking 39 Reproductive Effects Smoking reduces oxygen delivery to the fetus resulting in varying degree of fetal hypoxia Fetus does not receive as much oxygen Smoking may result in irreversible intellectual and physical deficiencies Increased prevalence of ADHD Lower IQ scores 40 Tolerance Nicotine does not appear induce a pronounced degree of biological tolerance Increased use in early stages which usually levels off as smoking is continued Smokers adjust nicotine intake to maintain 20 to 40 nanograms per milliliter of plasma Does induce physiological and psychological dependence Habituation Rebound effect 41 Withdrawal Symptoms Intense nicotine craving Irritability Anxiety Anger Difficulty concentrating Restlessness Impatience Increased appetite Weight gain Insomnia 42 Therapy Nicotine replacement therapy doubles successful quit rates Skin patches Gum Nicotine nasal spray The use of Zyban has also been shown to increase successful quit rates 43 Pharmacokinetics Easily absorbed in the body Lungs Buccal and nasal mucosa Skin Gastrointestinal tract Nicotine is suspended in the minute particles (tars) in smoke Orally administered blood levels of nicotine are comparable to smoking 44 Pharmacokinetics Only about 20% of the nicotine in a cigarette is inhaled and absorbed into the bloodstream Nicotine which is not immediately absorbed is rapidly metabolized by the hepatic enzyme CYP2A6 Inhalation allows controllability of dose Frequency of breaths Depth of breaths Time in lungs Number of cigarettes 45 Pharmacokinetics Nicotine is thoroughly distributed in the body The liver metabolizes 80 to 90% before excretion to the kidneys No barriers to nicotine distribution Rapid brain penetration Crosses placental barrier Appears in all bodily fluids Primary metabolite is cotinine The elimination half life in chronic users is about 2 hrs 46 Mechanism of Action Nicotine activates specific acetylcholine (ACh) receptors known as nicotinic receptors Nicotinic receptors are located throughout the body – Skeletal muscle – Sympathetic and parasympathetic neurons – CNS 47 Mechanism of Action ACh is released, broken down, and reabsorbed very quickly (microsecond) allowing the receptor to respond to new Ach ACh receptors work as a fast first messenger system – Attached directly to ion channels – Binding has an immediate response 48 Mechanism of Action picture courtesy pharyngula.org Nicotine replaces ACh at nicotinic receptor Beats out the ACh at the binding site Works as an agonist Opens ion channel allowing depolarization to occur 49 Peripheral Nervous System Activation of nicotinic receptors in the PNS Increases blood pressure and heart rate Causes the release of epinephrine from the adrenal glands Increases the tone, secretions, and activity of the gastrointestinal tract 50 Central Nervous System Nicotinic receptors are widely distributed and may be present at the presynaptic terminals of neurons which secrete Dopamine Acetylcholine Glutamine Activation by nicotine facilitates the release and increases the action in the brain of these neurotransmitters 51 Central Nervous System Dopamine levels are increased in the Ventral tegmentum Nucleus accumbens Forebrain Stimulation of these areas account for the behavioral reinforcement, stimulant, antidepressant, and addictive properties of nicotine 52 Central Nervous System Increases in acetylcholine contribute to the cognitive potentiation and memory facilitation properties of nicotine Facilitation of glutaminergic neurotransmissions contribute to the improvement in memory functioning 53 Smoking Diseases Smoking accelerates the depositing of fat in the arteries Increased risk of heart attack and stroke Smoking weakens the immune system Smoking irritates the lining in the lungs impairing respiration Smokers cough Emphysema picture courtesy quantumclinic.com 54 Smoking Diseases Lung cancer 90-95% of male deaths 70-75% of female deaths Cancer of the mouth and throat Chewing tobacco Picture courtesy quantumclinic.com 55 Smoking Diseases Cardiovascular disease Carbon monoxide decreases amount of oxygen delivered to the heart while nicotine increases the workload Carbon monoxide and nicotine increase narrowing (atherosclerosis) and clotting (thrombosis) in the coronary arteries Increased risk of coronary heart disease 56 Smoking Diseases About 4000 Americans per year die from lung cancer caused by second-hand smoke 37000 deaths per year from heart disease caused by second hand smoke 57 Sources Julien, Robert M. (2001). A Primer of Drug Action (ninth ed.). Caffeine and Nicotine (pp 220-248). NY, New York: Worth Publishers. Tompson, Richard M. (2000). The Brain: A Neuroscience Primer (third ed.). NY, New York: Worth Publishers. http://www.erowid.org/psychoactives/psychoactives.shtml http://home.howstuffworks.com/caffeine.htm http://www.nida.nih.gov http://pharyngula.org/~pzmyers/neuro/synapse/index.php?print http://www.quantumclinic.com/quitsmoking/quit-smoking-stopaddiction-cigarettes-nicotine-lung-cancer-photos.htm http://www.ccc.nottingham.ac.uk/~mqzwww/adenosine.html http://www.pbs.org/wgbh/nova/cigarette/nicotine.html 58