STIMULANTS

1. STIMULANTS Allen Fowler Mycheal Scott Psyc 472

2. 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

3. 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

4. COMMONLY USED STIMULANTS • Caffeine • Nicotine • Amphetamine • Cocaine • Ephedrine • Ritalin

5. CAFFEINE AND NICOTINE Allen Fowler

6. CAFFEINE (picture courtesy Erowid web site)

7. 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

8. 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 CAFFEINE CONTENT

9. 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

10. Effects • Caffeine may adversely effect tasks involving • delicate muscle coordination • Accurate timing • Arithmetic skills • Heavy doses - 1.5 grams • Agitation • Anxiety • Tremors • Rapid breathing • Insomnia • Lethal dose – 10 grams • 100 cups of coffee • 100 OTC stimulant capsules

11. 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

12. Effects • Caffeine constricts cerebral blood vessels • Decreases blood flow by about 30% • Can relieve headaches • Bronchial relaxation • Increased secretion of gastric acid • Increased urine

13. Effects • Chronic use associated with habituation and tolerance • Quitting may cause withdrawal • Headaches • Drowsiness • Fatigue • Negative mood

14. 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 • Higher doses increased intrauterine growth retardation • Another study shows 160 mg may cause 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

15. Therapeutic Uses • Asthma • Bronchial relaxation effects • Narcolepsy • To help maintain daytime wakefulness • Migraine • Restricts blood flow in the cerebral cortex • Headache and other minor pain syndromes • In conjunction with aspirin

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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”

23. Mechanism of Action • Adenosine A1 receptors • Inhibit the release of dopamine and glutamate • Limit the release of acetylcholine • Blockade of A1 receptors • Modest reward • Increased vigilance and mental acuity • Creates arousal effect

24. 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

25. 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

26. NICOTINE (picture courtesy Erowid web site)

27. 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

28. 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

29. 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

30. 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

31. 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

32. Background Information • Nicotine is only one of about 4000 compounds released by burning tobacco • Adverse cardiovascular, pulmonary, and carcinogenic effects are from the other compounds

33. Effects • Nicotine exerts powerful effects on • Brain • Spinal cord • Peripheral nervous system • Heart • Various other body structures

34. 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

35. Effects • Stimulates release of ADH (antidiuretic hormone) causing fluid retention • Reduces activity of afferent nerve fibers from muscles • Reduction in muscle tone • May be partially involved with relaxation effect • Higher doses • Can induce nervousness and tremors • Seizures in toxic overdose • Smoking associated with increased occurrence of panic attacks and panic disorders

36. Effects • In the CNS nicotine increases • Psychomotor activity • Cognitive functioning • Sensorimotor performance • Attention • Memory consolidation

37. 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

38. 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

39. 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

40. 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

41. 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

42. Withdrawal Symptoms • Intense nicotine craving • Irritability • Anxiety • Anger • Difficulty concentrating • Restlessness • Impatience • Increased appetite • Weight gain • Insomnia

43. 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

44. 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

45. 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

46. Pharmacokinetics • Nicotine is thoroughly distributed in the body • No barriers to nicotine distribution • Rapid brain penetration • Crosses placental barrier • Appears in all bodily fluids • The liver metabolizes 80 to 90% before excretion to the kidneys • Primary metabolite is cotinine • The elimination half life in chronic users is about 2 hrs

47. 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

48. 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

49. 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

50. 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