Drugsandthe Brain Part6 Stimulants


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Drugsandthe Brain Part6 Stimulants

  1. 1. Drugs & the Brain Part 6 Stimulants
  2. 2. What Are Stimulants? <ul><li>A group of drugs with many potential therapeutic uses, but also widely used and abused recreationally </li></ul><ul><li>Improve mood, quicken intellect, enhance alertness, some relieve depression </li></ul><ul><li>Includes more than one biochemical group with similar effects on the brain </li></ul><ul><li>All produce dependence, though degree varies </li></ul>
  3. 3. Cocaine <ul><li>Coca leaves, the source of cocaine, have been ingested for their psychoactive effect for a thousand years </li></ul><ul><li>The drug action of the leaves is the same as that of the pure chemical </li></ul><ul><li>More gradual & less intense only because leaves are chewed, passing through the digestive system to the blood stream, while pure cocaine is snorted or injected, a more direct route </li></ul>
  4. 4. History of Cocaine <ul><li>Ancient Inca society considered coca a symbol of divinity. </li></ul><ul><ul><li>Use was confined to royalty and priests. </li></ul></ul><ul><ul><li>After Spanish conquest, coca use became widespread among Peruvian commoners </li></ul></ul><ul><li>Mid 19 th C. coca became popular in Europe </li></ul><ul><li>Pure cocaine has been a drug of abuse for at least 100 years </li></ul>
  5. 5. Vin Mariani <ul><li>1863- Corsican chemist Angelo Mariani patented Vin Mariani, a coca extract in wine </li></ul><ul><li>Became Europe’s most popular beverage </li></ul><ul><li>Thought to have wide-ranging curative powers </li></ul><ul><li>Also developed coca tea & coca lozenges </li></ul><ul><li>Awarded a medal by the Pope </li></ul>
  6. 6. The Coca-Cola Connection <ul><li>Mariani was the inspiration for Georgia pharmacist John Pemberton </li></ul><ul><li>Developed Coca-Cola in 1886 </li></ul><ul><ul><li>Original preparation contained wine </li></ul></ul><ul><ul><li>Later substituted kola nut extract, a source of caffeine </li></ul></ul><ul><ul><li>In 1888 substituted soda water for plain water </li></ul></ul><ul><ul><li>This is basically “classic” coke – but today without the cocaine </li></ul></ul>
  7. 7. Things Go Better With Coke <ul><li>1892- rights were purchased by Asa Candler who founded the Coca-Cola Co. </li></ul><ul><li>Led to widespread distribution and the development of soda fountains. </li></ul><ul><li>Further mixed the pursuit of health and the pursuit of pleasure </li></ul>
  8. 8. Isolation of Pure Cocaine <ul><li>Cocaine abuse was not a significant problem until the development of the drug in pure form </li></ul><ul><li>1860- a chemist obtained pure cocaine by mixing plant juices into organic solvents </li></ul><ul><li>2 years later another chemist determined its chemical formula </li></ul>
  9. 9. Molecular Structure of Cocaine
  10. 10. Analyze This <ul><li>Sigmund Freud was one of the first to investigate medical use of purified cocaine </li></ul><ul><li>Thought cocaine might be used to treat nervous exhaustion </li></ul><ul><li>Obtained samples from Merck Pharmaceuticals </li></ul><ul><li>Ingested them himself </li></ul><ul><li>Conducted several medical studies </li></ul><ul><li>Demonstrated apparent increase in muscular strength </li></ul><ul><li>Published an article which initiated widespread prescription of cocaine for anxiety & depression </li></ul>
  11. 11. “Cocaine brings about an exhilaration and lasting euphoria which in no way differs from the euphoria of the healthy person . . .You perceive an increase of self-control and possess more vitality and capacity for works . . . In other words you are simply normal, and it is soon hard to believe that you are under the influence of any drug . . . Long intensive mental or physical work is performed without any fatigue . . .This result is achieved without any of the unpleasant after effects that follow exhilaration brought about by alcohol.” Sigmund Freud
  12. 12. An Error in Judgment <ul><li>Freud recommended cocaine to relieve morphine addiction </li></ul><ul><li>A close friend had developed a morphine addiction following use to combat pain associated with amputation of his thumb </li></ul><ul><li>Freud substituted cocaine </li></ul><ul><li>The patient was soon injecting larger and larger doses </li></ul><ul><li>Ultimately he developed cocaine psychosis </li></ul><ul><li>Similar experiences occurred throughout Europe </li></ul><ul><li>Freud was heavily criticized in the medical community for his initial embrace of cocaine </li></ul>
  13. 13. Medical Uses of Cocaine <ul><li>Cocaine was the first effective local anesthetic </li></ul><ul><li>Local anesthesia is safer than general anesthesia </li></ul><ul><li>Local anesthesia is required for some types of surgery </li></ul><ul><li>Cocaine injected into the peripheral nerves of an are creates a nerve-block </li></ul><ul><li>Use for local anesthesia prompted drug companies to develop related compounds that could be synthesized </li></ul><ul><ul><li>These include procaine, lidocaine & tetrocaine </li></ul></ul><ul><ul><li>These are still used for local anesthesia </li></ul></ul>
  14. 14. Caffeine <ul><li>Caffeine in coffee, tea, & many soft drinks is a member of a group of molecules called xanthines </li></ul><ul><li>Other xanthines are theophylline & theobromine </li></ul><ul><li>Causes stimulation, alertness, elevation of mood </li></ul><ul><li>Caffeine containing compounds in use since 900 A.D. </li></ul>
  15. 15. Coffee, Caffeine & Society
  16. 16. The Down Side of “Up” <ul><li>Excess caffeine produces symptoms of anxiety neurosis </li></ul><ul><ul><li>Can induce panic attacks in some subjects </li></ul></ul><ul><li>Is addicting & produces tolerance </li></ul><ul><li>Though from a different chemical family, effects are similar to amphetamines </li></ul>
  17. 17. Action of Caffeine <ul><li>Blocks the brain’s receptors for adenosine </li></ul><ul><ul><li>Adenosine is an inhibitory transmitter </li></ul></ul><ul><ul><li>Inhibits the release of other neurotransmitters </li></ul></ul><ul><li>Thus caffeine is a stimulant because it blocks the inhibiting action of adenosine </li></ul><ul><li>Arousal effect of caffeine is the result of increased norepinephrine in the cerebral cortex </li></ul>
  18. 18. Nicotine <ul><li>Found in tobacco </li></ul><ul><li>Increases arousal, alertness, mental efficiency </li></ul><ul><li>Is highly addictive & produces tolerance </li></ul><ul><li>Mimics acetylcholine in the brain </li></ul><ul><li>One type of acetylcholine receptor is called “nicotinic” because it binds nicotine </li></ul><ul><li>In the brain leads to release of many neurotransmitters, including endorphins & dopamine in the reward pathway </li></ul>
  19. 19. Understanding Nicotine <ul><li>Radiolabeled acrtylcholine incubated with brain slices – autoradiograph then slows where receptors are located by lighting up on x-ray film </li></ul><ul><li>Comparison of brains of smoker & non-smokers showed that smokers had more nicotinic receptors </li></ul><ul><ul><li>Nicotine desensitizes receptors </li></ul></ul><ul><ul><li>This stimulates brain cells to produce more receptors </li></ul></ul>
  20. 20. Mode of Action of Nicotine <ul><li>Nicotine is a cholinergic agonist </li></ul><ul><li>It acts by stimulating nicotinic acetylcholine receptors. </li></ul>
  21. 21. Structure of Caffeine & Nicotine
  22. 22. Genesis of Amphetamines <ul><li>Developed to treat asthma </li></ul><ul><li>Epinephrine was a common effective treatment for asthma </li></ul><ul><ul><li>Epinephrine is a bronchial dilator </li></ul></ul><ul><ul><li>But cannot be taken orally </li></ul></ul><ul><li>Chemists were looking for a derivative that could be taken by mouth </li></ul>
  23. 23. The Herbal Connection <ul><li>Investigated ma huang (Ephedra vulgaris), a plant used in Chinese herbal medicine to treat asthma </li></ul><ul><li>Ephedrine was the first successful asthma medication which could be taken orally </li></ul><ul><li>Ma huang was scare </li></ul><ul><li>Chemists attempted to create synthetic substitutes </li></ul><ul><li>Mid 1930s – synthesized amphetamine </li></ul>
  24. 24. Benzedrine <ul><li>Amphetamine could be dispensed in a volatile form that could be inhaled directly </li></ul><ul><li>Marketed as Benzedrine </li></ul><ul><li>Benzedrine inhalers were a non-prescription item widely marketed in the 1930’s & 1940’s </li></ul><ul><li>Usefulness to prevent sleepiness and increase mental alertness was quickly recognized by the general population, especially college students </li></ul><ul><li>People opened the inhalers & ingested the contents orally </li></ul><ul><li>Amphetamine abuse was also wide spread by service men from many countries during WW II </li></ul>
  25. 25. Multiple Effects <ul><li>Besides their stimulant effects, cocaine, amphetamines and other stimulant drugs suppress appetite </li></ul><ul><li>Amphetamines were widely used for appetite suppression until dangers were recognized </li></ul><ul><li>Are the stimulant & euphoric effects of these drugs directly related to appetite suppression? </li></ul><ul><li>Led to development of many new amphetamines </li></ul>
  26. 26. Attention Deficit Disorder <ul><li>Amphetamines have a claming effect on younger patients with attention deficit disorder (ADD) </li></ul><ul><li>Seems counter-intuituive </li></ul><ul><li>Actually, effect is not ‘calming’, but focusing – increases ability to concentrate </li></ul>
  27. 27. Stimulant Psychosis <ul><li>Cocaine & amphetamines induce identical psychoses </li></ul><ul><li>A functional psychosis: conscious and aware </li></ul><ul><li>Closely resembles paranoid schizophrenia </li></ul><ul><ul><li>Auditory hallucinations </li></ul></ul><ul><ul><li>“ idea of reference” (everything has to do with them) </li></ul></ul><ul><ul><li>Paranoid ideation (everyone is out to get them) </li></ul></ul><ul><ul><li>Touch hallucinations are unique to this condition </li></ul></ul><ul><li>Symptoms relieved by neuroleptic (anti-schizophrenic) drugs </li></ul><ul><ul><li>Barbiturates make the psychoses worse </li></ul></ul><ul><li>Schizophrenics in remission experience return of psychosis with small doses of amphetamine </li></ul>
  28. 28. The Norepinephrine Connection <ul><li>Amphetamines closely resemble norepinephrine & dopamine </li></ul><ul><li>Norepinephrine neurons originate in the locus coeruleus in the brainstem </li></ul><ul><li>The norepinephrine system forms many branching connections </li></ul><ul><ul><li>Axons from the locus coeruleus branch out to contact several billion neurons – 1/3 to ½ of the cells in the brain </li></ul></ul><ul><ul><li>Norepinephrine neurons touch cells in the cerebral cortex in a non-specific manner </li></ul></ul><ul><li>Norepinephrine neurons are most highly concentrated in the limbic system </li></ul>
  29. 29. Mode of Action of Amphetamines <ul><li>The major action of amphetamines is to release norepinephrine & dopamine from storage vesicles </li></ul><ul><li>Because amphetamines resemble neurotransmitters, they displace those molecules from their storage sites </li></ul><ul><li>Both inhibit the pump that ordinarily inactivates norepinephrine & dopamine </li></ul><ul><ul><li>same action as tricyclic anti-depressants </li></ul></ul><ul><li>Schizophrenia-like psychosis is due to increase in dopamine release </li></ul>
  30. 30. Mode of Action of Cocaine <ul><li>Molecular action of cocaine is not known, but may be same as amphetamines </li></ul><ul><li>Cocaine’s stimulant effects are closely associated with inhibition of dopamine reuptake </li></ul><ul><li>Stimulant effects of both amphetamines & cocaine are due to increased norepinephrine activity in the cerebral cortex </li></ul>
  31. 31. Comparing Molecules ephedrine amphetamine methamphetamine dopamine norepinephrine