Cocaine and other stimulants

1. Cocaine and other stimulants

2. Controlled Substance Act of 1970 •  the federal drug policy under which the manufacture, importation, possession, use and distribution of certain substances is regulated • Categorized certain drugs into 5 classes

3. Schedule 1 • high addictive potential – not considered of medicinal value • There is a lack of accepted safety for use of the drug or other substance under medical supervision • No prescriptions may be written for Schedule I substances, and such substances are subject to production quotas by the DEA. •  mescaline, lysergic acid diethylamide, heroin, and marijuana, gamma hydroxy butyrate (GHB), ibogaine

4. Schedule II • Drugs with a high abuse risk, but also have safe and accepted medicinal uses • Abuse of the drug or other substances may lead to severe psychological or physical dependence • stimulants, opiates, methadone, codeine, methylphenidate (Ritalin), mixed salt amphetamine (Adderall),

5. Schedule III • less abuse potential than Schedule I or II • has a currently accepted medical use in treatment in the United States. • abuse of the drug may lead to moderate or low physical dependence or high psychological dependence.“  • – includes barbiturates, anabolic steroids, ketamine (?), buprenorphine, marinol (synthetic THC)

6. Schedule IV • medical use, less abuse liablity, less risk of physical dependence • benzodiazepenes (?) – although n of prescriptions is controlled • some barbiturates • Schedule V • cough suppressants with small amounts of codeine

9. Cocaine and Amphetamine • History • Cocaine • Source: leaves of E. coca (indigenous to western South America • word spread through explorers, naturalists, botanists

11. Cocaine and Amphetamine • History • Cocaine • Source: leaves of E. coca (indigenous to western South America • word spread through explorers, naturalists, botanists • 1860’s – a variety of medicinal uses

12. Cocaine and Amphetamine • History • Cocaine • Source: leaves of E. coca (indigenous to western South America • word spread through explorers, naturalists, botanists • 1860’s – wine tonics

13. Launched in 1863- European success; the world's most popular prescription Some of its advocates; Henrik Ibsen, Jules Verne, Alexander Dumas, Robert Louis Stephenson, Sir Arthur Conan Doyle, Queen Victoria; King George 1 of Greece; King Alphonse XIII of Spain; the Shah of Persia; William McKinley, President of the United States.

14. Sears and Roebuck, 1900 "...sustains and refreshes both the body and brain....It may be taken at any time with perfect safety... it has been effectually proven that in the same space of time more than double the amount of work could be undergone when Peruvian Wine of Coca was used, and positively no fatigue experienced....."

15. Cocaine and Amphetamine • History • Cocaine • Source: leaves of E. coca (indigenous to western South America • word spread through explorers, naturalists, botanists • 1860’s – wine tonics • 1884 - Freud

16. Uber cocaine- Freud –7 diseases for which cocaine may be a useful pharmacotherapy • as a mental stimulant • as a possible treatment for digestive disorders • as an appetite stimulant in case of wasting diseases • as a treatment for morphine and alcohol addiction • as a treatment for asthma • as an aphrodisiac • as a local anaesthetic

17. mid 1880’s – • Atlanta druggist John Pemberton – devised a patent medicine that contained two naturally occurring stimulants; cocaine and caffeine • Coca-cola – advertised as an intellectual beverage • a temperance drink; a brain tonic • Pemberton sold 2/3 of his interest in 1887 for $283.29

18. late 1800’s until 1903 • Coca Cola had ~ 60 mg/ 8 ounces • 1903 Coca Cola stopped having cocaine • 1914 – Harrison Narcotic Act – • listed cocaine as a narcotic

19. Amphetamine • synthesized in the lab (in early 1900’s) • first marketed in 1927 • drug has been abused since its introduction • benzedrine inhalers used by a wide segment of population during 1930’s • amphetamines and war • amphetamines and weight reduction • 1967 – estimates of 23,000,000 prescriptions in US for weight reduction

20. history fluctuations • Cocaine use still rose during the 1920’s but then decreased in 1930’s because amphetamines became available (and at the time cost less, were more easily available AND the euphoria lasted longer) • Amphetamine took over in popularity during the 1940’s – 1960’s. In 1970’s restrictions on amphetamine tightened • made amphetamine a schedule II drug so….

21. Cocaine • some estimate 1.8 million Americans users of cocaine in 1998; majority between 18 and 34 • males more likely than females • males more likely to use higher amount • males more likely to use for longer duration • significant proportion met criteria for ADHD

22. Pharmacological Actions • coca leaves • leaves can be soaked and mashed to form coca paste • oral – 70 – 80% broken down by liver biotransformation • cocaine hydrochloride coca paste treated to form salt water soluble and can be taken intranasally or injected IV snorting – not very efficient because cocaine hydrochloride is ionized; also cocaine has vasoconstrictive properties (so it limits its own passage into blood vessels)

23. IV – onset is rush ~ 30 – 45 secs • duration lasts 10 – 20 min; • 100% reaches circulatory system • freebase- extracted from crystalline from with either ether or sodium hydroxide • vaporized at lower temps than cocaine hydrochloride and so can be inhaled • crack – freebase but extracted with alkaline water and premade (or prepackaged) • smoking not really efficient for delivering cocaine to body because significant portion is lost to pyrolysis – but remaining dose produces intense effect

24. methamphetamine • originally regional specificity • spreading across nation (ease of production although dangerous- explosions, toxic substances, etc)

25. Impact of amphetamines in recent years • illicit amphetamine production estimated to be in the billions/year • methamphetamine • made in growing numbers of clandestine labs • produces greater cortical stimulation than some other amphetamines • huge profit margin • ice – free base form of amphetamine

26. Environmental cost for methamphetamine • Estimated that for each pound of methamphetamine produced, between five and six pounds of highly toxic waste is generated.

30. mechanism of action • amphetamine • causes release of newly synthesized monoamines • also blocks reuptake of monoamines • cocaine • blocks reuptake of monoamines

31. Behavioral effects of cocaine and/or amphetamine • stereotypic behavior • high doses result in stereotyped behaviors representative for respective species • in rat, can be sniffing, licking, biting or gnawing • Appetite suppression • weight loss • Aggression • several descriptions of murder and other violent offenses attributed to amphetamine intoxication

33. Medical Side Effects and Consequences of Cocaine and Amphetamine Abuse • cardiovascular • heart disease increased risk for CVA • cardiac arrhythmia • increased blood pressure • respiratory • chest pain respiratory complications • difficulty breathing

34. neurotoxic • seizures intracranial hemorrhages • cocaine or amphetamine induced psychosis • formication

35. other drugs with similar pharmacological actions • methylphenidate (Ritalin) • causes release of newly synthesized DA • also blocks reuptake of DA

36. mixed salts amphetamine “Adderall”

37. New alternative • Strattera –atomexetine HCl • first non stimulant pharmacotherapy for ADHD • blocks reuptake of NE instead of DA

38. MDMA (Ecstasy) • methylated amphetamine – • text covers this in chapter with hallucinogens (affects 5HT as well)

39. Ephedrine • UNTIL RECENTLY - sold in health food stores and on internet • Now – no longer on US market! • ephedra – also known as ma huang; herb • FDA received many reports from doctors, government health authorities and others about adverse-based ephedrine based products • Currently – OTC subject to FDA regulations • HOWEVER herbal supplements currently are essentially unregulated – may soon change!

41. Do stimulants (cocaine, amphetamine) produce tolerance, dependence, withdrawal?

42. Do stimulants produce tolerance? • either decreased effectiveness or potency of a drug • How does tolerance occur?

43. So does tolerance occur with stimulants? • Data is mixed

44. some evidence • acute tolerance

45. some evidence • acute tolerance • animal models – • sensitization

46. Do stimulants produce dependence?

47. Why do people use drugs?

48. So what kind of dependence do we see with stimulants? • Psychological dependence – very strong! • Physical dependence – WD? • Cocaine crash

49. Do animals find stimulant rewarding?

50. Drug self-administration in rats • operant performance • animals will self administer in absence of tolerance, physical dependence, withdrawal or prior drug taking history • two bar test