Problem sets

1. Problem sets PS #7; Chapt 20 ; 1,18,20 (toxins etc) PS #8; Chapt 10 ; 1,5a-k,10,12,27a-d. (acids and bases) PS #9; Chapt 23 ; 1,12,18a,b; 31,32 (drugs)

2. 15. Medicines, Drugs - part 1 chapter 23

3. Drugs: Licit and illicit Licit: Aspirin, Tylenol, Ibuprofen, caffeine, nicotine, codeine, morphine, ethanol, steroids (birth control), ritalin, antibiotics • Illicit: heroine, cocaine, marijuana, crystal meth, ecstacy, LSD, steroids (anabolic) • Pharmaceutical Industry: $, names, placebos, addiction, OTC vs. prescription drugs, most prescribed

4. Generally - a drug is any substance that brings about a physiological, emotional or behavioral effect in an individual. Commonly- Drugs/medicines are compounds/ agents used for treating disease and injuries, ie. to relieve pain or cure illness. Lately, drugs carry the added connotation of narcotics and addiction. Chemotherapy (Paul Ehrlich, 1904) - the use of chemicals, more toxic to disease -bearing organisms than human cells, to control/cure infectious diseases.

5. Paul Erlich • Made 1st synthetic drug Salvarsan (also called 606) in 1908 after the synthesis and testing of a series of 606 arsenic containing aromatic compounds: lead compd approach • Diarsaphenamines • Used to treat syphilis, until penicillins were discovered in the 1940’s

6. Paul Erlich (1854-1915) • Father of the modern pharmaceutical industry

7. Drugs / Medicines/ Pharmaceuticals Begin with: drugs that affect the brain and spinal cord (CNS, Central Nervous System), ie. for pain, fever, mood (stimulants, tranquilizers), also hallucinogens, narcotics. Later survey: steroids (from sex hormones to anti- inflammatories), antibiotics, antivirals, heart disease, allergies, anticancer, etc.

8. Evolution of a Drug / Medicine Investigate a 'folk medicine' Isolate the 'active ingredient' and prove structure Synthesize 'natural' compound to confirm structure and provide material Test for physiological effects; often multiple effects Synthesize compounds with modified structure; to emphasize desired properties to 'delete' unwanted effects Test for efficacy and safety

9. Aspirin - a Case Study The beneficial effects of willow bark have been known for centuries: In ancient Greece, Hippocrates suggested chewing the bark for relief of fever In 1763 Edward Stone addressed the Royal Society in Britain on the benefits of 'willow tea' for pain/fever.

10. 1827 - isolation of salicin(glucose + salicyl alcohol) 1860 - 'break off' glucose and prepare salicylic acid 1875 - prepare sodium salt, to offset 'acidity' 1899 - introduction of ASA by Bayer 1893 - introduce phenacetin(acetanilide derivative) 1893 - introduce acetaminophen 2000 - Aspirin (Acetylsalicylic acid or ASA) is used at ~100 billion tablets/yr worldwide. In NA, ~100 million tablets/day or ~20,000 tons/yr!

11. Salicylic Acid and Derivatives petro- chemicals (salicyl alcohol) salicin (willow bark) salicylic acid methyl salicylate acetylsalicylic acid sodium salicylate

12. Aspirin - Multiple Physiological Effects Analgesic – reduces or eliminates pain. Antipyretic - lowers or eliminates fever. Anti-inflammatory agent - reduces or eliminates inflammation. Anti-coagulant - inhibits the formation of blood clots by decreasing platelet concentrations, ie. decreases incidence of heart attacks resulting from the formation of internal clots that can block the flow of blood to the heart.

13. Daily Low Dose of 75-81 mg aspirin • Maintains normal blood platelet aggregation • Recommended for all men (particularly) over 50 to reduce risk of strokes and heart attacks due to blood clotting • This new use was patented in 1990’s

14. Enterically coated Aspirin • Coating of wax, cornstarch, methylcellulose, KOH, methacrylic acid copolymer prevents capsulefrom dissolving in stomach-goes to small intestine before dissolution, thus helping to prevent stomach irritation

15. Modifications - the Good, the Bad …. Aspirin and it's analogs exhibit varying effects and are remarkably 'safe', when not overused. Basic structural features are: a) 2-hydroxybenzoic acid; acetylsalicylic acid b) 4-aminophenol(OH-benzene); acetaminophen c) 2-phenyl propanoic acid; ibuprofen a) = Aspirin. ~5% have some intestinal bleeding b) = Tylenol. No bleeding but not anti-inflammatory c) = Motrin/Advil. Little bleeding& anti-inflammatory; best for arthritis(NSAID)

16. Other Analgesics p-amino phenol phenacetin(banned-kidney damage, etc.) acetaminophen(Tylenol) –not anti-inflammatory- ibuprofen(Motrin/Advil) –not anticoagulant-

17. How Aspirin Works arachidonic acid COX2enzyme Aspirin a prostaglandin induces pain, blood clotting, labour, sleep regulation

18. ...and (possibly) the Ugly There can be possible complications to adults from the anti-coagulant properties of ASA when used frequently and in quantity. But the danger to children is much greater, eg. the LD50 of ~1.5g/kg means 40-50 tablets could kill a 10kg(22lb) child. can induce Reye's Syndrome(nausea, lethargy => death) in children treated for 'fever' from smallpox / flu. Solution - 'child-proof' caps and warning labels on containers have been very effective.

19. From Acids to Bases Alkaloids are basic(alkaline), bitter-tasting, nitrogen-containing compounds (amines) that are found in plants and that produce physiological reactions of various kinds and intensity. eg. Morphine,codeine, caffeine, nicotine

20. A narcotic* (opiate) is a substance that produces a stupefying, dulling effect that induces sleep. Usually very effective analgesics also. * from narcosis = a state of profound stupor

21. Morphine: Analgesic... and ?! (Morpheus - Roman god of dreams) ~10% of dried juice (opium) from seed pod of oriental poppy.

22. Pros: one of most powerful analgesics known 'soothes'/calms(19th cent. 'patent medicines') antitussive = cough suppresant Cons: confusion, euphoria, depresses respiratory system, chronic constipation, lethargy addictive Morphine binds to opiate receptor sites in the brain. ie. doesn’t interfere with the transmission of a pain signal but changes the reception of that signal.

23. Morphine Analogs/Derivatives Codeine - analgesic, not sleep inducing, not very addictivecough syrups (55,000kg/yr) Heroin - euphoria, stupor, analgesic, very addictive

24. Morphine & Analogs morphine codeine heroin

25. Other Morphine Analogs Naloxone: an “antagonist’-binds to heroin receptor site-used to treat heroin overdoses Methadone – long term treatment for heroin addition. No euphoria or withdrawal symptoms, but addictive. Allows return to “normalcy” if maintained Dextromethorphan - non-addictive, antitussive Fentanyl - analgesic/anesthetic in surgery (100x morphine); Moscow ‘hostage incident’(2002)

26. Multi-faceted Cocaine: the power & the gory Leaves of the coca plant - eastern slopes of the Andes mountains (Columbia, Ecuador, Peru) stimulant, pain reliever, but =>=> addictive increases stamina, reduces fatigue =>=> used by Peruvian Indians to 'survive'(walking hours in snow with heavy loads and little food) constricts blood vessels, local anesthetic =>=> many deaths from 'overdoses'

27. Cocaine'Techniques' = Applied Chemistry Cocaine = alkaloid = amine ie. base  forms HCl salt (ionic), thus water-soluble and easily ingested by 'snorting' through the watery mucous membranes of the nose or by direct injection as 'free' base(crack) it is more volatile and can reach the brain in 15 seconds when heated and inhaled by smoking (Peruvian Indians mix coca leaves with lime)

28. Cocaine and Analogs Cocaine - stimulant, intense euphoria, analgesic, addictive. Scopolamine - “truth drug”, preoperative sedative Atropine - heart stimulant (popular poison in Middle Ages, from deadly nightshade/ belladonna), eye drops Novocaine - topical anesthetic (dentistry) anesthetic - causes unconsciousness and/or insensitivity to pain

29. Cocaine & ‘Relatives’ cocaine atropine scopolamine

30. Cocaine Analogs cocaine Lidocaine(xylocaine) Procaine(novocaine)

31. Addiction … Dr. Freud & friends Addiction can take several forms: Physiological effects: watery eyes/nose, sweating goose flesh, yawning, dilated pupils, convulsions that occur during withdrawal, eg. heroin Psychological dependence: the uncontrollable desire for another euphoric 'high' when depression occurs after a 'hit' subsides, eg. cocaine Tolerance: increasing dosage to obtain the same 'results'

32. The PEA Connection -Phenylethylamine Many psychoactive compounds contain the -phenylethylamine substructure(or similar). PEA itself induces a 'high' similar to 'being in love'!

33. Some Neurotransmitters (nor)epinephrine dopamine -aminobutyric acid serotonin

34. Stimulants Benzedrine (N-CH3= methamphetamine methedrine/speed) Phenylpropanolamine(PPA) diet loss, ‘cold meds’ (banned 2001) Epinephrine(adrenaline)

35. Silken Laumann • Tested positive for PPA and lost her 1995 Pan Am gold medal • Took Benadryl to fight a cold

36. Bennies • Benzedrine: stimulants often used by Baseball players (pitchers) to get hopped up and put more speed on the fastball (they think!) • Jim Bouton’s 1969 book “Ball Four” diary of life on road with NY Yankees, Seattle Pilots, Houston Astros

37. A must read for baseball fans • A “Classic”

38. Crystal Meth • Crystalline form of methamphetamine (methedrine or speed) • Same as benzedrine except N-CH3. • Easily made from pseudoephedrine (in decongestant medications) • Can be snorted , smoked, injected or swallowed

39. Pseudoephedrine to crystal meth • Remove OH group!

40. But……..when smoked in its crystalline form • Produces effects similar to, but longer lasting than crack cocaine

41. Devastating Effects • After 10 years of use

42. Danger from west to east • Crystal meth labs started in US midwest • Reached Ontario in ~2001 • Possession, trafficking and production now can carry penalty up to life imprisonment in Canada

43. Ecstasy • Semi-synthetic, patented by Merck in 1914 and then abandoned for ~60 years • Used in late 70’s for psychotherapy • Popular at raves • Mood elevator • Raises blood pressure, heart rate, body temp.

44. Can be lethal • Deaths reported from dehydration • Should not be taken if any cardiovascular disorder or high blood pressure • Synthetic intermediates have unique odour

45. Anti ‘Parkinson’s’ Agents L - DOPA Deprenyl

46. Stereochemistry is important • The D-isomer of DOPA is inactive! • Synthesis of Chiral Drugs is now a major effort in Pharmaceutical Industry • Avoids possible harmful effects of other “handed” version-Thalidomide tragedy in early 1960’s

47. Ritalin(Methyl Phenidate) • Prescription drug for ADHD (attention deficit hyperactivity disorder) • CNS stimulant-details of mechanism of action not yet known • BUT………………

48. When end of term comes • The little white pill

49. Ritalin: “Competitive edge?” • U. Vic students using it as a “cognitive enhancing drug” (Metro, Ottawa 2008) • “brain doping” • Boosts studying powers • Ethical issue: unfair advantage?? • Nature: 2008 study~20% of students using drugs such as “Provigil” to fight fatigue

50. Placebos - the Power of the Mind A placebo is a harmless and, normally, ineffective substance given to someone who complains of a particular ailment, simply to please and pacify them.