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) 15. Medicines, Drugs - part 1 chapter 23 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 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. 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 Paul Erlich (1854-1915) • Father of the modern pharmaceutical industry 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 antiinflammatories), antibiotics, antivirals, heart disease, allergies, anticancer, etc. 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 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. 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! Salicylic Acid and Derivatives CH2OH OO CH2OH OH HO petroOH chemicals COOH (salicyl alcohol) salicin OH (willow bark) COOH O O CCH3 acetylsalicylic acid salicylic acid - + COO Na OH sodium salicylate O OCH3 OH methyl salicylate 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. 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 Enterically coated Aspirin • Coating of wax, cornstarch, methylcellulose, KOH, methacrylic acid copolymer prevents capsule from dissolving in stomach-goes to small intestine before dissolution, thus helping to prevent stomach irritation 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) Other Analgesics O HO NH2 CH3CH2O p-amino phenol acetaminophen(Tylenol) –not anti-inflammatory- NHCCH3 phenacetin(bannedkidney damage, etc.) CH3CHCH2 CH3 CHCOOH CH3 ibuprofen(Motrin/Advil) –not anticoagulant- How Aspirin Works COOH arachidonic acid COX2 enzyme Aspirin O COOH CH3 HO OH a prostaglandin induces pain, blood clotting, labour, sleep regulation ...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. 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 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 Morphine: Analgesic... and ?! (Morpheus Roman god of dreams) ~10% of dried juice (opium) from seed pod of oriental poppy. 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. Morphine Analogs/Derivatives Codeine - analgesic, not sleep inducing, not very addictivecough syrups (55,000kg/yr) Heroin - euphoria, stupor, analgesic, very addictive Morphine & Analogs CH3 morphine N O HO OH CH3 codeine N CH3 N heroin CH3O O OH O O H3C O O O CH3 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) 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' 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) 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 Cocaine & ‘Relatives’ CH3 N CO2CH3 O2 C cocaine CH3 CH3 N N O O atropine O O CH2OH scopolamine O CH2OH Cocaine Analogs CH3 N CO2CH3 O2 C cocaine N N O2 C Lidocaine(xylocaine) NH2 O HN Procaine(novocaine) 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' The PEA Connection CH2 CH2 NH2 -Phenylethylamine Many psychoactive compounds contain the -phenylethylamine substructure(or similar). PEA itself induces a 'high' similar to 'being in love'! Some Neurotransmitters HO HO HO NH(CH3) (nor)epinephrine HO NH2 HO H2N dopamine NH2 COOH -aminobutyric acid N serotonin HO CH3 Stimulants NH2 NH2 Phenylpropanolamine(PPA) diet loss, ‘cold meds’ (banned 2001) Benzedrine (N-CH3= methamphetamine methedrine/speed) HO HO NHCH3 HO Epinephrine(adrenaline) Silken Laumann • Tested positive for PPA and lost her 1995 Pan Am gold medal • Took Benadryl to fight a cold 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 A must read for baseball fans • A “Classic” 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 Pseudoephedrine to crystal meth • Remove OH group! But……..when smoked in its crystalline form • Produces effects similar to, but longer lasting than crack cocaine Devastating Effects • After 10 years of use 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 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. Can be lethal • Deaths reported from dehydration • Should not be taken if any cardiovascular disorder or high blood pressure • Synthetic intermediates have unique odour O NHCH3 O Anti ‘Parkinson’s’ Agents OH HOOC H2N H OH L - DOPA N CH2 C C Deprenyl 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 Ritalin(Methyl Phenidate) • Prescription drug for ADHD (attention deficit hyperactivity disorder) • CNS stimulant-details of mechanism of action not yet known • BUT……………… COOCH3 CH When end of term comes • The little white pill 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 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. The placebo effect - people experience typical drug effects when they believe they have taken a drug but actually have not (in pain relief maybe endorphins). In general, ~30% placebo effect Can a positive mental attitude 'cure‘ a disease? Placebo Effect - the Test ! The Double-Blind Study – Divide, randomly, a large number of people into two groups: 1) the control group receives a placebo, 2) the test group receives authentic medication Two sets of examiners, each 'blind' to the other: 1) codes each pill, 2) distributes the pills to the two test groups Other Morphine Analogs N Demerol (spinal ‘taps’) CH3 N O O Methadone (withdrawal therapy) H3C O H N O N N Fentanyl (70% of surgery in USA) CH3O Dextromethorphan (cough suppresant) Endorphins - Natural Human 'Narcotics' It was discovered(1973), from research on opiate receptors, that the human brain has its own narcotic analgesics. These are small peptides named endorphins/ enkephalins(pentas) that selectively intervene with signals of deep, severe pain but not other nerve signals.Twist into same 3D shape to fit on same 'receptors' as morphine. Effects(?): pain relief from acupuncture 'high' experienced by marathon runners no pain for wounded soldier during battle An Enkephalin Morphine analog ? O H3N N H H N O O N H H N O pentapeptide HO O Receptors: polysaccharides/polypeptides attached to cell walls to receive/fit specific molecules that are 'messengers/signals' for some specific metabolic reaction. eg. when opiate receptors interact with narcotic molecules some signal flowing through the nervous system is blocked/altered. Antagonists are compounds that counteract/block the action of a drug; eg. for heroin. Agonists are molecules that mimic the action of a drug(but usually not all the actions of that drug). Humans…. Successes & Failures Psychoactive/psychotropic drugs have some effect on the human mind/mental processes. In NA 1 of 10 people suffer from 'mental illness' and receive much relief from psychoactive drugs. Worldwide: ~$400 billion/yr spent on 'illegal' drugs; more than is spent on food. In USA: ~$200 billion/yr; ~25% on heroin(from mid& far East). Worldwide: cocaine = ~2000 tons/yr(75% from central/south America); ~70% is consumed in US Psychomimetics - 'Downers' Sedatives(+!) : barbiturates, carbamates Depressants: ethanol Anesthetics(?) : glue/gasoline sniffing Tranquilizers(antianxiety): benzodiazepines, buspirone Antipsychotics(anti-schizophrenia): reserpine (Indian snakeroot), chlorpromazine, Li2CO3; also narcotics Antipsychotics for Schizophrenia, etc. N N(CH3)2 Cl S chlorpromazine CH3O OCH3 OCH3 N N H O CH3O reserpine O O OMe OCH3 Benzodiazepines/Diazepams(GABA enhancers) CH3 N Cl O N Diazepam (Valium) N -O + N O H N O Cl N Lorazepam (ativan) O N N N N O N OH Cl F Rohypnol (date-rape drug) N O H Buspirone Sedatives (GABA agonists) O H2NC O O O CNH2 Carbamate = Meprobamate(Equanil, Miltown) O O N N O S N N O Phenobarbital (Luminal) O = Barbituates = Thiopental (Pentothal) Psychomimetics - 'Uppers' Antidepressants: Zoloft, Prozac, Nardil(MAO), Elavil; also L-Dopa/Deprenyl Stimulants: cocaine, adrenaline/epinephrine, amphetamines(benzedrine, methedrine (speed/ice); also caffeine, nicotine, ritalin, ? Hallucinogens: LSD, marijuana, PCP(angel dust), mescaline, psilocin Antidepressants NHCH3 Cl Zoloft1 (sertraline) Prozac1 (fluoxetine) Cl CH2CH2 NHNH2 Nardil2(phenelzine) 2008 Study on Antidepressants • Prozac only effective on extremely depressed patients • No effects on moderate or low depression vs. placebo • But: if presently on antidepressants, should not abruptly stop use • But…………………… Geriatric depression • Often successfully treated with Zoloft • Commonly used in Nursing Homes Endorphins and the Placebo effect • Brain scans have shown that brain chemistry is altered when placebo’s are taken. • Release of endorphins –causes pain relief Hallucinogens CON(C2H5)2 OH N(CH3)2 NCH3 N H Psilocin (‘magic mushrooms) HN Lysergic acid diethyl amide (LSD) OCH3 H3CO NH2 OCH3 Mescaline(peyote cactus) Phenylcyclidine N PCP (Angel dust) veterinary anesthetic