Section 13.2 Drugs (Book 3B, Chapter 36)

1. Section 13.2 Drugs(Book 3B, Chapter 36)

2. Syllabus for consideration

3. Syllabus for consideration (12.6)

4. Drugs and medicine – an introduction Key stages of drug development Some common drugs Dangerous drugs Chiral drugs overview

5. Drugs and medicine – an introduction Key stages of drug development Some common drugs Dangerous drugs Chiral drugs overview

6. Drugs: chemical substances producing physiological effects on human body Often act by altering a range of biological processes Carefully researched, monitored by doctors or pharmacists or else extremely hazardous Medicine: Drugs prescribed by doctors Poisons: if drugs taken abusively; excessive intake – death (e.g. excessive paracetamol (a painkiller,止痛藥撲熱息痛): coma or death) Drugs and medicine

7. Most drugs are natural products modified by chemical reactions or are synthetic chemical substances. • Categorized according to their use: • Painkillers (止痛藥) • Antacids (抗酸劑) • Antibiotics (抗生素) • Cancer drugs (抗癌藥) etc. • Categorized according to their biological effects: • Narcotics (麻醉劑) • Analgesics (止痛劑) • Hallucinogens (迷幻劑) • Depressants (抑制劑) • Stimulants (興奮劑) • Tranquillizers (鎮靜劑)etc. Drugs and medicine

8. In ancient times, drugs discovery related to finding of natural products showing medicinal effects • From extracts of animals, plants and even minerals • Nowadays, drug development is a systematic process including stages of • Lead compound discovery (先導化合物發現) • Molecular structural modeling (分子改良) • Dosage formulation (配方發展) • Safety tests and trials (安全測試及人體試驗) • Approval from government monitoring agency (批准銷售) • Two examples: aspirin (阿士匹靈) and cisplatin (順鉑) Drugs and medicine (3B: 194 – 196)

9. Drugs and medicine – an introduction Key stages of drug development Some common drugs Dangerous drugs Chiral drugs overview

10. Aspirin Cis-platin Key stages of drug development

11. Aspirin (Book 3B, p.191 – p.192) Cis-platin Key stages of drug development

12. Aspirin development originated from discovery of medicinal use of the bark of the willow tree (柳樹) 240 years ago In 1827, a Scottish physician used extracts to treat acute rheumatism (風濕病) Active ingredient found to be salicin (水楊苷) (isolated from willow bark and flowers of meadowsweet (繡線菊屬植物) plant) Key stages of aspirin development:Lead compound discovery

13. 1870, Prof von Nencki discovered : salicin was converted to salicylic acid (水楊酸) in the body. Synthesis of salicylic acid and prescribed to cure fevers BUT: salicylic acid causes serious burns and irritation to oral cavity, oesophagus and stomach.  patients taking salicylic acid: ulcers (潰瘍) Key stages of aspirin development:Molecular modiFication)

14. Reduce side effect, use sodium hydroxide to neutralize carboxylic acid group i.e. use sodium salicylate instead This salt derivative works as an antipyretic (退熱劑) and the irritation (發炎) is reduced. Key stages of aspirin development:molecular modification

15. BUT sodium salicylate tastes awful and the patient would vomit badly if a large dose is taken. 1897: Felix Hofmann from Bayer synthesized a new compound by acetylation of the phenol group producing acetyl salicylic acid (or ASA). ASA: a mild irritant, a reasonable taste, good fever-reducing and pain relieving properties Key stages of aspirin development:molecular formulation

16. ASA – large scale synthesis Initially as a powder in packers and later made into tablets Today ASA formulations include additives like buffers. Key stages of drug development: dosage formulation

17. Two stages • Preclinical trial • Clinical trial • Preclinical trials • On tissue samples and live animals • Provide useful information on the drug’s absorption, distribution (transportation inside the body), metabolism and elimination in the body. • Clinical trial • Involve human testing • Ethical and legal issues • To be conducted under stringent legal approval by a recognized ethical committee • If pass all the trials: certificates Key stages of aspirin development: safety tests and human trials

18. Aspirin: synthesized and marketed by Bayer Company Initially as a powder than as a 500 mg tablet One of the first drugs in the world to be available in a standardized dosage. Key stages of aspirin development: market approval

19. Aspirin Cis-platin (3B, p.193) Key stages of drug development

20. Discovered accidentally in 1961 by a biophysicist (Prof Barnett Rosenberg) Studying effect of electromagnetic radiation on the growth of E.coli. After the experiment, bacteria growth: inhibited by electrolysis product of the Pt electrodes. Rosenberg: Growth of E. coli. Was inhibited by a square planar complex, cisplatin (cis-dichlorodiamineplatinum(II)) and light Further investigated by other chemists Key stages of cis-platin development:Lead compound discovery

21. Rosenberg: use of cis-platin in animal tests in 1968 • Cis-platin: • capable of stopping the rapid cell division in bacteria at concentrations that are effective yet without significant toxicity. • Reduce the size of cancerous tumors in mice • Cisplatin: use in anti-cancer treatment Key stages of cis-platin development: lead compound discovery

22. Rosenberg: noticed that the trans isomeris thermodynamically more stable, it is a much less active complex for cancer treatment Other chemical derivatives (change its ligands): potent anti-tumor variants of cis-platin Key stages of cis-platin development:molecular modification

23. Common features in cis-platin and its derivatives: • Geometries (all square planar) • All electrically neutral • Two cis-monodentate ligands or a bidentate ligand • Cyclic ligands can enhance the antitumor activities of the complexes BUT the solubility of complex would be decreased Key stages of cis-platin development: molecular modification

24. Serious difficulties in formulation • Side effects: • Nausea (嚴重噁心) • Vomiting (嘔吐) • Renal failure (腎衰竭) Key stages of cis-platin development: dosage formulation

25. In vivo studies (活體研究): almost discontinued due to the toxicity • Clinical trial: • Cvitkovic and coworkers: aggressive diuresis (強力利尿) in minimizing renal damage • Gralla et al.: using antiemetic drugs (鎮吐劑) resolving nausea and vomiting problems Key stage of cis-platin development: safety test and human trials

26. Administered in a chloride containing solution • Side effects: several drugs taken together • Mannitol (甘露醇): increase urine flow (deal with renal failure) • Injecting anti-emetics (止吐針): minimize nausea and vomiting • Since 1970s, treat various cancers • Ovarian • Testicular • Lung Key stages of cis-platin development:market approval

27. Drugs and medicine – an introduction Key stages of drug development Some common drugs Dangerous drugs Chiral drugs overview

28. Over-the-counter drugs • Aspirin • Acetaminophen • Vitamin C • Prescription drugs • Albuterol • Amlodipine • Loratadine • Amoxicillin • Omeprazole Over-the-counter drugs and prescription drugs (3B, p.197)

29. Aspirin Over-the-counter drugs

30. Analysis of aspirin (See handout) Over-the-counter drugs

31. Acetaminophen (paracetamol, p-acetaminophenol) • An analgesic that relieves pains such as headaches • Less corrosive to stomach and is an alternative to aspirin • Present in Panadol, Saridon, Tylenol and Fortolin Over-the-counter drugs

32. Vitamin C (Ascorbic acid) Over-the-counter drugs

33. Common names of prescription drugs (3B, p.198)

34. Albuterol (舒喘靈) • Asthma medicine (哮喘藥) Common names of drugs: use common names for easier reference (3B, p.198)

35. Amlodipine (氨氯地平) • Reduces blood pressure • Peripheral arterial vascodilator (輔助性動脈血管擴張藥) Common names of drugs: use common names for easier reference (3B, p.198)

36. Prilosec (Omeprazole,奧美拉唑) • Treatment of heartburn, stomach ulcers Common names of drugs: use common names for easier reference (3B, p.198)

37. Loratadine (氯雷他定) • Antihistamine (抗組織胺) Common names of drugs: use common names for easier reference (3B, p.198)

38. Amoxicillin (阿莫西林、羥氨苄青霉素) • Antibiotic (抗生素) Common names of drugs: use common names for easier reference (3B, p.198)

39. Drugs and medicine – an introduction Key stages of drug development Some common drugs Dangerous drugs Chiral drugs overview

40. Narcotic drugs • Morphine and heroin • Stimulant drugs • Ketamine, methamphetamine and phenylethylamine Dangerous drugs

41. Narcotic drugs • Morphine and heroin • Stimulant drugs • Ketamine, methamphetamine and phenylethylamine Dangerous drugs

42. Chemical substances relieving pain by numbing the senses, inducing sleep • Highly addictive • Many countries ban their imports; manufacture; or possession • Commonly abused narcotic drugs: • Morphine (嗎啡) • Heroin (海洛英) Dangerous drugs: Narcotic drugs (麻醉藥物)

43. Opium (鴉片) and morphine (嗎啡) • From opium puppy (罌粟) • A mixture of alkaloids,有機生物鹼(organic bases) • Most abundant alkaloid: morphine (10% opium) Dangerous drugs: Narcotic drugs(3B, p.199)

44. Morphine and its analogues: most effective painkillers BUT strong addiction Codeine (可待因): less addictive while less pain-killing Replacing the hydroxyl group by methoxy group Dangerous drugs: narcotic drugs

45. Heroin (3B, p.199) • Two hydroxyl groups replaced by two acetoxy groups • More powerful narcotic BUT more addictive Dangerous drugs: narcotic drugs

46. Precursor chemicals: • Acetic anhydride (CH3 C – O – CCH3) || || O O • Acetyl bromide (CH3COBr) • Acetyl chloride (CH3COCl) • Acetone ((CH3COCH3) • Ethyl ether (CH3CH2OCH2CH3) Danerous drugs: Heroin

47. Methadone (美沙酮) http://en.wikipedia.org/wiki/Methadone accessed on 28/12/2007

48. Comparing structures of heroin and methadone Heroin

49. Contains Cannabinoids: Some examples Cannabis (大麻) http://en.wikipedia.org/wiki/Cannabinoids accessed on 28/12/2007

50. Cannabis