1. Option D: Medicines and Drugs Section D.1: Pharmaceutical Products pp 405-410 (Green and Damji)

2. Objectives B.1.1: List the effects of drugs and medicines. B.1.2: Outline the stages involved in research, development and testing of new pharmaceutical products. B.1.3: Describe the different methods of administering drugs. B.1.4: Discuss the terms lethal dosage (LD 50 ), tolerance, and side effects.

3. What exactly is a medicine? a drug ? Any chemical (natural or synthetic) that does one or more of the following… … alters mood or emotions … alters incoming sensory sensations … alters a physiological state including consciousness, activity level, or co-ordination

4. Why do people use medicines / drugs? … improve health …assist the body’s natural healing process …‘placebo affect’

5. Medicines and drugs can be… … helpful or harmful …natural or synthetic …legal or illegal …

6. How are new drugs developed in USA? (1)Research Disease is selected Vulnerable targets are identified Potential lead molecules are considered Lead molecule is selected

7. How are new drugs developed? (2) Preclinical trials – in vitro (lab environment) – in vivo (living organisms) cell cultures / animals usu 3 species ) – rats, mice, guinea pigs  purpose – identify lethal dose, effective dose, potential side effects

8. How are new drugs developed? (3) Phase 1 trials – initial clinical trials – small numbers healthy volunteers terminally ill patients (with their consent)  purpose: assess toxicity, effective dose, side effects

9. How are new drugs developed? (4) Phase II trials – clinical trial – several hundred – ill patients – treated with drug or placebo ‘blind’ test or ‘double-blind’ test – statistical study  purpose: determine dosage and administration; eliminate bias

10. How are new drugs developed? (5)Phase III trials – extended clinical trials – thousands – ill patients – treated with drug and closely monitored  purpose: adjust dosage and monitor side effects

11. How are new drugs developed? (6) Drug launched (7) Phase IV trials – Post-launching  purposes: new formulation, new dosage, new application, product extension

12. Drug Development… takes a long time and a lot of money… Time – as much as 10-15 years Cost – up to $800 million

13. Why does drug development require such an exhaustive process?... to protect users from harmful side-effects and/or death – drugs that make it through the approval process have a reasonable risk/benefit ratio – most proposed drugs never make it through the process

14. What is thalidomide and why was it such a problem?... non addictive sedative available in Europe 1958-1963 given to pregnant women to treat ‘morning sickness’ – (which it did)

15. Structure of Thalidomide Source: http://www.k-faktor.com/contergan/thalidomide.gif Thalidomide exists as a racemic mixture of TWO stereoisomers – each with their own special impact on the body!

16. Why was thalidomide such a problem?... babies born dead or with birth defects: – no arms &/or legs, – short arms &/or legs – missing bones – Intestinal abnormalities 460 cases in UK 3000 in former West Germany

17. What about thalidomide now? As a result of the impact, thalidomide was initially banned, but is currently available (under another name) to treat severe leprosy in Brazil, Mexico, USA – special warnings provided and is being considered for other applications (i.e. cancer treatment)

18. When are medicines/drugs considered hazardous? When they pose a risk to the – Physical – Mental – Social well-being of the user.

19. What are main vs side effects? Main effect = desired response Side effect = the unwanted response to the use of a medicine or drug Ex: Morphine – prescribed for pain Main impact = pain relief Side effect = constipation Ex: Morphine – prescribed for diarrhea Main impact = induced constipation Side effect = pain relief

20. What are side effects? NO drug is free of side effects… – range from trivial to serious – even death – allergies (over-reaction of immune system) Mild skin rashes… to fatal shock penicillin – damage to liver &/or kidney often long term alcohol damages liver users of one drug over a long time… or of multiple drugs often have periodic liver / kidney function test

21. What is toxicity? TOXICITY: – LD 50 value – Lethal dose of a substance that kills off 50% of a population Not humans – numbers extrapolated from animal studies – Molecules with small LD 50 numbers are the most toxic

22. Some interesting LD 50 SubstanceAnimal, RouteLD50 Vitamin CVitamin C (ascorbic acid)rat, oral11,900 mg/kg Paracetamol Paracetamol (acetaminophen) rat, oral1,944 mg/kg AspirinAspirin (acetylsalicylic acid) rat, oral200 mg/kg

23. Some interesting LD 50 SubstanceAnimal, RouteLD50 Grain alcoholGrain alcohol (ethanol)rat, oral7,060 mg/kg THCTHC (main psychoactive substance in Cannabis)Cannabis rat, oral 730 mg/kg females; 1,270 mg/kg males Caffeinerat, oral192 mg/kg Nicotinerat, oral50 mg/kg

24. Some interesting LD 50 SubstanceAnimal, RouteLD50 Metallic ArsenicArsenicrat, oral763 mg/kg Arsenic trisulfiderat, oral 185 mg/kg - 6400 mg/kg Strychninerat, oral16 mg/kg Arsenic trioxiderat, oral14 mg/kg

25. Some interesting LD 50 SubstanceAnimal, RouteLD50 Aflatoxin B1Aflatoxin B1 (from Aspergillus flavus) rat, oral 0.048 mg/kg Venom of the Inland taipanInland taipan (Australian snake) rat, subcutaneous 0.025 mg/kg Dioxin (TCDD) rat, oral 0.020 mg/kg VX (nerve agent) human, oral 0.0023 mg/kg (est) BatrachotoxinBatrachotoxin (from poison dart frog) human, sub- cutaneous injection 0.002-0.007 mg/kg (est) Botulinum toxinBotulinum toxin (Botox) human, oral, injection 0.000001 mg/kg (est)

26. What is tolerance? User needs increasing amounts of a drug to get the same physiological effect. – Due to use over time and with regular use Maximum daily tolerance – amount that can be taken into the body without undesirable symptoms occurring

27. Why is tolerance a problem? Body may become tolerant to the positive effect, not NOT to the harmful effect(s) – User needs more of the drug… and this intensifies the harmful effect(s). – Barbituates – users develop a tolerance to sedative but not to its effect on breathing (slows it down) – so they take so much of the drug their breathing stops.

28. Why is tolerance a problem? Tolerance changes after the user stops using… – Body’s tolerance decreases with time and non-use – User begins using again… but at former dose (which was increasingly higher with time…) User experiences more intense side effect(s) Overdose may occur

29. What is dependence? A person is ‘drug-dependent’ when an individual continues to use a drug because s/he does not feel ‘right’ without it Dependence can be – Physical Without the drug, user experiences physical symptoms – Mild discomfort…. Convulsions – ‘withdrawal’ – Psychological Intense craving for the drug and its effects – difficult to stop using – Drug Addiction

30. What is a therapeutic window? Measure of the relative margin of safety of the drug for a particular treament. Ratio of LD 50 to ED 50 – ED 50 is the therapeutic dose – the effective dose for 50% of the population. If the window is WIDE, the effective dose is below toxicity – so there is a safe margin If the window is NARROW, small doses need to be administered for successful treatment.

31. How are medicines/ drugs administered? (1) Oral – Through the mouth Tablet / capsule Syrup – adv: self-administer, easy – disadv: must be able to survive the digestive system

32. How are medicines/ drugs administered? (2) Rectal – suppository – adv: self-administer, efficiency – disadv: yuck factor

33. How are medicines/ drugs administered? (3) Inhalation – by breathing (i.e. via an inhaler) – adv: rapid – disadv: drug must be for the lungs – or able to be absorbed through the lungs

34. How are medicines/ drugs administered? (4) Injections – intravenous – into blood stream (quick, but spreads out dose) – subcutaneous – into body fat (good for fat-soluble molecules) – intramuscular – into muscle tissue – adv: put directly where it is needed, requires reduced dose, reduces chance of altercation by body – disadv: requires trained person, people don’t like shots

35. How are medicines/ drugs administered? (4) Injections – intravenous – into blood stream (quick, but spreads out dose) – subcutaneous – into body fat (good for fat-soluble molecules) – intramuscular – into muscle tissue – adv: put directly where it is needed, requires reduced dose, reduces chance of altercation by body – disadv: requires trained person, people don’t like shots

36. How are medicines/ drugs administered? Patches – Molecules absorbed through the skin barrier – gradually – Adv: continuous and controlled rate; people like them; can receive a strong medication without IV – Disadv: patch may come off; takes up to 72 hours for drug to saturate the body; heat (from fever or use of heating pad) may increase side effects