Development and Classification of Medicine

1. Development and Classification of Medicine Brenda McCartney 2nd February 2011

2. Development of a Medicine

3. What is a drug? • Any biologically active chemical that does not occur naturally in the human body that can affect living processes • It is used for the treatment, prevention or alleviating the symptoms of disease.

4. 16th century Egypt Ebers papyrus poppy juniper berries beer lead swine teeth goose grease lizard's blood donkey hooves crushed precious stones excreta from various animals A little light history

5. Where do drugs come from now? • Plants: Digoxin (foxglove) Belladonna (deadly nightshade) Diamorphine (opium poppy) • Animal tissue: Insulin, growth hormone • Synthetic manufacture: Most modern medicines

6. The Pharmaceutical Industry • Develops, produces and markets drugs licensed for use as medicine. • Companies can deal in generic and / or brand medications. • Average cost to develop a successful new drug £145million - £1.2 billion • Subject to variety of laws and regulations.

7. Stages in Drug Development 1 Drug discovery Research & identification of compounds 2 Pre-clinical testing Lab testing 3 Clinical trials Testing on humans.

8. 1. Drug Discovery • From traditional remedies • Aspirin • Penicillin

9. Aspirin – first synthetic drug • (460-377 BC) Hippocrates Pain relief treatments with powder made from the bark and leaves of the willow tree • (1829) Johann BüchnerIsolated pure salicin (salicylic acid (1838)) • (1853) Charles Frederic Gerhardt first synthesised acetyl-salicylic acid (ASA) • (1898) Felix Hoffman Chemist at Bayer synthesized pure sample of ASA • (1899) Bayer receives patent for Aspirin® • Sales today exceed 50 billion pills per year

10. Penicillin – the first antibiotic • Fleming was a researcher working in an untidy lab • After returning from holiday he noticed that bacterial plates had become contaminated with a fungus • Bacteria were not present near the fungus on the plate • He concluded that the fungus was secreting an antimicrobial agent • He extracted the agent and named it penicillin Fleming was presented the Nobel Prize for Medicine in 1945. He humbly said, "Nature makes penicillin; I just found it."

11. 2. Pre-clinical Testing. • In vitro testing • Test active compound against target cell • Provides evidence of beneficial / harmful effects • Very simplistic, target organs/tissues made up of multiple cell types • BUT lacks the homeostatic mechanisms and pathways found in animals / humans

12. Pre-clinical animal testing Pharmacology Testing • effects of drug on all major systems (absorption, metabolism, distribution, excretion, plasma levels, half life) Toxicology Testing • Acute toxicity (single dose) • Short term toxicity (daily dosing for 2 weeks – 3 months)

13. Pre-clinical Testing • ED50 – Effective Dose 50 the amount of the drug required to produce a specified effect in 50% of an animal population • LD50 Lethal Dose 50 The amount of the drug required to cause death in 50% of an animal population

14. But only human studies can tell use how useful and safe a drug is................ .....So clinical trials in human volunteers are needed.

15. Clinical Trials.

16. What are clinical trials? • Research studies involving humans • Used to determine if drug treatments are safe and effective • Are the safest and quickest way to find treatments that work

17. Types of clinical trails. • Treatment trials • Prevention trials • Screening trials • Diagnostic trials • Quality of life studies • Genetics studies

18. Clinical trial protocol • Strict scientific guidelines • Purpose of study • How many participants • Who is eligible • How study will be carried out • What information will be gathered • End points

19. Clinical trials – phases Stage 2 Preclinical Stage 1 Drug Discovery Stage 3 Clinical trials Phase I 20-100 volunteers Phase III 1000-5000 volunteers 10,000 compounds 250 compounds 5 compounds 1 approved drug Phase II 100-500 volunteers 6.5 years 7 years 1.5 yrs Adapted from Pharmaceutical Research and Manufacturers of America.

20. Phases I trials • Use healthy volunteers • How does the drug affect the human body? • Drug absorption, metabolism and excretion • Preferred method of administration • What dosage is safe?

21. Phase II trials • Use target patient group representative of those likely to benefit from the drug. • No pregnant women • Does the drug have a beneficial effect on the disease? • Determine therapeutic dose range. • Usually placebo controlled • Conducted by experts in the disease field

22. Phase III trials • Obtains all data for regulatory agencies • Often multi-centered, multinational • Long term safety evaluated • Is new drug better than standard?

23. Randomised controlled trial (RCT) • Volunteers randomly assigned to new treatment or best existing treatment • Doctors have no say in who goes in which group to reduce bias

24. What is a placebo? An inactive pill, identical in appearance to the treatment pill which is given to the control group. Used to control for the placebo effect Patient feels better due to belief in the treatment Test pill Placebo

25. Participants in Clinical Trials • Protocol sets out who can participate • Use inclusion / exclusion criteria • Factors that allow people in are inclusion criteria (study for males) • Factors used to reject are exclusion criteria (may have history of illness)

26. Clinical trials – the results • Endpoint used to test trials success • Ideally use a hard endpoint – cure from disease • Statisticians analyse results – is A better than B? • Only after analysis do you tell which is A and B.

27. Drug Licensing • Application submitted to Medicines and Healthcare products Regulatory Agency (MHRA) • MHRA carry out pre-marketing assessment of safety, quality and efficacy, examining all research and results in detail.

28. Medicines and Healthcare products Regulatory Agency • An executive agency of the Department of Health • Enhance and safeguard the health of the public by ensuring that medicines and medical devices work and are acceptably safe. No product is risk free. 

29. European Medicines Evaluation Agency (EMEA) • The EMEA co-ordinate drug licence applications within the European Union (EU). • Committee for Proprietary Medicinal Products (CPMP)

30. Product Launch • When a drug has marketing authorisation, it is not available straight away. The company first have to apply to market their product. In the UK, they will apply to the MHRA. When this is done, the product is ‘launched’, and doctors can prescribe it. • The time it takes from marketing authorisation to launch in the UK is one of the fastest in the world.

31. Black Triangle Drugs. • If the drug is an active substance which has been newly licensed for use in the UK. • If it contains a new combination of active substances. • If administration is via a new route or delivery system. • If the medicine is to be used in a new patient population. • If the drug is to be used for a new indication.

32. MHRA monitoring of Black Triangle Drugs • confirm risk/benefit profiles established during the pre-marketing phase • increase understanding of the safety profiles of new medicines • ensure identification of previously unrecognised side effects as quickly as possible. Uses Yellow Card Scheme.

33. Classification of a Medicine

34. Names of drugs • Chemical name: describes the chemical structure: acetyl-p-amino-phenol • Generic name: a name that can be used by anyone: paracetamol • Trade name: owned by the manufacturer: Calpol

35. Other ways to categorise drugs • What kind of molecule is it? • What organ system (or what disease) is it for? e.g., cardiac, psychotropic • What parts of cells are affected?

36. What is the drug used for? • To cure e.g., infections, cancer • To suppress diseases or symptoms without attaining a cure e.g., hypertension, diabetes, pain control • To prevent disease (prophylactic) e.g., immunisation

37. How does the drug act? • Replace a deficiency, e.g., vitamins, minerals, hormones • Interfere with cell function, e.g., block enzyme action • Kill / prevent growth of viruses, bacteria, fungi, protozoa, cancer

38. Categories of drug • Anti-inflammatory • Analgesic • Antipyretic • Vaccine • Antihypertensive • Vitamin supplement • Antitussive Anaesthetic Surfactant Laxative Antiviral Antifungal Antibiotic

39. How do drugs work? • Pharmacodynamics: study of how chemicals exert their effects The practical importance of this is enabling the design of new and better drugs

40. receptor Receptors • Receptors are proteins on the cell surface or inside the cell. • They bind the body’s own chemical messenger • Convert the binding event to a signal that the cell can recognize and respond to signal

41. “Lock & Key” • Interaction between a receptor and its signal molecule (ligand) is like “lock & key”. • Perfect fit depends on exact 3D shape and size of both molecules.

42. drug receptor Receptors • Drugs also bring information to cells by fitting into the same receptor molecules. • The drug picks the lock and triggers a response by the cell.

43. Agonists and Antagonists • Agonist: a drug that fits into a receptor and activates a response e.g., morphine, nicotine • Antagonist: a drug that fits into a receptor but blocks the receptor and does not activate a response e.g., beta-blockers

44. Non-specific effects • Acidic or alkaline properties • Surfactant properties (amphotericin) • Osmotic properties (laxatives, diuretics) • Interactions with membrane lipids (anaesthetics)

45. Side-effects and other effects • Not the “wanted” effect e.g. aspirin causes gastric ulcer • Diphenhydramine has a useful side-effect

46. Side-effects and other effects • Hypersensitivity / allergy: exaggerated adverse reaction to drug • Toxic effects e.g., Thalidomide: teratogenic • Tolerance: increasing amounts are needed to produce the same effect

47. Pharmacokinetics How the body deals with the drug We need to consider • Dose • Route of Administration • Absorption and distribution • Metabolism and excretion

48. Doseamount of drug taken at any one time • Aim is to give the patient a dose of drug that achieves the desired effect without causing harmful side effects • Therapeutic Index(TI) is the ratio of the therapeutic dose to the toxic dose • Egs of drugs with low TI include digoxin lithium and methotrexate

49. Administration Route of administration depends on • how easy it is to use for patient • how quickly a drug needs toreach site of action • where it has to work in the body

50. Routes of Administration Intravenous Inhaled Oral Transdermal Subcutaneous or intramuscular injection Topical Rectal