Lecture 2: Sources of Drugs and their Nature

Question 1

List the main sources of drugs, giving examples from each source

Answer 1

1909 – Paul Ehrlich shows syphilis can be treated w arsenical compounds

1932 - “Prontosil” the first sulphonamide antibacterial developed by the Bayer company. Led to era of drug development led by chemists

1961- Thalidomide withdrawn

196/70s and 80s era of “rational drug design” e.g. beta blockers, ACE inhibitors. Led by pharmacologists such as Sir James Black

1990s – the drug discovery process revolutionised by technique such as high throughput screening and combinatorial chemistry

2002 – human genome mapped

2000s to date – increasing development of “biologicals” e.g. human insulin or anti-cancer antibodies

Question 2

List the main sources of drugs, giving examples from each source

Answer 2

3 main sources of drugs:

1. natural products (e.g. plants),
2. compound libraries (pharmaceutical companies have many drug models all with potential to become drugs)
3. combinatorial chemistry (synthesise new molecules to add into the library that could be potential drugs)

Question 3

what are assay systems?

Answer 3

methods that are used to measure the presence, amount or activity of a substance e.g. a drug

Question 4

Morphine:

Source and Clinical use?

Answer 4

source: Poppy plant

clinical use: Pain relief

Question 5

Penicillin

Source and Clinical use?

Answer 5

source: Penicillium fungi

clinical use: treat bacterial infections

Question 6

Digoxin

Source and Clinical use?

Answer 6

source: Foxgloves plant: Digitalis purpurea

clinical use: Control heart problems

Question 7

Paclitaxel

Source and Clinical use?

Answer 7

source:Bark of pacific yew tree

clinical use: Anticancer drug

Question 8

Quinine

Source and Clinical use?

Answer 8

source: Bark of cinchona tree

clinical use: Treat malaria

Question 9

Hirudin

Source and Clinical use?

Answer 9

source: Body tissues of European medicinal leech

clinical use: Treat deep vein thrombosis

Question 10

Botulinum toxin

Source and Clinical use?

Answer 10

source: Low acid preserved vegetables e.g. green beans

clinical use: Treat disorders of muscle tone

Question 11

Explain what is meant by the term “structure-activity relationship” and why it is important in drug development

Answer 11

• Structure Activity Relationships (SAR) can be used to predict biological activity from molecular structure
• used in drug discovery to guide the acquisition or synthesis of desirable new compounds, as well as to further characterize existing molecules

Question 12

what is the basic drug discovery processes?

Answer 12

• basic research in university (leads to better understanding of physiology and disease mechanism)
• identification of potential drug targets (looking for molecular targets - usually proteins - that play a crucial role in the disease)
• hypothesis generated (a drug that acts on that target to change its activity will be effective in treating disease)

Question 13

what factors need to be considered during the drug development process?

Answer 13

Safety issues – will the drug harm patients or the environment?

Ethical issues – is development of such drug civilised behaviour? E.g. cognitive enhancers

Intellectual property – is the drug covered by a patent? Is the basic hypothesis someone else’s intellectual property?

Cost – does it make good business sense to develop a drug to treat a particular condition?

Question 14

List the four phases of clinical trials

Answer 14

Phase I – exploratory trials; first in human

Phase II – Efficacy, proof of concept and safety (Phase IIa, Phase IIb)

Phase III- Confirmatory

Phase IV Clinical Trials (ongoing)

Question 15

Explain the purpose of Phase I of Clinical trials

Answer 15

• exploratory trials; first in human

hronic toxicity of drug will have been assessed in at least 2 mammalian species (1 non-rodent)

Phase 1 trials lasts 6 months to a year and purpose is to check for;

1. Safety (potentially dangerous side effects)
2. Tolerability (unpleasant symptoms e.g. headaches, nausea)

more info:

• involves a small number (40-60) of healthy volunteers exposed to increasing doses. Carried out in specialised clinical facilities
• Placebo-controlled, randomised, double-blind
• May involve selected subject groups (male, female, elderly, different ethnicities)

Question 16

Explain the purpose of Phase II of Clinical trials

Answer 16

Primary purpose is to determine how clinically effective the drug is in patients, and to confirm safety and tolerability

Question 17

What occurs in Phase IIa of clinical trials?

Answer 17

Exploratory

5-200 patients; lasts approximately 1 year

Does and treatment regimen based on Phase 1 results

Usually placebo-controlled, randomised, double blind

Question 18

What occurs in Phase IIb of clinical trials?

Answer 18

Confirmatory

200-500 patients; lasts approximately 2 years

Safety and efficacy to placebo or current treatment in randomised, double-blind design

Question 19

Explain the purpose of Phase III (confirmatory) of Clinical trials

Answer 19

purpose: Full scale evaluation of how effective and safe the treatment is compared to current standard treatment (or placebo)

more info:
- Drug is tested in typically 2000-10,000 patients, often in multi-centres and including different groups (age etc.)

• Last several years (especially in chronic disease scenario)
• Provides data to support registration; once completed can apply for registration for use in specified condition

Question 20

Explain the purpose of Phase III (ongoing) of Clinical trials

Answer 20

• Designed to monitor consequences of increasing exposure in tens of thousands of patients
• Rare or very rare long-term adverse effects
• Unpredictable drug interactions

more info:

• Continue after drug is licensed and on the market;
• Pharmacovigilance
• Post-market surveillance
• “Yellow Card” system in UK

Also yield info on the drug’s efficacy in sub-groups of the population (elderly, young)