Drug Discovery & Development: Preclinical & Clinical Studies (Phases I-IV)

Posted on May 6, 2024 in Medicine & Health

Drug Discovery and Development

This is the process of identifying and bringing new drugs to market. New drugs can be discovered through:

1. New insights about diseases
2. Existing treatments with unanticipated effects
3. New technologies that provide new ways to target medical product sites

The development process involves understanding:

1. How the drug is absorbed, metabolized, distributed, and excreted
2. Benefits, mechanism of action, dosages, toxicity, adverse drug reactions, and interactions
3. How the drug affects different age groups
4. Comparison with similar drugs

Stages of New Medication Development

Stage 1: Preclinical Studies

These studies are done in vitro or in vivo, following good laboratory practices. They provide detailed information on dosing and toxicity, including pharmacological screening and pharmacokinetic/pharmacodynamic characteristics. The goal is to investigate the pharmacological effects and properties of the drug.

Stage 2: Clinical Studies

These studies are conducted on humans and consist of four phases:

Phase 1

• Participants: 20-100 healthy volunteers
• Length: Several months
• Purpose: To assess safety and dosages

Phase 2

• Participants: Up to 100 individuals with the disease
• Length: Several months to 2 years
• Purpose: To evaluate efficacy, side effects, and bioequivalence

Phase 3

• Participants: 300-3000 individuals with the disease
• Length: 1-4 years
• Purpose: To test efficacy, safety, and interactions in a specific patient group and monitor adverse reactions

Phase 4 (Post-Marketing Studies)

• This phase examines the drug’s long-term effects after it has been approved and marketed.

Good Clinical Practice Standards

These standards ensure the safety and well-being of participants in clinical trials. They include:

1. Ethical conduct of medical tests involving human subjects
2. Protection of participants’ safety and well-being
3. Planning and implementation of bioavailability and bioequivalence studies
4. Qualified physician supervision
5. Informed consent
6. Confidentiality of participant records

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs are classified as COX-1 selective (e.g., low-dose aspirin), non-selective (e.g., ibuprofen, diclofenac), and COX-2 selective (e.g., celecoxib).

Adverse Reactions

The main adverse reactions of NSAIDs include:

• Gastrointestinal: Irritation, ulcers, bleeding, perforation
• Cardiovascular: Increased risk of myocardial infarction and stroke (except aspirin)
• Renal: Chronic kidney disease
• Photosensitivity
• Pregnancy risks, especially during the third trimester

Mechanism of Action

NSAIDs work by inhibiting COX enzymes, which reduces the production of prostaglandins. This leads to anti-inflammatory, analgesic, and antipyretic effects. Non-selective COX inhibitors also have additional actions, such as reducing renal blood flow and inhibiting platelet function (aspirin).

Selective COX-2 Inhibitors

These drugs have an increased risk of cardiovascular events and safety restrictions for individuals with smoking, hypertension, or heart failure.

Examples of NSAIDs and their specific considerations:

• Nimesulide: High hepatotoxicity, restricted dose and duration, second-line option
• Diclofenac: Thrombosis risk at high doses, gastropathy
• Ketoprofen: Photosensitivity, prescription-only
• Ketorolac: Short-term use only

Rational Use of NSAIDs

Bronchial Obstruction: Sympathomimetic Agents

Mechanism of Action

Sympathomimetic agents bind to beta receptors on airway smooth muscle, causing bronchodilation.

Types of Sympathomimetic Agents

Non-Selective

• Epinephrine: Rapid onset, inhaled, short duration (0-90 minutes)
• Isoproterenol: Non-selective beta-1 and beta-2 agonist
• Ephedrine: Oral or injected, longer duration, infrequently used

Beta-2 Selective

These agents are typically inhaled and have a longer duration of action.

Older Generation

• Albuterol and Metaproterenol: Inhaled, short-acting beta-2 agonists

Newer Generation

• Salmeterol and Formoterol: Long-acting beta-2 agonists
• Indacaterol and Olodaterol: Ultra-long-acting beta-2 agonists

Methylxanthines (e.g., Theophylline)

These drugs inhibit phosphodiesterase and increase cAMP levels, leading to bronchodilation. They require therapeutic drug monitoring due to their narrow therapeutic index.

References

Please refer to your course materials and relevant pharmacology textbooks for detailed information on the topics covered in this document.