Pharmacology Chapter Overview

General Pharmacology Lecture Notes

• Pharmacology is the study of drugs (Greek: Pharmacon-drug; logos-discourse).
• A drug is any single chemical substance capable of producing a biological response.
• Pharmacology studies substances interacting with living systems, mostly by binding to regulatory molecules and activating or inhibiting normal body processes.
• Rudolf Buchheim founded the first pharmacology institute in 1847 in Germany.
• Oswald Schmiedeberg, considered the "father of pharmacology," along with his disciples (e.g., Langley, Frazer, Ehrlich, Clark, Abe) developed fundamental pharmacology concepts.

Nature of Drugs

• Drugs encompass a wide range of chemical compounds, including inorganic ions, nonpeptide organic molecules, small peptides, proteins, nucleic acids, lipids, and carbohydrates.
• Many natural drugs are alkaloids, characterized by a basic pH in solution, usually due to amine groups in their structure.
• Drugs vary in molecular weight (MW) from 7 (lithium) to over 50,000 (e.g., proteins).
• Most drugs have MWs between 100 and 1000.
• Small MW drugs are often less selective, while large MW drugs can be poorly absorbed and distributed.
• Drugs bind to receptors through various chemical bonds, including strong covalent bonds (often irreversible) and weaker electrostatic, hydrogen, van der Waals, and hydrophobic interactions.

Drug Development and Regulation

• The sale and use of drugs are regulated worldwide by governmental agencies.
• In the U.S., regulation is handled by the Food and Drug Administration (FDA).
• New drug approvals require extensive animal and human testing (clinical trials) before therapeutic use in humans.
• Animal studies evaluate relative safety (subacute and chronic toxicity), potential therapeutic action (pharmacologic profile), and carcinogenicity.
• The Ames test screens for mutagenicity, often correlating with carcinogenicity in some animal tests.
• Animal testing focuses on the drug's proposed use and urgency of application, with anticancer and anti-HIV drugs often having accelerated approval processes.

Animal Testing

• Acute toxicity studies determine lethal dose levels in at least two species.
• Subacute and chronic toxicity tests are performed for longer durations (2-4 weeks and 6-24 months, respectively), with multiple species.
• Pharmacologic profiles assess all the drug's effects (e.g., cardiovascular, gastrointestinal, and CNS).
• Reproductive toxicity tests focus on the drug's effect on fertility, teratogenicity (birth defects), and mutagenicity (DNA damage).

Clinical Trials

• Ethical review boards ensure informed consent, patient safety, and the scientific validity of drug studies.
• Manufacturers submit Investigational New Drug (IND) applications to the FDA for authorization to test drugs in humans.
• Clinical trials usually involve three phases—Phase I (small-scale dose-response studies in healthy volunteers); Phase II (moderate-scale studies in sick patients); and Phase III (large-scale studies in diverse populations).
• Phase IV clinical trials (post-marketing surveillance) monitor infrequent, long-term side effects.

Safety and Efficacy

• Drug efficacy focuses on the capacity for a drug to produce an effect and how well it works in practice.
• Drug safety emphasizes the identification, assessment, and prevention of side effects to mitigate/ manage risks and benefits.
• Phase I: Dose-response and pharmacokinetics in volunteers (20-100) or patient pool
• Phase II: Moderate dose study in sick patients (100-200); placebo or control group
• Phase III: Large-scale effectiveness study involving diverse populations and clinicians; placebo or positive control, often double-blind design
• Phase IV: Post-marketing surveillance for infrequent side effects