Rational Drug Use and FDA Approvals 2022

Rational Drug Use

• Rational drug use involves using medications for a defined therapeutic purpose, considering appropriate indication, dose, route, frequency, and duration.
• Medications should be clinically appropriate, FDA-approved, and administered at the lowest possible cost.
• Key factors include proper indication, dose, form, route, frequency, duration, and patient education. Follow-up is critical.

How Drugs Work

• Understanding disease mechanisms, including the flawed process and potential correction, is essential.
• Drugs often treat symptoms, not the root cause. The goal is to target underlying mechanisms for cures.
• Antibiotics can cure infections, but overuse leads to resistance. Replacement therapy addresses conditions like insulin deficiency.

FDA Drug Approvals and Statistics

• FDA approvals decreased from ~100 in 2021 to 37 in 2022, primarily due to new formulations/labels, not new indications.
• 2022 approvals were for various conditions, including rare diseases (54%).
• Over 10,000 prescription drugs are available. Over 6.7 billion prescriptions were filled in 2022 (3.6% increase YoY).
• ~81% of physician visits result in a prescription. Patients over 65 account for a disproportionate share (~34% of prescriptions).

Risk vs. Benefit

• A 1% risk of adverse effects is considered high.
• The course emphasizes drug mechanisms for optimal benefits and minimized side effects. Concepts include potency, efficacy, duration, pharmacogenomics, and PK parameters.

Historical Perspective

• "Medicine men" initially acted as healers, using varying agents.
• The Industrial Revolution introduced bottled remedies, often containing alcohol.
• Legislation emerged to promote rational and safe drug use.

Irrational Drug Use

• Irrational drug use includes misuse, overuse, polypharmacy, incorrect drug selection, and unsafe self-medication; this often results in negative health outcomes.

Legislation for Rational Drug Use

• Key legislation includes the 1906 Federal Pure Food and Drug Act (Wiley Act) and the 1938 Federal Food, Drug, and Cosmetic Act, which both addressed drug safety and labeling.
• Further legislation, like the 1951 Durham-Humphrey Amendment and the 1962 Kefauver-Harris Amendment, further refined safety and efficacy standards.

New Drug Approval Process

• Drug approval follows rigorous phases (1-4).
• Phase 4 involves a larger population, and rare side effects might not emerge until then.
• Black box warnings might be added post-approval.

Example: COX-2 Inhibitors

• COX-2 inhibitors (Vioxx, Celebrex, Bextra) were designed to reduce stomach issues associated with inhibiting COX-1.
• Vioxx faced withdrawal due to increased risk of heart attack. While Celebrex was not withdrawn due to its perceived acceptable risk-benefit profile in specific patient groups.

Pharmacist's Role in Rational Drug Use

• Pharmacists play a vital role in ensuring rational drug use, education, and communication to patients.
• Risk evaluation, mitigation strategies, education, counseling, and medication reconciliation are part of their duties.

Module 1.2: PK, PD, and Toxicology

What is Pharmacology?

• Pharmacology is the study of a "pharmakon" (cure or poison) concerning its therapeutic value.

Key Terms

• Pharmacodynamics (PD): What the drug does to the body (MOA).
• Pharmacokinetics (PK): What the body does to the drug.
• Toxicology: Study of potential harmful effects.

Pharmacodynamics in Detail

• Focuses on therapeutic benefit, MOA, and molecular drug targets.
• Drug targets include receptors, ion channels, enzymes.

Pharmacokinetics in Detail

• Drug absorption, distribution, metabolism, excretion.
• These processes influence how the drug acts.

Benefit vs. Risk

• Knowledge of both PD and PK is critical to understanding the drug balance.

Benefits of Rational Drug Use

• Examples of intended results (e.g., antihypertensives, birth control pills).
• Side effects can result even with intended drug use.

Maximizing Benefit and Minimizing Risk

• Understanding PD characteristics, target tissue, PK, and patient history is crucial.

Toxicology in Detail

• Studies potential harm from drug use, investigating both cause and patient variability.
• Toxicology assessments are done during development and post-marketing.

How PD Influences Toxicology

• Example: Opioids – increased potency, lipophilicity, lead to heightened side effects.
• More potent drugs pose greater environmental risk.

How PK influences Toxicology

• Potent and lipophilic opioids cause inhalation and membrane exposure risk.

Controlling Benefit-to-Risk Ratio

• PD factors (multiple targets, selectivity).
• PK factors (free drug concentration, distribution, metabolism).
• Patient variability is crucial.

Patient Variability

• Pharmacogenomics studies gene-drug interactions.
• Example: Coumadin (anticoagulant); CYP enzymes metabolize to inactive form.

Summary

• PK, PD, and toxicology are essential for managing drug use benefit ratio.
• Patient variability affects outcomes to various degrees.

Module 1.3: Mechanism of Action

• Focus on the "what" and "how" of drug mechanisms to better understand potential effects and benefits.
• Common drug targets include ion channels, receptors (especially GPCRs), transcription factors, enzymes, and nucleic acids.
• Understanding a drug's MOA improves selectivity and reduces side effects.

Importance of Knowing the Mechanism of Action

• Understanding a drug's MOA is key to differentiating beneficial effects from side effects.
• Relevant factors include how the drug works, where it acts, its molecular targets, potential side effects, and its therapeutic benefits.

Limitations

• Limitations in understanding include incomplete knowledge, multiple targets, and dynamic MOA (changing with drug use).

Common Drug Targets

• Ion channels, receptors, transcription factors, enzymes (kinases and proteases), nucleic acids, and cell-surface glycoproteins.

Example Drugs and MOA

• Morphine: Analgesic effects linked to opiate receptor activation.
• Acetaminophen: Pain modulation linked to COX inhibition.

Multiple Modes of Action

• Drug interactions can be additive, synergistic, or antagonistic. These interactions can both lead to benefits and unwanted side effects.

Side effects and MOA

• Side effects often arise from off-target interactions, while desired therapeutic effects derive from on-target interactions. Targeting specific downstream signaling can limit side effects.

MOA Changes with Repeated Exposure

• Both therapeutic effects and side effects can adapt and change over time. Drugs may lose effectiveness or create new sensitivities.

Tolerance

• Tolerance development may necessitate increased dosages, potentially leading to more intense side effects.

Module 1.4: Pharmacogenomic Variability

• Pharmacogenomics investigates how genetic variations affect drug responses, encompassing pharmacokinetics and pharmacodynamics.
• Variability in drug outcomes can range from lack of efficacy to adverse reactions.
• The benefit-to-toxicity ratio is crucial in drug choices.

Adverse Drug Events (ADEs)

• ADME (Absorption, Distribution, Metabolism, Excretion) are key stages of the drug in the body.
• Adverse drug events can be medication errors (preventable) or adverse drug reactions (unpreventable). These ADRs are more directly related to the drug.

Genetic Variability and Disease

• Genetic variation impacts disease presentation, risk, and recurrence, influencing treatment responses.

Pharmacogenomics

• Aims to understand how genetic variation alters drug responses.
• It studies interactions between genes and medication actions (PD and PK factors) and their impact.

Pharmacokinetics (PK)

• Genetic variations affect drug metabolism and pathways for Absorption, Distribution, Metabolism, and Excretion (ADME).
• Differences in drug metabolism affect the amount of available drug in the body.

Pharmacodynamics (PD)

• Genetic variation can affect drug target effects, impacting receptors, ion channels, immune activity, enzymes, patient-to-patient drug response, and overall benefit-risk analysis.

Pharmacogenomics and Treatment

• Pharmacogenomics helps guide treatment by considering individual genetic variations for optimizing dosages for better patient outcomes.

Impact of Genetic Polymorphisms on enzymes

• Genetic variations in enzymes affect specific metabolic pathways.
• This impacts the type of active metabolites produced and the concentration of free drug in the body, changing the benefit-to-risk ratio.

Cytochrome P450 (CYP) Enzymes

• CYP enzymes are essential in drug metabolism; genetic variations create distinct patient classifications.
• Rapid metabolizers handle drugs quickly, while poor metabolizers process them slowly. Both cases could lead to undesirable outcomes.

Example: Codeine (Prodrug)

• Codeine is a prodrug; CYP enzymes convert it to morphine. Varying metabolism can lead to significant differences in outcome.

Example: S-Warfarin (Active Drug)

• Warfarin is an anticoagulant; variations in metabolism affect efficacy and risk of adverse bleeding.

Variability among patients

• Variations in single CYP enzymes can substantially alter the benefit-to-risk ratio. The presence of multiple enzymes and pathways poses challenges to precise prediction.

Clinical Guidelines and Resources

• CPIC (Clinical Pharmacogenetics Implementation Consortium) provides guidelines for incorporating pharmacogenomics into clinical practice.

Pharmacogenomics and Pharmacodynamics

• Less studied than PK, PD variations exist in gene, RNA, protein, receptor levels, and post-translational modifications.

Precision Medicine

• Includes personalized treatment strategies based on many factors, including genetics, environment, and lifestyle.