Pharmacology Key Concepts

Introduction to Pharmacology

• Focus is on identifying key terms and concepts.

Recording Format for Lectures

• Lectures are recorded using a Word document, available in both Word and PDF formats.
• This format ensures organization, readability, and ease of navigation.
• All lectures follow a template-based structure, keeping materials in one file.

Primary Sources for Learning

• Main resource is lecture notes, tailored to the course and synthesizing information from multiple sources.
• Notes are comprehensive and relevant for exams and applications.
• Supplementary textbook is Lippincott's Illustrated Reviews due to detailed figures, diagrams, organized content, and concise review format.
• An additional reference is "Pharmacotherapy: A Pathophysiologic Approach" although students aren't required to read it; it serves as a reference for lecture preparation, covering epidemiology, patient presentation, and treatment options.

Instructor's Experience with Resources

• Instructor has lectured from Kaplan materials for 22 years, served as editor for 10+ years, and worked as author for 18 years.
• Lectures are compiled from multiple authoritative sources.
• Students should primarily use lecture notes with Lippincott's as a secondary reference.

Therapeutic Importance of Drugs

• Millions of prescriptions are written yearly.
• The pharmaceutical industry includes 1,600 active ingredients and 40,000 product/delivery forms.
• There are 100,000 over-the-counter (OTC) products available.
• Though new drugs are introduced frequently, they are rarely pulled off the market.
• A website tracks drug recalls (Center for Drug Evaluation and Research - CDER).
• CDER also monitors novel drug approvals, analyzing trends in new medication releases.
• In 2016, 22 new drugs were approved and in 2018, a high of 59 new drugs were approved.
• Annually, roughly 35-40 new drugs are approved each year.

Navigating the "Therapeutic Jungle"

• Physicians must carefully select appropriate treatments due to the vast number of drugs available.
• Challenges differ by medical specialty where cardiologists focus on heart-related medications.
• Family practice physicians must handle diverse patient cases, requiring broad pharmacological knowledge.
• General practitioners face greater challenges due to a wider range of diseases and treatment options.

Importance of Staying Updated

• Physicians must stay well-versed in pharmacological principles for effective treatment.
• Learning about newly released drugs is essential for modern practice.
• Medications introduced while in medical school or residency will be prescribed.

Drug Names and Classification

• There are three types of drug names which include, Chemical, Generic and Trade names.
• Chemical Name: Scientific molecular structure designation like N-acetyl-p-aminophenol, this is not used in clinical practice.
• Generic Name: Assigned by the U.S. Adopted Name Council and is a universal recognition found on all drug labels
• Trade Name: Brand name assigned by the developing company that can have multiple trade names for the same generic drug.
• Chemical names are precise, but too lengthy and complicated for daily use.
• Generic names allow for standardization and ease of accurate prescribing.
• Trade names allow companies to differentiate drugs with similar active ingredients.

Focus of Drug Names in Class

• Students must focus on learning generic names and trade names will appear in lecture notes for completeness but will not be tested.
• Boards and exams exclusively test generic names.

Definitions of Key Terms

• Pharmacology is the study of drugs and drug receptors, including their mechanisms and effects.
• Medical pharmacology is the application of drugs for diagnosis, prevention, and treatment of disease.
• Toxicology is a pharmacology branch that studies harmful effects of drugs and chemicals. Toxicology investigates adverse drug effects, environmental pollutants, poisons, and chemical exposure risks.

Pharmacodynamics vs. Pharmacokinetics

• Pharmacodynamics is how the drug acts on the body, including drug binding to its receptor and influencing mechanism of action.
• This explains both therapeutic benefits and toxic effects of medications.
• Pharmacokinetics is how the body processes the drug.
• Absorption: The drug enters the bloodstream from the administration site.
• Distribution: The drug spreads throughout the body to reach target sites.
• Metabolism: The body chemically transforms the drug, mainly in the liver.
• Excretion: The drug leaves the body, primarily through kidneys (urine) or bile (feces).
• Drug elimination is achieved through either metabolism or direct excretion, ensuring system clearance.

Drug Naming Conventions

• Healthcare professionals should be familiar with generic names because multiple trade names may exist for a single generic drug.
• The generic name appears on all labels, allowing consistent identification and prescription.

Pharmacokinetics Focus

• Pharmacokinetics focuses on how the body processes drugs, including absorption, distribution, metabolism, and excretion.
• This is different from pharmacodynamics, which examines how drugs affect the body.

Pharmacodynamics Actions

• Pharmacodynamics describes the actions of a drug on the body, including binding to receptors and influencing mechanisms of action.
• It explains both the therapeutic and toxic effects of medications.

Clinical Trial Phases

• Phase 2 clinical trials test efficacy of a new drug for the first time in a small number of patients (100-300).
• This phase often utilizes a placebo group for comparison and is single-blinded, where only the physician knows whether the patient got the new drug or placebo.
• Preclinical studies are done prior to clinical trials using animal models of disease that last several years.
• Phase 1 trials test for safety in 20-80 healthy volunteers and cannot test for efficacy.
• Phase 3 trials test for efficacy and safety using a larger patient population than phase 2 (1000-3000 patients). These studies are often double-blinded.
• Phase 4 trials are post-marketing surveillance and commence after FDA approval to confirm efficacy and gather data on rare side effects.

Drug Development Process

• Step 1: Discovery and synthesis of a new molecule where scientists identify or create a potential therapeutic molecule and determine which biological pathway to modify.
• Step 2: In vitro studies (laboratory testing) which helps determine the drug’s potential effectiveness and establishes safe starting doses for further testing.
• Step 3: Pre-clinical animal testing evaluates the drug’s toxicity, absorption, metabolism, and excretion and tests ensures long-term safety and effectiveness.

Clinical Trial Phases for Drug Development

• Phase 1 (Safety & Pharmacokinetics): Tests drug safety and pharmacokinetics with ~50 healthy volunteers.
• Since participants are healthy, researchers only monitor side effects rather than measure therapeutic benefits.
• Phase 2 (Scheduling & Response Measurement): Evaluates optimal drug scheduling and begins measuring drug efficacy in actual patients.
• The participants include are ~200 patients diagnosed with the condition being treated with many drugs failing at this stage.
• Phase 3 (Double-Blind Study Against Placebo): Conducts double-blind trials, comparing drug effectiveness with existing treatments or placebo. Participants include ~2,000 patients with Safety, dosing, and long-term effects across a broader patient group.
• Phase 4 (Post-Marketing Surveillance): Monitors long-term safety, effectiveness, and rare side effects in a real-world population including thousands or millions of patients.
• Some side effects only emerge in large populations, which earlier phases cannot detect due to limited sample sizes.

Pregnancy & Lactation Labeling Rule

• This was introduced in 2015 and has narrative-based descriptions on drug safety for pregnancy and breastfeeding.
• It includes effects on pregnancy, labor, delivery, lactation impact, and risks related to reproductive potential.

Older Pregnancy Categories (1979-2015)

• Category A - Safest (no known risk in human studies).
• Category B - Generally safe (animal studies show no risk, but human data is lacking).
• Category C - Unknown risk (limited studies; risk cannot be ruled out).
• Category D - Positive evidence of risk, but benefits may outweigh risks (used only if absolutely necessary).
• Category X - Contraindicated (clear fetal risk; strictly avoided in pregnancy).

Teratogenic Drugs (Category D & X)

• "D" Drugs have known teratogenic effects and must be Used only when benefits outweigh risks like life-threatening maternal conditions).
• "X" Drugs are strictly contraindicated and must never be used during pregnancy because they are known to cause severe fetal harm, even in small doses.

Current Pregnancy Labeling Approach

• Since 2015, all new drugs include narrative labeling instead of categories and Researchers track medication effects on pregnant patients using data from hospitals and patient reports.
• Because pregnant women do not typically enroll in drug trials, registry data is used to evaluate safety.
• Narrative Labeling includes dosing recommendations for pregnant patients and potential fetal risks based on case reports and observational studies.

Mitochondrial Inheritance

• Mitochondrial genome is maternally inherited and mitochondria are not passed on from the father—only from the mother during fertilization.
• Most genetic mutations affecting the electron transport chain are maternally inherited and each cell has many mitochondria.

Mitochondrial Genome

• Initially, each mitochondrion has multiple copies of the mitochondrial genome.
• Each cell has many copies of the mitochondrial genome.
• Heteroplasmy occurs occurs when variants in mitochondrial genes are not present in every copy of the mitochondrial genome within a cell.
• The proportion of mitochondria containing a variant is not consistent between cells within an individual and can vary between different affected individuals.
• This variability is a unique problem among mitochondrial diseases, where the severity of disease can vary from one person to the next.

Mitochondrial Myopathies Features

• Mitochondrial myopathies are diseases caused by dysfunctional mitochondria and tissues most affected by mitochondrial problems are those requiring the most cellular energy—primarily the brain, the eyes, and skeletal muscle.
• Symptoms include fatigue, myalgia, vision loss, ocular dysmotility, seizures, hearing loss, and impaired coordination and cognitive function.

3 Recognized Mitochondrial Disorders

• In MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes which increases blood acidity, leading to extreme fatigue and muscle weakness, difficulty breathing, abdominal pain, and vomiting.
• Stroke-like episodes result in hemiparesis (muscle weakness) and hemianopia (vision loss).
• In MERRF Syndrome; MERRF (Myoclonic Epilepsy with Ragged Red Fibers) one major distinguishing factor is myoclonic seizures.
• Genetic testing is the best method for distinguishing between MELAS and MERRF. The "ragged red fibers" are a key diagnostic feature of MERRF syndrome.
• In Leigh Syndrome which is similar to MELAS and MERRF. The most common presentation includes diarrhea, COVID-like symptoms, dysphagia, and developmental delays.
• Unique aspects of Leigh syndrome is that it can be caused by genetic variants in the nuclear genome where mutations in the mitochondrial genome found to be in 11 individuals while others had mutations in the nuclear genome.
• In Leber's Hereditary Optic Neuropathy ,which is relatively rare and primarily affects males. It causes optic neuron degeneration,leading to permanent vision loss.