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📚 Detailed Semester Preparation Notes

General Pharmacology IMT3003.3 - Lecture 1

History of Pharmacology, Drug Classifications, Drug Names and Sources

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COURSE OVERVIEW

• Subject: General Pharmacology IMT3003.3, Spring 2026
• Institution: Dai Nam University, Hanoi, Vietnam
• Lecturer: Dr. Thanh-Do Le (Ph.D. in drug-controlled release, Chosun University, South Korea, 2012)

1. Goodman & Gilman's The Pharmacological Basis of Therapeutics (Brunton, 2018) - Mandatory
2. Katzung's Basic & Clinical Pharmacology, 16th Edition (Vanderah, 2023) - Reference
3. Rang & Dale's Pharmacology (Ritter, 2023, Elsevier) - Reference

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LEARNING OBJECTIVES

1. Differentiate between the chemical name, generic name, and brand (trade) name of drugs
2. Identify the primary natural, semisynthetic, and synthetic sources of pharmacological agents
3. Categorize drugs into broad therapeutic and pharmacological classifications

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PART 1: HISTORY OF PHARMACOLOGY

1.1 Ancient Time - Egypt and Mesopotamia

• Disease prevention in early history was NOT based on science - it was tied to supernatural beliefs
• The Ebers Papyrus is the oldest known comprehensive medical document

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1.2 Ancient Time - Ancient China and India

• Herbal medicine has been practiced in nearly every culture throughout history
• Ayurveda established principles still used in traditional and integrative medicine today

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1.3 Ancient Time - Ancient Greece (Key Pioneers)

Hippocrates (4th century B.C.)

• Called the "Father of Medicine"
• Originated the Hippocratic Oath (still used today)
• Shifted medicine from supernatural to rational/observational

Theophrastus (372-287 B.C.)

• Contributed significantly to the early understanding of plant-based medicines
• Considered the "Father of Botany"

Rational medicine = treating disease based on natural causes and logic rather than magic or religion

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1.4 Ancient Time - Ancient Greece and Rome (Formalizing Knowledge)

Dioscorides (40-90 A.D.)

• Considered the "Father of Pharmacognosy"
• Wrote De Materia Medica in the 1st century - systematically categorized medicinal plants

Claudius Galenus (Galen, 131-201 A.D.)

• Pioneer of experimental physiology in Rome
• Created "galenic" preparations - extracting active principles from plants
• His preparations are the ancestor of modern pharmaceutical compounding

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1.5 Middle Ages (5th-15th Century)

• The Magna Carta of Pharmacy is particularly important - it established pharmacy as its own profession

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1.6 Early Modern Time - Paracelsus (1493-1541)

• "Father of Pharmacology"
• "Father of Toxicology"

1. Advocated using single drugs to treat individual diseases (NOT mixtures - revolutionary at the time)
2. Established the foundational concept: "Sola dosis facit venenum" = "The dose makes the poison"
   • ALL substances are potential poisons depending on their dosage
   • This is still a core principle of toxicology today

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1.7 Early Modern Time - 17th to 19th Century (Experimental Physiology)

William Harvey (17th century)

• English physiologist
• First explained the beneficial AND harmful effects of drugs
• Demonstrated intravenous (IV) drug administration for the first time
• The term "pharmacology" was first recorded during this era

François Magendie + Claude Bernard (late 18th - early 19th century)

• Developed methods of experimental physiology and pharmacology
• Laid the foundation for understanding how drugs work at organ and cellular levels

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1.8 Modern Time - Isolation of Active Principles (19th Century)

Active principles = the components of a substance that actually cause the medicinal effect

• The 19th century was when chemists moved from whole plant extracts to pure isolated compounds

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1.9 Modern Time - Birth of Pharmacology as a Discipline

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1.10 Modern Time - Chemotherapy and the Synthetic Era (End of 19th / Early 20th Century)

Felix Hoffman (1899)

• Developed Aspirin - called the "wonder drug"

Paul Ehrlich (1854-1915)

• Called the "Father of Chemotherapy"
• Discovered the first antibiotic compounds
• Introduced the concept: "Corpora non agunt nisi fixata" = "Drugs do not act unless they bind to targets"
• This established the concept of drug targets (receptors, enzymes, etc.) - foundational to modern pharmacology

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1.11 Modern Time - 20th Century Drug Milestones

• Industrialization brought: standardization, complex chemical synthesis, and biologically prepared products

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1.12 Modern Time - Pharmacokinetics

Torsten Teorell (1905-1992)

• "Father of Pharmacokinetics"
• Studied the distribution kinetics of substances in the body

Alfred J. Clark (by 1930)

• Advanced quantitative pharmacology and formal receptor concepts
• This era defined: optimal dosage ranges and therapeutic windows

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1.13 The Five Generations of Pharmacology

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1.14 Pharmacology History Timeline Summary (Pages 28, 29, 30)

• Page 28: Ancient era events (Babylonia, Egypt, China, India, Greece, Rome)
• Page 29: Middle Ages through 19th century (Baghdad pharmacies, Paracelsus, Harvey, Sertürner, quinine, Ehrlich, Aspirin)
• Page 30: 20th century to present (Insulin, Penicillin, antibiotics, pharmacokinetics, generations of pharmacology, precision medicine, AI)

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PART 2: DEFINITION OF A DRUG

Drug = a chemical substance of known structure, which, when administered to a living organism, produces a biological effect (by changing its structures or functions)

1. The substance must be administered (given intentionally)
   • Example: Insulin and thyroxine are endogenous hormones BUT become drugs when administered intentionally
2. A drug molecule typically interacts as an agonist / partial agonist (activator) or antagonist (inhibitor) with a specific target molecule, usually a receptor
3. Drugs have three names: chemical, generic, and brand
4. Drug sources: plants, animals, synthetic chemicals, or products of biotechnology (biopharmaceuticals)

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PART 3: DRUG CLASSIFICATION

Drug classification = organizing drugs into groups based on their properties, uses, or mechanisms

1. Formulations - how you take the medicine (administration route)
2. Therapeutic Use - what disease/symptoms the drug reduces or cures
3. Pharmacological Effect and Mechanism of Action - how the drug acts (more important for drug development)
4. Legal Status - levels of regulation
5. Sources and Chemical Structure - where the drug comes from and its structure (similar structures = similar effects)

Important: One drug can belong to different groups/categories depending on the classification system used

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3.1 Classification by Formulation (How Drug is Delivered)

• Oral (tablets, capsules, solutions) - most common
• Parenteral (IV, IM, SC) - bypasses GI tract
• Topical/Transdermal (creams, patches)
• Inhalation
• Rectal (suppositories)
• Sublingual/Buccal

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3.2 Classification by Therapeutic Use

Therapeutic classification = grouping drugs by their indication for specific diseases OR the biological changes they induce

• Very important for clinical practice
• Categories can be general (treating entire anatomical systems) or specific (treating specific conditions within a system)

Example: Cardiovascular System (Specific Classifications)

Many drugs have multiple therapeutic classifications based on different patient indications

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3.3 Classification by Pharmacological Mechanism

Pharmacologic classification = grouping drugs based on their specific mechanism of action at the cellular or molecular level

• Understanding a prototype drug allows professionals to predict the actions AND adverse effects of ALL other drugs in that pharmacologic class
• Very important for clinical practice AND research and development of medicines

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3.4 Legal Classification - Prescription Drugs

Prescription drugs (also called "legend drugs") = can ONLY be prescribed by legally authorized health practitioners for intended uses by appropriate patients

• Drug's name
• Dosage regimen
• Patient information
• Prescriber's authorization

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3.5 Legal Classification - The DEA Controlled Substances Schedules (U.S.)

• Potential for abuse
• Accepted medical use
• Safety and risk of dependence

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3.6 Legal Classification - Non-Prescription (OTC) Drugs

OTC (Over-the-Counter) drugs = can be bought and used WITHOUT a prescription, deemed safe if administration directions are followed

• Over 60 prescription medications have transitioned to OTC since the 1970s
• OTC drugs can still cause toxicity or interact with other substances - not completely without risk

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3.7 Legal Classification - Illicit Drugs

• Drugs that can be legally sold under certain circumstances but have been manufactured unlawfully, diverted, or stolen from normal distribution channels
• OR drugs that are not legal to be sold in specific nations
• Regulated by the Controlled Substances Act (CSA) and the DEA to prevent misuse, abuse, and illegal distribution

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PART 4: DRUG NAMES

4.1 The Three-Name System

Examples of Name Suffixes (Generic Names indicating class):

• "-cillin" = penicillin-type antibiotics (e.g., amoxicillin, ampicillin)
• "-olol" = beta-blockers (e.g., propranolol, metoprolol)
• "-statin" = HMG-CoA reductase inhibitors (e.g., atorvastatin, simvastatin)
• "-pril" = ACE inhibitors (e.g., lisinopril, enalapril)

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4.2 Drug Names in Practice (Page 48 Diagram)

• When prescribing by generic name, patients can receive ANY manufacturer's version (cheaper)
• When prescribing by brand name, only that specific manufacturer's product is dispensed
• Clinical question from the slide: "Which name of the same drug may you give to patients if you want them to have different choices?" - Answer: Generic name (allows substitution with equivalent products at potentially different price points)

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PART 5: SOURCES OF DRUGS

5.1 The Five Primary Drug Sources

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5.2 Plant Sources (Page 51 Diagram)

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5.3 Mineral Sources (Page 52 Diagram)

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5.4 Animal Sources (Page 53 Diagram)

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5.5 Biologics (Page 54 Diagram)

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QUICK-REFERENCE SUMMARY TABLE: KEY PEOPLE IN PHARMACOLOGY HISTORY

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EXAM-FOCUSED KEY CONCEPTS TO MEMORIZE

1. "Sola dosis facit venenum" = The dose makes the poison (Paracelsus) - applies to ALL substances
2. "Corpora non agunt nisi fixata" = Drugs do not act unless they bind to targets (Paul Ehrlich) - concept of drug targets/receptors
3. Ebers Papyrus (~1,500 B.C.) = 700+ remedies, most important ancient pharmaceutical record
4. Magna Carta of Pharmacy (1231-1240) = legally separated pharmacy from medicine
5. Prototype drug = knowing one drug in a class lets you predict all others in the class
6. Generic vs. Brand name: Generic = nonproprietary, multiple manufacturers; Brand = proprietary, one manufacturer
7. CSA Schedules I-V: Schedule I = no medical use (heroin); Schedule II = strict Rx (fentanyl, morphine); Schedule V = lowest risk
8. Five drug sources: plant, animal, mineral, synthetic, bio-engineered
9. One drug, multiple classifications - a single drug can fit into different classification categories
10. Active principles = the components of a substance that actually cause the medicinal effect

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📚 Detailed Semester Preparation Notes

General Pharmacology IMT3003.3 - Lecture 6

Drug Interactions and Adverse Drug Effects

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COURSE CONTEXT

• Subject: General Pharmacology IMT3003.3, Spring 2026
• Institution: Dai Nam University, Hanoi, Vietnam
• This lecture covers: Toxicology basics, drug biotransformation (metabolism), pharmacogenomics, and herb-drug interactions

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PAGE 3 - CONTENTS AND OBJECTIVES (Diagram Page)

1. Toxicology and Drug Toxicity - poisoning, dose-response, toxicokinetics, types of toxicity, treatment principles
2. Drug Biotransformation (Metabolism) - Phase I & II reactions, CYP450 system, enzyme induction/inhibition, metabolic toxicity
3. Pharmacogenomics & Herb-Drug Interactions - genetic polymorphisms, CYP2D6, CYP2C19, UGT1A1, herb interactions

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PART 1: INTRODUCTION TO TOXICOLOGY AND POISONING

Page 4 - Core Definitions

Key insight: A drug and a poison are not different things - the distinction lies in the dose and context (connects back to Paracelsus: "the dose makes the poison")

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Page 5 - Dose-Response Relationships (Diagram Page)

Two Types of Dose-Response Relationships:

• In a single individual, greater doses result in a greater magnitude of response
• The response increases proportionally with increasing dose
• Plotted as a continuous curve

• In a population, the percentage of affected individuals increases as the dose increases
• Used to determine population-level drug safety and toxicity thresholds
• Plotted as a sigmoidal (S-shaped) curve

Key Pharmacological Values Derived from Quantal Dose-Response:

• Left curve = therapeutic effect (ED₅₀ is lower)
• Right curve = lethal/toxic effect (LD₅₀/TD₅₀ is higher)
• The gap between the two curves = the therapeutic window
• The wider the gap, the safer the drug

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Page 6 - Pharmacokinetics vs. Toxicokinetics

How Poisoning Alters ADME:

• Absorption: May be prolonged (e.g., bezoar formation slows gastric emptying)
• Distribution: Altered protein binding (toxic doses can displace drug from protein binding sites)
• Metabolism: May be saturated or overwhelmed
• Elimination: May be impaired

Toxicokinetics = the pharmacokinetics of a drug under circumstances that produce toxicity or excessive exposure

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Page 7 - Aspirin Poisoning (Case Study in Toxicokinetics)

Aspirin Overdose - Toxicokinetic Changes vs. Therapeutic Dosing:

Enteric-Coated Aspirin in Overdose:

• Tablets can coalesce into bezoars (hardened masses) in the stomach
• Bezoars reduce effective surface area for absorption
• Can delay peak plasma concentrations by up to 35 hours (vs. 1-2 hours normally)
• Clinical implication: Patient may appear stable initially then deteriorate hours later

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Page 8 - Types of Therapeutic Drug Toxicity

The Spectrum from Therapeutic to Toxic:

• A drug typically produces numerous effects, but usually only one is sought (the therapeutic goal)
• Most other effects = undesirable effects for that specific indication

Three Categories of Drug Effects:

1. Primary (therapeutic) effect - the desired outcome
2. Side effects - usually bothersome but NOT harmful (e.g., dry mouth from antihistamines)
3. Toxic effects - harmful, undesirable effects that go beyond mere inconvenience

Side effects ≠ toxic effects. Side effects are predictable, usually dose-dependent. Toxic effects imply harm.

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Page 9 - Idiosyncratic Reactions and Pharmacogenetics

Genetic Basis of Idiosyncratic Reactions:

• Many interindividual differences in drug responses have a pharmacogenetic basis
• Caused by: genetic deficiencies in specific enzymes (e.g., CYP450 enzymes)

Classic Example - Isoniazid (TB Drug):

• NAT2 polymorphisms (N-acetyltransferase 2 gene) create a multimodal distribution of isoniazid acetylation and clearance
• Slow acetylators: higher plasma levels → peripheral neuropathy risk
• Fast acetylators: lower plasma levels → therapeutic failure risk

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Page 10 - Mechanisms of Drug-Drug Interactions

When Do Drug-Drug Interactions (DDIs) Occur?

• Patients commonly take multiple medications + OTC drugs + supplements
• Interactions can occur at multiple pharmacokinetic stages:

Drug-drug interactions are one of the most clinically important and preventable causes of adverse drug events

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Page 11 - Principles of Treatment of Poisoning

The Three Principles (in order of priority):

• Airway, Breathing, Circulation (ABCs)
• Without this, nothing else matters

• Reduce further entry of poison into the body
• Speed removal of what has already been absorbed
• Methods: activated charcoal, gastric lavage, forced diuresis, dialysis, urinary alkalinization

• Use specific antidotes
• Block the receptor or pathway where the toxin acts
• Examples: naloxone (opioid overdose), atropine (organophosphate poisoning), N-acetylcysteine (acetaminophen overdose)

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PART 2: DRUG BIOTRANSFORMATION (METABOLISM)

Page 12 - Introduction to Drug Biotransformation

Why Does Biotransformation Exist?

• Mammalian biotransformation systems evolved originally to detoxify plant and bacterial toxins
• These systems were later "co-opted" to process:
  • Modern therapeutic drugs
  • Environmental pollutants
  • Industrial chemicals

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Page 13 - Why Drug Metabolism is Necessary

The Problem with Lipophilic Drugs:

• Renal excretion works well for small, polar molecules
• But most pharmacologically active drugs are highly lipophilic
• Lipophilic drugs are reabsorbed by passive diffusion back through the nephron → can't be excreted efficiently

The Solution - Metabolism:

Metabolism converts lipophilic drugs into more hydrophilic (water-soluble) metabolites that can be renally excreted without tubular reabsorption

• Metabolism also terminates or alters the biological activity of these compounds

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Page 14 - Phase I Biotransformation Reactions

Phase I = modifying reactions - add or expose functional groups

What Happens:

• Convert the parent drug to a more polar metabolite by:
  • Introducing a functional group (-OH, -NH₂, -SH)
  • Unmasking a functional group (removing a protecting group)

Types of Phase I Reactions:

Outcomes of Phase I:

• Usually → inactive metabolite (detoxification)
• Sometimes → modified activity (reduced or changed)
• Sometimes → ENHANCED activity (prodrug activation) e.g., codeine → morphine
• If Phase I metabolite is sufficiently polar → directly excreted without Phase II

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Page 15 - Phase II Biotransformation Reactions

Phase II = conjugation reactions - attach large, polar molecules

What Happens:

• Phase I products that are NOT eliminated rapidly undergo conjugation with an endogenous substrate
• An endogenous molecule combines with the functional group from Phase I

Major Phase II Conjugation Reactions:

Outcome of Phase II:

• Produces highly polar metabolites
• Typically inactive
• Much more readily excreted from the body

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Page 16 - Sites of Drug Biotransformation

Primary Site: LIVER

• The liver is the principal organ of drug metabolism
• Contains the highest concentration of drug-metabolizing enzymes

Other Sites with Significant Activity:

Subcellular Locations of Drug-Metabolizing Enzymes:

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Page 17 - The First-Pass Effect

What Is It?

First-pass effect = extensive hepatic metabolism of an orally administered drug before it reaches systemic circulation

The Process:

1. Drug taken orally
2. Absorbed from small intestine
3. Transported via portal vein to the liver
4. Liver metabolizes a significant portion BEFORE it enters systemic blood
5. Reduced drug reaches the target tissues

Clinical Consequences:

• May drastically reduce bioavailability of oral drugs
• Example: Nitroglycerin has almost 100% first-pass metabolism orally → must be given sublingually
• Other examples: morphine, propranolol, lidocaine, verapamil

Why It Matters:

• Oral dose must be much HIGHER than IV dose to achieve same effect
• Alternative routes required for some drugs: sublingual, IV, transdermal, rectal

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Page 18 - Microsomal Mixed Function Oxidase (MFO) System

Location:

• Located in the lipophilic endoplasmic reticulum membranes of the liver
• When isolated, these membranes form vesicles called microsomes

What Are MFOs / Monooxygenases?

• Enzymes that require two substrates simultaneously (hence "mixed function"):
  1. The drug (substrate to be oxidized)
  2. Molecular oxygen (O₂)
• Also require a reducing agent: NADPH (electron donor)

Overall Reaction:

Drug (RH) + O₂ + NADPH + H⁺ → Drug-OH (ROH) + H₂O + NADP⁺

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Page 19 - The Cytochrome P450 (CYP450) Cycle

Key Facts:

• CYP450 = the terminal oxidase component of the microsomal electron transport system
• Named for their characteristic absorption at 450 nm when complexed with carbon monoxide

The Reaction:

In a typical CYP450 reaction:

• One molecule of O₂ is consumed per substrate molecule
• One oxygen atom → incorporated into the product (hydroxylated drug)
• One oxygen atom → forms water (H₂O)

Why CYP450 Is So Versatile:

• The "potent oxidizing properties of activated oxygen" allow oxidation of a massive number of structurally unrelated lipophilic drugs
• CYP450 is non-specific enough to handle hundreds of different chemicals

The CYP450 Catalytic Cycle (Simplified Steps):

1. Drug (RH) binds to oxidized CYP450 (Fe³⁺)
2. First electron donated (from NADPH via cytochrome P450 reductase)
3. O₂ binds to the reduced complex
4. Second electron donated
5. O-O bond cleaved; active oxygen species formed
6. Oxygen inserted into drug substrate → hydroxylated product (R-OH) released
7. CYP450 returns to oxidized state (Fe³⁺)

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Page 20 - CYP450 Enzyme Families and Specificity

Organization:

• CYP450 genes are arranged in gene families and subfamilies based on similarities in amino acid sequences
• The human CYP450 superfamily consists of 57 functional genes

The Most Important Drug-Metabolizing Families:

Families 1, 2, and 3 (CYP1, CYP2, CYP3) are responsible for oxidizing over 80% of all drugs

Common Structural Feature of CYP450 Substrates:

• High lipid solubility (lipophilicity) is the primary common feature
• This is why CYP450 can process such diverse chemicals

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Page 21 - Induction of CYP450 Enzymes

Enzyme induction = increased synthesis of CYP450 enzymes caused by certain drugs/substances → accelerated drug metabolism

Common CYP450 Inducers:

Consequence of Induction:

• Repeated use → more enzyme → faster metabolism of the substrate drug (and other co-administered drugs)
• Results in pharmacokinetic tolerance: the drug works less and less over time because it is cleared faster
• Also causes failure of co-administered drugs (e.g., rifampin reduces effectiveness of oral contraceptives)

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Page 22 - Mechanisms of Enzyme Induction

How Do Inducers Work?

• They bind to and activate intracellular receptors or transcription factors
• These receptors then increase gene transcription of CYP450 enzymes

Two Key Nuclear Receptors:

Remember: PXR and CAR are the two master regulators of drug metabolism enzyme induction

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Page 23 - Inhibition of CYP450 Enzymes

Enzyme inhibition = reduced CYP450 activity → slower metabolism → higher drug concentrations → potential toxicity

Types of Inhibition:

Where Inhibition Can Occur:

• At substrate attachment sites
• At oxygen binding sites
• At the level of substrate oxidation

Clinical Consequence:

When two drugs are given together and one inhibits CYP450:

• The more slowly metabolized drug accumulates to toxic levels
• Potentiates toxic effects

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Page 24 - Substrate-Mediated Enzyme Inactivation (Suicide Inhibition)

What Is Suicide Inhibition?

Some substrates are metabolized by CYP450 into a reactive intermediate that then covalently binds and permanently destroys the enzyme - the enzyme "commits suicide" in metabolizing this substrate

Mechanism:

1. Drug enters the CYP450 active site
2. CYP450 begins to metabolize it → generates a reactive intermediate
3. The reactive intermediate covalently binds to either the heme moiety or the protein component of CYP450
4. Enzyme is permanently inactivated
5. New CYP450 protein must be synthesized to replace it (takes days)

Most Clinically Important Example:

Grapefruit juice contains furanocoumarins that act as suicide inhibitors

• Irreversibly inactivate intestinal CYP3A4
• Effect lasts for days (until new CYP3A4 is synthesized)
• Drastically alters drug bioavailability of ~85 drugs (felodipine, simvastatin, cyclosporine, etc.)
• Even one glass of grapefruit juice can significantly increase plasma concentrations of susceptible drugs

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Page 25 - Metabolism to Toxic Products

When Metabolism Causes Harm:

Drug metabolism is NOT always detoxification - it can generate reactive intermediates that are toxic

How Toxic Metabolites Cause Damage:

1. High doses overwhelm normal detoxification mechanisms
2. Endogenous protective molecules like glutathione become exhausted/depleted
3. Without glutathione to neutralize reactive metabolites:
   • Reactive intermediates bind to cellular proteins (nucleophiles)
   • Causes: direct cellular damage or carcinogenesis

Key Concept - Reactive Intermediates:

• Are highly electrophilic (electron-seeking)
• Attack cellular nucleophiles: DNA, proteins, lipids
• Results: cell death, organ damage, mutations

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Page 26 - Acetaminophen Hepatotoxicity (Most Important Clinical Example)

Normal Therapeutic Dosing (Safe):

Acetaminophen → 90% → Glucuronidation (Phase II) → Safe, excreted in urine
                    → Sulfation (Phase II) → Safe, excreted in urine
                    → 5% → CYP2E1/CYP3A4 → NAPQI → neutralized by glutathione → Safe

In Overdose (Toxic):

Acetaminophen → Glucuronidation + Sulfation pathways SATURATED
              → CYP-dependent pathway takes over → NAPQI produced in EXCESS
              → Hepatic glutathione DEPLETED
              → NAPQI binds to liver cell proteins → HEPATOCELLULAR NECROSIS → LIVER FAILURE

This is THE classic example of metabolism-induced organ toxicity. Acetaminophen is safe at therapeutic doses (< 4g/day in healthy adults) but deadly in overdose or in patients with depleted glutathione (alcoholics, malnourished patients).

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Page 27 - Phase II: UGT Enzymes (Glucuronidation)

UGT = Uridine 5'-diphospho-glucuronosyltransferase

Why UGTs Are Important:

• Glucuronidation is the most common Phase II reaction
• Converts lipophilic molecules into highly polar, water-soluble conjugates
• Responsible for bilirubin metabolism - defects → jaundice (e.g., Gilbert syndrome, Crigler-Najjar)

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Page 28 - Other Phase II Conjugation Enzymes

GSTs are the body's frontline defense against reactive electrophiles - when glutathione is exhausted (as in acetaminophen overdose), damage occurs

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Page 29 - Role of Transporter Proteins

Transporters fundamentally control the excretion of drugs and their metabolites across cellular barriers

Two Key Transport Systems:

P-gp (P-glycoprotein) Clinical Significance:

• Acts as a drug efflux pump - pumps drugs OUT of cells
• Protects the brain from toxic substances (BBB)
• Also responsible for multidrug resistance (MDR) in cancer cells
• Can be inhibited by certain drugs → ↑ drug absorption/CNS penetration

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PART 3: PHARMACOGENOMICS

Page 30 - Introduction to Pharmacogenomics

What Pharmacogenomics Studies:

• Genetic variants in:
  1. Drug-metabolizing enzymes (CYP450, UGTs, NATs)
  2. Drug transporter proteins
  3. Drug target receptors
• These variants predict: therapeutic outcomes AND adverse drug outcomes

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Page 31 - Genetic Polymorphisms in Drug Metabolism

How Polymorphisms Affect Drug Metabolism:

• Mutations can alter the expression (how much enzyme is made) OR
• Alter the functional activity (how well the enzyme works)
• Affects Phase I and Phase II enzymes

Clinical Impact:

• Frequently requires dose adjustments
• Especially critical for drugs with narrow therapeutic indices (small difference between therapeutic and toxic dose)
• Examples: warfarin, phenytoin, digoxin, cyclosporine

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Page 32 - Phenotypes of CYP450 Polymorphisms (Table/Diagram Page)

This is the most testable table in this section - know all four phenotypes, their genetic basis, and clinical consequences

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Page 33 - CYP2D6 Genetic Variations

Key Facts About CYP2D6:

• Responsible for metabolizing up to one-quarter (25%) of all clinical drugs
• Gene is highly polymorphic - over 100 defined alleles
• Causes massive phenotypic variability across ethnicities

Ethnic Differences:

Drugs Metabolized by CYP2D6:

• Beta-blockers (metoprolol, propranolol)
• Antidepressants (fluoxetine, paroxetine, tricyclics)
• Opioids (codeine, tramadol)
• Antipsychotics (haloperidol, risperidone)

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Page 34 - Clinical Consequences of CYP2D6 Polymorphisms

Three Critical Clinical Scenarios:

• Standard doses of antidepressants → fail to achieve therapeutic plasma levels
• Drug is metabolized too fast
• Requires higher dosages to achieve effect

• Codeine is a prodrug → must be converted to active morphine by CYP2D6
• In UMs: codeine → morphine conversion is much faster and more complete
• Results: severe adverse effects including fatal respiratory depression
• Real cases reported in children given post-tonsillectomy codeine

• Tamoxifen is a prodrug → activated to endoxifen by CYP2D6
• In PMs: impaired activation of tamoxifen → less active endoxifen
• Result: drastically increased risk of breast cancer relapse
• Clinical guideline: consider CYP2D6 testing before prescribing tamoxifen

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Page 35 - CYP2C19 Genetic Variations

Key Facts:

• Preferentially metabolizes acidic drugs
• Important substrates: Proton-pump inhibitors (PPIs), antidepressants, antiplatelet agents (clopidogrel)

Ethnic Differences:

Clinical Example - Mephenytoin (Anticonvulsant):

• PMs exhibit profound toxicity from standard doses
• Due to total lack of stereospecific hydroxylase activity
• Drug accumulates to toxic levels

Other Clinical Implications:

• Clopidogrel (antiplatelet): Prodrug activated by CYP2C19 → PMs fail to respond → increased cardiovascular events
• PPIs (omeprazole): PMs have higher plasma levels → better acid suppression (this is one case where being a PM is clinically beneficial!)

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Page 36 - UGT1A1 Polymorphisms and Gilbert Syndrome

The UGT1A1*28 Allele:

• Features an extra TA repeat in the promoter region
• Extra TA repeat → reduces expression of UGT1A1 enzyme → less glucuronidation

Gilbert Syndrome:

Drug Interaction Risk:

• Patients with Gilbert syndrome have significantly increased risk for adverse drug reactions
• Particularly with drugs that are glucuronidated by UGT1A1
• Important example: Irinotecan (cancer chemotherapy) - active metabolite (SN-38) is glucuronidated by UGT1A1 → PMs have toxic SN-38 accumulation → severe diarrhea and bone marrow suppression

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Page 37 - Polygenic Effects on Drug Response (Warfarin)

Individual differences in clinical outcomes are often better explained by multiple genes together (polygenic influences)

Warfarin - The Classic Polygenic Example:

• Warfarin dosing is influenced by two key genes:

Clinical Impact:

• Standard dosing of warfarin using only body weight/age = empirical, inaccurate
• Gene-based dosing algorithms incorporating both CYP2C9 AND VKORC1 polymorphisms:
  • Clearly outperform traditional empiric dosing
  • FDA has updated warfarin labeling to encourage genetic testing
  • Reduces bleeding events and time to stable INR

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Page 38 - Pharmacogenomics and Hypersensitivity (HLA Testing)

HLA (Human Leukocyte Antigen) Polymorphisms:

• Genetic polymorphisms in HLA loci are strongly associated with predisposition to severe drug-induced hypersensitivity reactions (immune-mediated)

Most Important Clinical Example: Abacavir

This example shows how pharmacogenomics can be used PROACTIVELY to prevent life-threatening reactions before they occur

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PART 4: HERB-DRUG INTERACTIONS (HDI)

Page 39 - Introduction to Herb-Drug Interactions

The Problem:

• Herbal medicines are widely used globally
• Popular misconception: "natural" = safe
• Reality: Co-consumption of herbal medicines WITH prescription drugs often leads to clinically significant interactions

Types of HDI Outcomes:

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Page 40 - Mechanisms of Herb-Drug Interactions

Two Main Mechanisms:

• Herbs alter ADME of the co-administered drug
• Herbs contain complex secondary metabolites that act as:
  • Substrates (compete with drug for the same enzyme)
  • Inducers (increase enzyme expression → faster drug clearance)
  • Inhibitors (block enzyme → drug accumulates)
• Directly affects: maximum plasma concentration (Cmax), half-life (t½), duration of drug action

• Herbs interact at the receptor or physiological level
• Additive or synergistic effects without metabolic changes

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Page 41 - St. John's Wort Interactions (CRITICAL)

St. John's Wort (Hypericum perforatum):

• Popular herbal antidepressant
• Very potent CYP inducer - this makes it extremely dangerous in combination therapies

Critical Drug Interactions with St. John's Wort:

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Page 42 - Ginkgo Biloba and Garlic Interactions

Ginkgo Biloba:

• Contains ginkgolides (terpenoids) and flavonoids
• Pharmacodynamic interaction: Inhibits platelet aggregation
• When combined with warfarin: Drastically increases risk of severe bleeding
• Also combined with trazodone → severe CNS depression (page 46)

Garlic (Allium sativum):

• Active phytoconstituents alter both pharmacodynamics and pharmacokinetics

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Page 43 - Other Notable Herb-Drug Interactions

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Page 44 - Herbs That Inhibit CYP450

Not all herbs induce metabolism - many act as direct inhibitors of CYP450

Clinical Significance:

• Goldenseal + drugs metabolized by CYP3A4/2D6 (e.g., many antidepressants, antifungals, HIV drugs) → drug accumulation → toxicity
• These interactions are OPPOSITE to St. John's Wort (inhibition vs. induction)

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Page 45 - Herb-Induced Hepatotoxicity

Drug-Induced Liver Injury (DILI) from Herbs:

• Can occur via two mechanisms:
  1. Intrinsic toxicity of the herb itself
  2. Disruption of liver enzymes via HDI (metabolic interactions lead to toxic drug or herb metabolite accumulation)

Clinical Challenges:

• Over-diagnosis OR misdiagnosis is common
• Reason: Lack of clinical pharmacokinetic data for botanicals
• Patients often don't report herbal use

Critical Example - Danshen:

• Danshen (Salvia miltiorrhiza) + traditional medications
• Has provoked acute hepatitis and liver necrosis requiring liver transplantation
• Active compounds in Danshen inhibit CYP450 and alter the metabolism of co-administered drugs

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Page 46 - Pharmacodynamic Herb-Drug Interactions

Beyond enzyme effects - herbs can interact at the receptor or physiological level

Why This Is Important:

• Pharmacodynamic interactions occur even without changes in drug plasma concentration
• Standard blood level monitoring will appear normal but the patient is still at risk
• Clinicians must ask about herbal supplement use ROUTINELY

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Page 47 - Challenges in Monitoring Herb-Drug Interactions

Three Major Challenges:

Clinical Implication:

Clinicians MUST proactively ask all patients about herbal and supplement use as part of medication history

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Page 48 - Future Directions in Pharmacology and Safety

Three Key Future Directions:

1. Genome-Wide Association Studies (GWAS)
   • Will continue uncovering novel polygenic determinants of drug toxicity
   • Moving beyond single-gene to multi-gene analysis
2. Predictive Clinical Algorithms
   • Will incorporate:
     • Genetic biomarkers
     • Comorbidities
     • Known herb-drug interactions
   • AI-assisted drug dosing and safety prediction
3. Advancing Precision Medicine
   • Goal: Maximize therapeutic efficacy + minimize fatal adverse drug events
   • Individual genetic profiling before prescribing
   • Continuously updated drug safety databases

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COMPLETE SUMMARY TABLES FOR EXAM

Summary Table 1: CYP450 Inducers vs. Inhibitors

Summary Table 2: Pharmacogenomics Key Points

Summary Table 3: Herb-Drug Interactions Quick Reference

Summary Table 4: Phase I vs. Phase II Metabolism

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KEY MNEMONICS AND EXAM TIPS

1. "First pass = portal pass" - oral drugs go portal vein → liver BEFORE systemic circulation
2. "Grapefruit = gut killer" - furanocoumarins suicide-inhibit intestinal CYP3A4 → ↑ drug bioavailability
3. "St. John's Wort Wrecks Transplants" - CYP3A4 inducer → kills cyclosporine levels → organ rejection
4. CYP2D6 = Quarter of all drugs - 25% of all clinical drugs; codeine danger in UMs
5. "NAPQI needs NAC" - acetaminophen overdose → NAPQI toxicity → treat with N-acetylcysteine
6. Phenotypes: PM-IM-EM-UM - Poor/Intermediate/Extensive/Ultrarapid Metabolizers
7. "ABC pumps ABC drugs out" - P-glycoprotein (ABC transporter) = efflux pump = drug resistance
8. Gilbert = 10% Europeans - extra TA in UGT1A1 promoter → unconjugated bilirubin ↑ → irinotecan toxicity

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📚 Detailed Semester Preparation Notes

General Pharmacology IMT3003.3 - Lecture 5

Pharmacogenomics and Drug Toxicity: How an Individual's Genome Affects Drug Metabolism

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LECTURE OVERVIEW (Page 2)

1. Definitions and concepts of pharmacogenetics vs. pharmacogenomics
2. Types of genetic variants (SNPs, indels, CNVs)
3. Haplotypes and population diversity
4. Study designs (candidate gene vs. GWAS)
5. Phase I enzymes: CYP2D6, CYP2C19, CYP2C9, CYP2B6, DPD
6. Phase II enzymes: UGT1A1, TPMT
7. Other enzymes: G6PD
8. Transporter proteins: OATP1B1, BCRP
9. HLA-mediated drug hypersensitivity
10. Epigenomics and future directions

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PART 1: DEFINITIONS AND FOUNDATIONAL CONCEPTS

Page 3 - Definition of Pharmacogenetics

Pharmacogenetics = "one gene → one drug response" - focuses on single gene effects on drug behavior in individuals

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Page 4 - Definition of Pharmacogenomics

Pharmacogenetics vs. Pharmacogenomics:

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Page 5 - Variability in Drug Response

Two Drivers of Variable Drug Response:

• Patient diet (e.g., grapefruit juice, high-fat meals)
• Advanced age (altered metabolism, renal function)
• Drug interactions (CYP450 induction/inhibition)

• Directly alter target protein amino acid sequences
• Alter cellular levels of drug-metabolizing enzymes

The Three Categories of Key Genes in Drug Action:

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Page 6 - Monogenic vs. Multigenic Traits

Single genetic variants with massive clinical effect sizes are extremely rare - most drug response variation involves multiple genes interacting

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Page 7 - Phenotype-Driven Terminology

Clinical Importance:

• Many pharmacogenetic traits (CYP2D6 poor metabolizer, TPMT deficiency) are autosomal recessive
• Compound heterozygotes can have the same clinical phenotype as homozygous-null patients but through different mutations

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Page 8 - Codominance in Drug Metabolism

Why Codominance Matters in Pharmacogenomics:

• Heterozygotes demonstrate enzymatic phenotypes quantitatively intermediate to major (normal) and variant (null) homozygotes
• This creates the intermediate metabolizer (IM) phenotype
• Many polymorphic metabolic traits exhibit codominance

The Three-Point Spectrum (Monogenic Example):

Homozygous normal (EM)  >  Heterozygous (IM)  >  Homozygous variant (PM)
    Full enzyme activity     Reduced activity       No/minimal activity

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PART 2: TYPES OF GENETIC VARIANTS

Page 9 - Three Major Types of Genetic Variants

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Page 10 - Single-Nucleotide Polymorphisms (SNPs)

Key Facts:

• Each individual typically possesses more than 10 million distinct variant genome sites
• Occur throughout coding AND noncoding genomic regions
• By definition: allele frequency > 1% in the population (if < 1% = rare variant, not a polymorphism)

SNPs in Coding Regions:

SNPs in Noncoding Regions:

The vast majority of human DNA is noncoding - and SNPs in these regions significantly affect gene transcription levels (how much enzyme is made)

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Page 11 - Insertions and Deletions (Indels) / Copy Number Variations (CNVs)

Indels:

Copy Number Variations (CNVs):

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Page 12 - Haplotypes and Linkage Disequilibrium

Haplotypes:

Example: CYP2C19*2 is a haplotype defined by a specific combination of variants on chromosome 10

Linkage Disequilibrium (LD):

Why LD Matters:

• Allows us to genotype one SNP and infer the genotype of other nearby SNPs
• Forms the basis of haplotype-based genotyping arrays (cheaper than sequencing every base)
• Enables GWAS studies to work efficiently

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Page 13 - Ancestral Diversity in Pharmacogenomics

Three Key Principles:

1. Cosmopolitan polymorphisms - exist across ALL established global human ethnic groups (universal)
2. Ancestry-specific polymorphisms - reflect historical geographic isolation of specific human populations (found only in certain ethnicities)
3. African descent populations continuously display the highest specific polymorphism prevalence overall

Why This Matters Clinically:

• Drug response differences between ethnic groups are partly genetic
• Dosing guidelines developed in one population may not apply universally
• Examples:
  • CYP2D6 UM rates higher in African/Middle Eastern populations
  • CYP2C19 PM rates significantly higher in Asian populations (~16%)
  • G6PD deficiency more prevalent in malaria-endemic regions (Africa, Mediterranean, Middle East, Asia)

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PART 3: STUDY DESIGNS IN PHARMACOGENOMICS

Page 14 - Pharmacogenetic Study Design Principles

1. Consider diverse genetic backgrounds and potential environmental patient confounders (age, diet, co-medications)
2. Analyze continuous clinical traits representing both beneficial AND adverse drug effects
3. Measure biological endophenotypes (isolated intermediate biological measurements) separate from the complex whole patient

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Page 15 - Genotyping Quality Control

Hardy-Weinberg Equilibrium:

• In a population not under selection, allele frequencies remain stable across generations
• Deviation from HWE in a study sample = red flag for genotyping error or systematic bias

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Page 16 - Candidate Gene Approaches vs. Genome-Wide Association Studies (GWAS)

GWAS has revolutionized pharmacogenomics by discovering unexpected gene-drug associations that candidate gene studies would never have found

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Page 17 - Functional Studies of Polymorphisms

Computational prediction alone is insufficient - all predicted functional variants must be experimentally validated

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PART 4: PHASE I DRUG-METABOLIZING ENZYMES AND PHARMACOGENOMICS

Page 18 - Phase I Enzymes Overview

Phase I = "modify with small residues" (introduce -OH, -NH₂, -SH groups via oxidation, reduction, hydrolysis)

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Page 19 - Cytochrome P450 2D6 (CYP2D6) - Introduction

Key Facts:

Most Important CYP2D6 Alleles:

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Page 20 - CYP2D6 Clinical Phenotypes

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Page 21 - CYP2D6 and Codeine Administration (Critical Clinical Example)

The Codeine Pathway:

Codeine (PRODRUG - inactive) → CYP2D6 → Morphine (ACTIVE - analgesic)
                                            ↓
                              Opioid receptors → Pain relief

Clinical Consequences by Phenotype:

Real-World Tragedy - The UM/Codeine Problem:

• Multiple deaths reported in children given codeine for pain relief after tonsillectomy
• Children who were UMs received "normal" doses but developed fatal respiratory depression
• FDA and WHO have now issued warnings and restrictions on codeine in children
• CYP2D6 phenotyping/genotyping before codeine prescription is recommended by clinical pharmacogenomics guidelines (CPIC)

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Page 22 - Cytochrome P450 2C19 (CYP2C19)

Key Facts:

Key CYP2C19 Alleles:

PM Prevalence by Ethnicity:

• Asians: ~16% are PMs
• Europeans: ~2-5% are PMs
• Africans: ~2-5% are PMs

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Page 23 - CYP2C19 and Clopidogrel Efficacy (Critical Clinical Example)

The Clopidogrel Pathway:

Clopidogrel (PRODRUG - inactive) 
    → CYP2C19 (two sequential oxidations)
    → Active thiol metabolite (antiplatelet agent)
    → Inhibits platelet ADP receptor (P2Y12)
    → Prevents platelet aggregation
    → Protects against stent thrombosis

Clinical Consequences:

Clinical Guideline:

• FDA Black Box Warning on Clopidogrel: Poor metabolizers have reduced effectiveness
• CPIC guidelines recommend:
  • For CYP2C19 PMs and IMs: use alternative antiplatelet agents (prasugrel or ticagrelor - not CYP2C19-dependent)
  • For EMs: standard clopidogrel dose is appropriate

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Page 24 - Cytochrome P450 2C9 (CYP2C9)

Key Facts:

Variant Details:

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Page 25 - CYP2C9 and Warfarin Dosing

The Problem:

• Functional deficits decrease the metabolic clearance of active S-warfarin
• S-warfarin is 5 times more potent than R-warfarin as an anticoagulant

Clinical Consequences:

• Untested variant carriers face considerably elevated risk of massive clinical bleeding
• CYP2C9 works together with VKORC1 (warfarin's target enzyme) to determine warfarin dose
• Gene-based warfarin dosing (incorporating CYP2C9 + VKORC1 + age + body weight) is clinically validated and superior to empiric dosing

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Page 26 - Cytochrome P450 2B6 (CYP2B6)

Key Facts:

Most Important CYP2B6 Allele:

• *6 allele (516G>T + 785A>G) - the most common reduced/nonfunctional allele
• Much higher frequency in Sub-Saharan African populations (~50% allele frequency)

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Page 27 - CYP2B6 and Efavirenz Toxicity

Efavirenz Pharmacokinetics:

• Efavirenz (HIV non-nucleoside reverse transcriptase inhibitor - NNRTI)
• Metabolized primarily by CYP2B6 to its inactive metabolite
• Unique property: Normal chronic administration induces CYP2B6 → autoinduction → progressively faster self-metabolism

Clinical Consequences by Phenotype:

Ethnic Relevance:

• CYP2B6*6 PM phenotype is especially prevalent in African patients
• Many early HIV treatment programs had disproportionately high efavirenz-related psychiatric adverse events in African populations
• Supports pharmacogenomics-guided efavirenz dosing in high-prevalence populations

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Page 28 - Dihydropyrimidine Dehydrogenase (DPD) - Gene: DPYD

Key Facts:

Key DPYD Alleles:

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Page 29 - DPD and Fluoropyrimidine Chemotherapy (Critical Oncology Example)

Fluoropyrimidines (5-FU, Capecitabine):

• Mechanism: Target dividing cells → terminate cancerous DNA replication
• Used for: Colorectal, breast, head/neck, gastric cancers
• Elimination: ~80% of 5-FU is catabolized by DPD in the liver

The DPD Deficiency Problem:

5-Fluorouracil (5-FU)
    ↓ DPD (normal)
    → Inactive metabolites → safely excreted
    
5-Fluorouracil in DPD-deficient patient
    → DPD catabolism OBLITERATED
    → 5-FU accumulates at toxic levels
    → Attacks bone marrow (rapidly dividing cells)
    → SEVERE LIFE-THREATENING BONE MARROW TOXICITY
    → Also: severe mucositis, diarrhea, neurotoxicity, death

Regulatory Action:

• EMA (European Medicines Agency): Mandates DPD (DPYD) testing before initiating fluoropyrimidine chemotherapy
• Patients with complete DPD deficiency should NOT receive 5-FU or capecitabine
• Heterozygous DPD-deficient patients require dose reductions (50% starting dose)

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PART 5: PHASE II DRUG-METABOLIZING ENZYMES

Page 30 - Phase II Enzymes Overview

Phase II = "Detox" - conjugation reactions that make drugs safer and more excretable

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Page 31 - UGT1A1 (Uridine Diphosphoglucuronosyl Transferase)

Key Facts:

The UGT1A1*28 Allele:

Normal promoter:    (TA)₆TAA
*28 allele:         (TA)₇TAA  ← ONE extra TA repeat

• Extra TA repeat → reduces UGT1A1 transcription → less enzyme produced
• Homozygous *28/*28 = ~30-70% reduction in UGT1A1 activity

Gilbert Syndrome (UGT1A1*28 Homozygous):

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Page 32 - UGT1A1 and Irinotecan Toxicity (Critical Oncology Example)

Irinotecan (CPT-11):

• Drug type: Topoisomerase I inhibitor PRODRUG
• Indication: Metastatic colorectal cancer (primarily)

The Irinotecan Metabolic Pathway:

Irinotecan (CPT-11, prodrug)
    ↓ Carboxylesterase (activation)
    → SN-38 (ACTIVE, CYTOTOXIC metabolite)
    ↓ UGT1A1 (inactivation - "Detox")
    → SN-38-G (SN-38 glucuronide - INACTIVE)
    → Excreted in bile/urine (safe)

UGT1A1 Polymorphism Effect on Irinotecan:

UGT1A1 *28/*28 (Gilbert syndrome)
    → Reduced UGT1A1 activity
    → SN-38 NOT adequately conjugated
    → SN-38 accumulates to toxic levels
    → SEVERE LIFE-THREATENING NEUTROPENIA (bone marrow suppression)
    → Also: severe diarrhea (SN-38 is directly toxic to gut mucosa)

Genotype-Phenotype Relationship for Irinotecan:

FDA has updated irinotecan labeling to inform prescribers of UGT1A1*28 impact

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Page 33 - Thiopurine S-Methyltransferase (TPMT) and Thiopurine Drugs

TPMT:

Thiopurine Drugs:

The Thiopurine Metabolic Pathway:

6-MP / Azathioprine (Thiopurine prodrug)
    ↓ Activated
    → 6-Thioguanine nucleotides (TGNs) - ACTIVE, TOXIC
    ↓ TPMT (inactivation)
    → Methylthioinosine nucleotides (MTGNs) - INACTIVE, safe
    → Excreted

TPMT Deficiency Clinical Consequences:

Active TGNs:

• Cause severe dose-dependent bone marrow suppression (neutropenia, thrombocytopenia, anemia)
• Inactivation by TPMT successfully reduces potentially lethal cytotoxic intracellular metabolite exposure

TPMT genotyping/phenotyping before thiopurine therapy is standard clinical practice in many countries

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PART 6: OTHER IMPORTANT ENZYMES

Page 34 - Glucose-6-Phosphate Dehydrogenase (G6PD)

Key Facts:

Why X-Linked Matters:

• Males (XY): Only one X chromosome → if they carry the variant, they are hemizygous and fully express the deficiency
• Females (XX): Can be carriers (heterozygous) with intermediate phenotype, or homozygous deficient

Why Common in Malaria-Endemic Regions?

• Evolutionary protection: G6PD deficiency offers some protection against Plasmodium falciparum malaria (the parasite cannot thrive in oxidatively stressed RBCs)
• This is an example of balancing selection - heterozygous females gain malarial protection without full enzyme deficiency

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Page 35 - G6PD Deficiency and Rasburicase

Rasburicase:

The Rasburicase Reaction:

Uric acid (insoluble, causes gout/renal damage)
    ↓ Rasburicase (urate oxidase)
    → Allantoin (soluble) + H₂O₂ (TOXIC BYPRODUCT)
    
H₂O₂ must be neutralized by:
    Glutathione peroxidase → requires NADPH (from G6PD)
    
In G6PD deficiency:
    → Cannot regenerate NADPH
    → Cannot neutralize H₂O₂
    → H₂O₂ oxidizes hemoglobin → Heinz bodies
    → Red blood cell destruction
    → SEVERE HEMOLYTIC ANEMIA

Clinical Action:

• G6PD deficiency is an ABSOLUTE CONTRAINDICATION to rasburicase
• Must screen for G6PD deficiency BEFORE giving rasburicase
• Alternative: allopurinol (does not produce H₂O₂)

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Page 36 - G6PD Inhibitor + Chemotherapy Combination (Diagram Page)

What the Diagram Shows:

1. G6PD/TKT inhibitor - blocks the pentose phosphate pathway (PPP) in cancer cells, depleting NADPH → increased reactive oxygen species (ROS) → oxidative stress in cancer cells
2. Chemotherapy agents (standard cytotoxics)

• Combined therapy further promoted the apoptosis (programmed death) of breast cancer cells
• Combined therapy further inhibited the proliferation (growth) of breast cancer cells
• Synergistic cell death in cancer cell populations shown by multiple sequential panels

Significance:

• G6PD is actually overexpressed in many cancer types (cancer cells need NADPH to neutralize ROS from high metabolic activity)
• G6PD inhibitors are being studied as anticancer agents - not just a clinical liability but a potential therapeutic target
• This connects back to precision medicine: genetic status of G6PD affects both drug safety (rasburicase) AND cancer treatment strategies

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PART 7: TRANSPORTER PROTEIN PHARMACOGENOMICS

Page 37 - Organic Anion Transporting Polypeptide 1B1 (OATP1B1)

Key Facts:

The Key Variant - Val174Ala (c.521T>C):

Clinical Consequence - Simvastatin Myopathy:

• Possessing the *5 variant aggressively increases hazardous systemic simvastatin exposure
• Elevated plasma simvastatin concentrations → myopathy risk (muscle pain, weakness)
• Severe form: Rhabdomyolysis (muscle breakdown → renal failure)
• CPIC guideline: SLCO1B1 *5 carriers should use lower simvastatin doses or switch to rosuvastatin/pravastatin (less affected by OATP1B1)

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Page 38 - BCRP Efflux Transporter (ABCG2)

Key Facts:

The Key Variant:

• A prominent reduced-function variant maintains 30% allele frequency in East Asians
• This variant reduces BCRP efflux activity

Clinical Consequence - Rosuvastatin:

• BCRP normally effluxes rosuvastatin OUT of intestinal cells (limits absorption) and OUT of liver cells (promotes bile excretion)
• Reduced BCRP function → markedly increased systemic rosuvastatin levels
• Consequence: Higher rosuvastatin plasma concentrations → increased myopathy risk
• Regulatory action: Explicit clinical dosage halving recommendations globally for patients with reduced BCRP function

Both OATP1B1 and BCRP affect statin levels - OATP1B1 affects hepatic uptake, BCRP affects efflux. Both ultimately increase intracellular drug exposure when dysfunctional.

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PART 8: HLA-MEDIATED DRUG HYPERSENSITIVITY

Page 39 - Drug-Induced Hypersensitivity Reactions

Spectrum of Reactions:

Mechanism:

• Drugs form reactive antigens inside susceptible individuals
• These trigger inappropriate immune responses (T-cell mediated)
• Population-selective severe toxicities correlate directly with specific inherited HLA (Human Leukocyte Antigen) system polymorphisms

Why HLA?

• HLA molecules present peptides to T-cells
• Certain HLA variants present drug-modified peptides as "foreign" → immune attack on host tissues
• Because HLA allele frequencies differ by ethnicity → ethnic differences in drug hypersensitivity risk

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Page 40 - HLA-B*57:01 and Abacavir (Critical HIV Example)

Abacavir:

Mechanism of Abacavir Hypersensitivity:

HLA-B*57:01 protein (in susceptible patients)
    ↓ Binds abacavir-associated peptide
    → Abacavir-peptide complex presented to CYTOTOXIC T-CELLS
    → T-cells activated and proliferate
    → Immune attack on multiple organ systems
    → Hypersensitivity syndrome (fever, rash, GI symptoms, respiratory distress)
    → If drug continued → FATAL

Clinical Protocol:

This is one of the BEST examples of precision pharmacogenomics in clinical practice - a simple genetic test prevents a life-threatening reaction

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Page 41 - HLA Mechanism Diagram (Abacavir Hypersensitivity) - Diagram Page

What the Diagrams Show:

• The diagram shows a host cell with the HLA-B*57:01 molecule on its surface
• Abacavir enters the cell and modifies the peptide binding groove of HLA-B*57:01
• A "self" peptide that would normally be recognized as self is now perceived as foreign
• This altered HLA-peptide complex is presented to CD8+ cytotoxic T-cells (CTLs)

• CTLs recognize the abacavir-HLA-B*57:01-peptide complex as foreign
• Massive clonal expansion of reactive T-cells
• T-cells attack host tissues displaying the same HLA-B*57:01-abacavir-peptide complex
• Result: Multi-organ hypersensitivity syndrome (skin, gut, liver, lungs)

Key Concept Illustrated:

Abacavir does NOT trigger a hypersensitivity reaction in everyone - ONLY in individuals who carry the HLA-B*57:01 allele, because only this specific HLA protein can bind the abacavir-peptide complex in a way that activates T-cells. This is why genetic pre-screening is perfectly predictive.

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PART 9: FUTURE DIRECTIONS

Page 42 - Epigenomics and Future Directions

Epigenomics:

Two Key Epigenetic Mechanisms:

Future Directions:

1. Advanced algorithms will merge:
   • Multiple genetic variants (polygenic scoring)
   • Expansive epigenomic patient signatures
   • Environmental and lifestyle factors
2. Comprehensive precision medicine platforms will:
   • Predict individual drug response BEFORE prescribing
   • Prevent adverse drug reactions proactively
   • Optimize dosing continuously based on genetic + epigenetic profiles

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MASTER SUMMARY TABLES FOR EXAM

Table 1: Complete Phase I Enzyme Pharmacogenomics Summary

Table 2: Complete Phase II Enzyme Pharmacogenomics Summary

Table 3: Transporter Pharmacogenomics Summary

Table 4: HLA Pharmacogenomics Summary

Table 5: Four Metabolizer Phenotypes - Complete Reference

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KEY EXAM MNEMONICS

1. "Codeine Kills UMs" - Ultrarapid CYP2D6 metabolizers convert codeine → massive morphine → fatal respiratory depression
2. "Clopidogrel Clots PMs" - CYP2C19 poor metabolizers cannot activate clopidogrel → stent thrombosis
3. "Warfarin Bleeds PMs" - CYP2C9 poor metabolizers accumulate S-warfarin → bleeding
4. "Efavirenz Dreams PMs" - CYP2B6 poor metabolizers cannot autoinduce → CNS toxicity, hallucinations
5. "5-FU Kills DPD Deficients" - DPYD PM patients cannot catabolize 5-FU → fatal myelosuppression
6. "Gilbert Means Irinotecan Danger" - UGT1A1*28/*28 → cannot inactivate SN-38 → neutropenia
7. "TPMT Protects Against Thiopurine Myelosuppression" - without TPMT, TGNs accumulate → bone marrow destroyed
8. "G6PD + Rasburicase = Hemolysis" - H₂O₂ byproduct cannot be neutralized → RBC destruction
9. "SLCO1B1*5 = Simvastatin Myopathy" - reduced liver uptake → high plasma simvastatin → rhabdomyolysis
10. "HLA-B*57:01 + Abacavir = SCREEN FIRST" - one blood test prevents a fatal reaction