The Science of Drugs: Everything About Drugs, From New Drug Development to Side Effects

 

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Chapter 1: The Two-Edged Sword of Medicine - Humanity's Long-Standing Companion

1.1. Medicine, Poison, and the Boundary Between Them

The history of medicine runs parallel to the history of humanity, acting at times as a savior and at others as a deadly poison. Over two millennia ago, the Greeks used ground willow bark to ease pain, a source of salicin, the precursor to today's aspirin. Through a long process of trial and error, humanity has discovered substances with medicinal properties and learned how to use them. Modern medicine can be seen as an attempt to precisely control this duality by scientifically exploring the nature of drugs.

The fundamental characteristic of any drug is its dual nature. A drug is a substance used to treat a disease, but it also has unintended side effects. The paradox expressed by the Russian mystic Rasputin, "A medicine is a poison, and a poison is a medicine," concisely illustrates this duality. The same substance can be a cure or a toxin depending on its dosage and method of use. Therefore, the key to using drugs is to follow the prescribed dosage and regimen accurately to maximize the desired therapeutic effect and minimize adverse reactions. Accurately understanding and controlling this boundary is the most important goal of modern pharmaceutical science, requiring a deep understanding of how drugs act and travel within the human body.

Chapter 2: The Unseen Journey - The Scientific Mechanism of Drug Action

2.1. Pharmacokinetics (PK): What the Body Does to the Drug

For a drug to function effectively, it must first travel along its intended path within the body. Pharmacokinetics (PK) is the study of "what the body does to the drug," analyzing the processes of absorption, distribution, metabolism, and excretion (ADME) over time.

·         Absorption: The process by which a drug moves from its administration site into the bloodstream. Orally administered drugs are mainly absorbed in the stomach and small intestine, a process significantly influenced by the drug's physicochemical properties (e.g., non-ionized state) and the environment of the gastrointestinal tract (e.g., pH). Notably, drugs taken orally may undergo 'First-pass Metabolism' in the liver, which reduces the amount of drug reaching systemic circulation (bioavailability). For intravenous (IV) injections, this process is bypassed, and the drug enters the bloodstream immediately.

·         Distribution: The process of a drug spreading from the bloodstream into the body's tissues. A drug's lipophilicity determines how well it crosses cell membranes, and its binding to plasma proteins is another crucial factor. Drugs bound to plasma proteins cannot exit the blood vessels, limiting their distribution into tissues and reducing the amount of 'free drug' available to act.

·         Metabolism: A process, mostly occurring in the liver and mediated by enzymes, that chemically modifies the drug's structure, primarily to inactivate it and increase its water solubility for easier excretion. This process is vital for terminating a drug's effect and reducing its toxicity.

·         Excretion: The removal of a drug from the body, primarily through the kidneys via urine, but also through bile and respiration.

Pharmacokinetics is not just a study of a drug's path; it is a critical field that determines the success of new drug development. The most common reason for the failure of new drug candidates in clinical trials is unsatisfactory pharmacokinetic properties—the inability to undergo an effective ADME process. The ability to predict and control drug concentration in specific tissues through pharmacokinetics is essential for successful pharmacodynamic action.

2.2. Pharmacodynamics (PD): What the Drug Does to the Body

Pharmacodynamics (PD) is the study of "what the drug does to the body," examining the effects a drug produces within the body. Most drugs act by binding to specific proteins called 'receptors,' which are located on or inside cells. This interaction is highly selective, like a 'key fitting into a lock,' due to the specific three-dimensional structure of the molecules.

Drugs are broadly classified into two types based on their interaction with receptors :

·         Agonist: A drug that, similar to the body's natural substances (e.g., hormones, neurotransmitters), binds to and stimulates or activates the function of a cell's receptor. They have high affinity and intrinsic activity, leading to a strong therapeutic effect. For example, the painkiller morphine acts on the same brain receptors as endorphins to relieve pain.

·         Antagonist: A drug that binds to a receptor but does not activate it. Instead, it blocks the agonist from binding to the receptor, thereby inhibiting its effect. Antagonists are typically used to regulate excessive physiological responses or suppress specific signals.

One of the key concepts in pharmacodynamics is 'selectivity.' A drug is considered to have fewer side effects if it acts selectively on its target site. However, some drugs can act like a 'master key,' binding to multiple types of receptors throughout the body. This 'non-selectivity' is the fundamental biological reason for drug side effects. For example, a drug that acts on a certain receptor also found in the digestive system can affect gastrointestinal activity, causing side effects like nausea or diarrhea.

Category	Pharmacokinetics (PK)	Pharmacodynamics (PD)
Concept	What the body does to the drug	What the drug does to the body
Main Research Focus	Changes in drug concentration in the body (ADME)	Relationship between drug concentration, effect, and toxicity
Core Mechanism	Absorption, Distribution, Metabolism, Excretion	Drug-receptor interaction, agonists, antagonists
Goal	Predict and control drug concentration in specific tissues	Elucidate a drug's effects, mechanism of action, and toxicity

Chapter 3: The 0.01% Success Rate Challenge - The Monumental Journey of New Drug Development

3.1. A Long Journey Chasing Hope: The Step-by-Step Process of New Drug Development

The creation of a single new drug is a long and arduous process that requires an astronomical amount of time and money. New drug development is generally divided into two main stages: research and development.

·         Research Stage (Discovery): This is the stage where thousands of potential compounds are screened to find those with a likely effect on a disease. Out of over 10,000 initial compounds, an average of only about 250 move on to pre-clinical trials.

·         Pre-Clinical Trials: Before a drug is administered to humans, animal studies are conducted to evaluate the safety, toxicity, efficacy, and PK of the candidate substance. This is a crucial step to filter out substances with a high likelihood of failure before the costly clinical trial phase. On average, only about 5 substances from this stage advance to Phase 1 clinical trials.

·         Clinical Trials: These are studies conducted on humans, divided into Phase 1, Phase 2, and Phase 3, and they are the most expensive and difficult part of the development process, accounting for about 63% of the total cost.

o    Phase 1 Trials: A small group of healthy volunteers (20-80 people) is used to primarily assess the drug's safety and determine a safe dosage for humans.

o    Phase 2 Trials: A small number of patients (100-200 people) are enrolled to explore the drug's efficacy and side effects and determine the optimal dosage. This phase has the highest failure rate, with only about 25% advancing to the next phase.

o    Phase 3 Trials: A large-scale study involving hundreds to thousands of patients to finally confirm the drug's efficacy and safety and compare its effects with existing treatments.

·         Post-Marketing Surveillance (Phase 4): Even after a new drug is approved and marketed, its long-term efficacy, side effects, and interactions with other drugs are continuously monitored.

As shown, for a new drug to be created, over 10,000 candidate substances must compete, and numerous failures must be overcome. This massive failure rate and cost clearly demonstrate the difficulty of new drug development, which is a key economic factor behind the high prices of new drugs.

3.2. Small-Molecule Compounds vs. Biopharmaceuticals: The Two Pillars

The modern pharmaceutical market is divided into two major pillars: chemically synthesized small-molecule compounds and biopharmaceuticals, which are produced using living organisms.

Category	Small-Molecule Compounds (Chemical Drugs)	Biopharmaceuticals
Molecular Structure	Small, relatively simple	High-molecular-weight, very complex (100-1,000 times larger)
Manufacturing Process	Chemical synthesis	Culturing living organisms (microorganisms, animal cells, etc.)
Administration Method	Primarily oral (pills)	Primarily by injection
Replication Feasibility	Can be chemically synthesized identically	Impossible to replicate identically (only similar products can be made)
Replicated Drug Name	Generic	Biosimilar

Small-molecule compounds have a relatively simple molecular structure, making it possible to create chemically identical generic drugs. However, biopharmaceuticals have a complex, high-molecular-weight protein structure made by 'culturing' microorganisms or animal cells, making it impossible to create an exact replica of the original drug. Due to this unique characteristic, replicated biopharmaceuticals are called 'biosimilars' because they are 'similar' but not identical to the original. Biosimilars undergo a different manufacturing process but must prove 'equivalence' through clinical trials to show they produce nearly identical biological effects before they can be marketed.

3.3. The Compass for Future Drug Development: AI and Precision Medicine

To solve the challenges of high failure rates and enormous costs in new drug development, artificial intelligence (AI) is being used throughout the entire process. AI can analyze vast amounts of data to discover new drug candidates, significantly shortening the development time, and optimize clinical trial design and patient data analysis to increase the overall efficiency of the development process.

Furthermore, the future of medicine lies in 'precision medicine' or 'personalized medicine,' which provides treatments optimized for an individual patient by analyzing their genetic information (DNA). This approach leverages the fact that patients with specific genetic variations may respond better to certain drugs or have a higher risk of side effects. AI is a key tool for accelerating the realization of precision medicine by integrating and analyzing large-scale genomic and clinical data. This opens a new paradigm for drug science, moving beyond simply treating diseases to maximizing therapeutic effects and minimizing side effects by considering the unique characteristics of each patient.

Chapter 4: The Shadow and Light of Drugs - Understanding Side Effects and Overcoming Resistance

4.1. Unforeseen Reactions: The Scientific Causes of Side Effects

Side effects are not merely a matter of bad luck; they are predictable reactions based on scientific principles. The main causes of side effects can be classified as follows:

·         Non-selectivity of the Drug: As mentioned in pharmacodynamics, side effects occur when a drug acts on receptors in tissues other than its intended target. For example, the lung cancer drug osimertinib (Tagrisso) is effective against lung cancer with a specific genetic mutation, but it can also affect the skin and gastrointestinal tract, causing side effects like rash or diarrhea.

·         Drug Interaction: When two or more drugs are taken simultaneously, one drug can affect the absorption, distribution, metabolism, or excretion of the other, changing its efficacy or causing toxicity. For example, the antibiotic rifampin can activate an enzyme involved in the metabolism of oral contraceptives, thereby reducing their effectiveness. Additionally, 'polypharmacy,' which is the regular consumption of five or more medications per day, significantly increases the frequency of side effects.

·         Individual Genetic Factors: A person's drug response can vary greatly due to genetic polymorphisms of the enzymes involved in drug metabolism. Pharmacogenomics is the field that studies how these genetic differences affect drug efficacy and side effects. For example, a patient with a specific genetic variation may have a slower drug metabolism rate, leading to an accumulation of drug toxicity at a standard dose. This highlights the need for precision medicine, where genetic testing can be used to adjust the dose before using certain drugs.

Drug Type	Common Side Effects	Scientific Cause
Analgesics	Heartburn, hives	Non-selective action of the drug irritating the gastrointestinal tract
Antibiotics	Rash, anaphylactic shock	Immune allergic reaction (hypersensitivity reaction) to the drug
Chemotherapy	Nausea, vomiting, hair loss, bone marrow suppression	Non-selective action of the drug attacking normal cells as well
Rifampin	Loss of oral contraceptive effect	Drug interaction due to activation of liver enzymes (CYP)
Azathioprine	Bone marrow suppression	Genetic factors such as deficiency in TPMT enzyme activity

4.2. Humanity's Challenge, Drug Resistance: Focusing on Antibiotics and Cancer Drugs

Drug resistance is a phenomenon where a drug no longer has an effect, posing a serious threat to human health. The emergence of antibiotic-resistant bacteria is a major public health challenge , and resistance to cancer drugs is a primary reason for the failure of cancer treatment.

Cancer drug resistance occurs as cancer cells develop various biological mechanisms to resist the drug :

1.    New Genetic Mutations: When a targeted drug attacks a specific gene, cancer cells can develop new genetic mutations to evade the drug's target site.

2.    Activation of Alternative Signaling Pathways: If the main targeted signaling pathway is blocked, cancer cells can activate other bypass pathways to survive, rendering the drug ineffective.

3.    Overexpression of Drug Efflux Pumps: Cancer cells can overexpress protein pumps that pump the drug out of the cell, preventing it from reaching a sufficient concentration inside the cell.

This shows that cancer cells exhibit complex evolutionary resistance mechanisms to single-targeted therapies.

4.3. New Paradigms and Future Prospects for Overcoming Resistance

To overcome the challenge of drug resistance, scientists are exploring various solutions.

·         Multi-target Approach: To overcome the limitations of single-target therapies, 'combination therapy'—using multiple drugs with different mechanisms of action—is becoming increasingly important. The recently highlighted bispecific antibody is an attempt to overcome the limitations of existing treatments by designing a single drug that simultaneously attacks two different targets.

·         New Treatment Modalities: Beyond directly attacking cancer cells, 'immune checkpoint inhibitors,' which activate the patient's own immune system to help it eliminate cancer cells, are establishing themselves as a new standard of care. In addition, 'Antibody-Drug Conjugates (ADCs)' are drawing attention as next-generation precision-strike technology, as they use an antibody to precisely deliver a drug to cancer cells, minimizing damage to normal cells and reducing side effects.

·         Comprehensive Research and Development: To solve the antibiotic resistance problem, comprehensive national strategies are being implemented, including measures for appropriate antibiotic use, preventing the spread of resistant bacteria, and expanding R&D. Additionally, a multifaceted approach is being taken to overcome resistance, utilizing natural substances, microbiome research, and diagnostic technologies.

In conclusion, drug resistance is a complex problem that cannot be solved with simple drug development alone. It requires a new paradigm shift to 'multi-target' and 'combination therapies'. These innovations will ultimately lead to more precise control over the dual nature of drugs and the advancement of precision medicine, which provides treatment optimized for each individual patient.