Note
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Methods in Pharmacology II - Lecture Notes
Slide 2: First-Order Kinetics
Key Points:
In first-order kinetics, the rate of drug elimination is proportional to the drug concentration.
This means that:
A constant fraction (not a constant amount) of the drug is eliminated per unit time.
The mathematical formula for this process is:
C_{t}=C_0\cdot exp^{-\frac{CL_{\text{tot}}}{V_d}\cdot t}
C₀ = initial concentration
CL_{tot} = total clearance
V_d = volume of distribution
t = time
Explanation of Visuals:
Left: Diagram of a single dose entering the central compartment and being cleared over time.
Right (Graph A): Plasma concentration declines exponentially for drugs with different elimination rates (e.g., k_el = 0.05 vs 0.2/h).
Right (Graph B): Even with different initial doses, if elimination rate is the same, the curves are parallel (e.g., B and B').
Glossary:
Clearance (CL): The volume of plasma cleared of drug per time unit.
Volume of distribution (V_d): Theoretical space in the body where the drug distributes.
Key Takeaway:
In first-order kinetics, the drug is eliminated at a rate that depends on its current concentration — resulting in an exponential decay.
Slide 3: Rate of Drug Absorption
Key Points:
The absorption rate affects how quickly a drug reaches effective levels in the bloodstream.
Faster absorption → earlier and higher peak concentrations.
Slower absorption → delayed onset and possibly lower peak.
Explanation of Visuals:
Graph A: Simulated plasma levels with varying absorption half-times (0–6h).
IV injection (0 h) results in immediate peak (→ 0h means immediate absorption).
Oral forms show increasing delay and lower peaks with slower absorption.
Graph B: Real-world example with aminophylline:
Oral route has delayed onset.
IV route reaches peak much faster.
How could one achieve a perfectly stable absorption??
WIth being on a drip through an injection (like in the hospital)
Glossary:
Absorption half-time: Time required for 50% of the drug to be absorbed.
Minimum effective concentration: Lowest level at which the drug has therapeutic effects.
Key Takeaway:
The route and speed of drug absorption determine how quickly therapeutic levels are reached and how long the effect lasts.
Slide 4: First-Order vs. Zero-Order (Saturation) Kinetics
Key Points:
First-order kinetics:
Elimination rate depends on concentration.
Most drugs follow this pattern (e.g., theophylline, ethanol at low doses).
Zero-order kinetics:
Elimination rate is constant, regardless of concentration.
Happens when enzymes are saturated.
Seen in drugs like phenytoin and ethanol at high doses.
Explanation of Visuals:
Left Graph: First-order → predictable exponential decline.
Right Graph: Zero-order → linear decline due to enzyme saturation.
Right Graph: Zero-order kinetics → linear decline in concentration over time due to enzyme saturation.
This occurs when the metabolizing enzyme is fully saturated, meaning it is working at maximum capacity and cannot increase its rate further, even if more substrate is present.
As a result, the substance is eliminated at a constant amount per unit time (e.g., 10 mg/hour), rather than a constant percentage (as in first-order kinetics).
🍺 Example: Ethanol
Ethanol (alcohol) metabolism follows zero-order kinetics at typical physiological concentrations.
The liver enzyme alcohol dehydrogenase becomes saturated, so ethanol is eliminated at a constant rate, regardless of the blood concentration — about 7–10 g/hour in an average adult.
⚠ Important Distinction:
Zero-order = linear decline, fixed amount removed per time (e.g., ethanol).
First-order = exponential decline, fixed fraction removed per time (e.g., most drugs like caffeine, aspirin at low doses).
The blue and red lines show how increasing dose in zero-order kinetics makes predicting plasma levels very difficult.
Explanation of Visuals (Slide 4 Recap)
Left graph: First-order elimination curve – typical for most drugs and ethanol at low levels. The curve slopes downward more steeply at first and flattens as concentration drops.
Right graph: Zero-order elimination – straight line. Elimination happens at a fixed rate, no matter the starting concentration.
Blue and red lines show that in zero-order, increasing the dose leads to much more unpredictable plasma levels, making safe dosing difficult.
Glossary
Saturation: Enzymes are working at full capacity and can’t handle more drug.
Zero-order kinetics: A fixed amount is removed per unit time (e.g., 10 mg/hour).
First-order kinetics: A constant fraction is removed per unit time (e.g., 10%/hour).
Key Takeaway:
Ethanol is eliminated via zero-order kinetics at higher doses because its primary metabolic enzyme becomes saturated. This makes ethanol a classic and important example in pharmacology of how drug elimination can switch from predictable to risky, especially with overdose.
Key Takeaway:
While most drugs are eliminated by first-order kinetics, some switch to zero-order at high doses — making dosing and monitoring more challenging.
Slide 5: More Complex Models (Two-Compartment Model)
Key Points:
In two-compartment models, the drug distributes between:
Central compartment: Blood and highly perfused organs.
Peripheral compartment: Tissues like fat and muscle.
Drug is absorbed, moves between compartments, and is eventually eliminated.
Model Details:
Drug may accumulate in the peripheral compartment, creating a delay between plasma concentration and actual drug effect.
These models are needed for:
Drugs with slow tissue distribution.
Drugs with prolonged effects despite declining plasma levels.
Explanation of Visuals:
Diagram shows:
Drug entering central compartment.
Distribution to peripheral.
Elimination from the central compartment.
Glossary:
Two-compartment model: A pharmacokinetic model dividing the body into central and peripheral spaces.
Distribution phase: Initial period when drug spreads from blood to tissues.
Key Takeaway:
Two-compartment models are more accurate for drugs that distribute unevenly in the body — helping predict effects and plasma levels more reliably.
Slide 6: Proteresis (Clockwise) and Hysteresis (Counterclockwise)
Key Points:
These concepts describe nonlinear relationships between drug concentration and effect over time:
A. Proteresis (Clockwise Hysteresis)
Effect is stronger at earlier time points even when drug concentration is the same later.
May occur due to:
Tolerance or desensitization,
Antagonist formation,
Receptor downregulation.
B. Hysteresis (Counterclockwise Hysteresis)
Effect is stronger at later time points for the same concentration.
Often due to:
Delayed distribution of drug to the site of action,
Active metabolites,
Sensitization or upregulation.
Explanation of Visuals:
Two graphs showing effect vs. concentration over time.
Arrows point to how effect curves loop differently based on drug behavior.
Glossary:
Hysteresis: Lag between concentration and effect.
Proteresis: Clockwise hysteresis; diminishing effect.
Desensitization: Reduced receptor response over time.
Key Takeaway:
These time-dependent effects show that drug action cannot always be predicted by plasma concentration alone, especially for drugs with delayed distribution or receptor adaptation.
Slide 7: Antipyretic Analgesics (Overview)
Key Points:
Antipyretic analgesics are drugs that reduce fever (antipyretic) and pain (analgesic).
One of the earliest and most famous is:
Acetylsalicylic acid (ASA, Aspirin®) introduced in 1899 by Bayer AG.
Examples of Antipyretic Analgesics:
Metamizole (Novalgin®)
Ibuprofen (Brufen®)
Diclofenac (Voltaren®)
Naproxen (Proxen®)
Paracetamol (Panadol®)
Explanation of Visuals:
Top: Historical photo of early aspirin tablets.
Middle: Modern antipyretic drugs in blister packaging.
Glossary:
Analgesic: Pain reliever.
Antipyretic: Fever reducer.
Key Takeaway:
Antipyretic analgesics are widely used to treat fever and pain, with aspirin being the historical milestone in this class.
Slide 8: Antipyretic Analgesics – Effects & Side Effects
Key Points:
Therapeutic Effects:
Analgesic: Pain relief
Antipyretic: Fever reduction
Anti-inflammatory: Reduces swelling
Common Side Effects and Risks:
Upper gastrointestinal (GI) irritation: Nausea, ulcers
Bleeding: Especially due to platelet inhibition
Kidney impairment
Hyperuricemia: Elevated uric acid, risk of gout
Explanation of Visuals:
Background image evokes natural plant sources of some analgesics (e.g., willow bark for aspirin).
Glossary:
GI tract: Gastrointestinal system (stomach, intestines).
Hyperuricemia: Too much uric acid in blood, can cause gout.
Key Takeaway:
While antipyretic analgesics are effective for fever, pain, and inflammation, they come with notable risks — especially to the stomach and kidneys.
Slide 9: Acetylsalicylic Acid (Aspirin®)
Key Points:
1897: Synthesized by Felix Hoffmann and Arthur Eichengrün at Bayer.
1899: Launched commercially as Aspirin.
First used as a painkiller, fever reducer, and anti-inflammatory.
Later used for:
Cardiovascular protection (anti-platelet effect),
Pandemic treatment (e.g., flu in early 20th century).
Explanation of Visuals:
Top: Timeline of key dates in aspirin’s development.
Bottom: Historical photos of its inventors and the chemical structure of acetylsalicylic acid.
Glossary:
Acetylsalicylic acid (ASA): Active ingredient in aspirin.
Platelet inhibition: Prevents blood clotting.
Key Takeaway:
Aspirin is one of the most significant and versatile drugs in history, originally introduced for pain and fever but later found to have life-saving cardiovascular uses.
Slide 10: Other Antipyretic Analgesics – NSAIDs
Key Points:
NSAIDs = Non-Steroidal Anti-Inflammatory Drugs.
These drugs reduce:
Pain (analgesic effect)
Fever (antipyretic effect)
Inflammation (anti-inflammatory effect)
Common NSAIDs with chemical structures shown:
Indomethacin (MSD, 1963)
Ibuprofen (Boots, 1960/1969)
Diclofenac (Geigy, 1985)
Naproxen
Flurbiprofen
Glossary:
NSAIDs: Drugs that reduce inflammation without being steroids.
Key Takeaway:
NSAIDs form a chemically diverse group of drugs that share a common therapeutic profile: pain relief, fever reduction, and inflammation control.
Slide 11: Discovery of the Mechanism of NSAIDs
Key Points:
NSAIDs work by blocking prostaglandin synthesis, a key mediator of pain and inflammation.
Prostaglandins are produced from arachidonic acid via the COX enzyme (cyclooxygenase).
Discovery timeline:
1971: John Vane shows aspirin inhibits prostaglandin synthesis.
He was awarded the Nobel Prize in 1982 alongside Sune Bergström and Bengt Samuelsson.
Explanation of Visuals:
Left: Biochemical pathway showing prostaglandin production.
Right: Photos of the three scientists and molecular diagrams.
Glossary:
Prostaglandins: Lipid compounds that cause pain, fever, and inflammation.
Cyclooxygenase (COX): Enzyme converting arachidonic acid into prostaglandins.
Key Takeaway:
The anti-inflammatory effect of NSAIDs is due to their ability to block the enzyme COX, which stops prostaglandin production.
Slide 12: Mechanism of NSAIDs (Pathway Diagram)
Key Points:
NSAIDs inhibit COX enzymes, specifically:
COX-1: Constitutive enzyme → involved in protection of stomach lining and kidney function.
COX-2: Inducible enzyme → upregulated during inflammation.
Drug Selectivity:
Non-selective NSAIDs: Inhibit both COX-1 and COX-2 (e.g., ibuprofen, naproxen).
COX-2 selective inhibitors (coxibs): Aim to reduce inflammation with fewer gastric side effects (e.g., celecoxib).
Explanation of Visuals:
Central diagram shows the arachidonic acid cascade leading to prostaglandins and thromboxanes.
NSAIDs block COX, reducing pro-inflammatory prostaglandins.
Glossary:
Thromboxanes (TxA₂): Promote blood clotting and vasoconstriction.
Coxibs: COX-2-specific NSAIDs.
NSAIDs (nonsteroidal anti-inflammatory drugs)
Key Takeaway:
NSAIDs block prostaglandin production by inhibiting COX enzymes; COX-2 inhibitors aim to minimize inflammation while avoiding COX-1-related side effects.
Slide 13: Mechanism of NSAIDs (Text Summary)
Key Points:
1. Enzyme Inhibition:
NSAIDs inhibit COX enzymes in inflammatory cells.
This reduces prostaglandins, which mediate:
Pain
Fever
Inflammation
2. Undesired Side Effects (mostly from COX-1 inhibition):
Gastric mucosa irritation → ulcers, GI bleeding
Impaired kidney function
Increased bleeding tendency (via thromboxane inhibition)
3. Desired Effects:
Anti-inflammatory: Less swelling, redness, and heat
Analgesic: Pain relief
Antipyretic: Fever reduction
Antithrombotic (e.g., low-dose aspirin)
Glossary:
Thromboxane: Promotes blood clotting; inhibited by aspirin.
GI bleeding: Common NSAID-related side effect due to stomach lining irritation.
Key Takeaway:
While NSAIDs are effective against pain and inflammation, they also carry risks—especially to the GI tract and kidneys—due to their action on COX-1.
Slide 14: Biologically Active Prostaglandins (Pathway Overview)
Key Points:
Arachidonic acid, a fatty acid in cell membranes, is the precursor for prostaglandins, prostacyclin, and thromboxane.
These molecules are made via the cyclooxygenase (COX) pathway.
The products are bioactive lipids that regulate various physiological and pathological processes.
Explanation of Visuals:
Central molecule: Arachidonic acid
Arrows point to different derivatives:
PGD₂, PGE₂, PGF₂α (various prostaglandins)
PGI₂ (prostacyclin)
TXA₂ (thromboxane A₂)
Glossary:
Prostaglandins: Lipid mediators involved in inflammation, fever, and more.
Cyclooxygenase (COX): Enzyme that converts arachidonic acid into prostaglandins.
Bioactive lipids: Molecules that signal or regulate biological functions.
Key Takeaway:
Arachidonic acid is converted by COX enzymes into several biologically active molecules, which play key roles in inflammation, blood flow, and clotting.
Slide 15: Biologically Active Prostaglandins (Functions)
Key Points:
This slide categorizes the main types of arachidonic acid-derived molecules and their major biological roles:
Prostaglandins (PGs):
Promote inflammation, vasodilation, and pain
Regulate fever and gastric protection
Support kidney function
Prostacyclin (PGI₂):
Vasodilation
Inhibits platelet aggregation (prevents clotting)
Thromboxane (TXA₂):
Promotes vasoconstriction
Stimulates platelet aggregation (encourages clotting)
Explanation of Visuals:
Table format showing:
Each compound
Their physiological effects
Often opposing roles (e.g., prostacyclin vs. thromboxane)
Glossary:
Vasodilation: Widening of blood vessels.
Vasoconstriction: Narrowing of blood vessels.
Platelet aggregation: Clumping of platelets to form blood clots.
Key Takeaway:
Prostaglandins, prostacyclins, and thromboxanes have diverse — and sometimes opposing — roles in inflammation, blood pressure regulation, and clotting.
Slide 16: Two Cyclooxygenases (COX-1 vs. COX-2)
Key Points:
COX-1:
Always active in most tissues.
Supports normal functions ("housekeeping enzyme"):
Gastric protection
Platelet function
Kidney blood flow
COX-2:
Induced only during inflammation (by cytokines or tissue injury).
Responsible for:
Pain
Swelling
Fever
Clinical Implications:
Non-selective NSAIDs inhibit both COX-1 and COX-2, causing both anti-inflammatory effects and GI side effects.
COX-2 inhibitors (e.g. celecoxib) aim to avoid GI issues while still reducing inflammation.
Explanation of Visuals:
Split-box comparing COX-1 and COX-2 roles.
Highlighting therapeutic vs. side effect profiles.
Glossary:
Constitutively expressed: Always active.
Inducible enzyme: Only activated when needed (e.g., during inflammation).
Cytokines: Inflammatory signaling proteins.
Key Takeaway:
COX-1 supports tissue health and homeostasis, while COX-2 drives inflammation — making selective inhibition a therapeutic goal.
Slide 17: Two Cyclooxygenases and Their Binding Sites
Key Points:
COX-1 and COX-2 have similar structures, but their active sites differ:
COX-2 has a larger and more flexible binding pocket.
Makes it accessible for different drugs
This difference enables:
Selective inhibition of COX-2 by certain drugs (coxibs),
While sparing COX-1 to reduce gastric side effects.
Explanation of Visuals:
Top: 3D models comparing COX-1 and COX-2 enzyme binding sites.
Bottom: Structural diagram showing drug binding to each isoform.
Glossary:
Binding pocket: Part of an enzyme where a drug or molecule fits and interacts.
Selective inhibitor: A drug that targets one form of an enzyme but not another.
Key Takeaway:
The structural difference in COX enzymes allows for selective COX-2 inhibitors, offering anti-inflammatory effects with fewer gastrointestinal side effects.
Slide 18: Two Cyclooxygenases – Specific COX-2 Inhibition
Key Points:
Selective COX-2 inhibitors (coxibs) were developed to:
Retain anti-inflammatory and analgesic effects,
Avoid COX-1-associated side effects, especially GI irritation.
Examples of COX-2 Inhibitors (Look at the marked endings of the names → indicate drugs that inhibit COX2):
Rofecoxib (Vioxx®)
Celecoxib (Celebrex®)
Etoricoxib (Arcoxia®)
Benefits of COX-2 Selectivity:
Reduced risk of:
Stomach ulcers
Gastrointestinal bleeding
Maintains anti-inflammatory action
Glossary:
Coxibs: A class of NSAIDs that selectively inhibit COX-2.
Side effects: Unintended effects of a drug, e.g., GI irritation with traditional NSAIDs.
Key Takeaway:
Selective COX-2 inhibitors were designed to minimize gastrointestinal side effects while preserving the therapeutic actions of NSAIDs.
Slide 19: Aspirin – A Special Case (Historical Context)
Key Points:
Aspirin (acetylsalicylic acid) was one of the first NSAIDs, widely used since its commercial launch by Bayer.
It’s well known for its:
Anti-inflammatory
Pain-relieving
Fever-reducing properties
Also effective as an anti-thrombotic agent (blood thinner).
Explanation of Visuals:
Image: Vintage Aspirin® packaging from Bayer.
Key Takeaway:
Aspirin is a historically and pharmacologically significant NSAID, unique in its long-lasting effect on platelet function.
Slide 20: Aspirin – A Special Case (Mechanism and Duration)
Key Points:
Aspirin irreversibly inhibits COX enzymes, especially COX-1 in platelets.
Platelets cannot make new COX enzymes (they lack nuclei), so the effect lasts for their entire lifespan (~10 days).
This makes aspirin especially effective for:
Preventing blood clots
Reducing risk of heart attacks and strokes
Clinical Relevance:
Even low doses (75–100 mg/day) are enough to inhibit platelet COX-1.
This prolonged action makes aspirin unique among NSAIDs.
Since a proportion of platelets is replaced each day from the bone marrow, this inhibition gradually abates but a small daily dose of aspirin (e.g. 75mg/day) is all that is required to suppress platelet function to levels which benefit patients at risk for myocardial infarction and other cardiovascular problems.
Glossary:
Irreversible inhibition: Enzyme activity is permanently blocked.
Platelets: Blood cells that help with clotting; aspirin inhibits their aggregation.
Key Takeaway:
Aspirin’s irreversible inhibition of platelet COX-1 gives it a lasting anti-thrombotic effect, making it a cornerstone for cardiovascular disease prevention.
Slide 21: Aspirin – Mechanism Illustrated
Key Points:
Aspirin inhibits both COX-1 and COX-2, but its effect on platelets (COX-1) is the most clinically significant.
This leads to reduced production of thromboxane A₂ (TxA₂), a molecule that promotes:
Vasoconstriction
Platelet aggregation
Therapeutic Actions:
Low-dose aspirin (75–100 mg/day):
Reduces risk of heart attack, stroke
Used as cardiovascular prophylaxis
Higher doses (500 mg+):
Needed for analgesic and anti-inflammatory effects
Explanation of Visuals:
Left: Diagram showing aspirin blocking COX in platelets.
Right: Summary box listing the dual effects depending on dose.
Glossary:
Thromboxane (TxA₂): Promotes blood clotting and vessel constriction.
Prophylaxis: Preventive treatment.
Key Takeaway:
Aspirin's dose-dependent actions make it unique — small doses protect the heart, while higher doses fight inflammation and pain.
Slide 22: Aspirin – A Special Case (Mechanism Recap)
Key Points:
Low-dose aspirin (e.g. 75–100 mg) selectively inhibits platelet COX-1 in the portal circulation (gut-liver system) before it enters systemic circulation.
This results in:
Reduced thromboxane A₂ synthesis → decreased platelet aggregation.
Long-lasting inhibition (up to 7–10 days) of platelet function.
Clinical Significance:
Used for secondary prevention of:
Heart attacks
Strokes
Explanation of Visuals:
Diagram showing how low-dose aspirin acts before liver metabolism, blocking platelet COX-1 early and systemically.
Glossary:
Portal circulation: Blood flow from the gut to the liver.
Secondary prevention: Preventing a second occurrence of a disease (e.g., a second heart attack).
Key Takeaway:
Low-dose aspirin irreversibly inhibits platelet COX-1 in the portal system, giving it a lasting anti-thrombotic effect ideal for cardiovascular protection.
Slide 23: Classical Drug Discovery – General Stages
Key Points:
Drug discovery is a stepwise process involving several key phases:
Target Identification: Find a biological molecule involved in a disease.
Target Validation: Confirm that influencing the target improves disease outcomes.
Lead Identification: Find chemicals that affect the target.
Candidate Optimization: Improve chemical properties (efficacy, safety).
Pre-Clinical Testing: In vitro and animal testing to evaluate safety and mechanism.
Clinical Trials (Phases I–III): Human studies.
Approval: Regulatory review (e.g. FDA).
Post-Marketing (Phase IV): Monitor long-term effects and rare side effects.
Glossary:
Lead compound: A promising chemical with desired biological activity.
Pre-clinical: Before human testing begins.
Key Takeaway:
Classical drug discovery is a multi-stage process that moves from molecular research to clinical application over many years.
Slide 24: Classical Drug Development – Timeline & Phases
Key Points:
This slide illustrates a timeline and resource overview for drug development:
Drug Discovery: 3–6 years
5,000–10,000 compounds tested
~250 selected for further testing
Preclinical: 1–2 years
5–10 compounds enter
Clinical Development:
Phase I: Safety in 20–100 healthy volunteers
About half of the preclinically developed compounds get here.
Phase II: Efficacy and dose range in 100–500 patients
About another half gets cut out.
Phase III: Large-scale testing in 1,000–5,000 patients
About every fifteenth compound getts to this phase.
Regulatory Approval: ~1–2 years
Drug submitted for approval (e.g. to FDA or EMA)
Phase IV: Post-market monitoring
Explanation of Visuals:
Long horizontal bar shows duration and narrowing of candidates.
Emphasizes cost, time, and attrition rate.
Glossary:
Attrition: Loss of drug candidates along the development pipeline.
Key Takeaway:
Drug development is lengthy, expensive, and selective — only a few compounds from thousands make it to market.
Slide 25: Classical Drug Discovery – Success Rate & Volunteer Scale
Key Points:
Only 1 out of ~10,000 compounds screened makes it to market.
The process takes 10–15 years on average.
Clinical phases require increasing numbers of human participants:
Phase I: ~100
Phase II: ~500
Phase III: ~5,000
Financial and Logistical Impact:
Each phase gets more expensive and complex.
FDA review alone takes ~0.5–2 years.
Explanation of Visuals:
A funnel-like diagram shows number of compounds and volunteers decreasing/increasing per phase.
Glossary:
FDA: U.S. Food and Drug Administration — a key regulatory body.
Clinical trials: Studies on humans to evaluate drug safety and efficacy.
Key Takeaway:
Classical drug discovery is resource-intensive, with a high failure rate — but necessary to ensure safe, effective medications reach patients.
Slide 26: Re-Profiling / Re-Purposing
Key Points:
Re-purposing (also called re-profiling) refers to finding new therapeutic uses for existing drugs.
Instead of starting from scratch, this approach shortens development time and reduces risk and cost.
It still follows parts of the classical drug development pipeline but skips early discovery steps.
Advantages:
Faster transition to clinical testing (from ~6.5 years instead of ~12+).
Uses data mining to identify potential matches between known drugs and new indications.
Glossary:
Data mining: Analyzing large datasets to find patterns (e.g., drug-disease associations).
Re-profiling: Using an old drug for a new disease.
Key Takeaway:
Re-purposing offers a faster and cost-effective route to bring therapies to patients by reusing known drugs for new indications.
Slide 27: Re-Profiling / Re-Purposing – Examples
Key Points:
This slide presents a list of successfully re-purposed drugs, such as:
Thalidomide (from sedative to cancer treatment)
Sildenafil (Viagra) (from hypertension to erectile dysfunction)
Methotrexate (from cancer to autoimmune diseases)
Hydroxychloroquine (anti-malarial re-used in autoimmune diseases)
These examples show how a drug’s known mechanism or off-target effects can be beneficial in unrelated diseases.
Glossary:
Off-target effects: Unexpected drug actions on systems other than the intended target.
Indication: A disease or condition for which a drug is used.
Key Takeaway:
Many well-known drugs have been successfully re-purposed for entirely different medical conditions — highlighting the value of pharmacological flexibility.
Slide 28: Only Small Molecules? (Molecular Size Comparison)
Key Points:
While small molecules are common in drug development (e.g., aspirin), biologicals are increasingly important:
Therapeutic antibodies
Recombinant proteins (e.g., hormones)
Immunosuppressants
These molecules are much larger:
Small molecule: ~0.3 kDa
TNF-alpha: ~25.6 kDa
TNF-alpha receptor: ~55 kDa
Explanation of Visuals:
Circles illustrate size differences between molecule types.
Glossary:
kDa (kilodalton): Unit of molecular weight (larger = heavier).
Biologicals: Protein-based drugs derived from living cells.
Key Takeaway:
Not all drugs are small molecules — modern therapies increasingly use large biological molecules like antibodies and receptors.
Slide 29: Only Small Molecules? (Antibodies Example)
Key Points:
This slide continues the size comparison, adding a real-world antibody drug example:
Infliximab (Remicade®), a monoclonal antibody used against TNF-alpha.
Molecular weight: ~144 kDa — significantly larger than typical small molecules.
Application:
Used in autoimmune diseases (e.g., Crohn’s, rheumatoid arthritis).
Binds TNF-alpha, a key inflammatory cytokine.
Explanation of Visuals:
3D structure of infliximab shown for context.
Size circles again compare small molecule vs. antibody vs. receptor.
Glossary:
Infliximab: Antibody drug that neutralizes TNF-alpha.
Monoclonal antibody: Lab-made antibody targeting a specific molecule.
Key Takeaway:
Drugs like infliximab demonstrate how large biologicals can precisely target disease molecules, expanding treatment options beyond small molecules.
Slide 30: Only Small Molecules? (Growth of Biologicals)
Key Points:
Biological drugs (e.g., antibodies, recombinant proteins) have seen rapid growth over the last two decades.
The graph shows:
Steady increase in biological approvals and market share from ~2000 onward.
Clear trend: Biologics are becoming dominant in the pharmaceutical landscape.
Main Types:
Therapeutic antibodies
Hormonal proteins
Immunosuppressants
Antidiabetics
Glossary:
Biologics: Drugs derived from living organisms or their components.
Small molecules: Chemically synthesized drugs, typically <1 kDa in size.
Key Takeaway:
While small molecules still exist, biologics are increasingly important in modern medicine — offering precise, targeted therapies for complex diseases.
Slide 31: Pharmacoeconomics – Cost of Drug Therapies
Key Points:
Pharmacoeconomics evaluates the cost-effectiveness of medications, especially in public healthcare systems.
The table (from the 2017 German Arzneimittelreport) shows:
Per-patient costs of therapies for selected diseases.
Variation in price between drug types and treatment areas.
Key Findings:
Cancer drugs and biologics are often the most expensive.
Treatments for chronic diseases like rheumatoid arthritis can cost tens of thousands of euros per patient annually.
Glossary:
Per-patient cost: Average annual cost to treat one person with a drug.
Health insurance burden: Total cost paid by healthcare systems.
Key Takeaway:
Some life-saving drugs come with extremely high treatment costs, making pharmacoeconomic analysis essential for healthcare policy and budgeting.
Slide 32: Pharmacoeconomics – Insurance Costs
Key Points:
This table breaks down total reimbursement costs to health insurers per disease and medication group.
It highlights:
High-spending disease areas, like cancer, diabetes, and autoimmune diseases.
The growing financial burden of modern therapies (e.g., biologics).
Use in Decision-Making:
Helps insurers and governments:
Prioritize funding
Negotiate drug prices
Support cost-effective interventions
Glossary:
Reimbursement: Payment by insurance or government for drug costs.
Cost-effectiveness: Relationship between cost and therapeutic benefit.
Key Takeaway:
Pharmacoeconomics supports smart healthcare decisions by comparing therapeutic benefits to treatment costs at a population level.
Slide 33: Animal Models of Human Disease
Key Points:
Animal models are essential for:
Testing drug safety and efficacy
Understanding disease mechanisms
Types of Validity:
Face validity: Animal symptoms look like human disease.
Construct validity: Same biological cause as human disease.
Predictive validity: Same response to treatment.
Challenges:
Some diseases are hard to model:
Diseases unique to humans (e.g., Alzheimer’s)
Diseases with unknown causes
Psychiatric disorders
Glossary:
Animal model: Use of animals to mimic human disease for research.
Pathophysiology: Biological mechanisms behind disease symptoms.
Key Takeaway:
While animal models are vital for preclinical research, they often struggle to replicate complex human diseases — especially psychiatric or idiopathic conditions.
Slide 34: Genetically Modified Mice in Pharmacology
Key Points:
Genetically modified mice help model human diseases and test drugs. There are three main types:
1. Knockout Mice:
A gene is inactivated ("knocked out").
Used to study:
Whether a gene is important for a disease.
If a gene is the target of a drug.
2. Knock-in / Point Mutated Mice:
A specific mutation is inserted (e.g., from a human disease).
Useful for modeling genetic disorders and drug binding to altered proteins.
3. Humanized Mice:
Contain human genes or proteins.
Helpful when a drug only works on the human version of a protein.
Glossary:
Knockout: Gene is completely removed.
Knock-in: A gene is modified, often to mimic a human mutation.
Humanized: Mouse expresses a human gene/protein.
Key Takeaway:
Genetically modified mice allow precise modeling of human diseases and help evaluate the effects of new drugs in a controlled, biologically relevant way.
Slide 35: Clinical Trials – Core Concepts
Key Points:
Controlled clinical trials compare a new treatment to:
A placebo
An active placebo
A standard treatment
Key Design Elements:
Randomization: Assigns participants to treatment groups randomly to reduce bias.
Pseudo-randomization: Less rigorous version; may introduce bias.
Double-blind: Neither the patient nor the doctor knows which treatment was given → eliminates placebo effect and observer bias.
Glossary:
Placebo: Inactive substance used as a control.
Double-blind: Ensures unbiased results by keeping treatment assignment hidden.
Key Takeaway:
Robust clinical trial design (randomized and double-blinded) ensures that the outcomes reflect true drug effects, not bias or expectation.
Slide 36: Clinical Trials – Statistical Considerations
Key Points:
Statistical Factors:
Power: Probability of detecting a true effect.
Effect size: Magnitude of drug impact.
Sample size: Number of participants.
Bias: Sources include design flaws, publication bias, and patient selection.
Meta-Analysis:
Combines data from multiple studies for a stronger overall conclusion.
Helps uncover hidden effects or reinforce findings.
Interim Analyses:
Ongoing evaluation during a trial to ensure safety and effectiveness.
Key Outcome Measures:
Subjective outcomes (e.g., pain ratings) must be interpreted carefully.
Objective outcomes (e.g., blood pressure) are more reliable.
NNT (Number Needed to Treat): Number of patients who must be treated to benefit one person.
NNH (Number Needed to Harm): Number needed to cause one adverse effect.
Glossary:
NNT / NNH: Help quantify drug benefits vs. risks in clinical terms.
Meta-analysis: A "study of studies."
Key Takeaway:
Good clinical trials rely on careful statistics and clear outcome measures to interpret whether a drug truly works—and whether it’s worth the risk.
Slide 37: Clinical Trials – The Four Phases
Key Points:
Clinical trials are conducted in four main phases, each with a specific purpose:
Phase 1:
Participants: Healthy volunteers (usually 20–100).
Focus:
Pharmacokinetics (how the drug moves through the body).
Tolerability (early safety and side effects).
Phase 2:
Participants: Small group of patients with the disease.
Focus:
Therapeutic efficacy (does it work?).
Optimal dose selection.
Phase 3:
Participants: Large number of patients in controlled trials.
Focus:
Efficacy under realistic conditions (how well it works in daily life).
Safety and side effects.
Phase 4:
Conducted after drug approval (post-marketing).
Focus:
Long-term safety and tolerability in a broader population.
Glossary:
Pharmacokinetics: How a drug is absorbed, distributed, metabolized, and excreted.
Tolerability: How well patients can handle the drug without major side effects.
Post-marketing: Surveillance of drug use after it's on the market.
Key Takeaway:
Clinical trials progress from testing in healthy volunteers to widespread patient use, ensuring a drug is safe, effective, and usable under real-life conditions before and after approval.