Lecture 2 Flashcards
What are the three main components of a cell?”
Cell membrane, cytoplasm, and nucleus.”
What must a drug first cross to enter a cell?”, “
The plasma membrane.”
To enter a cell, a drug must first cross the plasma membrane, which is the outer boundary of the cell. This membrane regulates the movement of substances into and out of the cell and is crucial for controlling cell interactions and substance transport. The term “plasma membrane” is used to emphasize its role in these processes, while “cell membrane” can refer more broadly to any membrane within the cell.
Before a drug gets into the blood and lymph, what are the three main ways drugs move through the plasma membrane?”
Transcellular, paracellular, and efflux transporter.”
What is transcellular transport?
Drug moves through all the layers of the cell to the blood and lymph via passive diffusion, active transport, or facilitated transport until equilibrium is reached.
“What factors affect transcellular transport?”
“How does lipophilicity affect drug permeability?”,
“Why do water-soluble drugs find it difficult to get into the cell?”
“How does molecular size affect drug permeability?”
“How does the degree of ionization affect drug permeability?”,
“How does molecular structure influence drug transport?”,
“How do functional groups affect drug transport?
“How does surface area influence drug permeability?
“What factors affect transcellular transport?”, “Lipophilicity, molecular size, degree of ionization, molecular structure, functional groups, surface area.”
“How does lipophilicity affect drug permeability?”, “More lipophilic drugs are more permeable due to the lipid bilayer of the cell membrane.”
“Why do water-soluble drugs find it difficult to get into the cell?”, “Because the lipid bilayer of the cell membrane is less permeable to them.”
“How does molecular size affect drug permeability?”, “Smaller size means higher permeability.”
“How does the degree of ionization affect drug permeability?”, “Non-ionized molecules diffuse more easily.”
“How does molecular structure influence drug transport?”, “H-donor/acceptor properties: Proton donors (acids) and proton acceptors (bases).”
“How do functional groups affect drug transport?”, “Determine chemical structure and reactivity, influencing how the drug reacts with other drugs.”
“How does surface area influence drug permeability?”, “Larger surface areas, like the gut with many villi, facilitate greater permeability. Large, polar, and more charged molecules move more slowly.”
What is paracellular transport?”
“What example illustrates paracellular transport?
“What factors influence paracellular transport?”
What is paracellular transport?”, “Drug moves along the border of cells through spaces between adjacent cells via passive diffusion, important for polar hydrophilic drugs.”
“What example illustrates paracellular transport?”, “Water molecules moving through aquaporins.”
“What factors influence paracellular transport?”, “Molecular size, size and density of junctions, surface area.”
Size and Density of Junctions: Tight junctions between cells can restrict movement; less dense or larger gaps allow easier passage.
What is an efflux transporter?
“What is an example of an efflux transporter?”
What is an efflux transporter?”, “Transport mechanism that can reduce oral absorption by transporting drugs back into the intestinal lumen.”
How to remember:
Efflux is opposite of influx. Influx means to go in. Efflux is to go out. So the drug is being pushed out of the cells and into either the intestinal lumen or the blood but mostly the intestinal lumen. This reduces absorption of drugs Can decrease the amount of drug that gets absorbed into the bloodstream by transporting it back into the intestinal lumen.
EFFLUXX = EXIT”: Think of “EFFLUXX” as a way to remember that it helps substances exit or leave the cell. The “X” can symbolize “exit.”
Efflux systems function via an energy-dependent mechanism (active transport) to pump out unwanted toxic substances through specific efflux pumps
An efflux pump is an active transporter in cells that moves out unwanted material. Efflux pumps are an important component in bacteria in their ability to remove antibiotics.
“What is an example of an efflux transporter?”,
1.P glycoprotein, which affects drugs like paclitaxel.
2. Breast Cancer Resistance Protein (BCRP)
3.Multidrug Resistance-associated Protein (MRP):
• Function: Includes several types (e.g., MRP1, MRP2) that transport drugs and conjugates out of cells.
• Role: Plays a role in drug excretion from cells and can reduce drug absorption.
4. ATP-binding Cassette (ABC) Transporters
5. Efflux Pumps in Bacteria (e.g., AcrAB-TolC): contributing to antibiotic resistance
What role do tight junctions play in paracellular transport?
“What strategies are used to overcome barriers to paracellular transport?
What role do tight junctions play in paracellular transport?”, “They regulate the passage of ions and small molecules between epithelial cells, maintaining tissue integrity.”
“What strategies are used to overcome barriers to paracellular transport?”, “Use of prodrugs, carrier systems, and formulation optimization.”
How Prodrugs Help:
• Improved Absorption: Prodrugs can be designed to have better properties for crossing epithelial barriers compared to their active forms. For instance, they might be more easily absorbed through tight junctions or epithelial cells.
Formulation Optimization:
• Adjusting the drug formulation, such as altering particle size or using permeation enhancers, can enhance the drug’s ability to cross epithelial barriers and improve paracellular transport.
What are functional groups?
What transport mechanisms do Drugs enter into the lipid bilayer?
Osmosis,active transport,diffusion?
“How do polar functional groups affect drug transport?”
“How do non-polar functional groups affect drug transport?”
“How do acidic(say for ionized acidic and non ionized acidic) functional groups affect drug transport?
“How do basic(say for basic ionized and basic non ionized) functional groups affect drug transport?
What are functional groups?”, “Specific groups of atoms within molecules that have characteristic properties and reactivity.”
“How do polar functional groups affect drug transport?”, “Increase hydrophilicity and generally decrease lipophilicity, making it harder for the drug to diffuse through the lipid bilayer.”
“How do non-polar functional groups affect drug transport?”, “Increase lipophilicity, enhancing the ability of the drug to pass through the lipid bilayer via simple diffusion.”
“How do acidic functional groups affect drug transport?”, “Can ionize to form -COO- in physiological pH, making ionized forms less lipophilic and more hydrophilic, reducing membrane permeability.”
“How do basic functional groups affect drug transport?”, “Can ionize to form -NH3+ in physiological pH, making ionized forms less lipophilic and more hydrophilic, reducing membrane permeability.”
Hydrophilicity of Ionized Forms: Both basic and acidic functional groups become more hydrophilic when ionized because they carry charges that attract water molecules.
• Hydrophilicity of Non-Ionized Forms: The non-ionized forms of these groups can be less hydrophilic. For example, non-ionized carboxylic acids (-COOH) are less hydrophilic compared to their ionized form (-COO⁻), and non-ionized amines (-NH₂) are less hydrophilic compared to their ionized form (-NH₃⁺).
How do functional groups capable of hydrogen bonding affect drug transport?
“How do bulky functional groups affect drug transport?
“How do flexible or rigid structures influence drug transport?
What is steric hindrance
“How do esters and amides affect drug transport?
“How do halogens affect drug transport?”
If you want a drug to be more lipophilic,state two molecules you can add to it to make it so
How do functional groups capable of hydrogen bonding affect drug transport?”, “Increase hydrophilicity, can form hydrogen bonds with water, increasing solubility in aqueous environments but decreasing lipid solubility.”
“How do bulky functional groups affect drug transport?”, “Increase the overall size of the drug molecule, making it harder to diffuse through the lipid bilayer, may require transport proteins.”
“How do flexible or rigid structures influence drug transport?”, “Flexibility can aid in fitting through membrane channels, while rigid structures might face steric hindrance.”Steric Hindrance: Occurs when bulky groups or atoms in a molecule occupy space and physically block or hinder the approach or interaction of other molecules or functional groups.
2. Effects on Reactions:
• Reaction Rates: Steric hindrance can slow down or prevent chemical reactions by obstructing the active sites or reducing the accessibility of reactants.
“How do esters and amides affect drug transport?”, “Esters increase lipophilicity facilitating passive diffusion; amides are more polar and may require transport mechanisms.”
Esters increase lipophilicity primarily due to the presence of long hydrocarbon chains that dominate over the ester’s polar functionality, reducing overall polarity and hydrogen bonding capability. This makes esters more soluble in lipids
Hydrophilicity vs. Lipophilicity:
• Hydrophilic Character: Amides are generally more hydrophilic because they can engage in hydrogen bonding with water. This makes them relatively soluble in water.
• Lipophilicity: While amides are more hydrophilic than many other functional groups, their lipophilicity can still vary. The size of the R group influences this property. Larger, non-polar R groups can increase the molecule’s lipophilicity.
“How do halogens affect drug transport?”, “Increase lipophilicity, enhancing membrane permeability for passive diffusion.”
However, this does not mean that large molecules cannot be lipophilic.
• Lipophilicity: Refers to the affinity of a molecule for lipids or fats, indicating how easily it dissolves in or interacts with lipid environments.
2. Role of Large Halogens:
• Halogens: Halogens like chlorine (Cl), bromine (Br), and iodine (I) are large compared to hydrogen, and their size affects the molecule’s lipophilicity.
• Effect of Size: When large halogens are incorporated into a molecule, they increase its bulk and hydrophobic character. This increase in hydrophobicity often enhances lipophilicity because the molecule’s overall non-polar surface area increases, making it more soluble in lipid environment
You can add an ester or a halogen to it
What is diffusion?”
What are the two types?
What is simple diffusion?”,
What is facilitated diffusion?
What are the characteristics of diffusion?”
What is diffusion?”
Passive movement of molecules from an area of higher concentration to an area of lower concentration.”
“What is simple diffusion?”, “Direct passage through the cell membrane (e.g., oxygen, carbon dioxide).”
“What is facilitated diffusion?”, “Passage through the cell membrane via specific carrier proteins or channels (e.g., glucose entering cells via glucose transporters).”
“What are the characteristics of diffusion?”, “No energy required, moves down the concentration gradient, influenced by lipophilicity, molecular size, degree of ionization, and surface area.”
Moves Down the Concentration Gradient:
• Gradient Direction: Molecules move from an area of higher concentration to an area of lower concentration. This movement from high to low can also be termed as moving down a concentration gradient and moving from
Low to high is moving up a concentration gradient
This movement continues until equilibrium is reached, where the concentration of molecules is uniform across the space.
3. Influenced by Several Factors:
• Lipophilicity:
• Effect: Molecules that are lipophilic (fat-loving) tend to diffuse more easily through lipid membranes, such as cell membranes, which are composed primarily of phospholipid bilayers.
• Molecular Size:
• Effect: Smaller molecules generally diffuse more readily compared to larger molecules. Larger molecules face more resistance due to their size and can diffuse more slowly.
• Degree of Ionization:
• Effect: Molecules that are ionized (charged) are less likely to diffuse through lipid membranes because they are more hydrophilic and less able to pass through the non-polar lipid bilayer. Non-ionized (neutral) forms of molecules can diffuse more easily through membranes.
• Surface Area:
• Effect: An increased surface area for diffusion (such as a larger area of membrane) allows for more molecules to pass through at a given time, enhancing the rate of diffusion.
What is active transport?
What is primary active transport? Give examples
What is secondary active transport? Give examples
What are the characteristics of active transport?”
What are the characteristics of active transport?”
What is active transport?”, “Active movement of molecules against their concentration gradient, from an area of lower concentration to an area of higher concentration.
“What is primary active transport?”, “Direct use of ATP to transport molecules (e.g., sodium-potassium (Na+/K+) pump).”
“What is secondary active transport?”, “Indirect use of ATP, relying on the electrochemical gradient created by primary active transport (e.g., glucose-sodium co-transport).”
“What are the characteristics of active transport?”, “Requires energy (ATP), moves against the concentration gradient, influenced by availability of ATP, carrier proteins, and cellular conditions.”
Cellular conditions can significantly impact active transport in several ways. Here’s how different conditions affect active transport processes:
- Energy Availability• ATP Levels: Active transport relies on energy, typically from ATP. Low ATP levels can reduce the efficiency or halt active transport because there is insufficient energy to drive the transport pumps.
• Energy Sources: If cells have alternative energy sources, like ADP or AMP, they might still perform active transport, but less efficiently. - Ion Concentrations• Electrochemical Gradients: Active transport often works to maintain or establish ion gradients. Changes in ion concentrations (e.g., sodium or potassium) outside or inside the cell can impact the functioning of ion pumps like the sodium-potassium pump (Na⁺/K⁺ ATPase).
• Ion Imbalance: Imbalances can affect the transport rate and lead to cellular dysfunction. - pH Levels• Acidity or Alkalinity: The pH of the cellular environment can affect the activity of transport proteins. For example, some transporters are pH-sensitive and may not function optimally under extreme pH conditions.
• Proton Pumps: In cells with proton pumps (e.g., in the stomach), pH changes can impact the efficiency of these pumps. - Membrane Integrity• Damage to Membranes: Physical or chemical damage to the cell membrane can affect the activity of transport proteins and disrupt active transport processes.
• Fluidity: Changes in membrane fluidity (e.g., due to temperature) can influence the activity and mobility of transport proteins. - Transport Protein Availability• Expression Levels: The amount of transport protein present on the membrane affects active transport. Cellular conditions that alter protein synthesis (e.g., stress or nutrient availability) can change the number of transport proteins available.
• Inhibition or Modulation: Specific inhibitors or modulators can affect the activity of transport proteins. - Cellular Volume and Osmotic Pressure• Volume Changes: Changes in cell volume (e.g., due to osmotic pressure) can impact transport processes. Cells may adjust their transport activities to manage volume and osmotic pressure.
• Pressure Conditions: High or low osmotic pressure can alter the functioning of transport proteins. - Temperature• Optimal Temperature: Active transport proteins have an optimal temperature range. Deviations from this range can reduce the efficiency of transport processes.
- Cellular Signaling• Regulatory Signals: Cellular signaling pathways can regulate the activity of transport proteins. For example, signaling molecules or hormones can enhance or inhibit the function of specific transporters.
Summary
Cellular conditions such as energy availability, ion concentrations, pH levels, membrane integrity, transport protein availability, osmotic pressure, temperature, and signaling can all impact the effectiveness and efficiency of active transport. Proper functioning of active transport is crucial for maintaining cellular homeostasis and responding to changing conditions.
What is absorption in pharmacokinetics?
What factors affect drug absorption?
What does disposition refer to in pharmacokinetics?
What is elimination in pharmacokinetics?”,
What is absorption in pharmacokinetics?”, “Process from the time a drug enters the body to the time it enters the bloodstream to be circulated. The key term is blood stream.
“What factors affect drug absorption?”,
Dosage form
Route of administration-is it being taken in by mouth? Even with by mouth, is it sub lingual,a syrup,a tablet,a capsule
blood flow to the site of administration-more blood flow to site of administration means more drug gets distributed
gastrointestinal function, presence of food or other drugs.”
“What does disposition refer to in pharmacokinetics?”, “Comprises both distribution of the drug and its elimination OR Distribution,Metabolism,Excretion.
disposition means to dispose of something. So remember it this way, disposition is distribution and elimination but not distribution and excretion because disposition is a detailed process that contains metabolism and excretion too. So if you pick disposition as distribution and excretion, you don’t take into consideration the metabolism
Part. But saying disposition is distribution and elimination takes this into account. Don’t use D+E to remember cuz you may forget that the E in ADME is Excretion and not elimination.
To remember that excretion is what is in ADME, in JHS, we heard of excretion. Kidneys for excretion. We didn’t hear of elimination
“What is elimination in pharmacokinetics?”, “Comprises both metabolism and excretion.”
The disposition,elimination,absorption terms are defined with respect to the site of measurement which is usually drug in the blood or plasma in Vivo as opposed to in vitro
True or false
True
In pharmacokinetics:
- Disposition refers to the overall process of how a drug is absorbed, distributed, metabolized, and eliminated in the body.
- Elimination includes both the metabolism and excretion of the drug.
- Absorption describes how the drug enters the bloodstream from its site of administration.
These terms are typically defined and measured in in vivo conditions, focusing on drug concentrations in blood or plasma. In vitro studies provide preliminary data but do not fully represent drug dynamics in a living organism.
In vitro studies are usually done outside the body and in labs
• In Vivo: Inside the living organism (think “in life” or “inside the vivo”). • In Vitro: Outside the living organism (think “in glass” or “in the lab”).
What is bioavailability?
What factors influence bioavailability?
How does IV administration affect bioavailability?
What allows mucous membranes to facilitate drug absorption?
How does subcutaneous administration compare to oral administration in terms of absorption?”,
What is bioavailability?”, “The portion or a dose that reaches the systemic circulation and is available to act on body cells.
Bio” + “Available”
• “Bio” refers to life or the body.
• “Available” means accessible or able to be used.
• Think of “bioavailable” as how much of a drug is actually available to the body after it enters the bloodstream.
“What factors influence bioavailability?”
Dosage form, route of administration, blood flow to the site of administration, gastrointestinal function, presence of food or other drugs.”
“How does IV administration affect bioavailability?”, “IV administration is 100% bioavailable because it doesn’t pass through any tissue to get to the blood.
“How does subcutaneous administration compare to oral administration in terms of absorption?”, “Subcutaneous administration has more rapid absorption than oral route.”
“What allows mucous membranes to facilitate drug absorption?”, “Mucous membranes allow for rapid and direct absorption into the bloodstream.”Mucous membranes facilitate drug absorption due to their large surface area(villi), rich blood supply, thin barrier, and high permeability, allowing for rapid and direct entry into the bloodstream. mucous membranes of areas like the oral cavity or nasal passages , Gastrointestinal Tract:
• Sublingual Area,rectal mucosa,
Conjunctiva,vaginal mucosa
