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Questions and Answers
What is the primary physiological role of bile?
What is the primary physiological role of bile?
What is used to estimate hepatic clearance?
What is used to estimate hepatic clearance?
What occurs during enterohepatic recycling?
What occurs during enterohepatic recycling?
How do gut bacteria affect Phase II drug conjugates after biliary excretion?
How do gut bacteria affect Phase II drug conjugates after biliary excretion?
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What is the significance of molecular weight in drug conjugates excreted via bile?
What is the significance of molecular weight in drug conjugates excreted via bile?
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What does a high Volume of Distribution (Vd) indicate about a drug's behavior in the body?
What does a high Volume of Distribution (Vd) indicate about a drug's behavior in the body?
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Which characteristic is associated with a drug that has low lipophilicity?
Which characteristic is associated with a drug that has low lipophilicity?
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What is the primary organ responsible for drug metabolism?
What is the primary organ responsible for drug metabolism?
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Which phase of drug metabolism involves the breakdown of drugs through processes like oxidation and hydrolysis?
Which phase of drug metabolism involves the breakdown of drugs through processes like oxidation and hydrolysis?
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What effect does drug metabolism typically have on metabolites compared to the parent compound?
What effect does drug metabolism typically have on metabolites compared to the parent compound?
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Which type of drug tends to accumulate in pigmented tissues due to its affinity for melanin?
Which type of drug tends to accumulate in pigmented tissues due to its affinity for melanin?
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What is the primary goal of Phase II drug metabolism?
What is the primary goal of Phase II drug metabolism?
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What characteristic defines drugs with an apparent Volume of Distribution (Vd) approximately equal to 3L?
What characteristic defines drugs with an apparent Volume of Distribution (Vd) approximately equal to 3L?
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What effect do partial agonists have when all receptors are occupied?
What effect do partial agonists have when all receptors are occupied?
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Which of the following statements is true about spare receptors?
Which of the following statements is true about spare receptors?
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What is the intrinsic efficacy of an antagonist?
What is the intrinsic efficacy of an antagonist?
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What characterizes competitive antagonism on a dose-response curve?
What characterizes competitive antagonism on a dose-response curve?
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What does a Schild Plot indicate about competitive antagonism?
What does a Schild Plot indicate about competitive antagonism?
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How does insurmountable antagonism differ from competitive antagonism?
How does insurmountable antagonism differ from competitive antagonism?
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What is a characteristic of allosteric antagonism?
What is a characteristic of allosteric antagonism?
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What demonstrates physiological antagonism?
What demonstrates physiological antagonism?
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What does a small Km value indicate about an enzyme's affinity for its substrate?
What does a small Km value indicate about an enzyme's affinity for its substrate?
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Which statement about Kcat is true?
Which statement about Kcat is true?
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In competitive inhibition, what happens to Vmax as substrate concentration increases?
In competitive inhibition, what happens to Vmax as substrate concentration increases?
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What is the effect of non-competitive inhibition on Km and Vmax?
What is the effect of non-competitive inhibition on Km and Vmax?
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How does uncompetitive inhibition affect both Km and Vmax?
How does uncompetitive inhibition affect both Km and Vmax?
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What property distinguishes competitive inhibitors from non-competitive inhibitors?
What property distinguishes competitive inhibitors from non-competitive inhibitors?
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What defines the inhibitory constant Ki in enzyme inhibition?
What defines the inhibitory constant Ki in enzyme inhibition?
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Which type of inhibition cannot be overcome by increasing substrate concentration?
Which type of inhibition cannot be overcome by increasing substrate concentration?
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What effect does increasing substrate concentration have on competitive inhibition?
What effect does increasing substrate concentration have on competitive inhibition?
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In relation to enzyme inhibition, what does mixed inhibition involve?
In relation to enzyme inhibition, what does mixed inhibition involve?
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What is the significance of chemical shift in NMR spectroscopy?
What is the significance of chemical shift in NMR spectroscopy?
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In 13C NMR spectroscopy, what does the number of peaks indicate?
In 13C NMR spectroscopy, what does the number of peaks indicate?
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How can the number of hydrogen atoms attached to a carbon be determined in 13C NMR?
How can the number of hydrogen atoms attached to a carbon be determined in 13C NMR?
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What results in a singlet peak in 1H NMR spectroscopy?
What results in a singlet peak in 1H NMR spectroscopy?
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Why do NH and OH peaks appear broad and variable in 1H NMR?
Why do NH and OH peaks appear broad and variable in 1H NMR?
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What is typically observed in spin-spin coupling in 1H NMR?
What is typically observed in spin-spin coupling in 1H NMR?
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What happens to the peaks of NH and OH signals upon addition of D2O?
What happens to the peaks of NH and OH signals upon addition of D2O?
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What effect does increased electron density have on the magnetic field experienced by a nucleus?
What effect does increased electron density have on the magnetic field experienced by a nucleus?
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How does the presence of quaternary carbons affect the NMR spectrum?
How does the presence of quaternary carbons affect the NMR spectrum?
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Why do normal nuclei with even atomic numbers typically not interact with the magnetic field in NMR?
Why do normal nuclei with even atomic numbers typically not interact with the magnetic field in NMR?
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Study Notes
Drug Distribution
- Most drugs are distributed by passive diffusion.
- Volume of distribution (Vd) represents the hypothetical volume the total amount of drug would occupy if it were equally distributed throughout the body at the same concentration as in the plasma.
- Vd is influenced by a drug's lipophilicity, distribution into tissues, and binding to plasma proteins.
- High Vd means the drug leaves the plasma and distributes into other tissues, while low Vd indicates that it largely remains in the plasma.
- Hydrophilic drugs tend to remain in the plasma, resulting in a Vd close to the plasma volume (3L).
- Drugs with high lipophilicity readily cross membranes and have a higher Vd (greater than 3L).
- Some drugs accumulate in specific tissues due to affinity.
- Plasma protein binding can keep drugs in the blood longer, delaying distribution to cells.
Drug Metabolism
- The body primarily metabolizes drugs through metabolic reactions that increase water solubility, aiding elimination via urine and faeces.
- Metabolism can also increase toxicity or pharmacological effects in some instances.
- Two main phases of drug metabolism:
- Phase I: Catabolic reactions (oxidation, reduction, hydrolysis) that introduce polar groups to lipophilic compounds.
- Phase II: Conjugation reactions, attaching chemical groups to drugs or Phase I metabolites, further increasing polarity.
- Major metabolic organ: liver.
- Drug metabolism generally results in less-active and more polar metabolites.
Liver and Bile Excretion
- Liver is the major site for drug metabolism, with hepatocytes (liver cells) playing a key role.
- Bile, produced by the liver and stored in the gallbladder, contributes to the excretion of cholesterol, lipid absorption, and intestinal motility.
- Conjugated drug metabolites are often taken up by biliary cells and excreted in bile, eventually reaching the faeces through the intestine.
- Large molecular weights (over 500 Da) favor biliary excretion.
First-Pass Metabolism
- Orally administered drugs do not reach systemic circulation at 100% due to pre-systemic metabolism in the liver.
- Hepatic clearance is estimated using hepatic blood flow rate (QH) and hepatic extraction ratio (EH): Cl Hepatic = EH X QH.
Enterohepatic Recycling
- Gut bacteria in the intestines can cleave Phase II drug conjugates, releasing the drug or Phase I metabolite back into circulation.
- This reabsorption process can increase blood levels and prolong therapeutic effects, leading to a secondary phase of drug action.
- With repeated cycles of enterohepatic recycling, drug levels gradually decline due to some faecal elimination.
Pulmonary Elimination
- Lung elimination is the main route for gaseous and volatile substances that do not require metabolism.
Enzyme Kinetics
-
Km: Michaelis-Menten constant, representing substrate concentration at half-maximal velocity (Vmax).
- Low Km suggests high enzyme affinity for the substrate.
- Kcat: Rate of conversion of substrate to product when the enzyme is saturated with substrate.
- Catalytic efficiency: Ratio of Kcat/Km, reflecting how efficiently an enzyme uses its substrate at physiological concentrations.
Enzyme Inhibition
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Reversible Inhibtion: Inhibitor-enzyme interactions are temporary.
-
Competitive Inhibition: Inhibitor binds to the active site, competing with the substrate. Can be overcome by increasing substrate concentration.
- Vmax remains unchanged, but apparent Km increases.
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Non-competitive inhibition: Inhibitor binds to an allosteric site, changing the enzyme's conformation and reducing activity. Cannot be overcome by increasing substrate concentration.
- Km remains unchanged, but Vmax decreases.
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Uncompetitive Inhibition: Inhibitor binds only to the enzyme-substrate complex.
- Both Km and Vmax decrease, but with the same ratio.
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Competitive Inhibition: Inhibitor binds to the active site, competing with the substrate. Can be overcome by increasing substrate concentration.
- Irreversible Inhibition: Inhibitor forms strong, often covalent bonds with the enzyme, permanently disrupting activity.
Pharmacodynamic Antagonism
- Antagonists bind to receptors without activating them, reducing the affinity and efficacy of agonists.
- Competitive Antagonists: Bind reversibly to the same site as the agonist, shifting the agonist dose-response curve to the right and reducing its potency. Can be overcome by increasing agonist concentration.
- Insurmountable Antagonists: Irreversible or extremely high affinity antagonists that cannot be overcome by high agonist doses due to their permanent binding.
- Allosteric Antagonists: Bind to an allosteric site, reducing the affinity of the agonist without directly affecting receptor activation.
- Physiological (Functional) Antagonists: Agonists that have opposing effects on the same tissue, achieving antagonism by counteracting each other's actions.
Nuclear Magnetic Resonance (NMR) Spectroscopy
- Principle: Uses a magnetic field to detect and analyze the magnetic properties of atomic nuclei in a molecule, particularly 1H and 13C.
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Chemical Shift: Indicate the electron density around a specific nucleus in a molecule.
- Measured in ppm (parts per million) and displayed on a NMR spectrum as a unique peak location for different atomic environments.
- More shielded nuclei (higher electron density) will have larger chemical shifts (shifted further to the right) on the spectrum.
- 1H NMR: Provides information on the number of protons (integral), their chemical environment (chemical shift), and their interactions with neighboring protons (splitting patterns). .
- 13C NMR: Provides information on the number of unique carbon environments (peaks) in a molecule.
How NMR Spectroscopy Helps Determine Structure
- Analyzing the number and chemical shift of peaks in both 1H and 13C NMR spectra allows for identification of functional groups and their arrangement in the molecule.
Spin-Spin Coupling (Splitting Patterns):
- The splitting of NMR signals in 1H NMR is caused by the interaction of magnetic fields from neighboring protons.
- The number of peaks in a split signal (n+1 rule) corresponds to the number of neighboring protons plus one.
- The size of the splitting (coupling constant) depends on the type and number of bonds between the coupled nuclei.
- Singlet: A single peak results when there are no neighboring protons.
- Doublet: Two peaks indicate one neighboring proton.
- Triplet: Three peaks indicate two neighboring protons.
Drug Development and Inhibition
- Enzyme inhibition is a significant strategy in drug development, targeting specific enzymes to modulate their activity.
- Reversible Inhibition: Temporary blocking of an enzyme, typically accomplished by competing with the substrate for the active site or interacting with an allosteric site.
- Irreversible Inhibition: Permanent inactivation of an enzyme by forming a strong bond (covalent or non-covalent).
- Ki (Inhibitory Constant): Measures the strength of an inhibitor, with lower values indicating stronger binding affinity.
- Spare Receptors: Maximum drug response can be achieved with less than 100% receptor occupancy, suggesting spare receptors contribute to the response.
- Partial Agonist: Produces less than the maximal response, even when all receptors are occupied. In the presence of a full agonist, it reduces the maximal response.
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Description
Explore the intricate processes of drug distribution and metabolism in this pharmacology quiz. Understand concepts like volume of distribution, lipophilicity, and how various factors influence drug behavior in the body. Test your knowledge on how drugs are distributed across tissues and the metabolic pathways that alter their solubility.
