What are the two metabolic phases of drug metabolism?
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Phase I and Phase II
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What are the main reactions involved in Phase I metabolism?
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Oxidation, reduction, and/or hydrolysis
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What is the typical fate of a drug after Phase I metabolism?
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Activated, unchanged, or inactivated
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What are Phase I metabolic reactions?
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• non-synthetic reactions catalyzed by hepatic microsomal enzymes,
• oxidation, reduction, and hydrolysis → hydrophilic compounds
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What are Phase I reaction results
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• Inactivation of drugs (many drug groups).
• Conversion: inactive drug → active metabolite (codeine to morphine, cortisone to cortisol)
• Conversion: drug → toxic compound (methanol to formaldehyde)
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Which enzymes are mainly involved in Phase I reactions?
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hepatic microsomal enzymes, CYP450 enzymes
47
What are Phase II metabolic reactions?
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• Synthetic reactions
• conjugation of parent compound/its metabolite with glucuronic acid, acetic acid, or glycine
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How do Phase II reactions typically affect drug activity?
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usually lead to drug inactivation
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Phase II reaction pathway
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• convert drug to more hydrophilic form for renal excretion
• lead to drug inactivation
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What is portal circulation in the context of drug metabolism?
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rate of blood flow to the liver and plasma protein binding
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How does liver function affect drug metabolism?
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Patients with decompensated livers will have lower metabolic activity.
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What role do genetic factors play in drug metabolism?
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Individuals vary in their inherited ability to metabolize drugs.
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What is the main organ for drug excretion?
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The kidney
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what are the routes of elimination
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urine, feces, saliva, sweat, tears, milk and lungs
55
What is renal clearance of drugs?
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measures the volume of plasma that is cleared from the drug per minute
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What is the formula for calculating renal clearance (CL)?
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CL (ml/min) = Rate of drug elimination / plasma drug concentration
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What are the three mechanisms by which renal excretion occurs?
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Glomerular filtration
active transport via plasma protein binding
tubular reabsorption
58
How does glomerular filtration contribute to renal excretion?
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Most chemicals and drugs with low molecular weight are excreted by glomerular filtration.
59
What is first-order elimination in drug kinetics?
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constant fraction of drug is eliminated per unit time
depending on the plasma drug concentration
most drugs
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What is zero-order elimination in drug kinetics?
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constant amount of drug is eliminated per unit time regardless of plasma concentration
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What is the definition of half-life (t ½)?
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The time needed for the plasma drug concentration to be reduced by 50%
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Which type of drug kinetics does elimination half-life apply to?
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First order kinetics
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How long does it take for most drugs to be cleared from the body?
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After 4-5 half-lives
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What is the formula for calculating half-life (t½)?
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t½ = 0.693 Vd/CL
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What is the effect of a CYP inducer on clearance (CL) and half-life (t½)?
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A CYP inducer increases CL and decreases t½.
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How many half-lives are typically required to reach a steady state in drug kinetics?
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Usually, 4 half-lives are required to reach a steady state.
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What is pharmacodynamics?
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The study of how drugs interact with the body to produce a pharmacological effect.
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What percentage of drug targets are receptors according to the pie chart?
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47%
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T/F: the magnitude of a pharmacological response is proportional to the number if receptors available for a drug
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True
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What is a ligand and ligand detector in pharmacodynamics?
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ligand: substance that binds to a receptor (drug)
ligand detector: receptor
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How do drug-receptor interactions typically occur?
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Drug-receptor interactions are usually reversible.
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What are the three stages of signal transduction?
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Reception, Transduction, Cell Response
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What happens during the Reception stage of signal transduction?
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Receptors bind to ligands
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What occurs during the Transduction stage of signal transduction?
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Receptor protein changes and activate intracellular molecules (2nd messengers)
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What are Ligand-gated ion channels and how do they function?
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• cell surface receptors
• open in response to ligand binding
• allowing ion exchange → initiates cell signaling
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Provide an example of a Ligand-gated ion channel and its ligand.
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Cholinergic nicotinic receptors -- acetylcholine
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What are G protein-coupled receptors?
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• Seven-transmembrane receptors
• common drug targets for hydrophilic molecules
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What happens after G protein-coupled receptors are activated?
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G proteins bind secondary messengers → signal amplification
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What are some effector molecules activated by G protein-coupled receptors?
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Adenyl cyclase (cAMP) and phospholipase C (increase calcium concentration).
80
What are enzyme-linked receptors and how do they function?
What are intracellular receptors and how do they work?
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• receptors that can diffuse through the plasma membrane
• bind to hydrophobic ligands
• interact with specific DNA sequences to activate/deactivate transcription of target genes
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What is receptor-mediated drug action?
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process by which drugs interact with specific receptors on/within cells to produce a biological effect
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What is the definition of intrinsic activity?
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measure of the drug's ability to activate a receptor after binding
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What are full agonists
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• drugs capable of binding to receptors causing maximal activation
• intrinsic activity equal to 1
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what are partial agonists?
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• can occupy all receptors without producing maximal response
• Intrinsic activity<1
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What is an antagonist in pharmacology?
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• drug that binds to the receptor without activation or initiating a response
• blocks action of an agonist or substance that activates that receptor
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What is a competitive antagonist?
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binds to the receptor in the same site for the agonist without causing receptor activation
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What is a noncompetitive antagonist?
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noncompetitive antagonist does not bind to the same site as an agonist
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What is a competitive antagonist?
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A medication that reversibly binds to the same receptor site where an agonist binds but does not activate it.
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What is receptor downregulation?
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where repeated exposure to agonists leads to a diminished response of the cell
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What is the term for the diminished response to repeated exposure to agonists?
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Tolerance or tachyphylaxis.
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What is desensitization or tachyphylaxis?
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• rapid decrease in the body's responsiveness to a drug
• often occurring with the initial dose
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How does tolerance differ from desensitization or tachyphylaxis?
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• Tolerance: more gradually, repeated doses
• desensitization/tachyphylaxis: rapid, initial dose, not fixed with increased dose
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What is EC50
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• Effective Concentration 50
• concentration of a drug that produces 50% of its maximum response
95
What is the maximal efficacy of a drug (Emax)
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drug occupying all receptors, yielding the maximum response
96
What is the definition of potency in pharmacology?
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concentration (EC50) of a drug required to produce 50% of its maximal response
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How is potency used in comparing drugs?
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Potency is used to compare drugs within the same group.
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What is efficacy in pharmacology?
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ability of a drug to elicit the maximal pharmacologic response
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How does efficacy differ from potency?
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Efficacy is the maximal response
potency is the dose required to achieve that response
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What is the treatment for opioid overdose?
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Naloxone
101
What is pharmacotherapeutics?
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The study of the use of drugs in the treatment of diseases.
What is the definition of an ultrarapid metabolizer?
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has an accelerated drug metabolism with a higher rate of drug elimination and possibly lower efficacy
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What is the definition of a poor metabolizer?
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• has slower drug metabolism leading to drug accumulation
• higher potential for adverse events, drug-drug interactions, and lower efficacy
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What does Category A indicate about the potential risk to the fetus in the first trimester of pregnancy?
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No potential risk
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Category B pregnancy risk status
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• Animal studies failed to demonstrate a risk
• no adequate, well-controlled studies in pregnant women
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Category C pregnancy risk status
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• Animal studies demonstrated adverse effect on the fetus
• no adequate, well-controlled studies in humans
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What does Category D indicate about the potential risk to the fetus based on human studies?
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• positive evidence of human fetal risk
• adverse reaction data from investigation or human studies
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Category X pregnancy risk status
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• Studies in animals/humans have demonstrated fetal abnormalities
• positive evidence of human fetal risk
122
What year did the FDA replace the prescription drug categories with a new labeling system?
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2016
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What is the new labeling system for prescription drugs called?
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Pregnancy and lactation labeling final rule
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What information is provided in the pregnancy section of the new labeling system?
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• Pregnancy: info relevant to pregnant women (dosing, fetal risks)
• Lactation: safety of drug while breastfeeding (amount in milk, effects on breastfed child)
• Reproductive potential: info on pregnancy testing, contraception, infertility
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What is pharmacokinetic drug interaction?
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A drug alters the absorption, distribution, metabolism, or excretion of another drug, changing the amount available to produce the desired effect.
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What is pharmacodynamic drug interaction?
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Drugs influence each other's effects directly
Ex. 2 meds ↑ BP
Ex. med ↑BP by opposing effect of other med
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What is synergistic effect?
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Two drugs increase the effect of each other, such as two drugs increasing blood pressure.
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What is potentiation
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a drug with no effect can enhance the effect of a 2nd drug
0+1 = 2