AME Study Guide (Distribution, Protein Binding, and Volume) PDF

Distribution, protein-binding and distribution volume. 1. What are the factors that influence distribution of drugs in the body? a. Organ Blood Perfusion: Highly perfused organs (e.g., heart, liver, kidneys) receive drugs more rapidly. b. Lipid Solubility of the Drug: Lipophil...

Distribution, protein-binding and distribution volume. 1. What are the factors that influence distribution of drugs in the body? a. Organ Blood Perfusion: Highly perfused organs (e.g., heart, liver, kidneys) receive drugs more rapidly. b. Lipid Solubility of the Drug: Lipophilic drugs cross membranes more easily. c. Regional Differences in pH: Affects ionization and distribution. d. Extent of Protein Binding: Bound drugs are restricted to plasma, while unbound drugs distribute freely. e. Other important factors: i. Disease states: Conditions like liver, heart, and kidney disease alter perfusion and distribution. ii. Special anatomical barriers: Blood-brain barrier (BBB) restricts entry of polar drugs. 2. Draw a plasma level time curve and a tissue distribution curve following IV administration of a drug and cite similarities and differences between them. Identify a distribution phase in this curve. a. b. Plasma concentration curve (blue line): i. Rapid initial decline due to distribution into tissues. ii. Slower decline after distribution due to elimination. c. Tissue concentration curve (green line): i. Gradual increase as the drug distributes into tissues. ii. Reaches a peak before slowly decreasing due to elimination. d. Identification of the Distribution Phase: i. Marked between 0 to ~2 hours (steep decline in plasma concentration). ii. This phase represents drug movement from plasma to tissues. e. Similarities Between the Two Curves: i. Both curves show drug distribution initially. ii. Eventually, both decline due to drug elimination.  f. 3. Distinguish between a one compartment and a two- compartment distribution model. What is the basic concept involved in compartmentalization of the body to describe distribution? a. One-Compartment Model: i. Assumes the drug distributes instantaneously throughout the body. ii. No delay in equilibrium between plasma and tissues. iii. Example: Drugs that stay in plasma (e.g., aminoglycosides). b. Two-Compartment Model: i. Assumes an initial distribution phase where the drug moves from central (plasma) to peripheral (tissues). ii. After equilibrium, the drug is eliminated. iii. Example: Lipophilic drugs that distribute into fat/muscle (e.g., Digoxin). c. Basic Concept of Compartmentalization i. Organs/tissues with similar drug distribution patterns are grouped into compartments. ii. Highly perfused organs (heart, liver, kidneys) = Central compartment. iii. Less perfused organs (fat, muscle) = Peripheral compartment. 4. What are the organs and tissues grouped together in a peripheral compartment? In a central compartment? a. Central Compartment (Highly Perfused Organs) i. Heart ii. Liver iii. Kidneys iv. Lungs v. Blood Plasma b. Peripheral Compartment (Less Perfused Tissues) i. Muscle ii. Fat (adipose tissue) iii. Skin iv. Bone v. Cerebrospinal fluid (CSF) c. The central compartment receives drugs first, while the peripheral compartment acts as a reservoir, leading to a delayed equilibrium. 5. Elimination of a drug takes place mainly from which compartment and why? a. Drug elimination primarily occurs from the central compartment, which includes highly perfused organs such as: i. Liver (metabolism) ii. Kidneys (excretion) iii. Lungs (for volatile drugs) b. Reason: i. These organs receive high blood flow, allowing efficient metabolism and excretion. ii. The liver metabolizes lipophilic drugs, converting them into water-soluble metabolites for renal elimination. iii. The kidneys excrete hydrophilic drugs and metabolites through filtration, secretion, and reabsorption. 6. What are the components of the blood that binds to drugs? a. Albumin – Major plasma protein binding site. b. Alpha-1-Acid Glycoprotein – Binds to basic (cationic) drugs. c. Lipoproteins (HDL, LDL, VLDL) – Bind to lipophilic drugs. d. Red Blood Cells (RBCs) – Bind some drugs like phenytoin and cyclosporine. 7. What types of drugs are bound to each of these components? Cite examples. a. 8. Describe the protein-binding changes of a drug in hypoalbuminemia with reference to phenytoin a. Phenytoin is highly bound (~90%) to albumin. b. In hypoalbuminemia (low albumin levels due to liver disease, kidney disease, malnutrition, or pregnancy): i. Less albumin is available to bind phenytoin. ii. More free (active) drug is present in plasma. iii. Risk of toxicity increases, even if total plasma concentration appears normal. c. Example Calculation i. Normal binding: 90% bound → 10% free (active). ii. In hypoalbuminemia: Free drug fraction doubles (e.g., from 10% to 20%). iii. If total plasma phenytoin is measured at 18 mg/L, free phenytoin is 3.6 mg/L (above therapeutic range, leading to toxicity). 9. What is an acute-phase protein? Cite conditions when the concentration of this protein increases in the blood. a. Acute-phase proteins are proteins whose plasma concentrations increase during inflammation, infection, trauma, and stress. b. Example: Alpha-1-acid glycoprotein (AAG) is a major acute-phase protein. c. Conditions that increase AAG levels: i. Myocardial infarction (heart attack) ii. Surgery iii. Inflammatory diseases (e.g., arthritis) iv. Trauma v. Stress-related conditions 10. What type of drugs are bound to this acute phase protein? Give examples. a. Alpha-1-acid glycoprotein (AAG) primarily binds to basic (cationic) drugs. b. Examples of Drugs Bound to AAG: i. Propranolol (beta-blocker) ii. Lidocaine (local anesthetic) iii. Imipramine (antidepressant) 11. Explain why some drugs have extremely high volume of distribution? Give examples of such drugs. a. Volume of distribution (Vd) is high when a drug extensively distributes into tissues rather than remaining in the plasma. b. Factors that increase Vd: i. High lipophilicity (fat-soluble drugs move into tissues) ii. Low plasma protein binding (more free drug available for tissue uptake) iii. Binding to tissue components (fat, muscle, etc.) iv. Slow release from tissues back to plasma c. Examples of Drugs with High Vd: i. Digoxin (Vd = 7.3 L/kg, binds to cardiac tissue) ii. Amiodarone (Vd = 4600 L, accumulates in fat and muscle) iii. Chloroquine (Vd > 1000 L, accumulates in tissues) 12. Why is it important to measure the unbound concentration of some drugs in the blood? a. Only the free (unbound) drug is pharmacologically active. b. Factors affecting unbound drug concentration: i. Changes in protein binding (e.g., hypoalbuminemia) ii. Drug-drug interactions (displacement from binding sites) iii. Diseases affecting plasma proteins (e.g., liver/kidney disease) c. Example: Phenytoin i. 90% bound to albumin, but in hypoalbuminemia, binding decreases. ii. More free phenytoin → Increased drug effect → Risk of toxicity.  iii. Measuring only total concentration can be misleading because free drug levels may be higher than expected. 13. What are the clinical consequences of displacement of a drug from its binding sites by another drug? What happens to the displaced drug? Use an example of phenytoin and valproic acid. a. Displacement occurs when a drug competes with another drug for the same binding site on plasma proteins. b. Effect: Increased free drug concentration → Greater pharmacological activity → Potential toxicity. c. Example: Phenytoin & Valproic Acid i. Phenytoin is 90% bound to albumin. ii. Valproic acid competes for the same albumin binding sites and displaces phenytoin. d. Effect: i. Increased free phenytoin concentration → Increased drug effect & toxicity. ii. Phenytoin’s volume of distribution (Vd) increases, leading to increased drug distribution in tissues. iii. Potential toxicity symptoms: Nystagmus, ataxia, dizziness. 14. Define volume of distribution of a drug. How is Vd of a drug determined from a plasma level-time data? a. Definition: Volume of Distribution (VdV_dVd) is a pharmacokinetic parameter that describes how extensively a drug distributes throughout the body compared to plasma. b. Formula to determine Vd i. c. Oral Dosing: i. ii. Small Vd (e.g., 3-5 L): Drug stays mostly in plasma (e.g., warfarin). iii. Large Vd (e.g., >100 L): Drug distributes extensively into tissues (e.g., digoxin, amiodarone). 15. How is the loading dose of a drug estimated? Give an equation to determine the loading dose of an orally administered drug. a. Loading dose (LD): The initial higher dose given to rapidly achieve therapeutic drug levels in the body. b. Formula for IV Loading Dose:  i. c. Equation for Orally Administered Drugs: i. d. Example Calculation (Based on PowerPoint): i. A patient needs 1.5 mcg/L of digoxin. ii. Vd = 7.3 L/kg, Body weight = 70 kg. iii. F (bioavailability from tablet) = 0.7. iv. Total Vd = 70×7.3=51170 \times 7.3 = 51170×7.3=511 L. v. LD = 511×1.50.7=1095\{511 \ 1.5}{0.7} = 10950.7511×1.5=1095 mcg = 1.1 mg. Drug metabolism 16. What is the purpose of biotransformation of drugs? Why is a metabolite of a drug more readily excreted in to the urine than the parent drug? a. Purpose of Biotransformation (Metabolism): i. Converts lipophilic drugs into more hydrophilic metabolites for excretion. ii. Detoxification: Some metabolites are less active or inactive. iii. Activation: Prodrugs (e.g., codeine) are converted into active metabolites (e.g., morphine). b. Why Metabolites Are More Readily Excreted in Urine: i. Increased water solubility makes renal excretion easier. ii. Reduced ability to cross membranes prevents reabsorption in renal tubules. iii. Higher polarity and ionization facilitate elimination via urine. 17. What is Phase 1 and phase 2 biotransformation processes? Give two examples of each. a. Phase 1 Reactions (Functionalization Reactions) i. Introduce or expose functional groups (e.g., -OH, -NH2, -SH). ii. Mainly oxidation, reduction, and hydrolysis. iii. Examples: 1. Oxidation (by CYP450 enzymes) – Lidocaine → Monoethylglycinexylidide. 2. Hydrolysis – Aspirin → Salicylic Acid. b. Phase 2 Reactions (Conjugation Reactions) i. Conjugation of the drug/metabolite with endogenous molecules (e.g., glucuronic acid, sulfate). ii. Highly water-soluble products are formed for excretion.  iii. Examples: 1. Glucuronidation – Morphine → Morphine-6-glucuronide. 2. Sulfation – Acetaminophen → Acetaminophen sulfate. 18. Is dealkylation of a drug considered as Phase 1 or phase 2 metabolism? Give an example of dealkylation of a drug and the product formed. a. Dealkylation is a Phase 1 metabolic reaction. b. Example: i. N-demethylation of Codeine → Morphine (via CYP2D6 enzyme). ii. Other drugs that undergo dealkylation: Amitriptyline → Nortriptyline. 19. What functional groups in a drug molecule are likely to undergo a phase 2 biotransformation reaction? a. Hydroxyl (-OH) → Glucuronidation (e.g., Morphine) b. Carboxyl (-COOH) → Amino Acid Conjugation (e.g., Salicylic Acid) c. Amine (-NH2) → Acetylation (e.g., Sulfonamides) d. Sulfhydryl (-SH) → Glutathione Conjugation (e.g., Acetaminophen Detoxification) 20. List two enzymes involved in a Phase 2 biotransformation process and two enzymes involved in a phase 1 process. a. Phase 1 Enzymes (Functionalization Reactions) i. Cytochrome P450 (CYP) enzymes: Involved in oxidation reactions. 1. Example: CYP3A4 (Metabolizes ~50% of drugs, including midazolam). ii. Esterases: Involved in hydrolysis reactions. 1. Example: Aspirin → Salicylic Acid. b. Phase 2 Enzymes (Conjugation Reactions) i. UDP-glucuronosyltransferase (UGT): Catalyzes glucuronidation. 1. Example: Morphine → Morphine-6-glucuronide. ii. Glutathione S-transferase (GST): Detoxifies harmful metabolites. 1. Example: Acetaminophen detoxification. 21. List two enzymes involved in the deconjugation of phase 2 metabolites. a. Beta-glucuronidase: Hydrolyzes glucuronides back to the parent drug. i. Example: Recycles bilirubin glucuronides. b. Sulfatase: Hydrolyzes sulfate conjugates, reversing sulfation. i. Example: Hydrolyzes estrogen sulfate conjugates. 22. Cite an example of a true detoxification process. a. Glutathione Conjugation of Acetaminophen: i. Acetaminophen undergoes phase 1 metabolism, producing a toxic metabolite (NAPQI). ii. Glutathione S-transferase (GST) conjugates NAPQI with glutathione. iii. This prevents liver toxicity and allows safe excretion. 23. Cite examples of two drugs whose metabolites are more active than the parent compounds. a. Codeine → Morphine (via CYP2D6) b. Codeine is a prodrug; morphine is the active analgesic metabolite. c. Diazepam → Desmethyldiazepam (via CYP3A4) d. Desmethyldiazepam is a longer-acting active metabolite. 24. What are the consequences of enzyme induction and enzyme inhibition? Give two examples of enzyme inducers and enzyme inhibitors. a. Enzyme Induction: i. Increases the synthesis and activity of drug-metabolizing enzymes. ii. Leads to faster metabolism, decreased drug levels, shorter half-life, and reduced pharmacological effects. iii. Examples of Enzyme Inducers: 1. Rifampin (induces CYP3A4, reduces bioavailability of digoxin). 2. Phenytoin (induces metabolism of warfarin, reducing its anticoagulant effect). b. Enzyme Inhibition: i. Decreases enzyme activity, leading to slower metabolism, higher drug levels, longer half-life, and potential toxicity. ii. Examples of Enzyme Inhibitors: 1. Ketoconazole (CYP3A4 inhibitor, increases levels of cyclosporine). 2. Cimetidine (CYP1A2 inhibitor, increases theophylline levels). 25. Describe the clinical consequences of enzyme induction and enzyme inhibition with specific examples. a. Enzyme Induction Consequences: i. Loss of therapeutic effect: 1. Example: Rifampin induces CYP3A4, reducing the effectiveness of oral contraceptives, leading to unintended pregnancy. ii. Need for dose adjustment: 1. Example: Phenytoin induces warfarin metabolism, reducing its anticoagulant effect, requiring higher warfarin doses. b. Enzyme Inhibition Consequences: i. Increased drug levels → Toxicity risk: 1. Example: Cimetidine inhibits CYP1A2, increasing theophylline levels, leading to toxicity (nausea, seizures). ii. Drug interactions: 1. Example: Ketoconazole inhibits CYP3A4, increasing cyclosporine levels, leading to nephrotoxicity. 26. Distinguish between competitive and noncompetitive inhibition. a.