PK_PD Review PDF

Review & Supplement for PHARMACO KINETICS & DYNAMICS Presented by Kelly Elmore Grab a pen & paper. Unless you’re brave enough to answer in your head! Let’s get started... What is pharmacokinetics the study of? Describe the 4 major processes of pharmacokinetics. ...

Review & Supplement for PHARMACO KINETICS & DYNAMICS Presented by Kelly Elmore Grab a pen & paper. Unless you’re brave enough to answer in your head! Let’s get started... What is pharmacokinetics the study of? Describe the 4 major processes of pharmacokinetics.  Spotlight on Fetal Pharmacokinetics Absorption A Placenta most important route Passive diffusion most important mechanism Anesthetics (opioids, volatile anesthetics, benzodiazepines, etc.) can rapidly cross the placenta Neuromuscular blockers (succinylcholine, rocuronium) can s...l...o...w..l...y cross  Spotlight on Fetal Pharmacokinetics Distribution D Increased delivery to fetal brain (related to cardiac output) Decreased protein binding increases free drug concentration Lower body fat, higher body water can affect distribution Ion trapping in amniotic fluid becomes a reservoir for water soluble drugs  Spotlight on Fetal Pharmacokinetics Metabolism M Enzyme function Some function at adult levels Some are functionally less active with delayed metabolism (eg, opiates, NSAIDs, local anesthetics) Decreased clearance in hypoxia - shunted drug bypasses liver and goes directly into systemic circulation  Spotlight on Fetal Pharmacokinetics Elimination E Fetal renal excretion (into amniotic fluid) Transfer to mother via umbilical vessels and placenta Drug recirculation possible through re-ingestion of amniotic fluid Question #1 Drugs taken by mouth (PO) most likely follow what sequence for drug transfer and absorption? A Gut > artery > brain > vein > heart B Artery > gut > lung > vein > heart > brain C Gut > liver > vein > heart > lung > heart > artery D Lung > vein > gut > heart > artery > liver Question #2 Intravenous drugs undergo first pass hepatic metabolism. A TRUE B FALSE C UNKNOWN Question #3 Your goal is to match #1 (PO drug), #2 (IV drug), and #3 (INHaled drug) to curves A, B, or C. Maternal-Fetal Pharmacokinetics......ready for the next question? Question #4 You remember from advanced pharmacology that... A ionized drugs are always lipid soluble. B acidic drugs accept protons. C nonionized drugs are more lipophilic. D the lower the pKa, the stronger the base. Question #5 Which of the following is NOT a characteristic of unionized drugs? A Lipophilic B Hydrophilic C Pharmacologically active D Easy diffusion across placenta Question #6 Question #7 Aspirin (acetylsalicylic acid, pKa 3.5) is primarily in a lipid-soluble form at pH 2.5. A TRUE B FALSE Question #8 The basic drug promethazine (pKa 9.1) is more ionized at pH 7.4 than at pH 2. A TRUE B FALSE Question #9 Absorption of a weakly basic drug is likely to occur faster from the stomach than from the intestine. A TRUE B FALSE Question #10 Acidification of the urine accelerates the secretion of a weak base, pKa 8. A TRUE B FALSE Question #11 Uncharged molecules more readily cross cell membranes than charged molecules. A TRUE B FALSE What is defined as the amount of a drug divided by the desired plasma concentration?  Water or Lipid? ________________ - soluble (or, ____________philic) drug distribution EXCEEDS total body volume/water. ________________ - soluble (or, ____________philic) drug distribution is often LESS THAN total body volume/water. Question #12 Distribution of drugs to specific tissues... A is independent of blood flow to the organ. B is independent of the solubility of the drug in that tissue. depends on the unbound drug concentration gradient between plasma and C the tissue. D is increased for drugs that are strongly bound to plasma proteins. E has no effect on the half-life of the drug.  Matching Hofmann First-order Induction Conjugation Hydrolysis Elimination Kinetics 3. 1. Constant fraction of drug 5. Phase II reaction adding metabolized due to the presence Reaction to break an ester bond a polar group of more enzymes than drug 2. 4. Increasing activity of CYP enzymes Spontaneous chemical reaction and drug clearance dependent on temperature Question #13 Regarding termination of drug action... A drugs must be excreted from the body to terminate their action. B metabolism of drugs always increases their water solubility. C metabolism of drugs always abolishes their pharmacologic action. hepatic metabolism and renal excretion are the two very important D mechanisms. E distribution of a drug out of the bloodstream terminates the drug’s effects.  Matching Extraction Capacity Clearance Redistribution Steady State Ratio Limited 3. 1. Drug clearance mostly 5. Dosing interval is independent of liver blood flow Indirectly related to half-life equivalent to clearance 2. 4. Drug moves from tissues into Fraction of drug removed from the plasma based on change in plasma entering the clearing organ concentration gradient  mor! le hu me! a litt eso w Just logy is a ac o arm Ph Let’s test your knowledge on pharmacodynamics...  The Neuronal Action Potential 1. Voltage-gated _____________________ channels open when a stimulus arrives causing the neuron to reach threshold potential. This causes ____________________________. 2. Voltage-gated _______________________ channels open as a delayed response causing the now positive membrane potential to become more negative, leading to ___________________________. 3. Active transport of ions by the ______________________ returns the neuron back to its resting membrane potential. Hotspot Matching Match the following terms with the corresponding structure on the diagram. NT Calcium Synaptic Receptor transporter channel Neurotransmitter vesicle  Spotlight on Biophase & Anesthetics Effect Site Hypothetical compartment Drug concentration in the biophase (effect site - where drug acts) cannot E be measured Inaccessible in humans Challenge in measuring at molecular level (typically grossly measure levels in brain or CSF for example) Used as measure to relate time course of plasma drug concentration with time course of drug effect  Spotlight on Biophase & Anesthetics Effect-Site Equilibration Plasma concentration following intravenous bolus peaks almost instantaneously E Additional time required for drug to reach site of effect (e.g., central nervous system) and induce a therapeutic effect (e.g., unconsciousness) Plasma = transport mechanism for drug distribution Delay between peak plasma concentration and peak CNS concentration = hysteresis  Spotlight on Biophase & Anesthetics Effect-Site Elimination ke0 = rate constant of drug elimination from the effect site Time to peak effect site concentration is function of plasma pharmacokinetics and ke0 T 1/2 ke0 = time required for biophase concentration to reach 50% of plasma concentration Equilibration between plasma and effect site is rapid for thiopental, propofol, alfentanil Equilibration between plasma and effect site is intermediate for fentanyl, sufentanil, non- depolarizing muscle relaxants Equilibration between plasma and effect site is s..l..o..w.. for morphine, ketorolac  Spotlight on Biophase & Anesthetics E Effect-Site Elimination Affected by size of bolus dose and/or use of infusion Important to time induction drugs appropriately to intubate patients at peak biophase concentrations (vs. plasma peak)! Question #14 A ligand binds to a receptor increasing cellular response. This is known as signal: A amplification B integration C relay D inhibition Question #15 Receptor activation causes another intracellular chemical messenger to cause a cellular or tissue response. This is known as signal: A amplification B integration C relay D inhibition Question #16 What typically happens immediately upon activation of a G-protein coupled or ion channel receptor? A Genetic expression B Homeostasis C Change in cellular metabolism D Conformational change  EXCITATORY OR INHIBITORY? A The acetylcholine-nicotinic acetylcholine receptor complex. B The glutamate-N methyl D aspartate receptor complex. C The glycine-glycine receptor complex. D The serotonin-5HT3 serotonin receptor complex. E The gamma-aminobutyric acid-GABA receptor complex.  Drug Dose-Response 1. The ability of a drug to cause a maximum response is known as ____________________. 2. The concentration or amount of drug necessary to cause a specific clinical response is ______________________________. 3. The equation for therapeutic index is _________________________ divided by ________________________.  Drug Dose-Response 4. A drug which has reduced efficacy and a ceiling effect is known as a/an ____________________________________. 5. A drug which does not activate a receptor is known as a/an _____________________________________. Question #17 Drugs X and Y have the same mechanism of action. Drug X in a dose of 5 mg produces the same effect as 500 mg of drug Y. This suggests that: A Drug Y is less efficacious than drug X. B Drug X is about 100 times more potent than drug Y. C The toxicity of drug X is less than drug Y. D Drug X is a safer drug than drug Y. E Drug X will have a shorter duration of action than drug Y. Question #18 Which best describes the new drug? A Full competitive antagonist B Irreversible antagonist C Partial competitive agonist D Full agonist E Inverse agonist Question #19 Which provides information about the largest response a drug can produce regardless of dose given? A Drug potency B Max efficacy C Mechanism of action D Therapeutic index E Therapeutic window How did you do? Answers: Pharmacokinetics = study of what body does to a drug Absorption, Distribution, Metabolism, Elimination 1. C 2. B 3. Routes - (1) PO = C, (2) IV = B, (3) INH = A 4. C 5. B 6. D 7. A Answers: 8. B 9. B 10. A 11. A Volume of distribution Water vs. Lipid - Lipid-soluble (lipophilic) exceeds; Water-soluble (hydrophilic) is less than 12. C Matching - (1) Conjugation, (2) Induction, (3) 1st Order Kinetics, (4) Hofmann, (5) Hydrolysis Answers: 13. D Matching - (1) Steady state, (2) Redistribution, (3) Capacity-limited, (4) Extraction ratio, (5) Clearance Neuronal AP - (1) Na sodium; depolarization, (2) K potassium; repolarization, (3) Na-K ATPase Hotspot matching - (A) Neurotransmitter, (B) Synaptic vesicle, (C) Calcium channel, (D) Neurotransmitter transporter, (E) Receptor Answers: 14. A 15. C 16. D Excitatory vs Inhibitory - (A) Excitatory, (B) Excitatory, (C) Inhibitory, (D) Excitatory, (E) Inhibitory Dose-Response - (1) Efficacy, (2) Potency, (3) LD50 / ED50, (4) Partial agonist, (5) Antagonist 17. B 18. C 19. B Thank you!