Answer KeyNAME___Rosow_____________ Answer Key Principles of Pharmacology Final Exam March 24, 2005 This is a closed book exam. All questions are multiple choice or short answer. Numerical computations should not require a calculator (although you may use one). Please keep your answers brief and legible. Write your name on all pages. Good Luck! Harvard-MIT Division of Health Sciences and Technology HST.151: Principles of Pharmocology Instructors: Dr. Carl Rosow, Dr. David Standaert and Prof. Gary Strichartz HST-151 Final Exam p.1HST - 1511. The graph below shows the results of experiments in which contraction of a segment of guinea pig ileum was used to test the effects of fentanyl and an opioid peptide, D-Ala, D-Leu Enkephalin (DADL). The concentration-response curves for fentanyl or DADL alone were identical. Each was then tested in the presence of 10-7M drug X. What is the nature of the interaction between Fentanyl or DADL and X? [3] X is a competitive antagonist of both fentanyl and DADL What is the Ka in each case? What does this tell you about the two drugs? [8] []AKA1antag without EC50antag with EC50=− []M1004.2491M101105x101M101antag without EC50antag with EC501A)(K977-6-7A−−−×=×=−×=−×=fent M102.541M101105x101M10)(K877-7-7A−−−×=×=−×=DADL Different KA for X = different receptors for Fentanyl and DADL HST-151 Final Exam p. 2 NAME___Rosow_____________2. You are asked to consult for a company developing a new antiepileptic drug. It suppresses seizure activity in mice, and it has the following in vitro properties: Octanol:Water = 1000 GABA kd = 10-10 M 50% protein bound Hydrolyzed to inactive products by plasma cholinesterase. Using each of these pieces of information, make a prediction about the eventual pharmacological profile of this compound (explain). [8] Numerous answers possible. Here are a few: Highly fat soluble – Drug probably has large Vd, gets into brain, good tissue penetration; probably well-absorbed through skin and mucous membranes High affinity for GABA receptor – Potent CNS depressant effects; may be fairly selective. Coupled with lipid solubility, might be good drug for use in a transdermal patch. Moderate to low protein binding – Unlikely to have drug-drug interactions due to binding displacement. Not a large reservoir of drug in blood. Hydrolyzed by pseudocholinesterase – Clearance may be rapid, probably unaffected by renal or hepatic dysfunction. Probable genetic variability in drug clearance due to abnormal pseudocholinesterase. Drug action prolonged by pseudoChE inhibitors (neostigmine, echothiophate). 3. Which of the following acts primarily at ligand gated ion channels? (Check all that apply) [5] a. Hemicholinium b. l-Dopa c. Phenylephrine d. Midazolam***** e. Thiopental***** HST-151 Final Exam p. 3 NAME___Rosow_____________4. S is an inhaled anesthetic with a blood-gas solubility coefficient that is only ½ that of isoflurane. What implications does this have for the clinical effects of S? [5] Anesthetic effect is proportional to partial pressure, not dissolved gas. Low blood-gas solubility means faster rise and fall of end-tidal partial pressure when inspired concentration is changed. Clinically, this means faster induction and emergence. Blood gas solubility does not determine potency. 5. The following graph shows the relationship between the daily dose of phenytoin and the steady state concentration. What is the explanation for this? What implication does it have for patient care? [6] The drug obeys dose-dependent (saturation) kinetics rather than first order. Half-life is lengthening as dose is raised. Non-linear kinetics means that a small dosage increment can potentially cause a very large increase in phenytoin concentration and produce toxicity. This is why plasma concentrations are often monitored during titration. HST-151 Final Exam p. 4 NAME___Rosow_____________6. Piroxicam is an NSAID with a terminal half-life of ~60 hr. Other than the frequency of dosing, how does this property affect its clinical use? [5] Slow onset and slow clearance. In chronic dosing, steady state will not be achieved for almost two weeks. This means that a loading dose would be needed for rapid effects, and manifestations of toxicity could be delayed. This drug is best suited to chronic dosing rather than acute pain. 7. Which of the following immunosuppressant drugs inhibits calcineurin? (check all that apply) [5] a. Prednisone b. Cyclosporine***** c. Azathioprine d. Sirolimus e. Tacrolimus***** 8. How do the following combinations change efficacy or toxicity? [12] Imipenem – Cilastatin Imipenem is hydrolyzed by peptidases in renal tubule to produce a nephrotoxic metabolite. Cilastatin specifically inhibits these peptidases. l-Dopa – Entacapone Entacapone inhibits metabolism of l-DOPA to 3 methoxydopa in systemic circulation, so more is available for transport into CNS. Increased duration, less “wearing-off.” Meperidine – Pargyline The “Libby Zion” interaction. The opioid, meperidine, and MAOI can cause severe CNS excitation with fever – sometimes coma and death. Methotrexate – Leucovorin High-dose MTX kills rapidly dividing leukemic cells by inhibiting dihydrofolate reductase. “Rescue” with leucovorin (folinic acid) can salvage many normal cells. HST-151 Final Exam p. 5 NAME___Rosow_____________9. Terfenadine is off the market and replaced with its metabolite, fexofenadine. What was the reasoning behind this move? [5] All the therapeutic antihistaminic effects came from the metabolite, but the toxicity came from the parent drug. Terfenadine inhibited Ikr and caused torsades de pointes, especially if metabolism was inhibited by another drug. The metabolite is now sold as Allegra®. 10. How can an antidysrhythmic drug promote a re-entrant dysrhythmia? [5] A reentrant dysrthymia occurs when a local unidirectional conduction block sets up an electrical loop, whereby an electric impulse returns to restimulate the same area of myocardium. In order to sustain restimulation, the returning impulse must be slow