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PRINCIPLES OF PHARMACOLOGY FINAL EXAM (200 points total) March 7, 2003 PART I: Answer 4 out of 5 questions in this part. Please be brief; confine your answers to front sides of pages, if possible. 1. A number of agents that are clinically useful act by modifying the strength of synaptic transmission. Using your knowledge of synaptic physiology and pharmacology, please indicate the similarities and significant differences between the actions of each of the following pairs of drugs that act upon synaptic transmission. a. The neuromuscular blocking agents succinylcholine and tubocurarine. (5 points). b. The anticholinesterase drugs pyridostigmine and edrophonium. (5 points) c. The sympathomimetic agents ephedrine and cocaine. (5 points) d. The symphatholytic/antihypertensive agents clonidine and prazosin. (5 points) e. The sedative/hypnotic agents triazolam (a benzodiazepine) and secobarbital (a barbiturate). (5 points) 2. Parkinson’s disease is a neurodegenerative disease that is effectively treated in its early stages by the drug Sinemet, which is a combination of L-DOPA and the aromatic acid decarboxylase inhibitor carbidopa. a. What is the basis for the therapeutic effect of L-DOPA in Parkinson’s disease? (10 points) b. Please describe two advantages of administering carbidopa in combination with L-DOPA. (5 points) c. Some patients who are being treated with Sinemet for Parkinson’s disease note psychosis as a disturbing side-effect. Please offer a mechanistic explanation for this phenomenon, and suggest a potential pharmacologic strategy to mitigate this effect. (10 points) 3. A fourth-year medical student who is doing research on drug addiction “takes a slider” while skateboarding one Saturday afternoon. Although he sustains a friction burn on his left hand, he comes to the lab to complete the experiment he had planned for that day. His research involves the effects of pleasorphine (a novel opioid receptor agonist) on cyclic GMP levels in isolated neurons of the nucleus accumbens. He accidentally splashes a small amount of pleasorphine onto his injured hand. About 30 minutes later, he notices that the area of abraded skin exposed to pleasorphine is no longer burning or painful, while the surrounding area remains painful. Over the next 24 hours, the student notes markedly increased swelling and tenderness of the left hand. An X-Ray shows that he has sustained a fracture of the 5th metacarpal. Surgery is planned for the following week. In the interim, his hand is placed in a splint and he is given Percocet (a combination preparation of oxycodone, an opiate agonist, and acetaminophen, a COX inhibitor) for his pain. While the Percocet provides adequate pain relief, he remains fascinated with the surprising effect of pleasorphine on his wound. The night before his surgery, in an attempt to repeat the effect he had previously observed, he applies a small amount of pleasorphine to his abrasion. This time, however, he notes almost no effect from this “treatment.” a. Please provide a mechanism by which pleasorphine could have reduced the pain of the student’s abrasion. (10 points) b. What is the likely cellular mechanism of action for the analgesic action of pleasorphine? (5 points) c. Please provide a mechanism that could explain the loss of effectiveness between pleasorphine’s initial application on the wound and its reapplication the night before surgery. (10 points) 4. Mr. Smith comes to your office complaining of palpitations and increasing shortness of breath. He is 55 years old and in good health, except for a remote history of asthma. His pulse is rapid (100/min) and irregular, but his blood pressure is within normal limits (130/88 mm Hg). An electrocardiogram shows atrial flutter with a ventricular rate of 100 beats per minute. You prescribe warfarin for anticoagulation. After waiting a sufficient period of time for full anticoagulation to become manifested, you attempt to convert his atrial flutter to a normal rhythm. You initiate therapy with quinidine but, because of Mr. Smith’s history of asthma, you do not prescribe a betaadrenergic blocker. (Quinidine is a class IA antiarrhythmic agent that also has an anticholinergic, or vagolytic, effect.) One week later, Mr. Smith presents to the ER complaining of frequent fainting spells and diarrhea. An electrocardiogram shows atrial flutter with a ventricular rate of 200 beats/minute. a. What is the most likely cause for Mr. Smith’s increase in heart rate between his initial visit to your office and his presentation one week later in the ER? (9 points) Mr. Smith is admitted to the hospital, and quinidine is discontinued. His ventricular rate returns to 150, but he is now in atrial fibrillation. He is started on ibutilide (a class III antiarrhythmic). b. What is the mechanism of action of ibutilide? (8 points) Mr. Smith returns one month later for a follow-up visit. He is still in atrial fibrillation but he is well-anticoagulated and he has had no more palpitations. You offer to perform electro-cardioversion, but Mr. Smith does not like this idea and asks for another medication instead. You start therapy with a low dose of the antiarrhythmic agent amiodarone. c. Please explain the mechanism of action of amiodarone, and list two organs whose function you should monitor carefully while Mr. Smith is taking this drug. (8 points) 5. Anti-anginal drugs are often used in combination, sometimes leading to adverse consequences, and sometimes enhancing the therapeutic response. Below are listed three pairs of drugs, each of which can be used individually in the treatment of angina. For each pair, describe the cardiovascular consequences that could arise from the concurrent use of the drugs, and briefly explain the mechanisms whereby these consequences (either beneficial or adverse) could result. a. Verapamil and nifedipine (two Ca2+ channel blockers) (9 points) b. Metoprolol (a beta-adrenergic antagonist) and verapamil (a Ca2+ channel blocker) (8 points) c. Metoprolol and atenolol (two beta-adrenergic antagonists) (8 points) PART II: Answer 4 out of 5 questions in this part. Please be brief; confine your answers to the front sides of pages, if possible. 6. Adverse drug-drug interactions have been reported for patients taking two or more of the following drugs in combination: 1) the antituberculosis antibiotic rifampicin; 2) the calcium channel blocker nifedipine; and 3) the microtubule-directed antimitotic drug paclitaxel. In particular, in patients chronically treated with one of these drugs (e.g., rifampicin), it was found to be difficult to achieve therapeutic levels of the second or the third drug (e.g., nifedipine or paclitaxel). Please describe a detailed molecular mechanism that could explain this adverse drug-drug interaction, and estimate the minimum amount of time for which the patient would have to be treated with the first drug in order to manifest this adverse reaction. (25 points) 7. As Medical Director of the fledgling biotech firm Noswellagen, you are beginning clinical trials of a promising class of enzyme inhibitors. Structure-based drug design has been used to develop a derivative of acetaminophen called HMS-100. In vitro studies have suggested that HMS-100 could be a powerful analgesic and anti-inflammatory drug with low toxicity. More specifically, HMS-100 has been found to inhibit brain cyclooxygenase (COX-3) at low concentrations (Ki = 1 nM), but the drug has little effect at these concentrations on cyclooxygenases 1 and 2 (COX-1 and COX-2). Further, HMS-100 does not block conversion of arachidonic acid by human 15-lipoxygenase. HMS-100 is actively taken up by cells and displays little toxicity in animal studies. In phase I clinical trials on 20 human subjects given 100 mg of HMS-100 orally once per day, the drug has an elimination half-life of 10 hours. After one dose of the drug, however, all of the subjects have prolonged bleeding times, platelet function studies show marked impairment of platelet activation and aggregation, and urinary levels of 6-ketoprostaglandin F2are significantly diminished. a. On the basis of these observations, what is HMS-100’s likely mechanism of action? Please include in your answer the pathways, intermediates, and autacoids that are being affected when HMS-100 is administered in vivo. (9 points) b. Sixteen of the 20 healthy individuals taking HMS-100 in the phase I trial complain of new asthma-like symptoms that are brought on by exercise. Please provide a potential mechanism that could explain this side-effect, including the endogenous mediators that could be giving rise to the asthmalike symptoms. (7 points) c. In a phase II clinical trial, patients treated with HMS-100 note that they feel less joint pain after long strenuous jogging. Importantly, the arthritis symptoms of the subjects are completely eliminated – no stiffness, joint pain, or swelling. Propose a plausible mechanism for this action of HMS-100 in vivo, including the mediators that are likely to be affected by administration of the drug. 8. Several years from now, you are asked to treat a health care worker who has recently been vaccinated against smallpox. The vaccination had used vaccinia virus (a pox virus related to smallpox). The patient has become very ill with symptoms of encephalitis, which you presume was a result of the vaccination. Fortunately, the nation’s biodefense program has resulted in the development of antiviral drugs that are active against both smallpox and vaccinia. You begin intravenous treatment with one of these drugs, called poxnomoravir, which is a nucleoside analogue similar in structure to acyclovir. a. What is the basis for the antiviral selectivity of nucleoside analogues like acyclovir? (7 points) b. The developers of poxnomoravir had discovered, to their surprise, that the molecular target of the drug is a virally-encoded topoisomerase, and that the drug inhibits the viral topoisomerase at concentrations that do not inhibit cellular topoisomerases. What experiments could have been done to show that poxnomoravir targets the poxvirus topoisomerase? (6 points) c. When investigators examined poxvirus infected cells that had been treated with poxnomoravir, the discovered that the viral DNA contained many broken strands. Based on the information in part (b), describe how this could have occurred, and briefly discuss how this result could be advantageous therapeutically. (6 points) d. Would you expect poxnomoravir to be a highly-selective agent against smallpox? If so, why, and if not, why not? (6 points) 9. You are about to begin a clinical trial of a new anti-cancer drug. Mendostatin, which is derived from an East Asian herb, acts by blocking the repair of damaged DNA. The major toxicities of mendostatin are suppression of hematopoiesis in the bone marrow, and bladder irritation and bladder hemorrhage. You present your proposal to the Scientific Review Committee at your hospital, and several questions arise. a. You propose to combine mendostatin with the alkylating agent cyclophosphamide in the treatment of breast cancer. What are the two principal advantages of this combination therapy? What is the major disadvantage of this combination? (8 points) b. You had attempted to generate data, in tissue culture models of breast cancer, to support your use of this combination. You found, however, that when you added cyclophosphamide to the flasks of breast cancer cells, either alone or in combination with mendostatin, the cyclophosphamide had no inhibitory effect on cell growth. Why was this the case, and how could this problem have been circumvented? (5 points) c. As part of your laboratory studies, you had tested the effect of mendostating on the growth of a number of cell lines that were resistant to anti-cancer drugs used in the treatment of breast cancer, including vinca alkaloids, paclitaxel (a microtubule-directed antimitotic agent), and doxorubicin (an anthracycline). These cell lines were also found to be resistant to mendostatin. Please offer one mechanism that could explain this finding. (8 points) d. In a phase I clinical trial of mendostatin, the drug is administered orally at a dose of 100mg/m2/day for the first five days of each four-week treatment cycle. All of the patients who enroll in this study have severe and prolonged suppression of their white blood cell counts. Why is this a serious side-effect, and what could be done to ameliorate this side-effect? (4 points) 10. Diabetes is becoming endemic in the United States. Fortunately, an increasing array of treatments is available for therapy of Type 1 and Type 2 diabetes. Please discuss the mechanism of action of each of the following classes of drugs used in diabetes treatment. Include in your answer the molecular and cellular targets of these classes of drugs. Also include in your answer whether (and why) these drug classes could be used to treat Type 1 diabetes, Type 2 diabetes, or both types of diabetes. a. a-Glucosidase inhibitors. (5 points) b. Sulfonylureas. (5 points) c. Insulin. (5 points) d. Biguanides. (5 points) e. Thiazolidinediones. (5 points)