Based on the information in the official labeling, please answer the following:

Transcription

1 Quiz # 1 HuBio 543, Autumn 2007 Consider the official labeling (FDA) of three drug products listed below. They are listed by Trade Name. Generic products typically do not have official labeling available online. One of the products is a combination of two drugs. You will be provided with PDF files of the latest official labeling of these drug products Pravachol Vytorin Zyprexa Based on the information in the official labeling, please answer the following: Simple Questions (2 points each) 1. Which of the products is a combination of two drugs? Vytorin 2. What is an NDC number? National Drug Code (an umbiguous way of identifying drug products). 3. Is ezetimibe metabolized mainly by phase I and/or phase II drug metabolic reactions? Glucuronidation is a phase II reaction. 4. Is SIMVASTATIN metabolized by phase I and/or phase II drug metabolic reactions? Mainly phase I, no mention of glucuronide or other conjugation metabolites. 5. What are the approved indications for treatment with Pravachol? Prevention of primary coronary events Prevention of secondary coronary events Hyperlipidemia

2 6. Are there any contraindications to treatment with Pravachol? Hypersensitivity to any component of the medication Active liver disease or elevated serum transaminases Pregnancy and lactation 7. Are there any contraindications to treatment with Zyprexa? Known hypersensitivity to the product 8. Which, if any, of the products is a controlled substance? If so, what is the Schedule? None of these drug products is a controlled substance. What is the Use-in-Pregnancy rating of: 9. Pravachol X 10. Vytorin X 11. Zyprexa C 12. Which, if any, of the drugs is given as a pro-drug? Simvastatin is an inactive lactone. 13. Which, if any, of the drugs has an active metabolite? Simvastatin is converted to an active beta-hydroxy acid Ezetimibe is converted to an active glucuronide (It is not necessary to point out, but interesting to note, that in common parlance simvastatin is a pro-drug [i.e., it has no activity per se], and that ezetimibe is a drug [it has activity per se], that happens to have an active metabolite]. If you picked up on the fact that pravastatin has a low activity metabolite (which I ignored), then do not mark yourself down. Consider that you are more thorough than me in answering such a question.

3 14. About how long would be required for ezetimibe to achieve a steady state plasma level when dosing at a once daily dosage of 10 mg is begun? How did you arrive at this estimate? Both the drug and its glucuronide have a half-life of about 22 hours. So steady state should be achieved in about 5 days. If you were a little more compulsive and multiplied 22 * 4 or 22 * 5, that s fine also. Short answer questions (4 points each) 15. What accounts for the low and variable bioavailability of pravastatin? The liver takes up (extracts) about 66% of pravastatin on the first pass. It may be taken up into liver at different rates during different times of the day. 16. Which, if any, of the drugs contains a black box warning? Try to summarize such black box(es), if any, in one or two sentences. Zyprexa contains a black box warning against its use in patients with dementia-related psychosis. Such patients have an increased risk (about fold) of death. 17. A patient is being treated with ketoconazole, a drug that inhibits CYP3A4. Which, if any, of the products should be avoided in this patient? Simvastatin in Vytorin is a substrate of CYP3A4. (It is not necessary to mention, but it is a useful teaching point that pravastatin is not metabolized by CYP). 18. What is the approximate apparent Kd of olanzapine from the following receptors? Beta adrenergic receptors (> 10 µm) Dopamine (1-4) receptors (11-31 nm) Serotonin receptors 5HT2A (4 nm) 5HT2C (11 nm) 5HT6 (5nM) Muscarinic receptors M2 (96 nm) M3 (132 nm)

4 19. Based on the above estimates, approximately how much more tightly does olanzapine bind to the 5HT6 receptor than to: muscarinic M2 receptors (~20 times) muscarinic M3 receptors (~26 times) beta adrenergic receptors (More than 2000 times) 20. What would be the predicted approximate pa2 value of olanzapine versus serotonin at the 5HT2A receptor? What is implied by this question about the relative intrinsic activities of serotonin and olanzapine, respectively, at the 5HT2A receptor? The Kd of olanzapine from the 5HT2A receptor is 4 nm. The predicted pa2 of olanzapine versus any agonist of that receptor would be approximately 8.4 (anywhere between 8.1 and 8.9 is acceptable, half credit for 8 or 9). The implication is that olanzapine has a much lower (maybe even zero) intrinsic activity at the 5HT2A receptor than does serotonin (maybe even one). The pa2 informs one as to how tightly olanzapine binds to the receptor. However, it does not provide any information on how tightly serotonin binds. (Knock off a point if you missed this distinction). 21. Assume that olanzapine has a pka of 7.4. What percentage of olanzapine will be ionized and non-ionized in the stomach at a ph of 3.4, and in tubular urine, ph 8.4, of a patient with metabolic alkalosis? At ph 3.4 ~ 99.99% ionized, ~0.01% non-ionized At ph 8.4 ~ 10% ionized, ~ 90% non-ionized I did not specifically tell you that olanzapine is a base. If you think you can convince me that it is an acid, send me an explaining that. I will consider no promises. Discussion/calculation questions (44 points total) A 70 kg patient arrives in the Emergency Department in a comatose state. Blood sugar was within normal limits. Injection of Narcan (naloxone) did not improve the mental status. 22. What is naloxone and why was it injected in the patient? How is it supposed to work? What inference is reasonably drawn if naloxone does not improve the mental status? (15 points)

5 Naloxone is an opioid receptor antagonist. It works by blocking opiod receptors. If naloxone does not improve the mental status of an obtunded patient, then the usual inference is that the cause of the CNS depression is not an opoid drug. 23. A prescription bottle for Zyprexa is found among the patient s effects. If the patient is overdosed on olanzapine, why is renal or peritoneal dialysis unlikely to be very effective in removing olanzapine from this patient? (5 points) The volume of distribution of olanzapine is very large. Furthermore, a large percentage of the drug is bound to plasma proteins. So, a small fraction of the drug is in the plasma when the drug is distributed in the body, and an even smaller fraction of that drug is free to diffuse to a lower concentration as in dialysis fluid. 24. Typical of patients with olanzapine overdosage, this patient remained in a coma for several days and died. Followup investigation of the patient s home revealed many empty prescription bottles for Zyprexa with the instructions to take 10 mg per day. What would be the approximate predicted steady state plasma concentration of olanzapine if the patient had taken the drug as directed? (12 points) Css = dosing rate * bioavailability/cl * dosing interval = (10 mg/24h * 0.6)/(25 L/h) = (0.417 mg/h * 0.6)/(25 L/h) = = (0.25 mg/h)/(25 L/h) = 0.01 mg/l OR Css = (dose * F)/(CL * dosing interval) = = (10 mg * 0.6)/(25 L/h * 24 h) = = (6 mg)/(600 L) = 0.01 mg/l

6 0.01 mg/l (If you used a different number for clearance or bioavailability, justify those numbers). If the calculation is otherwise correct, OK. It is not OK to forget to include bioavailability in the calculation). I am willing to accept a bioavailability of 0.12 instead of 0.6. If that was your assumption, then the predicted plasma level of olanzapine in the steady state would be about: Css = dosing rate * bioavailability/cl * dosing interval = (10 mg/24h * 0.12)/(25 L/h) = (0.417 mg/h * 0.12)/(25 L/h) = = (0.05 mg/h)/(25 L/h) = mg/l OR Css = (dose * F)/(CL * dosing interval) = = (10 mg * 0.12)/(25 L/h * 24 h) = = (1.2 mg)/(600 L) = mg/l 25. It was subsequently determined, based on blood drawn at the time of ED admission, that the blood concentration of olanzapine was 1.2 mg/l. Toxicological analyses are normally based on blood concentrations and the blood concentration of olanzapine is typically twice that of the plasma concentration.

7 What was the approximate total amount of olanzapine in the patient at the time of the blood draw? (12 points) Official labeling says the Vd of olanzapine is 1000 L (without specifying per liter so an average body mass such as 70 kg can be inferred). Vd is based on plasma, so the blood concentration must be divided by 2 to estimate the plasma concentration. 0.6 mg/l * 1000 L = 600 mg (equivalent to 60 tablets)