Pharmacokinetics Applied to the Treatment of Asthma

Transcription

1 Pharmacokinetics Applied to the Treatment of Asthma 2016 edition by David C. McMillan, PhD Department of Pharmacology and Experimental Neuroscience College of Medicine University of Nebraska Medical Center Originally developed by K.W. Renton, PhD Department of Pharmacology Faculty of Medicine Dalhousie University and A. H. Neims, MD, PhD Department of Pharmacology College of Medicine University of Florida Note to Students The fundamental purposes of all activities in the health-care professions are to help other people. Like all behavior, helping behavior becomes more effective and natural with practice. This exercise enables you to practice by helping your fellow students to learn basic science. Your skill at helping your fellow students should relate to your ability to help your patients in the future. This is a Patient-Oriented Problem-Solving (POPS) exercise designed for four students. Before beginning this session, you should have (a) studied the objectives designed to prepare you for it, (b) taken the pretest, and (c) reviewed the topics listed at the end of the pretest. Now, each of you should take one of the four color-coded parts and follow the directions in it. If your group has only three students, one of you should take two parts. If your group has more than four students, two should take turns with a part. Please begin by discussing the answers to the pretest.

2 Correct Answers to Pretest Questions In the discussion to follow, you are given the correct answers to some of the 10 pretest questions, along with explanations. Other students in your group have been given the answers to other questions. This allocation of answers and explanations is designed to encourage all members of your group to actively exchange ideas and concepts. First, study the answers in your part and then EXPLAIN them to your group. Don't simply read the answers to your classmates, and don't let your classmates read their answers to you. In explaining something to another person, most people gain and often transmit a better understanding of the subject. The pretest discussion and patient-oriented problem-solving parts of this activity are "open book"; be sure to refer to textbooks, notes, and other written resources whenever questions arise. To help you review any questions that you may have missed, you probably will want to make notes on your pretest answer sheets. However, avoid "collecting pages" for later study and understanding." Learn the concepts now so that later you will only need to review them. 4. A is correct. The plasma concentration of drug falls exponentially with time. In first-order kinetics, a constant fraction of drug is removed per unit of time. When concentration of drug is plotted on a logarithmic scale versus time, a straight line is obtained. Refer your colleagues to the Answer Aid for Pretest Question 4 on Handout 1. A two-compartment, first-order system would have yielded a bi-exponential curve in which the first and more rapid disappearance of drug relates more to distribution and the latter portion of the curve relates more to drug metabolism or excretion. At saturation (zero-order) kinetics the plasma concentration-time curve (not the log concentration-time curve) is linear. In zeroorder kinetics, the process by which the drug is eliminated is at a maximum velocity (Vmax). 9. A is correct. The area under the concentration-time curve indicates how much drug in each of the tablets reached the systemic circulation. The areas under the curve for tablets A and B are nearly equal. Although all of the drug in tablets A and B reaches the systemic circulation, comparisons of peak concentrations and times to reach these peaks indicate that the drug is more slowly absorbed from tablet B than from tablet A. The drug in tablet C is much less bioavailable. There may be several reasons for this. The drug might be unstable in tablet C; tablet C might not be absorbed because it does not disintegrate; or the drug in tablet C may be released in such a way that it is metabolized by the liver or GI tract before it reaches the systemic circulation (first-pass effect). When your group has finished discussing the pretest, read the Instructions for the Clinical Problem on the next page of your booklet. 2

3 HANDOUT 1 - aid to pretest questions Aid for Pretest Question 3: Aid for Pretest Question 4: Aid for Pretest Question 7: Css = mmmmmmmmmmmmmmmmmmmmmm dddddddd CCCC Half-life = Vd Cl

4 Instructions for the Clinical Problem In the remainder of this package, you are to use your knowledge of pharmacokinetics to determine appropriate therapy for Mr. Wheeze. Each member of your group has information about one episode in Mr. Wheeze's medical history and part of the data necessary to determine the best therapy for him. Therefore, you must share information and work together to treat Mr. Wheeze. When the episode for which you are responsible comes up, read it to the group and lead a discussion of the questions that are included with the episode. Pose each question to a different member of the group. Use the Discussion Notes provided as a guide for the discussion. DO NOT SIMPLY READ THEM to the group. The interaction with your fellow students should go much farther than just sharing data. You should do your best to teach each other, seek additional information from your textbooks, and determine the appropriate therapy in a logical way. At the end of each part of this exercise, everyone in the group should agree on appropriate therapy. You should also understand the pharmacokinetic principles involved in making the decision. The group member whose booklet contains Episode 1 should begin the discussion. 3

5 HANDOUT 2 - for use with Episode 1 Figure 1. Relationship between plasma theophylline concentration and the one-second forced expiratory volume (FEV1) among six otherwise healthy asthmatic patients during an acute attack. Plots for each subject are presented individually. The dashed line depicts the response of non-asthmatic individuals. Redrawn from: Mitenko, P.A. and Ogilvie R.I. Rational intravenous doses of theophylline. NEJM, 289:602,1973. Abstracted by permission of The New England Journal of Medicine. Figure 2. Mean (±SE) peak expiratory flow in 31 patients treated with high-dose budesonide and 31 patients given low-dose budesonide plus theophylline (250 or 375 mg) twice daily for 3 months. Median serum theophylline concentration was 8.7 µg/ml. Redrawn from: Evans, D.J. et al. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. NEJM 337:1412, 1997.

6 HANDOUT 3 - for use with Episode 2 Figure 1. Number of acute asthmatic attacks in a group of patients who received placebo or theophylline. Patients who received theophylline are further subdivided according to their peak serum theophylline concentrations. Redrawn from: Weinberger, M. Theophylline for treatment of asthma. J. Pediatrics 92:2,1978. Figure 2. Relationship between serum theophylline concentration and prevention of exerciseinduced deterioration in pulmonary function. V50 is a measure of rate of expiration. Redrawn from: Pollock J., Kiechel F., Cooper D., and Weinberger M. Relationship of serum theophylline concentration to inhibition of exercise-induced bronchospasm and comparison with cromolyn. Pediatrics 60:843,1977.

7 HANDOUT 4 - for use with Episode 2 Time (hr) Serum conc. (µg/ml)

8 GRAPH A Time (hr) Serum conc. (µg/ml)

9 GRAPH B Time (hr) Serum conc. (µg/ml)

10 HANDOUT 5 - for use with Episode 3 Serum theophylline concentrations following IV administration of theophylline to adults in an intensive care unit. Seventeen of 49 patients experienced varying degrees of theophylline toxicity as a result of elevated serum drug concentrations. Mild toxicity included nausea, vomiting, headache, insomnia and nervousness. Potentially serious adverse effects included sinus tachycardia with or without symptoms of mild toxicity. Severe toxicity included cardiac arrhythmias and seizures. Redrawn from: Hendeles, L., Bighley, L., Richardson, R.H., Hepler C.D. and Carmichael J. Frequent toxicity from IV aminophylline infusions in critically ill patients. Drug Intell. Clin. Pharm.11:14, 1977.

11 Episode Four Mr. Wheeze has continued to take cimetidine along with his asthma drug regimen for several months. His asthma is well controlled. During the summer, he and his friends go on a camping trip. One week later, Mr. Wheeze experiences a severe asthma attack and is taken to the emergency department of a local hospital. He tells the physician on call that he has asthma that is usually well controlled by ICS and theophylline. The physician immediately treats Mr. Wheeze with albuterol and draws blood for measurement of the theophylline concentration. Use the following questions and the Discussion Notes to guide the discussion Each member of the group should take the lead in answering at least one of the questions. 4.1 Why was albuterol administered? 4.2 Mr. Wheeze does not respond to albuterol. Should theophylline be given to him at this time? Why did Mr. Wheeze not respond to albuterol? 4.3 Mr. Wheeze's serum theophylline concentration is now reported to be <1 µg/ml. Do you believe this report and why? 4.4 Why is there virtually no theophylline in Mr. Wheeze's serum? 4.5 What should be done now? 4.6 Mr. Wheeze admits that he accidentally left his theophylline in his medicine cabinet at home, and he hasn't taken any of the drug for one week. He did remember his cimetidine, however. Is it rational to administer theophylline at this stage? 4.7 The physician plans to give Mr. Wheeze his usual dose of theophylline (400 mg) as the sustained-release tablet every 12 hours. Is this the correct approach? 4.8 How should theophylline be given to get an immediate effect? 4.9 Provide your group with the following information for theophylline: half-life = 12 hours, Vd = 0.45 L/kg, and clearance = L/kg/hr. Then have them calculate a loading dose of theophylline for Mr. Wheeze that will attain a serum concentration of 10 µg/ml. Inform them that theophylline will be administered in an IV drip as aminophylline (80% theophylline) What maintenance dose of aminophylline should be administered by constant intravenous infusion to keep the serum theophylline concentration at 10 µg/ml? 4

12 Discussion Notes for Questions in Episode Four 4.1 To produce bronchodilation. Albuterol is a short-acting bronchodilator by virtue of its action on beta-2 adrenergic receptors on bronchiolar smooth muscle. 4.2 A more common practice would be to administer another dose or two of albuterol at 15- to 30-minute intervals. However, there is still no response. It is important to know Mr. Wheeze's serum theophylline concentration before you give more theophylline. The reason Mr. Wheeze did not respond to albuterol is unknown, but he may have a single-nucleotide polymorphism in the ADRB2 gene for the beta-2 adrenergic receptor that renders him non-responsive to beta-2 agonist bronchodilators. 4.3 It is wise to question an unexpected lab value. In this case, however, we have more than the lab test result. We also have the lack of pharmacologic effect. The low serum theophylline level plus the lack of effect should make you fairly confident in the laboratory report. 4.4 There are two possibilities: he has not taken his medication or, for some reason, he has become a rapid metabolizer. The latter explanation is unlikely. 4.5 It is important to distinguish between the two possibilities in 4.4. The best initial approach is to gently ask Mr. Wheeze again about whether he has taken his theophylline. 4.6 Yes, it is. We know Mr. Wheeze is responsive to theophylline, so it should relieve his symptoms 4.7 No, it s not. It will take 4-5 half-lives to reestablish a therapeutic steady-state concentration of theophylline. The half-life of theophylline is 12 hours; thus, 2-3 days of therapy would be required to achieve a maximally effective concentration. Mr. Wheeze needs the drug's full action immediately. 4.8 An intravenous loading dose of theophylline should be given to rapidly achieve a therapeutic response. 4.9 Remember: loading dose = Vd x Css Therefore, the theophylline loading dose = 0.45 L/kg x 10 mg/l = 4.5 mg/kg. However, aminophylline only contains 80% theophylline by weight. Therefore, the loading dose of aminophylline is 100/80 x 4.5/1 = 5.6 mg/kg. The loading dose should be administered over 30 minutes. Although the distribution of theophylline between blood and other tissues is rapid, it is not instantaneous. Therefore, if the drug is infused too rapidly, most of the dose is in the blood initially and the concentration of theophylline is quite high. Highly perfused tissues such as the heart and brain could be exposed to potentially toxic concentrations during this phase. 5

13 4.10 Remember: maintenance dose = CL x Css For maintenance dosing, the amount of drug lost during each dosage interval must be replaced. The clearance of theophylline in Mr. Wheeze is L/kg/hr, which means that L of serum is completely cleared of the drug every hour for every kg of body weight. Mr. Wheeze's serum concentration of theophylline needs to be maintained at 10 mg/l. Therefore, every hour he will lose 10 mg/l x L/kg/hr of theophylline, i.e., he loses 0.25 mg/kg/hr. Therefore, the rate of administration of the maintenance dose of theophylline should be 0.25 mg/kg/hr. That's about 420 mg per day very close to his oral dose of theophylline before he went camping! As aminophylline, the dose will be 0.30 mg/kg/hr. When you have finished discussing this episode, you have completed the clinical problem. Now, please have each group member, individually, answer the questions on the posttest. 6