Thyophylline

CASE TEACHING NOTES
for
"Does a One-Size Drug Dose Fit All?
Or, Why All the Variability in the Theophylline Blood Concentrations?"

by
Kathleen Boje
School of Pharmacy
University at Buffalo, State University of New York


INTRODUCTION

The purpose of this case is to make students aware that some patients may require individualized drug dosing regimens based on a variety of patient variables. Many manufacturer-recommended dosages are for the "average adult" patient, as determined by FDA-mandated clinical trials. The recommended dose is based on a positive clinical response of the majority of patients with minimal or tolerable side effects. In many instances, the recommended drug dosage is appropriate for the majority of the average population. However, for some drugs, the prescribed dose may need to be individualized for patients suffering from other diseases that require other medications, advanced age, body weight, gender, etc.

This case was used in an introductory pharmaceutical sciences course, where junior (third year collegiate) students have little specific knowledge of the pharmaceutical sciences. This case would be suitable for other students with a biological, biomedical, health sciences, or chemistry/medicinal chemistry background.

Objectives

As a result of working with this case, the student should be able to:

MAJOR ISSUES

Pharmacokinetics - The Study of Drug Absorption, Distribution, Metabolism, and Elimination

Absorption:
When a drug is administered by the oral, subcutaneous, intramuscular, bucal, pulmonary, nasal, or transdermal routes, it first must be absorbed from the site of administration into the bloodstream, whereupon the drug circulates to all regions of the body. In the case of an intravenously administered drug, there is no absorption process, as the drug is directly delivered into the bloodstream.
 
Distribution:
The extent of the drug's lipophilicity (a measure of how lipophillic, or "fat-loving," a drug is) determines how well the drug will differentially distribute into various organs and tissues. A fraction of the absorbed dose distributes to the organ or tissue that is the site of pharmacologic action, where a drug effect may be observed.
 
Metabolism and Elimination:
Concomitantly, as a drug is distributing into (and out from) organs and tissues, the drug is distributing into the liver, where it is metabolically changed into an inactive form in the process of metabolism. The drug is also filtered into the urine by the kidneys in the process of elimination. Drug metabolism and elimination effectively remove the drug from the body, and in the process reduce drug concentrations to a point where insufficient drug is at the site of action to cause a pharmacologic effect.

The amount of drug (how much) that enters the bloodstream is determined by absorption processes; how much drug arrives at the site of action is determined by distribution processes; lastly, how rapidly the drug is removed from the body (thereby terminating the drug's pharmacologic effect) is determined by the metabolism and elimination processes.

Pharmacodynamics - The Study of Pharmacologic Effects in Relationship to Drug Concentrations

A pharmacologic effect is exerted when the drug concentration at the site of action attains a minimum level. In many instances, the intensity of the pharmacologic effect is proportional to the drug concentration, with a greater effect attained at higher drug levels. However, there is an upper limit where drug concentrations trigger a maximal (100%) effect, and additional increases in drug concentrations do not promote a greater than maximal (100%) effect. At this point, higher drug concentrations may lead to a variety of adverse effects, either due to too high of a drug level at the site of action and/or high drug levels exerting undesired effects at other organ and tissue sites of the body.

The onset of a pharmacological effect occurs when a minimum amount of drug distributes to the site of pharmacologic action. The offset of a pharmacological effect occurs when sufficient drug distributes away from the site of action such that the amount of drug is less than a minimum amount to elicit an effect. Following drug administration, absorbed drug distributes into the bloodstream. The drug then distributes into various organs and tissues, including the site of pharmacologic action. When enough drug distributes into the pharmacologic action site, a minimal effect is observed. As more drug distributes to the pharmacologic action site, a larger effect is observed. However, drug in the bloodstream is also distributing into the liver and kidneys, which are working to eliminate the drug. Eventually, as the liver and kidneys eliminate more drug, blood concentrations decrease. Drug in other organs and tissues, including the site of pharmacologic action, distributes out of the organs and tissues back into the bloodstream. In this manner, drug concentrations in the body continually decrease. Eventually the amount of drug at the site of pharmacologic action reaches an amount just below the minimum amount to trigger an effect. At this point, the pharmacologic effect is terminated.

Therapeutic Drug Blood Concentration Range

Clinically effective drugs often have a therapeutic concentration range, whereby the minimum blood concentration is that concentration which triggers a minimal pharmacologic effect and the maximum blood concentration is that concentration that gives a maximum pharmacologic effect with no or minimal (tolerable) side effects.

The therapeutic concentration range is determined by measuring the drug concentrations in a person's bloodstream and the intensity of the pharmacologic effect.

Blood concentrations of drug that are below the therapeutic range frequently lead to inadequate or subtherapeutic drug therapy, and a lack of medical control of the disease state. Blood drug concentrations within the therapeutic range lead to effective drug therapy, with the intensity of the desired drug effect proportional to the blood concentration. Blood drug concentrations that are above the therapeutic range frequently lead to minor and/or major drug-related toxicities.

Individual Variability in Drug Response

For some drugs, when individuals are given identical doses of a drug, large differences in pharmacologic responses may be seen. Also, the dose required to elicit a desired response may vary widely from individual to individual. Many factors contribute to the variability in the relationship between the administered dose and blood drug concentrations. Age, genetic factors, environmental factors, other concurrent diseases, and other drugs are examples of factors that contribute to inter-individual variability.

During the clinical study phase of the drug development process, carefully designed and executed clinical studies shed light on the subtherapeutic, effective, and toxic blood concentrations of a drug, as well as the various patient population factors that influence drug disposition. In actual clinical practice, therapeutic drug monitoring may be performed whereby measurement of a person's blood drug concentrations provides guidance for drug dosage adjustment based on whether the blood concentrations are within or outside of the therapeutic range.

Background on Theophylline Therapeutics

Theophylline is a drug that is prescribed to patients who have chronic asthma. Theophylline has been in clinical use for over three decades. However, inter-individual variability requires that theophylline be carefully dosed to each patient so that the blood concentrations are within the therapeutic concentration range. Failure to individualize a theophylline dosing regimen may result in poor clinical management of the patient's asthmatic condition. Theophylline blood concentrations that are too low may result in continued, life-threatening asthmatic attacks; theophylline blood concentrations that are too high may result in toxic, adverse effects, such as nausea, vomiting, headache, life-threatening heart arrhythmias, seriously low blood pressure, seizures, brain damage, and death.

CLASSROOM MANAGEMENT

This case is divided into two parts (Part A and B), which can be done sequentially or separately. Part A is a classroom discussion of the factors that influence drug dosing, and is based on a pre-class assigned reading of an article that appeared in Newsweek entitled "The One-Size Dose Does Not Fit All" by Jay S. Cohen, M.D. (December 6, 1999, p. 97). Part B is a case study entitled "Why All the Variability in Theophylline Blood Concentrations?" This case study requires that students working in groups examine hypothetical patient data profiles to make inferences about patient factors that influence theophylline blood concentrations. This case was designed for a single two-hour session for a class of 30 students. Alternatively, each part (A or B) can be completed in two separate 50- to 60-minute sessions. Part A is a preparatory activity that helps students focus on the issues presented in Part B. If time is limited, Part A could be omitted.

Part A: "Does One-Size Dose Fit All?" (Discussion of Pre-Class Reading Assignment)

Materials:

  1. Pre-class assigned reading
    The following article should be read by all students in advance of the class session: "The One-Size Dose Does Not Fit All" by Jay S. Cohen, M.D. Newsweek, December 6, 1999, pg. 97.
     
  2. Whiteboarding
    3M Post-it Easel Pad poster paper and markers.

Classroom Activities:

  1. First Activity: General Class Discussion (10 minutes)
    The instructor/facilitator initiates a class discussion on the central theme of the pre-class assigned reading. If desired, the instructor (or designated student) can summarize and write down student responses on the blackboard, overhead, or poster paper.
     
    Opening, instructor-posed questions may include:  
  2. Second Activity: Group Brainstorming (10 minutes)
    Students are asked to form groups of three. Each group is given a sheet of 3M Post-it Easel Pad paper and marker. Students are asked to brainstorm in response to the question: "What are possible factors that may contribute to the central theme of the assigned reading?" Students should be as specific as possible and write concise responses on the 3M Post-it Easel Pad poster paper.
     
  3. Third Activity: Class Discussion of Each Group's Responses (10-15 minutes)
    A representative of each group is asked to briefly discuss why they listed each item on their paper. All groups are called upon to share their brainstorming responses with the class.
     
  4. Optional Fourth and Last Activity: Discussion of the Major Concepts (10-15 minutes)
    The instructor/facilitator can introduce the concepts of pharmacokinetics, pharmacodynamics, therapeutic drug blood concentration range, and individual variability in drug response. However, a discussion of these points may be optional, depending on student major, background and interest level.

Part B: "Why all the variability in theophylline blood levels?" Case Study

Materials:

  1. Pre-class assigned reading
    Distribute the case study handout, "Why all the variability in theophylline blood levels?" The handout should be read by all students in advance of the class session. Students should be prepared to discuss the questions at the end of the case study.
     
  2. Hypothetical Patient Data Cards
    Approximately 144 hypothetical patient data cards are prepared in advance of class. The cards are consecutively numbered from 1 to144 and contain patient information on name, age, gender, theophylline blood level, etc. (see Figure 1). Appendix A is a PDF file that contains the data cards. Data cards may be prepared by one of the following methods: (1) Cut the patient data cards from a hardcopy of Appendix A or (2) Cut and paste the patient data cards (Appendix A) onto 4x6 index cards.

    Figure 1: Patient data card format

    Patient Name: ____________________ Theophylline level: ____µg/mL
                                  Clinical Response Notes ___________
    Age and Gender: _____________________________________
    Weight: ____________________________________________
    Other diseases / conditions: _____________________________
    Other medications: ____________________________________
    Lifestyle:
              Alcohol consumption: ____________________________
              Cigarette smoking (packs/day): _____________________
              Caffeine intake (cups coffee/tea per day): ______________
              Street drug use: _________________________________
              Exercise activity level: ____________________________
     
  3. Numeric Grid Tracking Sheet
    One grid tracking sheet is prepared per group. This sheet (see below) consists of a list of numbers, from 1 to144, corresponding to the number of patient data cards. This sheet is used to track which patient data cards have been examined by the group. On the grid tracking sheet, the patient number (located on the card) is crossed out after a group has evaluated the data. This grid tracking sheet is also available in Appendix A.
     
    1    11    21    31    41    51    61    71    81    91    101    111    121    131    141    
    2    12    22    32    42    52    62    72    82    92    102    112    122    132    142    
    3    13    23    33    43    53    63    73    83    93    103    113    123    133    143    
    4    14    24    34    44    54    64    74    84    94    104    114    124    134    144    
    5    15    25    35    45    55    65    75    85    95    105    115    125    135     
    6    16    26    36    46    56    66    76    86    96    106    116    126    136     
    7    17    27    37    47    57    67    77    87    97    107    117    127    137     
    8    18    28    38    48    58    68    78    88    98    108    118    128    138     
    9    19    29    39    49    59    69    79    89    99    109    119    129    139     

Classroom Activities:

  1. First Activity: Discussion of the Major Concepts (10-15 minutes)
    If Part A is omitted, then an introduction of the major concepts can be done at this point. The instructor/facilitator can introduce the concepts of pharmacokinetics, pharmacodynamics, therapeutic drug blood concentration range, and individual variability in drug response. However, a discussion of these points may be optional, depending on student major, background, and interest level.
     
  2. Second Activity: Introduction to the Scientific Problem (General Class Discussion) (10 minutes)
    The instructor/facilitator initiates a class discussion on the concept of the scientific method as applied to the problem posed in the case study handout. If desired, the instructor (or designated student) can write down student responses on the blackboard, overhead, or poster paper.
     
    Opening, instructor-posed questions may include:  
  3. Third Activity: Group Investigative Activity (30 minutes)
    The instructor then divides the class into groups of three to four students and asks each group to assume the role of Dr. Chris Brason. Each group must analyze the patient data cards to identify patient characteristics that influence the theophylline blood levels.

    Each group is given 10 to15 data cards and a numeric grid sheet. Students are to analyze the data cards to identify important patient population factors that influence a person's theophylline pharmacokinetics. Students should also attempt to discern the therapeutic concentration range for theophylline. One member of the group should write down patient population factors and the theophylline blood concentration(s) associated with that population factor.

    After examination of the initial data card set, groups should trade cards among themselves for new sets of data cards. Groups should be encouraged to swap data card sets to identify as many factors as possible. Groups can track which cards they've examined by marking off the patient number on their numeric grid tracking sheet.

    At the discretion of the instructor, groups may/may not be given additional information on how to analyze the data cards. The instructor may not offer additional guidance, leaving each group to interpret and deduce the data on their own, as occurs in the "real scientific world." Alternatively, the instructor may offer "hints" about how to track down the important patient population factors and the therapeutic concentration range.

    Hints:  
  4. Final Activity: Summative Discussion (10+ minutes)
    One can go from group to group, calling upon a group spokesperson, or one can just open the floor to anyone. Ask the students to identify the factors and the theophylline concentrations. As the information is verbalized, it is useful to write down the information on the blackboard. Questions to facilitate a class wide discussion include:

    After the information is collated, student groups could also be asked to consider how they would summarize these results and report the data to Dr. Walther. This might involve descriptive statistics; creating graphs, charts, or other graphical representations; or designing a poster.

    At the instructor's discretion, the instructor may require a follow-up homework assignment where students are asked to do a web search on theophylline, with a focus on its indications, dosing regimens, and adverse effects.

Key: Factors Influencing Theophylline Concentrations

Age less than 20 years old:

 Male 8 µg/ml
 Female 12 µg/ml

Age more than 20 years old and less than 40 years old:

 Normal, healthy, lean (male or female) 15 µg/ml
 Obesity 12 µg/ml
 Heavy cigarette smoker (> 2 packs/day) 8 µg/ml
 Marijuana use (> 1 joints/week) 11 µg/ml
 Female on oral contraceptives 9 µg/ml

Age greater than 40 years old:

 Normal, healthy, (male or female) 20 µg/ml
 Heavy ethanol ingestion 39 µg/ml
 Heavy cigarette smoker (> 2 packs/day) 10 µg/ml
 Congestive heart failure 31 µg/ml
 Congestive heart failure+heavy cigarette smoker 24 µg/ml

Clinical Response Notes:

Dosing Adjustments:

Brief Explanation of Factors:

Age
Age is clinically important for pediatric (<20 years old) patients; however, this is also modified by the interplay of gender. Pediatric male patients have lower (subtherapeutic) theophylline concentration levels compared to pediatric females. This is most likely due to hormonal and physiological body differences between the genders during the pre-teen and teen years. Because pediatric male patients may have subtherapeutic (ineffective) theophylline concentrations, these patients may require higher theophylline doses to attain concentrations in the therapeutic range.

Age is also an important factor for patients >20 years old. In general, the older the patient, the greater probability that the person's theophylline blood concentration will be higher. For theophylline, the liver and kidney's ability to metabolize and eliminate drug tends to decrease with age. In general, between the ages of 20 and 70, the theophylline concentration tends to fall within the therapeutic range when dosed at the recommended adult dosage. However, clinical importance is relevant in the elderly (>70 years old), where one may need to decrease the theophylline dosage to compensate for poorer liver and kidney function.

Obesity
Theophylline levels tend to be lower in obese patients as compared to lean control patients. This is because obese people have a larger body mass, composed of more fat tissue but also more lean tissue too. While theophylline distributes somewhat into the extensive fat deposits of the obese, it also distributes into the larger mass of lean tissue, thereby causing lower drug concentrations in the bloodstream. However, usually the lower theophylline concentrations in the obese still tend to fall within the lower end of the therapeutic concentration range.
 
Heavy Cigarette Smoking (> 2 packs per day)
Persistent exposure to inhaled cigarette smoke causes the liver to express more drug metabolism enzymes. Heavy smokers have lower theophylline concentrations compared to nonsmoking (or light smoking) controls because their livers are more efficient at eliminating theophylline.
 
Marijuana Use
Same explanation as for heavy cigarette smokers.
 
Use of Oral Contraceptives
Persistent exposure to supplementary female hormones (estrogen and progesterone) causes the liver to express more drug metabolism enzymes. Females on oral contraceptives have lower theophylline concentrations compared to age-match female controls because their livers are more efficient at eliminating theophylline.
 
Heavy Ethanol Ingestion
Persistent consumption of alcoholic beverages over time will lead to cirrhotic liver damage, which results in lowered expression of liver drug metabolizing enzymes and poorer liver function. Alcoholics and patients with cirrhotic liver disease will have higher theophylline concentrations compared to age-matched, healthy controls due to poor liver function. Alcoholics and patients with cirrhotic liver disease will need lower doses of theophylline to maintain theophylline concentrations within the therapeutic range without adverse effects.
 
Congestive Heart Failure
Patients with congestive heart failure have hearts that cannot adequately pump blood for adequate organ perfusion. Because of poor blood perfusion to the liver, theophylline concentrations are higher in congestive heart failure patients compared to healthy controls. Patients with untreated or poorly treated congestive heart failure will need lower doses of theophylline to maintain theophylline concentrations within the therapeutic range without adverse effects.
 
Congestive Heart Failure and Heavy Cigarette Smoking
Congestive heart failure tends to cause elevated theophylline concentrations; heavy smoking causes decreased theophylline concentrations. The two factors oppose one another such that patients with congestive heart failure and who smoke heavily will have theophylline concentrations near the upper limit of the theophylline therapeutic concentration range.

REFERENCES

Print:

  1. Cohen, J. "The One-Size Dose Does Not Fit All." Newsweek December 6, 1999, p. 97.
     
  2. Gibaldi, M. Biopharmaceutics and Clinical Pharmacokinetics. Fourth ed. Philadelphia: Lea & Febiger, 1991, pp. 406.
     
  3. Gibaldi, M., and G. Levy. "Pharmacokinetics in Clinical Practice: I. Concepts." Journal of the American Medical Association 253: 1864-1867 (1976).
     
  4. Gibaldi, M., and G. Levy. "Pharmacokinetics in Clinical Practice: II. Clincal Practice." Journal of the American Medical Association 253: 1987-1992 (1976).
     
  5. Jusko, W.J., M.J. Gardner, A. Mangione, J.J. Schentag, J.R. Koup, and J.W. Vance. "Factors Affecting Theophyllline Clearances: Age, Tobacco, Marijuana, Cirrhosis, Congestive Heart Failure, Obesity, Oral Contraceptives, Benzodiazepines, Barbiturates, and Ethanol." Journal of the Pharmaceutical Sciences 68:1358-1366 (1979).

Internet:

  1. Rx List: The Internet Drug Index:  http://www.rxlist.com
    One can search for theophylline at this site. A list of brand names with corresponding generic names will appear. Click on any hypertext link that shows "theophylline SR" ("SR" stands for sustained release.) Alternatively, go directly to: http://www.rxlist.com/cgi/generic/theosr.htm.


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Acknowledgements:  This case was developed with support from The Pew Charitable Trusts and the National Science Foundation as part of the Case Studies in Science Workshop held at the University at Buffalo on June 12-16, 2000.


Image Credit:  A ray-traced, space-filling model of theophylline generated by Sam Mikes. Used with permission.
Date Posted: 1/21/02 nas

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