university of illinois at chicago college of pharmacy uic integrated, evidence-based /...

University of Illinois at Chicago College of PharmacyUniversity of Illinois at Chicago College of PharmacyUICUIC

Integrated, Evidence-based Integrated, Evidence-based / Patient-centered / Patient-centered Teaching and Learning in Teaching and Learning in Pharmacy Education –Pharmacy Education – October 17, 2011 at NCKUOctober 17, 2011 at NCKU

Matthias C. Lu, PhDMatthias C. Lu, PhD

Professor Emeritus of Medicinal Professor Emeritus of Medicinal Chemistry and Pharmacognosy, College Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at of Pharmacy, University of Illinois at ChicagoChicago

UIC 1995 Excellence in Teaching Award UIC 1995 Excellence in Teaching Award UIC 2001 Teaching Recognition Program AwardUIC 2001 Teaching Recognition Program AwardGolden Apple Awards from 2000, 2001, 2003, 2005, (2006),2007 ClassesGolden Apple Awards from 2000, 2001, 2003, 2005, (2006),2007 ClassesUIC 2007 Urban Health Program Distinguished Faculty AwardUIC 2007 Urban Health Program Distinguished Faculty Award


I.I. Why Evidence-based Why Evidence-based Practice and Teaching in Practice and Teaching in Pharmacy Education?Pharmacy Education?II. A Brief Overview of the II. A Brief Overview of the Current Curriculum Current Curriculum Standard in the United Standard in the United States.States.III. Examples of Evidence-III. Examples of Evidence-based / based / Patient- Patient-centered Teachingcentered Teaching


The U.S. Pharmacy The U.S. Pharmacy EducationEducation

The Doctor of Pharmacy (PharmD) degree is the highest level of The Doctor of Pharmacy (PharmD) degree is the highest level of professional education in pharmacy and has been approved by professional education in pharmacy and has been approved by the American Council on Pharmaceutical Education (ACPE) as the American Council on Pharmaceutical Education (ACPE) as the sole entry-level degree for the pharmacy profession since the sole entry-level degree for the pharmacy profession since 2000. [2000. [UIC started PharmD as the sole program in 1985UIC started PharmD as the sole program in 1985]]

The PharmD curriculum is designed to produce a scientifically The PharmD curriculum is designed to produce a scientifically and technically competent pharmacist who can apply his/her and technically competent pharmacist who can apply his/her education in such a manner as to provide maximum health care education in such a manner as to provide maximum health care services to patients.services to patients.

The PharmD degree program requires at least 2-years of The PharmD degree program requires at least 2-years of specific pre-professional (undergraduate) coursework followed specific pre-professional (undergraduate) coursework followed by 4-academic years (or 3-calendar years) of professional study.by 4-academic years (or 3-calendar years) of professional study.


The Curriculum in The Curriculum in PharmacyPharmacy

The teaching and learning strategies such as active, student-The teaching and learning strategies such as active, student-centered, and problem-based learning as well as performance- centered, and problem-based learning as well as performance- and outcomes-based assessment have greatly transformed the and outcomes-based assessment have greatly transformed the Doctor of Pharmacy programs in the U.S. in the last 15 years.Doctor of Pharmacy programs in the U.S. in the last 15 years.

In 2001-02, a task force on “Best Evidence Pharmacy In 2001-02, a task force on “Best Evidence Pharmacy Education (BEPE)” was established by the Chair of AACP Education (BEPE)” was established by the Chair of AACP Council of Faculties to explore – “ Council of Faculties to explore – “ Can an evidence-based Can an evidence-based approach will make our instruction better tomorrow than approach will make our instruction better tomorrow than today in the pharmacy education?today in the pharmacy education?

A 2003 Institute of Medicine report on “Health Profession A 2003 Institute of Medicine report on “Health Profession Education: A Bridge to Quality” recommends that Education: A Bridge to Quality” recommends that all health all health professionalsprofessionals should be educated to deliver should be educated to deliver patient-centered patient-centered carecare as members of an interdisciplinary team, emphasizing as members of an interdisciplinary team, emphasizing evidence-based practiceevidence-based practice..


AACP Report on Best AACP Report on Best Evidence Pharmacy Evidence Pharmacy

Education (July 2004)Education (July 2004)The Task Force on The Task Force on Best Evidence Pharmacy EducationBest Evidence Pharmacy Education at the at the

2004 Annual Meeting of AACP has identified eight specific 2004 Annual Meeting of AACP has identified eight specific areas that pertinent for pharmacy educatorsareas that pertinent for pharmacy educators..

1.1. Integrated CoursesIntegrated Courses

2.2. Distance EducationDistance Education

3.3. Early Clinical ExperiencesEarly Clinical Experiences

4.4. Clinical RelevanceClinical Relevance

5.5. Communication SkillsCommunication Skills

6.6. ProfessionalismProfessionalism

7.7. Student Learning and RetentionStudent Learning and Retention

8.8. Faculty DevelopmentFaculty Development

The Task Force also recommends that these topics be the focus The Task Force also recommends that these topics be the focus of the Teacher’s Seminar at the 2005 Annual Meeting. of the Teacher’s Seminar at the 2005 Annual Meeting. [UIC [UIC started an integrated courses curriculum in 1997]started an integrated courses curriculum in 1997]


Why Evidence-based Practice Why Evidence-based Practice and Teaching in Pharmacy and Teaching in Pharmacy

Education?Education?Evidence-based decision making (EBDM) is the gathering and Evidence-based decision making (EBDM) is the gathering and critically assessment of relevant information before taking action.critically assessment of relevant information before taking action.

In healthcare setting, EBDM has been defined as “the systematic In healthcare setting, EBDM has been defined as “the systematic application of the best available evidence to the evaluation of application of the best available evidence to the evaluation of options in making clinical, management and policy decisions”.options in making clinical, management and policy decisions”.

The teaching of evidence-based medicine (EBM) is an integral The teaching of evidence-based medicine (EBM) is an integral part of medical curriculum at many institution since Sackett first part of medical curriculum at many institution since Sackett first applied EBDM’s principle to his teachings of medical students in applied EBDM’s principle to his teachings of medical students in mid 90s.mid 90s.

The vast majority of pharmacy educators are scientists, clinicians, The vast majority of pharmacy educators are scientists, clinicians, or both. Although, they routinely base their work on current or both. Although, they routinely base their work on current evidence and knowledge of their fields to direct their research and evidence and knowledge of their fields to direct their research and patient care, but this practice has not been used in their patient care, but this practice has not been used in their teachings. teachings.


What is evidence-based What is evidence-based medicine?medicine?

Rosenberg and Donald outlined EBM as proceeding in Rosenberg and Donald outlined EBM as proceeding in the following four steps:the following four steps:

1.1. Select specific clinical questions from patient’s Select specific clinical questions from patient’s specific problems such as:specific problems such as: Among patients with NIDDM who are having Among patients with NIDDM who are having

MI’s, does tight control of their blood sugar MI’s, does tight control of their blood sugar reduce their risk of dying?reduce their risk of dying?

2.2. Search the literature or databases for relevant Search the literature or databases for relevant clinical informationclinical information

3.3. Appraise the evidence for validity and usefulness to Appraise the evidence for validity and usefulness to the patient and practicethe patient and practice

4.4. Implement useful findings in everyday practiceImplement useful findings in everyday practice


From UK National Health From UK National Health Service on Levels of EBMService on Levels of EBM

Level A: Level A: Consistent Randomized Controlled Clinical Consistent Randomized Controlled Clinical Trial, Cohort Study, All or none, Clinical Trial, Cohort Study, All or none, Clinical Decision Rule validated in different Decision Rule validated in different population.population.

Level B: Level B: Consistent Retrospective Cohort, Exploratory Consistent Retrospective Cohort, Exploratory Cohort, Ecological Study, Outcome Research, Cohort, Ecological Study, Outcome Research, Case-control Study, or extrapolations from Case-control Study, or extrapolations from level A studies.level A studies.

Level C: Level C: Case-series Study or extrapolations from Case-series Study or extrapolations from level B studieslevel B studies

Level D: Level D: Expert opinion without explicit critical Expert opinion without explicit critical appraisal or base on physiology or bench appraisal or base on physiology or bench research research


How to Use EBM in Teaching? How to Use EBM in Teaching? (Sackett’s recommendations)(Sackett’s recommendations)

Become a self-directed, lifelong learner – keep up-to-date with Become a self-directed, lifelong learner – keep up-to-date with the current literature.the current literature.

Even the latest edition of textbook was outdated.Even the latest edition of textbook was outdated.

The old paradigm of a professor who has used the same The old paradigm of a professor who has used the same lecture notes for 20 years is no longer tenable.lecture notes for 20 years is no longer tenable.

Seek and apply summaries generated by others – just like what Seek and apply summaries generated by others – just like what you do with your research projects.you do with your research projects.

Critical reviews of the literature and update you lecture Critical reviews of the literature and update you lecture accordingly.accordingly.

Accept evidence-based protocols from colleagues – Accept evidence-based protocols from colleagues – collaborative effort in your teaching (i.e., integrate teachings).collaborative effort in your teaching (i.e., integrate teachings).

Is your colleague’s opinion based on evidence or just a Is your colleague’s opinion based on evidence or just a hunch?hunch?


Examples of Scenarios for Examples of Scenarios for Teaching EBM in Primary Teaching EBM in Primary

Care Care Is serum ferritin really the best way to determine iron Is serum ferritin really the best way to determine iron deficiency in a 70-yos who is complaining of fatigue?deficiency in a 70-yos who is complaining of fatigue?What is the survival time and the quality of life after What is the survival time and the quality of life after the onset of congestive heart failure?the onset of congestive heart failure?What is the relationship between cholesterol and What is the relationship between cholesterol and mortality? Is the ratio of LDL/HDL still the most valid mortality? Is the ratio of LDL/HDL still the most valid factor?factor?What are the most cost effective mechanisms of What are the most cost effective mechanisms of reducing coronary risk factors in primarily care?reducing coronary risk factors in primarily care?In a woman with micro-invasive squamous cell In a woman with micro-invasive squamous cell carcinoma of the cervix who wishes to start a family, carcinoma of the cervix who wishes to start a family, what is the best treatment option?what is the best treatment option?


II. A Brief Overview of II. A Brief Overview of Current Curriculum Current Curriculum Standard in the United Standard in the United States.States.


The Curricular Reform is The Curricular Reform is Support and Facilitated at the Support and Facilitated at the

National LevelNational Level American Association of Colleges of Pharmacy American Association of Colleges of Pharmacy (AACP)(AACP)

In 1992, AACP initiated a series of initiatives In 1992, AACP initiated a series of initiatives under the Center for the Advancement of under the Center for the Advancement of Pharmaceutical Education (CAPE) to provide Pharmaceutical Education (CAPE) to provide support and facilitate the efforts of colleges and support and facilitate the efforts of colleges and schools of pharmacy’s curricular revision. (see schools of pharmacy’s curricular revision. (see 2004 CAPE Outcomes) 2004 CAPE Outcomes)

American Council on Pharmacy Education (ACPE)American Council on Pharmacy Education (ACPE)Curriculum Standard 2007 was approved at the Curriculum Standard 2007 was approved at the 2006 AACP Annual Meeting in San Diego in July 2006 AACP Annual Meeting in San Diego in July 2006. 2006. [Effective date for using this Standard for [Effective date for using this Standard for ACPE Accreditation is January 2009].ACPE Accreditation is January 2009].


2004 CAPE Outcomes2004 CAPE Outcomes

Pharmaceutical CarePharmaceutical CareProvide patient-based care.Provide patient-based care.Provide population-based careProvide population-based care

System ManagementSystem ManagementManage human, physical, medical, informational, Manage human, physical, medical, informational, and technological resources.and technological resources.Manage medication use systems.Manage medication use systems.

Public Health Public Health Assure the availability of effective, quality health and disease prevention services. Develop public health policy.


Pharmaceutical CarePharmaceutical Care

based upon sound therapeutic principles and based upon sound therapeutic principles and evidence-based data, evidence-based data,

taking into account relevant legal, ethical, social, taking into account relevant legal, ethical, social, economic, and professional issues, economic, and professional issues,

emerging technologies, and evolving biomedical, emerging technologies, and evolving biomedical, socio-behavioral, and clinical sciences that may socio-behavioral, and clinical sciences that may impact therapeutic outcomes.impact therapeutic outcomes.

Provide pharmaceutical care in cooperation with Provide pharmaceutical care in cooperation with patients, prescribers, and other members of an inter-patients, prescribers, and other members of an inter-professional health care team:professional health care team:


Provide patient-Provide patient-centered carecentered care

Design, implement, monitor, evaluate, and adjust Design, implement, monitor, evaluate, and adjust pharmaceutical care plans that are pharmaceutical care plans that are patient-specificpatient-specific and and evidence-basedevidence-based. .

Communicate and collaborate with prescribers, patients, care Communicate and collaborate with prescribers, patients, care givers, and other involved health care providers to engender a givers, and other involved health care providers to engender a team approach to team approach to patient-centeredpatient-centered care. care.

Carry out duties in accordance with legal, ethical, social, Carry out duties in accordance with legal, ethical, social, economic, and professional guidelines.economic, and professional guidelines.

Retrieve, analyze, and interpret the professional, lay, and Retrieve, analyze, and interpret the professional, lay, and scientific literature to provide drug information to patients, their scientific literature to provide drug information to patients, their families, and other involved health care providers. families, and other involved health care providers.

Maintain professional competence by identifying and analyzing Maintain professional competence by identifying and analyzing emerging issues, products, and services that may impact emerging issues, products, and services that may impact patient-specificpatient-specific therapeutic outcomes.therapeutic outcomes.


Provide population-Provide population-based carebased care

Develop and implement population-specific, Develop and implement population-specific, evidence-based evidence-based disease management programsdisease management programs and protocols based upon and protocols based upon analysis of epidemiologic and pharmacoeconomic data, analysis of epidemiologic and pharmacoeconomic data, medication use criteria, medication use review, and risk medication use criteria, medication use review, and risk reduction strategies. reduction strategies.

Retrieve, analyze, and interpret the professional, lay, and Retrieve, analyze, and interpret the professional, lay, and scientific literature to provide drug information to other health scientific literature to provide drug information to other health care providers and to the public. care providers and to the public.

Maintain professional competence by identifying and analyzing Maintain professional competence by identifying and analyzing emerging issues, products, and services that may impact emerging issues, products, and services that may impact population-based, therapeutic outcomespopulation-based, therapeutic outcomes. .


Systems ManagementSystems Management

Manage and use resources of the health care Manage and use resources of the health care system, in cooperation with patients, prescribers, system, in cooperation with patients, prescribers, other health care providers, and administrative and other health care providers, and administrative and supportive personnel,supportive personnel,

to promote health; to promote health;

to provide, assess, and coordinate safe, to provide, assess, and coordinate safe, accurate, and time-sensitive medication accurate, and time-sensitive medication distribution; and distribution; and

to improve therapeutic outcomes of medication to improve therapeutic outcomes of medication use.use.


Public HealthPublic Health

Promote health improvement, wellness, and Promote health improvement, wellness, and disease prevention in cooperation with disease prevention in cooperation with patients, communities, at-risk populations, patients, communities, at-risk populations, and other members of an inter-professional and other members of an inter-professional team of health care providers.team of health care providers.


ACPE Curriculum ACPE Curriculum Standard 2007Standard 2007The pharmacy practice experiences should:

Ensure that every student has multiple opportunities to perform patient-centered care activities in a variety of settings

Be in-depth, structured, and carefully coordinated with the components of the curriculum

Require active participation and patient care responsibilities, in a progressive fashion, designed in develop the practice skills, judgment, professional behavior, attitudes and values, confidence, and personal responsibility needed for each student to embark on an independent and collaborative practice.


2005-06 AACP Educational Outcomes 2005-06 AACP Educational Outcomes and Objectives Supplement and Objectives Supplement

Development Task ForceDevelopment Task ForceTo coordinate the development of supplements to the 2004 To coordinate the development of supplements to the 2004 CAPE CAPE Educational OutcomesEducational Outcomes that describe content-specific that describe content-specific and/or discipline-specific, ability-based learning objectives. and/or discipline-specific, ability-based learning objectives.

Such supplements will help schools and colleges of pharmacy Such supplements will help schools and colleges of pharmacy to:to:

better incorporate and integrate content across the better incorporate and integrate content across the pharmacy curriculum; pharmacy curriculum;

describe the progressive nature of student development describe the progressive nature of student development of requisite knowledge, skills, and abilities for practice; of requisite knowledge, skills, and abilities for practice; and and

facilitate the teaching and assessment of the abilities facilitate the teaching and assessment of the abilities needed to practice pharmacyneeded to practice pharmacy.

When completed, these supplements will serve as resources When completed, these supplements will serve as resources for the design of curricula, courses, and instructional units.for the design of curricula, courses, and instructional units.


The Medicinal Chemistry The Medicinal Chemistry SupplementSupplement

(only the major headings are shown (only the major headings are shown here)here)

Acquire, comprehend, apply, analyze, synthesize, Acquire, comprehend, apply, analyze, synthesize, and evaluate information about the chemical and evaluate information about the chemical structure of drugs and drug classes in order to structure of drugs and drug classes in order to design, implement, monitor, evaluate, and adjust design, implement, monitor, evaluate, and adjust pharmaceutical care plans that are pharmaceutical care plans that are patient-specific patient-specific and evidence based.and evidence based.

Recommend changes in pharmacotherapeutic Recommend changes in pharmacotherapeutic regimens based on chemical differences among regimens based on chemical differences among drugs that relate to solving patient problems, drugs that relate to solving patient problems, providing providing patient-centered carepatient-centered care, and providing , and providing population-based care.population-based care.


The Medicinal Chemistry The Medicinal Chemistry SupplementSupplement

(only the major headings are shown (only the major headings are shown here)here)

Resolve drug therapy problems of individual patients Resolve drug therapy problems of individual patients by applying knowledge of drug chemistry across by applying knowledge of drug chemistry across pharmacological classes.pharmacological classes.

Use appropriate chemical terminology to explain Use appropriate chemical terminology to explain chemical, pharmacological and basic therapeutic chemical, pharmacological and basic therapeutic concepts.concepts.

Maintain professional competence by employing Maintain professional competence by employing knowledge of structural features to predict knowledge of structural features to predict mechanisms, adverse effects, metabolism, solubility, mechanisms, adverse effects, metabolism, solubility, acid/base characteristics, potential drug interactions, acid/base characteristics, potential drug interactions, and therapeutic effects of future drug products. and therapeutic effects of future drug products.


The Pharmacy Practice The Pharmacy Practice Supplement Supplement

(only the major headings are shown (only the major headings are shown here)here)1.1. Formulate a patient-centered pharmaceutical care Formulate a patient-centered pharmaceutical care

plan in collaboration with other health care plan in collaboration with other health care professionals, patients, and/or their caregivers.professionals, patients, and/or their caregivers.

Gather and organize accurate and comprehensive patient Gather and organize accurate and comprehensive patient information to identify ongoing or potential therapy information to identify ongoing or potential therapy problems.problems.Interpret and evaluate patient and drug-related data Interpret and evaluate patient and drug-related data needed to identify actual or potential drug therapy needed to identify actual or potential drug therapy problems.problems.Develop a complete medical and drug therapy problem Develop a complete medical and drug therapy problem list.list.


1. Formulate a patient-1. Formulate a patient-centered centered

pharmaceutical care plan pharmaceutical care plan (continued)(continued)

Retrieve, analyze, and interpret the Retrieve, analyze, and interpret the professional, lay, and scientific literature to professional, lay, and scientific literature to make informed, rational, and make informed, rational, and evidence-evidence-based decisionsbased decisions..Select and recommend appropriate drug and Select and recommend appropriate drug and non-drug therapy.non-drug therapy.Devise and implement a patient monitoring Devise and implement a patient monitoring plan to ensure achievement of desired plan to ensure achievement of desired therapeutic outcomes.therapeutic outcomes.


2. Prepare and dispense 2. Prepare and dispense medications medications

prescribed as part of the patient’s prescribed as part of the patient’s care plancare plan

Review and interpret prescription orders for patientsReview and interpret prescription orders for patients

Accurately prepare and dispense medications and/or Accurately prepare and dispense medications and/or supervise the preparation of medications.supervise the preparation of medications.

Accurately compound individual or bulk medications.Accurately compound individual or bulk medications.

Prepare, store, and assure quality of sterile dosage Prepare, store, and assure quality of sterile dosage forms.forms.

Comply with federal, state, and local statutes and Comply with federal, state, and local statutes and regulations that affect pharmacy practice.regulations that affect pharmacy practice.

Resolve ethical and moral decisions faced by Resolve ethical and moral decisions faced by pharmacists.pharmacists.


3.3. Develop population-specific, Develop population-specific, evidence-based disease evidence-based disease management programmanagement program

Assess the health needs of a specific patient population by Assess the health needs of a specific patient population by analyzing epidemiologic data and identify risk factors that would analyzing epidemiologic data and identify risk factors that would adversely affect patient health.adversely affect patient health.

Develop appropriate criteria and outcome indicators and conduct Develop appropriate criteria and outcome indicators and conduct medication reviews in specific population.medication reviews in specific population.

Evaluate pharmacoeconomic data relevant to appropriate Evaluate pharmacoeconomic data relevant to appropriate disease-specific treatment plans.disease-specific treatment plans.

Design evidence-based disease management program that Design evidence-based disease management program that incorporate outcome indicators, drug treatment protocols, risk incorporate outcome indicators, drug treatment protocols, risk reduction strategies, and education programs for health care reduction strategies, and education programs for health care providers and patients.providers and patients.


III. A Few Examples of III. A Few Examples of Evidence-based / Patient-Evidence-based / Patient-centered Teaching at UIC centered Teaching at UIC (All examples are from the (All examples are from the

Spring 2007 P-2 year, Spring 2007 P-2 year, integrated course known as integrated course known as

the “Principles of Drug the “Principles of Drug Actions and Therapeutics Actions and Therapeutics

(PDATs)”(PDATs)”


An Example of a Case Study An Example of a Case Study for Pain Managementfor Pain Management

Mrs. Jones, an 85 year old woman, sought Mrs. Jones, an 85 year old woman, sought medical attention two 2 months ago for moderate to medical attention two 2 months ago for moderate to severe back pain. She was diagnosed with a severe severe back pain. She was diagnosed with a severe lumbar vertebral compression fracture of her spine for lumbar vertebral compression fracture of her spine for which she has seen several different physicians over which she has seen several different physicians over the past year. Her past medical history includes atrial the past year. Her past medical history includes atrial fibrillation and osteoporosis. She comes to your fibrillation and osteoporosis. She comes to your pharmacy to have her blood pressure checked. pharmacy to have her blood pressure checked.

Her husband tells you that she has not been able Her husband tells you that she has not been able to lie down and sleep in her bed for days. He also tells to lie down and sleep in her bed for days. He also tells you that she is in too much pain to drink or eat her you that she is in too much pain to drink or eat her meals. She is unable to give her pain a number but she meals. She is unable to give her pain a number but she said “it hurts pretty bad all the time”. said “it hurts pretty bad all the time”.


Mrs. Jone Current Mrs. Jone Current MedicationsMedications

(Isn’t this an example of a non-EBM practice? She is (Isn’t this an example of a non-EBM practice? She is 85Yos!85Yos!))DarvocetDarvocet®® N 100 one tablet q 8 hours – alternate with N 100 one tablet q 8 hours – alternate with

Tylenol #3 one tablet every 8 hoursTylenol #3 one tablet every 8 hours

MS Contin MS Contin ®® 15mg q 12hrs 15mg q 12hrs

Morphine (IR) 15mg q 2-4hrs prnMorphine (IR) 15mg q 2-4hrs prn

Extra Strength Tylenol 500mg capsules Extra Strength Tylenol 500mg capsules

Celecoxib (Celebrex Celecoxib (Celebrex ®®) 100mg BID) 100mg BID

Alprazolam (Xanax Alprazolam (Xanax ®®) 0.25mg BID) 0.25mg BID

Temazepam (Restoril Temazepam (Restoril ®®) 15mg q HS prn sleep) 15mg q HS prn sleep

Amitriptyline (Elavil) 25mg q HSAmitriptyline (Elavil) 25mg q HS

Warfarin 5mg q day for 4 weeks following cardioversion (i.e., Warfarin 5mg q day for 4 weeks following cardioversion (i.e., a brief electroshock) to return her heart rhythm to normala brief electroshock) to return her heart rhythm to normal

Docusate (Colace Docusate (Colace ®®) 100mg two capsules daily) 100mg two capsules daily

Milk of magnesia 30-60cc prnMilk of magnesia 30-60cc prn


Mrs. Jone Case Mrs. Jone Case continued..continued..

Many of her bottles of medication are still full. Many of her bottles of medication are still full.

Upon questioning, Mr. Jones tells you that his wife Upon questioning, Mr. Jones tells you that his wife has been taking the celecoxib twice a day, 3-4 tablets has been taking the celecoxib twice a day, 3-4 tablets of morphine (IR) during the day and the Darvocet® of morphine (IR) during the day and the Darvocet® and Xanax® at bedtime. and Xanax® at bedtime.

She only takes the MS Contin® (i.e., a controlled She only takes the MS Contin® (i.e., a controlled release morphine formulation) when the pain is really release morphine formulation) when the pain is really bad (once a week or so). bad (once a week or so).

Her blood pressure now is 140/90. In the past, her Her blood pressure now is 140/90. In the past, her blood pressure was 112/72. blood pressure was 112/72.

She also said that her ankles often feel swollen.She also said that her ankles often feel swollen.


In this case, our students was In this case, our students was asked, in a small group of four asked, in a small group of four students per group, to …students per group, to …

Evaluate each medication that has been prescribed for Mrs. Evaluate each medication that has been prescribed for Mrs. Jones by various physicians by answering the following Jones by various physicians by answering the following questions:questions:

1.1. What is each medication used for?What is each medication used for?

2.2. Are the doses appropriate?Are the doses appropriate?

3.3. Is there an indication for each medication? Is there an indication for each medication?

4.4. Is there a concern for actual or potential drug interactions?Is there a concern for actual or potential drug interactions?

5.5. Which medications are unnecessary? Why?Which medications are unnecessary? Why?

Do you think Mrs. Jones is experiencing a side effect from her Do you think Mrs. Jones is experiencing a side effect from her celecoxib. What is the side effect and what is the mechanism?celecoxib. What is the side effect and what is the mechanism?

You realize that Mrs. Jones is in moderate-severe pain. You realize that Mrs. Jones is in moderate-severe pain. Identify all of the problems with Mrs. Jones’s currently Identify all of the problems with Mrs. Jones’s currently prescribed pain medications prescribed pain medications


Is there a concern for actual or potential Is there a concern for actual or potential drug interactions? Students were asked drug interactions? Students were asked to find answer(s)…to find answer(s)…

Some sources say there is an increased risk for bleeding Some sources say there is an increased risk for bleeding due to a drug interaction between due to a drug interaction between warfarin and celecoxibwarfarin and celecoxib since both are substrate for CYP2C9). since both are substrate for CYP2C9). What is your What is your opinion?opinion?

If this is what you found in the literature regarding how If this is what you found in the literature regarding how warfarin is metabolized warfarin is metabolized in vivoin vivo: Warfarin is metabolized by : Warfarin is metabolized by CYP 1A2, 2C9, and 3A4CYP 1A2, 2C9, and 3A4. . What will be your conclusion?What will be your conclusion?

But as a scientist, you realize that warfarin is marketed as But as a scientist, you realize that warfarin is marketed as a racemic mixture and that the (S)-Warfarin is four times a racemic mixture and that the (S)-Warfarin is four times more potent than (R)-warfarin. more potent than (R)-warfarin.

So, shouldn’t you check to see where or not there are So, shouldn’t you check to see where or not there are differences in the metabolism of these stereoisomers differences in the metabolism of these stereoisomers before making your conclusion, right?before making your conclusion, right?


Kaminsky, L.S. and Zhang, Z.Y. (1997) Kaminsky, L.S. and Zhang, Z.Y. (1997) Human P450 metabolism of warfarin. Human P450 metabolism of warfarin. Pharmacol Ther, 73, 67-74.Pharmacol Ther, 73, 67-74.

O O

O

OHH

O O

O

OHH

S-Warfarin

6

7

8

4

10

10

4

87

6

R-Warfarin

CYP2C9CYP2C8CYP2C18CYP2C19

CYP2C9

CYP2C19

CYP1A1CYP1A2

CYP1A1CYP1A2CYP2C8

CYP3A4

CYP2C9CYP2C18

CYP1A1CYP1A2CYP2C19

So, is there So, is there an drug an drug

interactions?interactions?

You make the You make the call!call!


Another example from a colleague’s Another example from a colleague’s lecture on the MOA of Lilecture on the MOA of Li++ and and

Thiazide interactionsThiazide interactionsWhat he presented in his pharmacotherapy of bipolar disorder’s lecture What he presented in his pharmacotherapy of bipolar disorder’s lecture that my P-4 (i.e., doing her academic rotation) and I attended three that my P-4 (i.e., doing her academic rotation) and I attended three years’ ago:years’ ago:

Thiazides produce diuresis and initial sodium loss via distal tubules.A compensatory occurs that sodium reabsorbed via in proximal tubules.Proximal tubules do not distinguish sodium from lithium.Thus, lithium also reabsorbed from the proximal tubules and accumulates.

What he said is exactly what we found in the textbook and on-line What he said is exactly what we found in the textbook and on-line sources from an expert, Dr. X who gave an excellent lecture on “Basic sources from an expert, Dr. X who gave an excellent lecture on “Basic Principles of Drug Interaction”Principles of Drug Interaction”But my P-4 happened to recall her lecture from me during her P-2 when But my P-4 happened to recall her lecture from me during her P-2 when we discussed “pharmacotherapy of diuretics” during a two-hours we discussed “pharmacotherapy of diuretics” during a two-hours cases discussion.cases discussion.She also indicated that lithium/thiazide interaction is not a delay She also indicated that lithium/thiazide interaction is not a delay reaction so it can’t be compensatory (i.e., she is using her logic here). reaction so it can’t be compensatory (i.e., she is using her logic here).


Diuretics: Sites of ActionDiuretics: Sites of Action

S ATPase

Na+

K+

Na+

K+

Na+

Cl-

Cl-

Cl-

Tubule epitheliumLumen(urine)

Interstitial(blood)

Distal convoluted tubule

inhibited by thiazide and related diuretics

N

NS

H

H

O O

Cl

H2NO 2S

HydrochlorothiazideSulfonamideSulfonamide


She also recalled that one of the She also recalled that one of the question we discussed in the question we discussed in the patient case was .. patient case was .. What would be the rationale of adding a “weaker” diuretic such as What would be the rationale of adding a “weaker” diuretic such as metolazone to a “strong” loop diuretic (i.e., furosemide) for a patient, metolazone to a “strong” loop diuretic (i.e., furosemide) for a patient, PZ with severe congestive heart failure and fluid retention but has PZ with severe congestive heart failure and fluid retention but has become refractory to furosemide?become refractory to furosemide?

One reason that PZ’s becoming refractory to the effects of large doses of One reason that PZ’s becoming refractory to the effects of large doses of furosemide may be that his kidneys are simply not delivering much furosemide may be that his kidneys are simply not delivering much sodium and chloride to the loop of Henle because of extensive proximal sodium and chloride to the loop of Henle because of extensive proximal reabsorption (resistant edema). reabsorption (resistant edema). The thiazide-like diuretics, such as metolazone, prevent the reabsorption The thiazide-like diuretics, such as metolazone, prevent the reabsorption of salt and water in the proximal tubule (due to its carbonic anhydrase of salt and water in the proximal tubule (due to its carbonic anhydrase inhibitory action) as well as in the early segments of the distal tubule inhibitory action) as well as in the early segments of the distal tubule (due to its blockade of sodium chloride symporter). (due to its blockade of sodium chloride symporter). Thus, giving metalozone in addition to furosemide makes sense based Thus, giving metalozone in addition to furosemide makes sense based upon the different sites of action of the two diuretics. upon the different sites of action of the two diuretics.

So, it was obvious that Dr. X and my clinical colleagues reasoning for So, it was obvious that Dr. X and my clinical colleagues reasoning for Lithium/thiazide interaction is NOT EBM, but why? I told her I had no Lithium/thiazide interaction is NOT EBM, but why? I told her I had no idea, let’s look it up and she did (she found it quicker than I did idea, let’s look it up and she did (she found it quicker than I did because of her better computer skills).because of her better computer skills).


An article published in 2006 by Klaus Thomsen An article published in 2006 by Klaus Thomsen and D.G. Shirley, “A hypothesis linking sodium and D.G. Shirley, “A hypothesis linking sodium and lithium reabsorption in the distal nephron”, and lithium reabsorption in the distal nephron”, Nephrol Dial Transplant, 2006, 21:869-880Nephrol Dial Transplant, 2006, 21:869-880..

In this article she found:In this article she found:Under normal circumstances, filtered Li+ ions are reabsorbed in the proximal tubule (and to some extent in the loop of Henle), but virtually no Li+ is reabsorbed in the distal nephron. This is the basis for the use of Li+ clearance as an index of proximal tubular fluid output .However, when rats are given a diet that is low in either Na+ or K+, substantial Li+ reaborption does takes places in the distal nephrons as reported earlier [ M. Shalmi, et al., Am J Physiol Renal Physiol 1998, 274: F445-F452; M. Emamifar, et al., Kidney Blood Press Res 2000, 23: 83-88.]


The followings are excerpts The followings are excerpts from the abstract of this article :from the abstract of this article :

A hypothesis is proposed linking Na+ and Li+ reabsorption in the distal nephron. The handling of these two ions in the distal nephron is related because they share the same apical membrane entry mechanism: the amiloride-sensitive Na+

channel (ENaC). However, the two ions exit the cell through different transport mechanisms: Na+ via the Na+-K-ATPase and Li+ via the Na+/H+exchanger. Studies in rats have shown that under normal circumstances hardly any Li+ is reabsorbed in the distal nephron, so that the urinary excretion of Li+, expressed as a fraction of the delivery to the early distal tubule (FELi dist), amounts to approximately 0.97. In contrast, during severe dietary Na+ restriction, FELi dist decreases to 0.50–0.60. Our hypothesis is that the absence of distal Li+ reabsorption during intake of a normal diet can be explained by a negative driving force for Li+ entrance across the apical membrane in those segments in which ENaC is active.So, isn’t this a better explanation for Li+ and thiazide interactions? My colleague think so and thanks us for this important findings because he has always felt uncomfortable using the compensatory mechanism to explain this important interaction.


Another example in Another example in SchizophreniaSchizophrenia

(Using Student Audience Response) (Using Student Audience Response) A 26 year-old man walks into your pharmacy hesitantly, A 26 year-old man walks into your pharmacy hesitantly,

glancing throughout the store and behind him. Initially, he stares at glancing throughout the store and behind him. Initially, he stares at you during his visit. He tells you that over the past few years you during his visit. He tells you that over the past few years demons have been pursuing him. While he has never seen them, demons have been pursuing him. While he has never seen them, he hears their threats and growls throughout the day. Over the last he hears their threats and growls throughout the day. Over the last month the demons have become louder and he is certain that they month the demons have become louder and he is certain that they are about to attack. He says he is terrified and as a result is are about to attack. He says he is terrified and as a result is unable to sleep. unable to sleep.

He admits to being tired at night but says that he lies in bed He admits to being tired at night but says that he lies in bed fearful that falling asleep will result in the demons killing him. He fearful that falling asleep will result in the demons killing him. He denies ever experiencing any episodes of overwhelming denies ever experiencing any episodes of overwhelming depression in the past, but says that he is frightened and needs depression in the past, but says that he is frightened and needs help. He admits to drinking occasionally when a teenager but has help. He admits to drinking occasionally when a teenager but has not used any alcohol for 10 years. He admits to a history of not used any alcohol for 10 years. He admits to a history of intravenous drug usage for 5 years but states that he stopped 8 intravenous drug usage for 5 years but states that he stopped 8 months ago when the voices began. months ago when the voices began.

He has never seen a psychiatrist before, has no significant He has never seen a psychiatrist before, has no significant medical history, and is not presently on any medications.medical history, and is not presently on any medications.


Some of the questions for this Some of the questions for this case are…case are…

A significant concern with some antipsychotic agents is weight gain, often accompanied with hyperlipidemia and, perhaps, the development of Type II diabetes.

Which group of antipsychotic agents are more likely to cause weight gain, hyperlipidemia, and diabetes?

Which group of antipsychotic agents are the least sedative and are least likely to cause bradykinesia (pseudoparkinsons)?

A.A. Group 1: Risperdone, aripiprazole, ziprazidone, Group 1: Risperdone, aripiprazole, ziprazidone, paliperidone paliperidone

B.B. Group 2: Olanzapine, quetiapine, clozapineGroup 2: Olanzapine, quetiapine, clozapineC.C. Group 3: Haloperidol, fluphenazine, thiothixeneGroup 3: Haloperidol, fluphenazine, thiothixeneD.D. Group 4: Chlorpromazine, mesoridazine, thoridazineGroup 4: Chlorpromazine, mesoridazine, thoridazine


After six months receiving risperidone, the patient’s After six months receiving risperidone, the patient’s symptoms have only moderately improved. symptoms have only moderately improved. Olanzapine is prescribed. After three months on Olanzapine is prescribed. After three months on olanzapine, the patient still is without further olanzapine, the patient still is without further improvementimprovement..

2.2. What factor would diminish the effectiveness of What factor would diminish the effectiveness of olanzapine? Justify your answer.olanzapine? Justify your answer.

A.A. Drinks grapefruit juice for breakfast dailyDrinks grapefruit juice for breakfast dailyB.B. Heavy alcohol consumptionHeavy alcohol consumptionC.C. Heavy cigarette smokerHeavy cigarette smokerD.D. Drinks 6-8 caffeinated beverages dailyDrinks 6-8 caffeinated beverages daily


Benzisothiazole & Benzisoxazole AnaloguesBenzisothiazole & Benzisoxazole Analogues

All of these atypical antipsychotics exhibit potent 5-HT2/D2 antagonist as well as high 5-HT1A agonist activity.

Risperidone (Risperdal®) is degraded by two metabolic pathways: 1) Alicyclic hydroxylation to give 9-hydroxyrisperidone (via CYP2D6/3A4), an active metabolite and 2) Oxidative N-dealkylation (via CYP3A4), resulting in two acidic inactive metabolites (from risperidone and 9-hydroxyrisperidone).

Ziprasidone and perospirone undergo only N-dealkylation catalyzed by CYP3A4 and thus is said to have no active metabolites.

O N

FN

N

N

O

H3C

S N

N

NN

O

O

H

H

Risperidone

benzisoxazole

S N

N

N

Cl NO

H

Benzisothiazole

PerospironeZiprasidone

9

(NOTE: (NOTE: BenBen = benzene ring fused onto = benzene ring fused onto zolezole = 5-membered ring with a nitrogen ( = 5-membered ring with a nitrogen (azaaza))and an oxygen (and an oxygen (oxooxo) or sulfur () or sulfur (thiothio) atoms on the ring) atoms on the ring

Paliperidone (INVEGA, Dec

2006)


Atypical AntipsychoticsAtypical Antipsychotics

Dibenzodiazepines Derivatives: Clozapine (Clozaril®) and Olanzapine (Zyprexa, ®, Dibenzodiazepines Derivatives: Clozapine (Clozaril®) and Olanzapine (Zyprexa, ®, 1996)1996)

Clozapine was the first atypical antipsychotic marketed. Clozapine exhibits Clozapine was the first atypical antipsychotic marketed. Clozapine exhibits high high antagonistic affinity for antagonistic affinity for 11-adrenergic, histamine H-adrenergic, histamine H11, muscarinic M, muscarinic M11, and serotonin 5-, and serotonin 5-HTHT2A2A receptors receptors, which contribute to its unique antipsychotic properties. It has , which contribute to its unique antipsychotic properties. It has relatively relatively low antagonistic affinity for brain dopamine Dlow antagonistic affinity for brain dopamine D11 and D and D22, but it has moderate , but it has moderate affinity for Daffinity for D44 receptors receptors

Olanzapine is somewhat different from clozapine in that it is a more potent Olanzapine is somewhat different from clozapine in that it is a more potent antagonist at dopamine Dantagonist at dopamine D22 and especially at the serotonin 5-HT and especially at the serotonin 5-HT2A2A receptors. receptors.

N

N

N

N

Cl

H

CH3

N

N

N

N

Cl

H

CH3

S CH3

CYP2D6

CYP1A2

N-Glucuronide formation

clozapine Olanzapine


Aripiprazole (Abilify® Aripiprazole (Abilify® 2002)2002)

Aripiprazole offers a novel mechanism of action as a partial DAripiprazole offers a novel mechanism of action as a partial D22 receptor receptor

agonist/antagonist (i.e., agonist/antagonist (i.e., under conditions of dopamine excess, aripiprazole under conditions of dopamine excess, aripiprazole acts as an antagonistacts as an antagonist), 5-HT), 5-HT2A2A antagonist (a common trait of all atypical antagonist (a common trait of all atypical

antipsychotics which help alleviate negative symptoms) and 5-HTantipsychotics which help alleviate negative symptoms) and 5-HT1A1A agonist agonist

(this action at the somatodendritic autoreceptors may offer extra help in (this action at the somatodendritic autoreceptors may offer extra help in mediating EPS due to Dmediating EPS due to D22 blockade because of the inhibitory actions on blockade because of the inhibitory actions on

serotonergic neurons leading to an increase in dopaminergic transmission in serotonergic neurons leading to an increase in dopaminergic transmission in the striatum and thus decreases EPS) the striatum and thus decreases EPS)

Aripiprazole also has minimal affinity for Aripiprazole also has minimal affinity for 11-adrenergic, H-adrenergic, H11 and M and M11 receptors. receptors.

N

NO N O

H

Cl

Cl CYP2D6/3A4

Dehydroaripiprazole(major active metabolite)Aripiprazole

hydroxylation (CYP2D6/3A4)

N-dealkylation (via CYP3A4)

N

NO N O

H

Cl

Cl

Genetic variation & potential Food

interactions


What did we learn from What did we learn from theophylline metabolism?theophylline metabolism?

Theophylline, used to treat Theophylline, used to treat asthma.asthma.

Metabolized by P450 Metabolized by P450 CYP1A2CYP1A2

Inducing agent, cigarette Inducing agent, cigarette smoke.smoke.

Clinical outcome, asthma Clinical outcome, asthma attackattack

N

N

N

N

H3C

H

O

O

CH3


So, back to the question So, back to the question regardingregarding

Olanzapine and food Olanzapine and food interactionsinteractions

The original choice of resperidone was because it is least likely The original choice of resperidone was because it is least likely to cause weight gain, hyperlipidemia, and diabetes. It also is to cause weight gain, hyperlipidemia, and diabetes. It also is least sedative and unlikely to cause pseudo Parkinson-like least sedative and unlikely to cause pseudo Parkinson-like symptoms.symptoms.

However, since most Schizophrenia's patients are heavy However, since most Schizophrenia's patients are heavy smokers. Thus, the therapeutic effects of olanzapine is greatly smokers. Thus, the therapeutic effects of olanzapine is greatly reduced due to its rapid metabolic inactivation via CTP1A2 show reduced due to its rapid metabolic inactivation via CTP1A2 show earlier.earlier.

Grapefruit should have no effect on olanzapine metabolism Grapefruit should have no effect on olanzapine metabolism since its only inhibits CYP3A4 while heavy caffeine intake will since its only inhibits CYP3A4 while heavy caffeine intake will increase the blood levels of olanzapine.increase the blood levels of olanzapine.

An recent literature on “Correlation of CYP1A2 activity using An recent literature on “Correlation of CYP1A2 activity using caffeine phenotyping and olanzapine disposition in healthy caffeine phenotyping and olanzapine disposition in healthy volunteers” supported the above conclusion.volunteers” supported the above conclusion.


Schizo’s case continued…Schizo’s case continued…

His physician decides to try clozapine, which has been shown to His physician decides to try clozapine, which has been shown to be effective in controlling psychotic symptoms resistant to more be effective in controlling psychotic symptoms resistant to more conventional antipsychotics. The manufacturers guidelines conventional antipsychotics. The manufacturers guidelines suggest that the use of clozapine be considered only after two suggest that the use of clozapine be considered only after two different antipsychotics have been tested and failed.different antipsychotics have been tested and failed. You realize that when the patient is started on clozapine, he will need weekly blood tests. What is the reason for the weekly blood tests?

A.A. To monitor serum clozapine levelsTo monitor serum clozapine levelsB.B. To check white cell countsTo check white cell countsC.C. To monitor electrolyte levelsTo monitor electrolyte levelsD.D. To guard against the onset of diabetesTo guard against the onset of diabetes

Structurally, what part of the clozapine molecule would most likely be responsible for inducing agranulocytosis? Does the structurally-related antipsychotic, olanzapine, cause a similar incidence of agranulocytosis? Why or why not?


Clozapine-induced agranulocytosis: Nitrenium Ion Clozapine-induced agranulocytosis: Nitrenium Ion Neutrophil-generated reactive metaboliteNeutrophil-generated reactive metabolite

Taken from S. Iverson et al, Chemico-Biological Interactions 142: 175-199 (2002)

MPO: myeloperoxidase


So if you believe today’s pharmacistSo if you believe today’s pharmacist

Product OrientedPatient Oriented

Competes on expertise……………not on products!Competes on expertise……………not on products!


Today’s Pharmacist need to Today’s Pharmacist need to practice evidence-based…practice evidence-based…

Product OrientedProduct Oriented

Product knowledge - factual Product knowledge - factual basisbasis

Legal guardian/Dispenser of Legal guardian/Dispenser of drug supplydrug supply

Professionally isolatedProfessionally isolated

Patient-centered Patient-centered therapeutics knowledgetherapeutics knowledge

Manager/Coordinator of Manager/Coordinator of drug therapy processesdrug therapy processes

Collaborative, Team-Collaborative, Team-oriented practice; system oriented practice; system involved performanceinvolved performance

Patient OrientedPatient Oriented


Shouldn’t we start using evidence-Shouldn’t we start using evidence-based / patient-centered in teachings?based / patient-centered in teachings?

You make the call


A Vision for the Future A Vision for the Future of Pharmacy Educationof Pharmacy Education

“ “ The future ain’t The future ain’t what is used to be”what is used to be”

Yogi Berra, 1974Yogi Berra, 1974


Any Questions?Any Questions?

university of illinois at chicago college of pharmacy uic integrated, evidence-based /...

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