Saturday Handouts

Transcription

Saturday Handouts

1/6/2009
Objectives
Medication Errors
Continuing Education
Ana Salgado, PharmD; Frank Diaz, PharmD
Timothy Gauthier, PharmD; Mara Zuzel Carrasquillo
1. Define a medication error
2. Suggest ways to decrease risk, reduce
errors and improve patient safety
errors,
3. Review the process and requirements for
RCAs (root cause analysis) for sentinel
events
4. Discuss the role of technology in
reducing the occurrence of medication
errors.
“ Incompetent
To Err is Human: Why 2 Hours
of Medication Errors?
Ana Salgado, Pharm.D.
PGY1 Pharmacy Practice Resident
Jackson Memorial Hospital
[email protected]
people are, at
most 1% of the problem. The
other 99% are good people
trying
y g to do a g
good jjob who
make very simple mistakes
and it’s the process that set
them up to make these
mistakes.”
Dr. Lucien Leape. Harvard School of Public Health
Statistics
Medication Error Definition
9 More Americans die from medical errors than
from car accidents, breast cancer, or AIDS
annually, 44,000-98,000 deaths/year
9 Medication errors result in at least 1 death per
day and 1.5 million people injured per year
9 Estimated US annual cost of drug-related
morbidity and mortality is nearly $17 billion
9 Preventable adverse drug events cost the
healthcare system $2.5 billion annually
9 Any preventable event that may cause or lead to
inappropriate medication use or patient harm while the
medication is in the control of the health care
professional, patient, or consumer. Such events may
b related
be
l t d tto professional
f
i
l practice,
ti
h
health
lth care
products, procedures, and systems, including
prescribing; order communication; product labeling,
packaging, and nomenclature; compounding;
dispensing; distribution; administration; education;
monitoring; and use."
NCC MERPÆ National Coordinating Council for Medication Error Reporting and Prevention
Institute of Medicine, Preventing Medication Errors, 2006
National Coordinating Council for Medication Error Reporting and Prevention. Medication Error. Index.www.nccmerp.org.
Accessed 12/22/2008
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Where Do Errors Occur?
Prescribing 39%
Prescribing,
Administration 38%
Administration,
P
Prescribing
ibi
Transcribing
Dispensing
Administration
Dispensing, 12%
Transcribing, 11%
Leape LL, Bates DW, Cullen DJ, Cooper J, et al. Systems analysis of adverse drug events. JAMA 1995; 274:35-43
Swiss Cheese Model
Med Error
Patient Harm
Physical
Environment
Organizational
Conditions
Individual &
Cognitive processing
Automated-dispensing
technology
Task
Sheryl Szeinbach,et al.Dispensing errors in community pharmacy: perceived influence of sociotechnical factors.International
Journal of Quality in Health Care.June 2007 9.pp203-209
Human Factors
System Factors
9 Fear
9 Stress
9 Boredom
9 Substance abuse
9 Frustration
9 Fatigue/Lack of sleep
9 Illness
9 Lack of experience
9 Inefficient workflow
9 Poorly designed technology
9 Noise
9 Clutter
9 Heat
9 Motion
9 Lighting
9 Distractions
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Failed Communication
High Risk Patient Population
9Handwriting
9Multiple medications
9Oral orders/prescriptions
9Children
9U off nonstandard
9Use
t d d abbreviations
bb i ti
9Eld l
9Elderly
9Incomplete orders
9Multiple allergies
9Dosage errors
9Non-English speakers
9Discharge from hospital
High Risk Medications
IF YOU DON’T KNOW, ASK!!!!
9Anticoagulants
9 There are no stupid questions
9Chemotherapy
9 Being “pretty sure” doesn’t count
9I
9Insulin
li
9 If something seems wrong
wrong, it just might be
9Opiates
9Theophylline
9 Ask many questions to clarify your concern
9 Be sure you are asking the question clearly
9Adrenergic agonists
ALWAYS THINK 5 RIGHTS RULE
9 The RIGHT
9 person
9 dose
9 medication
9 frequency
9 route
When taking a verbal prescription…
9Read back
9Spell the name of the medication
9Make
9M
k sure you h
have allll needed
d d
information
9Ask for indications
9Do not use unapproved abbreviations
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KEEP AN EYE OUT FOR ADE’s
9 ADE: Adverse Drug Event
9 Side Effect
9 Adverse Reaction
9 Be familiar with side effects and adverse
reactions that may occur with medications you
have dispensed
9 Document and speak with other healthcare
professionals for specific monitoring required
or additional patient care
Entiende? Not necessarily?
REPORT ERRORS & POTENTIAL
ERRORS
9 Errors will happen, you must know how to deal
with them
9 Understand definitions to classify errors
9 Harm, Monitoring, Intervention, Intervention
Necessary to Sustain Life
9 Know process for reporting errors
9 Collect as much information as possible
9 Errors that may error are just as important to
report to avoid them from happening
Errors will Happen
9Do not assume that patients who speak
English will understand a prescription
label written in English
9Report incidents and reactions that occur
9Assess patient’s level of comprehension
9Learn from each others mistakes
9Engage patients
9Provide education sheets
9 Tracking incidents will help put actions into
place to make sure they don’t
don t happen again
9 When incidents occur act calmly and ask
questions to develop ways to put changes
into practice
Question #1
Question #2
9 The NCC MERP defines a medication error
as:
9 The Institute for Safe Medication Practices
(ISMP) identifies the following areas as
potential causes of medication errors:
A. Any preventable event that may cause or lead to
inappropriate
pp p
medication use or p
patient harm while
the medication is in the control of the health care
professional, patient, or consumer
B. An event that may cause or lead to inappropriate
medication use or patient harm while the medication
is in the control of the health care professional,
patient, or consumer
C. Any preventable event that may cause or lead to
inappropriate medication use while the medication is
in the control of the health care professional
D. None of the above
A.
B.
C.
D.
E.
Complex or poorly designed technology
Stressful Workplace environment
Dose miscalculations
Lack of patients' understanding of their therapy
All of the above
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Background
Drug Information Sources and
Medication Errors
Frank Diaz, PharmD
[email protected]
9 Drug information (DI) resources are an
integral part of the medication use system
9 Lack of knowledge of the medication in use
increases the risk of error
9 Pharmacists must be able to use, evaluate
and apply pertinent drug information available
in these resources
9 Pharmacists should be involved in internal
informational resources to prevent errors
Ideal Characteristics of a DI Source
Information on Unlabeled Uses
9 Sound editorial policies
9 High quality controlled content development
9 Expert
p review
9 Unbiased
9 Ongoing updating process
9 Correction notification
9 Guideline incorporation
9 Some DI sources will include information only
on uses specifically described in the
medication’s package insert
Evidence Based Medicine
Drug Information Development
9 Medical databases and guidelines
9DI resources should help with guiding
clinician decisions
9 Primary literature
9 Randomized Controlled Trials (RCT)
(
)
9 Meta and pooled analysis
9 Can be found in medical journals
9 Should be evaluated by a qualified group of
practitioners for inclusion in a resource
9 Physician’s
Ph i i ’ D
Desk
kR
Reference
f
(PDR)
9 Information tracking and gathering
9 Medical information databases
9 eg. Medline, Pubmed
9 Guidelines
9 www.guidelines.gov
9Should include guideline information
9 Dosing recommendations
9 Place in therapy
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FDA Approved Labeling Deficiencies
Currently Available DI Resources
9 Referred to as the “Package Insert”
9 Can only contain information regarding FDA
approved indications and information related
to the studies submitted for approval
9 Will never contain “off-label” use information
9 A wide variety of references exist
9 Gabapentin
9 Current place in therapy of medication in
question
9 The government recognizes three references
9 AHFS DI
9 Drugdex
9 USP DI
9 The preferred option for information is primary
literature
Internet Based Information
Criteria for Internet Information
9 Offers wide variety and fast access to
information
9Authority
9 No wayy to standardize how the information is
gathered, put together and presented
9Content
9Obj ti it
9Objectivity
9 Difficult to know information origination
9Attribution
9 Growing as a source of medical information
9Currency
9Accessibility
Disclosure on the Internet
Internal Information Sources
9 The US Department of Health and Human
Services suggest disclosure of:
9 Drug utilization evaluation
9
9
9
9
9
9
Identity of developers and contact information
Purpose of the site
References
Protection of privacy and confidentiality
Evaluation of the site
How the content is updated
9 Root Cause Analysis
9 Failure Mode and Effects Analysis
9 Process improvement
9 “Dashboards”
9 And other quality improvement and assurance
initiatives
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Definitions
When to Use RCA?
9Root Cause Analysis (RCA)
9Should be used when an error has
occurred to find a cause
9 A retrospective tool used to find the true
cause of an error
9Sentinel Event
9 An unexpected occurrence involving death
or serious physical or psychological
injury, or the risk thereof.
9Even “near
near-misses
misses” should prompt RCA
9Sentinel events should always be
followed up with a RCA
How to Conduct a RCA?
What’s next?
9 After an error or near-miss has occurred a
multidisciplinary team should be assigned to
the analysis
9After analyzing the events leading up to
the error:
9 Gather all the facts related to the case
9 Analyze all events that led up to the error
9 Confidentiality and a nonpunitive environment
are required
Examples of Areas to Review
9
9
9
9
9
9
9
9
9
9
Patient-identification
Staff levels
Competency assessment
Supervision of staff
Availability of information
Adequacy of technological support
Equipment maintenance and management
Physical environment
Storage and access of medication
Labeling of medication
9 Summarize the event and outcomes
9 Identify processes that were involved in this
event that are susceptible to error
9 Propose an action plan to address
limitations in the system that can cause
errors
Failure Mode and Effects Analysis
(FMEA)
9A team-based, systematic, and proactive
approach for identifying the ways that a
process or design can fail
fail, why it might
fail, and how it can be made safer
Hospital Pharmacy. 41(5); 470-6.
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FMEA process
In summary
9 Select a high-risk process & assemble a team
9 Diagram the process
9 Brainstorm potential failures
9 Prioritize failure modes
9 Identify root cause of failure modes
9 Redesign the process
9 Analysis and test the new process
9 Implement and monitor the redesign process
9Be proactive!
Question #1
Question #2
9 Which one of the following is NOT an
ideal characteristic of a drug information
source?
9 Why is the Physician’s Desk Reference
limited as a drug information resource?
A.
B.
C.
D.
E.
Sound editorial policies
An ongoing updating process
Evidence based objectivity
Inclusion of off label uses
Dependence on pharmaceutical
manufacturers
Dangerous Abbreviations
&
Illegible Writing
9Remember that not all information
sources are created equal
9Get involved in or start up internal
sources of information gathering
A. It only contains information found in FDA
approved labeling
B. Does not ensure safe and effective use of a given
medication according to contemporary clinical
practice
C. Provides little therapeutic perspective such as first
line drugs vs. secondary options
D. Its is provided to healthcare professionals for free
by pharmaceutical manufacturers
E. All of the above
“Let them adhere to the Latin, or Fejee, if they
choose, but discard abbreviations, and form
their letters as if they had been to school one
day in their lives, so as to avoid the possibility
Timothy Gauthier, Pharm.D.
[email protected]
of mistakes on that account.”
-Mark Twain, October 1, 1864
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TJC “Do Not Use” List
The Joint Commission (TJC)
Do Not Use
9 Committed to…
Potential Problem
U (unit)
9 continually enhance the value of its accreditation and
certification programs
9 developing, utilizing, and maintaining valid and
reliable performance measures
9 ensure that the accreditation process is publicly
accountable.
9 making patient safety an imperative in all
accredited organizations.
9 addressing pressing public policy issues that
impact the quality and safety of health care.
Use Instead
Mistaken for 0 (zero), the
number 4 (four), or “cc”
Mistaken for IV
(intravenous) or the
number 10 (ten)
IU
(International
Unit)
“unit”
“International
International
Unit”
Q.D., QD, q.d., qd Mistaken for each other
(daily)
Q.O.D., QOD,
Period after Q mistaken
q.o.d., qod
for “I” and the “O”
(every other day) mistaken for “I”
“daily”
“every other day”
Available at: http://www.jointcommission.org/
Possible Inclusions for TJC
Do Not Use List
TJC “Do Not Use” List - 2
Do Not Use
Trailing zero
(X.0 mg)
Lack of leading
zero (.X mg)
MS
MSO4 &
MgSO4
Potential Problem
Use Instead
Decimal point is missed
“X mg”
Do Not Use
Potential Problem
Use Instead
> (greater than)
&
< (less than)
Misinterpreted for the
number 7 (seven) or the
letter L; confused for one
another
“greater than”
&
“less than”
Decimal point is missed
“0.X mg”
Can mean morphine
sulfate or magnesium
sulfate
Confused for one another
“morphine sulfate”
Abbreviations for Misinterpreted because
drug names
of similar abbreviations
for multiple drugs
“magnesium
sulfate”
Apothecary Units Unfamiliar to many
practitioners, confused
with metric units
@
cc
µg
Potential Problem
Mistaken for the
number 2 (two)
Mistaken for U (units)
when poorly written
Mistaken for mg
(milligrams), resulting in
1,000 fold overdose
Use metric units
Error-prone Abbreviations Examples
Possible Inclusions for TJC
Do Not Use List - 2
Do Not Use
Write drug names
in full
Use Instead
Abbreviations
AS
OD
AD
AU
“at”
OU
BT
cc
D/C
IJ
““mL””
or
“milliliters”
HS
OJ
qhs
ss
q1d
“mcg”
or
“micrograms”
OS
Drug Names
ARA
AZT
CPZ
HCl
HCTZ
PCA
PTU
T3
TNK
ZnSO4
Full list available at ISMP website: http://www.ismp.org/Tools/errorproneabbreviations.pdf
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Transcription Error
Legibility Error
Avandia
“U” for units
looks like a 4.
Coumadin
10u (units) qam & 8u qpm
10u (units) qam, 28u qpm
When ordering
Humalog, the
physician misread
U on the patient
history as 4
6u (units) Regular Insulin Now
60 Regular Insulin Now
Abbreviation Error
25 units / hour OR 25 cc / hour
QD mistaken for QID
Abbreviation Example
Patient Cases
9Dosing error
QD or Q8
9Route of administration error
9Misplaced decimal / abbreviation error
9Prescribing errors
Misread as Morphine by “neb”, not “sub q”
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Case #2
Case #1
944-year-old women from Florida died in an
emergency department after receiving
8,000 mg of phenytoin IV instead of 800
mg.
9Experienced nurse administered overdose
9 32 vials of 50mg/mL 5mL
9 Required removing medication from several
automated dispensing machines
9An elderly woman from Ohio died
after she received and IV injection of
potassium phosphate that was
supposed to be administered via a
feeding tube
ISMP Medication Safety Alert, March 8, 2007
ISMP Medication Safety Alert, March 8, 2007
Case #3
Case #4
9 9-month old dies after misplaced decimal causes 10fold morphine overdose
9 Physician orders Morphine .5 mg IV for post-op pain,
unit secretaryy does not see the decimal and
transcribes the order as Morphine 5 mg IV
9 Experienced nurse administers 5 mg of Morphine and
repeats the dose 2 hours later
9 Four hours later baby stops breathing
9 Dana Farber Cancer Institute, Boston Mass. - 1995
9 39 year old female being treated for metastatic
breast CA
9 Cyclophosphamide was ordered as “4 gram per
meter square days 1 - 4”
9 meaning 1 gram/meter squared daily
9 The patient received the total dose each dayWashington Post, April 20, 2001
Changing Current Practices
9 Education / Awareness
9 Secretaries
9 Nurses
9 Physicians
Ph i i
9 Pharmacists
9 Changing current systems
9 Standardized order forms
9 Enhanced error reporting
9 Employer-specific initiatives
a massive overdose and died of cardiotoxicity
Regulations
9TJC (The Joint Commission)
9 Do not use abbreviations
9 National Patient Safetyy Goals
9 (NPSG.02.02.01)
9ISMP (Institute for Safe Medication
Practices)
9 Error-prone abbreviations list
9 High-alert Medication list
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National organization support
9NCCMERP
9 National Coordinating Council for Medication
Error Reporting and Prevention
9 Composed
C
d off 24 iindependent
d
d
organizations
i i
9 Error Reporting, Practice Recommendations
9ADA no longer uses “u” in publications
9American Journal of Nursing has
incorporated TJC Do Not Use list into its
editorial style
http://www.nccmerp.org/
Avoidance of Ambiguous or
Unclear Orders
9Write out instructions, do not use
abbreviations
Do not use vague instructions (e.g. use
9Do
as directed, PRN without a reason, etc)
9Specify dose
9Avoid un-established abbreviated
names
9If unsure of spelling, look-up or ask
9Use the metric system
Resources / Advocacy
9 TJC – The Joint Commission
9 Formerly known as JCAHO
9 ISMP – Institute for Safe Medication Practices
9 NCCMERP – National Coordinating Council for
Medication Error Reporting and Prevention
9 FDA – Food and Drug Administration
Safe Medication Prescribing
9Order should be complete
9Intent should be clear and unambiguous
9Written orders should be legible
g
9Use verbal or telephone orders only when
necessary
9Patient account of medication history does
not confirm appropriateness or accuracy
ASHP guidelines on preventing medication errors in hospitals. Am J Hosp Pharm
1993;50:305-14
Discussion
9Despite flow of error reports, practitioners still
question evidence supporting
q
pp
gp
prohibiting
g
dangerous abbreviations
9 Difficult to perform studies
9 Lack of data
Questions
9 1. Which one of the following is a
dangerous abbreviation?
a))
b)
c)
d)
e)
25 u insulin
3.0 grams
.3 grams
MgSO4
All of the above are dangerous
abbreviations
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Questions
92. Which dangerous abbreviation is not
matched with the appropriate preferred
term?
a)
b)
c)
d)
e)
f)
U & “unit”
Q.D. & “daily”
D/C & “discharge”
MgSO4 & “Mag. SO4”
IU & “International unit”
All of the above are matched correctly
Using Technology to Prevent
Medication Errors
Mara Zuzel Carrasquillo, B.S., Pharm. D.
PGY2 Critical Care Pharmacy Resident
[email protected]
Medication Use Processes in Acute Care Setting with Roles for Tech
History Taking
Pharmacy Computer Systems (PCS)
Wireless Devices for
Medication History
Capture, etc.
Medication Inventory Management
Ordering
9 Vendors
9 Ability to detect unsafe errors
9 System complexity and time consuming for MAXIMUM
system performance
Physician Order Entry
Robotic
Dispensing
Di
i
System
Pharmacyy management
g
9 User friendly and functionality vs. cost
Pharmacy Information System
Surveillance
Administration Management
Automated surveillance
Monitor/Evaluate Response
Document
Administer Medication
Education
Bar Coding Administration
9 Maximize system capabilities by
incorporating alerts and clinical decision
support
9 Safety recommendations
9 New information from literature
Safety Features
Alerts and Warnings
9Drug information database
9UPDATED with EACH admission and
DURING hospital stay (prior admissions)
9Allergies weight and diagnosis
9Allergies,
9HIGHLIGHT the information
9FLASH the information
9HARD STOP
9 Allergies, interactions, duplications, maximum
doses, patient weight, disease or diagnosis
contraindications
9 It SHOULD be integrated or interfaced with
laboratory
9 Easy to ADD alerts and warnings
9 Verification of ALL orders before dispensing
9 HARD STOPS
9 Default review of current orders before new
orders are entered
9 Medications Administration Records (MARs)
9 Best mechanism to ensure the verification step
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Presentation of information on labels,
MAR’s and screens
System Support
9CLEAR and contain recommendations
9 Information sharing across systems
9 Ensuring that the correct medication is
administered properly
9FREE off error prone abbreviations
bb i ti
9Format allow tall-man lettering
9 Look-alike names (reduce errors 35%)
9COMMA in strength field
9 Example: heparin 1000
9 Integration of drug information in a facility’s
pharmacy system and other electronic systems
SHOULD be considered
9 Without interoperability it is impossible to maximize drugs
order entry.
9 Example: Potassium supplements in a hyperkalemic patient
9 System maintenance and support
9 Updated
9 Financial commitment
9DO NOT USE: Mnemonics
9 Example: ACTO: Actos for Actonel
Automated Dispensing Cabinets
(ADCs)
Productivity
9 Designed to control the storage and documentation of
medications in patients care areas
9 Offer automated charge capture and inventory control
9 Access with password or fingerprint
9 Levels of access
9 Advanced features
9 *Direct interface with PCS to limit access*
9 Screen alerts
9 Bar-code
9 Medication specific storage cubicles, patient specific
bin
9 Improved productivity within the pharmacy
Limitations
ADC Safety Steps
9 CANNOT improve medication safety unless an adequate
number of cabinets are available for each patient
9 Financial and space
9 Nurses waiting in line
9 Storage outside
9 Nurses taking medications from other patients
9 Override for routine and emergency meds
9 Choosing wrong medication from list
9 No physical check of product or reading of label
9 Misconception: automated = SAFE
9 Stocking: double check vs bar code, look alike
9
9
9
9
9
9
Streamlines dispensing and delivery process
Reduce time for obtaining 1st doses
Phone calls (nurses!!)
More time to spend reviewing new orders
Eliminate needs to return unused medications
Not necessary to credit for unused
9 Improved nursing and pharmacy productivity
9 Cost reduction
9 Improved charge capture
9 Bar-code technology
9 Selection of drugs and quantities that will be
stocked
9 Separation of medications
9 Look alike medications
9 Different strength of same medication
9 Separate adults vs pediatric doses
9 Periodically reassess drugs stocks
9 Screen alerts for certain medications
9 Override medications reports
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Computerized Prescriber Order Entry
(CPOE)
9 Essential technology for health care settings
9 Veterans Health Administration (VA)
9 One of the 3 safety initiatives
9 Prevent medication errors
Challenges
9 Challenges for implementation
9 Analyze technology to invest and HOW to
implement it effectively
9 GREATEST effect
ff t on physicians’
h i i
’ practice
ti
9 Physicians MUST be involved from earliest stages
9 Illegible handwriting
9 Decision support tools
9 2010: prescribers to order meds electronically
and for all pharmacies to receive electronic Rx
9 Two documents from the First Consulting Group
provide guidelines:
9 CPOE: Costs, Benefits and Challenges: A Case Study
Approach
9 CPOE in Community Hospitals: Lessons from the Field
Point-of-care bar code medication
administration (BCMA)
Integrate or interface?
9 CPOE and pharmacy systems
9 MAR Support
9 CPOE ----- Pharmacy system ----- MAR
9 Staff involvement (“multidisciplinary team”)
9 Drug versus lab orders
9 Clinical Decision Support
9 ADE’s
BCMA
ADMISSION:
Bar coded wristband
Scan
Employee identifier
Check
Electronic MAR
91930’s: Bar codes at grocery stores
91970’s: Universal Product Code (UPC)
ADE Prevention Study
9ADE
9 38% of medication errors occur during drug
administration
9 2% are intercepted
9VA
9 Can reduce medication errors 65-86%
BCMA
Right
RULE
Approval
1.
Administration instructions
2. Information of drug
3. Monitoring parameters
4. Other
Medication to be
administered
p
drug
g reference information
9Up-to-date
9Customize comments or alerts and
reminders
WARNING!
Scan
9Increased accountability and capture of
charges for items
9Data capture for analysis of trends
9Identification of laboratory specimens and
blood for transfusions
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Workarounds
9 Typed social security number INSTEAD
9 Second set of wristbands next to bedside
9 Manually entering NDC
9 Bypassing warnings
9 Alerts and Overrides
9 Bypasses PHARMACIST
9 ALERTS for CPOE, pharmacist and BCMA
Bar coding
9 Bar codes on ALL doses
9 Repackage many meds and relabel with bar code
9 Purchase of equipment
9 Maintenance, accuracy, readability
9 Increase
I
in
i staff
t ff
9 Space
9 Orientation of bar codes
9 RIGHT RULE!
9 Print readable bar codes for IV with multiple
components
9 Bar codes ON END PRODUCT
9 Patient specific doses
Radio Frequency Identification (RDI)
“Smart” Pumps
9 Track inventory and prevent theft
9Incorrect pump setting =
CATASTROPHIC!!
9 Cloth
9 Sunpass
9 FDA
9 Combat the shipment of counterfeit drugs
9 Clinical drug studies
9 Track and record the meds participants are taking
9 Hospitals
9 Inventory: track, document, and confirm
administration of blood products and IV solutions
9 Movement of equipment
9Multiple clinical areas
9Error pump programming
9 67kg patient was about to receive an
insulin infusion at 7 units of insulin/kg/hr,
when the ordered dose was 7 units/hr.
Definition
Standalone Data Monitoring Tech
9 Medication safety software
9 “Listen” to a wide variety of information
sources
9
9
9
9
9
9
Usual concentrations
Dosing units
Dose limits
Area (ICU)
Programmed doses
Access to transaction data (report)
9 Can improved patient care ONLY to the
extent of SAFETY features are FULLY
used.
9 Implementation
9 “Watch” for specific
p
p
problems p
predefined
9 “Notify” clinicians of situations that may
represent risk as soon as available
9 Personal digital assistant, pager, cell phone, e-mail
or fax
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E-script or SureScripts
Definition
9 2001
9 A physician’s use of real-time, patient-specific
clinical and economic information, for
consenting patients, to:
9 National Association of Chain Drug Stores
(NACDS)
9 National Community Pharmacists Association
(NCPA)
9 Pharmacy Health Information Exchange™
(PHIE), operated by SureScripts is the largest
network to link electronic communications
between pharmacies and physicians, allowing
the electronic exchange of prescription
information
Safe-Rx
9P
Prescribe
ib the
h most medically
di ll appropriate
i
and
d cost
effective prescription at the point of care, and
9 Transmit the prescription electronically to the
patient’s pharmacy of choice
9 Pharmacies can also request refills by sending an
electronic refill request to the physician office for
approval
POWER
9Central Pharmacy
9 Rx refills
9 Rx are delivered to the pharmacy next day
9Pharmacist as consultants
70% of pharmacies
2008 expect 45,000 pharmacies
Safe-Rx Information
2005
Safe-Rx™ State Ranking
5
13
19
% of Total Prescriptions Transmitted
Electronically
0.45%
2006
0.63%
2007
1.62%
Conclusion
9 Integrated technology will help to prevent ADR’s.
9 Implementation requires planning, preparation,
and commitment
9 Technology CANNOT eliminate all errors
9 Intercepted errors reduction can be achievable
only through devoting time and resources to the
planning, implementation, and continued
maintenance of the tech, and to analyzing the
data collected in the light of current information on
error prevention
Questions
9 1. True or False: Hospitals that are planning
to implement BCMA must be prepared to
repackage medications and re-label each one
with bar code.
9 2. CPOE has been proposed to eliminate
problems. Which statement is FALSE?
a. Eliminate problems with ineligible handwriting
b. Alert prescribers for potential safety issues
c. Pharmacist will not have to verified prescriptions
d. Negatives experiences with the system have
been related to poor planning and implementation.
17
1/6/2009
Questions?
Thank you!!
18
1/5/2009

Define and discuss the terms ergogenic aid and muscle dysmorphia

Discuss potential advantages and disadvantages of using performance enhancing supplements

Review current regulatory guidelines affecting the advertising of ergogenic aids
Presented by: Shine Ann Joseph, Pharm. D., M.B.A.
Nova Southeastern University, College of Pharmacy – West Palm Beach
2

Reverse Anorexia Æ Muscle Dysmorphia
‘Bigorexia’
•Bodybuilding: pursuit of a muscular physique through weight training and tailored nutrition program
•Today 45 million American men and women bodybuilders
•Over $11.8 Billion spent on supplement products
•Continual increase in anabolic steroid use
Compr Psychiatry 47; 2006; 127‐135 Am Fam Phys 2001; 63; 913‐922
Compr Psychiatry; 1993; 34:406‐9
Intern J Eating Disord; 26; 65‐72
3
Obsessive‐
Compulsive Disorder
1.
4
Obsession that body should be more lean/muscular.
2. At least 2 of the following 4 criteria:
a.
Body Dysmorphic Disorder
b.
c.
d.
Muscle Dysmorphia
3.
(DSM IV‐TR). 4th ed. Washington, DC.: American Psychiatric Association; 2000.
5
Misses out on career, social and other activities due to uncontrollable focus on pursuing training regimen
Circumstances involving body exposure preferably avoided
Performance in work and social arenas affected by presumed body deficiencies
Relentlessly pursues hazardous training practices, regardless of potentially detrimental effects
Believes that his or her body is insufficiently small or muscular
6
1
1/5/2009

Media Popularization and Advertising
Male
Adult
Adolescent
Muscle Dysmorphia
Int J Eat Disord. 2001; 29:373‐379.
JAMA. 1988; 260: 3441‐3445.

7
Definition: performance enhancing device or substance

8
Abuse and Misuse
Most products are banned in sports
Adolescent steroid use
▪ 3% to 7 %
Examples
E
l
Heart rate monitor
Dietary supplements
Steroids
Am Fam Phys 2001; 63; 913‐922 Am J Sports Med. 2004;32;6:1543‐1553
Psychother and Psychosom; 70; 189‐192

Risk for drug interactions and toxicity
9
Anabolic‐Androgenic Steroids (Drug)
Pediatrics. 2006; 117; e577‐e589
•MOA
Testosterone derivatives
▪ Anabolic: muscle building
▪ Androgenic: masculinizing
Skeletal muscle growth
Strength & healing of muscle
Most abused class of drugs by athletes
▪ “Stacking”
▪ “Cycling”
▪ “Pyramiding”
11
10

Adverse Effects

Acne
Prostate enlargement
Infertility
Gynecomastia
Cholesterol & lipid disorders
Hypercalcemia
Edema Hypertension
Thromboembolic events
Liver dysfunction
Psychiatric effects
Cancer
Premature morbidity
Premature closure of epiphyseal plates
12
2
1/5/2009

Caffeine (Drug/Dietary Supplement)

MOA
Ephedrine (Drug/ Dietary Supplement)

Stimulates the CNS
Increases adrenaline release
Increases hydrolysis and Adverse Effects

MOA

Additional quantities
▪ OTC medications
▪ Soft drinks
▪ Sports and energy drinks
▪ Herbal products
utilization of fats

Clinical Pearls

y p
Sympathomimetic
Stimulant properties
Adverse Effects

Insomnia
Tremors
Nervousness
Restlessness
Tachycardia
Palpitations

Restlessness
Nervousness
Tachycardia
Arrhythmias
Hypertension
Clinical Pearls
p
Pseudoephedrine & Phenylpropanolamine
Herbal ephedrine (Ma Huang)
Bitter orange (Citrus aurantium)
13
Creatine (Dietary Supplement)

MOA
Increase creatine & creatine phosphate levels
Produce and replenish ATP

Androstenedione & Dehydroepiandrosterone (DHEA)‐ Dietary Supplements
Clinical Pearls
Placebo effect may be seen
Adverse Effects
Fluid retention/ weight gain
Dehydration
Vomiting/diarrhea
Fatigue
Muscle cramps
Myopathy
Migraines
Renal impairment
Rash Dyspnea
14

MOA
Endogenous precursors to testosterone
g
p
Increasing testosterone concentrations

Adverse Effects
Potentially similar to Anabolic steroids

Clinical Pearls
Performance enhancing effects are mostly theoretical
15
16
Dietary Supplement Health Education Act (DSHEA)

Dietary supplements regulated as food not
Print, radio, TV, and Internet
Pharmaceuticals
No requirement to demonstrate safety or efficacy
Prohibits claims of diagnose, cure, treat, or prevent disease
J Community Health; 2008; 33: 22‐30
Increase in marketing of ergogenic aids
Federal Trade Commission (FTC)
Guidance & oversight of advertising
Does not approve individual product ads 17
Food Drug Law J. 2007; 62 Int J Eating Disorder. 31:334‐338
18
3
1/5/2009

Physique Concerns
“Drugs” marketed as Dietary Supplements
E.g. Androstenedione & DHEA

Excessive Exercise
DTCA
Dietary Supplements Muscle Dysmorphia
Increased potential for mislabeling and contamination with banned substances
Ergogenic Use
Dietary Behavior
19

20

Treatment Options
Dissatisfied with body, heavily involved in weight‐
Antidepressant medications
lifting and may also use ergogenic supplements
Cognitive behavioral therapy

Patient Identification

P ti t A
Patient Assessment
t
Ask questions about behavior patterns non‐
Prevention confrontationally
Develop awareness

Patient Education

Patient Referral
21
1.
Men with muscle dysmorphia exclusively use performance enhancing substances in place of exercising or strength training.
JAPhA. 2004; 44; 4: 501‐516
1.
True
False
2.
Men with muscle dysmorphia exclusively use performance enhancing substances in place of exercising or strength training.
True
False
The Federal Trade Commission is currently in charge of approving e ede a ade Co
ss o s cu e t y c a ge o app o g
individual product advertisements before they are marketed to consumers.
2.
True
False
3.
22
The Federal Trade Commission is currently in charge of approving e ede a ade Co
ss o s cu e t y c a ge o app o g
individual product advertisements before they are marketed to consumers.
True
False
The interaction potential for fitness supplements and other drugs is minimal and therefore can be safely managed through patient self‐care, without health provider intervention.
3.
True
False
The interaction potential for fitness supplements and other drugs is minimal and therefore can be safely managed through patient self‐care, without health provider intervention.
True
False
23
24
4
1/5/2009
Goals and Objectives
The Skinny on Eating
Disorders in Men
Tatiana Yero, PharmD
Psychiatric Pharmacy Practice Resident
Nova Southeastern University College of Pharmacy
DCPA Residency Program
January 10, 2009

Provide an overview of selected eating
disorders
Discuss the prevalence of these eating
disorders in men
Discuss medical complications associated
with selected eating disorders
Provide a review of literature addressing
treatment strategies
Eating Disorders (ED)

Anorexia nervosa (AN)
Bulimia nervosa (BN
(BN))
Binge--eating disorder (BED)
Binge
Usually associated with females
5 to 15% of cases of AN and BN occur
in men
40% of cases of BED occur in men
Difficult to assess in men because less
information is available
Muise AM, Stein DG, Arbess G. Eating disorders in adolescent boys: a review of the adolescent and
young adult literature. J Adol Health 2003;33:427-435.
DSM-IV Criteria
DSMAnorexia Nervosa
A. Refusal to maintain body weight at or above a
minimally normal weight for age and height
B. Intense fear of gaining weight or becoming
f t even th
fat,
though
h underweight
d
i ht
C. Disturbance in the way in which one’s body
weight or shape is experienced, undue
influence of body weight or shape on selfselfevaluation, or denial of the seriousness of the
current low body weight
Eating disorders. In: Diagnostic and statistical manual of mental disorders, text revision. 4th ed. Washington:
American Psychiatric Association; 2000:583-97.
Manorexia. www.insideedition.com
DSM-IV Criteria
DSMAN Cont’d
D. In postmenarcheal females,
amenorrhea

Types
– Restricting
– Binge-eating/purging
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1/5/2009
DSM-IV Criteria
DSMBulimia Nervosa
DSM-IV Criteria
DSMBN Cont’d
A. Recurrent episodes of bingebinge-eating.
B.
An episode of bingebinge-eating is
characterized by both:
1) Eating, in a discrete period of time, an
amount of food that is definitely larger
than most people would eat during a
similar period of time and under similar
circumstances
2) A sense of lack of control over eating
during the episode
DSM-IV Research Criteria
DSMBinge--Eating Disorder
Binge
A.
B.
Recurrent episodes of binge eating
The binge
binge--eating episodes are associated
with ≥ 3 of the following:
1)
2)
3)
4)
5)
Eating much more rapidly than normal
Eating until feeling uncomfortably full
Eating large amounts of food when not feeling
physically hungry
Eating alone because of being embarrassed by
how much one is eating
Feeling disgusted with oneself, depressed, or
very guilty after overeating
Differentiating Factors
Women
Focus is on hips and
thighs
Men
Focus is on waist and
chest
Social practice
Weight loss is the goal
Means to an end
Media influence – how
to be thin
Media influence – how
to be bulkier
Only interested in
attaining thinness
Value change in shape
or tallness
Andersen AE, Holman JE. Males with eating disorders: challenges for treatment and research.
Psychopharmacology Bulletin, 1997;33,3:391.
Recurrent inappropriate compensatory
behavior in order to prevent weight gain
C. Criteria A and B both occur, on average, at
least twice a wk x 3 mths
D. Self-evaluation is unduly influenced by
body shape and weight
E. The disturbance does not occur exclusively
during episodes of anorexia nervosa

Types: Purging vs non-purging
DSM-IV Research Criteria
DSMBED Cont’d
C. Marked distress regarding binge
eating is present
D The binge eating occurs,
D.
occurs on average,
average
at least 2 days/wk x 6 months
Male Reasons for Dieting
To avoid repetition of childhood
teasing for fatness
To improve sports performance
To avoid weight-related health
problems their fathers had
To improve gay relationships

Robb AS, Dadson MJ. Eating disorders in males. Child Adolesc Psychiatric Clin N Am, 11(2002); 399-418.
2
1/5/2009
Characteristics - AN
High-Risk Groups

– BMI, height/weight ratio for age, upper
arm circumference, subscapular and
triceps skinfold thickness
Homosexual and bisexual men
Severe physical abuse and
adverse family background
Athletic involvement

Characteristics - BED
High prevalence of premorbid obesity
Heavier at time of dx
Less troubled by the disorder
Higher rates of substance abuse and
depression
Later age of onset (18-26) than
females (15-18)

Dental
– Tooth erosion
– Dental caries
– Xerostomia

Cerebral
– Cortical atrophy
on CT

Rare to have full criteria met
Consume more during binging
episodes than females
Higher depression scores
Complications

Tachycardia and s/sx of CHF
Attaining idealized masculine shape
Cortical atrophy on CT
Premorbid athletes
Otherwise similar to females
Characteristics - BN

Abnormal measurements
Complications Cont’d
Cardiac
– Ventricular
tachyarrhythmias
– Hypotension,
bradycardia
– Tachycardia
– CHF
– IpecacIpecac-induced
myopathy
Little JW. Eating disorders: dental implications. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2002;93:138-43.

Gastrointestinal
– Aspiration
– Esophageal
p g
or
gastric rupture

Skeletal
– Loss of bone mass
– Stature

Dehydration
Electrolyte imbalance
Dermatological
– LanugoLanugo-like body hair
– Russell’s sign
– Acne
– Hyperpigmentation
Little JW. Eating disorders: dental implications. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;93:138-43.
Misra M. Long-term skeletal effects of eating disorders with onset in adolescence. Ann NY Acad Sci 2008; 1135:212
218.
Strumia R. Dermatologic signs in patients with eating disorders. Am J Clin Dermatol 2005;6(3):165-73.
3
1/5/2009
Common Comorbidities

Substance abuse
Major depression
Personality disorders
Anxiety disorders
Autism spectrum disorders
Phobias
Pharmacological Treatment
Antidepressants

Selective Serotonin
Reuptake Inhibitors
(SSRIs
SS )
SSRIs)
– Fluoxetine Î only
drug FDA
FDA--approved
for BN
– Fluvoxamine

Tricyclics (TCAs)
– Imipramine
– Desipramine
– Amitriptyline

Monoamine Oxidase
Inhibitors (MAOIs)
Amphetamine
Benzphetamine
Cisapride
Dextroamphetamine
Lisdexamfetamine
Phentermine
Diethylpropion
Phendimetrazine

Individual psychotherapy
– CognitiveCognitive-behavioral (CBT)
– Supportive

Group psychotherapy
Nutrition counseling
Kotler LA, Walsh BT. Eating disorders in children and adolescents: pharmacological therapies. Eur Child
Adolesc Psychiatry, 2000:9, Suppl. 1.
Pharmacological Treatment
Miscellaneous

Antipsychotics
Anticonvulsants
– Topiramate

Prokinetic agents

Appetite enhancers

Zinc supplementation
– Metoclopramide
– Cyproheptadine
Mood stabilizers
– Lithium
– Phenelzine
– Isocarboxazide
*Contraindicated Medications*
Anorexia
Non-Pharmacological
NonTreatment
Anorexia and
Bulimia
Ephedra, Ma Huang
Orlistat
Sibutramine
Bupropion
Summary
Drug monograph. www.clinicalpharmacology-ip.com. Accessed 12/26/08.
T/F Test Questions

Paxil® has an FDAFDA-approved indication for
treatment of moderate to severe bulimia
nervosa.

False
The recommended dose of Prozac® for
bulimia nervosa is 60mg/day
60mg/day.

True
Wellbutrin® may be used safely in patients
with anorexia nervosa.
False
4
1/7/2009
Objectives
Review pathophysiology, etiology,
Depression in Men
Stanley Baptiste, Pharm. D.
PGY 1 Pharmacy Practice Resident
Pathophysiology
epidemiology, prognosis
Identify gender differences in response to
depression in men
Understand therapeutic options available
Hypotheses
Biogenic Amine Hypothesis
Depression caused by a deficiency of monoamines
Neurotransmitters
Receptor Sensitivity Hypothesis
Relief from depression symptoms comes from a
normalization of receptor sensitivity
released from presynaptic cell
Neurotransmitters bind
Serotonin-only Hypothesis
Focuses on the role of serotonin (5-HT) in depression
to post synaptic cells
and signals are
transmitted
Permissive Biogenic Amine Hypothesis
Balance between norepinephrine (NE) and 5-HT
controls emotional behavior
Gartside S, Cowen P. Pathophysiological basis of mood disorders. Psych 2006 (162-166).
Etiology
Epidemiology
Medical conditions
Thyroid disorders
Chronic heart failure,
myocardial infarction
Anemia
Malnutrition
Cortisol levels
Situational factors
Stress
Illness
Economic status
Loss of family or
significant other
Medications
Cardiovascular agents
CNS medications
Hormones
Genetic factors
First degree relatives
have higher incidence
Depression can occur
generation after
generation
Zanni GR, PhD. Men and depression. Pharm times, Aug. 2005. 40-42.
Gartside S, Cowen P. Pathophysiological basis of mood disorders. Psych 2006 (162-166).
Highest rates of major depression in adults
25-44 years of age (yoa)
Lifetime prevalence in those 65
65-80
80 yoa

20.4% in women and 9.6% in men
8-18% of patients with major depression have
at least one first degree relative with
depression
DiPiro JT, et al. Pharmacotherapy: a pathophysiologic approach, 6th edition. New York: Mcgraw-Hill Medical Publishing Division,
2005.
1
1/7/2009
Prognosis
Major Depression
70-90% have a complete recovery
Diagnostic and Statistical Manual of Mental Health,
After

1st
episode
50% relapse over a two year period
After 2nd episode within five years

75% relapse
Solomon DA, et al. Multiple recurrences of major depressive disorder. Am J Psych 2000 Feb;157(2):229-33
Fourth Edition (DSM-IV)
5 of the following must be present for at least 2 weeks
Depressed Mood
S leep decreased
I nterest decreased in activities
G uilt or worthlessness
E nergy decreased
C oncentration difficulties
A ppetite disturbance or weight loss
P sychomotor retardation/agitation
S uicidal thoughts
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision, American
Psychiatric Association, Washington, DC 2000.
Physiology
6 million men and 12 million women diagnosed with
depression each year
Before puberty: equal rates of depression between
males and females
During
gp
puberty:
y depression
p
rate for females far
exceeds males
Suicide attempts higher in females than males
Gender Difference

Success rates higher in males than females
75% to 80% of all people who commit suicide in
the U.S. are men
Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity
Survey Replication (NCS-R). JAMA. 2003;289:3095-3105.
Kytle R et al. Men and depression. The National Institute of Mental Health (NIMH). 2005.
Symptoms
Men
Anger, ego inflation,
irritability
Suspicious, guarded
Feel ashamed
Strong fear of failure
Sleeplessness
Expression
Men
Women
Feel sad, apaththetic,
worthless
Anxious, scared
Guilt
Problems with success
Use alcohol, TV, sports, and
sex to cope
Women
Use food, friends, and love to
cope
Blame others
Blame themselves
Hostile
Please others
Attacks when feeling hurt
Withdraw when feeling hurt
Restless and agitated
Lethargy
Compulsive time keeper
Procrastination
Create Conflicts
Avoid conflicts at all costs
Reckless behavior and risks
Passive
Excessive sleep
Shiels C, et al. Depression in men attending a rural general practice: factors associated with prevalence of depressive symptoms and
diagnosis. Brit J Psych 2004, (185) 239-244
http://www.midlife-passages.com/depressi.htm. Last Accessed 12/2008.
http://www.midlife-passages.com/depressi.htm. Last Accessed 12/2008.
2
1/7/2009
Diagnosing
Treatment Options
Depression in men goes unrecognized by themselves, family
members, and even physicians
Psychotherapy
Anger, violence, or escaping behaviors- primary presenting
symptoms in males

Cognitive behavioral therapy (CBT)
Interpersonal therapy (IPT)
Not associated with diagnostic criteria of depression
Men are reluctant in talking about mental health issues or
Pharmacotherapy
seeking help
Electroconvulsive Therapy (ECT)
Fear of being labeled
Brownhill et al. ‘Big build’: hidden depression in men. Aus. and New Zeal. J. Psy. 2005; (39):921–931
Treatment Phases
Acute
Phase
Continuation
Phase
Cuijpers P Ph.D, et al. Preventing the onset of depressive disorders: a meta- analytic review of psychological Interventions.
Am J Psychiatry 2008; 165:1272–1280
Pharmacotherapy
Maintenance
Phase
Psychotherapy/
Lasts for 16-20 wks
Duration depends on
Medication started
lasts 6-16 wks
after symptoms
subside
patient’s history
Goal: Reduce
Goal: Facilitate the
Goal: Prevent further
symptoms of acute
depression
patient’s return
functioning level
episodes of depression

Selective Serotonin Reuptake Inhibitors (SSRIs)

Serotonin (5-HT) and Norepinephrine (NE) reuptake inhibitors

Aminoketone

Tetracyclics

Triazolopyridine

Tricyclic Antidepressants (TCAs)

Monoamine Oxidase Inhibitors (MAOIs)
2005.
Duval F,et al. Treatments in depression. State of the Art. p191(2006).
FDA Black Box Warning
SSRIs
Specifically inhibit reuptake of 5-HT [e.g. Fluoxetine
May 2, 2007
“The FDA proposed that makers of all
p
medications update
p
the existing
g black
antidepressant
box warning on their products’ to include warnings
about increased risks of suicidal thinking and
behavior, known as suicidality, in young adults ages
18-24 during initial treatment.”
(Prozac®), Escitalopram (Lexapro®), Paroxetine (Paxil®)]
Effects of SSRIs may not appear for three to six weeks
after initiation
Adverse Effects
Sexual dysfunction
↓ libido, ejaculatory disturbances
Agitation
GI effects (nausea, vomiting, weight gain)
Anderson IM. SSRIs versus tricyclic antidepressants in depressed inpatients: a metaanalysis of efficacy and tolerability. Depression
Anxiety. 1998;7(suppl 1): 11-17
http://www.fda.gov/bbs/topics/NEWS/2007/NEW01624.html
2005.
3
1/7/2009
TCAs/MAOIs
Miscellaneous
Mechanism of Action
(MOA)
Class
Inhibit presynaptic
reuptake of NE & 5HT
TCAs
MAOIs
Increases epinephrine,
NE, dopamine (DA),
and 5-HT through
inhibition of
monoamine oxidase
Adverse Effects
•Anticholinergic
•Lower seizure
threshold
•Cardiac
•High rate of death
from overdose
•Anticholinergic
•Sexual dysfunction
•Serotonin syndrome
•Tyramine containing
foods
Anderson IM. SSRIs versus tricyclic antidepressants in depressed inpatients: a metaanalysis of efficacy and tolerability. Depression
Anxiety. 1998;7(suppl 1): 11-17
Miscellaneous
Medications
Mirtazipine
(Remeron ®)
Nefazodone
(Serzone ®)
Trazadone
(Desyrel ®)
Advantages
Disadvantages
Alpha 2 antagonist,
post synaptic block of
5-HT2 and 5-HT3
•↓ sexual
dysfunction
•Weight gain
•Sedation
SRI/5-HT2A antagonist
Weak dopmine
Bupropion
(DA) and NE
®
p
(Wellbutrin ) reuptake
inhibition
Duloxetine
(Cymbalta ®)
Venlafaxine
(Effexor ®)
Advantages
•Improved sexual
function
•Less associated
ith weight
i ht gain
i
with
Disadvantages
•Increases risk of
seizures (limit
d )
dose)
•Smoking cessation
5-HT and NE
reuptake
inhibitor
•Used for chronic
pain, diabetic
neuropathy
Increase in
blood pressure
observed
5-HT>
NE>>DA
reuptake
inhibitor
•More effective
acutely than SSRIs
•Hypertension at
higher doses
Duval F et al. Treatments in depression. St. Art. p191 (2006).
• ↓ sexual
dysfunction
•Effective for
anxiety with
depression
•Combo with
SSRIs for
insomnia
•Hepatotoxicity
•Sedation
•Priapism
Duval F et al. Treatments in depression. St. Art. p191 (2006).
Summary
Men and women often experience and cope with
depression differently
Depression in men often goes unrecognized since
signs and symptoms not usually associated with
diagnostic criteria of depression
Low compliance of men with SSRIs due to hormonal
issues and sexual side effects

Mechanism of
Action (MOA)
Treatment Algorithm
Mechanism of Action
(MOA)
5-HT >> NE reuptake
inhibitor /5-HT2
antagonist
Medication
Start low and go slow for decreased side effects
Fochtmann LJ, Gelenberg AJ: Guideline watch: practice guideline for the treatment of patients with major depressive disorder, 2nd Edition.
Arlington, VA: American Psychiatric Association, 2005.
True or False
•At least six million men in the United States suffer from
depression every year.
•More than four times as many women as men die by
suicide in the United States.
•SSRIs are drugs of choice for depression men due to a
very low incidence of sexual dysfunction.
Drugs of choice for men include:
Bupropion, nefazodone, mirtazapine
4
Objectives
Once Daily Dosing of Cialis
for Erectile Dysfunction
Courtney Tichauer, PharmD
General Pharmacy Practice Resident
Broward General Medical Center/
NSU College of Pharmacy
Erectile Dysfunction (ED)
• Definition
– Failure to achieve a penile erection suitable
for sexual intercourse
• Possible etiologies
– Vascular
– Neurological
– Hormonal
– Psychological
– Lifestyle
– Medications
Wells BG, Dipiro JT, Schwinghammer TL, et al. Pharmacotherapy Handbook. 6th ed. New York, NY: McGraw-Hill; 2006:854-861.
• Understand pathophysiology of erectile
dysfunction
• Discuss mechanism of action and provide
therapeutic
h
i comparisons
i
off
phosphodiesterase 5 inhibitors
• Compare the dosings of Cialis®
• Evaluate pertinent trials
Medications that can cause ED
• Antihypertensives
– Beta-blockers
– Diuretics
• Antihistamines
A tihi t i
• Antidepressants
• Tranquilizers
– Benzodiazepines
• Appetite suppressants
Wells BG, Dipiro JT, Schwinghammer TL, et al. Pharmacotherapy Handbook. 6th ed. New York, NY: McGraw-Hill; 2006:854-861.
Physiology
Phosphodiesterase 5 (PDE5)
NO
PDE
http://upload.wikimedia.org/wikipedia/commons/b/b7/Penis_Anatomy2.gif
cGMP
Increased
Blood Flow
Clinical Pharmacology: Gold Standard Inc. Copyright @ 2008
1
Phosphodiesterase 5 (PDE5)
Inhibitors
Onset of
action (mins)
NO
PDE
cGMP
PDE5 Inhibitors
Increased
Blood Flow
D ti off
Duration
action (hrs)
Half-life (hrs)
Unique Side
effects
Cialis®
(tadalafil)
30-45
U tto 36
Up
17.5
backache,
myalgia
PDE Inhibitors
Viagra®
(sildenafil)
30-120
(~ 60)
24
2-4
Levitra®
(vardenafil)
30-120
(~ 60)
_________
4
4-5
rash,
rhinitis
diarrhea,
indigestion
Micromedex® Healthcare Series, (electronic version). Thomson Micromedex, Greenwood Village, Colorado, USA. Available at: http://0www.thomsonhc.com.novacat.nova.edu (cited: 11/30/2008).
Absolute Contraindication
Nitrates
• PDE5 Inhibitors exert its effects on the
NO/cGMP pathway
• Nitrates are converted to NO and stimulates
cGMP
Nitrates
• PDE5 Inhibitors may potentiate hypotensive
effects of nitrates
• What would you do if a patient came into the
pharmacy/hospital with chest pain and is on
a PDE5 Inhibitor?
www.googleimages.com
Tadalafil
Pertinent Trials
Traditional
Dosing
New Dosing
Dose range
(mg)
5 to 20
2.5 to 5
Frequency
As needed
Once daily
Timing
30 mins prior to Without regard
sexual activity to timing of
sexual activity
• Three significant trials
– 12 week trial: Porst H et al.
– 24 week trial: Rajfer J et al.
– Diabetic males ((12 week trial):
)
Hatzichristou D et al.
• Tadalafil significantly improved ED when
compared to placebo
Hatzichristou D, et al. Efficacy of tadalafil once daily in men with diabetes mellitus and erectile dysfunction. Diabet Med. 2008 Feb;25(2):138-46.
Porst H, et al. Evaluation of the Efficacy and Safety of Once-a-Day Dosing of Tadalafil 5 mg and 10 mg in the Treatment of Erectile Dysfunction: Results of a
Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial. Eur Urol. 2006 Aug;50(2):351-9.
Rajfer J, et al. Tadalafil dosed once a day in men with erectile dysfunction: a randomized, double-blind, placebo-controlled study in the US.Int J Impot Res
2007;19:95-103.
2
Pertinent Trials
Porst H et al.
• Primary Outcomes
– International Index of Erectile Function Erectile
Function (IIEF EF) domain score
• Mild (17-30)
• Moderate (11-16)
• Severe
S
(1-10)
(1 10)
– Sexual Encounter Profile (SEP)
• SEP2
–“Were you able to insert your penis into
your partner’s vagina?”
• SEP3
–“Did your erection last long enough for
you to have successful intercourse?”
• Multicenter, randomized, double-blind,
placebo-controlled, parallel-group study
• Daily dosing
– Placebo, tadalafil 5 mg, and tadalafil 10mg
• 268 men randomized from October 2001
to March 2002
– Age Range (yrs): 21-78
– Average age (yrs): 56
Porst H et al.
Porst H et al.
Placebo*
Placebo
Tadalafil
5 mg
Tadalafil
10 mg
IIEF EF Domain
range
14.1
13.1
13.4
Depression (%)
4
28
2
26
4
34
Hypertension (%)
90
13
17
12
Tadalafil 10 mg
80
81
80
67
70
60
73
52
50
37
40
30
Diabetes Mellitus (%)
Tadalafil 5mg
100
20
23
23
15
10
0
Mean Domain
Score
Insertion
"Yes"
Response
*P<0.001
Rajfer J et al.
• Randomized, double-blind, placebocontrolled, parallel-design study
• Daily dosing
– Placebo, tadalafil 2.5 mg, tadalafil 5 mg
• 287 men randomized from October 2003
to June 2004
– Age Range (yrs): 25.5-82.3
Successful
Intercourse
"Yes"
Response
Rajfer J et al.
IIEF EF Domain range
Insertion “Yes” ((%))
Successful intercourse
“Yes” (%)
Depression (%)
Hypertension (%)
Diabetes Mellitus (%)
Placebo Tadalafil Tadalafil
2.5 mg 5 mg
13.4
13.1
13.8
45.9
21.8
41
18.8
43.9
21.8
7.4
46.8
13.8
7.3
40.6
16.7
8.2
41.2
11.3
3
Rajfer J et al.
Placebo*
100
90
80
70
60
50
40
30
20
10
0
*P<0.001
Tadalafil 2.5 mg
Tadalafil 5 mg
• Randomized, double-blind, placebocontrolled, multicenter, 12-week study
71
65
57
51
50
• Daily dosing
– Placebo, tadalafil 2.5 mg, tadalafil 5 mg
31
15
19
21
Mean Domain
Score
• 298 men randomized
Insertion "Yes"
Response
– Age Range (yrs): 30-77
– Type 2 Diabetes: 88.9%
Successful
Intercourse
"Yes" Response
Placebo*
Placebo Tadalafil Tadalafil
2.5 mg 5 mg
IIEF EF Domain range 13.5
13.5
12.6
Insertion “Yes”
Yes (%)
37.7
41.8
32.2
Successful intercourse 20.1
“Yes” (%)
Depression (%)
5
6
9
Hypertension (%)
55
54
53
20.1
100
90
80
70
60
50
40
30
20
10
0
16.1
Conclusions
• Evaluation of literature indicates that successful
insertion and intercourse is attainable with the
use of Cialis® without regards to administration
time and sexual activity
Tadalafil 5 mg
61
46
43
41
28
14.7
18 17
Insertion "Yes"
Response
Successful
Intercourse
"Yes" Response
True and False Questions
•
Men can attempt sexual activity without
regard to timing of Cialis dose.
•
Th maximum
The
i
d
dosage off once d
daily
il
Cialis is 10 mg.
•
Resistance of Cialis did not occur
through the course of the 24 week-trial.
• PDE5 Inhibitors relax smooth muscle and
stimulate an erection in the presence of sexual
stimulation
• Providing patients with as needed or once daily
dosing options may improve both patient
compliance and overall quality of life.
62
Mean Domain
Score
*P<0.005
• Causes of ED can include various disease
states, medications, or social habits
Tadalafil 2.5 mg
4
Objectives
Review the mechanism involved with
sexual dysfunction and testosterone.
Discuss the causes and diagnosis of
testosterone deficiency
deficiency.
Evaluate the different testosterone
treatments available as well as alternative
drug therapy for erectile dysfunction.
Discuss the types of patients who should
be treated for testosterone deficiency.
Testosterone Deficiency in
Sexual Dysfunction
Viviene Heitlage, Pharm.D.
PGY--1 Pharmacy Resident
PGY
Cleveland Clinic Florida
Weston, FL
Testosterone
Androgenic hormone
– Development of the male sex
– Male reproductive organs
– Sex drive (Libido) in both sexes
D
Development
l
t off secondary
d
male
l
sex characteristics
–
–
–
–
–
–
Musculature
Fat distribution
Hair patterns
Laryngeal enlargement
Vocal chord thickening
Aggression
The Link with ED and Testosterone
Libido
– Anderson et.al. – 4-week single
single-- blind
placebo--controlled trial
placebo
– 31 normal eugonadal men
– Testosterone administration above baseline
– In both groups – no changes in any moods
reported except the testosterone group
showed increased interest in sex
– Suggested that sexual awareness and
arousability can be increased by
testosterone
RA Anderson, J Bancroft and FC Wu. The effects of exogenous testosterone on sexuality and mood of normal men. J of Clin Endocrinol Metab. 1992;75: 1503
1503--1507
Mikhail N. Does testosterone have a role in erectile function? Am J Med. 2006;119(5):373-82
Testosterone
Normal testosterone levels in men (testes) (350(3501200ng/dl) maintain:
–
–
–
–
Energy level
Healthy mood
Fertility
Sexual desire
Normal for women (ovaries) is 15 to 100 ng/dl
The normal calculated free testosterone (2(2-3%)
– 6.6 - 26.5 pg/ml or higher for men
– 0.0 - 2.2 pg/dl for women
Testosterone report - http://www.primev.com/Testoste.htm
Mikhail N. Does testosterone have a role in erectile function? Am J Med. 2006;119(5):373-82
The Link with ED and Testosterone
Hypogonadism and ED
– Wide variations
– Mccullagh and Renshaw
16 castrated men with prostate cancer
– 58
58--100% of men suffered either
complete or partial ED
– some men could still experience
arousal
Possible Central Mechanisms
Chamness, S L et.al. The effect of androgen on nitric oxide synthase in the male reproductive tract of the rat. Fertil Steril.
Steril. 1
1995;
995; 63(5): 11011101-7
McCullagh, JF Renshaw. The effects of castration in the adult male. JAMA. 1934;103:1140-1143
1
Tertiary
Testosterone Deficiency
Secondary
Aging (Andropause)
Male Hypogonadism
– Primary
– Secondary
– Tertiary
2X increased risk
Primary
–
–
–
–
Diabetes
Smoking
Hypertension
Obesity
Gary C. Bellman, M.D., PC, Stanley J. Swierzewski, III, M.D. Jun 1998Testosterone
Testosterone Deficiency http://www.urologychannel.com/testosteronedeficiency/index.shtml
Other Causes of Testosterone
Deficiency
Testicular or Head trauma
Infection (e.g., meningitis, syphilis, mumps)
Tumors of the pituitary gland,
hypothalamus or testicles
hypothalamus,
Chemotherapy/Radiation/Surgery
Glandular malformation
Congenital causes
– Klinefelter's syndrome (XXY)
– Anorchism
– Cryptorchidism
Treatment-- Hormone replacement
Treatment
Therapy
Oral testosterone (methyltestosterone,
Testred®) ($6/cap)
Transdermal
Mucoadhesive
Intramuscular injection
All C
C--III
Diagnosis
Serum and blood testing
– Testosterone
– Leutenizing hormone (LH)
– Gonadotropin
Gonadotropin--releasing hormones (GnRH) in
the body
body.
Normal or high GnRH levels
– Primary testosterone deficiency
Low GnRH levels
– Tertiary testosterone deficiency
Testicular biopsy
Treatments
Striant® (testosterone buccal system)
- Delivers testosterone twice daily through a
tablet--like buccal system. ($4/tab)
tablet
2
Treatments
Intramuscular injection (IM)
– Depo
Depo--Testosterone (Testosterone Cypionate)
($30/vial)
most popular and most used testosterone
– Testosterone
Enanthate
T t t
E
th t (Delatestryl)
(D l t t l)
derivative of the primary endogenous androgen
testosterone. ($70/vial)
– Testosterone Propionate ($40/vial)
painful injection.
– Nandrolone Decanoate
Monitoring
Testosterone levels
A digital rectal examination (DRE)
Prostate specific antigen (PSA)
– All men before initiating treatment
– These should be repeated at
approximately 3 to 6 months
– annually in men >40 years of age
Hematocrit level
Bone mineral density
Adverse effects
Azoospermia
Lipid abnormalities
Polycythemia
Sleep apnea
Potential for prostate changes
Acne
Blood glucose
Alopecia
Testosterone Products
Transdermal delivery
– Androderm®
(nonscrotal)($4/patch)
– Testoderm® (scrotal)($4/patch)
– Intrinsa® (women) (N/A)
Transdermal gels
– AndroGel® (nonscrotal)
($8/pack)
– Testim® (nonscrotal) ($9/tube)
Patients that should not receive
therapy
Hypersensitivity to the drug
Patients with serious cardiac, hepatic or
renal disease
Men with carcinoma of the breast or
prostate
Severe benign prostatic hypertrophy
(BPH)--related bladder outlet obstruction.
(BPH)
Should not be administered with the intent
of reversing the aging process or to
improve athletic performance
Other Alternatives
Anti-estrogens
Anti– Clomiphene Citrate (Clomid®)
– Danocrine ($4/cap)
5-PDEs
– Sildenafil (Viagra®
(Viagra®)
– Tadalafil (Cialis
(Cialis®
®)
– Vardenafil (Levitra
(Levitra®
®)
Alprostadil
– Edex
Edex®
®
– MUSE
MUSE®
®
– Caverject
Caverject®
®
3
Combination Therapy
PDE-5 work best for eugonadal males
PDEPatients that fail to respond to PDEPDE-5
inhibitors alone
Testosterone therapy + PDE - 5
improves erectile function
improves the response to PDEPDE-5
inhibitors in patients with ED and
hypogonadism.
Emanuela A. Greco, Giovanni Spera, Antonio Aversa“Combining Testosterone and PDE5 Inhibitors in Erectile Dysfunction: Basic Rationale and Clinical Evidences” [European Urology
March 2007 Vol. 51, Issue 3, Page 872
Yassin AA, Saad F. Testosterone and erectile dysfunction. J Androl. 2008 NovNov-Dec;29(6):593
Dec;29(6):593--604.
Testosterone patch for women
New England Journal of Medicine (11/2008)
Women into two groups
– 264 women –150 or 300 micrograms of
testosterone changed twice a week
– 277 women – placebo
l
b patch
t h
Intrinsa patch group - 4.6 satisfying
episodes in the previous four weeks (6
months)
Fake patch - 3.2 satisfying episodes (6
months)
J. R. Heiman Treating Low Sexual Desire — New Findings for Testosterone in Women N Engl J Med Nov 2008
Testosterone Deficiency in
Women
Girls during childhood
– Delays puberty
– Short stature
– Absence of menstruation (amenorrhea)
– Underdeveloped breasts
Symptoms in women:
– Absence of menstruation
– Diminished sex drive (libido)
– Hair loss
– Hot flashes
Outcomes
Does testosterone therapy work?
Depends on
– Type of testosterone deficiency
– Psychosocial issues
– Other co
co--morbidities and factors
Yale study (2009) (Not started)
– Andropause
– Multi
Multi--centered, placebo controlled –
testosterone replacement therapy
Men with low testosterone and symptoms of
low testosterone (physical or sexual function,
vitality, cognition, and anemia)
http://www.yaletrials.org/clinicalTrials/displayTrial.asp?nctID=NCT00799617&pageID=1&row=5
T/F questions
1. Testosterone declines naturally with the
aging process.
2. Some studies have demonstrated that
combining testosterone replacement
therapy with sildenafil (Viagra®
(Viagra®) shows
improved results than with sildenafil
(Viagra®
(Viagra
®) therapy alone.
3. Testosterone replacement therapy is safe
with no side effects.
+
=
4
Objectives
Alopecia:

Treatment of Hair Loss in the
Community Setting

Stephen M. Berkowitz, PharmD

PGY‐1 Pharmacy Resident
PGY‐
Memorial Regional Hospital
Hollywood, Florida
Differentiate between the various
pathophysiological processes seen in
patients presenting
p
p
g with alopecia
p
Recommend over
over--the
the--counter or
prescription hair loss medications for
patients
Counsel patients on the proper usage
of medications for hair loss
2

Defined as loss of hair anywhere on the body

– Traction alopecia
May be sign of systemic disease
Many types of hair loss
– Most common is androgenic
alopecia (male/female pattern
baldness)
– Heredity dependant
Levinbook WS. Merck Manual 2007.
Patches of scattered scalp baldness
Hair typically grows back over time
3

Thinning secondary to use of hair accessories
that tightly pull hair
Tight braids, curling irons
– Tinea capitis

Fungal infection of scalp
Treated with shampoos, creams
Springer K, et al. Am Fam Physician 2003. 68(1): 93-103.
Etiology

Behavioral (twisting, pulling hair)
Easy hair breakage (‘!’ follicle)
Overuse of hair dryers
– Telogen effluvium

Alteration of the hair growth rhythm
Due to a shock to the system
Catagen
(3‐6 years)
(1‐2 weeks)
Telogen
Exogen
Classification
(5‐6 weeks)
Resting Phase
– Focal or Diffuse
– Scaring or NonNon-scaring
Hair
Growth
Cycle
Transsition

Anagen
Hair Loss
– Trichodystrophies/mania
http://www.trichotillomani
auk.com/USERIMAGES/24
thmarch06. jpg
Less common types of hair loss

4
Hair growth
http://www.revivogen.com
m/
images/photos/Tel_Af.jpg
g

http://www.hairtherap
yforwomen.com/image
s/traction_alopecia.jpg

http://www.nlm.nih.gov/medlineplus/
ency/images/ency/fullsize/17083.jpg

Less common types of hair loss
– Alopecia areata
– Most often defined as loss of hair from the scalp
– Concern to many for psychological and cosmetic
reasons
http://www.provlab.ab
.ca/mycol/image/derm
/ tcapitis9.jpg

Etiology
http://imagescdn01.associated
content.com/image/ A1720/
17
72080/300_172080.jpg
Etiology
Goldstein BG, et al. UpToDate 2008.
5
Image sources: http://www.uptodate.com/patients/content/images/prim_pix/Normal_hair_cycle.jpg
1
Pathophysiology

Pathophysiology
Approximately 100 hairs fall out per day
Clinical definition of hair loss

(male-- or female
(male
female--pattern hair loss)
– Loss of over 100 hairs in late exogen
g phase
p

– Androgens
g
(dihydrotestosterone
( y
[DHT])
[
])
In alopecia, one of three processes occur

– Amount of hair lost in exogen phase exceeds
follicles created in anagen phase

– Trauma occurs to the follicle
7
Pathophysiology

Passed from generation to generation

Does not guarantee complete hair loss

Antimitotic chemotherapeutic agents
Anticoagulants
Retinoids,
Retinoids Vitamin A excess
Oral contraceptives
ACE inhibitors, β-blockers
Lithium, Heavy metals
AntiAnti-thyroid drugs
Anticonvulsants
Immunosuppressants
Role of DHT is unknown, although elevated
concentrations are seen in hair loss
8
Treatment
Drugs that can induce hair loss
–
–
–
–
–
–
–
–
–
↑ production of DHT = shortened follicle lifecycle
– Familial / Genetic
– Hair enters telogen phase prematurely due to
chemical, physical, or psychological stressor
Androgenetic alopecia
Specific to androgenic alopecia
– Treatments hold true for other pathologies
– FDA approved therapies

minoxidil (Rogaine)

finasteride (Propecia)
– OffOff-label therapies
– Surgery
9
10
Treatment Algorithm for Androgenic Alopecia
Minoxidil (Rogaine)

Topical Dosing
– Solution: 1 mL to scalp BID
– Foam: ½ capful to scalp BID

I di ti
Indication
– Male pattern hair loss
– Female pattern hair loss

Mechanism
– Exact mechanism unknown
– Due to direct effects on follicle?
– Vasodilatation ↑ blood flow
Shapiro J, Price VH. Hair regrowth: therapeutic agents. Dermatol Clin 1986; 16: 341-56.
Rogaine (minoxidil) [package insert]. Upjohn; April 2006.
Over‐the‐Counter
Men’s solution:
2%, 5%
Men’s foam:
5%
Women’s solution: 2%
12
2
Minoxidil (Rogaine)

Rogaine Clinical Pearls
Minoxidil enters the
follicle from scalp

Use of minoxidil causes
– A prolonged anagen growth phase
– Miniaturized follicles to achieve mature growth
Solution absorbs
into the dermal
papilla

Inhibits DHT
formation through
inhibition of
5α-reductase

Indefinite treatment to maintain regrowth
No significant drug interactions
Side effects
– Scalp irritation
– Contact dermatitis
– Increased facial hair
Image source: http://www.hairgenesis.net/images-2/does_rogaine_minoxidil_work.gif
13
Rogaine Counseling

Finaseride (Propecia)
Patients should use product for a minimum of
12 months

Dosing
Results typically take 8 to 12 months of
continuous use

Indication

Treatment must be continued to retain results

Apply medication to the apex of the scalp
– 1 mg tablet PO daily
– Male pattern hair loss
(androgenic alopecia)
– Only for male use

Image source: Thompson MicroMedex
Mechanism
– 5α-reductase inhibitor
– Inhibits production of DHT
14
15
Prescription Only
Tablets:
1 mg
Propecia (finasteride) [package insert]. Merck; May 2007.
16
Propecia Clinical Pearls

Use of finaseride causes reduced levels of DHT
in vivo, specifically in the scalp
Must be kept away from pregnant women, as
teratogenic to the male fetus
Indefinite treatment needed to maintain
follicular regrowth
No significant drug interactions
Side effects:
– Decreased libido, erectile/ejaculatory dysfunction
– Hypersensitivities, gynecomastia, myopathy
Image source: http://www.dolcera.com/wiki/images/5-alpha-reductase_inhibition.jpeg
18
3

Other Medications
Patients should use product for a minimum of
12 months

– cimetidine (Tagamet)
Strong antianti-androgenic properties
Available overover-the
the--counter
Similar effects as Propecia

Results typically take 6 to 8 months of
continuous use

Treatment must be continued to retain results
– progesterone
19
Other Medications

Prostate Specific Antigen levels were reduced in
older patients, prostate screenings still required

– Treatment of alopecia only caused by
hormonal or environmental factors
– Off-label treatment

estrogen

Oral contraceptives
Alopecia

Treatment options
– OTC: Rogaine

PO tablet
For men only
– Results for only as long as med is taken
21
True or False?

Topical spray, foam for men and women
Only 2% to be used by women
– Rx: Propecia

20
– Hairs lost overtake new hairs grown
– Androgenic alopecia most common
– Increased production of androgens
spiranolactone (Aldactone)
Strong inhibitor of DHT
Used in menopausal and postpost-menopausal
women
Summary
Women with hyperandrogenemia

For use in men and women
Image source: T
Thompson MicroMedex
Propecia Counseling
22
Works Cited
Adults typically lose approximately
100 scalp hairs per day in the hair
growth cycle.
g
y
Patients receiving minoxidil should
begin to see results in 8 to 12
months.
Hair loss will return to pretreatment
levels after minoxidil is stopped.

Goldstein BG, Goldstein AO. Androgenic alopecia. UpToDate. 2008
2008--Sep
Sep--27.
Retrieved on 2008
2008--Dec
Dec--03 from http://www.utdol.com/online/content/topic.
do?topicKey=pri_derm/13813&selectedTitle=2~150&source=search_result
Levinbook WS. Alopecia: Hair disorders. Merck Manual for Healthcare
P f i
Professionals.
l Merck
M k and
d Company,
C
Inc.
I
2008-Aug.
2008A
Retrieved
R i
d on 20082008-Dec
D -04
Decfrom http://www.merck.com/ mmpe/sec10/ch124/ch124b.html.

Propecia [package insert]. Merck and Company, Inc. 20072007-May. Retrieved on
2008-Dec
2008Dec--03 from http://www.merck.com/product/usa/pi_circulars/p/
propecia/propecia_pi.pdf.

23
Rogaine [package insert]. Upjohn Pharmaceuticals. 20062006-April.
Spranger K, Brown M, Stulberg DL. Common hair loss disorders. American
Family Physician. 68(1): 20032003-July
July--01.
24
4
A Coffee Nation:
Effects of caffeine intake on
bone mineral density in young
women
Angela S. Garcia, PharmD
Drug Information Resident
Nova Southeastern University College of Pharmacy
DCPA Residency Program
January 10, 2009
Peak Bone Mineral Density

Calcium intake optimizes peak bone
mass, slows rate of bone loss and
reduces risk of osteoporosis1
10% increase of peak bone mass in
adolescence may reduce osteoporotic
fractures by 50%2
1.
Review the relationship between peak bone
mineral density, bone health and the
development of osteoporosis
2.
Discuss hypothesized effects of caffeine on
calcium excretion
3.
Review pertinent studies regarding caffeine
and bone mineral density in young adult
women as compared to postmenopausal
women
Bone Mineral Density…
What’s the Big Deal?

~34 million people have osteopenia1
Low BMD determines development of
osteopenia and osteoporosis2
Interventions to maximize BMD in youth
decreases incidence of osteopenia2
Healthy adults reach peak bone mass by
20 years of age2
Percival, M. Bone health & osteoporosis. Applied Nutritional Science Reports. 1999;5(4):1-6.
Bonjour, JP. Youth report: Invest in your bones. International Osteoporosis Foundation. 2001:1-12.
1.
2.
Goals and Objectives
1. http://www.nof.org/osteoporosis/diseasefacts.htm (accessed 12/15/08)
2. DeBar LL, et al. YOUTH – a health plan-based lifestyle intervention increases bone mineral
density in adolescent girls. Arch Pediatr Adolesc Med 2006;160:1269-1276.
Bone Health

Bones reflect mineral nutrition throughout
a person’s life
Bone continuously undergoes remodeling
– Bone resorption: osteoclasts
– Bone formation: osteoblasts

Important minerals for healthy bone
development
Calcium
Vitamin D
Magnesium
Women consumed <60% RDA of calcium
Vitamin
Vi
i D Æ mineralization
i
li i off bones;
b
increases
i
serum calcium; stimulates calcium absorption
Magnesium important for quality of bone matrix &
bone growth
Achieving optimal peak bone mass Æ less likely to
decrease to levels prone for fracture
http://www.nof.org/osteoporosis/bonehealth.htm (accessed 12/15/08)
1
Calcium Debt:
Development of Osteoporosis
Calcium Savings Account $$

1.
2.
You can’t spend what you don’t have…
Inadequate acquisition of skeletal mass
by young adult age predisposes a
person to fractures1

Low peak bone mass / poor bone health

Imbalances in bone remodeling cycle
Can be increased by certain risk factors
http://www.nof.org/osteoporosis/bonehealth.htm (accessed 12/15/08)
http://www.nof.org/osteoporosis/diseasefacts.htm (accessed 12/15/08)
Independent Risk Factors for
Low BMD and Osteoporosis
The four strongest risk factors that
predict fracture risk:
Brown JP, Josse RG. 2002 Clinical practice guidelines for the diagnosis and
management of osteoporosis in Canada. CMAJ 2002;167(10):S1-S34

– Low peripheral bone mineral density (BMD)
– Prior fragility fracture
– Advanced age
– Family history of osteoporosis

~ 10 million have osteoporosis
– Bone resorption > bone formation
– Bone loss Æ fractures & osteoporosis
At peak bone mass, the more dense the
bone, the greater protection against
osteoporosis once bone loss begins2
Dependent Risk Factors for
Osteoporosis

Nutrition & physical activity modify development
of healthy bones
Gains in bone mass most rapid in adolescence
Increasing calcium intake increases BMD in youth;
higher BMD in experimental group
Preventative lifestyle interventions Æ increased
BMD in adolescent girls Æ healthy adult behavior

Tobacco use (past or current)

Excessive alcohol intake

Inactive or sedentary lifestyle

Medical conditions/medications

Low calcium intake

Excessive caffeine intake
http://iofbonehealth.org/patients-public/about-osteoporosis/symptoms-risk-factors (accessed 12/15/08)

Key age of bone development (11
(11--14)
“Milk--displacement
“Milk
di l
t effect”
ff t”
Adolescent girls consume ~ 60% of
recommended calcium (less in soda drinkers)
Smoking and alcohol have negative impacts on
bone development
Exercise and diet/nutrition are essential for
healthy bone development
2
Saving for the Future:
Prevention of Osteoporosis
Bone Mineral Density
Insults
Recovery
Nutritional deficits
National Osteoporosis
Foundation recommends
Phosphorous intake
High Protein diet

calcium intake < age 50

vitamin D intake < age 50
Prevention is most effective method1

Maximizing calcium intake in 20s20s-30s1

1000mg daily
High Caffeine intake
Calcium and vitamin D
deficits

80-- 100 IU daily
80
10% increase in peak bone mass Æ 50%
reduction in osteoporotic fractures2
Modify independent risk factors
– increase calcium & decrease caffeine intake
1.
2.
http://www.nof.org/prevention/risk.htm (accessed 12/15/08)
http://www.iofbonehealth.org/publications/youthhttp://www.iofbonehealth.org/publications/youth-report.html (accessed 12/15/08)
Coffee: Good or Bad?

1.
2.
3.
88% of the total caffeine consumed is
in the form of coffee1
Over 50% of Americans 18 years and
older drink coffee every day2
Young adults aged 1818-24 consume
about 3 cups of coffee per day3
Conlisk A, Galuska D. Is caffeine associated with bone mineral density in young adult women?
Preventitive Medicine. 2000;31:562-568
http://www.e-importz.com/Support/specialty_coffee.htm (Coffee Statistics Report 2008 Ed)
http://www.ncausa.org/i4a/pages/index.cfm?pageid=201

Hypothesized to increase urinary excretion of
calcium
Premenopausal women compensate for ((-) calcium
balance from modest caffeine consumption
Estrogen provides benefits for BMD maintenance;
outweighs ((-) effects of caffeine intake
Modest caffeine intake ≠ predict low BMD
regardless of calcium intake
Calculating Caffeine Intake
http://www.energyfiend.com/huge--caffeinehttp://www.energyfiend.com/huge
caffeine-database

High caffeine intake = marker for low calcium
i t k
intake
Inadequate calcium intake Æ (-) calcium balance
from decreased calcium absorption efficiency
Caffeine effect dependent on low calcium intake
Increased calcium intake voids wasting effect of
caffeine
http://www.cspinet.org
Starbucks Grande Coffee
320mg
Monster Energy drink
160mg
Starbucks Chai Tea Latte
100mg
2 Excedrin
130mg
TOTAL CAFFEINE INTAKE
710mg
3
Patient Case:

23 year old female pharmacy student
Poor diet & no vitamin supp
Very little time to exercise
Consumes ~ 600mg caffeine daily
Is this patient at risk for low BMD or
osteopenia?
Patient Case:
What if…?

Asthma
Epilepsy
Diabetes
Oral Contraception
Gastrointestinal disorders
Endocrine disorders
Breast cancer
http://iofbonehealth.org/patients-public/about-osteoporosis/symptoms-risk-factors (accessed 12/15/08)
Patient Counseling:
Optimizing Bone Health
Moving in a New Direction:
Osteoporosis & Young Adults
1.
Recommend calcium and vitamin D

2.
Regular weightweight-bearing & musclemusclestrengthening exercise

3.
Avoid smoking & excess alcohol intake

4.
Talk to your healthcare provider about bone
health
5.
Get a bone density test and take medications
if appropriate

National Institute of Child Health & Health
Development
National Osteoporosis Foundation
International Osteoporosis Foundation
National Institutes of Health
Prevention of adult osteoporosis by
targeting adolescents and young women

Increasing bone mineral density
Improving bone health
Education about risk factors
http://www.nof.org/osteoporosis/diseasefacts.htm (accessed 12/15/08)
T/F Test Questions
Failure to achieve peak bone mineral density prior to age
30 can contribute to low BMD in older adults.
TRUE
Adequate studies of young women with clearly defined
levels of high caffeine consumption have shown a
correlation with an increased rate of bone mineral density.
FALSE
Consumption of adequate levels of calcium
supplementation may have protective effects against
caffeine’s depletion of bone mineral density.
TRUE
4
1/6/2009
Objectives
MENOPAUSE

An Le, PharmD
PGY1 Pharmacy Resident
Memorial Regional Hospital
Hollywood, FL
Define menopause
Discuss the epidemiology of menopause
Identify signs and symptoms of menopause
List medications used to treat vasomotor
symptoms (Sx)
Definitions

Menopausal Transition - variation in menstrual
length and cycles
Perimenopause - from the transition to end of
12 months
th after
ft the
th llastt menstrual
t l period
i d
Menopause - last 12 months of perimenopause
Postmenopause - from menopause to death
Epidemiology

Casper RF. Uptodate. 2008
Soules MR et. al. Fertil Steril 2001
Average age – 51 years
May be genetically determined
Not influenced by
physical characteristics
age at
t menarche
h or llastt pregnancy
socioeconomic status
alcohol consumption
Cigarette smoking may decrease age of
menopause by 1
1--2 years
75% of postmenopausal women in U.S.
experience vasomotor symptoms
Casper RF and Santen RJ. Uptodate. 2008
Parente RC et. al. Maturitas. 2008
McKinlay SM. Ann Intern Med 1985
Menstrual Cycle
Menopause
↓ # of follicles
and ↓ follicular
activity
↓ inhibin
↑ FSH
↓ estrogen and
progesterone
↑ LH
Kalantaridou SN et. al. Pharmacotherapy: A Pathophysiology Approach. 2008
Welt CK. Uptodate 2008.
1
1/6/2009
Clinical Manifestations

Bleeding pattern changes
Vasomotor symptoms

Hot Flashes

Hot flashes – most common acute change
g
Genitourinary atrophy
Sleep disturbance
Depression
Sexual dysfunction

Feeling of warmth in the chest, neck and face
Episodic
Highest incidence during the 2 years after
menopause
Proposed causes

Triggered by diet, stress and environment
Casper RF and Santen RJ. Uptodate. 2008
Kalantaridou SN et. al. Pharmacotherapy: A Pathophysiology
Approach. 2008
Diagnosis

Estrogen withdrawal
Thermoregulatory pathway: norepinephrine,
alpha--2 adrenergic, serotonin activity
alpha
Hormonal Treatment
Clinical manifestations
FSH (not for use during transition)
Menopause - amenorrhea for at least 12
months in women above age 45

Most effective regimen for vasomotor Sx
Intact uterus - estrogen + progestin
* Use p
progestin
g
with estrogen
g to prevent
p
endometrial
hyperplasia or endometrial cancer

Without uterus - estrogen alone
Loose DS. Goodman and Gilman’s. 2006
Estrogen for Treatment of
Vasomotor Symptoms
Estrogen
Oral
Conjugated equine estrogens
(Premarin)
Standard Dose
Low Dose
Frequency
0.625 mg
0.3 or 0.45 mg
Once daily
Estrogen Adverse Effects

Black Box WarningWarning- not used to prevent
cardiovascular disease or dementia
Increase risks of:
Esterified estrogens (Menest)
0.625 mg
0.3 mg
Once daily
Estropipate (Ogen, OrthoOrtho-est)
1.5 mg
0.625 mg
Once daily
Evamist (spray)
1 - 3 sprays
1 spray
Once daily
Divigel, EstroGel, Elestrin (gel)
0.25 - 1 g
0.25 g
Once daily

50 mcg/24hr
25 mcg/24 hr
Once or twice weekly

0.05 - 0.1 mg
0.05 mg
Every 3 months

Topical

Transdermal Patch
Climara, Menostar, Alora, Esclim, etc.
Vaginal Ring
Femring
Intramuscular
Depo-Estradiol
DepoDelestrogen
www.medicalletter.org. 2008,
1-5 mg
10 – 20 mg
-
Drugdex. Micromedex. 2008,
Every 3
3--4 weeks
Every 4 weeks
LexiComp. 2008

Myocardial
M oca dial infarction
infa ction
Stroke
Breast cancer
Venous thromboembolism (VTE)
Nausea, heavy bleeding, headache
Drugdex. Micromedex. 2008
2
1/6/2009
Progestin Adverse Effects
Progestin Doses
MOA
↓ nuclear estradiol receptor concentrations
↑ enzyme that converts estradiol to estrone
Progestin
Medroxyprogesterone
(Provera, MPA)
Progesterone
(Prometrium)
Prometrium)
Dose *
5 - 10 mg oral daily

Vaginal bleeding
Irritability
Depression
Headache
Premenstrual--like symptoms
Premenstrual

200 mg oral qhs

*Used for 12-14 days per menstrual cycle, in conjunction
with estrogen
Mood swings
Bloating
Sleep disturbance
Micromedex 2008
Drugdex. Micromedex. 2008
Loose DS. Goodman and Gilman’s. 2006
Hormone Therapy
Benefits vs. Risks
Other Combination Therapies

Oral

Angeliq (estradiol/drospirenone)
Activella (estradiol/norethindrone acetate)l
Prefest (estradiol/norgestimate)
Femhrt (ethinyl estradiol/norethindrone acetate)
Benefits
¾Decrease
w
w
Risks
risks of
¾Increase
Osteoporotic fracture
Colorectal cancer
w
w
w
Most effective in treating menopausal
symptoms
Transdermal patch

w
w
¾May
w
w
Combipatch (estradiol/norethindrone acetate)
Climara Pro (estradiol/levonorgestrel)
w
w
risks of
Coronary heart disease (CHD)†
Stroke
Venous thromboembolism
Breast cancer
Gallbladder disease
increase risks of
Seizure
Bronchospasm
Ovarian cancer
Uterine leiomyomas
Complete physical exam performed to rule out any contraindications
† CHD risk occurs in older but not younger (50-59 years) postmenopausal women
Rossouw JE et. al. JAMA 2002
Medicalletter.org. 2008
Hulley S et. al. JAMA 2002
Micromedex 2008
Lexicomp 2008
Alternatives to Estrogen
Drug*
Dosage
Comments
Clonidine
(Catapres,
Catapres, Catapres
Catapres-- TTS)
0.1 mg once daily
oral or transdermal
Not wellwell-tolerated due to
drowsiness or dry mouth
Gabapentin (Neurontin)
900 mg oral
divided in 3 doses
Dizziness and
somnolence
Megestroll acetate
(Megace)
20 - 40
0 mg orall
once daily
May be
b linked
l k d to breast
b
cancer etiology
Fluoxetine (Prozac)
20 mg oral
once daily
Modest improvement
seen in hot flushes
Paroxetine (Paxil)
12.5 - 25 mg oral
once daily
Headache, nausea,
insomnia
37.5 - 150 mg oral
once daily
Dry mouth, nausea,
constipation
Venlafaxine (Effexor)
Hulley S et. al. JAMA 1998
Grady D et.al. JAMA 2002
Nonpharmacological Therapy

Lifestyle modifications

Easily removable clothing
Reduction in intake of hot spicy foods,
caffeine,
ff i
h
hott b
beverages
Exercise
Smoking cessation
Natural medicines
* Non FDA-approved indication
Micromedex 2008
www.naturaldatabase.com. 2008
3
1/6/2009
Natural Medicines

Phytoestrogens
Most commonly used
MOA: bind to estrogen
receptors
Flaxseed, ipriflavone

Other Natural Products
Soy (Glycine max)
http://www.dkimages.com/discover/previews/
962/65013052.JPG. Accessed Dec 14, 2008

MOA: serotonin agonist and
estrogen--like effects
estrogen
Monitor liver function

Black cohosh

Dehydroepiandrosterone (DHEA)
Dong quai
Evening primrose oil
Wild yam
Panax ginseng
http://www.inhousepharmacy‐
europe.com/images/remifemin.jpg. Accessed Dec 14, 2008
Drug Interactions

Warfarin

In Summary

Red clover (phytoestrogen) : anticoagulant
effectsÆ
effects
Æ additive?
Flaxseed: decrease platelet aggregation Æ
increase bleeding
Black cohosh: inhibit CYP2D6

Majority of postmenopausal women
experience vasomotor symptoms
Hot flashes is the most common vasomotor
symptom
Treatments

Hormone therapy
Alternative therapies if HT is contraindicated
Lifestyle modification
Natural products - insufficient data
References

Casper RF. Clinical Manifestations and Diagnosis of Menopause. Uptodate 2008. www.uptodate.com. Accessed
December 6, 2008.
Casper RF and Santen RJ. Menopausal Hot Flashes. Uptodate. 2008. www.uptodate.com. Accessed December 18,
2008.
Grady D, Herrington D, Bittner V et. al. Cardiovascular disease outcomes during 6.8 years of hormone therapy:
Heart and Estrogen/progestin Replacement Study followfollow-up (HERS II). JAMA 2002; 288:49.
Hulley S, Grady D, Bush T, et. al. The Heart and Estrogen/progestin Replacement Study (HERS) Research Group.
Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in
postmenopausal women. JAMA 1998; 280:605.
Hulley S, Furberg C, BarrettBarrett-Connor E et. al. Noncardiovascular disease outcomes during 6.8 years of hormone
therapy: Heart and Estrogen/progestin Replacement Study followfollow-up (HERS II). JAMA 2002; 288:58.
Kalantaridou SN, Davis SR and Calis KA. Hormone Therapy in Women. In: DiPiro JT, Talbert RL, Yee GC et. al.
Pharmacotherapy: A Pathophysiology Approach
Approach. 7th ed.
ed China: McGraw
McGraw--Hill; 2008.
2008 www
www.accesspharmacy.com.
accesspharmacy com
Accessed December 14, 2008 Lexicomp Web site. www.lexi.com. Accessed December 18, 2008.
Loose DS and Stancel GM. Estrogens and Progestins. In: Brunton LL and Parker KL. Goodman and Gilman’s The
Pharmacological Basis of Therapeutics. 11th ed. United State: McCrawMcCraw-Hill; 2006. www.accesspharmacy.com
Accessed December 18, 2008
Martin KA and Barbieri RL. Postmenopausal Hormone Therapy. Uptodate 2008. www.uptodate.com. Accessed
December 6, 2008
McKinlay SM, Bifano NL, McKinlay JB et. al. Smoking and Age at Menopause in Women. Ann Intern Med 1985;
103:350--355.
103:350
Micromedex Healthcare Series Web site. www.thomsonhc.com. Accessed December 18, 2008.
Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. Accessed December 14, 2008.
Parente RC, Faerstein E, Celeste RK et. al. The Relationship between Smoking and Age at the Menopause: A
Systemic Review. Maturitas 2008; (61):287(61):287-298. www.elsevier.com/locate/maturitas. Accessed January 5, 2009.
Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy
postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA
2002; 288:321.
Soules MR, Sherman S, Parrott E, Rebar, R. Executive summary: Stages of Reproductive Aging Workshop
(STRAW). Fertil Steril 2001; 76:874
The Medical Letter. Treatment Guidelines from The Medical Letter. The Medical Letter. 2008;6(74):71.
www.medicalletter.org. accessed December 18, 2008
Welt CK. The normal menstrual cycle. Uptodate 2008. www.uptodate.com. Accessed December 14, 2008
True or False
1.Menopausal symptoms include hot flashes,
urogenital dysfunction, sexual dysfunction and
depression
2.Hormone replacement therapy (HRT) includes
estrogen, progestin
i and
d corticosteroids
i
id
3.Risks associated with HRT include
thromboembolism, osteoporotic fracture and
breast cancer
4
1/5/2009
Objectives
Polycystic Ovary Syndrome in
Adults
{
Presented by: Michelle Nguyen, Pharm.D.
{
[email protected]
{
Review epidemiology, etiology and
pathogenesis of polycystic ovary
syndrome
Di
Discuss
clinical
li i l manifestations
if t ti
and
d
diagnosis of polycystic ovary
syndrome
Understand treatment options for
polycystic ovary syndrome
Pathogenesis
Polycystic Ovary Syndrome (PCOS)
{
Epidemiology
z
z
{
Most common endocrine disorder of women
in reproductive years
Affects 5-10% of women in their
reproductive years
Neuroendocrine
{
Ovarian
{
Etiology
z
z
Genetics
{ ~45-50% of sisters of PCOS patients
have PCOS
{ Paternal versus maternal transmission
In utero androgen excess
{ Fetal versus maternal androgen
Homburg R. Polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol 2008;22(2):261-274.
Adrenal
Metabolic
Rotterdam Definition
z
Presence of 2 of the
following 3 conditions:
Oligo/anovulation
{ Clinical or biochemical
evidence of
hyperandrogenism
{ Polycystic ovaries on
ultrasound examination
{ Adrenal disorder causing excessive 5α-reductase
activity
{ 5α-reductase converts testosterone to more
potent dihydrotestosterone (DHT)
Insulin inhibits synthesis of sex hormone
binding-globulin (SHBG) which binds to
testosterone
{ Elevated free testosterone
{
{
Hyperandrogenism
z
z
{
{
Anovulation and infertility
z
{
Hirsutism: 17-83%
Acne: Up to 50%
~83% of infertile women had
polycystic ovaries on ultrasound
Metabolic Disorders
z
Overweight or obese: ~38-50%
z
Insulin resistance and diabetes
{
{
z
Ehrmann DA. Polycystic ovary syndrome. NEJM 2005;352(12):1223-123
Dysregulation of P450c17α enzyme activity and
theca cells
{ More efficient in converting to testosterone
Ehrmann DA. Polycystic ovary syndrome. NEJM 2005;352(12):1223-1236.
Norman RJ. Polycystic ovary syndrome. Lancet 2007;370:685-697.
Diagnosis
{
Hypothalamus defect and hypersecretion of
gonadotropin-releasing hormone (GnRH)
{ GnRH secreted in rapid pulsatile manner
{ Lutenizing hormone (LH) elevation in response
to GnRH secretion
Intensifies symptoms
~30-40% of lean women versus ~80% in
obese
Dyslipidemia: ~46%
Franks S. Assessment and management of anovulatory infertility in polycystic ovary syndrome. Endocrinol Metab Clin N Am
2003;32:639-651.
Magnotti M, Futterweit W. Obesity and the polycystic ovary syndrome. Med Clin N Am 2007;91:1151-1168.
Orio F, Vuolo L, et al. Metabolic and cardiovascular consequences of polycystic ovary syndrome. Minerva Ginecol 2008;60:39-51.
1
1/5/2009
Treatment
Insulin Resistance
Obesity
Endocrine Manifestation
{
{
Metabolic Manifestation
z
z
Hyperinsulinemia
LiverÆ ↓SHBG
OvaryÆ ↑Androgen Activity
Glucose Intolerance
Dyslipidemia
Hirsutism/Acne
Infertility
Menstrual Disturbances
Diabetes
Vascular Diseases
z
{
z
{
z
z
Dunaif A. Insulin resistance and the polycystic ovary syndrome: Mechanism and implications for pathogenesis.
Endocr Rev 1997;18(6)774-800.
Desirability of pregnancy
Degree of androgen excess
Goals
z
Impaired metabolic response to insulin
Fasting hyperinsulinemia
{ >17-20 mU/L
Insulin-mediated glucose uptake decreased by 35-40%
Skin abnormalities
Weight gain or inability to lose weight
Anovulation and infertility
y
Individualized treatment
z
Insulin resistance
z
Treatment directed at symptoms of
disorders
z
z
Reduce excess androgen
Reduce insulin resistance
Correct anovulation
Lobo RA. Choice of treatment for women with polycystic ovary syndrome. Fertil Steril 2006;86 Supp 1:S22-S23.
Treatment Options
{
{
{
{
{
{
{
{
{
Lifestyle Modifications
Lifestyle modifications
Oral contraceptives
Antiandrogens
5α-reductase inhibitors
Antiestrogens
Aromatase inhibitors
Biguanides
Thiazolidinediones
Surgery
{
Diet and exercise
z
z
z
z
z
Restores ovulation in ~24%
Increases pregnancy rates by ~77%
R d
Reduces
miscarriages
i
i
rate
t b
by ~18%
18%
Reduces insulin resistance
Improves hirsutism
Moran LJ, Brinkworth GD, et al. Dietary therapy in polycystic ovary syndrome. Semin Reprod Med 2008;26:85-92.
Hirsutism and Acne
{
Oral Contraceptives
First line treatment is weight loss
z
{
Hirsutism and Acne
5-10% loss of body weight greatly
improves hirsutism within 6 months of
weight reduction
Pharmacologic Agents
z
z
Oral contraceptives
Antiandrogens
{
{
z
o
MOA
Doses
Spironolactone (Aldactone®)
Flutamide (Eulexin®)
5α-reductase inhibitors
{
EE &
desogestrel
Finasteride (Propecia®, Proscar®)
o
Traits
{
EE &
drospirenone
Suppress ovarian androgen production
Estrogen- Increase SHBG
Progestin- Suppress LH and FSH
Progestin
0.03 mg/0.15 mg
once daily
SE
{
ACOG Practice Bulletin. Polycystic ovary syndrome. Obestet Gyne 2002;100(6):1389-1402.
o
EE &
norgestimate
0.035 mg/0.25 mg
once daily
0.03 mg/3 mg
once daily
Edema, rash, bloating, abdominal cramps, weight changes
o
Non-androgenic
o
Non-androgenic
o Antimineralocorticoid
o
Antiandrogenic
Most common treatment for menstrual abnormalities and
skin manifestations
Preferred for women who do not desire to become pregnant
Ehrmann DA. Polycystic ovary syndrome. NEJM 2005;352(12):1223-1236.
2
1/5/2009
MOA
Hirsutism and Acne
Hirsutism and Acne
Antiandrogens
5α-reductase Inhibitors
Spironolactone
Flutamide
Binds to androgen
receptor, inhibits ovarian
and adrenal androgen
production, elevates SHBG
levels and increases
testosterone clearance
Blocks androgen
receptor, promotes
androgen metabolism,
reduces hair diameter,
and improves lipid
profiles
Doses
100-200 mg/day
250-500 mg/day
SE
Menstrual irregularity,
polyuria, fatigue and
hyperkalemia
Greenish urine, skin
dryness and
hepatotoxicity
Concerns
Renal impairment,
teratogenicity
Hepatotoxicity,
teratogenicity
Moghetti P. Use of antiandrogens as therapy for women with polycystic ovary syndrome. Fertil Steril 2006;86 Supp 1:S30-S31.
Finasteride
MOA
Competitive inhibitor of type II 5α-reductase;
Inhibits conversion of testosterone to DHT
Dose
2.5-5 mg/day
SE
GI disturbances, headaches, dry skin and
decreased libido
Concerns
Feminization of male fetus
Anovulation and Infertility
Comparison in Treatment of Hirsutism
{
Objective: Compare the clinical efficacy in
hirsute women in a 6 month course of double-blind,
placebo-controlled treatments
Spironolactone
Free
Testosterone*
(pg/mL)
Hair Diameter
(μm)
(P < 0.01)
Flutamide
(n = 10)
PreTxÆPostTx
(n = 10)
PreTxÆPostTx
3.47Æ3.43
3.36Æ2.78
164Æ144
172Æ164
Finasteride
{
z
z
Placebo
(n = 10)
PreTxÆPostTx
(n = 10)
PreTxÆPostTx
3.50Æ4.24
3.21Æ3.25
172Æ139
Lifestyle Modification
{
77.6% pregnancy rate versus control group
Absolute risk reduction of miscarriage was 57%
Pharmacologic
g Agents
g
z
Antiestrogen
z
Aromatase Inhibitors
{
153Æ146
{
{
Score+
F-G
(P < 0.01)
16.9Æ10.0
17.5Æ11.1
18.4Æ13.0
Clomiphene citrate (Clomid®, Serophene®)
Letrozole (Femara®)
Anastrozole (Arimidex®)
17.2ÆØ
*Not statistically significant; +F-G- Ferriman-Gallwey; Ø Not presented
Moghetti P, Tosi F et al. Comparison of spironolactone, flutamide and finasteride efficacy in the treatment of hirsutism:
A randomized, double blind, placebo-controlled trial. J Clin Endocrin Met 2000;85(1):89-94.
Clark AM, Thornley B, et al. Weight loss in obese infertile women results in improvement in reproductive outcome for all
forms of fertility treatment. Hum Reprod 1998;13(6):1502-1505.
Antiestrogen
Clomiphene Citrate
MOA
Stimulates endogenous FSH secretion leading to
development of dominant follicle and ovulation
Dose
50 mg/day for 5 days starting day 2, 3, 4 or 5 of
menstruation;
t
ti
If no ovulation, may increase in increments of 50 mg in
subsequent cycles (max: 150 mg/day)
SE
Dose-dependent: Hot flashes, abdominal distension and
visual disturbances
Concerns
Multiple pregnancies
{
Treatment of choice
z
Restores ovulation ~75% and induce pregnancy in 35-40%
{
Effects on endometrium thickness
Polyzos NP, Tsappi M, et al. Aromtase inhibitors for infertility in polycystic ovary syndrome. The beginning
or the end of a new era? Fertil Steril 2008;89(2):278-280.
Letrozole and Anastrozole
MOA
Dose
{
Inhibits aromatase, the enzyme that converts
androstendione and testosterone to estrogens
Letrozole
Anastrozole
2.5-5 mg/day
1 mg/day
SE
Vasodilation, mood disturbances, pain,
headache, rash, weakness and hot flashes
Concerns
Infant cardiac and bone abnormalities
Advantages over clomiphene citrate
z
No effect on cervical mucus or endometrium
Lower incidences of multiple pregnancies
z
Half-life ~2 days versus 5-7 days
z
Elizur SE and Tulandi T. Drugs in infertility and fetal safety. Fertil Steril 2008;89(6):1595-1602.
3
1/5/2009
Metabolic Disorders
{
{
Metabolic Disorders
Insulin Sensitizing Agents
Pharmacologic Agents
z
Biguanides
{
z
Metformin
Metformin (Glucophage®)
Thiazolidinediones
{
Rosiglitazone (Avandia®)
{
Pioglitazone (Actos®)
MOA
Increases insulin
sensitivity of peripheral
tissues to insulin
Doses
1500-2500 mg/day
SE
Concerns
Comparison of Metformin and
Pioglitazone
Compare effectiveness of
pioglitazone and metformin in insulin resistance and
hyperandrogenism
Pioglitazone
(n = 18)
(n = 17)
{
PreTxÆPostTx
PreTxÆPostTx
16.0Æ11.1
(P < 0.001)
14.9Æ10.4
(P < 0.05)
----
Fasting Insulin
31.1Æ11.0
(P <0.008)
31.1Æ11.1
(P <0.008)
<0.05
(µU/mL)
Free
Testosterone
2.67Æ1.81
(P <0.05)
3.07Æ2.12
(P < 0.05)
Pregnancy
&
Miscarriage
(%)
16.7
29.4
33.3
60
Pioglitazone
4-8 mg/day
15-45 mg/day
GI disturbances
Hepatotoxicity, peripheral edema
Renal impairment, lactic
acidosis
Unknown teratogenicity risk
Laparoscopic Ovarian Drilling
z
Metformin vs.
Pioglitazone
Hirsutism
(FG Score)
Rosiglitazone
Surgical Treatment
Objective:
Metformin
Enhance insulin action at targettissue
Nestler JE. Metformin for the treatment of polycystic ovary syndrome. NEJM 2008;358(1):47-54.
Nestler JE, Stovall D et al. Strategies for the use of insulin-sensitizing drugs to treat infertility in women with
polycystic ovary syndrome. Feril Steril 2002;77(2):209-215.
Pasquali R and Gambineri A. Insulin-sensitiving agents in women with polycystic ovary syndrome. Fertil Steril
2006;86 Suppl 1:S28-S29.
{
Rosiglitazone and
Pioglitazone
z
P Value
z
z
{
----
(pg/mL)
{
----
Ortega-Gonzalez C, Luna S, et al. Responses of serum androgen and insulin resistance to metformin and pioglitazone in
obese, insulin-resistant women with polycystic ovary syndrome. Clin Endocrin Met 2005;90(3):1360-1365.
Effective in treatment-resistant
Reduction in ovarian mass
Four to ten punctures in cortex
Destroys androgen-producing stroma
Ovulation restored in
92% of patients
Pregnancy rate of
80%
Treatment Summary
Questions?
Examples
Hirsutism
Acne
Oligo/
Amenorrhea
Ovulation
Induction
Insulin
Lowering
Weight Loss
X
X
X
X
Estrogen and
Progestin
Ortho-Cyclen®
Orthocept®
Yasmin®
X
X
Antiandrogens
Spironolactone
Flutamide
X
5α-reductase
inhibitors
Finasteride
X
Antiestrogen
Clomiphene
citrate
Letrozole
Anastrozole
Biguanide
Metformin
X
X
X
X
Thiazolidinediones
Pioglitazone
Rosiglitazone
X
X
X
X
Surgery
Ovarian Drilling
{
True or False?
z
z
X
X
z
Three main characteristics of PCOS include,
but are not limited to, chronic anovulation,
polycystic ovaries on ultrasonography, and
hypoandrogenism.
Clinical consequences of PCOS include
impaired glucose tolerance, obesity,
dyslipidemia, and skin abnormalities.
Clomiphene citrate can be used in PCOS to
induce ovulation.
X
4
Objectives
HPV Vaccine:
Issues and Controversies
Nayle
N
l Moya
M
Ph
Pharm.D.
D
PGY1 Pharmacy Resident 2008
[email protected]

Review history, epidemiology and etiology of
Human Papillomavirus (HPV)
Understand the clinical manifestations
Review available prophylactic treatment
Discuss issues related to HPV vaccine
Emphasize current controversies of HPV
vaccine
History of HPV Infection

Papilloma viruses
{ Produce warts on the hands
and feet or condyloma
accuminata on the pubic
area
{ Warts were considered
nuisance rather than
precursors to cancer
Hutchinson and Klein.Human papillomavirus disease and vaccines.
Am I Health-Syst Pharm-Vol 65 Nov 15,2008
Epidemiology
The most common sexually transmitted disease (STD)
20 million individuals are currently infected in the
United States
6.2 million new infection occur each year among age
14-44 years
{

~ 80% of sexually active women will acquire genital
HPV infection by age 50
Quadrivalent Human Papillomavirus Vaccine.
Recommendations of the Advisory Committee on Imunization Practices (ACIP).March23,2007/56(RR02);1-24
Etiology

Risk factors associated with HPV infection
{ Sexual behavior
{ Partner’s sexual history
{ Immune status
{ Age < 25 yo
Diagnosis
{ Direct visual examination
{ Pap smear test
{ Colposcopy examination
74% of annual HPV infections occur among age 14-24
years
Pathogenesis

Human papillomavirus
{
{
{
Small double-stranded circular DNA viruses
More than 100 HPV genotypes identified
Infect squamous epithelia
Genital tract / cervical cancer
Anal and perianal areas / anogenital
neoplasia
Cutaneous epithelium / planter warts
Mucosal epithelium of the larynx / juvenile
recurrent respiratory papillomatosis (RRP)
1
Physiology
HPV Infection

Median duration of new infections is 8 months
Most infections are transient and asymptomatic

Immune system controls or destroys the virus

{
{
{

Mild cytologic changes
{
{
Absence of lesions and treatment
{

90% clear within two years
Younger patients, 60-80% of new cases clear
within 1 year of infection
Persistent infection
{
{

Low
ow risk
s
6 and 11
High risk
16 and 18
Precancerous lesion
Cervical cancer
Development of cervical cancer ~ 20 years
HPV
genotypes
Atypical cells morphology
Low-grade intraepithelial lesions
C i l intraepithelial
Cervical
i
i h li l neoplasia
l i (CIN) grade
d 1,2,3
123
Prophylactic Treatment
Response
90% of genital warts (condyloma
acuminata)
10% of cervical intra
intra-epithelial
epithelial
neoplasia (CIN1)
Gardasil®
CervarixTM
M k/S fi Pasteur
Merck/Sanofi
P t
Gl
Glaxo
S
Smith
ith Kline
Kli
70% of cell cancer
83% of cervical adenocarcinomas
50 to 60% of high-grade CIN,
vulvar intra-epithelial neoplasia (VIN)
25% of low-grade CIN

2006
FDA approved
Seeking
FDA approval
Prophylactic efficacy of a quadrivalent human papillomavirus (HPV) vaccine in women with virological evidence of HPV infection.
JID 2007:196
Prophylactic Treatment
Issues
CervarixTM
Gardasil®
Genotype coverage
VLP derived from HPV 6,
11, 16, and 18
VLP derived from HPV 16
and 18

Composition
Produced in a yeast
system
Produced in a insect-cell
system

Vaccination schedule
0, 1, 6 months
0, 2, 6 months
Age, trial subjects
16-23 years
15-25 years
Sustained efficacy
Effective through 5 yrs
Effective through 4.5 yrs
Immune response
Antibody titers
10-20 times natural
infection
50-80 times natural infection
Licensed for public use
> 60 countries
Australia (women ≤ 45 yrs)
Human papilloma virus (HPV) prophylactic vaccination:
Challenges for public health and implications for screening. M Adams et al. /Vaccine 25(2007)3007-3013

Appropriate age of vaccination
Parental concerns about the vaccination
for a STD
Routine vaccination for men or women
age 26 years or older
Long-term efficacy and safety data
VLP- Virus-like particles
2
Appropriate Age of Vaccination
Early age before exposure provides optimal
protection

Parental Concerns
Marlow et al. indicates strong parenteral acceptance of the
vaccination for protection against cervical cancer vs. HPV
transmission
{ 75% might or definitely would vaccinate their children
{ 19% were unsure

29% of 9th grade females have engaged in sexual
intercourse
19% are sexually active
By 12th grade, ~ 52% of these females are sexually
active with 20% having at least 4 sexual partners
{
{
{

ACIP recommend vaccination at 11 or 12 years

Better serological response to HPV vaccine
Theoretically, longer lasting immunity
{
{

Gardasil® is not FDA approved in men
Immunization in men may potentially prevent
p
, oral,, head and neck cancers
anal,, penile,
Efficacy trials are ongoing
{

Collection of cells to detect HPV DNA
Discomfort during peniscopy with biopsy
Women Older Than 26 Years

The level of efficacy of HPV vaccine is unknown

Vaccine may still be beneficial for women not infected
with
ith HPV ttypes iincluded
l d d in
i the
th vaccine
i
Women who eradicate infection with own immunity,
prevention of re-infection later in life unknown
{

Benefit during the time between initial HPV
infection and the development of cervical cancer
is unknown
Need for booster vaccine to maintain efficacy is
unknown
Continued monitoring of efficacy will be essential
to assess the duration of vaccine efficacy
David J..Human papillomavirus disease and vaccines.
Benefit is unlikely in detectable HPV DNA women
Goods Administration of Australia approved
CervarixTM for use in females age 10-45 years
Long-Term Efficacy

May create an illusion of invulnerability against HPV
transmission
Marlow et al. Parental attitudes to pre-pubertal HPV vaccination.
Vaccine 25 (2007) 1945-1952
Limitations to assess the efficacy of the vaccine

May increase sexual behavior
{
Vaccination in Men

Negatively impact on family morals
6% definitely would not
{
Safety Data

Post-marketing data from VAERS reported 2,531
adverse events related to HPV vaccine
{ 95% was classified as nonserious
{ 5% as serious
Syncopal episodes and seizures
Arthralgia, joint pain, and fever
13 unconfirmend reports of Guillain-Barre
syndrome
VAERS: Vaccine adverse event reporting system
3
Lifetime Impact of
HPV 16/18
Controversies of HPV Vaccine

Lifetime impact of HPV 16 and 18
prophylactic vaccine

Effect on cervical screening

Pregnancy Concerns

Implementation of HPV vaccine in U.S.
Difficult to predict its effect on the incidence of preinvasive and invasive cancer
{ A cohort study of HPV 16 and 18 vaccine on the
burden of cervical disease
70% reduction in the prevalence of high-grade,
and 76% in cervical cancer cases and mortality
of 12 year old females if 100% coverage was
achieved
50-60% reduction in cytology results diagnostic
tests, biopsies, and colposcopies
Human papilloma virus (HPV) prophylactic vaccination:
Challenges for public health and implications for screening. M Adams et al. /Vaccine 25(2007)3007-3013
Effect on Cervical Screening
Cervical cancer screening recommendations
need to be continued
Sexually active females infected before
vaccination
Females vaccinated could be infected with
HPV types not provided in the vaccine
HPV vaccine’s genotypes are responsible for
~70% of cervical cancer
Pregnancy Concerns

Gardasil® is not a live-virus vaccine
1,244 pregnancies in the vaccine group and
1,272 occurred in the placebo group
{ 5 congenital malformation vs none in the
placebo group who received the vaccine
within 30 days of estimated onset of
pregnancy
FDA category B
Implementation of HPV Vaccine
True or False?
Current Recommendations for Immunization in United States
FDA approved for
9-26 years
June 2006

ACIP/CDC recommended
AAP Committee on Infectious Diseases
For 11-12 years or 9 years old
Recommended for 11-12 years
Catch-up for 13-26 years not vaccinated
and early as 9 years old
March 2007
September 2007
Mandating the vaccine for school entry?
{
{
{
HPV is not readily spread in the school environment
HPV vaccine may lead to sexual disinhibition
Economic impact
1. HPV is a sexually transmitted virus that can be passed
on through genital contact and skin-to-skin contact.
2 Gardasil®
2.
G d il® is
i effective
ff ti against
i t HPV types
t
6,
6 11,
11 16,
16 18.
18
3. Gardasil® is recommended for women over age 26 and
started as young as 9 years of age.
FDA-Food and Drug Administration
ACIP-Advisory committee in immunization practices
CDC-Center of disease control
AAP-American Academy of Pediatrics
4