Transcript Psychoactive medications (Antipsychotics)

A Drug Therapy Smorgasbord
Practical Issues for Dietitians
Presented by
David B. Goldwater R.Ph
Clinical Consultant Pharmacist
Objectives
1. Review Practical Pharmacokinetic
principals to create a deeper understanding
of absorption, distribution and excretion of
drugs.
2. Review several commonly used drugs often
reviewed for consideration by Dietitians
which involve considerations of
pharmacokinetics and specific drug/ food
interactions.
2
Objectives continued….
3. Discuss important considerations for
Warfarin interactions with enteral feedings
4. Review the Pharmacodynamic effects of
antipsychotics with specific focus on weight
gain and blood sugar control
3
Closer Collaboration between
Pharmacists and Dietitians
 Changes to revised Dietary F Tag: F325.
June 2008 AND
 Definition of MRR in revised Pharmacy
F Tag F425 (Dec 2006)
 BOTH REVISIONS have strengthened the
need for communications between our two
disciplines.
4
Changes to F428 –Med
Regimen Review (Dec 2006)
 Thorough evaluation of the medication
regimen of a resident by a pharmacist with
the goal of promoting positive outcomes and
minimizing adverse consequences
associated with medications;
 The review includes: preventing, identifying,
reporting, and resolving medication-related
problems, medication errors, or other
irregularities AND
 collaborating with others members of the
interdisciplinary team.”
5
Personal impact of working
closer with dietitians
Appreciation of the positive influence on
outcome for residents due to collaborations
with Dietitians in LTC.
2. A strong interest in speaking to you as a group
today.
3. The topics chosen for review today, have come
directly from collaborations and discussions
with individual Dietitians in my personal
practice.
4. On a lighter note………….
1.
6
Personal Impact of Working
closer with Dietitians
British
dietiCIAN
Canadian
dietiTIAN
American
dietiTIAN
Basic Concepts of
Pharmacokinetics
Practical Issues For
Dietitians
Pharmacokinetics
Study of what the body
does to a drug.
How the body → moves drug in and
out. (Absorption Distribution Excretion)
9
Pharmacodynamics
Study of the influence
(dynamics) of the DRUG
on the BODY
10
FIRST ORDER KINETICS
1. The majority of drugs are eliminated in this
way.
2. A constant fraction of the drug in the body is
eliminated per unit time.
3. The rate of elimination is proportional to the
amount of drug in the body.
11
FIRST ORDER ELIMINATION
Concentration
in plasma
Time
12
Volume of Distribution
(For drugs which follow first order kinetics)
 The Volume of Distribution (Vd) is the
amount of drug in the body divided by the
concentration in the blood.
 Highly LIPID SOLUBLE DRUGS, such as
digoxin, have a very High Vd.(500liters).
 LIPID INSOLUBLE DRUGS, such as
neuromuscular blockers, remain in the blood,
and have a Low Vd.
13
Clearance (Cl)
(For drugs which follow first order kinetics)
 The Clearance (Cl) of a drug is the VOLUME
of plasma from which the drug is
COMPLETELY removed per unit time.
 The amount of drug eliminated is
PROPORTIONAL to the concentration of the
drug in the blood.
14
Elimination
(For drugs which follow first order kinetics)
RATE of elimination
EQUAL TO
Clearance x Concentration in the blood.
_______________________________________________________________________________________
Elimination HALF LIFE (t1/2)
EQUAL TO
Time taken for plasma conc. to reduce by 50%.
15
RULE OF THUMB
100% Elimination After 5 HALFLIVES
(Symbol for Half-life is t ½ )
16
Half-life: Implications
 We can determine how long it
takes to reach steady state
E.g. DIGOXIN ……t ½ = 40hrs
1.
2.
It takes approximately 200 hrs ~8 days
for DIGOXIN to reach STEADY STATE LEVELS.
It takes approximately ~8 days for DIGOXIN
to be COMPLETELY ELIMINATED from the
system.
17
Simple, isn't it?
 What we discussed above is a SINGLE




COMPARTMENT model,
This is what would occur if the bloodstream was the
only compartment in the body
(or if the Vd = the blood volume).
But the human body is more complex than this!
There are many compartments: muscle, fat, brain
tissue etc.
In order to describe this, we use MULTICOMPARTMENT models.
18
MULTICOMPARTMENT
MODELS
Q.
Why does a patient wake up after 5 minutes after an injection
of Thiopentone, when we know that it takes several hours
to eliminate this drug from the body?
A. Initially the drug is ALL in the blood and this blood goes to
"vessel rich" organs; principally the brain.


The drug then redistributes into other tissue compartments.
(fat, muscle etc)
In response to the decrease in brain concentration the net
effect is that the patient wakes up 5 minutes later!
19
Elimination: MULTI COMPARTMENT MODEL
Rapid distribution phase
α
Equilibrium phase (Plateau)
Concentration
Elimination phaseβ
Time
20
A SIMPLE
TWO COMPARTMENT MODEL
 The first part is the rapid redistribution phase:
(alpha phase.)
 The plateau (equilibrium phase)
(where blood concentration = tissue concentration)
 The slower phase, the beta phase, is the
elimination phase where blood and tissue
concentrations fall in tandem
21
BIOAVAILABIILITY
 This is the fraction of the administered dose that
reaches the systemic circulation.
 Bioavailability is 100% for intravenous injection.
 It varies for other routes depending on


incomplete absorption,
first pass hepatic metabolism etc.
 When we plots plasma concentration Vs. time, the
bioavailability is the area under the curve.
22
BIOAVAILABILITY
(for a drug given orally)
Concentration
BIOAVAILABILITY is
the AREA UNDER THE
CURVE
in plasma
Time
23
DOSAGE REGIMEN
The strategy for ADMINISTRATION DOSING is to
administer ONLY, sufficient amounts of drug to
attain therapeutic effect, but not enough to produces
toxicity!
THEREFORE WE APPLY THESE PRINCIPLES……
 STEADY STATE CONCENTRATION is achieved
AFTER FIVE half lives, therefore….
 At STEADY STATE
Maintenance Dose
= Rate of Elimination
 WE THEREFORE CONCLUDE THAT……
Rate of Administration = Rate of Elimination
24
DOSAGE REGIMEN
 Drugs will accumulate within the body if the drug has not
been fully eliminated before the next dose.
 This is OK only IF, we are willing to wait 5 half lives for the
drug to be fully effective ………but what if we cannot wait
that long?
 Then we need to "load" the volume of distribution WITH the
drug to achieve target plasma concentrations RAPIDLY.
25
Hepatic Drug Clearance
 Many drugs are extensively metabolized by the
liver.
 The rate of elimination depends on:


The liver's inherent ability to metabolize the drug
The amount of drug presented to the liver for
metabolism.
26
Hepatic Drug Clearance
(First Pass effect)
 This is important because orally administered drugs
go from Ingestion →gut → portal vein → liver.
 The liver DIVERTS a varying chunk of the administered
drug by (pre-systemic elimination) and therefore less is
available to the body for therapeutic effect.
EXAMPLE:
This is why we give a higher dose of ORAL morphine,
for the equipotent INTRAVENOUS dose
30 MG ORAL Morphine is EQIPOTENT TO
1 MG IV Morphine.
ORAL: PARENTERAL RATIO = 3 : 1
27
Drug distribution
FACTORS THAT EFFECT WHERE THE DRUG ENDS UP:
1.
BLOOD FLOW

tissues with the highest blood flow receive the drug first.
2.
PROTEIN BINDING

drugs stuck to plasma proteins are crippled, because
they can only go where the proteins go
3.
LIPID SOLUBILITY & DEGREE OF IONIZATION

this describes the ability of drugs to enter tissues

(highly lipid soluble / un-ionized drugs can basically go
anywhere).
28
Protein Binding
 Most drugs bind to proteins:
 Albumin OR
 Alpha-1 Acid Glycoprotein (AAG),
 FREE drug is usually the preferred state,
because FREE drug can travel throughout
the body, in and out of tissues and exert a
biological effect.
 Free drug on the other hand is subject to
metabolizing enzymes.
29
Protein Binding

HIGHLY BOUND drug has a longer
duration of action and a lower volume of
distribution.
Why is this important?
1.
For HIGHLY protein bound drugs, we need
to give more of it to get a therapeutic effect;
as so much is stuck to protein.
2.
If another drug comes along and starts to
compete with the drug for the binding site on
the protein →
the amount of FREE drug is ↑
↑
INCREASED
30
Clinical Implications for HIGHLY
Protein Bound Drugs
 DRUG-A ------ 97% BOUND TO ALBUMIN……3% free drug.
 Addition of DRUG-B displaces DRUG-A from its binding sites
 Causing 3% reduction in Protein binding for DRUG-A
RESULTS in a 50% increase in FREE DRUG-A
concentration from 3% to 6%
 DRUG-X ------ 70% BOUND TO ALBUMIN……30% free drug.
 Addition of DRUG-Y displaces DRUG-X from its binding sites
 Causing 3% reduction in Protein binding for DRUG-X
RESULTS in a NEGLIGIBLE increase
of FREE DRUG-X concentration from 30% to 33%
31
Clinical Implications for HIGHLY
Protein Bound Drugs
The HIGHLY BOUND drugs that we really need to focus on are:
warfarin, diazepam, propranolol, phenytoin.
 For example, a patient on warfarin is admitted with
seizures, you treat the patient with phenytoin, next
thing you know - his INR is 10.
 The amount of albumin does not appear to be hugely
relevant.
 In disease states such as sepsis, the serum
albumin drops drastically, but the free drug
concentration does not appear to increase
 HOWEVER: For residents with LOW serum Albumin there is a
formula that we apply to DILANTIN levels results to adjust the
DILANTIN level
32
Warfarin Resistance & Enteral
feeding: New understanding
of An Old Problem
Practical Issues For
Dietitians
History of
Enteral feedings & Warfarin
 Warfarin resistance first reported in the
early 1980’s was POSITIVELY associated
with CONTINUOUS enteral tube feedings.
 Attributed to large amounts of vitamin K
contained within the feedings.
 Patients commonly received several
hundred micrograms per day of vitamin K!
34
CORRECTIVE ACTIONS TAKEN
 The pharmaceutical industry subsequently
responded to this problem……
 Resulting in significantly reduced vitamin
K content of liquid enteral nutrition
formulations.
 Most current liquid enteral formulations
NOW CONTAIN LESS THAN 80
MCG/LITER OF VITAMIN K.
35
Why does this issue still occur?
 Still some anecdotal reports of difficulty in achieving
therapeutic anticoagulation when warfarin was given
concomitantly with CONTINUOUS LIQUID
ENTERAL FEEDINGS
 Still some anecdotal reports of significant increases
in the (INR) when the enteral feeding was
discontinued.
 Schurgers and associates (2004) performed a study
to ascertain the CLINICAL IMPACT OF VITAMIN K
SUPPLEMENTATION on the anticoagulation effect
of the ORAL ANTICOAGULANT
ACENOCOUMAROL.[6]
36
Is VIT K CONTENT In Enteral Feeding
STILL THE ISSUE?
NOT LIKELY !
 They concluded that other factors outside of
enteral vitamin K intake were playing a greater
role in these ANECDOTAL observations
BECAUSE….
 ……..THE TOTAL VIT K INGESTED IN ENTERAL
FEEDING WAS SIGNIFICANTLY LOWER THAN
THE SUPPLEMENTAL DOSES USED IN THE
STUDY
37
Guidelines for Daily Vit K Intake
 Guidelines from the Food and Nutrition Board
of the Institute of Medicine for adequate
intake of Vit K are as follows:
in healthy adult men :
 Vit-K 120 mcg/day
In healthy adult women:
 Vit-K 90 mcg/day
38
Findings by Schurgers and
colleagues [5]
 A statistically significant decrease in INR by
0.4 was found when….
 The subjects’ supplemental vitamin K intake
was increased to 150 mcg/day. This was in
addition to their baseline 55 mcg/day
______________________________________
The GRAND TOTAL of dietary vitamin
K intake was 205 mcg /day
39
Findings by Schurgers and
colleagues [5]
 They confirmed that supplemental intake of
up to 100 mcg/day of vitamin K did NOT
significantly interfere with oral anticoagulant
therapy in healthy individuals already
receiving about 55 mcg of dietary vitamin K.
THEY CONCLUDED:
vitamin K intake of about
150 mcg daily is NOT likely to affect
 That a total
warfarin requirements.[5]
40
Dickerson and Colleagues Review
 Dickerson and colleagues studied (INR) values in 6
patients requiring continuous enteral feeding during
the first 10 days of warfarin therapy.[6]
 For 3 consecutive days, feedings were interrupted for
1 hour before and after warfarin administration.
 On 3 other consecutive days, feedings were NOT
interrupted for warfarin administration.
 The INR increased by a mean of 0.74 during the 3day interval when the enteral feedings were
interrupted for warfarin.
 In contrast, the INR decreased by a mean of 0.13
during the 3-day interval when enteral feedings were
NOT interrupted .
41
Dickerson and Colleagues
CONCLUSION
Holding enteral feeding 1 hour BEFORE and
1 hour AFTER warfarin administration
…….lessens warfarin resistance
This strategy is recommended for warfarin
administration DURING CONTINUOUS
ENTERAL FEEDINGS.
42
KEY POINTS:
Warfarin Management in Enteral Nutrition 1,6,7
1. Consider an alternative method of
anticoagulation.
2. Monitor INR frequently.
3. Administer warfarin BETWEEN feedings
for patients receiving INTERMITTENT tube
feedings.
4. Stop feedings ONE hour before and ONE
hour after warfarin administration for
patients receiving CONTINUOUS tube
feedings,.
43
KEY POINTS:
5. Consider increasing the rate of feedings
to avoid loss of calories.***
6. Administer warfarin consistently (ie, hold
feedings for all doses)
7. Do not add warfarin directly to the enteral
nutrition.
8. Warfarin dose requirements may change
if the enteral regimen is altered or if the
oral diet is resumed.
44
KEY POINTS:
9. Warfarin dose requirements may change
if the enteral regimen is altered or if the
oral diet is resumed.
10. If Enteral feedings are Initiated in a
patient stable on warfarin, the warfarin
may require a dose increase
11. If WARFARIN is initiated in a patient
currently receiving enteral nutrition, the
warfarin may require a dose decrease
upon resumption of oral diet.
45
Selected References
1. Lourenco R. Enteral feeding: drug/nutrient interaction. Clin Nutr. 2001;20:187-
193.
2. Penrod LE, Allen JB, Cabacungan LR. Warfarin resistance and enteral
feedings: 2 case reports and a supporting in vitro study. Arch Phys Med
Rehabil. 2001; 82:1270-1273.
3. Coumadin (package insert). Princeton, NJ: Bristol-Myers Squibb; 2007.
4. Food and Nutrition Board, Institute of Medicine. In: Dietary Reference Intakes
for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron,
Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington,
DC: National Academy Press; 2001:162-196.
3. Schurgers LJ, Shearer MJ, Hamulyak K, Stocklin E, Vermeer C. Effect of
vitamin K intake on the stability of oral anticoagulant treatment: dose-response
relationships in health subjects. Blood. 2004;104:2682-2689.
4. Dickerson RN, Garmon WM, Kuhl DA, Minard G, Brown RO. Vitamin K-
independent warfarin resistance after concurrent administration of warfarin
and continuous enteral nutrition. Pharmacotherapy. 2008; 28:308-313.
5. Engle KK, Hannawa TE. Techniques for administering oral medications to
critical care patients receiving continuous enteral nutrition. Am J Health Syst
Pharm. 1999; 56:1441-1444.
Other Drug-Enteral feeding
interactions
Practical Issues For
Dietitians
Study by Dickerson et. Al.
Roland N. Dickerson, George O. Maish III, Gayle Minard and Rex O. Brown.
Clinical Relevancy of the Levothyroxine −
Continuous Enteral Nutrition Interaction
Nutr Clin Pract 2010 25: 646
48
STUDY CONCLUSION:
1. More than half of our patients receiving
concurrent Levothyroxine–continuous EN
developed subclinical or overt hypothyroidism
within the first 2-3 weeks of therapy.
2. Holding EN for ONE hour PRE- and POST
Levothyroxine administration, may be
ineffective for some patients.
3. If a Levothyroxine dosage escalation is
attempted following development of
hypothyroidism, only a 25-mcg dosage
increment is suggested.
49
STUDY CONCLUSION:
4. Serial (e.g. weekly) monitoring of TFT’s for all
patients receiving concurrent levothyroxine and
EN therapy is recommended.
5. TFT monitoring should be continued until a
pharmacokinetic-pharmacodynamic steady
state is achieved.
6. If an incremental dosage increase is chosen
for therapeutic management of hypothyrotic
patients, the dosage should be reduced
when the EN is discontinued.
7. Further study to ascertain the best method for
managing patients with concurrent
levothyroxine-EN is warranted.
50
Megace-ES
Vs.
PLAIN Megace?
Practical Issues For
Dietitians
Indications
FDA APPROVED:
 Megace® ES oral suspension is indicated for
the treatment of anorexia, cachexia, or an
unexplained significant weight loss in patients
with a diagnosis of acquired
immunodeficiency syndrome (AIDS)
NON-FDA-APPROVED INDICATION †
† For the treatment of anorexia, cachexia, or
unexplained weight loss in the elderly.
52
PLAIN Megace vs. Megace ES
 Plasma concentrations of Megestrol Acetate
after administration of 625 mg (125 mg/mL) of
Megace® ES oral suspension
IS EQUIVALENT UNDER FED CONDITIONS
TO
 800 mg (40 mg/mL) of Megestrol Acetate oral
suspension (see figure below).
53
EQUIVALENT under FED STATE
54
 Megace-ES 625mg/5ml
.
(Empty Stomach)
EFFECTIVE SERUM LEVEL
in UNFED Condition
= Megace 800mg/20ml (Original Formulation)
Serum level NOT EFFECTIVE
in UNFED Condition
- ES = Empty Stomach
 Megace ES has improved bioavailability
in the UNFED condition vs. original
formula Megace and
 ORIGINAL has equivalent bioavailability in
the FED condition
 The fed condition is achieved by subjects
eating a high-calorie (800-1000 calories)
and high-fat (approximately 50% of total
calories) meal.
57
FDA Definition
The fed condition is achieved by subjects
eating a high-calorie & high-fat meal.
HIGH-CALORIE (800-1000 calories)
*** Plus ***
HIGH-FAT (aprox 50% of total calories)
58
An FDA example meal
 2 eggs fried in butter
 2 strips of bacon,
 2 slices of toast with butter,
 4 ounces of hash brown potatoes,
 8 ounces of whole milk.
59
Could a resident who is not eating actually ingest
100% of this meal prior to admin of Regular
Megace suspension?
60
Assess Effectiveness
 The trial studies for the treatment weight loss
in patients with a diagnosis of acquired
immunodeficiency syndrome (AIDS) only
looked at effectiveness at 12 weeks duration.
 Use Megace-ES for 12 weeks.
 If NO or LITTLE response after 12 weeks,
then taper and then D/C
61
Serious and Otherwise Important
Adverse Reactions
 Hypersensitivity
 Pregnancy Fetal Effects
 Thromboembolic Disease
 Adrenal Insufficiency
62
WARNINGS AND PRECAUTIONS
 Use with caution in patients with a history of
thromboembolic disease
 Clinical cases of overt Cushing’s Syndrome have
been reported in association with the chronic use of
Megestrol acetate.
 In addition, clinical cases of adrenal insufficiency
have been observed in patients receiving or being
withdrawn from chronic Megestrol acetate in the
stressed and non-stressed state.
 New onset and exacerbation of pre-existing diabetes
have been reported.
63
Megace: Adverse Consequences
of DVT or PE
 Thromboembolism is of most significant
concern
 Residents of long term care who are less
mobile in general and more prone to mild
dehydration, may be at greater risk for the
these complications.
 For the clinician in the long term care setting,
a careful evaluation of risk benefit ratio must
be considered and based on the evidence to
date.
64
Advantages of MEGACE-ES
 LESS VOLUME and reduced viscosity
 Megace ES has 75% less total volume per dose




compared with Megace 800 mg/20 mL.
Megace ES is also 94% less viscous than original
formula Megace.
This may be important for patients struggling with
their ability and desire to eat.
Megace ES is substantially less viscous than some
common OTC products, including Mylanta®‡1
Lower viscosity may make Megace ES easier to
take and may be important for patients who have
trouble swallowing
65
Mirtazepine (Remeron)*
 Although commonly used for the purposes of
promoting weight gain…….
 No studies exist to date that have specifically
explored the use of Mirtazepine as an
appetite stimulant in the long term care
setting.
* D. Rudolph : Appetite Stimulants in Long Term Care: A Literature Review. The
Internet Journal of Advanced Nursing Practice. 2010 Volume 11 Number 1
66
Newest ORAL Anticoagulant
Since The Approval of Warfarin
(Over 50 Years Ago)
Practical Issues For
Dietitians
Newest ORAL Anticoagulant Since The
Approval of Warfarin (Over 50 Years Ago)
PRADAXA® (Dabigatran)
Pronounced…..
D a – bee – g´a t t – t r a n
Approved October 2010
68
PRADAXA® (Dabigatran)
THE FIRST DIRECT ORALTHROMBIN
INHIBITOR
69
PRADAXA® (Dabigatran)
Pronounced…..D a – bee – g´a t t – t r a n
USA INDICATIONS AT THIS TIME !
 Indicated to reduce the risk of stroke and
systemic embolism in patients with NON
VALVULAR ATRIAL FIBRILLATION.
ADDITIONAL INDICATION
(Approved in Canada and Europe (Only!)
 For thromboprophylaxis in patients S/P
hip and knee replacement surgeries
70
Warfarin… DISADVANTAGES
Warfarin has a long history of SUCCESSFUL clinical
use but also has many limitations to its use.
 Warfarin has an unpredictable and variable effect,
 It has a narrow therapeutic window requiring
frequent INR monitoring
 It possesses numerous food and drug
interactions, which all contribute to poor compliance
in the ambulatory setting.
71
Particularly Dangerous Drug Interactions In Long
Term Care
Compiled by AMDA American Medical Directors Association & ASCP American
Society of Consultant Pharmacists
 WARFARIN
 WARFARIN
 NSAIDS
 SULFA DRUGS
 Bactrim
 WARFARIN
 WARFARIN
 MACROLIDS
 E- mycin
 Azithromycin
 QUINALONES
 Levaquin
 Cipro
 WARFARIN
 PHENYTOIN
72
Major Advantage of Warfarin
 Warfarin has an antidote available for
patients with major bleeding,
73
Dabigatran…. Pros and Cons
MAJOR ADVANTAGE
 Dabigatran DOES NOT REQUIRE
ROUTINE MONITORING
 Few drug interactions are seen with
Dabigatran.
DISADVANTAGE
 There is no specific antidote for Dabigatran
in patients with major bleeding.
74
MECHANISM OF ACTION
 Dabigatran and its metabolites, Acyl-Gluc-u-ron-ides
(Acyl-Gluc) are competitive, DIRECT THROMBIN
INHIBITORS.
 THROMBIN (aka Serine Protease) enables the
conversion of FIBRINOGEN into FIBRIN during the
coagulation cascade…..
 Inhibition of THROMBIN prevents the development of a
thrombus.
 Dabigatran and Acyl-Gluc INHIBIT:


Clot-bound and Un-bound THROMBIN …..in addition to
INHIBITING thrombin-induced platelet aggregation
75
Pharmacokinetics
 Dabigatran is metabolized to 4 different acyl
glucuronides and both the glucuronides and
dabigatran have similar pharmacological
activity.
 Dabigatran displays dose-proportional
pharmacokinetics in healthy subjects and
patients in the range of doses from 10 to 400
mg.
76
ABSORPTION
 The absolute bioavailability of dabigatran
following oral administration is approximately
3 to 7%. (Area under the curve)
 After oral administration of dabigatran
etexilate, Cmax occurs at 1 hour postadministration in the fasted state.
77
ABSORPTION
 Co-administration of PRADAXA with a
HIGH-FAT meal …..ONLY DELAYS the
TIME to Cmax by approximately 2 hours
HOWEVER
 Has NO EFFECT ON THE ACTUAL
BIOAVAILABILITY OF DABIGATRAN
itself.
Key
Cmax = Maximum Concentration
78
DISTRIBUTION
 Dabigatran is approximately 35% bound to
human plasma proteins.
 The volume of distribution of dabigatran is 50
to 70 L.
 Dabigatran pharmacokinetics are dose
proportional after single doses of 10 to 400
mg. Given twice daily.
79
ELIMINATION
 Dabigatran is eliminated primarily in the urine
 After oral administration of radio labeled
dabigatran, 7% of radioactivity is recovered in
urine and 86% in feces.
 The half-life of dabigatran in healthy
subjects is 12 to 17 hours.
80
METABOLISM
 After oral administration, dabigatran etexilate
is converted to dabigatran by esterase
catalyzed hydrolysis to the active principal
dabigatran.
 DABIGATRAN IS NOT A SUBSTRATE
INHIBITOR OR INDUCER OF CYP450
ENZYMES.
81
ADMINISTRATION CAUTION
1. The oral bioavailability of PRADAXA increases
by 75% when the pellets are taken without the
capsule shell ………………
compared to the intact capsule formulation.
2. PRADAXA capsules should therefore NOT BE
BROKEN, CHEWED, OR OPENED before
administration.
3. PRADAXA may be administered WITH or
WITHOUT FOOD
82
CRITICAL IMPLICATIONS
DABIGATRAN is NOT APPROPRIATE
in the following situations:
 Administration via G-Tube
 In residents who have difficultly
swallowing whole capsules
83
Drug Interactions
Interacting
Drug
Dabigatran Comments
Effect
Rifampin

Ketoconazole

However, the manufacturer of dabigatran does not
recommend a dosage adjustment
Clopidogrel

However capillary bleeding times were not further
prolonged compared to clopidogrel monotherapy
Amiodarone

However, the manufacturer of dabigatran does not
recommend a dosage adjustment
Quinidine

At present, the use of dabigatran is
contraindicated with quinidine, a potent Pglycoprotein inducer
Verapamil
 Increased If
VERAPAMIL given 1
hr BEFORE
Dabigatran
Verapamil
NO change If
VERAPAMIL given 2
hr AFTER Dabigatran
However, the manufacturer of dabigatran does not
recommend a dosage adjustment
Always give Dabigatran 2 hr BEFORE
VERAPAMIL
DOSAGE AND ADMINISTRATION
 PRADAXA 150 mg by mouth TWICE daily,
with or without food.
(For creatinine clearance (CrCl) >30 mL/min)
 PRADAXA 75 mg by mouth TWICE daily,
with or without food.
(For creatinine clearance (CrCl) 15-30 mL/min)
85
Metabolic Effects of
Atypical
Antipsychotics
Practical Issues For
Dietitians
SCHIZOPHRENIC SYMPTOM
CLUSTERS
POSITIVE
SYMPTOMS
NEGATIVE
SYMPTOMS
COGNITIVE
SYMPTOMS
Suspicious
Affective flattening
Impaired alertness
Unusual thought
content
Alogia
Impaired working
memory
Delusions
Anhedonia
Inability to speak due to mental
deficiency or a manifestation of
dementia.
Absence of pleasure from the
performance of acts that would
ordinarily be pleasurable
Hallucinations
Impaired executive
function-
Avolition
Lack of motivation
Conceptual
disorganization
87
ATYPICAL Antipsychotics
COMMON SIDE EFFECTS
 Movement disorders
 HypERprolactinemia
 Sleep disorders
 Weight gain/ obesity
 Diabetes
 Cardiovascular
 Dyslipidemia
 Extrapyramidal side effects
 Cognitive effects
88
Adapted from Diepiero J 6th Edition 2005. page 1221
RELATIVE SIDE EFFECTS OF ATYPICAL
ANTIPSYCHOTICS
Brand
Generic
ANTICHOLINERGIC
ORTHO- EPS
STASIS
Abilify®
Aripiprazole
Risperdal®
Risperidone
+
+
+
++
+
++
Geodon®
Ziprasidone
Zyprexa®
Olanzapine
Seroquel®
Quetiapine
Clozaril®
Clozapine
+
++
+
++++
+
++
++
++++
++
++
+
+
+
NEGLIGIBLE
+ LOW
++
+++
MODERATE
MODERATE-HIGH
++++ HIGH
89
ADA CONSENSUS ON ANTIPSYCHOTIC
DRUGS, OBESITY AND DIABETES
Brand
Generic
Clozaril®
Clozapine
+++
+
+
Zyprexa®
Olanzapine
+++
+
+
Risperdal®
Risperidone
++
D
D
Seroquel®
Quetiapine
++
D
D
Abilify®
**
Aripiprazole
+/-
--
--
Geodon® **
Ziprasidone
+/-
--
--
WEIGHT DIABETES
GAIN
RISK
DYSLIPIDEMIA
[+] increased effect [D] discrepant results [─] no effect [ ** ] Newer Drugs w/ limited long term data
American Diabetes Assoc; American Psychiatric Assoc; American Assoc of Clinical
Endocrinologists; North American Assoc for the Study of Obesity.
Diabetes Care. 2004; 27:596
Diabetes Secondary to Atypical
Antipsychotics
 Schizophrenia has been identified as a risk
factor for diabetes Mellitus independent of
medication.28
 An increased prevalence of diabetes has
been associated with bipolar disorder.29
 End organ damage may begin 7 yrs before a
diabetes Dx. 30
91
Diabetes Secondary to Atypical
Antipsychotics
 Use of antipsychotics may be associated with a
higher risk of diabetes & glucose
dysregulation 6.17


Symptoms include fatigue, wt loss, polyuria &
polydipsia.
Risk factors may be difficult to interpret in
patients.
 Diabetes is a risk factor for cardiovascular
disease, kidney disease, retinopathy and
neuropathy.17,28
92
Weight Gain &Obesity
 Individuals with Schizophrenia or bipolar D/O
are more at risk than the general population
for weight gain & obesity. 23, 24
 Antipsychotics have been associated with
various degrees of weight gain. 17,25
 Weight gain can decrease medication
compliance. 17
93
Weight Gain &Obesity
Body Mass Index17,26
Abdominal obesity waist circumference17
= BMI (kg/m2)
Overweight BMI =25-29
Obesity BMI> 30
MEN > 102 cm (40 in)
Women >88 cm (35 in)
Management Strategies
• Monitor weight, BMI wait circumference at baseline & at
regular intervals
• Intervention recommended if BMI> 25&/or abdominal 1 BMI
unit obesity, or if INCRESE of 1 BMI unit (except if
underweight)
Selected References
6.
17.
28.
23.
24.
25.
Lahaman AF et al: Working Group on Schizophrenia. American Psychiatric Association.
Practice Guidelines for the treatment of patients with schizophrenia, 2nd edition. Am J
Psychiatry 2004;161 (suppl-2):1-56
Marder SR, et al. Physical health monitoring of patients with schizophrenia. Am J Psychol.
2004;161(8):1334-49
Canadian Database Association .Screening & prevention.2003 Clinical Practice Guideline.
Avail on the web: www.databasecalcpg2003/downloads/screenprevent.pdf
Alison DB et al. The distribution of body mass index among individuals with and without
schizophrenia. J Clin Psychiatry 1999; 60 (4):215-220
Keck PE et al. Bipolar disorder, obesity & pharmacotherapy-associated weight gain. J Clin
Psychiatry 2003:64(121) 1426-1435
Schwartz TL et al. Psychiatric medical induced obesity: treatment options. Obs. Rev.
2004:5(4);233-238
28.
Canadian Database Association: Screening and Prevention. 2003 Clinical Practice
Guidelines.
29.
Reginold WT et.al. Increased prevalence of type 2 DM among psychiatric inpatients with
Bipolar-1 affective and schizoaffective D/O independent of psychotropic drug use. J Affect
Disord. 2002 70(1): 19-26
30.
Lelter LA et.al. Diabetes Screening in Canada. DAIASCAN Study:Prevelence of
undiagnosed diabetes and glucose intolerance in family physician offices. DIABETES
CARE 2001 24(6) 1038-43
Weight gain with Antipsychotics
Greatest gain
Olanzapine (Zyprexa)
Clozapine (Clozaril)
Significant gain
Most ( Older original TYPICAL Antipsychotics)
Moderate gain
Risperidone (Risperdal)
Quetiapine (SeroQUEL)
Little or No gain
Aripiprazole (Abilify)
Ziprasidone (Geodon)
American Diabetes Association: American Psychiatric Association: American society of
Clinical Endocrinologists: North American Association for the Study of Obesity. Diabetes Care
2004: 27: 596. Gangul R. J Clin Psychiatry: 1999; 60 (Suppl 21): 20-24.
96
Metabolic Complications of Atypical Antipsychotics:
Results from the CATIE Study *
Reference
value
compared to
baseline
OLANZAPINE
QUETIAPINE
RESPERIDONE
ZIPRASIDONE
CLOZAPINE
ARIPIPRAZOLE
Zyprexa
Seroquel
Risperdal
Geodon
Clozaril
Abilify
Weight
Change lbs/
Month
2 lbs
0.5 lbs
0.4 lbs
-0.3 lbs
0.5 lbs
---
HbA1c (%)
0.4
0.04
0.07
0.1
0.1
---
13.7
7.5
6.6
2.9
13.2
0.9
9.4
6.6
-1.3
-8.2
7.3
-0.7
40.5
21.2
-2.4
-16.5
52.6
0.6
Blood
Glucose
(mg/dl)
Total
Cholesterol
*
*
(mg/dl)
Triglyceride
(mg/dl)
The CATIE TRIAL (Clinical Antipsychotic Trials of Intervention Effectiveness)
Eng J Med 2005;353:1209-1223 * Data for Clozapine & Aripiprazole are from separate sources
N
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