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Study of identification and assessment of drug-drug interactions
1Shekar
H.S., 2Dr. Chandrashekhar H.R., 1Alirezasahebdel
1. Dept. Of Pharmacy Practice, KIMS Hospital and Research Centre, VIPS,
Bangalore.
2. Dept. Of General Medicine, KIMS Hospital and Research Centre, Bangalore.
ABSTRACT
Introduction
Drug –drug interactions can be defined as pharmacological or clinical response to the
administration of drugs combination that is different from its known effects of two or more than
two medicines. It frequently conjures images of a sudden catastrophic and even fatal outcome.
While such an event can occur and it is important to prevent in the clinical set up.
Drug interactions can occur by pharmacokinetic & pharmacodynamic interactions.
The antipsychotics are known to have drug interactions compared to any other class of drugs
hence we aimed for the identification of drug interactions of psychiatric drugs..
Methodology
The data was collected from medication chart and discharge medication order of inpatient of
psychiatric department and analyzed the interactions using Stockley’s drug interactions, Dipiro
etc..
Results and Discussion
The study includes 508 samples out of which 368 case were found to have interactions. alcohol
with lorazepam accounts for 26.18% and 20.47% respectively .
INTRODUCTION
Drugs interaction is the phenomenon which occurs when the effects of one drug modified by the
prior or concurrent administration of another (or the same) drug(s). Drug interactions may arise
either from alteration of the absorption, distribution, biotransformation or excretion of one drug
by another, or from combination of their actions or effects.1
Drug-drug interactions (DDIs) occur when the presence of a co-prescribed drug (the perpetrator)
alters the nature, magnitude, or duration of the effect of a given dose of another drug (the
victim). Altered nature means that the effect produced when the two drugs are used together is
qualitatively different than would be expected when either drug is used alone. An example of
serotonin syndrome, which consists of marked autonomic instability, can be fatal. This syndrome
can occur when a serotonin uptake pump inhibitor is used in combination with a monoamino
oxidase inhibitor (MAOI).
Altered magnitude, on the other hand, means that the nature of the effect is the same as can be
reasonably expected from the victim of drug alone but is either more than or less than what
would normally be expected for the specific dose ingested.
Altered duration means that the nature of the effect is reasonably the same as can be expected
from the victim drug alone, but the effect is either shorter or longer lived than would normally be
expected for the dose given.2
DDI can be a consequence of various situations that reflects the growing number of drugs
available in the market increasing complexity of polytherapy and the very widespread practice of
self-medication makes the situation more severe and difficult. Most of the studies evaluated,
analysed and estimated that drug interactions may affects up to 63% of all hospitalized
patients.3,4,5 These may occur due to several reasons. For example, accidental misuse or younger
people tend to metabolize drugs faster than older people or those who smoke the cigarettes
metabolize clonazepam and olanazapine faster than those who do not. Co-morbid medical
conditions that decreases the hepatic functions, such as cirrhosis or congestive heart failure, are
likely to decrease the rate of drug metabolism. CytochromeP450 enzymes are polymorphic; there
exist ethnic differences in hepatic enzymes that influence the pharmacokinetics of drugs and also
due to lack of knowledge about the active ingredients involved in the relevant substances.
Drug interactions are to be avoided, due to the possibility of poor or unexpected outcomes. A
contemporary example of selective serotonin reuptake inhibitors (SSRIs) inhibits the metabolism
of tricyclic antidepressants (TCAs) toxicity. (fluoxetine and imipiramine), Co-administration of
SSRIs and mono amino oxidaze inhibitors (MAOIs) causes severe depression, Combination of
SSRIs with pimozide or Tramadol hydrochloride causes seizure and hepatic failure. SSRIs with
lithium, diuretics and CNS depressants increases the toxicity and NSAIDS interferes with SSRIs
decreases its efficiency.6
Drug-drug interactions (DDIs) are a concern for the prescriber because they have the potential
for causing untoward outcomes for everyone involved, morbidity and even
mortality for the patients, liability for the prescriber and increased costs for the healthcare
system. The risk of unintended and untoward DDIs is increasing in concert with both the
increasing number of pharmaceuticals available and the number of patients on multiple
medications. Health and Human Services research in the year of 2004 reports around 7% of
Americans more than 18 years of age and more than 20% of Americans more than 65 years of
age had taken 5 prescriptions medications in a week preceding the survey.
Many studies have found that patients on psychiatric medications, such as antidepressants, are on
more medications than patients not on psychiatric medications. It is important for prescribers to
appreciate that medications interact not on the basis of their therapeutic use but on the basis of
their pharmacodynamic and pharmacokinetic characters. For these reasons, the prescriber must
consider all the medications prescribed and the patient consuming, this educational review
emphasizes the role of pharmacologic principles to guide the safe and effective use of multiple
medications when such use is necessary.2
IMPORTANCE OF DRUG-DRUG INTERACTIONS
It is easy to understand the occurrence of DDIs and can mimic virtually any clinical presentation
imaginable from catastrophic to the everyday problems seen in practice.
DDIs can present in the following ways:
A multitude of different types of serious adverse events (SAEs), such as sudden death,seizures,
cardiacrhythm disturbances, serotonin syndrome, malignant hypertension, neuroleptic malignant
syndrome, and delirium. 7-17 Poor tolerability (ie, patients ―sensitive‖ to adverse drug effect )1822
Lack of efficacy (ie, patient is ―resistant‖ to beneficial drug effect) 23 Symptoms that mimic
or lead to a misdiagnosis of a new disease 24-26 The apparent worsening of the disease being
treated. 18-20 Withdrawal symptoms or drug-seeking behavior on the part of the patient.6
The term DDI frequently conjures images of a sudden catastrophic and even fatal outcome.
While such an event can occur and is important to prevent, DDIs can present as virtually
anything, including the worsening of the illness being treated or the emergence of a new illness.
For this reason, such ―masked‖ DDIs can ironically lead to the use of more medications to treat
the apparent worsening of the primary condition or to treat the apparent emergence of a new
condition.
As psychiatric drugs are more rationally developed to affects brain, their adverse effects will not
be on peripheral systems. Thus, the result of psychiatric DDIs could present as changes in
mentation, reality testing, emotional control, inter-personal relationships and memory function.
The prescribers must be a good behavioral pharmacologist as well as a good diagnosticians and
must also keep in mind that changes in these outputs of the human brain may be because of the
medications that the patients receiving rather in spite of them.27
Guide to Psychiatric Drug Interactions
The prescriber should be aware of generic names of medications of their personal formulary,
without which it is impossible to search the medical literature on them. As medicine becomes
more international and the world becomes smaller, the physician must be aware that medications
have different brand names in different countries and frequently have multiple brand names. The
use of generic drugs decreases total count of the patients when they are available, Despite claims
to the contrary, there are only a small number of examples where an approved generic drugs are
not an effective sub- stitutes for the brand name drug.28
Special Considerations for How DDIs Present in Psychiatric patients
All drugs, except anti-infectives, are administered to change human physiology. 29 Those changes
can present in every way clinically imaginable. For this reason, the prescriber should keep in
mind that the patient may not be doing well because of the medications he is receiving rather
than despite the medications receiving.30 Understanding and identifying DDIs with psychiatric
medications is perhaps more challenging than in any other area of medicine. The reason is
complexity of the organ they affect and its output. 31
Every identified neurotransmitter has 2-17 receptor subtypes. Thus, the human brain may contain
thousands of receptors, which are the primary targets of drug action. There are different enzymes
for the synthesis and degradation of these neurotransmitters, different uptake pumps and storage
mechanisms. These regulatory proteins can be the target for drug action. Thus, current drugs may
interact pharmacodynamically in ways that are neither understood nor predictable at the present
time. 32 Their detection is dependent on the careful assessment at the time of a medication
prescribed by the prescriber.28
Mechanism of drug-drug interactions
Two types of mechanism:
1-Pharmacodynamic interactions
2-Pharmacokinitic interactions.
Drugs are approved and generally considered from the perspective of their therapeutic use;
however, they interact on the basis of their pharmacodynamics and pharmacokinetic properties.
They are frequently used for reasons other than their initial labeled indication. For example,
selective serotonin reuptake inhibitors were initially approved as antidepressants, but several
have subsequently gained approved labeling for the treatment of a variety of anxiety disorders.2
Pharmacodynamic DDIs
Number of neuropsychiatric medications including tertiary amines and atypical antipsychotics
affect more than one mechanism of action under clinically relevant dosing conditions. For
example, quetiapine binds most avidly to the α1-adrenergic receptor and binds almost as avidly
to the histamine H1-receptor33-36, but requires 23-fold increase in dose to bind to the dopamine
D2 receptor That indicates why do low doses of quetiapine can be used for sedative effects and
higher doses are needed for antipsychotic efficacy. For the same reason, quetiapine can have the
same pharmacodynamic DDIs as other potent H -receptor antagonists even though those other
drugs might not have any efficacy as an antipsychotic medication.2
Pharmacokinetic DDIs
These outline potential CYP enzyme-mediated DDIs. Parenthetically, CYP-mediated DDIs are
the most common, clinically meaningful type of pharmacokinetic DDIs. 37-38
The chelation of drugs in the gastrointestinal tract formed by iron salts prescribed to treat anemia
or by antacids with high aluminum content; interactions that occur prior to the administration of
intravenous (IV) drugs due to the incompatibility of IV solutions;
interaction with drug-secreting transporters that line the renal tubules and the blood-brain barrier
(eg, lithium intoxication due to co-administration with ibuprofen and possibly other nonsteroidal
anti-inflammatory drugs); and nutritional interactions that deplete the cofactors required for the
phase II metabolism of some drugs (ie, reduced acetylation and glycosylation due to persistent
hypoglycemia or clinically significant malnutrition).33
potential mechanisms underlying pharmaceutics‘ drug-drug interactions are Protein binding/
Phase I enzymes / CYPs and non CYPs / Phase II enzymes / ABC transporters / Nuclear
receptors. 33
METHODOLOGY
The 508 patients who have fulfilled study criteria were included for the study, among which 200
patients were from psychiatric in patient department and 308 were from MRD, the data was
collected form the discharged case notes at KIMS hospital and research centre. The study was
conducted for a period of 9 months. The data was collected from medication chart, discharge
patients medication order, Patient attenders. The patients who are admitted to psychiatric
department with the clinical conditions and treated with two or more than two drugs and fulfils
study criteria at KIMS Hospital and research centre. Patient discharge against medical advice.
Patients who disagree with consent form
MATERIAL AND METHODS:
A prospective study is conducted on inpatients of psychiatric department at KIMS hospital &
research center who have fulfilled inclusion criteria and on therapy. The patient consent form is
taken from the patient care taker. The Medical records, case sheets of patients is reviewed and
the drug data was collected. Any identified DDIs assessment was done for their mild, moderate
and severity of reactions and analyzed the mechanism and time of onset of DDIs using recourses
like Stockley‘s drug drug interaction, patient drug facts etc.
Ethical clearance was obtained from the ethical committee and submitted to RGUHS before
starting the study.
RESULTS
The work illustrate the drug drug interactions at psychiatric depatment in kims hospital and
research centre, Bangalore. Around 508 patients were included for the study, among this 368
patients were found to have drug interactions in 17 different forms has been observed as shown
in the table-1 and figure-1.
SERIAL
NO
NAME OF
DRUG
DRUG
INTRACTION
WITH
DDRU-DRUG INTERACTION
NUMBER
OF THE
PATIENT
OUT OF
508
26
PERCENTAGE
OUTCOME
%
1
CHLORDIA
ZPOXIIDE
DISULFIRAM
CHLORDIAZPOXIDE
+DISULFIRAM=INCREASE SERUMLEVEL
OF CHLORDIAZPOXIDE AND CAUSE
DROWSNESS (STOCKLY’S DDLs PAGE
725)
2
PANTAPRAZOL
3
INJ
NEUROBIO
N/VIT B12
ALCOHOL
VIT B12+PANTAPRAZOL=DECREASE EFFECT
OF VIT B12
133
26.18%
LORAZPAM
ALCOHOL+LORAZEPAM=AGGRESION/ANXIE
TY/AMNESIA/IMPAIRED
PERFORMANCE(STOCKLY’S DDLs PAGE 53)
ALCOHOL+CLONAZPAM=POOR
CONCENTRATION/DIZZINESS/SEXUAL
DISFUNCTION DIPIRO PAGE 1302
104
20.47%
4
ALCOHOL
CLONAZPPAM
1
0.19%
5
ALCOHOL
olanzapine
POSTURAL HYPOTENSION
DROWSNESAS/INCREASE HEART
RATE/CNS DEPPRESION (STOCKLY’S DDLs
PAGE 72)
ALCOHOL+DISULFIRAM=FLUSHING
&FULLNESS OF THE
FACE/TACHYCARDIA/BRADYCARDIA/GID
DINESS/HYPOTENSION (STOCKLY’S DDLs
PAGE 61)
3
0.59%
6
ALCOHOL
DISULFIRAM
6
1.18%
7
ALCOHOL
QUITIPIN
ALCOHOL +QUITIPIN=POSTURAL
HYPOTENSION&DROWSNESS(STOCKLY’S
DDLs PAGE 76)
1
0.19%
9
ALCOHOL
NSAIDs
MAY INCREASE GIT
HAEMORHAGE(STOCKLY’S DDLs PAGE 71)
1
0.19%
10
OLENAZPI
LORAZPAM
OLANAZPINE+LORAZPAM=ADDITIVE
31
6.10%
5.18%
NE
11
TOXICITY OF LORAZPAM/CNS
DEPPRESION/SEIZURE/HF/STROKE
(STOCKLY’S DDIs page 756)
DIVALPOR
AX
SODIUM(V
APORIC
cid)
DIVALPOR
AX
SODIUM(V
APORIC
cid)
DIVALPOR
AX
SODIUM(V
APORIC
cid)
DIVALPOR
AX
SODIUM(V
APORIC
cid)
RISPERIDO
N
LORAZPAM
DIVALPORAX+LORAZEPAM=INCREASE
LORAZPAM CLEARANCE AND DECREASE
THE VALPORIC ACID CLEARANCE
HF/STROKE (STOCKLY’S DDLs PAGE 719)
10
1.96 %
OLENAZPINE
DIVALPORAX+OLANAZPINE=ADDITIVE
TOXICITY /TACHY
CARDIA/AGITATION/COMADYSTHERMIA(
STOCKLY’S DDLs PAGE 719 )
7
1.37%
CLONAZPAM
DIVALPORAX+CLONAZEPAM=INCREASE
CLONAZPAM CLEARANCE AND
DECREASE THE VALPORIC ACID
CLEARANCE(STOCKLY’S DDLs PAGE 719)
11
2.16%
RISPERIDON
VALPORIC ACID + RESPERIDON =
OEDEMA (STOCKLY’S DDLs PAGE 767)
4
0.78%
HALOPERIDOL
REPERIDONE + HOLOPERIDOL=NEUROLEPTIC
MALIGNANT SYNDROM(STOCKLY’S DDLs PAGE
755)
19
3.70%
16
RISPERIDO
N
FLOUXETIN
RESPERIDON+FLOUXETIN=
AKATASIAPAINFUL BILATERAL BREAST
ENLARGMENT/OBSSESIVE AND
COMPULSIVE DISORDER/SEDATIVE AND
CONSTIPATION(STOCKLY’S DDLs PAGE
766)
7
1.37%
17
BUPRION
HALOPERIDOL
BUPRION INCREASE PLASMA LEVEL OF
HALOPERIDOL(STOCKLY’S DDLs PAGE
1206)
1
.019
18
FLOUXETIN OLENAZPINE
FLOUXETIN+OLENAZPINE=SEROTONIN
SYNDROM(STOCKLY’S DDLs PAGE 754)
3
0.59
12
13
14
15
30
26.18
percentage
25
20.47
20
15
10
5
5.8
0.19
6.1
3.7
2.16 1.37
1.96 0.781.370.59
0.19 0.19 0.59 0.19 1.18
0
DISCUSSION
26 patients were treated with Anxiolytics (chlordiazpoxide) with antidotes and detoxifying agent
(disulfiram), accounts for 5.18 % of drug drug interactions by increasing concentration of
Chlorodiazapoxide and causes drowsiness .
Antipsychotics(Bioprion) with antidotes/detoxifier is given to one patient out of 508 patients
acoounts for 0.19 % of DDIs and Buprion is reported to increase plasma concentration of
haloperidol .
Out of 368 patients 133 patients drug interactions were between cobalamine and proton pump
inhibitors which accounts for 26.18 % of the total sample size. Pantaprazole was found to
decreases the effects of vitamin B 12 .
Alcohol and anxiolytics / anticonvulsants were prescribed for 105 patients, accounts for 20.66 %
of drug interactions. Out of 105 cases 104 patients wereprescribed with alcohol+lorazepam
causes aggression/anxiety/amnesia/impaired performance accounts for 20.47 % and 1 patient
was treated with alcohol+clonazpam which causes poor concentration/dizziness/sexual
dysfunction accounts for 0.19 % drug interaction .
The combination of Alcohol and analgesics prescribed to one patient accounts 0.19 % of drug
interaction which increases gastrointestinal hemorrhage.
The combination of Alcohol and antipsychotics were prescribed for 4 patients, out of 508
patients, accounts for 0.78 % of drug interactions and Causes postural hypotension, drowsiness,
increased heart rate and CNS depression. 3 patients were prescribed with olenzapine with alcohol
causes postural hypotension, drowsiness/increased heart rate/CNS depression accounts 0.59% of
drug interactions and one patient was treated with alcohol and quitipin which accounts 0.19% of
interaction, causes postural hypotension & drowsiness .
The administration of Alcohol with antidotes/detoxifiers (disulfiram) prescribed for 6 patients,
accounts 1.18 % of drug interactions and causes flushing & facial puffiness, tachycardia,
bradycardia, giddiness and hypotension .
The combination of antipsychotics /anticonvulsants with anxiolytics /anti convulsants were
prescribed with 52 patients, which accounts 10.22 % of drug interactions. Among 52 patients 31
patients were with olanazpine+lorazpam which causes additive toxicity of lorazpam, CNS
depression, seizures, stroke accounts 6.10% of interactions. Ten patients were prescribed with
valproic acid +lorazepam which causes increased lorazpam clearance and decreases the valporic
acid clearance, which account for 1.96 % of drug –drug interaction. The 11 patients were treated
with valproic acid +clonazepam accounts for 2.16% causes increased clonazpam clearance and
decreases valproic acid clearance accounts 2.16 % of drug interactions.
The co-administration of Antipsychotics /anticonvulsants with antipsychotics were prescribed for
30 patients out of 508 patients accounts 5.85% of total DDIs. the 7 patients were treated with
valproic acid and olanzapam which accounts for 1.37% of DDIs, causes additive toxicity,
tachycardia, agitation, comadysthermia and 4 patients were treated with valproic acid and
risperidon which causes edema accounts for 0.78 % of DDIs and 19 patients were treated with
risperidone and holoperidol which causes neuroleptic malignant syndrome accounts 3.70 % of
drug- drug interactions .
The co-administration of Antipsychotics /anticonvulsants with antidepressants were 10 patients
out of 508 cases accounts for 1.96 % of DDIs. The 7 patients were treated with risperidon and
flouxetin which causes akatasia, painful bilateral breast enlargement, obcessive and compulsive
disorder. Three patients were prescribed with sedatives and constipation accounts 1.37% of
(flouxetin+olenazpine) drug drug interactions causes serotonin syndrome .
CONCLUSION
Drug drug interactions are more serious around the world, to be avoided unintended and
untoward DDIs. The prescriber must understand the fundamental principles of pharmacology and
good clinical practice and must follow the knowledge of the pharmacokinetic and
pharmacodynamic characteristics of the drugs prescribed to patients. This educational review has
addressed these principles summarizing the major pharmacodynamic and pharmacokinetic
interactions affecting and/or caused by commonly used neuropsychiatric medications.
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