FACULTY OF PHARMACY

Research Proposal

NMRR ID: NMRR-16-638-29903

TITLE OF RESEARCH PROPOSAL:

A Study of Psychoactive Medicines and Risk of Falls among Malaysian Elderly in

Hospital Tuanku Ja’far

Name of principal researcher : Dr. Izyan Abdul Wahab*

Name of co-researcher(s) : Assoc. Prof. Dr. Zainol Akbar Zainal*
Prof. Datin. Dr. Rosnani Hashim*
Nurdiana Jamil*
Nabilah binti Mohd Nasir*
: Mohd Farizh Che Pa**
: Pn. Basariah binti Naina**
Name of institution : *Faculty of Pharmacy, Cyberjaya University College of
Medical Sciences, Malaysia
: **Jabatan Farmasi, Hospital Tuanku Ja’far, Seremban,
Malaysia
Introduction / Background to the Study

Psychoactive medicines are substances that can alter mood, thought processes, or
behaviour by causing sedation, hypnosis and muscle relaxation [1-3]. Some of these
medicines are approved to treat anxiety, insomnia, depression and other related central
nervous system diseases. Examples of psychoactive medicines with sedative properties
that are approved for treatments are antipsychotics (chlorpromazine and thioridazine),
hypnotics and sedatives (alprazolam and amobarbital), anxiolytics (clonazepam and
diazepam) and anti-epileptics (gabapentin and lamotrigine).

Studies have shown that psychoactive medicines with sedative properties can
cause adverse effects such as fall [4]. Fall is one of the major public health problems
among elderly people and is the leading cause of injury and death [5-7]. In one study
undertaken in Netherlands, approximately 30% to 70% of nursing home residents fall at
least once a year [8]. Although there are various factors that led to falls, medication use is
one of the important risk factors for falls in elderly people and is considered as
potentially modifiable risk factors [6, 10].

Studies have shown that psychoactive medicines are commonly prescribed for the
elderly [6]. In one meta-analysis study, it is stated that the multiple use of psychoactive
medicine increases risk of falls that resulting in hospitalisation [11]. There are limited
information regarding the use of psychoactive medicines and its association with falls in
Malaysian elderly. The only study that was undertaken in Malaysia is to determine the
fall risk factors among Malaysian older adults [5].This study found that the strongest
predictor that contributed to the high level of fall risk was medical condition (OR 10.63;
95% CI 1.617- 69.950) instead of medication (OR 0.609; 95% CI 0.221 – 1.682). The
study however did not investigate types of medications that lead to fall risk among the
elderly. Thus, this study is an attempt to identify the association between use of
psychoactive medicines and risk of falls among elderly in Malaysia.

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Literature Review

Geriatrics/Elderly

Elderly is an age group of people that is not easy to define precisely [12]. Older
people or older adult is sometimes preferred but is equally imprecise and > 65 is the age
often used. In developed country, the elderly is at the age of 65 and over because the
economic status, education and health status is higher compared to developing country
[13]. Meanwhile, the age of elderly in developing country such as Malaysia is 60.

Geriatrics and gerontology refer to fields of study related to aging and older
adulthood [14]. Geriatrics is the branch of medicine specializing in the medical care and
treatment of the diseases and health problems of older adults. Gerontology is the study of
the biological, behavioral, and social phenomena that occur from the point of maturity to
old age. In other terms, geriatrics applied to the study of the disease-related aspects of
aging, while gerontology refers to the study of healthy older adults.

Globally, the number of older people (aged 60 years or over) is expected to be

more than double, from 841 million people in 2013 to more than 2 billion in 2050 [15].
Another statistics shown that in the year around 1900 in the US, people who are more
than 65 accounted for 4% of the population, but now, they account for more than 13%
which is about 40 million [16]. In 2026, estimates suggest that more than 20% which is
almost 80 million will be more than 65. In Malaysia, the senior citizens aged 60 and
above made up 2.8 million or 9% of Malaysia's population of 31 million in the year of
2015 [17]. The National Statistics Department projected that Malaysia will be expected to
reach ageing nation status by 2035 when senior citizens make up 15% or 5.6 million of
its population. Consistent with the statistics, it illustrates that the elderly is increasing in
number and the need to increase health concern among this population is really crucial.

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Geriatric Health

The elderly is unique and not same as the young people. This is because they
often have multiple medical problems, different patterns of disease presentation, often
slower response to treatment and requirements for social support [18]. “Geriatric Giants”
is a term created by Bernard Isaacs, is refers to the principal chronic disabilities of old
age that impact on physical, mental and social domains of older adults [19]. The other
term which is also known as 5 I’s are the expression for incontinence, immobility,
instability, intellectual impairment and iatrogenic. There are actually a lot more I’s such
as infection, impotence, impaired vision and hearing as well as insomnia.

Incontinence means a condition of involuntary loss of urine because of smaller

bladder capacity and greater night time glomerular filtration rate (GFR). In males, the
urethra is obstructed by the prostate gland while in females the urethra may be
traumatised by frequent pregnancies. Immobility is the impairment of the ability to move
independently which results in the limitation of life space. Whereas, instability or fall
defined as a subject unintentionally coming to rest on the ground, not as a result of a
major intrinsic event or overwhelming hazard. Intellectual impairment or focus on
dementia is a syndrome in which progressive deterioration in intellectual abilities is so
severe that it interferes with the person’s usual social and occupational functioning. Last
but not least is iatrogenic which is closely related to medication intake; polypharmacy
and adverse drug reactions (ADR) in elderly.

Instability (Falls)

The definitions of falls are varying between studies and there is no specific
operational definition of fall yet [20, 21]. Most studies characterised the fall to be
‘unintentional’ and in the form of contact with the ground and most studies have also
excluded falls caused by road accidents and violence [20]. As stated in WHO Global
Report on Falls Prevention in Older Age 2008, falls are generally defined as
“inadvertently coming to rest on the ground, floor or other lower level, excluding
intentional change in position to rest in furniture, wall or other objects” [21]. Other

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definition by Kellogg International Work Group, a fall is an “event which results in a
person coming to rest inadvertently on the ground and other than a consequence of the
following: loss of consciousness, sudden onset of paralysis, or epileptic seizure” [22].
Besides, falls are coded as E880-E888 in International Classification of Disease-9 (ICD-
9), and as W00-W19 in ICD-10, which include a wide range of falls including those on
the same level, upper level, and other unspecified falls [21, 23].

Falls in elderly are a major health problem that can cause morbidity and mortality
[24]. It is expected that one in three persons over the age of 65 is likely to fall at least
once each year [25]. According to Ferri, the incidence of falls among community-
dwelling older adults is 30% to 40%. Two thirds of falls in the community are
preventable; 6% to 7% of these falls result in fracture. The incidence of falls for nursing
home and hospitalized older adults is three times the rate of community-dwelling older
adults. Over 50% of nursing home residents fall during their stay [23]. In another study
conducted by Rubenstein and Josephson, in community dwelling older adults, the annual
mean of falls is 34% (range 30-60%) and the incidence rate of falls is 0.7 per person per
year. Meanwhile, in institutionalized older adults, the annual mean of falls is 43% (range
16-75%) with the incidence rate of 1.4 falls per person per year in hospital setting [26].
Moreover, a study was conducted in primary care clinic in Kuala Lumpur, Malaysia to
determine the prevalence and patterns of falls in community dwelling older people. A
total of 151 respondents showed that the prevalence of falls was 47% with 57% reported
experiencing recurrent falls [27].

Falls were found to be a leading cause of injuries, hospitalisation and deaths

among the elderly [28]. 61% of older people who fell sustained an injury and most
required medical attention [29]. In consequences, the healthcare cost for the elderly
would also increase. According to Stevens et al, direct medical care costs was $0.2 billion
for fatal and $19 billion for non-fatal fall related injuries among people aged < 65.
Surprisingly, fractures were both the most frequent (n=0.9 millions) and most expensive
($12 billions) type of non-fatal injury in USA in the year of 2000 [27].

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 Multiple risk factors such as intrinsic and extrinsic factors contributed to the
increment of fall rates. The intrinsic factors can be such as medical condition, sensory
deficit, mobility limitation and age [5]. According to Todd C and Skelton D. (2004) in
their article entitled What are the main risk factors for falls amongst older people and
what are the most effective interventions to prevent these falls?, they mentioned the types
of medical conditions that predispose to risk of falls. They are circulatory disease,
chronic obstructive pulmonary disease (COPD), depression and arthritis. The prevalence
of fall increases with rising chronic disease burden. In addition, thyroid dysfunction,
diabetes and arthritis also increase risk of falls [33]. For the extrinsic factors which also
known as environmental hazards, the risk factors for falls are slippery flooring, poor
lighting as well as the unstable ground surface [5]. Medication use which can be
categorized as intrinsic factor [5] is an important risk factor for falls in older people [11].
Moreover, medication use is also considered as one of the most easily reversible risk
factors for falls [11] and medicines review is suggested in most guidelines for the
prevention of falls in elderly [8, 30].

Medicines Used in Geriatrics

According to a study that was conducted in the western country, about 38% of the
elderly consume prescribed medications. Elderly in community consumes about 4.5
medications while in the nursing homes setting, more than 7 medications are consumed
[18]. Usually, they have multiple co-morbidities and hence, more medications are
prescribed. The commonly prescribed drugs for elderly are non-steroidal anti-
inflammatory drugs (NSAIDs), antihypertensives, and anticholinergics but antipsychotics
are the most prescribed. Table 1 below shows some drugs that contribute to risk of falls.

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 Table 1: Some Drugs That Contribute to Risk of Falls

Drugs Mechanism
Aminoglycosides Direct vestibular damage
Analgesics (especially opioids) Reduced alertness or slow central
processing
Antiarrhythmics Impaired cerebral perfusion
Anticholinergics Confusion/delirium
Antihypertensives (especially vasodilators) Impaired cerebral perfusion
Antipsychotics Extrapyramidal syndromes, other
antiadrenergic effects
Diuretics (especially when patients are Impaired cerebral perfusion
dehydrated)
Loop diuretics (high-dose) Direct vestibular damage
Psychoactive drugs (especially Reduced alertness or slow central
antidepressants, antipsychotics, and processing
benzodiazepines)

Source: Merck Manual, Falls in the Elderly 2013

Prevalence of Psychoactive Medicines Used

In a Netherland nursing home study, Sterke et al found the prevalence of

psychoactive medicines used [8]. In the group of anti-psychotics, the most common drugs
used are haloperidol (13.3% of person-time) and pipamperone (17.0% of person-time).
For anxiolytics, the most prevalent drug used was oxazepam (19.3% of person-time).
Meanwhile, temazepam (13.0% of person-time) was the most prescribed hypnotic drug
and citalopram (8.2% of person-time) which is a member of selective serotonin reuptake
inhibitors (SSRIs) was the most prescribed antidepressant.

Another study which is conducted in the day clinic of the department of geriatric
medicine of the Academic Hospital Utrecht, Netherlands showed that short acting
benzodiazepines and hypnotics were the most common psychotropic medications
prescribed with 18.6% number of users [31]. This percentage was followed by
antidepressants with 18.3% number of users. The least percentage number of users was
3.0% which is for anti-dementia medications.

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Association between psychoactive medicines used and hospitalization for falls.

A study conducted by Pratt et al showed a significantly increased risk of falls

when patients were on one or more psychoactive medicines per day [6]. The incident rate
ratios (IRRs) were 1.22 (95 % confidence interval [CI] 1.08–1.38) for those on one
psychoactive medicine, 1.70 (95 % CI 1.45–1.99) for those on two, 1.96 (95 % CI 1.58–
2.43) for those on three or four, and 3.15 (95 % CI 1.90–5.23) for those on five or more.

A similar result was observed when the data were analysed by dose, with the
highest risk being found for those taking three or more DDD per day (adjusted IRR 4.26,
95 % CI 2.75–6.58).The DDD is the assumed average maintenance dose per day for a
drug used for its main indication in adults [9].

Sterkeet all found significant dose-response relationships for the use of

antipsychotics (hazard ratio [HR], 2.78; 95% confidence interval [CI], 1.49-5.17),
anxiolytics (1.60; 1.20-2.14), hypnotics and sedatives (2.58; 1.42-4.68), and
antidepressants (2.84; 1.93-4.16) [8]. Fall risk increased significantly with 28% at 0.25 of
the defined daily dose (DDD) of an antipsychotic or antidepressant, with 8% at 0.2 of the
DDD of an anxiolytic, and with 56% at 0.5 of the DDD of a hypnotic or sedative; it
increased further with dose increments and with combinations of psychotropics. Even at
low dosages, psychotropic drugs are associated with increased fall risk in nursing home
residents with dementia.

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PROBLEM STATEMENT

Studies have been conducted in Western countries to evaluate the prevalence of

use of psychoactive medicines in elderly. The results showed there is significantly
increase risk of falls when patients were on one or more psychoactive drugs.

As Malaysia will reach ageing population in 20 years ahead, there will be more
people aged 60 years and older [32]. Recognizing falls as a public health problem is still
low in developing countries. There is still lack of information and study regarding the use
of psychoactive medicines in elderly of this country and its association with falls. Hence,
this study is conducted as an attempt to provide the information regarding to both
statements. If the result shows is significant, the authorities or related personnel or body
can find solutions to encounter these problem.

Significance/Rational of the study

The findings of the study will provide an evidence-based data regarding the
prevalence of use of psychoactive medicines in elderly and its association with falls in
Malaysia. Preventive measures can be taken if the result is significant. This can give a
contribution to the geriatric care in Malaysia.

Study Aim

The purpose of this study is to find out about psychoactive medicines and its
association with falls in elderly as medications related can be a potentially modifiable
risk factor for falls.

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Objectives

Main Objective

1) To investigate the magnitude of use of psychoactive medicines among Malaysian

elderly.

Specific Objectives

1) To evaluate the prevalence of psychoactive medicines used in hospitalized elderly

patients.

2) To identify the association between psychoactive medicines used and

hospitalization for falls in Malaysian elderly.

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METHODOLOGY

Study Design and Setting

The study will be conducted as a retrospective, cross-sectional study using
medical record data from 1st July 2015 until 31st December 2015 (6 months). Patients
who were admitted to geriatric ward of Hospital Tuanku Ja’far (HTJ) will be chosen.
The medical record data contains details of patient particulars, reason for
hospitalization and all prescription medications. All medicine will be classified as either
psychoactive medicine with sedative properties or not. List of psychoactive medicine
with sedative properties can be found in Appendix B.

Sampling Method
Convenient sampling with completed medical record in 6 months (1st July 2015 –
31st December 2015) will be used in this study. The medical record contains all
information on the demographic profile, cause of hospitalisation and medications intake
for a single patient. Our sample would be geriatric patients who were admitted in the
geriatric ward for any diagnosis from 1st July 2015 until 31st December 2015. For a
patient who had more than one admission would be count as one sample. Our sample
would be based on number of patients but not number of admissions. We would count the
number of admission or hospitalisation as a separate event. Figure 1 shows how we
planned our design for selection of sample of an individual patient.

Figure 1: Design for selection of sample of an individual patient.

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Sample size determination
Sample size = Z2 x (p) x [(1-p) / C2] where,
Z = Z value (e.g.: 1.96 for 95% confidence interval)
P = percentage picking a choice, expressed as a decimal (0.5 used for sample size
needed)
C = confidence interval
Sample Size = [(1.96)2 x (0.5) x (1-0.5)] / (0.05)2 = 384.16
Corrected sample size for finite population = Sample Size / [1 + (SS – 1) / Estimated
Population]
= 384.16/ (1 + (384.16 – 1) / 200)
= 131.75
≈ 132
 The actual value of the estimated population will be obtained from Geriatric
Department of Hospital Tuanku Ja’far.

Inclusion and Exclusion Criteria

The following are inclusion and exclusion criteria for patients eligible to be
included in this study.

Inclusion criteria:
1. Hospitalized patient who is > 60 years old.
2. Completed medical record in 6 months (from 1st July 2015 until 1st December
2015) including demographic profile, cause of hospitalization and medications
intake.
3. Patient who is admitted to Geriatric Ward in Hospital Tuanku Ja’far.

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These patients will be excluded from further analysis.

Exclusion criteria:
1. Hospitalized patient who is < 60 years old.
2. Incomplete medical record in 6 months (from 1st July 2015 until 1st December
2015) including demographic profile, cause of hospitalization and medications
intake.
3. Elective hospitalization for surgery and investigation.

Patient Involvement

As this is a retrospective study, no patient were involved in setting the research

question or the outcome measures, nor were they involved in developing plans for design
or implementation of the study. No patients were asked to advice on interpretation or
writing up of results. There are no plans to disseminate the results of the research to study
participants or the relevant patient community.

Data Extraction

All relevant data will be collected from the medical record unit. These data
include patient’s demographic profile, reason for hospitalisation and all prescription
medication. All of this data will be recorded in a Data Collection Form that is attached in
Appendix A.

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Data Analysis

Descriptive analyses for demographic data will be undertaken. The baseline

demographic characteristics of the study would be age, gender, number of medicines
used, number of hospitalisations (for any diagnosis) in the 3 months prior the study and
number of co-morbidities.
The prevalence of psychoactive medicines will be quantified over the period of 6
months which is from 1st July 2015 until 31st December 2015. It will be calculated by
using the formula:

Number of patients with psychoactive medicines with sedative properties x 100

Number of patients within the specified period

Multivariate analyses will be undertaken to determine the predictors of

hospitalization for falls including patient’s demographic data (age, disease condition, and
gender), intake of psychoactive medicine with sedative properties before hospital
admission.
All analyses will be undertaken using STATA Version 20.

Limitation of the Study

There would be few limitations on this study. Firstly would be the sample
selection. We only choose patients who were admitted in the geriatric ward, although we
notice that some elderly patients who had fall might be admitted to orthopaedic ward as
well as medical ward. This is a preliminary study of medications and medical conditions
that could lead to fall in geriatric patients. Future study will be expended to include
geriatric patients in other wards.

Secondly, we only choose patients who are hospitalised only and not the one who
also fall at the community or in the nursing homes or their own home. This is because, in
this study we are dealing with severe cases of fall only and we assume that persons who
fall and not being admitted to the hospital might have mild or moderate fall severity. It
might be impossible to identify all elderly people who fall at homes without actually
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going to hospital. Hence, the outcome of this study might underestimate the real situation
which will fall under limitation of this study.

Ethical approval of the study

All aspects of the study protocol will be reviewed and authorized by National
Medical Research Register (NMRR)and Clinical Research Centre (CRC) Hospital
Tuanku Ja’far, Malaysia.

Gantt Chart/Research Timeline

Month Feb March April May June July Aug Sept Oct Nov Dec Jan Feb
‘16 ‘16 ‘16 ‘16 ‘16 ‘16 ‘16 ‘16 ‘16 ‘16 ‘16 ‘17 ‘17

Activity
Choosing
research
topic
Meeting
with
supervisor
Literature
review
Research
proposal
Ethics
approval &
permission
for data
collection
Research
proposal
presentation
Data
collection
Data
analysis
Thesis
writing
Viva
presentation
Preparing
manuscript
for
publications

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Appendix A

Study no.: ………..…………

A. Demographic Data
1. Patient’s age
2. Gender o Male
o Female
3. Ethnicity o Malay
o Chinese
o Indian
o Others:
4. Nationality o Malaysian
o Others:
5. Date of admission o ___ / ___ / 2015
6. Date of discharge o ___ / ___ / 2015
7. Days in the ward o ___ days
8. Reason of hospitalisation
(current)
9. Diagnosis

10. Number of hospitalisation (for

any diagnosis) 3 months prior
to the study
11. Co-morbidities &
Number of co-morbidities

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 12. History of fall o Yes. Specify: ……………….
(within 10 years) o No
13. History of confusion o Yes. Specify: ……………….
(within 1 year) o No
14. History of fracture o Yes. Specify: ……………….
(within 10 years) o No
15. Social/Family history

16. Past medication history

B. Medication on hospital admission

Drug Regimen Day start Day stop Indication

C. Medication during hospitalisation

Drug Regimen Day start Day stop Indication

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Appendix B

Psychoactive Medicines with Sedative Properties Index

N02A Opioids
N02AA Natural opium alkaloids N02AE Oripavine derivatives
N02AA01 Morphine N02AE01 Buprenorphine
N02AA02 Opium
N02AA03 Hydromorphone
N02AA04 Nicomorphine
N02AA05 Oxycodone
N02AA08 Dihydrocodeine
N02AA10 Papaveretum
N02AA51 Morphine, combinations
N02AA55 Oxycodone, combinations
N02AA58 Dihydrocodeine, combinations
N02AA59 Codeine, combinations
excluding psycholeptics
N02AA79 Codeine, combinations with
psycholeptics

N02AB Phenylpiperidine derivatives N02AF Morphinan derivatives

N02AB01 Ketobemidone N02AF01 Butorphanol
N02AB02 Pethidine N02AF02 Nalbuphine
N02AB03 Fentanyl
N02AB52 Pethidine, combinations
excluding psycholeptics
N02AB72 Pethidine, combinations with
psycholeptics

N02AC Diphenylpropylamine N02AG Opioids in combination with

derivatives
N02AC01 Dextromoramide
N02AC03 Piritramide
N02AC04 Dextropropoxyphene
N02AC05 Bezitramide
N02AC52 Methadone, combinations
excluding psycholeptics
N02AC54 Dextropropoxyphene,
combinations excluding psycholeptics
N02AC74 Dextropropoxyphene,
combinations with psycholeptics
antispasmodics
N02AG01 Morphine and antispasmodics
N02AG02 Ketobemidone and
antispasmodics
N02AG03 Pethidine and antispasmodics
N02AG04 Hydromorphone and
antispasmodics
N02AD Benzomorphan derivatives N02AX Other opioids
N02AD01 Pentazocine N02AX01 Tilidine
N02AD02 Phenazocine N02AX02 Tramadol
N02AX03 Dezocine
N02AX05 Meptazinol
N02AX06 Tapentadol
N02AX52 Tramadol, combinations

N02C Antimigraine preparations

N02CA Ergot alkaloids
N02CA01 Dihydroergotamine
N02CA02 Ergotamine
N02CA04 Methysergide
N02CA07 Lisuride
N02CA51 Dihydroergotamine,
combinations
N02CA52 Ergotamine, combinations
excluding psycholeptics
N02CA72 Ergotamine, combinations with
psycholeptics

N02CB Corticosteroid derivatives

N02CB01 Flumedroxone

N02CC Selective serotonin (5HT1)

agonists
N02CC01 Sumatriptan
N02CC02 Naratriptan
N02CC03 Zolmitriptan
N02CC04 Rizatriptan
N02CC05 Almotriptan
N02CC06 Eletriptan
N02CC07 Frovatriptan

N02CX Otherantimigraine preparations

N02CX01 Pizotifen
N02CX02 Clonidine
N02CX03 Iprazochrome
N02CX05 Dimetotiazine
N02CX06 Oxetorone

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N03A Antiepileptics
N03AA Barbiturates and derivatives N03AE Benzodiazepine derivatives
N03AA01 Methylphenobarbital N03AE01 Clonazepam
N03AA02 Phenobarbital
N03AA03 Primidone
N03AA04 Barbexaclone
N03AA30 Metharbital

N03AB Hydantoin derivatives N03AF Carboxamide derivatives

N03AB01 Ethotoin N03AF01 Carbamazepine
N03AB02 Phenytoin N03AF02 Oxcarbazepine
N03AB03 Amino(diphenylhydantoin) N03AF03 Rufinamide
valeric acid N03AF04 Eslicarbazepine
N03AB04 Mephenytoin
N03AB05 Fosphenytoin
N03AB52 Phenytoin, combinations
N03AB54 Mephenytoin, combinations

N03AC Oxazolidine derivatives N03AG Fatty acid derivatives

N03AC01 Paramethadione N03AG01 Valproic acid
N03AC02 Trimethadione N03AG02 Valpromide
N03AC03 Ethadione N03AG03 Aminobutyric acid
N03AG04 Vigabatrin
N03AG05 Progabide
N03AG06 Tiagabine

N03AD Succinimide derivatives N03AX Other antiepileptics

N03AD01 Ethosuximide N03AX03 Sultiame
N03AD02 Phensuximide N03AX07 Phenacemide
N03AD03 Mesuximide N03AX09 Lamotrigine
N03AD51 Ethosuximide, combinations N03AX10 Felbamate
N03AX11 Topiramate
N03AX12 Gabapentin
N03AX13 Pheneturide
N03AX14 Levetiracetam
N03AX15 Zonisamide
N03AX16 Pregabalin
N03AX17 Stiripentol
N03AX18 Lacosamide
N03AX19 Carisbamate
N03AX21 Retigabine
N03AX22 Perampanel
N03AX23 Brivaracetam
N03AX30 Beclamide

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N04 Anti-Parkinson Medicines
N04AA Tertiary amines N04BB Adamantane derivatives
N04AA01 Trihexyphenidyl N04BB01 Amantadine
N04AA02 Biperiden
N04AA03 Metixene
N04AA04 Procyclidine
N04AA05 Profenamine
N04AA08 Dexetimide
N04AA09 Phenglutarimide
N04AA10 Mazaticol
N04AA11 Bornaprine
N04AA12 Tropatepine

N04AB Ethers chemically close to N04BC Dopamine agonists

antihistamines
N04AB01 Etanautine N04BC01 Bromocriptine
N04AB02 Orphenadrine (chloride) N04BC02 Pergolide
N04BC03 Dihydroergocryptinemesylate
N04BC04 Ropinirole
N04BC05 Pramipexole
N04BC06 Cabergoline
N04BC07 Apomorphine
N04BC08 Piribedil
N04BC09 Rotigotine

N04AC Ethers of tropine or tropine N04BD Monoamine oxidase B inhibitors

derivatives N04BD01 Selegiline
N04AC01 Benzatropine N04BD02 Rasagiline
N04AC30 Etybenzatropine

N04BA Dopa and dopa derivatives N04BX Other dopaminergic agents

N04BA01 Levodopa N04BX01 Tolcapone
N04BA02 Levodopa and decarboxylase N04BX02 Entacapone
inhibitor N04BX03 Budipine
N04BA03 Levodopa, decarboxylase
inhibitor and COMT inhibitor
N04BA04 Melevodopa
N04BA05 Melevodopa and decarboxylase
inhibitor
N04BA06 Etilevodopa and decarboxylase
inhibitor

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N05A Antipsychotics
N05AA Phenothiazines with aliphatic
sidechain
N05AA01 Chlorpromazine
N05AA02 Levomepromazine
N05AA03 Promazine
N05AA04 Acepromazine
N05AA05 Triflupromazine
N05AA06 Cyamemazine
N05AA07 Chlorproethazine
N05AF Thioxanthene derivative
N05AF01 Flupentixol
N05AF02 Clopenthixol
N05AF03 Chlorprothixene
N05AF04 Thiothixene
N05AF05 Zuclopenthixol

N05AB Phenothiazines with piperazine N05AG Diphenylbutylpiperidine

structure derivatives
N05AB01 Dixyrazine N05AG01 Fluspirilene
N05AB02 Fluphenazine N05AG02 Pimozide
N05AB03 Perphenazine N05AG03 Penfluridol
N05AB04 Prochlorperazine
N05AB05 Thiopropazate
N05AB06 Trifluoperazine
N05AB07 Acetophenazine
N05AB08 Thioproperazine
N05AB09 Butaperazine
N05AB10 Perazine
N05AC Phenothiazines with piperidine N05AH Diazepines, oxazepines,
structure thiazepines and oxepines
N05AC01 Periciazine N05AH01 Loxapine
N05AC02 Thioridazine N05AH02 Clozapine
N05AC03 Mesoridazine N05AH03 Olanzapine
N05AC04 Pipotiazine N05AH04 Quetiapine
N05AH05 Asenapine
N05AH06 Clotiapine
N05AD Butyrophenone derivatives N05AL Benzamides
N05AD01 Haloperidol N05AL01 Sulpiride
N05AD02 Trifluperidol N05AL02 Sultopride
N05AD03 Melperone N05AL03 Tiapride
N05AD04 Moperone N05AL04 Remoxipride
N05AD05 Pipamperone N05AL05 Amisulpride
N05AD06 Bromperidol N05AL06 Veralipride
N05AD07 Benperidol N05AL07 Levosulpiride
N05AD08 Droperidol
N05AD09 Fluanisone N05AN Lithium
N05AN01 Lithium

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N05AE Indole derivatives N05AX Other antipsychotics
N05AE01 Oxypertine N05AX07 Prothipendyl
N05AE02 Molindone N05AX08 Risperidone
N05AE03 Sertindole N05AX10 Mosapramine
N05AE04 Ziprasidone N05AX11 Zotepine
N05AE05 Lurasidone N05AX12 Aripiprazole
N05AX13 Paliperidone
N05AX14 Iloperidone
N05AX15 Cariprazine
N05AX16 Brexpiprazole

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N05B Anxiolytics
N05BA Benzodiazepine derivatives N05BD Dibenzobicyclooctadiene
N05BA01 Diazepam derivatives
N05BA02 Chlordiazepoxide N05BD01 Benzoctamine
N05BA03 Medazepam
N05BA04 Oxazepam
N05BA05 Potassium clorazepate
N05BA06 Lorazepam
N05BA07 Adinazolam
N05BA08 Bromazepam
N05BA09 Clobazam
N05BA10 Ketazolam
N05BA11 Prazepam
N05BA12 Alprazolam
N05BA13 Halazepam
N05BA14 Pinazepam
N05BA15 Camazepam
N05BA16 Nordazepam
N05BA17 Fludiazepam
N05BA18 Ethyl loflazepate
N05BA19 Etizolam
N05BA21 Clotiazepam
N05BA22 Cloxazolam
N05BA23 Tofisopam
N05BA56 Lorazepam, combinations

N05BB Diphenylmethane derivatives N05BE Azaspirodecanedione derivatives

N05BB01 Hydroxyzine N05BE01 Buspirone
N05BB02 Captodiame
N05BB51 Hydroxyzine, combinations

N05BC Carbamates N05BX Other anxiolytics

N05BC01 Meprobamate N05BX01 Mephenoxalone
N05BC03 Emylcamate N05BX02 Gedocarnil
N05BC04 Mebutamate N05BX03 Etifoxine
N05BC51 Meprobamate, combinations N05BX04 Fabomotizole

27 | P a g e
N05C Hypnotics and sedatives
N05CA Barbiturates, plain N05CF Benzodiazepine related drugs
N05CA01 Pentobarbital N05CF01 Zopiclone
N05CA02 Amobarbital N05CF02 Zolpidem
N05CA03 Butobarbital N05CF03 Zaleplon
N05CA04 Barbital N05CF04 Eszopiclone
N05CA05 Aprobarbital
N05CA06 Secobarbital
N05CA07 Talbutal
N05CA08 Vinylbital
N05CA09 Vinbarbital
N05CA10 Cyclobarbital
N05CA11 Heptabarbital
N05CA12 Reposal
N05CA15 Methohexital
N05CA16 Hexobarbital
N05CA19 Thiopental
N05CA20 Ethallobarbital
N05CA21 Allobarbital
N05CA22 Proxibarbal

N05CB Barbiturates, combinations N05CH Melatonin receptor agonists

N05CB01 Combinations of barbiturates N05CH01 Melatonin
N05CB02 Barbiturates in combination N05CH02 Ramelteon
with other drugs N05CH03 Tasimelteon

N05CC Aldehydes and derivatives N05CM Other hypnotics and sedatives

N05CC01 Chloral hydrate
N05CC02 Chloralodol
N05CC03 Acetylglycinamide chloral
hydrate
N05CC04 Dichloralphenazone
N05CC05 Paraldehyde
N05CM01 Methaqualone
N05CM02 Clomethiazole
N05CM03 Bromisoval
N05CM04 Carbromal
N05CM05 Scopolamine
N05CM06 Propiomazine
N05CM07 Triclofos
N05CM08 Ethchlorvynol
N05CM09 Valerianae radix
N05CM10 Hexapropymate
N05CM11 Bromides
N05CM12 Apronal
N05CM13 Valnoctamide
N05CM15 Methylpentynol
N05CM16 Niaprazine
N05CM18 Dexmedetomidine

28 | P a g e
N05CD Benzodiazepine derivatives
N05CD01 Flurazepam
N05CD02 Nitrazepam
N05CD03 Flunitrazepam
N05CD04 Estazolam
N05CD05 Triazolam
N05CD06 Lormetazepam
N05CD07 Temazepam
N05CD08 Midazolam
N05CD09 Brotizolam
N05CD10 Quazepam
N05CD11 Loprazolam
N05CD12 Doxefazepam
N05CD13 Cinolazepam
N05CX Hypnotics and sedatives in
combination, excluding barbiturates
N05CX01 Meprobamate, combinations
N05CX02 Methaqualone, combinations
N05CX03 Methylpentynol, combinations
N05CX04 Clomethiazole, combinations
N05CX05 Emepronium, combinations
N05CX06 Dipiperonylaminoethanol,
combinations

N05CE Piperidinedione derivatives

N05CE01 Glutethimide
N05CE02 Methyprylon
N05CE03 Pyrithyldione

29 | P a g e
N06A Antidepressants
N06AA Nonselective monoamine N06AG Monoamine oxidase A inhibitors
reuptake inhibitors N06AG02 Moclobemide
N06AA01 Desipramine N06AG03 Toloxatone
N06AA02 Imipramine
N06AA03 Imipramine oxide
N06AA04 Clomipramine
N06AA05 Opipramol
N06AA06 Trimipramine
N06AA07 Lofepramine
N06AA08 Dibenzepin
N06AA09 Amitriptyline
N06AA10 Nortriptyline
N06AA11 Protriptyline
N06AA12 Doxepin
N06AA13 Iprindole
N06AA14 Melitracen
N06AA15 Butriptyline
N06AA16 Dosulepin
N06AA17 Amoxapine
N06AA18 Dimetacrine
N06AA19 Amineptine
N06AA21 Maprotiline
N06AA23 Quinupramine

N06AB Selective serotonin reuptake N06AX Other antidepressants

inhibitors N06AX01 Oxitriptan
N06AB02 Zimelidine N06AX02 Tryptophan
N06AB03 Fluoxetine N06AX03 Mianserin
N06AB04 Citalopram N06AX04 Nomifensine
N06AB05 Paroxetine N06AX05 Trazodone
N06AB06 Sertraline N06AX06 Nefazodone
N06AB07 Alaproclate N06AX07 Minaprine
N06AB08 Fluvoxamine N06AX08 Bifemelane
N06AB09 Etoperidone N06AX09 Viloxazine
N06AB10 Escitalopram N06AX10 Oxaflozane
N06AX11 Mirtazapine
N06AX12 Bupropion
N06AX13 Medifoxamine
N06AX14 Tianeptine
N06AX15 Pivagabine
N06AX16 Venlafaxine
N06AX17 Milnacipran
N06AX18 Reboxetine
N06AX19 Gepirone
30 | P a g e
 N06AX21 Duloxetine
N06AX22 Agomelatine
N06AX23 Desvenlafaxine
N06AX24 Vilazodone
N06AX25 Hypericiherba
N06AX26 Vortioxetine

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