DRUG INDUCED PARKINSONISM – A CAUSALITY, SEVERITY

AND PREVENTABILITY ASSESSMENT STUDY

IN A TERTIARY CARE HOSPITAL

Dissertation submitted to

THE TAMILNADU DR.MGR MEDICAL UNIVERSITY

In partial fulfillment of the regulations for

the award of the degree of

M.D.PHARMACOLOGY

Branch VI

DEPARTMENT OF PHARMACOLOGY

KILPAUK MEDICAL COLLEGE

CHENNAI-600010

THE TAMILNADU DR.M.G.R MEDICAL UNIVERSITY

CHENNAI-600032

APRIL- 2017
 CERTIFICATE

This to certify that the dissertation entitled “Drug Induced

Parkinsonism – A Causality, Severity, and Preventability Assessment
Study In A Tertiary Care Hospital” by the candidate Dr. P.Priya for
M.D. Pharmacology (Branch VI) is a bonafide record of the
research done by her during her course period (2014 -2017) in
the Department of Pharmacology, Kilpauk Medical College,
Chennai – 600010.

Dr. R. Narayana Babu, M.D. DCH Dr. C. Ramachandra Bhat,M.D

DEAN, PROFESSOR & HEAD,
Kilpauk Medical College, Department of Pharmacology,
Chennai – 10 Kilpauk Medical College,
Chennai – 10

Date: Date:

Station: Station:
 DECLARATION

I solemnly declare that this dissertation entitled “Drug Induced

Parkinsonism – A Causality, Severity, and Preventability Assessment

Study In A Tertiary Care Hospital” was written by me in the

Department of Pharmacology, Kilpauk Medical College, Chennai, under

the guidance and supervision of Prof. Dr.C.Ramachandra Bhat, M.D.,

Professor and Head, Department of Pharmacology, Kilpauk Medical

College, Chennai – 600 010.

This dissertation is submitted to THE TAMILNADU Dr. M.G.R

MEDICAL UNIVERSITY Chennai, in partial fulfillment of the

university regulations for the award of DEGREE OF M.D

PHARMACOLOGY (BRANCH - VI) examinations to be held in

APRIL– 2017.

Date:

Place: Chennai Dr. P. PRIYA

 ACKNOWLEDGEMENT

“Gratitude is the humble gift; I can give to my beloved

Teachers”.

I express my profound gratitude to the Dean, Dr. R. Narayana Babu,

M.D.DCH, Kilpauk Medical College and Hospital, Chennai for granting me

permission to conduct the study at the Department of Pharmacology and

Psychiatry, Kilpauk Medical College, Chennai.

I thank my respectful Prof. Dr.C. Ramachandra Bhat, M.D., HOD,

Department of Pharmacology, Kilpauk Medical College, for having been very

much supportive and encouraging me for conducting this study.

I express my sincere thanks to Prof. Dr. Malar Sivaraman, M.D, and

Prof. Dr. T. Aruna, M.D, Department of Pharmacology, Kilpauk Medical

College, for their valuable help and suggestions throughout this study.

I express my thanks to Prof. Dr.Malaiappan M.D, HOD, Department

of Psychiatry, Kilpauk Medical College and Hospital, Chennai, and all the

Assistant Professors , Department of Psychiatry, Kilpauk Medical College and

Hospital, Chennai for their valuable help and suggestions throughout my

study.

I express sincere my thanks to Assistant Professors

Dr. S.Jeya ponmari M.D., Dr.G. Sasikala M.D., Dr. G. Komathi M.D.,
Dr.G.Rajesh kumar M.D, Dr.R.Keerthana Brattiya M.D, Department of

pharmacology for their valuable help and suggestions throughout my study.

I am very much thankful to Dr. A. Meera Devi M.D, Assistant

Professor, Department of Pharmacology, Madras Medical College, Chennai,

for her immense support and valuable suggestions for this study. I also thank

Mr. Ravananan, statistician for guiding me in the biostatistics.

I also thank Tutors Dr. J. Valamathi, Mrs. Senthil Kumari and

Mr.Stalin for their help.

I also thank my co-postgraduates Dr. Divya John Stephy,

Dr.D. Thamizh Vani, and Dr. R.Gayathiri , for their support.

I thank our department Lab technicians Mrs. Alwar and

Mrs. Mahalakshmi for their help and support.

I sincerely thank my family members who have been my moral strength

and support and for providing constant encouragement throughout my entire

endeavor.

I also sincerely thank my patients, and their care takers for their co-

operation.

I thank the Almighty for giving me good health and blessings

throughout the phase of this study.

 CONTENTS

NO TITLE PAGE NO
1. ABBREVIATIONS
2. INTRODUCTION 1
3. REVIEW OF LITERATURE 4
4. AIM & OBJECTIVES 41
5. MATERIALS & METHODS 42
6. RESULTS 46
7. DISCUSSION 80
8. CONCLUSION 89
9. BIBILIOGRAPHY
10. ANNEXURES
I. WHO CAUSALITY CLASSIFICATION
II. NARANJO ALGORITHM
III. MODIFIED SCHUMOK AND THORTON
SCALE
IV. MODIFIED HARTWIG AND SIEGEL SCALE
V. SUSPECTED ADR REPORTING FORM
VI. CONSUMERS SUSPECTED ADR REPORTING
FORM
VII. PROFORMA
VIII. CONSENT FORM – ENGLISH
IX. CONSENT FORM – TAMIL
X. ETHICS COMMITTEE APPROVAL
CERTIFICATE
XI. MASTER SHEET
XII. TURNITIN DIGITAL RECEIPT
 ABBREVIATIONS

WHO - World Health Organisation

ADRs - Adverse Drug Reactions

DIDM - Drug Induced Movement Disorder

DIP - Drug Induced Parkinsonism

PD - Parkinson’s disease

TD - Tardive Dyskinesia

FGAs - First Generation Antipsychotics

SGAs - Second generation Antipsychotics

EPS - Extrapyramidal syndrome

PvPI - Pharmacovigilance Programme of India

CIOMS - Centre for International Organization of Medical

Sciences

CDSCO - Central Drugs Standard Control Organization

MoHFW - Ministry of Health & Family Welfare

GOI - Government of India

SUSAR - Suspected unexpected serious adverse reaction

SSAR - Suspected serious adverse reaction

NCC - National Coordination Centre

AIIMS - All India Institute of Medical Sciences

IPC - Indian Pharmacopeia Commission

FDA - Food and drug administration

ICMR - Indian Council of Medical Research

AMC - ADR monitoring centres

ICSR - Individual Case Safety Report

UMC - Uppsala Monitoring centre

L- DOPA - L- 3, 4- dihydroxy phenylalanine

AADC - L- Aromatic Acid Decarboxylase enzyme

BBB - Blood Brain Barrier

VMAT-2 - Vesicular Monoamine Tranporter

DAT - Dopamine Transporter

MAO - Monoamine Oxidase

COMT - Catecholamine – O- methyl transferase

DOPAC - 3,4- Dihydroxyphenylacetic Acid

HVA - Homovanilic Acid

DA - Dopamine

5 HT - Serotonin

Type 2 DM - Type 2 Diabetes Mellitus

THP - Trihexyphenidyl

OPD - Out Patient Department

 INTRODUCTION

A Drug is an active chemical molecule used for diagnosis, prevention,

and treatment of a disease.1 These Drugs when prescribed for medical illness

also produce adverse effects which manifest differently according to various

systems involved.

WHO definition : “Adverse drug reaction is defined as any noxious or

unintended response to a drug, which occurs at doses normally used in man for

prophylaxis, diagnosis or therapy of disease, or for modification of

physiological function” .2

About 0.1% of medical and 0.01 % of surgical patients die due to

adverse drug reactions. Although the magnitudes of patients affected by ADRs

are few, they grossly affect the quality of life.

The morbidity and mortality associated with adverse effects of drug are

often underestimated, as they present as diagnostic problems because they

involve every organ and system of the body. They are commonly mistaken for

signs of underlying disease, resulting in increase in the costs of patient care

because of unnecessary investigations, delay in treatment, prolonged

hospitalization, and added to it is the cost of treatment of ADRs as such.

Drug-induced movement disorders (DIDM) include tardive dyskinesia

(TD), drug-induced Parkinsonism (DIP), akathisia, tardive dystonia, tremor,

1
and myoclonus. Among these, DIP is the most common drug induced

movement disorder.3

In the elderly, after Parkinson's disease (PD), Drug-induced

Parkinsonism (DIP) is the second-most-common cause of Parkinsonism. DIP

may be misdiagnosed with PD because the clinical manifestations of DIP are

very similar to those of Parkinson's disease (PD). Moreover in patients with

DIP, neurological deficits are severe enough to affect their daily routine

activities. Hence these patients are commonly prescribed with antiparkinsonian

drugs which will not improve the condition, for longer periods of time

unnecessarily, despite the fact that recovery being possible by simple measure

of discontinuing the offending drugs. 4

DIP may be caused by typical antipsychotics, gastrointestinal

prokinetics, calcium channel blockers, atypical antipsychotics, and antiepileptic

drugs. Among these typical antipsychotics is the most common offending drug

to cause DIP. Even though atypical antipsychotics are less potential to cause

DIP, they cannot be totally excluded.

Although, such adverse drug reactions are common, comprehensive

information about their incidence, severity, and ultimate health effects are not

available. Even though, there are published pharmaco-epidemiological studies

from other countries on drug usage patterns in Parkinson's disease and DIP, till

date there are only very few reported studies assessing the safety of the drugs

commonly used in such clinical setting especially in India.

2
 Hence this study was done to assess causality, severity, preventability of

DIP in patients attending the Psychiatry and Neurology clinic and to highlight

the need for awareness for this iatrogenic condition and to evaluate the current

trends in DIP.

3
 REVIEW OF LITERATURE

HISTORY

The concern about the fact that a drug might cause both beneficial

effects and harmful effects started to develop in 19th century.

1848 -a young girl named Hannah Greener was given anaesthesia with

chloroform for treatment of in-growing toe nail & had died during anaesthesia

due to ventricular fibrillation. A commission was set up by “The Lancet

journal” to report the events related to anaesthesia and the reports were

published in 1893. This incident became the forerunner of spontaneous

reporting system for adverse drug reactions. But unfortunately this system was

neither retained nor extended to report various ADRs.5

In 20th century, due to the introduction of a wide range of new drugs, the

frequency and severity of ADRs began to get exposed. But its implications and

importance were not considered seriously by the existing authorities.

In 1934, amidopyrine which was a component of many patent drugs was

found to cause agranulocytosis and was then registered as Schedule 4 drug of

the pharmacy and poisons act 1933.6

In 1937, elixir sulfanilamide preparation containing diethyl glycol

(DEG) caused mass death toll of about more than 100. This report began to

create awareness about the potential risk of ADRs and as a result “Federal food

and drug act” was passed in USA in 1938.7

4
 In 1961, thalidomide disaster came to the light, known to have caused

nearly 6000-250000 neonates born with a condition known as phocomelia

which was later attributed due to thalidomide prescribed for the pregnant

mother without proper clinical trials.8 This paved the way for setting up

“Committee on the safety of drugs” (CSD) by UK govt in 1964 and

subsequently yellow card system for reporting ADRs was introduced.

In 1968 under the guidance of WHO, International drug safety

monitoring centre was setup in Uppsala, Sweden also known as “The Uppsala

drug monitoring centre”.

In 1972, pharmacovigilance centres were started initially in 10 countries

which work in collaboration with WHO International drug safety monitoring

centre.

In 1980s, a programme on drug development and use was launched in

collaboration with WHO, by CIOMS- The Council for International

Organizations of Medical Sciences.

In 1990s, the International Conference on Harmonization (ICH) adopted

the regulations put forth by CIOMS. Both created a notable effect on drug

regulation and its proper use.

In India, drug safety monitoring system was proposed in the year 1986

with 12 regional centres. Since then reporting system began to act in

collaboration with WHO “The Uppsala monitoring centre” (UMC).

5
Widening the horizon

In 2005, “National Pharmacovigilance Programme of India” was

launched with the support of WHO and funding aid from World Bank.

Additional support was gained with the implementation of Schedule Y. So it is

now mandatory to report all adverse events including those suspected serious

adverse reactions occurring during clinical trials.9

WHO states that the ADRs database in Uppsala currently contains over

three million reports of suspected ADRs.

Patient reporting system

A novel concept in pharmacovigilance is the consumer adverse drug

reporting system. This system exists in 44 countries. This reporting system

contributes about 9% of total adverse reactions reports.

HISTORY OF ANTIPSYCHOTICS IN RELATION TO MOVEMENT

DISORDERS 10

In 1952 – the first antipsychotic drug, Chlorpromazine was introduced

into clinical practice which revolutionized the treatment of millions of patients

with psychosis.

Then the phenothiazine group and several other classes of FGAs were

synthesized which were grouped into drugs with lower potency and those with

high potency.

6
 Side effects like sedation, anticholinergic effects, postural hypotension,

with low potency drugs lead to the development of more potent and more

specific D 2 receptor blockers such as Haloperidol in 1968.

Problems with drug induced movement disorders went unnoticed until

the introduction of high potency drugs. Since these high potent drugs were

producing more EPS, search for newer drugs with lower propensity to cause

EPS was deeply sought for and as a result of this extensive quest, SGAs were

introduced which showed lower propensity to cause EPS.

Before the introduction of SGAs, a common practice was to increase the

dose of high potency drugs, with a belief that the effective treatment for

positive symptoms could only be attained at the cost of extrapyramidal side

effects. This strategy resulted in an increased incidence of EPS and low

compliance as the patients felt that the treatment was not worth the side effects.

Because of this, change in treatment approach came into effect with use

of low potency drugs with weaker D 2 antagonism. This alternative approach in

treatment modality was supported with introduction of lower potency D 2

antagonist, Clozapine, in 1990.

Subsequently, a number of SGAs were synthesized and now the clinical

use with these drugs has overridden the conventional drugs.

After the large scale use of neuroleptics, a broad list of “drug induced

extrapyramidal reactions” was reported. Apart from neuroleptics, many other

drugs were also reported to cause similar reactions, hence the concept of “drug

induced movement disorders” (DIMDs) was evolved in 1970s as a distinct

clinical entity.

7
 BASIC DEFINITIONS

 Adverse effect is defined as “any undesirable or unintended

consequence of drug administration”. It is a broad term, which includes

all kinds of noxious effect – trivial, serious or even fatal.11

 Adverse drug event is defined as “any untoward medical occurrence

that may present during treatment with a medicine, but which does not

necessarily have a causal relationship with the treatment”.11

 Adverse drug reaction is defined as “any noxious or unintended

response to a drug, which occurs at doses normally used in man for

prophylaxis, diagnosis or therapy of disease, or for modification of

physiological function”.11

 Serious adverse reaction: is defined as ADR which results in death, is

life threatening, requires in-patient hospitalization or prolongation of

existing hospitalization, results in persistent or significant disability or

incapacity, or is a congenital anomaly/ birth defect. 11

 Side effect is defined as “any unintended effect of a pharmaceutical

product occurring at doses normally used by a patient which is related to

the pharmacological properties of the drug. 11

 Signal is defined as reported information on a possible causal relation

between an adverse event and a drug, the relation being previously

unknown or incompletely documented. Usually more than one report is

required to generate a signal, depending on the seriousness of the event

and the quality of the information.12

8
  Dechallenge: 13

With type A reaction (dose dependent) : it means reducing the dose of a

drug or stopping the drug altogether. With type B reaction (Bizarre): it

means stopping the drug.

 Rechallenge: 13

It means restarting a drug after stopping it.

CLASSIFICATION OF ADR

ADR is classified into many types based on type of effect, causality,

severity, preventability, dose, frequency, and time.

A) CLASSIFICATION BASED ON TYPE OF EFFECTS:

(Pharmacological classification)14

Two principle types of ADR:

1. Type A (Augmented): these reactions are predictable and based on

pharmacological properties of the drug. They are dose related and

are more common. They are reversible and preventable. Ex:

hypoglycaemia caused by insulin injection.

2. Type B (Bizarre): these reactions are due to the peculiarities of the

patient and not due to drug effect. They are not dose related and are

less common. They are fatal and more serious, mandating

withdrawal of the drug. Ex: anaphylaxis caused by penicillin.

9
Four subordinate types

1. Type C (Continuous/ chronic): reactions occurring during long

term use of drugs. Cushing’s syndrome caused on prolonged use of

prednisolone.

2. Type D (Delayed effects): adverse effects that occur lately from

therapy for many years. Ex: secondary cancer due to use of

alkylating agents for Hodgkin’s disease.

3. Type E (End of use): adverse effects occurring after abrupt

discontinuation of the drug. Ex: adrenocortical insufficiency after

withdrawing corticosteroids.

4. Type F (Failure of therapy): failure of oral contraceptive therapy

when given along with enzyme inducer

B) CLASSIFICATION ACCORDING TO THE SEVERITY16

1) Mild - Bothersome but requires no change in therapy.

2) Moderate-Requires change in therapy, additional treatment,

hospitalization. Definite biochemical or structural changes occurs due

to moderate involvement of vital organs.

3) Severe - Potentially life threatening, causing permanent damage.

Definitely require hospitalization due to severe impairment of vital

organs.

10
C) WHO CAUSALITY CLASSIFICATION15

CAUSALITY ASSESSMENT
Certain • Event or laboratory test abnormality, with plausible
time relationship to drug intake
• Cannot be explained by disease or other drugs
• Response to withdrawal plausible(pharmacologically,
pathologically)
• Event definitive pharmacologically or
phenomenological(i.e. an objective and specific
medical disorder or a recognized pharmacological
phenomenon)
• Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable
time relationship to drug intake
• Unlikely to be attributed to disease or other drugs
• Response to withdrawal clinically reasonable
• Rechallenge not required
Possible • Event or laboratory test abnormality ,with reasonable
time relationship to drug intake
• Could not be explained by the disease or other drugs
• Information on drug withdrawal may be lacking or
unclear
Unlikely • Event or Laboratory test abnormality with a time to
drug intake that makes a relationship improbable(but
not impossible)
• Disease or other drugs provide plausible explanations
Conditional/ • Event or Laboratory abnormality
Unclassified • More data for proper assessment needed, or
• Additional data under examination
Unassessable / • Report suggesting an adverse reaction
Unclassifiable • Cannot be judged because information is insufficient
or contradictory
• Data cannot be supplemented or verified

11
D) CLASSIFICATION ACCORDING TO SERIOUSNESS 17

1) Suspected Unexpected Serious Adverse Reaction (SUSAR)

2) Suspected Serious Adverse Reaction (SSAR)

Both results in death, life threatening situations and require intervention to

prevent permanent damage. Both may result in disability and also causes

congenital anomalies.

E) CLASSIFICATION BASED ON DOSE RELATIONSHIP 18

1) Dose related: a) Pharmaceutical variation b) Pharmacokinetic variation –

Pharmacogenetic variation, hepatic disease, renal disease, cardiac disease,

thyroid disease, drug interactions. c) Pharmacodynamic variation - Hepatic

disease, altered fluid and electrolyte balance, drug interactions.

2) Non-dose-related: a) Immunological reactions b) Pseudoallergic reactions

c) Pharmacogenetic variation.

3) Long term effects: a) Adaptive changes b) Rebound phenomenon c) Other

long term effects.

4) Delayed effects: a) Carcinogenesis b) Effects concerned with reproduction-

1) impaired fertility 2) Teratogenesis- Adverse effects on the foetus during

early pregnancy, late pregnancy 3) Adverse effects due to drugs in breast milk

F) FREQUENCY CLASSIFICATION19

Report from CIOMS (Centre for international organization of medical

sciences) working group III, Geneva 1995

1) Very common (Optional) : >10%

2) Common (Frequent) : >1% and ≤ 10%

12
 3) Uncommon (Infrequent) : >0.1% and ≤ 1%

4) Rare : 0.01% and ≤ 0.1%

5) Very rare (Optional) : <0.01%

G) REACTION TIME CLASSIFICATION20

Reaction time is defined as the time between the last drug exposure and

the appearance of the first symptoms.

1) Acute : 0-60 Minutes (4.3 % of reactions)

2) Sub-acute : 1-24 Hours (86 % of reactions)
3) Chronic : day to several weeks (3.5% of reactions)

PHARMACOVIGILANCE

Pharmacovigilance is defined as “the science and activities relating to

the detection, assessment, understanding and prevention of adverse dugs

reactions or any other drug related problems” 21.

Aims of Pharmacovigilance: 21

1. To enhance patient care and safety in relation to the use of medicines;

2. To support the public health programmes by providing more reliable and

balanced information for the effective assessment of the benefit – risk

profile of medicines,

3. To improve public health and safety in relation to the use of medicines,

4. To contribute the assessment of effectiveness, benefit, risk and harm of

medicines, encouraging their effective (including cost effective),

rational and safe use,

13
 5. To promote clinical training, education and understanding in

pharmacovigilance ,

6. To promote effective communication about pharmacovigilance to the

public.

Classical examples of serious and unexpected adverse reactions 21

Medicine Adverse reaction

Aminophenazone (amidopyrine) Agranulocytosis
Chloramphenicol Aplastic anaemia
Clioquinol Myelooptic neuropathy
Erythromycin estolate Cholestatic hepatitis
Methyldopa Haemolytic anaemia
Oral contraceptives Thromboembolism
Reserpine Depression
Statins Rhabdomyolysis
Thalidomide Congenital malformations

WHO PROGRAMME FOR INTERNATIONAL DRUG MONITORING21

In 1968, WHO's Programme for International Drug Monitoring was

started with the concept of pooling existing data on ADRs. A pilot project with

established national reporting systems for ADRs was started initially in10

countries. Since then the network has expanded to include many more

countries, co-ordinated by WHO, under “The Upssala Monitoring Centre”,

Sweden. This centre maintains the global ADR database known as “Vigibase”.

Currently the database contains more than 3 million reports in it.

14
The Upssala Monitoring Centre analyses the reports in the database:

 To identify the early warning signals of serious adverse reactions to

medicines;

 To undertake research to aid the development of more effective and

safer medicine;

 To evaluate the hazard.

ROLE OF PHARMACOVIGILANCE 21

 To serve public health, and to provide a sense of trust among patients in

the medicines they use that would create a confidence in the health

service;

 To ensure that the risks in drug use are anticipated and managed

effectively;

 To provide the regulators with all the necessary information to amend

the recommendations on the proper use of the medicines;

 To improve the communication between the public and the health

professionals;

 To educate the health professionals to understand the benefit and risk of

medicines that they prescribe.

MONITORING THE SAFETY OF MEDICINES: KEY PARTNERS 21

 World Health Organization

 Government

 Hospitals and academia

15
  Medical and pharmaceutical associations

 Poisons and medicines centres information

 Health professionals

 Patients

 Consumers

 Media

 Industry

SPONTANEOUS REPORTING SYSTEM

A spontaneous report is an unsolicited communication given by the

healthcare professionals or the consumers to a regulatory authority, company,

or other organization like WHO-regional centre / poison control centre. This

report describes about one or more adverse drug reactions occurring in a patient

who was prescribed one or more medicinal product that does not derive from a

study or any organised data collection scheme.22 Spontaneous report system

has paved way for identification of signal.

SIGNAL

Signal is the possible relationship between a drug and an adverse event,

the relationship being unknown or incompletely documented previously.23

More than one report is needed for signal generation.

IMPORTANCE OF REPORTING

When an adverse effect or toxicity appears especially when it is

unknown previously, it is essential that they should be reported, analysed and

16
their significance should be effectively communicated to an audience who has

the knowledge to interpret the information and create an awareness globally.

PHARMACOVIGILANCE PROGRAMME OF INDIA (PvPI) 24

CDSCO (Central Drugs Standard Control Organization), under the aid

of Ministry Of Health & Family Welfare (MoHFW), Government of India

(GOI) in collaboration with All India Institute of Medical Sciences, New Delhi

as the National Coordination Centre (NCC), has initiated a nationwide

pharmacovigilance programme for protecting the health of the patients by

ensuring drug safety in July 2010. To ensure the effective implementation of

the programme, the NCC was shifted from AIIMS to Indian Pharmacopeia

Commission (IPC), Ghaziabad on 15th April 2011. IPC is an autonomous

institution of MoHFW, GOI. This centre will operate under the guidance of a

steering committee. In 2010 PvPI was started with 22 ADR monitoring centres

(AMCs). Then new AMCs were added by the NCC-PvPI to strengthen the

reporting of ADRs.

ADR reporting at PvPI: 24

PvPI has spontaneous reporting system to collect data on drug safety. A

spontaneous report is an unsolicited communication by health care

professionals, or consumers, or pharmaceutical companies to the regulatory

authority. To ensure this purpose the NCC has designed a “Suspected Adverse

Reaction Reporting Form”.

17
ICSR (Individual Case Safety Report) - is defined as “a report that contains

information describing a suspected adverse reaction related to the

administration of one or more medicinal products to an individual patient”.

To encourage the direct participation of patients in the PvPI, IPC has

launched the novel “Medicines Side Effect Reporting Form for

Consumers”. This form will be reported by the patient to the AMCs. This

form is available in Hindi, Tamil, Gujarati, Oriya, Kannada, Malayalam, &

Bengali. This empowers the patient to report the ADRs irrespective of the

language barrier. Soon this form will be translated to other regional languages

as well.

DOPAMINE 25

HISTORY

 In 1910 - Dopamine was first synthesized

 In the same year, Henry Dale characterized the biological properties

of dopamine and described dopamine as a weak, adrenaline like

substance.

 In 1930 – dopamine was recognised as a transitional substance in the

synthesis of epinephrine and norepinephrine.

 In 1950 – dopamine stores were found in tissues and was found to

have signalling function of its own.

 1n 1960 – Carlsson and Montagu- has discovered dopamine stores in

the brain.
18
  Horneykiewicz – discovered the deficit of dopamine in Parkinsonian

brain.

 These discoveries had fuled the interest in the role dopamine in

neurological disorders in the susequent years.

CHEMISTRY:

Dopamine consists of a catechol moiety linked to an ethyl amine, and

hence classified as catecholamine. Dopamine is a polar molecule, that doesnot

cross blood brain barrier ( BBB).

SYNTHESIS, STORAGE AND RELEASE:

The aminoacids like tyrosine, and phenylalanine serve as the precusors

for dopamine synthesis. L-Phenylalanine is converted to L-tyrosine by the

enzymatic action of phenylalanine hydroxylase. Tyrosine can cross readily into

brain through uptake which is then converted to L-DOPA by tyrosine

hydroxylase, which is the rate limiting step in dopamine synthesis. L-DOPA is

rapidly converted ultimately into dopamine by L- aromatic acid decarboxylase

(AADC) enzyme. AADC activity is very high in both CNS and periphery.

L-DOPA readily crosses the BBB. L-DOPA is thus taken up into the storage

vesicles by vesicular monoamine tranporter, VMAT-2. Then it is released into

the synaptic cleft by exocytosis.

19
METABOLISM

The released dopamine is then subjected to both transporter clearance by

DAT ( dopamine transporter) and metabolism by MAO (monoamine oxidase)

and COMT ( Catecholamine – O- methyl transferase). Reuptake of dopamine

by DAT is the primary mechanism of termination of dopamine action.

Metabolism of dopamine is primarily done by MAO, localized both

presynaptically and postsynaptically. MAO metabolizes dopamine into

DOPAC ( 3,4- dihydroxyphenylacetic acid) . DOPAC is further metabolized by

COMT into HVA (homovanilic acid). HVA is principal metabolite of

dopamine in humans. In the periphery, COMT also metabolizes dopamine into

3-O-methyldopa.

DOPAMINE RECEPTORS 25

Dopamine receptors are Metabotropic receptors or G- protein coupled receptors

There are 5 DA receptors: D₁ to D₅

Divided into 2 families

 D₁ - like family
 Includes D₁ & D₅
 Gs - Activates adenylate cyclase → ↑ cAMP
 D₂ - like family
 Includes D₂ , D₃ , D₄
 Gі - inhibits adenylate cyclase → ↓ cAMP
 ↓K⁺ currents
 ↓ voltage gated Calcium currents

20
RECEPTOR DISTRIBUTION

D₁ D₂
Substatia nigra pars reticulata Striatum
Frontal cortex Substatia nigra pars compacta
Nucleus acumbens Pituitary
Hypothalamus Prefrontal cortex

DOPAMINE PATHWAYS 25

 Dopamine in brain projects via four main pathways -

1. Mesolimbic pathway

2. Mesocortical pathway

3. Nigrostriatal pathway

4. Tuberoinfundibular pathway

SIGNIFICANCE OF EACH DOPAMINE PATHWAYS

MESOLIMBIC PATHWAY

Anatomy: Projects from ventral tegmental area to nucleus accumbens.

Physiology: It governs - motivation, reward, emotions & negative symptoms of

schizophrenia.

Implication: in psychoses, schizophrenia, & in ADHD

21
MESOCORTICAL PATHWAY

Anatomy: projects from ventral tegmental area to prefrontal cortex.

Physiology: cognition & executive functions (DLPFC), emotions & affect

(VMPFC)

Implication: Schizophrenia, ADHD

NIGROSTRIATAL PATHWAY

Anatomy: projects from substantia nigra (pars compacta ) to striatum (caudate

& putamen)

Physiology: co-ordination of movements

Implication: Parkinson’s disease, DIP

TUBEROINFUNDIBULAR PATHWAY

Anatomy: hypothalamus to infundibular region

Physiology: dopamine inhibits prolactin release

Implication: D₂ antagonism causes hyperprolactinemia

22
ANTIPSYCHOTIC DRUGS: NEUROLEPTICS 25

CLASSIFICATION:

I. Classical / Typical antipsychotics

1. Phenothiazines :

Chlorpromazine

Triflupromazine

Thioridazine

Trifluoperazine

Fluphenazine

2. Butyrophenones

Haloperidol

Trifluperidol

Penfluridol

Thioxanthenes

Flupenthixol

3. Other heterocyclics

Pimozide , Loxazipine

II. Novel /Atypical antipsychotics

Clozapine Aripiprazole

Risperidone Ziprasidone

Olazapine Amisulpride

Quetiapine Zotepine
23
Also classified as:

Typical
First generation
antipsychotics
Antipsychotics
Atypical
Second generation
antipsychotics

MECHANISM OF ACTION OF ANTIPSYCHOTICS 25

TYPICAL ANTIPSYCHOTICS

All the typical antipsychotics have potent D₂ receptor blocking effect.

Reduction of dopamine transmission is their major mechanism of action. Their

potency show good correlation with their ability to bind to D₂ receptor and to

block them. Blockade of D₂ receptor in “limbic system & mesocortical” areas

is responsible for the antipsychotic effect. In addition these drugs have α₁

adrenergic blocking action, M₁ muscarinic blocking action and H₁

histaminergic blocking action.

The delayed onset of effects of these drugs is due to initial increase in

release of dopamine from dopamine neurons. But on repeated drug

administration, they enter a state of physiological depolarization inactivation,

with gradual decrease in production and release of dopamine with continued

receptor blockade.

24
ATYPICAL ANTIPSYCHOTICS

Atypical antipsychotics have more potent 5-HT₂ blocking action, and

weak D₂ receptor blocking action in addition to α₁ adrenergic blocking action.

Some of them are relatively selective for D₄ receptors. Thus antipsychotic

action depends on specific profile of action of these drugs acting on various

neurotransmitter receptors with varying binding activity.

ADVERSE DRUG EFFECTS OF ANTIPSYCHOTICS 25

 Classified into 2 broad categories

 Adverse effects predicted by monoamine receptor affinities

 Adverse effect not predicted by monoamine receptor affinities

I. ADVERSE EFFECTS PREDICTED BY MONOAMINE RECEPTOR

AFFINITIES

A) D₂ RECEPTOR BLOCKADE: leads to extrapyramidal side effects (EPS).

Typical antipsychotics are more prone for EPS since they are potent D₂

blockers, while atypical antipsychotics cause less EPS as they are weak

blockers. EPS consists of 6 categories. They are

1. Drug induced Parkinsonism

2. Acute muscular dystonia
3. Akathisia
4. Malignant neuroleptic syndrome
5. Perioral tremors
6. Tardive dyskinesia

25
PROFILE OF EXTRAPYRAMIDAL SYNDROMES

Time of
Proposed
Syndromes Features onset & Treatment
mechanism
risk info
Acute Spasm of 1-5 days Acute Resolves
dystonia muscles, Young dopamine spontaneously,
mostly linguo- antipsychot antagonism Central
facial muscles ic naïve anticholinergics,
patients are promethazine or
at risk hydroxyzine
Parkinsonism Bradykinesia, 5-30 days Dopamine Dose reduction
variable Elderly at antagonism Central
tremor, greatest anticholinergics,
rigidity, risk Amantadine,
shuffling gait, change of
mask facies antipsychotics to
atypical drugs
Akathisia Restlessness, 5-60 days Unknown Change drug or
compelling reduce dose
desire to move Clonazepam,
about without Propranolol,
anxiety central
anticholinergics
Neuroleptic Marked Weeks- Dopamine Stop
malignant rigidity, fever, months antagonism neuroleptics
syndrome tremor, Supportive care,
fluctuating BP, i.v. dantrolene,
myoglobinemia bromocriptine
, can be fatal
Perioral Perioral Months or Postsynaptic Treatment
tremor (rabbit tremors – late years of dopamine unsatisfactory,
syndrome) variant of treatment receptor prevention
parkinsonism Elderly at supersensitiv crucial, may
5-fold risk ity, & subside months
neuronal or years after
degeneration discontinuation
of the drug

26
B) H₁ receptors:

Antagonism of H₁ receptors centrally causes two important side effects,

sedation and weight gain via appetite stimulation. Low potency typical

antipsychotic drugs like thioridazine and chlorpromazine, atypical

antipsychotic drugs like clozapine and quietiapine possess high H₁ receptor

affinity and hence cause more sedation.

C) M₁ receptors:

Muscarinic receptor antagonism is responsible for the peripheral and

central anticholinergic effects. Most of the atypical antipsychotics have no

muscarinic affinity, so no anti-muscarinic side effects are produced. But the

drugs like Clozapine and low potency phenothiazines have marked and

significant anti-musarinic adverse effects. The drugs with significant

anticholinergic affinity should be avoided in elderly, particularly in those with

dementia or delirium.

D) α₁ receptors:

α₁ adrenergic antagonism results in risk of orthostatic hypotension. These

drugs should be avoided in elderly with poor vasomotor tone. Low potency

drugs have more affinity towards α₁ adrenergic receptors when compared to

high potency drugs and are greater risk of causing orthostatic hypotension.

27
II. ADVERSE EFFECT NOT PREDICTED BY MONOAMINE

RECEPTOR AFFINITIES

A) ADVERSE METABOLIC EFFECTS:

These have become the greatest concern during long term antipsychotic

drug treatment. There is high prevalene of Type 2 DM and prediabetic

conditions, and 2-fold increase in cardiovascular mortality among those on

antipsychotic drug treatment for longer duration. Also these patients suffer

from weight gain, dyslipidemia, elevated TGL, and impaired glycemic control.

Atypical drugs like Clozapine, Olanzapine and low potency phenothiazines

have significant metabolic adverse effects.

B) ADVERSE CARDIAC EFFECTS:

Two most significant cardiovascular side effects are ventricular

arrhythmia & sudden cardiac death. Most of the older antipsychotic drugs have

the tendency to inhibit cardiac K⁺ channels. All these antipsychotic drugs carry

the label warning regarding QTc prolongation.

C) OTHER ADVERSE EFFECTS:

 Blue pigmentation of exposed skin, lenticular and corneal opacities,

retinal degeneration, are more with thioridazine.

 Cholestatic jaundice – is more common with phenothiazines (low

potency).

 Agranulocytosis – is rare and more common with clozapine.

28
  Myocarditis – is seen in few patients taking clozapine.

 Skin rashes, contact dermatitis, utricaria, and photosensitivity is

more common with chlorpromazine.

 Lowering of seizure threshold in epileptic patients using

antipsychotic drugs.

DRUG INDUCED MOVEMENT DISORDERS (DIMDs) 26

Various Classifications

I. Classified based on their

A) Temporal profile

 Acute : those occurring within hours or days after exposure

 Subacute: developing slowly after days to weeks of exposure

 Chronic : developing after long term therapy with the offending drug

B) Phenomenology

 Dystonia, tremor, parkinsonism, dyskinessia, akathisia, myoclonus,

chorea, tic

C) Drugs involved

 Neuroleptics – typical & atypical

 Other D 2 blockers

 Antidepressants

 Anti-epileptics

 Recreational drugs

 Toxins
29
II. Classification of Medication induced movement disorders27

A) Categorized into

1. Hypokinetic disorders – with paucity of movements

(e.g. akinesia, bradykinesia)

2. Hyperkinetic disorders – with excessive movements

(e.g. dyskinesia, akathisia)

B) Divided into those associated with use of

1. Antipsychotics (Neuroleptics)

2. Other psychotropic agents

3. Non- psychotropic agents

III. DSM-IV-TR: fourth edition of the “DIAGNOSTIC AND

STATISTICAL MANUAL OF MENTAL DISORDERS”28

Categorises medication induced movement disorder into 7 categories

S.No Category Features

1 Neuroleptic induced Triad of tremor, rigidity, and
parkinsonism akinesia.
Develops within a few weeks of
starting or increasing the dose of
the neuroleptics.
2 Neuroleptic malignant Elevated temperature, severe
syndrome muscular rigidity and other features
developing after the use of
neuroleptics.
3 Neuroleptic induced dystonia Spasm or abnormal positioning of
the muscles of head & neck, limbs
or trunk.
Develops within few days of
starting or increasing the dose of
the neuroleptics.

30
 4 Neuroleptic induced akathisia Subjective compliant of
restlessness associated with
observed movements.
Develops within a few weeks of
starting or increasing the dose of
the neuroleptics.

5 Neuroleptic induced tardive Involuntary choreiform, rhythmic,

dyskinesia or athetoid movements of the jaw,
tongue,or limbs developing after
the use of neuroleptics.
6 Medication induced postural Fine tremor which occurs during
tremor an attempt to maintain a posture
developing after the use of
neuroleptics.
7 Medication induced movement This category consists of
disorder not otherwise specified medication induced movement
disorders not classified by any of
the above specific disorders

DRUGS ASSOCIATED WITH MOVEMENT DISORDERS AND THEIR

IMPACT ON RECEPTORS29

D2 5-HT 2 mACh
Type Name
blockade blockade blockade
ANTIPSYCHOTICS
Phenothiazine Chlorpromazine L H H
Phenothiazine Thioridazine L M H
Phenothiazine Trifluoperazine M M M
Fluphenazine H L L
Perphenazine H M L
Thioxanthene Thiothixene H M L
Dibenzoxazepines Loxapine M H L
Butyrophenones Haloperidol H L L
Droperidol H M -
Diphenylbutyl Pimozide H M L
piperidies
Dihydroindolones Molindone M L L
31
Dibenzodiazepine Clozapine L H H
Benzisoxazoles Risperidone H H L
Paliperidone H H L
Thienobenzodiazepines Olanzapine L H H
Dibenzodiazepine Quetiapine L/M L/M L
Benisothiazolyls Ziprasidone M H L
Quinolones Aripiprazole H (PA) H L
NON-ANTIPSYCHOTIC PSYCHOTROPICS
Ions Lithium - - -
Anticonvulsants L L L
Antidepressants L Varies Varies
(except
Amoxa
pine)
NONPSYCHOTROPICS
Prochlorperazine H M L
Metoclopramide H H -
H- High; L-Low; M- Medium

SPECTRUM OF DRUGS CAUSING ACUTE EPS 29

Maximum Minimum
..…………………………………………………………………………………
…….

High potency Risperidone Olanzapine Clozapine

FGAs Paliperidone Ziprasidone Quetiapine
Aripiprazole

………………………………… (Dose related) ..……………………………

32
RECEPTOR OCCUPANCY AND CLINICAL RESPONSE OF

ANTIPSYCHOTICS25

 D₂ RECEPTOR OCCUPANCY / D₂ ANTAGONISM:

• Receptor occupancy > 60% by the drug - provides antipsychotic

effects

• Receptor occupancy > 80% by the drug – causes extrapyramidal

symptoms (EPS)

 5HT₂ ANTAGONISM / INVERSE AGONISM:

• Atypical antipsychotics have more potent 5HT₂

antagonism/inverse agonism with weak D₂ receptor blockade

leading to reduced EPS

PROKINETIC DRUGS 1

 These drugs promote gastric transit and increase the gastric emptying by

enhancing propulsive motility.

 Drugs in this category are metoclopramide and domperidone. These

drugs act by D₂ antagonism.

Features Metoclopramide Domperidone

Mechanism of Action D₂ antagonism D₂ antagonism
5HT₂ and 5HT₃ antagonism
Adverse effects Sedation, muscular dystonia, Galactorrhea, , loose
dizziness, loose stools stools, headache, and
On long term use : rashes,
Parkinsonism, galactorrhea, EPS rare
and gynaecomastia

33
DRUG INDUCED PARKINSONISM (DIP) 26

DIP is defined as Parkinsonism secondary to medications. DIP is the

second most common form of Parkinsonism after Parkinson’s disease in the

elderly.

EPIDEMIOLOGY 30

DIP is often misdiagnosed as Parkinson’s disease, hence exact incidence

and prevalence are not clearly known. Chlorpromazine (CPZ) was the first

antipsychotic drug to be studied for extapyramidal side effects, which stated

that about 40% of patients on CPZ developed drug induced Parkinsonism. A

population based survey and a community based survey found that the

prevalence rate of DIP was 1.7% and 2.7% respectively, whereas the

prevalence rate of Parkinson’s disease was 4.5% and 3.3% respectively. But

6.8% of patients who have been diagnosed with Parkinson’s disease was later

rediagnosed as having DIP, which clearly emphasises the difficulties in

classifying the patients as DIP or Parkinson’s leading to unclear prevalence.

Age is the most common risk factor for DIP and found to be more

common in elderly (> 60yrs). Gender is another risk factor in which females

are more susceptible which suggests that oestrogen plays a role in suppression

of the expression of the dopamine receptors. Genetic factors may also play a

role in the manifestation of DIP, because all the patients who are taking

dopamine receptor blocking drugs do not develop DIP. Genetic screening may

help to find the vulnerable patients but it is not practically possible in the

developing countries.

34
ETIOPATHOLOGY 25

DIP results from deficiency of dopamine in nigrostiatal dopamine

pathway. This can be caused by

 Main causative agents like

• Dopamine depleters, (e.g., reserpine),

• Dopamine blocking agents (e.g. Antipsychotics),

• Calcium channel blockers (e.g. Cinnarazine),

• Antiemetics (e.g. Metoclopramide).

 Other drugs causing DIP: are antiepileptics, antidepressants &

anticancer drugs

 Toxins causing DIP: are MPTP, OPC, methanol, manganese,cyanide,

& CO.

DRUGS FREQUENTLY CAUSING DRUG INDUCED

PARKINSONISM- (Higher risk) 30

Typical Antipsychotics Phenathiazine: Chlorpromazine, Prochlorperazine,

perphenazine, fluphenazine, promethazine
Butyrophenones: Haloperidol
Diphenylbutylpiperidine: Pimozide
Benzamide substitutes: Sulpiride
Atypical Antipsychotics Risperidone, Ziprasidone, Olanzapine,
Aripiprazole
Dopamine depleters Reserpine, Tertrabenazine
Antiemetics Metoclopramide, Levosulpride, Clebopride
Calcium channel Flunarazine, Cinnarazine
blockers

35
DRUGS INFREQUENTLY CAUSING DRUG INDUCED

PARKINSONISM - (Intermediate risk) 30

Atypical antipsychotics Clozapine, Quetiapine

Mood stabilizer Lithium

Antidepressants SSRI: Citalopram, Fluoxetine, Paroxetine,

Sertraline

Antiepileptic dugs Valproic acid, Phenytoin

Antiemetics Domperidone, Itopride

DRUGS RARELY CAUSING DRUG INDUCED PARKINSONISM –

(Lower risk) 30

Antihypertensives Diltiazem, Captopril

Antiarrythmics Amiodarone, procaine

Antidepressants Fluoxetine, TCAs, MAO inhibitors- Phenelzine

Immunosuppressants Cyclosporine, tacrolimus

Antibiotics Co-trimoxazole

Antifungals Amphotericin – B

Antivirals Vidarabine, Acyclovir

Chemotherapeutics Cytosine arabinoside, Ifosfamide, Vincristine

Hormones L-Thyroxine, Medroxyprogesterone

Statins and Others Lovastatin, Donepezil, Bethanecol,

Pyridostigmine

36
CLASSIC TRIAD OF SYMPTOMS: 30

Bradykinesia

Tremors

Rigidity

• All three symptoms may be present, but only one is required for the

diagnosis.

OTHER SYMPTOMS

• Are Speech difficulties (poverty of speech), gait disturbances (shuffling

gait), expression less face.

DIP VERSUS PARKINSON’S DISEASE 30

DIP Parkinson’s disease

Symptoms – symmetrical Symptoms – asymmetrical

Onset – acute or subacute Chronic

Reversible once the offending drug is Chronic & progressive

stopped
Postural tremor Resting tremor

Subacute onset after starting the drug Slow, progressive course

Not responsive to antiparkinson drug Responsive to antiparkinson drug

treatment treatment
Caused by drugs No known cause

No brain degeneration Brain degeneration +

More common in females More common in males

Associated features: Absent

Akathisia and Orobuccal dyskinesia are
present
Motor fluctuations absent Motor fluctuations present

37
RISK FACTOR FOR DEVELOPMENT OF DIP: 31

• High dose of neuroleptics

• High potency neuroleptics

• Piperazine side chain chain neuroleptics

• Females (F:M ratio is 2:1)

• Elderly

• Preclinical Parkinsonism

• Co-existence of tardive dyskinesia

• AIDS

CLUES TO DIAGNOSE DIP CLINICALLY: 31

• Presence of symptoms of DIP

• Symmetrical

• Exposure to a drug +

• Onset of DIP symptoms during the use of offending drug

• No history of DIP before starting the offending drug

• Progression of symptoms in relation to mediation intake

• Early presence of postural tremor

• Concurrent presence of oral-buccal dyskinesia

RADIOLOGICAL DIAGNOSIS 30

Dopamine transporter (DAT) imaging: is useful for diagnosing

presynaptic Parkinsonism. DAT uptake in nigrostriatum is markedly decreased

even in the early stages of PD, since the motor symptoms in PD appear only
38
when 60-80% of dopaminergic neurons degenerate. This feature helps to

differentiate PD from DIP

Single – photon emission tomography (SPECT) and positron- emission

tomography (PET) scans are used for DAT ligands. The drugs which cause DIP

have negligible affinity to DAT. In DIP, DAT scans shows symmetrical uptake

of radiotracer in the bilateral striatum in those patients affected by pure DIP,

but in those with PD, DAT shows decreased and asymmetrical uptake in the

striatum.

PREVENTION OF DIP 30

 Identify high risk population and avoid prescribing offending drugs in

them

 Avoid unnecessary medications

 Wise and judicious use of favorable medications

 Using lowest dose of drugs

 Avoid unnecessary prolonged therapy

 Elicit proper drug history and its previous adverse effects

TREATMENT OF DIP 25

 Cessation of offending drugs.

 Switch to another drug which has lower propensity to cause DIP

(typical antipsychotic drug to atypical antipsychotic drug).

 Dose reduction in those who respond only to the given drug.

39
  Treatment with centrally acting anticholinergics which includes

trihexyphenidyl (THP), benztropine. Usually THP is given at the dose

of 2 mg twice daily.

 Amantadine is also used o treat DIP which is equally effective as

anticholinergics.

OUTCOMES OF DIP 30

Usually DIP resolves within weeks to months after the cessation of the

offending drug. Sometimes DIP may progress or persists in 10- 50% of

patients.

 Outcome falls into 4 types.

1. Complete and long lasting recovery with no subsequent

development of Parkinsonism

2. Persistence but progressing to Parkinsonism

3. Persistence and progression to Parkinsonism

4. Full recovery and remission, but reappearance in later stages

after discontinuing the offending drug

 Only those patients falling under type 1 & 2 are classified as having

pure DIP, whereas those patients classified under 3 & 4 may be in the

preclinical stages of PD.

40
 AIM AND OBJECTIVES OF THE STUDY

PRIMARY OBJECTIVE

 To analyze the different group of drugs causing drug induced

Parkinsonism (DIP).

SECONDARY OBJECTIVES

 To describe the Causality analysis of drug induced Parkinsoism using

WHO causality assessment scale and Naranjo algorithm.32

 To describe the severity analysis of drug induced Parkinsoism by using

Hartwig and Siegel scale.33

 To describe the preventability assessment by using Modified Schumok

and Thorton Scale. 34

 To describe the profile of manifestations of DIP.

 To describe the socio-demographic profile in DIP.

 To analyze the predisposing factors for DIP.

41
 METHODOLOGY

MATERIALS AND METHODS

 Study design: Descriptive study - A Cross Sectional Study

 Study period: June 2015 to June 2016

 Study duration: One year

 Study centre: Out- patient department of Psychiatry and Neurology

 Study population: Patients diagnosed with drug induced Parkinsonism

attending the out- patient department of Psychiatry and Neurology

 Sample size: All the patients diagnosed with drug induced

Parkinsonism attending the out- patient department of Psychiatry and

Neurology during the period of one year.

INCLUSION CRITERIA

 Patients of all ages, of either gender presenting to the out- patient

department of Psychiatry and Neurology with drug induced

Parkinsonism.

 Patients referred from other specialities to the department of Psychiatry

and Neurology OPD for the treatment of DIP.

EXCLUSION CRITERIA

 Patients with Parkinson’s disease

 Patients not willing to participate in the study

42
ETHICS CONSIDERATION

 The study was approved by the institutional ethics committee.

 Confidentiality and identity of the patient’s information were maintained

during and after the study

 Care and treatment of the patient was not interfered during the study

period.

STUDY PROCEDURE

All the patients diagnosed with DIP, attending the department of

Psychiatry and Neurology OPD was registered after obtaining proper informed

consent. Since the study was undergone in Psychiatry, for those patients who

were unable to give consent, the consent was obtained from their guardian

accompanying them. Those with Parkinson’s disease were excluded from the

study.

All the details of the patient like basic demographic data, presenting

illness, past medical history, any associated co-morbidites, family history and

usage of concomitant medications were collected and recorded in the proforma.

The diagnosis of DIP was confirmed by the Psychiatrist and Neurologist.

Detailed clinical history and physical examination was done by the Psychiatrist

and Neurologist before arriving to the diagnosis of DIP. After their diagnosis,

details of the manifestations of DIP and the drugs suspected to cause DIP were

collected and recorded in the proforma. Complete prescription details before

and after the manifestation of DIP was collected and recorded.

43
 All the information was recorded in the “Suspected Adverse Drug

Reporting Form” given by Central Drugs Standard Control Organisation

(CDSCO), New Delhi. While uploading the form, only the patient initials not

their name was recorded to maintain the confidentiality and privacy of the

patient. The following were the data’s recorded in the form,

 Demographic data- age, sex, weight

 Details of manifestation of DIP: like description of the reaction, onset

and recovery of the reaction

 Details of the suspected drug causing ADR

 Details of the concomitant medications

 Relevant and other past medical history

 Relevant laboratory investigations

 Seriousness of the reaction

 Outcome of the reaction

ASSESSMENT: Totally 50 patients with DIP were enrolled in the study over

the study period of one year.

 All these data were analyzed and causality assessment was done using

WHO causality assessment scale and Naranjo algorithm.32

 The severity analysis was done using Hartwig and Siegel scale.33

 The preventability assessment was done using Modified Schumok and

Thorton Scale.34

44
STATISTICAL ANALYSIS

The data collected were categorically entered in Microsoft excel sheet

and was analyzed using SPSS software 2.0 version. Appropriate diagrams and

charts were used for pictorial representation of the data. Statistical significance

was analyzed using Chi- square test.

45
 RESULTS

Totally 50 patients with DIP were enrolled in the study over the study period of

one year.

AGE:

Age wise distribution of ADRs in various age groups is shown below.

Table 1: Age wise distribution

Age (yrs) Frequency Percent

21-30 6 12.0
31-40 3 6.0
41-50 13 26.0
51-60 22 44.0
61-70 6 12.0
Total 50 100.0

Figure 1: Age wise distribution

25 22

20
Frequency
13
15

10 6 6
3
5

0
21-30 31-40 41-50 51-60 61-70

Age (yrs)

 44% of ADR was common in the age group of 51-60 yrs. 6% of ADR

was seen in the age group of 61-70 yrs.

46
GENDER:

Table 1: Gender distribution of patients with ADRs

Gender Frequency Percent

Male 15 30.0
Female 35 70.0
Total 50 100.0

Figure 2: Gender distribution of patients with ADRs

Gender

Male
30%

Female
70%

 DIP was found to be more common in females when compared to males.

47
PROFILE OF DRUG REACTION

Table 3A: Frequency of different types of drug induced reactions

Profile of drug Yes No Total

reaction Count % Count % Count %
Bradykinesia 41 82.00 9 18.00 50 100.00
Rigidity 30 60.00 20 40.00 50 100.00
Akathisia 8 16.00 42 84.00 50 100.00
Tremor 33 66.00 17 34.00 50 100.00
Gait disturbance 17 34.00 33 66.00 50 100.00
Poverty of
25 50.00 25 50.00 50 100.00
speech
Muscular
1 2.00 49 98.00 50 100.00
dystonia
Neuroleptic
malignant 1 2.00 49 98.00 50 100.00
syndrome
Perioral tremors 2 4.00 48 96.00 50 100.00
Oculogyric crisis 1 2.00 49 98.00 50 100.00
Tardive
9 18.00 41 82.00 50 100.00
dyskinesia
Siaalorrhea 4 8.00 46 92.00 50 100.00
Sleeplessness 2 4.00 48 96.00 50 100.00

48
Table 3B: Distribution of Combinations of Manifestations of DIP:

Number of
S.No Combinations of Manifestations patients Percentage
affected
1 Bradykinesia + Rigidity 6 12
2 Bradykinesia + Rigidity + Muscular 1 2
dystonia
3 Bradykinesia + Rigidity + Akathisia 7 14
4 Bradykinesia + Rigidity + Akathisia + 1 2
Neuroleptic malignant syndrome
5 Bradykinesia + Rigidity + Oculogyric crisis 1 2
6 Bradykinesia + Tremor + Poverty of speech 2 4
+ Sialorrhea + Sleeplessness
7 Gait disturbances + Poverty of speech + 1 2
Tardive dyskinesia
8 Tremor + Bradykinesia + Rigidity 5 10
9 Tremor + Bradykinesia + Rigidity + 1 2
Tardive dyskinesia
10 Tremor + Bradykinesia + Rigidity + 1 2
Poverty of speech + Perioral tremors
11 Tremor + Bradykinesia + Rigidity + 8 16
Poverty of speech
12 Tremor + Gait disturbances + Poverty of 4 8
speech
13 Tremor + Gait disturbances + Poverty of 4 8
speech + Tardive dyskinesia
14 Tremor + Bradykinesia + Gait disturbances 5 10
+ Poverty of speech
15 Tremor + Bradykinesia + Gait disturbances 1 2
+ Poverty of speech + Tardive dyskinesia
16 Tremor + Bradykinesia + Gait disturbances 2 4
+ Poverty of speech + Tardive dyskinesia +
Sialorrhea

49
 Figure 3: Frequency of different types of drug induced reactions

45 41
40 Profile of drug reaction
33
35
30
30
25
25

20 17

15
8 9
10
4
5 1 1 2 1 2

 Most common drug reaction was in the following order, bradykinesia >

tremor > rigidity > poverty of speech.

 There were different combinations of drug reactions occurring in the

patients.

 More than one reaction occurred in the same patient.

50
SUSPECTED DRUGS

Table 4A: Frequency of various drugs suspected to be the causative agents

Suspected drug Frequency %

Haloperidol 24 48.00

Risperidone 32 64.00

Chlorpromazine 13 26.00

Domperidone 1 2.00

Figure 4A: Frequency of various drugs suspected to be the causative

agents

Suspected drugs

40
24 32
30

20
10
13
0

1
Haloperidol
Risperidone
Chlorpromazine
Domperidone

 Most common suspected drug to cause DIP is risperidone followed by

haloperidol & chlorpromazine. Domperidone was found to cause DIP,

which was considered as new signal.

51
Table 4B: Distribution of combination of suspected drugs prescribed

S.No Suspected drugs combination Frequency Percentage

1 Chlorpromazine + Haloperidol 4 8
2 Risperidone + Chlorpromazine 3 6
3 Risperidone + Chlorpromazine + 4 8
Haloperidol
4 Haloperidol + Chlorpromazine 2 4
5 Haloperidol + Risperidone 4 8
6 Risperidone only 21 42
7 Domperidone only 1 2
8 Haloperidol only 11 22

Figure 4B: Distribution of combination of suspected drugs prescribed

Combination of suspected drugs

Frequency

Haloperidol only 11

Domperidone only 1

Risperidone only 21

Haloperidol + Risperidone 4

Haloperidol + Chlorpromazine 2

Risperidone + Chlorpromazine + Haloperidol 4

Risperidone + Chlorpromazine 3

Chlorpromazine + Haloperidol 4

52
  About 66% of patients were treated with monotherapy (Risperidone,

Haloperidol, Domperidone). Whereas 34% of patients were initially

prescribed with any one of the above antipsychotics which has lead to

the development of DIP, then the drug was discontinued and prescribed

with another antipsychotic drug which also was stated to cause DIP.

 Two drugs with the same potential to cause EPS were prescribed to the

same patient, even after development of EPS with one drug.

USE OF CONCOMITANT MEDICATIONS

Table 5: Pattern of use of Concomitant Medications

Use of Concomitant Medications Frequency Percent

Yes 50 100.0

Figure 5: Pattern of use of Concomitant Medications

Use of Concomitant Medications

100%

 All the patients were using one or more than one concomitant

medications.

53
DIAGNOSIS

Table 6: Different diagnosis pattern of patient with ADRs

Diagnosis Pattern Frequency Percent

Acute psychosis 4 8.0
Schizophrenia 26 52.0
Behaviour disorder 3 6.0
BPAD 5 10.0
Chronic depression 4 8.0
Depressive psychosis 3 6.0
GERD 1 2.0
OCD 1 2.0
Psychosis 1 2.0
Alcoholic psychosis 2 4.0
Total 50 100.0

54
Figure 6: Different diagnosis pattern of patient with ADRs

Alcoholic psychosis 2
Frequency of Diagnosis
pattern
Psychosis 1

OCD 1

GERD 1

Depressive psychosis 3

Chronic depression 4

BPAD 5

Behaviour disorder 3

Schizophrenia 26

Acute psychosis 4

0 5 10 15 20 25 30

 Most common diagnosis was schizophrenia followed by bipolar

affective disorder (BPAD).

55
DURATION OF ILLNESS

Table 7: Distribution of Duration of illness

Duration of illness (yrs) Frequency Percent

Upto 2 21 42.0
3- 4 14 28.0
5- 6 9 18.0
Above 6 – 10 6 12.0
Total 50 100.0

Figure 7: Distribution of Duration of illness

Frequency of Duration of illness

25
20
15
10
5
0

Upto 2 yrs
3- 4 yrs
5- 6 yrs

Above 6 yrs

Upto 2 yrs 3- 4 yrs 5- 6 yrs Above 6 yrs

Series1 21 14 9 6

 Duration their diagnosed primary illness varied from 2 years to more

than 6 years maximum up to 10 years.

56
ONSET OF REACTION AFTER TREATMENT

Table 8: Onset of reaction after treatment in years

Onset of reaction after

treatment in years Frequency Percent
1 month to Below 1year 13 26.0
1-2 20 40.0
3-4 11 22.0
Above 4 - 6 6 12.0
Total 50 100.0

Figure 8: Frequency of Onset of reaction after treatment in years

Onset of reaction after treatment

20

13
11

Below 1yr 1-2 yrs 3-4 yrs Above 4 yrs

 Most of the patient developed drug reaction after 1to 2yrs of starting the

treatment.

57
SERIOUSNESS OF REACTION

Table 9: Distribution of seriousness of reaction

Seriousness of reaction Frequency Percent

Hospitalization initial 20 40.0
Hospitalization prolonged 5 10.0
Required intervention 25 50.0
Total 50 100.0

Figure 9: Distribution of seriousness of reaction

Seriousness of reaction

40%
50% Hospitalization initial
Hospitalization prolonged
Required intervention

10%

 25 % 0f cases required intervention to prevent permanent damage due to

ADR, 20 % of cases required initial hospitalization & 5 % required

prolonged hospitalization due to ADR.

58
OUTCOME

Table 10: Distribution of outcome

Outcome Frequency Percent

Recovering 31 62.0
Recovered 14 28.0
Life threatening 2 4.0
Continuing 3 6.0
Total 50 100.0

Figure 10: Distribution of outcome

Frequency of Outcome

31

14

3
2

Recovering Recovered Life threatening Continuing

 31 cases were in recovery phase, 14 cases recovered from ADR, 3 cases

were in continuing phase & 2 cases developed serious life threatening

ADR.

59
CAUSALITY ASSESSMENT - WHO SCALE

Table 11: Causality assessment - WHO scale

Causality assessment -
WHO scale Frequency Percent
Probable 44 88.0
Possible 6 12.0
Total 50 100.0

Figure11: Causality assessment - WHO scale

Causality assessment - WHO scale

44

6
0 0 0 0

Certain Probable Possible Unlikely Conditional /

Unclassified

 Maximum ADRs were probable (88%) and rest of them were possible

(12%).

60
CAUSALITY ASSESSMENT – NARANJO SCALE

Table 12: Causality Assessment – Naranjo Scale

Causality Assessment –
Naranjo Scale Frequency Percent
Definite 0 0
Probable 44 88
Possible 6 12
Doubtful 0 0

Figure 12: Causality Assessment – Naranjo Scale

Causality assessment - Naranjo Scale

Frequency

Doubtful 0

Possible 6

Probable 44

Definite 0

 Maximum ADRs were probable (88%) and rest of them were possible

(12%).

61
ADR SEVERITY ASSESSMENT SCALE

Table 13: ADR severity assessment scale (Modified Hartwig and Siegel
scale)

Severity scale Frequency Percent

Mild –
Level – 1 0 0
Level – 2
Moderate –
Level – 3
50 50
Level – 4a
Level – 4b
Severe
Level - 5
0 0
Level – 6
Level - 7

Figure 13: ADR severity assessment scale (Modified Hartwig and Siegel

scale)

ADR severity assessment scale

Frequency

50

0 0

Mild Moderate Severe

 All the ADRs were of moderately severe requiring dose reduction or

discontinuation of the suspected drug and change to another drug.

62
PREVENTABILITY ASSESSMENT SCALE

Table 14: Preventability Assessment Scale

Preventability Assessment Scale Frequency Percent

Definitely preventable 0 0
Probably preventable 30 60.0
Not preventable 20 40.0
Total 50 100.0

Figure 14: Preventability Assessment Scale

Preventability assessment scale

frequency

30

20

Definitely
preventable Probably
preventable
Not preventable

 60 % of ADRs were probably preventable & 40 % were not preventable.

63
PROPHYLACTIC TREATMENT WITH THP

Table 15: Prophylactic treatment with THP

Prophylactic treatment with

Frequency Percent
THP
Yes 30 60.0
No 20 40.0
Total 50 100.0

Figure 15: Prophylactic treatment with THP

Prophylactic THP

No
40%

Yes
60%

 60% of patients were prophylactically treated with THP

64
IMPROVEMENT AFTER TREATMENT WITH THP

Table 16: Improvement after treatment with THP

Improvement after treatment with

Frequency Percent
THP
Yes 50 100.0

Figure 16: Improvement after treatment with THP

Improvement after treatment with THP

Improved

100%

 The entire patients with ADRs improved after treatment with THP.

65
AGE VERSUS SERIOUSNESS OF REACTION

Table 17: Age versus Seriousness of Reaction

Seriousness of reaction Total

Required
Hospitalizat Hospitalizati
interventi
ion initial on prolonged
on
Age in
21-30 Count 3 2 1 6
years
% within Age
50.0% 33.3% 16.7% 100.0%
in years
% within
Seriousness of 15.0% 40.0% 4.0% 12.0%
reaction
31-40 Count 1 1 1 3
% within Age
33.3% 33.3% 33.3% 100.0%
in years
% within
Seriousness of 5.0% 20.0% 4.0% 6.0%
reaction
41-50 Count 7 0 6 13
% within Age
53.8% .0% 46.2% 100.0%
in years
% within
Seriousness of 35.0% .0% 24.0% 26.0%
reaction
51-60 Count 6 2 14 22
% within Age
27.3% 9.1% 63.6% 100.0%
in years
% within
Seriousness of 30.0% 40.0% 56.0% 44.0%
reaction
61-70 Count 3 0 3 6
% within Age
50.0% .0% 50.0% 100.0%
in years
% within
Seriousness of 15.0% .0% 12.0% 12.0%
reaction
Total Count 20 5 25 50
% within Age
40.0% 10.0% 50.0% 100.0%
in years
% within
Seriousness of 100.0% 100.0% 100.0% 100.0%
reaction

66
Chi-Square Tests

Asymp. Sig.
Value df (2-sided)
Pearson Chi-Square 11.022(a) 8 .200
Likelihood Ratio 11.505 8 .175
Linear-by-Linear
1.708 1 .191
Association
N of Valid Cases 50

Figure 17: Age versus Seriousness of Reaction

16

14

12

10 S erio usne ss o f re

8 H os pita liza tion

ia l
6
H os pita liza tion
4
onge d

2
Count

R e quire d inte rv
0 n
21-30 41-50 61-70
31-40 51-60

Age in years

 All ADRs required various interventions in all age groups.

67
 AGE VERSUS OUTCOME OF ADR

Table 18: Distribution of Outcome of ADR in different age groups

Outcome Total
Life
Recovering Recovered Continuing
threatening
Age in 21-30 Count 3 2 1 0 6
years % within Age in 100.0
50.0% 33.3% 16.7% .0%
years %
% within 12.0
9.7% 14.3% 50.0% .0%
Outcome %
31-40 Count 1 1 0 1 3
% within Age in 100.0
33.3% 33.3% .0% 33.3%
years %
% within
3.2% 7.1% .0% 33.3% 6.0%
Outcome
41-50 Count 8 4 1 0 13
% within Age in 100.0
61.5% 30.8% 7.7% .0%
years %
% within 26.0
25.8% 28.6% 50.0% .0%
Outcome %
51-60 Count 15 5 0 2 22
% within Age in 100.0
68.2% 22.7% .0% 9.1%
years %
% within 44.0
48.4% 35.7% .0% 66.7%
Outcome %
61-70 Count 4 2 0 0 6
% within Age in 100.0
66.7% 33.3% .0% .0%
years %
% within 12.0
12.9% 14.3% .0% .0%
Outcome %
Total Count 31 14 2 3 50
% within Age in 100.0
62.0% 28.0% 4.0% 6.0%
years %
% within 100.0
100.0% 100.0% 100.0% 100.0%
Outcome %

68
Chi-Square Tests

Value df Asymp. Sig. (2-sided)

Pearson Chi-
10.776(a) 12 .548
Square
Likelihood Ratio 10.446 12 .577
Linear-by-Linear
1.141 1 .286
Association
N of Valid Cases 50

Figure 18: Distribution of Outcome of ADR in different age groups

16

14

12

10

8
Outcome
6
Recovering

4 Recovered

2 Life threatening
Count

0 Continuing
21-30 31-40 41-50 51-60 61-70

Age in years

69
  Most of the patients in all age groups were in recovery phase especially

more in the age group ranging from 51-60 yrs. Very few patients

recovered. There is no significance between age groups and outcome as

the P value = .548

GENDER VERSUS SERIOUSNESS OF REACTION

Table 19: Distribution of Gender versus Seriousness of reaction

Seriousness of reaction Total

Hospitali Hospitalizati Required
zation on interventio
initial prolonged n
Gender Male Count 9 1 5 15
% within Gender 60.0% 6.7% 33.3% 100.0%
% within
Seriousness of 45.0% 20.0% 20.0% 30.0%
reaction
Female Count 11 4 20 35
% within Gender 31.4% 11.4% 57.1% 100.0%
% within
Seriousness of 55.0% 80.0% 80.0% 70.0%
reaction
Total Count 20 5 25 50
% within Gender 40.0% 10.0% 50.0% 100.0%
% within
Seriousness of 100.0% 100.0% 100.0% 100.0%
reaction

Chi-Square Tests

Value df Asymp. Sig. (2-sided)

Pearson Chi-
3.571(a) 2 .168
Square
Likelihood Ratio 3.537 2 .171
Linear-by-Linear
3.172 1 .075
Association
N of Valid Cases 50

70
Figure 19: Distribution of Gender versus Seriousness of reaction

30

20

Seriousness of react

Hospitalization init

ial
10
Hospitalization prol

onged

Required interventio
Count

0 n
Male Female

Gender

 The distribution of seriousness of reaction was different among male

and female patient. Female patients required more intervention and

hospitalization than male patients. But there is no statistical significant

difference found between sex and seriousness of reaction when

Chi-square test is applied as the P value is .168

71
GENDER VERSUS OUTCOME OF ADR

Table 20: Distribution of Gender versus Outcome of ADR

Outcome Total
Recov Recover Life
Continuing
ering ed threatening
Gender Male Count 10 3 1 1 15
% within
66.7% 20.0% 6.7% 6.7% 100.0%
Gender
% within
32.3% 21.4% 50.0% 33.3% 30.0%
Outcome
Female Count 21 11 1 2 35
% within
60.0% 31.4% 2.9% 5.7% 100.0%
Gender
% within
67.7% 78.6% 50.0% 66.7% 70.0%
Outcome
Total Count 31 14 2 3 50
% within
62.0% 28.0% 4.0% 6.0% 100.0%
Gender
% within 100.0
100.0% 100.0% 100.0% 100.0%
Outcome %

Chi-Square Tests

Asymp.
Sig. (2-
Value df sided)
Pearson Chi-
.962(a) 3 .810
Square
Likelihood Ratio .961 3 .811
Linear-by-Linear
.001 1 .971
Association
N of Valid Cases 50

72
Figure 20: Distribution of Gender versus Outcome of ADR

30

20

Outcome

10 Recovering

Recovered

Life threatening
Count

0 Continuing
Male Female

Gender

 The distribution of gender versus outcome varies among male and

female patients. Female patients showed better outcome when compared

with male patients. But there is no significant difference found between

gender and outcome of ADR when Chi-square test is applied as the P

value is .810

73
 PROPHYLACTIC THP VERSUS OUTCOME

Table 21: Distribution of Prophylactic THP versus Outcome

Outcome Total
Life
Recovering Recovered threatening Continuing
Prophylactic Yes Count 16 12 1 1 30
THP % within
Prophylactic 53.3% 40.0% 3.3% 3.3% 100.0%
THP
% within
51.6% 85.7% 50.0% 33.3% 60.0%
Outcome
No Count 15 2 1 2 20
% within
Prophylactic 75.0% 10.0% 5.0% 10.0% 100.0%
THP
% within
48.4% 14.3% 50.0% 66.7% 40.0%
Outcome
Total Count 31 14 2 3 50
% within
Prophylactic 62.0% 28.0% 4.0% 6.0% 100.0%
THP
% within
100.0% 100.0% 100.0% 100.0% 100.0%
Outcome

Chi-Square Tests

Asymp.
Sig. (2-
Value df sided)
Pearson Chi-
5.738(a) 3 .125
Square
Likelihood Ratio 6.283 3 .099
Linear-by-Linear
.076 1 .783
Association
N of Valid Cases 50

74
Figure 21: Distribution of Prophylactic THP versus Outcome

20

10
Outcome

Recovering

Recovered

Life threatening
Count

0 Continuing
Yes No

Prophylactic THP

 The outcome of ADR was slightly better when the patients were

prophylactically treated with THP. The recovery from ADR was found

to more when patients were prescribed with prophylactic THP. But there

is no significant difference found between gender and outcome of ADR

when Chi-square test is applied as the P value is .810

75
SUSPECTED DRUGS VERSUS AGE

Table 22: Distribution of Suspected drugs versus age

Age in years
Suspected Total
drugs
21-30 31-40 41-50 51-60 61-70
Haloperidol 3 0 8 11 2 24
Risperidone 4 3 7 13 5 32
Chlorpromazine 1 1 3 8 0 13
Domperidone 0 0 0 1 0 1

Figure 22: Distribution of Suspected drugs versus age

Suspected drug vs Age

Haloperidol Risperidone Chlorpromazine Domperidone

13

11

8 8
7

5
4
3 3 3
2
1 1 1
0 0 0 0 0 0

21-30 31-40 41-50 51-60 61-70

Age (yrs)

 Suspected drugs were more commonly used in age group of 51-60 years

and least commonly used in age group of 31-40 years.

76
SUSPECTED DRUG VERSUS GENDER
Table 23: Distribution of Suspected Drug versus Gender

Gender
Suspected drugs Total
Male Female
Haloperidol 9 15 24
Risperidone 9 23 32
Chlorpromazine 5 8 13
Domperidone 0 1 1

Figure 23: Distribution of Suspected Drug versus Gender

Suspected drug vs Gender

Male Female

23
15

8
9 9
5 1

Haloperidol Risperidone Chlorpromazine Domperidone

 All the suspected drugs were more commonly used by female patients

when compared with male patients.

77
SUSPECTED DRUG VERSUS SERIOUSNESS OF REACTION

Table 24: Distribution of Suspected Drug versus Seriousness of Reaction

Seriousness of reaction
Suspected drugs Hospitalization Hospitalization Required Total
initial prolonged intervention
Haloperidol 12 0 12 24
Risperidone 10 5 17 32
Chlorpromazine 3 3 7 13
Domperidone 0 0 1 1

Figure 24: Distribution of Suspected Drug versus Seriousness of Reaction

Suspected drug vs Seriousness of reaction

Hospitalization initial Hospitalization prolonged Required intervention

17

12 12

10

3 3

1
0 0 0

Haloperidol Risperidone Chlorpromazine Domperidone

 The patients requiring initial hospitalization were almost equal in those

using Haloperidol & Risperidone. Whereas prolonged hospitalization

and intervention was highly required in those using Risperidone.

78
SUSPECTED DRUG VERSUS OUTCOME OF THE ADR

Table 25: Distribution of Suspected Drug versus Outcome of the ADR

Outcome of ADR
Suspected drugs Life Total
Recovering Recovered threatening Continuing
Haloperidol 16 8 0 0 24
Risperidone 19 8 2 3 32
Chlorpromazine 4 6 0 3 13
Domperidone 1 0 0 0 1

Figure 25: Distribution of Suspected Drug versus Outcome of the ADR

Suspected drug vs Outcome of ADR

Domperidone Chlorpromazine Risperidone Haloperidol

0
3
Continuing 3
0

0
Life 0
threatening 2
0

0
6
Recovered 8
8

1
4
Recovering 19
16

 Among the above suspected drugs, Risperidone produced a life threatening

reaction. Recovery was almost similar with Risperidone , Haloperidol, &

Chlorpromazine. Majority of the patients using all these

79
 DISCUSSION

AGE

Table 1 and Figure 1 shows that 44% of DIP was common in the age

group of 51- 60 years. 26% of DIP was common in the age group of 41–50

years followed by 12% in the age groups of 61-70 years and 21-30 years.

About 6% of DIP was seen in the age group of 31- 40 years. Hence the most

common age group affected was 51- 60 years. Bondon-Gitton E et al in their

study found that DIP were mostly seen in the age group of 60-79 years.35 R J

Harde et al in their study found that Harde R J et al in their study found that the

median age group who developed DIP was 61years.36

GENDER

Table 2 and Figure 2 shows that DIP was found to be more common in

females (70%) compared to males (30%). Bondon-Gitton E et al in their study

found that DIP was mostly seen in females (60%), which was almost similar to

our study.35 In an another study done by Harde R J et al, found that DIP was

mostly seen in females (60%) in their study, which was almost similar to our

study.36

PROFILE OF DRUG REACTION

Table 3A and Figure 3 had shown the various manifestation profile of

DIP. Totally 13 types of manifestations occurred in the patients. Among these,

bradykinesia was found to be the most common manifestation (82%), followed

80
by tremor (66%), rigidity (60%), and poverty of speech (50%). Less than 50%

of patients developed gait disturbances (34%), Tardive dyskinesia (18%),

Akathisia (16%). Less than 10% of patients developed Sialorrhea (8%),

Sleepleesness and Perioral tremors (4%). 1% of patients developed Muscular

dystonia, Neuroleptic malignant syndrome, and Oculogyric crisis.

Bondon-Gitton E et al in their study found that rigidity was the most

common manifestation.35 Harde R J et al; also found that in their study rigidity
36
was the most common manifestation. But in our study we found that

bradykinesia was found to be the most common manifestation.

Table 3B showed different combinations of manifestations of DIP. More

than one symptom occurs in the same patient. 10% of the patients developed

the classical triad of DIP, bradykinesia, rigidity, and tremor.16% people

developed a combination of tremors, rigidity, bradykinesia, and poverty of

speech, which is the most common combination of symptom. Jimenz- Jimenz F

J et al in their study has stated that it is possible for a single drug to cause 2 or
37
more types of extrapyramidal symptoms in the same patient, which was

proved to be similar in our study also where the same patient has developed

two or EPS.

SUSPECTED DRUGS

Table 4A, 4B and Figure 4A, 4B show the frequency of various drugs

involved in causing DIP. These drugs fall under the group of dopamine

antagonists like antipsychotics, and prokinetics. Atypical antipsychotic drug,

81
risperidone (64%) was the most common suspected drug causing DIP. Of the

typical antipsychotic drugs, Haloperidol (48%), and Chlorpromazine (26%)

were found as suspected drug to cause DIP. Of the prokinetics, domperidone

(2%) was found as suspected drug to cause DIP.

So in our study, the most common causative drug group to cause DIP

belongs to antipsychotic drugs, in which atypical antipsychotic drug

risperidone was found to cause more DIP than typical antipsychotics. This was

because most of the patients were treated with risperidone when compared to

other drugs. The usage of typical antipsychotics was not so common when

compared to atypical antipsychotics for treating various psychiatric diseases.

Most of the psychiatrist prefers to use atypical antipsychotics as they found to

cause less extrapyramidal symptoms with good efficacy when compared to

typical antipsychotics.

Eventhough risperidone was an atypical antipsychotic drug, it has more

affinity towards D₂ receptor and hence it causes more extrapyramidal

symptoms when compared to other atypical antipsychotics. This indicates that

risperidone have brought only relative avoidance of EPS, which urges for the

search for novel antipsychotic drug without EPS. Weiden P J, in his study has

stated that EPS remains as a significant problem even in the era of second

generation (SGAs) or atypical antipsychotics. He states that most of the novel

atypical antipsychotics can still cause EPS, and when it occurs they tend to be

less severe when compared to typical antipsychotics. He also states that

reduced EPS was not the same as no EPS. He states that EPS incidence differs
82
among the newer SGAs, with risperidone ranking as the most common

causative agent, and clozapine and quietiapine with least propensity to cause

EPS. 38

Domperidone being a D₂ receptor antagonist has found to cause DIP in

this study. K.D. Tripathi states the reason behind this as follows; it is

chemically related to haloperidol but pharmacologically related to

metoclopramide. It is used as antiemetic and prokinetic drug, attributed to D₂

receptor blockade in upper gastro intestinal tract. It crosses blood brain barrier

poorly, hence extrapyramidal side effects are rare.1 Bolegha et al in his review

states that domperidone has safe neurological profile attributed to its poor

penetration of blood brain barrier; yet, there were many reports on

domperidone causing extrapyramidal side effects. This was explained by the

presence of defective blood brain barrier in case of elderly, post brain surgery

and cerebral infarction.39

Table 3B show that, even after development of EPS with a drug, two

drugs with same potential to cause EPS were prescribed to the same patient.

Bondon-Gitton E et al in their study found that antipsychotics were the most

common group of drug to cause DIP.35

CONCOMITANT MEDICATIONS AND CO-MORBID CONDITIONS

All the patients were prescribed with one or more concomitant

medications. These drugs were prescribed for the associated co-morbidities like

83
alcoholic dependence, depression, hypertension, T2DM, hypothyroidism,

seizure disorder, GERD, monilial esophagitis, and mental retardation.

DIAGNOSIS

Table 6 and Figure 6 show that all these drugs were used to treat

psychiatric diseases except domperidone which was used to treat GERD. Most

common psychiatric disease for which the patients were taking antipsychotic

drugs was schizophrenia (52%). 10% of patients suffered from BPAD,

followed by acute psychosis and chronic depression (8%), behaviour disorder

and depressive psychosis (6%), alcoholic psychosis (4%), GERD, OCD and

psychosis (1%). Harde R J et al; found that in their study schizophrenia was the

most common diagnosis for which the patients were taking antipsychotic drugs

which exactly found to be similar in our study.36

DURATION OF UNDERLYING ILLNESS

Table 7 and figure 7 shows that duration of illness varies from less than

2 years to maximum of 10 years. Less than 2 years (42%) was found to be the

most common duration of illness followed by 3-4 years (28%), 5-6years (9%),

and 6-10 years (6%).

ONSET OF REACTION:

Table 8 and Figure 8 show that onset of reaction after drug introduction

varies from 1 month to 6 years. Onset of reaction denotes the duration of

exposure to suspected antipsychotic drugs. Most of the patient developed drug

84
reaction after 1to 2yrs of starting the treatment, followed by 1 month to below

one year of duration. The maximum onset of reaction was found to be 6 years

after starting of treatment.

Harde R J et al; found that in their study the duration of exposure varied

widely from 4 weeks to 22yrs. The median duration of exposure was 3 years

and the mean duration of exposure was 6.3years, 36 and this study co-relates

similarly with our study in the minimal onset range and median and but differs

in maximal onset range and mean.

SERIOUSNESS OF REACTION

Table 9 Figure 9 show the seriousness of the adverse drug reactions.

Most of the patients required interventions (50%) like cessation of the

suspected drug, treatment with one of the centrally acting anticholinergic drugs

and change of drug to those having less potential to cause EPS. Rest of the

patients required hospitalization initially (40%), or their hospitalization was

prolonged (10%) due to EPS.

Table 17 and Figure 17 show that all the ADRs required various

interventions in all age groups and no statistical difference was found in

between age and seriousness of reaction. Table 19 and Figure 19 show that the

distribution of seriousness of reaction was different among male and female

patient. Female patients required more intervention and hospitalization than

male patients. But there is no statistical significant difference found between

85
sex and seriousness of reaction when Chi-square test is applied as the

P value is .168

OUTCOME

Table 10 and Figure 10 show the distribution of the outcome of the drug

induced reaction. Most of the patients were in recovering state (62%). About

28% of patients recovered from their illness. Few of the patients had their

reaction continuing (6%) and few had life threatening reactions (4%). Bondon-

Gitton E et al in their study found that about 88.7% patients were improving

from their illness, showing good favourable outcome when compared to our

study where 62% were improving.35 Harde R J et al; found that in their study

8% of people got completely recovered from the reaction, which is very low

when compared to our study which had complete recovery in 28% of patients.36

Table 18 and Figure 18 show that Most of the patients in all age groups

were in recovery phase especially more common in the age group ranging from

51-60 yrs. Very few patients recovered. There is no significance between age

groups and outcome as the P value = .548

CAUSALITY ASSESSMENT- WHO SCALE and NARANJO SCALE

Table 11 & 12; Figure 11 & 12 show the causality assessment of the

drug induced reaction. When the above two scales were used to assess the

causality, they both had shown same results as follows. Maximum ADRs were

categorized as probable (88%) and rest of them were of possible category

(12%). Mandal et al in their study used Naranjo’s scale for causality

86
assessment and found that most of the ADRs were of “probable” and

“possible” category, which was found to be similar to our study.40

ADR SEVERITY ASSESSMENT SCALE

Table 13 and Figure 13 show that all the ADRs (100%) were of

moderately severe requiring dose reduction or discontinuation of the suspected

drug and change to another drug. Bondon Guitton et al in their study states that
41
43.9% of cases found to be of “serious” category among 155 cases of DIP ,

which varied widely when compared to our study which consists of 100% of

moderate severity.

PREVENTABILITY ASSESSMENT SCALE

Table 14 and Figure 14 show that 60 % of ADRs were probably

preventable & 40 % were not preventable. All the drugs were indicated for

their psychiatric illness, but sometimes when the patient develops DIP for one

antipsychotic drug, after discontinuing it they were given another antipsychotic

drug of the same group or different group which also has the high propensity to

cause EPS. This overlapping of drugs with same potency to cause DIP could

have been avoided to prevent the development of DIP.

PROPHYLAXIS AND TREATMENT WITH THP

Table 15 and Figure 15 show that about 60% of the patients were

prophylactically treated with THP. Harde R J et al, states that anticholinergics

were traditionally used either as prophylaxis or as treatment against DIP. 36

87
 Table 16 and Figure 16 show that the entire patient who developed DIP

was treated with THP, and all of them showed improvement after treatment.

Mamo, D.C.,et al states that in younger patients anticholinergic agents remain

the mainstay pharmacological management of DIP caused by antipsychotics.in

elderly patients, amantadine was better tolerated with efficacy similar to

anticholinergic agents. And also they state that routine use of the prophylactic

anticholinergics was not needed and was clearly contraindicated in the elderly

patients.

Limitations of the Study: The study was done in small group of 50

patients. It was done only in the departments of Psychiatry and Neurology; if

this study was extended to other departments then other suspected drugs

causing DIP would have been identified. Therapeutic drug monitoring was not

done which may be helpful to avoid the toxic dose concentration. In this study

rechallenge for drug induced reaction with suspected drug was not performed

due to ethical consideration.

88
 CONCLUSION

The study was undergone to analyze the profile of drug induced

Parkinsonism, and to assess the causality, severity and preventability in the

outpatient department of Psychiatry and Neurology. Total patients enrolled

with DIP during one year study duration were 50. The aim and objectives of

the study were met. Most common age group affected with DIP is 51-60 yrs.

DIP was found to be more common in females when compared to males.

Antipsychotics were the most common group of drug suspected to cause DIP.

Domperidone was found to cause DIP, which was found in one patient.

Bradykinesia was considered as most common symptom of DIP,

followed by tremor and rigidity. Risperidone, the atypical antipsychotic was

most commonly used and was highly found to cause DIP. All the patients were

using one or more than one concomitant medications. Most common diagnosis

was schizophrenia followed by bipolar affective disorder. Most of the patient

developed drug reaction after 1to 2yrs of starting the treatment.

Maximum ADRs were probable (88%) and rest of them were possible

(12%). All the ADRs were moderately severe requiring dose reduction or

discontinuation of the suspected drug and change to another drug. 60 % of

ADRs were probably preventable & 40 % were not preventable. All the

patients with ADRs showed improvement after treatment with THP.

Thus this study gives overall view about drug induced Parkinsonism

among the attended the outpatient department of Psychiatry and Neurology in a

89
tertiary care hospital. And this study shows that drugs were important

etiological factor for DIP and clinicians should be vigilant about the safety

profile monitoring of the medications prescribed. Hence Pharmacovigilance

programmes to be implemented efficiently and continuous vigilance is needed

to detect ADRs thereby making drug therapy safe and effective.

IMPACT ON THE PATIENT

DIP can cause considerable physical disability, subjective discomfort

and distress to the patients. It was stated as the most common reason for the

poor compliance with the medications. It unnecessarily increases the cost of

treatment which adds to financial burden of the patient. It can confuse the

clinical assessment of the exact medical condition of the patient as the

symptom overlaps with that of the psychiatric illness. Hence DIP was harmful

and serves no beneficial purpose to the patient.

PREVENTIVE APPROACH

 Prevention is always better than cure. Since the treatment of drug

induced movement disorders remains challenging, a preventive

approach is always better and preferable.

 The use of the suspected and offending drugs should be strictly

restricted to appropriate indications and should be definitely avoided

when a better drug is available for the same.

 Early process to avoid DIP is to keep a high index of suspicion for all

the possible causes, by maintaining a thorough list of the drugs

90
 prescribed to the patient and also search for other possible sources of

getting the offending drugs.

 Prescribers should be vigilant for DIP, especially in elderly, in those

patients taking multiple drug therapy, in those who have previous

history of EPS, in those on prolonged treatment profile, familial history,

and in those with genetic variants to develop idiopathic Parkinson’s

disease.

 “ADR alert card” can be issued to the patients who had developed

DIP, stating the type of ADR and the suspected drug causing the ADR.

This will help in future to identify the patients vulnerable to develop

ADR and helps to avoid prescribing the offending drug in such patients.

FUTURE SCOPE

 Better characterisation of the neurochemical profile of the affected

system and its function should be focused to have better treatment.

 Novel drugs with high selectivity, good efficacy and less side effect

profile should be developed to ensure good patient compliance.

 Further pharmacovigilance studies on DIP for long duration should

be conducted to widen the knowledge about the existing trends,

changing trends and overall profile of DIP.

91
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00002018-199920030-00006
 ANNEXURE: I

WHO CAUSALITY CLASSIFICATION15

CAUSALITY ASSESSMENT
Certain • Event or laboratory test abnormality, with plausible time
relationship to drug intake
• Cannot be explained by disease or other drugs
• Response to withdrawal plausible(pharmacologically,
pathologically)
• Event definitive pharmacologically or
phenomenological(i.e. an objective and specific medical
disorder or a recognized pharmacological phenomenon)
• Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable
time relationship to drug intake
• Unlikely to be attributed to disease or other drugs
• Response to withdrawal clinically reasonable
• Rechallenge not required
Possible • Event or laboratory test abnormality ,with reasonable
time relationship to drug intake
• Could not be explained by the disease or other drugs
• Information on drug withdrawal may be lacking or
unclear
Unlikely • Event or Laboratory test abnormality with a time to drug
intake that makes a relationship improbable(but not
impossible)
• Disease or other drugs provide plausible explanations
Conditional/ • Event or Laboratory abnormality
Unclassified • More data for proper assessment needed, or
• Additional data under examination
Unassessable / • Report suggesting an adverse reaction
Unclassifiable • Cannot be judged because information is insufficient or
contradictory
• Data cannot be supplemented or verified
 ANNEXURE: II

NARANJO ALGORITHM

To assess causality of adverse drug reaction, answer the following

questionnaire and score it

S.no Questions Yes No Do not Score

know
1 Are there previous conclusive reports +1 0 0
on this reaction?
2 Did the adverse event occur after the +2 -1 0
suspected drug was administered?
3 Did the adverse reaction improve when +1 0 0
the drug was discontinued or a specific
antagonist was administered?
4 Did the adverse reaction reappear when +2 -1 0
the drug was re-administered?
5 Are there alternative causes (other than -1 +2 0
the drug) that could have on their own
caused the reaction?
6 Did the reaction reappear when the -1 +1 0
placebo was given?
7 Was the drug detected in the blood (or +1 0 0
other fluids) in concentrations known
to be toxic?
8 Was the reaction more severe when the +1 0 0
dose was increased or less severe when
the dose was decreased?
 9 Did the patient have a similar reaction +1 0 0
to the same or similar drugs in any
previous exposure?
10 Was the adverse event confirmed by +1 0 0
any objective evidence?
Total

Category Score

Definite >9

Probable 5-8

Possible 1-4

Doubtful 0
 ANNEXURE: III

MODIFIED SCHUMOK AND THORTON SCALE –

PREVENTABILITY ASSSESSMENT SCALE

Definitely preventable

1. Was there a history of allergy or previous reactions to the drug?

2. Was the drug involved inappropriate for the patient’s clinical condition?

3. Was the dose, route or frequency of administration inappropriate for the

patient’s age, weight or disease state?

4. Was a toxic serum drug concentration (or laboratory monitoring test)

documented?

5. Was there a known treatment for the adverse drug reaction?

Probably preventable

6. Was required therapeutic drug monitoring or other necessary laboratory

tests not performed?

7. Was a drug interaction involved in the ADR?

8. Was poor compliance involved in ADR?

9. Were preventive measures not prescribed or administered to the patient?

Not preventable

If all above criteria not fulfilled

 ANNEXURE: IV

MODIFIED HARTWIG AND SIEGEL SCALE -

ADR SEVERITY ASSESSMENT SCALE

Mild
Level 1: The ADR requires no change in treatment with the suspected drug
(or)
Level 2: The ADR requires that the suspected drug be withheld, discontinued
or otherwise changed, and there is no increase in the length of the stay
Moderate
Level 3: The ADR requires that the suspected drug be withheld, discontinued
or otherwise changed, and / or an antidote or other treatment is required. There
is no increase in the length of the stay
(or)
Level 4 (a): Any level 3 ADR that increase the length of the stay by at least
one day
(or)
Level 4 (b): The ADR is the reason for the admission
Severe
Level 5: Any level 4 ADR that requires intensive medical care
(or)

Level 6: The ADR causes permanent harm to the patient

(or)

Level 7: The ADR either directly or indirectly leads to the death of the patient
 ANNEXURE: V

PROFORMA

REF. NO:

DATE:

NAME:
AGE/SEX:

ADRESS/PHONE NUMBER:

HISTORY:

DRUG H/O:

Medication details:

Name of the Dose , dosing Route of Duration of ADRs Outcome

medication schedule administration prescription

SUMMARY OF ILLNESS:

Duration Severity Impact of Reason for change Impact of treatment

disease of drug, if any

DIAGNOSIS:

INVESTIGATIONS:

TREATMENT:
 ANNEXURE: VI

CONSENT FORM

Title: ‘Drug Induced Parkinsonism – A Causality, Severity, & Preventability

Assessment Study In A Tertiary Care Hospital ’

Study Centre: Govt. Kilpauk Medical College, Chennai-10

Patient’s Name: O.P. No.:

Patient’s Age/sex:

I confirm that I have understood the purpose and procedure of the above study. I had
the opportunity to ask questions and all my doubts have been answered satisfactorily.

I understand that my participation in the study is voluntary and that I am free to

withdraw at any time without my legal rights being affected.

I understand that the members of the ethics committee and the investigators involved
in the study will not need my permission to look at my health records, both in respect
to the current study and any other further research that may be conducted in relation
to it. However, I understand that my identity will not be revealed in any information
released to third parties or published, unless as required under the law. I agree not to
restrict the use of any data or results that may arise from this study.

I hereby consent to participate in this study.

Patient’s Signature/ Thumb Impression:

Patient’s Name and address:

Witness Signature/ Thumb Impression:

Witness Name and address:

Investigator’s Signature:

Name of the Investigator:

Date:

Place:
 ANNEXURE: XII

TURNITIN DIGITAL RECEIPT

 ANNEXURE- XI
MATER SHEET
Profile
Onset of
of
Duration reaction
Age adverse Suspected concomitant Seriousness
No Gender Diagnosis of illness after
(yrs ) drug drugs medications of reaction
(yrs ) Treatment
reaction
(yrs)
(DIP)
T, GD,
1 62 F R Y 1 3 0.6 1
PS
2 62 F B, R R Y 6 9 6 3
T, B,
3 60 M R , CPZ Y 1 3 1 2
PT,TD
T, GD,
4 59 F D Y 7 2 0.6 3
PS
5 58 F T, B, R CPZ, HLP Y 2 6 5 3
6 58 F B, R CPZ, HLP Y 2 6 5 3
B, T,PS ,
7 53 M HLP , CPZ Y 10 5 4 1
SL, S
T, B, R,
8 53 F HLP , R Y 2 2 1 3
PS
T, B, R,
9 53 F R Y 2 1 0.9 3
PS
B, T,PS ,
10 53 M HLP , CPZ Y 10 5 4 1
SL, S
11 50 F T, B, R R Y 2 3 2 3
T, GD,
12 50 F R Y 4 1 0.2 3
PS
13 50 F B, R R Y 2 3 2 3
T, GD,
14 48 M HLP Y 3 4 11 1
PS ,TD
GD, PS ,
15 48 F HLP Y 3 4 1 1
TD
T, GD,
16 48 M HLP Y 3 4 1 1
PS ,TD
T, B, R ,
17 46 F R Y 2 1 0.1 1
PS,PT
T,B, GD,
18 45 M R Y 6 5 4 1
PS
19 45 F T, B, R R, CPZ, HLP Y 4 1 0.2 3
T,B, GD,
20 42 F R, CPZ, HLP Y 2 3 2 3
PS
B, R ,
21 42 F CPZ, HLP Y 2 5 1 1
MD
22 37 M B, R R Y 4 1 0.2 3
T,B, GD,
23 65 F HLP , R Y 5 7 3 1
PS ,S, TD
24 35 F B, R, A R Y 5 7 6 1
T,B, GD,
25 60 M R Y 8 1 0.8 1
PS
26 55 F T, B, R HLP Y 2 2 1 3
T,B, GD,
27 57 M HLP , R Y 5 7 3 1
PS ,S, TD
28 55 F B, R, A R Y 5 7 6 1
 T, GD,
29 31 F R , CPZ Y 1 2 2 2
PS ,TD
30 61 M B, R,OC R Y 2 2 3 1
T, GD,
31 53 F R , CPZ Y 1 2 2 2
PS ,TD
32 60 F B, Rj HLP Y 2 1 0.3 1
33 30 F B, Rj HLP Y 2 1 0.3 1
B, R, A,
34 29 F R Y 2 6 2 2
NMS
35 28 F B, R, A R Y 9 3 2 `
T, B, R,
36 47 F HLP Y 2 2 1 1
PS
T, B, R,
37 27 M HLP Y 2 2 1 1
PS
T,B, GD,
38 52 M R Y 2 3 2 3
PS , TD
T, B, R,
39 24 F R Y 2 1 0.2 1
PS
T,B, GD,
40 22 M R, CPZ, HLP Y 2 4 3 3
PS
T, B, R,
41 55 F HLP , R Y 2 1 0.3 3
PS
42 50 F B, R, A HLP Y 2 2 1 3
T, B, R,
43 60 F R Y 2 3 2 3
PS
T, GD,
44 52 F R Y 2 1 0.2 3
PS
45 57 F B, R, A HLP Y 4 2 1 3
46 65 M B, R, A HLP Y 2 4 3 3
47 62 F T, B, R R Y 6 6 3 3
T, B, R,
48 56 F CPZ, HLP Y 2 4 2 3
PS
T,B, GD,
49 51 M R, CPZ, HLP Y 2 6 3 3
PS
50 54 F B, R, A R Y 4 7 4 3
 ADR
Improvement
WHO Naranjo severity Preventability Prophylactic Lab
No after Outcome
scale scale assessment assessment THP investigations
treatment
scale
1 2 2 2 3 Y N 1 N
2 2 2 2 3 Y N 2 N
3 2 2 2 3 Y Y 4 N
4 2 2 2 3 Y N 1 N
5 2 2 2 2 Y Y 2 N
6 2 2 2 2 Y Y 2 N
7 3 3 2 2 Y Y 1 N
8 2 2 2 2 Y N 1 N
9 2 2 2 3 Y N 1 N
10 3 3 2 2 Y Y 1 N
11 2 2 2 3 Y Y 1 N
12 3 3 2 3 Y Y 2 N
13 2 2 2 3 Y Y 2 N
14 2 2 2 2 Y N 1 N
15 2 2 2 2 Y N 1 N
16 2 2 2 2 Y N 1 N
17 2 2 2 3 Y Y 1 N
Focal
demyelination
18 2 2 2 3 Y N 3
(Drug
induced)
19 2 2 2 2 Y Y 2 N
20 2 2 2 2 Y Y 1 N
21 2 2 2 2 Y Y 2 N
22 2 2 2 3 Y Y 2 N
23 2 2 2 2 Y N 1 N
24 2 2 2 2 Y N 1 N
25 2 2 2 2 Y N 1 N
26 2 2 2 2 Y Y 2 N
27 2 2 2 2 Y N 1 N
28 2 2 2 2 Y N 1 N
29 3 3 2 2 Y N 4 N
30 2 2 2 3 Y Y 1 N
31 3 3 2 2 Y N 4 N
32 2 2 2 2 Y Y 2 N
33 2 2 2 2 Y Y 2 N
34 2 2 2 3 Y Y 3 N
35 2 2 2 3 Y N 1 N
36 2 2 2 2 Y Y 1 N
37 2 2 2 2 Y Y 1 N
38 2 2 2 3 Y N 1 N
39 2 2 2 2 Y Y 1 N
40 2 2 2 2 Y Y 2 N
41 2 2 2 2 Y N 1 N
42 2 2 2 2 Y Y 1 N
43 2 2 2 3 Y Y 1 N
44 3 3 2 3 Y Y 1 N
45 2 2 2 3 Y Y 1 N
46 2 2 2 2 Y Y 1 N
47 2 2 2 3 Y N 2 N
48 2 2 2 2 Y Y 1 N
49 2 2 2 2 Y Y 2 N
50 2 2 2 3 Y Y 1 N
Figure (A): Communication channels in PvPI 24

Pharmaceutical industries
CDSCO, Headquarter in India
New Delhi
National Immunization
Programme
The Uppsala
Monitoring Centre Professional bodies

National coordination centre

IPC, Ghaziabad
Signal review panel
Steering Working Core training panel
committee group Quality review panel

CDSCO Zonal Offices

ADR monitoring centres South Zone, Chennai
West Zone, Mumbai
Health care professionals & East Zone, Kolkata
patients North Zone, Ghaziabad
Figure (B): Synthesis of Dopamine
Figure (C): Storage, Release, and Metabolism of Dopamine
Figure (D): Dopamine Receptor Family and Distribution
Figure (E): Anatomy of Dopamine Pathway Areas

Figure (F): Dopamine pathways

Figure (G): Mechanism of action of Antipsychotics
Figure (H): Receptor occupancy & clinical response of antipsychotics
 SUSPECTED ADVERSE DRUG REACTION REPORTING FORM
For VOLUNTARY reporting of Adverse Drug Reactions by healthcare professionals

CDSCO (AMC/ NCC Use only

Central Drugs Standard Control Organization AMC Report No.
Directorate General of Health Services,
Ministry of Health & Family Welfare, Government of India,
FDA Bhavan, ITO, Kotla Road, New Delhi Worldwide Unique no.
www.cdsco.nic.in

A. Patient Information 12. Relevant tests / laboratory data with dates

1.Patient Initials 2.Age at time of 3. Sex M F
_____________ Event or date of
birth 4. Weight ____Kgs

-------------------
B .Suspected Adverse Reaction
5. Date of reaction stated (dd/mm/yyyy) 13. Other relevant history including pre-existing medical
6. Date of recovery (dd/mm/yyyy) conditions (e.g. allergies, race, pregnancy, smoking, alcohol use,
hepatic/ renal dysfunction etc)
7. Describe reaction or problem

14. Seriousness of the reaction

 Death (dd/mm/yyy)____  Congenitial anomaly
 Life threatening  Required intervention
 Hospitalization-initial or to prevent permanent
prolonged impairment / damage
 Disability  Other (specify)

15. Outcomes
 Fatal Recovering Unknown
 Continuing Recovered Other (specify)____

C.Suspected medication(s)
S.No 8. Name Manufactu Batch Exp. Date Dose Route Frequency Therapy dates (if known give Reason for use of
(brand and /or rer (if No./ Lot (if used used duration) prescribed for
generic name) known) No. (if known)
known) Date Date stopped
started
i.
ii.
iii.
iv.
Sl.No 9. Reaction abated after drug stopped or dose 10. Reaction reappeared after reintroduction
As per C
reduced
Yes No Unknown NA Reduced dose Yes No Unknown NA If reintroduced
dose
i.
ii.
iii.
iv.
11. Concomitant medical product including self medication and D. Reporter (see confidentiality section in first page)
herbal remedies with therapy dates (exclude those used to treat 16. Name and Professional Address :___________________________
reaction) _______________________________________________________
Pin code : ______________ E-mail _______________________
Tel. No. (with STD code): ______________________________
Occupation ________________Signature ______________
17. Causality Assessment 18. Date of this report (dd/mm/yyyy)
ADVICE ABOUT REPORTING Suspected Adverse Drug
Report adverse experiences with medications
Report serious adverse reactions. A reaction is
Reaction
serious when the patient outcome is: Reporting Form
For VOLUNTARY reporting
death of suspected adverse drug reactions by
life-threatening (real risk of dying)
hospitalization (initial or prolonged)
health care professionals
disability (significant, persistent or permanent
congenital anomaly
required intervention to prevent permanent
impairment or damage

Report even if:

You’re not certain the product caused adverse

reaction
you don’t have all the details, however, point nos. 1, 5,
7, 8, 11, 15, 16 & 18 (see reverse) are essentially Central Drugs Standard Control Organization
required. Directorate General of Health Services,
Ministry of Health & Family Welfare, Government of India
FDA Bhawan, ITO Kotla Road, New Delhi – 110002
Who can report: www.cdsco.nic.in

Any health care professional (Doctors including

Dentists, Nurses and Pharmacists) Pharmacovigilance
Where to report: Programme
Please return the completed form to the nearest
of
Adverse drug reaction Monitoring Centre (AMC) or to
National Coordinating Centre
India
A list of nationwide AMCs is available at: for
http://cdsco.nic.in/pharmacovigilance.htm
Assuring Drug
What happens to the submitted information:

Safety
Information provided in this form is handled in strict
confidence. The causality assessment is carried out at
Adverse Drug Reaction Monitoring Centres (AMCs) by
using WHO-UMC scale. The analyzed forms are
Pharmacovigilance Programme of India
forwarded to the National Coordinating Centre through the
ADR database. Finally the data is analyzed and forwarded (PvPI)
to the Global Pharmacovigilance Database managed by
WHO Uppsala Monitoring Center in Sweden. National Coordinating Centre,
Indian Pharmacopoeia Commission
The reports are periodically reviewed by the National Ministry of Health & Family Welfare,
Coordinating Centre (PvPI). The information generated on Govt. of India
the basis of these reports helps in continuous assessment Sector-23, Raj Nagar, Ghaziabad-201 002.Tel.:0120-
of the benefit-risk ratio of medicines. 2783400, 2783401, 2783392, FAX: 0120-2783311
E.mail: [email protected]
The information is submitted to the Steering
Committee of PvPI constituted by the Ministry of Health
Confidentiality: The patient’s identity is held in strict confidence and
and Family Welfare. The Committee is entrusted with the
protected to the fullest extent. Programme staff is not ex- pected to
responsibility to review the data and suggest any
and will not disclose the reporter’s identity in response to a request
interventions that may be required.
from the public. Submission of a report does not constitute an
admission that medical personnel or manufacturer or the product
caused or contributed to the reaction.
 Version 1.0

MEDICINES SIDE EFFECT REPORTING FORM (FOR CONSUMERS)

Indian Pharmacopoeia Commission, National Coordination Centre- Pharmacovigilance Programme of India,
Ministry of Health & Family Welfare, Government of India.

This reporting is voluntary, has no legal implication and aims to improve patient safety. Your active participation is valuable.

1.Patient Details
Patient Initials: Gender (√): Male Female Other Age (Year or Month) :
2. Health Information
a. Reason(s) for taking medicine(s)(Disease/Symptoms):

b. Medicines Advised by (√): Doctor Pharmacist Friends/Relatives Self (Past disease experienced/No
past disease experienced)
3. Details of Person Reporting the Side Effect
Name (Optional):
Address:

Telephone No: Email:

4. Details of Medicine Taking/Taken
Name of Medicines Quantity of Medicines taken (e.g. Expiry Date of Date of Start Date of Stop of
250 mg, Two times a day ) Medicines of Medicines Medicines
dd/mm/yy dd/mm/yy
dd/mm/yy dd/mm/yy
dd/mm/yy dd/mm/yy
Dosage form (√) : Tablet Capsule Injection Oral Liquids If Others (Please Specify.................................)
5. About the Side Effect
When did the side effect started? dd/mm/yy Side Effect Continuing ( Yes/No):
When did the side effect stopped? dd/mm/yy
6.How bad was the Side Effect? (Please √ the boxes that Apply)
Did not affect daily activities Affect daily activities
Admitted to hospital Death
Others
7.Describe the Side Effect (What did you do to manage the side effect?)

The information provided in this form will be forwarded to ADR Monitoring Centre for follow-up. You are requested to cooperate with the
programme officials when they contact you for more details. Please do report if you do not have all the information.

Please turn the page to read the instructions

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