Drug induced parkinsonism

Presented by
Sai Siddharth M
M. Pharm 2nd semester
Department of Pharmacy Practice
JSS College of Pharmacy, Mysuru
DRUG INDUCED
PARKINSONISM

INTRODUCTION
Parkinson's disease (PD) is a neurodegenerative disorder that affects predominately dopamine-producing
(“dopaminergic”) neurons in a specific area of the brain called substantia nigra.
Drug Induced Parkinson's Disease, JSSCPM 2

A patient with Parkinson’s disease has
parkinsonism, but not all patients with parkinsonism
have Parkinson’s disease
Drug induced parkinsonism (DIP) is the most common
movement disorder induced by drugs that affect dopamine
receptors. Since the clinical manifestations of DIP are very
similar to those of Parkinson’s disease (PD), patients with
DIP are frequently misdiagnosed as having PD.

• About 7% of people with parkinsonism have developed their symptoms following treatment with particular
medications. This form of parkinsonism is called ‘drug-induced parkinsonism’.
• Drug-induced parkinsonism (DIP) is the second-most-common etiology of parkinsonism in the elderly after
Parkinson’s disease (PD).
• Since the clinical manifestations of DIP are very similar to those of Parkinson’s disease (PD), patients with
DIP are frequently misdiagnosed as having PD.
• These patients are often prescribed antiparkinsonian drugs unnecessarily for long periods of time, despite
recovery being possible simply by discontinuing the offending drugs.
Parkinson’s disease
{idiopathic
parkinson’s disease}
Parkinsonism
Drug induced
Parkinsonism

EPIDEMIOLOGY
 Lack of standard criteria for DIP and misdiagnosis rate undoubtedly have a significant impact on
epidemiological data.
 Several scales are available to document DIP, and the most widely used are: -
62.5
87.5
39.3
The prevalence of PS in a group of older
adults medicated for chronic schizophrenia
DSM Classification
Simpson Agus Scale
UKPDSBB step 1
• (The Diagnostic and Statistical
Manual of Mental Disorders)
DSM
classification
Simpson–Angus
Scale
• (UK Parkinson’s
Disease Society
Brain Bank)
UKPDSBB Step 1 criteria

• Drug-induced extrapyramidal symptoms (EPS) were first described in 1954 in patients who were treated with
chlorpromazine and reserpine.
• Ayd conducted the first major study of the clinical epidemiology of DIP
• The study surveyed 3775 phenothiazine-treated patients for all identifiable extrapyramidal reactions.
• It was observed that: -
• women were almost twice as likely to suffer DIP than males in all age groups except for those below 10
and above 80 years old (both groups had small numbers of patients).
• that DIP was related to drug potency with trifluoperazine causing a 42% higher incidence than
chlorpromazine.
• that older patients were at greater risk than the younger in both sexes.
• A study of parkinsonism in Olmsted County, Minnesota from 1976 to 1990 found DIP to account for 20% of
all parkinsonian patients. The incidence increased with age and was higher in women across all age groups,
though the incidence of both parkinsonism and IPD was higher in men.
• In one study, a patient receiving 480 mg trifluoperazine had no DIP and it was also observed that a patient on
long-term haloperidol 200 mg per day without parkinsonism.
• Hence, the development of DIP is notoriously unpredictable.

RISK FACTORS ASSOCIATED WITH DIP
Patient related risk factors for drug induced parkinsonism
• Age
• Female sex
• Pre-existing extrapyramidal disorders
• Brain damage and atrophy
• Dementia
• HIV infection
• Severe psychiatric disease
• Severe unexplained hyposmia
• History of familial parkinsonism

ETIOLOGY OF DRUG-INDUCED
PARKINSONISM
Any drug that blocks the action of dopamine (referred to
as a dopamine antagonist) is likely to cause
parkinsonism.
Drugs used to treat schizophrenia and other psychotic
disorders such as behaviour disturbances in people with
dementia (known as neuroleptic drugs) are possibly the
major cause of drug-induced parkinsonism worldwide.
Parkinsonism can occur from the use of any of the
various classes of neuroleptics.
Drugs associated with DIP may be classified as
neuroleptic versus nonneuroleptic, according to their
propensity for causing PS or in terms of the pathogenic
mechanism of interference of dopamine
neurotransmission.
DIP
Neuroleptics
Conventional
antipsychotics
Atypical
antipsychotics
Phenothiazine derivatives
&
Benzamide substitutes
Non-neuroleptics
Gastroprokinetic
Monoamine
depleters
Sympatholytics
Calcium channel
antagonists
Antidepressants
Inorganic ion
Anticonvulsants
Miscellaneous

NEUROLEPTICS INDUCED
PARKINSONISM

Drug Induced Parkinson's Disease, JSSCPM
Conventional anti-psychotics Atypical anti-psychotics
11
ANTI-PSYCHOTIC DRUGS
• Zuclopenthixol
• Diphenylbutylpiperidines
• Pimozide
• Dibenzoxazepines
• Loxapine
• Amoxapine
• Butyrophenones
• Haloperidol
• Phenothiazines
• Chlorpromazine
• Levomepromazine
• Thioridazine
• Perphenazine
• Fluphenazine
• Thioxanthenes
• Flupentixol
• Thiothixene
• Thienobenzodiazepine
• Olanzapine
• Pyridopyrimidine
• Risperidone
• Dibenzothiepine
• Zotepine
• N-arylpiperazine
• Aripiprazole
• Quetiapine
• Clozapine

PATHOPHYSIOLOGY
Three pathophysiologic mechanisms are most commonly reported in DIP:
 Alteration in dopaminergic function, which can be due to
• presynaptic dopamine depletion (reserpine, tetrabenazine),
• false transmitter (methyldopa),
• D2 receptor blockage (dopamine receptor blocker, antiemetic agents, tetrabenazine, calcium channel
blockers),
• serotonergic inhibition (selective serotonin reuptake inhibitors)
 Alteration at the cellular level, including mitochondrial respiratory chain dysfunction (calcium channel
blockers, valproic acid)
 Alteration at the motor circuitry level, such as overactivity in the γ-aminobutyric acid (GABA)ergic system
(valproic acid) or cholinomimetic action (tacrine, bethanechol).

Drugs that cause dopamine depletion
in the presynaptic terminal (eg,
reserpine, tetrabenazine).
Atypical antipsychotics, illustrated as
biochemical structures that donot have grooves
or teeth. These cannot lock and attach firmly to
the D2 receptor in the postsynaptic terminal, so
they slip off easily after brief attachment to the
D2 receptor, in a process called rapid dissociation
(“hit and run”).
Typical (conventional ) antipsychotics
are illustrated as structures that have a
groove or teeth to join the D2 receptor
in the postsynaptic terminal, allowing
it to attach firmly for long periods.
A
B
C
Deaminated
products
Nor-
epinephrine
A. Interference with
vesicular storage
B. Blocking autoreceptors
(atypical anti-psychotics)
C. Blocking autoreceptors
(typical anti-psychotics)
PRE SYNAPTIC
POST SYNAPTIC

• Autopsy studies have confirmed that some patients who
recover from DIP after discontinuing the offending drug have
pathological findings characteristic of preclinical PD.
• Single-photon emission computed tomography (SPECT)
imaging with FP-CIT has been a useful tool to identify
preclinical PD, which may be unmasked by drugs.
• There is reduced dopamine transporter (DAT) uptake in PD
and in preclinical degenerative PD, but the uptake is normal in
pure DIP. In spite of the large number of DIP cases observed
in clinical practice, very few autopsies have been reported in
such cases.

MANAGEMENT OF PSYCHOSIS &
PARKINSONISM
• The risk of EPS was thought to be low for atypical antipsychotics.
• It was originally thought that their relatively low frequency of associated EPS was due to them being more
strongly antagonistic toward serotonin-2A receptors than toward dopamine receptors.
• This serotonin-dopamine hypothesis has long been considered a useful model for developing atypical
antipsychotics that exhibit superior antipsychotic efficacy with a lower incidence of EPS compared to typical
antipsychotics.
• The recent ‘fast-off’ theory suggested that their rapid dissociation from D2 receptors after they have blocked
them can explain their lower risk of EPS.
• In 1989, clozapine became the first atypical antipsychotic drug to be approved by the US Food and Drug
Administration. It is effective in schizophrenia patients with drug-resistant negative symptoms, with an almost
complete absence of EPS.

• DIP due to clozapine has not been reported, and it was found to improve psychosis without aggravating
parkinsonism even in PD patients.
• However, clozapine has been associated with agranulocytosis in about 1% of patients, making physicians
reluctant to prescribe this drug.
• Other atypical antipsychotics without the risk of agranulocytosis were developed to control psychosis with
minimal EPS.
• Risperidone was expected to have a minimal risk of EPS because it has a high affinity for serotonin
receptors.31 However, it binds D2 receptors in a dose-dependent manner, thus inducing parkinsonism and EPS
to a similar extent as high doses of typical antipsychotics.
• Quetiapine is an atypical antipsychotic with a low risk of EPS and a low risk of aggravation of parkinsonism
when used to treat psychotic symptoms in patients with PD, and is therefore apparently safe for use in elderly
patients.
• Aripiprazole is the most recently introduced novel atypical antipsychotic, and has a unique mechanism of
action. Although it was expected to have a low risk of EPS, clinical experiences have been disappointing.
Thus, to date, only clozapine and quetiapine are associated with low rates of DIP in older patients.
MANAGEMENT OF PSYCHOSIS &
PARKINSONISM

PHENOTHIAZINE DERIVATIVES AND
BENZAMIDE SUBSTITUTES
• Besides antipsychotics, other dopamine receptor-blocking agents are well known to induce DIP.
• Phenothiazine derivatives (eg, prochlorperazine, promethazine, and first generation H1
antihistamines such as hydroxyzine, alimemazine, and aceprometazine)
• Benzamide substitutes (eg, metoclopramide, sulpiride, clebopride, veralipride) used for the relief of
nausea, vertigo, or post-menopausal syndrome carry an intermediate-to-high risk of producing DIP.
• Metoclopramide has a great capacity to accumulate in the substantia nigra, even more so in
Alzheimer’s disease

NON-NEUROLEPTICS
INDUCED PARKINSONISM
A whole range of drugs has been reported to cause DIP. Most of these
are based on sporadic or isolated case reports, although some associations may
be more robust and will be considered separately.

GI PROKINETICS
 These medicine are used clinically to manage motor disorders of the upper GI tract, including purposeful
dyspepsia and emesis.
 The prokinetic impact of those medicine is mediate through their blockade of enteric inhibitory D2 receptors.
 Besides binding to receptors in the peripheral end organs, they also antagonize central D2 receptors, leading
to adverse effects including hyperprolactinemia and EPS. All prokinetics with D2-receptor-antagonizing
properties have been found to induce EPS, although the extent of symptoms varies.
Metoclopramide Levosulpiride Clebopride Itopride domperidone

GI PROKINETICS
 Among the GI prokinetics, metoclopramide is the most-well-known cause of drug-induced movement
disorders.
 Furthermore, levosulpiride is used widely in several Asian and European countries to treat nausea, vomiting,
and functional dyspepsia.
 Until recently, the drug-induced movement disorders related to levosulpiride were under-recognized, but it
has now been shown that levosulpiride frequently causes parkinsonism.
 Although metoclopramide and levosulpiride have the same mechanism of action, they show different patterns
of adverse effects, the reason for which remains to be clarified.
 In general, domperidone is considered to be safe for the management of GI discomfort, even in patients with
PD, because it does not cross the blood-brain barrier.37 However, although rare, acute dystonic reactions to
this drug may occur.

VESTIBULAR SEDATIVES
• Cinnarizine and its derivative Flunarizine are the common calcium channel antagonists that
induce parkinsonism.
• Cinnarizine induced parkinsonism was first reported in 1985, and its ability to aggravate PD was
reported in 1986.
• A retrospective study spanning 15 years revealed 74 cases of DIP due to cinnarizine among 172
cases of DIP.
• Cinnarizine-induced parkinsonism was more common in women, similar to neuroleptic-induced DIP,
and complete recovery occurred in most subjects within 1–16 months after withdrawal of
cinnarizine.
• However, 11 patients developed PD and in 4, PD developed 12–72 months after recovery from
cinnarizine-induced parkinsonism.
• Drug dose is important, and the risk appears to be low in those taking less than 150 mg of
cinnarizine.

VESTIBULAR SEDATIVES
• The mechanism is unclear and is possibly linked to the calcium-antagonist action of vestibular
sedatives.
• Studies have indicated that cinnarizine can inhibit lipid peroxidation and block postsynaptic striatal
dopamine receptors.
• More recent studies show that cinnarizine is a potent uncoupler of the H-ATPase in catecholamine
storage vesicles, thus possibly inhibiting dopamine uptake into storage vesicles in vivo.
• Cinnarizine is also thought to have a toxic effect on monoamine and serotonin neurons, and in old
mice treated with cinnarizine there is reduced numbers of dopamine D1 and D2 receptors in
different brain regions.
• It is likely, therefore, that a combination of presynaptic dopamine depletion, postsynaptic dopamine
receptor blockade, and effects on nondopaminergic neurons may be responsible for cinnarizine-
induced parkinsonism.

CALCIUM CHANNELANTAGONISTS
• Dihydropyridine and non-dihydropyridine calcium channel antagonists are frequently used to
control cardiovascular conditions such as angina, hypertension, and tachy-arrythmias.
• Various movement disorders have been described with their use, and drugs such as amlodipine,
manidipine, diltiazem, and verapamil have been reported to aggravate or unmask parkinsonism.
• The effects are reversible, and rechallenge in one case caused reemergence of parkinsonism.
• These agents inhibit L-type voltage-gated calcium channels, and it is known that the burst activity of
dopaminergic nigral neurons is mediated through L-type voltage-gated calcium channels.
• Another possible mechanism may be mediated via an L-type calcium channel-independent
inhibition of anatoxin-a, a potent nicotinic agonist which facilitates dopamine release from striatal
synaptosomes.

ANTI-CONVULSANTS
• A range of motor abnormalities including postural tremor and parkinsonism has been reported after
chronic valproate use.
• Parkinsonism related to valproate use is of insidious onset and typically mimics PD.
• In a study evaluating 36 patients in an epilepsy clinic taking therapeutic levels of valproate for at
least 12 months, 32 patients had very mild to advanced forms of parkinsonism on formal
assessment.
• This parkinsonian syndrome is reversible, and discontinuation of valproate led to subjective and
objective improvement in 96% of affected subjects after 3 months of follow-up.
• The mechanism of valproate-induced parkinsonism is poorly understood and is likely to be complex
and multifactorial.
• Valproate increases brain levels of GABA, suppresses repetitive firing of neurons, and also
attenuates current through the T-calcium channel.

The first step in treating DIP involves discontinuing the provoking drugs,
if possible.
MANAGEMENT OF DRUG-INDUCED
PARKINSONISM

Anticholinergics such as benztropine and trihexyphenidyl, which have been used to
treat tremor in PD, have been used to treat DIP with predominant rigidity. They are
usually given for less than 3 months.
Anticholinergics may worsen classic tardive dyskinesia and should not be used
prophylactically. The incidence of tardive dyskinesia is higher in patients receiving
neuroleptics and anticholinergics prophylactically to prevent parkinsonism.
Compared with other drugs, biperiden has a slightly higher affinity for the
muscarinic receptors that predominate in the central nervous system. This means
that biperiden may have fewer peripheral effects, although it still has potential to
cause confusion and memory changes.
ANTI-CHOLINERGICS

AMANTADINE
Amantadine (100–200 mg/d) may be effective in treating neuroleptic-induced
parkinsonism, presumably by releasing dopamine from neuronal storage sites.
Amantadine is often better tolerated than anticholinergics and is less likely to
cause confusion, dry mouth, blurred vision, or urinary problems
The physician should be cautious in patients with renal failure because 90% of
amantadine is excreted in the urine
With long-term use, amantadine may cause livedo reticularis, a benign skin
condition, in the lower extremities, through depletion of catecholamine stores in
peripheral nerve terminals.

LEVODOPA Levodopa (L-dopa) should be used with caution, because it may aggravate
the underlying psychiatric problem for which neuroleptic treatment was
initiated
CLOZAPINE Clozapine (starting with 12.5 mg/d, increased as needed) has been reported
to improve tremors in parkinsonism.
Blood monitoring is required to monitor for the rare occurrence of
agranulocytosis. Monitoring should be performed weekly for the first 6
months, and then bimonthly.

EXPERIMENTAL DRUGS FOR PS: -
Symptomatic
experimental
treatments
Treatments in Phase 1
and 2 clinical trial
Tasigna (nilotinib)
Mavoglurant
(AFQ056)
clinical trial
CVT-301
Pitolisant (BF2.649)
Neuroprotective
experimental
treatments
Treatments in
preclinical phase
Stem cells therapy
and 2 clinical trials
MSDC-0160 &
Affitope (PD01A)
clinical trials
DynaCirc (isradipine)
Others
Bee’s venom Cobra venom

ANY LINK BETWEEN COVID-19 & DIP?
• Scientists have developed three theories about mechanisms that could be involved in the appearance of
parkinsonism following a SARS-CoV-2 infection. They describe their hypotheses in the journal Trends in
Neurosciences.
• First, SARS-CoV-2 is known to cause vascular complications in the brain and other organs, and the scientists
suggest that this process could harm brain pathways. This damage is similar to what happens during the
progression of vascular parkinsonism.
• Second, because there is a known association between inflammation and an increased risk of Parkinson’s
disease, inflammation caused by the immune response to a SARS-CoV-2 infection could potentially trigger
parkinsonism.
• Studies have also shown that some people with COVID-19 have elevated levels of interleukin-6, an immune
system protein, as well as disruptions in the kynurenine pathway. Both are mechanisms associated with
Parkinson’s disease.

ANY LINK
BETWEEN COVID-19
& DIP?
• In addition, the neuro-invasive nature of SARS-CoV-2 may
contribute to a possible association between COVID-19 and
parkinsonism. Researchers have discovered viral RNA in the
brain tissue of people who have died from COVID-19,
indicating that the virus may invade brain cells and pathways.
• Meanwhile, some research suggests that the progression of
Parkinson’s disease may begin in the olfactory system, where
the sense of smell originates. Because COVID-19 can present
with a loss of smell and taste, scientists wonder whether
SARS-CoV-2 can gain access to the same brain pathways
associated with Parkinson’s disease.
• While experiencing parkinsonism during a SARS-CoV-2
infection is currently quite rare, scientists say that the
appearance of these symptoms in relation to COVID-19 merits
further exploration.
• They recommend close monitoring for Parkinson’s-like
symptoms in a large cohort of people with COVID-19.
Determining whether a link between parkinsonism and
COVID-19 exists could help scientists better understand both
health issues and develop more effective treatments.
According to the most recent data, published in The
Lancet Neurology on November 27, 2020, three
people with COVID-19 have also experienced
Parkinson’s-like symptoms.
Two men, aged 45 and 58 years, and one woman,
aged 35 years, reported slowness of movement
accompanied by muscle stiffness, muscle spasms,
irregular eye movement, and tremor.
All three showed reduced function of the brain’s
dopamine pathway system on imaging tests. Two of
the three responded positively to medication and
one recovered spontaneously.
None had a family history or clinical signs of
Parkinson’s disease before their illness.

CONCLUSION
• DIP is important because it is a common etiology of parkinsonism and is frequently either unrecognized or
misdiagnosed as PD. In addition, parkinsonism in DIP patients is sufficiently severe to affect daily activities
and may persist for long periods of time even after cessation of the offending drug. DAT imaging may be
useful for accurately diagnosing patients with DIP and may help to identify the clinical characteristics and
exact prognosis of this disorder.
• About 50% of patients with DIP and other movement disorders are treated with DRBAs for conditions
unrelated to psychosis, including depression, GI disturbance, anxiety, and insomnia.
• Physicians should avoid prescribing DRBAs and CCBs for inappropriate reasons such as anxiety, insomnia,
dizziness or dyspepsia in elderly patients and should monitor these patients’ neurological signs, especially
parkinsonism and other movement disorders, when prescribing these drugs.
• Autopsy findings in reversible or irreversible DIP have shown Lewy-body midbrain pathology and
neuronal loss in a fraction of cases only, leaving many cases unexplained.
• DIP management is challenging and requires a team approach with the treating psychiatrist to
achieve the best outcome.

REFERENCES
1. M. Hubert H. Fernandez, “Current Treatment Options in Neurology,” in Drug-Induced
Parkinsonism, Gainesville, FL 32610-0236, USA, Current Medicine Group LLC, 2009, pp. 162-
169.
2. S. Ovallath, “Drug Induced Parkinsonism: An Overview,” Open Access Journal of Neurology and
Neurosurgery, vol. 3, no. 4, 2017.
3. P. J. Blanchet, “Drug-induced parkinsonism: diagnosis and management,” Journal of
Parkinsonism and Restless Legs Syndrome, pp. 83-91, 2016.
4. M. Umar A. Shuaib, “Neuroleptic-Induced Parkinsonism: Clinicopathological Study,” Movement
Disorders, vol. 31, no. 3, pp. 360-365, 2016.
5. F. J. A. Jr, “A Survey of Drug-Induced Extrapyramidal Reactions,” J.A.M.A., pp. 1054-1060,
1961.

REFERENCES
K. D. Sethi, Drug-Induced Movement Disorders, Augusta, Georgia, U.S.A.: MARCEL DEKKER,
INC, 2004.
D. D. Forsyth, “Drug-induced Parkinsonism,” Parkinson’s Disease Society, Vauxhall Bridge Road,
London, 2013.
M. V. G, “Understanding drug-induced parkinsonism: Separating pearls from oy-sters,” Neurology,
vol. 70, no. 10, pp. 32-34, 2008.
S. A. Factor, Drug induced movement disorders, Atlanta, USA: Blackwell Publishing, 2005.
V. A. Muthukumar, “Drug-induced parkinsonism: A review,” Drug Invention Today, pp. 212-216,
2018.
H.-W. Shin, “Drug-Induced Parkinsonism,” REVIEW, vol. 8, pp. 15-21, 2012.

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