Parkinson's Disease is one of the second most common neurodegenerative disease. Let's go through the pathophysiology and management of PD.

1. AmeenaKadarK A
SecondSem,M pharm
Dept.of PharmacyPractice
SanjoCollegeof PharmaceuticalStudies

2. PARKINSON’S DISEASE (P D)
 PD is a type of movement disorder that can affect the ability to perform common,
daily activities.
 PD is a slowly progressive degeneration of dopaminergic neurons within the
substantia nigra that can lead to altered motor movements.
 It is characterized by tremor, rigidity, akinesia (sluggish neuromuscular
responsiveness), and postural instability (TRAP)
 Parkinson disease was first described by Dr. James Parkinson in 1817 as “shaking
palsy”.
 It is the second most common neurodegenerative disease, after Alzheimer's disease.
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3. EPIDEMIOLOGY
• Parkinson's disease affects 1% of the population over 65 years of age, rising to 2%
over the age of 80.
• One in 20 patients is, however, diagnosed before their 40th year.
• Most epidemiological studies have indicated a small male-to-female predominance.
• The prevalence for these conditions is approximately 5.0 per 100,000.
• Drug-induced Parkinsonism is a common form of so-called symptomatic
Parkinsonism.
• It affects 10–15% of individuals exposed to dopamine receptor blocking agents
including neuroleptics and some labyrinthine sedatives.
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4. AETIOLOGY
1. Primary (idiopathic) Parkinson disease
a. This is also called classic Parkinson disease or paralysis agitans.
b. The cause is unknown; and although treatment may be palliative, the disease is
incurable.
c. Most patients suffer from this type of parkinsonism.
d. Hypotheses of neuronal loss in idiopathic Parkinson disease are as follows:
(1) Absorption of highly potent neurotoxins
(2) Exposure to the free radicals.
e. Genetics factors.
Genes that link to Parkinson disease, such as alpha-synuclein and parkin, are further being
studied in treatment and diagnosis of Parkinson disease.
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5. 2. Secondary parkinsonism —from a known cause
a. Only a small percentage of cases are secondary, and many of these are curable.
b. Secondary parkinsonism may be caused by drugs, including dopamine antagonists,
such as the following:
(1) Phenothiazines (e.g., chlorpromazine, perphenazine)
(2) Butyrophenones (e.g., haloperidol)
(3) Reserpine
c. Poisoning by chemicals or toxins may be the cause; these include
(1) Carbon monoxide poisoning
(2) Heavy-metal poisoning, such as that by manganese or mercury
(3) MPTP, a commercial compound used in organic synthesis and found (as a side
product) in an illegal meperidine analog
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6. d. Infectious causes include:
(1) Encephalitis (viral)
(2) Syphilis
e. Other causes include
(1) Arteriosclerosis
(2) Degenerative diseases of the central nervous system (CNS), such as progressive
supranuclear palsy
(3) Metabolic disorders such as Wilson disease.
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Drug-Induced Parkinsonism
 The most important differential diagnosis to consider when a patient presents with
Parkinsonism is whether their symptoms and signs may be drug induced.
 This is because drug-induced Parkinsonism is potentially reversible upon cessation
of the offending agent.
 Reports linking drug-induced Parkinsonism with the neuroleptic chlorpromazine
were first published in the 1950s.
 Drug-induced Parkinsonism is more common in the elderly and in women.
 The clinical features can be indistinguishable from Parkinson's disease, although
the signs in drug-induced Parkinsonism are more likely to be bilateral at the onset.
 Withdrawal of the offending agent will lead to improvement and resolution of
symptoms and signs in approximately 80% of patients within 8 weeks of
discontinuation.

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 Examples of non-neuroleptic drugs associated with drug-induced Parkinsonism

9. PATHOPHYSIOLOGY
 Parkinson’s disease is a disorder of the extrapyramidal system of the brain
involving the basal ganglia.
 The extrapyramidal system is involved with maintaining posture and muscle tone
and with regulating voluntary smooth motor activity.
 For reasons not understood, melanin-containing cells within the substantia nigra are
lost in PD.
 The pars compacta of the substantia nigra in the midbrain is particularly affected.
 Dopaminergic neurons within this nucleus project to the striatum, which is,
therefore, deprived of the neurotransmitter dopamine.
 In Parkinson's disease, there is a loss of over 80% of nigral neurons before
symptoms appear.
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 The ‘Braak hypothesis’ has been proposed to account for spread of pathology
within the Parkinsonian brain and suggests that α-synuclein may first accumulate
in the lower brainstem and then gradually ascend rostrally to affect critical brain
regions including the substantia nigra and ultimately the cerebral cortex.
 Dopaminergic neurons are not the only cells to die within the brainstem, and a
plethora of other nuclei and neurotransmitter systems are also involved.
 For example, cholinergic neurons within the pedunculopontine nucleus degenerate,
providing potential clinicopathological correlates with postural instability,
swallowing difficulty (dysphagia) and sleep disturbance (REM sleep behavioral
disturbance).
 The involvement of this nucleus in Parkinson's disease may explain why
dopaminergic therapy is relatively ineffective in treating these particular clinical
problems.

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 Within the striatum, changes occur within γ-aminobutyric acid-containing neurons,
as a consequence of nigrostriatal dopaminergic deficiency and also non-
physiological dopaminergic replacement.
 These changes are thought to play a key role in mediating the development of
involuntary movements (dyskinesias) which develop after a number of years of
levodopa treatment. The loss of noradrenergic and serotonergic neurones within the
locus coeruleus and the raphé nucleus, respectively, may provide a
pathophysiological basis for depression, which is common in Parkinson's disease.
 In PD, dopamine (the inhibitory neurotransmitter) is progressively lost in the
nigrostriatal tracts, and acetylcholine (the excitatory neurotransmitter) is relatively
increased.

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13.  On pathologic examination of postmortem basal ganglia, the presence of Lewy
bodies (spherical, abnormal intra-neuronal protein aggregates) are noted within the
remaining dopaminergic cells of the substantia nigra.
 The presence of Lewy bodies is considered pathognomic for the disease.
 Summary of pathophysiological processes believed to be
central to Parkinson's disease.
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 Role of substantia nigra in Parkinson
disease.
 DA = dopamine
 GABA = γ-aminobutyric acid
 ACh = acetylcholine.

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16.  Clinical features of Parkinson’s disease
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17. 1. Tremor
a. Tremor may be the initial complaint in some patients. It is most evident at rest
(resting tremor) and with low-frequency movement. When the thumb and fore-finger
are involved, it is known as the pill-rolling tremor. Before pills were made by
machine, pharmacists made tablets (pills) by hand, hence the name.
b. Some patients experience action tremor (most evident during activity), which can
exist with or before the resting tremor develops.
2. Limb rigidity is present in almost all patients. It is detected clinically when the arm
responds with a ratchet-like (i.e., cog wheeling) movement when the limb is moved
passively. This is owing to a tremor that is superimposed on the rigidity.
3. Akinesia or bradykinesia, Akinesia is characterized by difficulty in initiating
movements, and bradykinesia is a slowness in performing common voluntary
movements, including standing, walking, eating, writing, and talking.
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 Pill rolling Tremor
 Cog-wheel Rigidity

19. The lines of the patient’s face are smooth, and the expression is fixed (masked face)
with little evidence of spontaneous emotional responses.
4. Gait and postural difficulties. Characteristically, patients walk with a stooped,
flexed posture; a short, shuffling stride; and a diminished arm swing in rhythm with the
legs. There may be a tendency to accelerate or festinate.
5. Changes in mental status. Mental status changes, including depression (50%),
dementia (25%), and psychosis are associated with the disease and may be precipitated
or worsened by drugs.
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20.  SYMPTOMS
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Unified Parkinson disease rating scale (UPDRS)
a. To evaluate the clinical efficacy of antiparkinson drugs and to monitor disease
progression, most investigators have used the UPDRS.
(1) The disadvantages associated with the use of scales for rating the functional
and motor disabilities of patients with Parkinson disease include the
potential of interrater variability and imprecision because of the semi-
quantitative scoring.
(2) The result of testing depends highly on the stage of the disease, whether the
patient is being evaluated during an on or off period, and the relative
distribution of the improvement across all the items evaluated.
b. Part I of the UPDRS is an evaluation of mentation, behavior, and mood.
c. Part II is a self-reported evaluation of the activities of daily living (ADLs) and
includes speech, swallowing, handwriting, ability to cut food, dressing, hygiene,
falling, salivating, turning in bed, and walking.

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d. Part III is a clinician-scored motor evaluation.
(1) Patients are evaluated for speech, rest-tremor facial expression and mobility,
action or postural tremor of hands, rigidity, finger taps, hand movements,
rapid alternative pronation– supination movement of hands, leg agility, ease
of arising from a chair, posture, postural stability, gait, and bradykinesia.
(2) Each item is evaluated on a scale of 0 to 4.
(a) A rating of 0 on the motor performance evaluation scale indicates
normal performance.
(b) A rating of 4 on the motor performance evaluation scale indicates
severely impaired performance.
e. Part IV is the Hoehn and Yahr staging of severity of Parkinson disease.
f. Part V is the Schwab and England ADL scale

23. STAGING OF DISABILITY IN PARKINSON’S DISEASE
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DIAGNOSIS
1. Depends on clinical findings.
2. Tests (including imaging) are most often used to rule out an origin of secondary
Parkinson disease.
3. New technologies—for example, positron emission tomography (PET) scan—are
used to visualize dopamine uptake in the substantia nigra and basal ganglia. The
PET scan measures the extent of neuronal loss in these areas.
4. A specific form of single photon emission computed tomography (SPECT) can be
helpful for diagnosis of parkinsonian syndromes and nonparkinsonian syndromes,
particularly essential tremor.
5. Other investigational diagnostic tools:
(1) Transcranial ultrasound
(2) Examine deficits in olfaction
(3) Detection of oligometric alpha-synuclein in blood of patients.

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 Positron-emission tomographic scan of
the brain showing the difference in
Fluorodopa (FDOPA) levels between
those with and without Parkinson’s
disease.

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NON- PHARMACOLOGICAL TREATMENT
a. Exercise is an important adjunctive therapy and is most beneficial. Although exercise
does not help with the symptoms of Parkinson disease, regular focused exercise,
stretching, and strengthening activities can have a positive effect on mobility and
mood.
b. Nutrition. Patients with Parkinson disease are at increased risk of poor nutrition,
weight loss, and reduced muscle mass. Examples of the beneficial effects of proper
nutrition in this group of patients include the following:
(1) Sufficient fiber and fluid intake help prevent constipation associated with
Parkinson disease and the medications used to treat the disease.
(2) Calcium supplementation helps maintain the existing bone structure.
(3) Excessive dietary protein in the late stages of the disease causes erratic
responses to levodopa therapy.

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(4) A large body of literature supports the pathophysiological role of antioxidants as a
neuroprotective agent and its role in decreasing progression of Parkinson disease.
Products such as α-tocopherol or vitamin, creatine, coenzyme Q10 act as scavengers of
free radical which are harmful to cells.

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PHARMACOLOGICAL TREATMENT
Goals of Treatment:
• Reduce Symptoms
• Provide General Support
• Prevent Further Degeneration
• Induce Reversal Or Regeneration.
 The primary objective of drug therapy is to enhance dopaminergic activity
within the damaged areas of the Basal Ganglia, and this is achieved in various
ways.

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 Pharmacological rationales for enhancing dopaminergic transmission in the
basal ganglia

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 Dopamine Precursor - Levodopa
 The ideal treatment for Parkinson’s disease would be to replace the depleted
dopamine in the BG.
 There is an important drug delivery problem because dopamine, being polar, is
poorly absorbed orally and does not readily cross the blood–brain barrier.
 Further, dopamine has potent peripheral adverse effects.
 Thus direct delivery of dopamine to the CNS is impractical and its natural amino acid
precursor levodopa (L-dopa, L-dihydroxy phenylalanine) is used.
 Levodopa is extremely effective for all symptoms of Parkinson’s disease, and
especially for bradykinesia; it is up to five times more effective than anti-
muscarinics.
 Levodopa is poorly tolerated, especially if given orally, when it produces severe
gastrointestinal side-effects.

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 Synthesis of dopamine from levodopa in the absence and presence of
carbidopa, an inhibitor of dopamine decarboxylase in the peripheral tissues.

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Mechanism of action:
 a. Levodopa: Because parkinsonism results from insufficient dopamine in specific
regions of the brain, attempts have been made to replenish the dopamine deficiency.
 Dopamine itself does not cross the blood-brain barrier, but its immediate precursor,
levodopa, is actively transported into the CNS and is converted to dopamine in the
brain.
 Large doses of levodopa are required, because much of the drug is decarboxylated to
dopamine in the periphery, resulting in side effects that include nausea, vomiting,
cardiac arrhythmias, and hypotension.
 b. Carbidopa: It is a dopa decarboxylase inhibitor, diminishes the metabolism of
levodopa in the gastrointestinal tract and peripheral tissues, thereby increasing the
availability of levodopa to the CNS.
 The addition of carbidopa lowers the dose of levodopa needed by four- to five fold
and, consequently, decreases the severity of the side effects arising from peripherally
formed dopamine.

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 Levodopa in combination with carbidopa is a potent and efficacious drug regimen
currently available to treat Parkinson disease.
 In approximately two-thirds of patients with Parkinson disease, levodopa–carbidopa
treatment substantially reduces the severity of the disease for the first few years of
treatment.
 Patients then typically experience a decline in response during the third to fifth year
of therapy.
 Absorption and metabolism: The drug is absorbed rapidly from the small intestine
(when empty of food).
 Levodopa has an extremely short half-life (1 to 2 hours), which causes fluctuations in
plasma concentration.
 This may produce fluctuations in motor response, which generally correlate with the
plasma concentrations of levodopa.

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 Motor fluctuations may cause the patient to suddenly lose normal mobility and
experience tremors, cramps, and immobility.
 Ingestion of meals, particularly if high in protein, interferes with the transport of
levodopa into the CNS.
 Large, neutral amino acids (for example, leucine and isoleucine) compete with
levodopa for absorption from the gut and for transport across the blood-brain barrier.
 Thus, levodopa should be taken on an empty stomach, typically 45 minutes before a
meal.
 Withdrawal from the drug must be gradual.
 Adverse effects:
 Peripheral effects: Anorexia, nausea, and vomiting occur because of stimulation of
the chemoreceptor trigger zone of the medulla.
 Tachycardia and ventricular extra systoles result from dopaminergic action on the
heart.

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 Hypotension may also develop.
 Adrenergic action on the iris causes mydriasis, and, in some individuals, blood
dyscrasias and a positive reaction to the Coombs test are seen.
 Saliva and urine are a brownish color because of the melanin pigment produced from
catecholamine oxidation.
 CNS effects: Visual and auditory hallucinations and abnormal involuntary movements
(dyskinesias) may occur.
 These CNS effects are the opposite of parkinsonian symptoms and reflect the over
activity of dopamine at receptors in the basal ganglia.
 Levodopa can also cause mood changes, depression, psychosis, and anxiety.

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Some drug interactions observed with
levodopa.
*MAO = monoamine oxidase
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MAO – B INHIBITORS
Selegiline And Rasagiline
 Selegiline also called deprenyl, selectively inhibits MAO Type B (which metabolizes
dopamine) at low to moderate doses but does not inhibit MAO Type A (which
metabolizes nor-epinephrine and serotonin) unless given at above recommended doses,
where it loses its selectivity.
 By, thus, decreasing the metabolism of dopamine, selegiline has been found to increase
dopamine levels in the brain.
 Therefore, it enhances the actions of levodopa when these drugs are administered
together.
 Selegiline substantially reduces the required dose of levodopa.

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 However, if selegiline is administered at high doses, the selectivity of the drug is lost,
and the patient is at risk for severe hypertension.
 Selegiline is metabolized to methamphetamine and amphetamine, whose stimulating
properties may produce insomnia if the drug is administered later than midafternoon.
 Rasagiline, an irreversible and selective inhibitor of brain monoamine oxidase Type
B, has five times the potency of selegiline.
 Unlike selegiline, rasagiline is not metabolized to an amphetamine like substance.
 Adverse effects: Postural hypotension, nausea, confusion, accentuation of levodopa
induced involuntary movements and psychosis.
 Selegiline is contraindicated in patients with convulsive disorders.
 Selegiline interacts with pethidine possibly by favoring its metabolism to norpethidine
which causes excitement, rigidity, hyperthermia, respiratory depression.
 It may also interact with tricyclic antidepressants and selective serotonin reuptake
inhibitors.

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CATECHOL-O-METHYL TRANSFERASE INHIBITORS
 Normally, the methylation of levodopa by catechol-O-methyltransferase (COMT) to
3-O-methyldopa is a minor pathway for levodopa metabolism.
 However, when peripheral dopamine decarboxylase activity is inhibited by carbidopa,
a significant concentration of 3-O-methyldopa is formed that competes with levodopa
for active transport into the CNS.
 Inhibition of COMT by entacapone or tolcapone leads to decreased plasma
concentrations of 3-O-methyldopa, increased central uptake of levodopa, and greater
concentrations of brain dopamine.
 Both of these agents have been demonstrated to reduce the symptoms of “wearing-off
” phenomena seen in patients on levodopa–carbidopa.
 Entacapone and tolcapone are nitrocatechol derivatives that selectively and reversibly
inhibit COMT.
 The two drugs differ primarily in their pharmacokinetics and in some adverse effects.

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 Effect of entacapone on dopa concentration in the central nervous system (CNS).
COMT = catechol-O-methyltransferase.

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 Pharmacokinetics: Oral absorption of both drugs occurs readily and is not influenced
by food.
 They are extensively bound to plasma albumin (>98 percent), with limited volumes of
distribution.
 Tolcapone differs from entacapone in that the former penetrates the blood-brain barrier
and inhibits COMT in the CNS.
 However, the inhibition of COMT in the periphery appears to be the primary
therapeutic action.
 Tolcapone has a relatively long duration of action (probably due to its affinity for the
enzyme) compared to entacapone, which requires more frequent dosing.
 Both drugs are extensively metabolized and eliminated in feces and urine. Dosage may
need to be adjusted in patients with moderate or severe cirrhosis.

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 Adverse effects: Both drugs exhibit adverse effects that are observed in patients taking
levodopa–carbidopa, including diarrhea, postural hypotension, nausea, anorexia,
dyskinesias, hallucinations, and sleep disorders.
 Most seriously, fulminating hepatic necrosis is associated with tolcapone use.
 Therefore, it should be used, along with appropriate hepatic function monitoring, only
in patients in whom other modalities have failed.
 Entacapone does not exhibit this toxicity and has largely replaced tolcapone.

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 DOPAMINE-RECEPTOR AGONISTS
 This group of anti-Parkinson compounds includes bromocriptine, an ergot derivative,
and newer, non-ergot drugs, ropinirole, pramipexole, and rotigotine.
 These agents have durations of action longer than that of levodopa and, thus, have
been effective in patients exhibiting fluctuations in their response to levodopa.
 Initial therapy with the newer drugs is associated particularly with less risk of
developing dyskinesias and motor fluctuations when compared to patients started with
levodopa therapy.
 Bromocriptine, pramipexole, and ropinirole are all effective in patients with advanced
Parkinson disease complicated by motor fluctuations and dyskinesias.
 However, these drugs are ineffective in patients who have shown no therapeutic
response to levodopa.
 Apomorphine is also used in severe and advanced stages of the disease as an injectable
dopamine agonist to supplement the oral medications commonly prescribed.

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1. Bromocriptine: Bromocriptine is a derivative of the vaso-constrictive alkaloid,
ergotamine, is a dopamine-receptor agonist.
 The dose is increased gradually during a period of 2 to 3 months.
 Side effects severely limit the utility of the dopamine agonists.
 The actions of bromocriptine are similar to those of levodopa, except that
hallucinations, confusion, delirium, nausea, and orthostatic hypotension are more
common, whereas dyskinesia is less prominent.
 In psychiatric illness, bromocriptine and levodopa may cause the mental condition to
worsen.
 Serious cardiac problems may develop, particularly in patients with a history of
myocardial infarction.
 In patients with peripheral vascular disease, a worsening of the vasospasm occurs,
and in patients with peptic ulcer, there is a worsening of the ulcer.
 Because bromocriptine is an ergot derivative, it has the potential to cause pulmonary
and retroperitoneal fibrosis.

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2. Apomorphine, pramipexole, ropinirole, and rotigotine: These are non-ergot
dopamine agonists that have been approved for the treatment of Parkinson disease.
 Pramipexole and are agonists at dopamine receptors.
 Apomorphine and rotigotine are newer dopamine agonists available in injectable
and transdermal delivery systems, respectively.
 Apomorphine is meant to be used for the acute management of the hypo mobility
“off” phenomenon.
 These agents alleviate the motor deficits in both levodopa-naïve patients (patients
who have never been treated with levodopa) and patients with advanced Parkinson
disease who are taking levodopa.
 Nausea, hallucinations, insomnia, dizziness, constipation, and orthostatic
hypotension are among the more distressing side effects of these drugs, but
dyskinesias are less frequent than with levodopa.

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 Rotigotine is a dopamine agonist used in the treatment of the signs and symptoms of
early stage Parkinson disease.
 It is administered as a once-daily transdermal patch that provides even
pharmacokinetics over 24 hours.
Some adverse effects of dopamine agonists

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GLUTAMATE (NMDA receptor) ANTAGONIST (Dopamine
facilitator)
Amantadine
 Developed as an antiviral drug for prophylaxis of influenza A2, it was found
serendipitously to benefit parkinsonism.
 It acts rapidly but has lower efficacy than levodopa, which is equivalent to or higher
than anticholinergics.
 About 2/3rd patients derive some benefit.
 However, tolerance develops over months and the efficacy is gradually lost.
 Amantadine promotes presynaptic synthesis and release of DA in the brain and has
anticholinergic property.
 However, an antagonistic action on NMDA type of glutamate receptors, through
which the striatal dopaminergic system exerts its influence is now considered to be
more important.

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 Amantadine can be used in milder cases, or in short courses to supplement levodopa
for advanced cases.
 In the latter situation, it serves to suppress motor fluctuations and abnormal
movements.
 Fixed dose of 100 mg BD is used (not titrated according to response).
 The effect of a single dose lasts 8–12 hours;
Side effects: These are generally not serious: insomnia, restlessness, confusion,
nightmares, anticholinergic effects and rarely hallucinations.
 A characteristic side effect due to local release of CAs resulting in postcapillary
vasoconstriction is livedo reticularis (bluish discolouration) and edema of ankles.
 Side effects are accentuated when it is combined with anticholinergics.

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CENTRAL ANTICHOLINERGICS
 These are drugs having a higher central : peripheral anticholinergic action ratio than
atropine, but the pharmacological profile is similar to it.
 In addition, certain H1 antihistaminics have significant central anticholinergic
property.
 They act by reducing the unbalanced cholinergic activity in the striatum of
parkinsonian patients.
 Anticholinergics are the only drugs effective in drug (phenothiazine) induced
parkinsonism.
 The side effect profile is similar to atropine: Impairment of memory, organic
confusional states and blurred vision are more common in the elderly.
 Urinary retention is possible in elderly males.
 The antihistaminics are less efficacious than anticholinergics, but are better tolerated
by older patients. Their sedative action also helps.

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 Orphenadrine has mild euphoriant action.
 Trihexyphenidyl It is the most commonly used drug. Start with the lowest dose in
2–3 divided portions per day and gradually increase till side effects are tolerated.
1. Trihexyphenidyl (benzhexol): 2–10 mg/day; PACITANE, PARBENZ 2 mg tab.
2. Procyclidine: 5–20 mg/day; KEMADRIN 2.5, 5 mg tab.
3. Biperiden: 2–10 mg/day oral, i.m. or i.v.: DYSKINON 2 mg tab., 5 mg/ml inj.
4. Orphenadrine: 100–300 mg/day; DISIPAL, ORPHIPAL 50 mg tab.
5. Promethazine: 25–75 mg/day; PHENERGAN 10, 25 mg tab

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DOSAGE RANGE OF DRUG TREATMENT

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SURGICAL TREATMENTS
 Globus pallidus internus (Gpi) pallidotomy
 Deep-brain stimulation
 Fetal nigral transplantation
 Neuronal regeneration.

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 Some Definitions related to drug therapy
1. On–off effect: describes oscillations in response (at the receptor site) and sudden
changes in mobility from no symptoms to full parkinsonian symptoms in a matter
of minutes. No direct relationship between the on–off effect and drug levels has
been found. Usually, a second drug is added to the therapy regimen to correct the
effect. Reducing the dose of one drug and adding a second drug may also be useful.
Could be managed by adding entacapone, dopamine agonist, amantadine, or
selegiline.
2. End-dose effect: known also as the wearing-off effect, occurs at a latter part of the
dosing interval; it happens after a few years of L-dopa therapy. Reduce the single L-
dopa dose and spread the total L-dopa dose over a larger number of single doses.

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Change to a dopamine agonist and use a sustained-release formulation of L-dopa.
Could be managed by adding entacapone, dopamine agonist, amantadine, or selegiline.
3. Drug holiday: Long-term levodopa use results in down regulation of dopamine
receptors. A drug holiday allows striatal nigra dopamine receptors to be resensitized,
although controversy exists regarding the consequences and the outcome of this
holiday.

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REFERENCES
1. Pathology and Therapeutics for Pharmacists, A basis for clinical pharmacy practice
Third Edition Russell J Greene, Norman D Harris. Page No: 426-436.
2. Clinical Pharmacy and Therapeutics, Roger Walker, Cate Whittlesea, Fifth Edition.
Page No: 507-516.
3. Pharmacotherapy: A Pathophysiological approach, Tenth Edition, Joseph T Dipiro
et.al., Page No: 2655-2687.
4. Applied Therapeutics: The Clinical Use Of Drugs Ninth Edition, Mary Anne Koda-
Kimble, et.al., Page No:53.1-53.7.
5. Comprehensive Pharmacy Review for NAPLEX Eighth Edition, Leon Shargel, Alan H.
Mutnick, Paul F. Souney, Larry N. Swanson, Page No: 773-790.
6. Lippincott’s Illustrated Reviews: Pharmacology Michelle A. Clark. Page No. 101 -109.
7. Essentials of Medical Pharmacology Seventh Edition K D Tripathi M D,
Page No. 426-433.

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HAVE A GOOD DAY!!