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SAHAR AFFENDY | BP-0550-154
TOXICOLOGY - ANTIPARKINSON DRUGS --
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What is Parkinson Disease?
Parkinson's disease (PD) is a chronic, progressive neurodegenerative
condition characterized by a slow and relatively selective loss of
dopaminergic neurons in the substantia nigra.
What actually causes Parkinson Disease?
The common pathologic feature in PD and secondary
parkinsonism is striatal dopamine deficiency.
What is clinical presentation of the disease?
TRAP acronym describes PD¶s 4 most salient features:
Tremor at rest : Shaking or trembling
R igidity: Stiffness settles in the muscles
Akinesia (or bradykinesia):The movement of the person becomes slow
Postural instability : Difficulties to balance or walk are encountered
What is mean age of onset of disease?
y 60¶s to 70¶s
y 10 % of patients before age 40 which termed as
Young Onset PD (YO PD)
What is prevalence of disease in Pakistan?
y There are around one million patients in the country with PD.
y Nearly half or 500,000 people with Parkinson¶s Disease are not
taking medication at all in Pakistan.
y Of these patients, around 400,000 to 450,000 are being
treated by family doctors.
ANTIPARKINSON DRUGS
According to Pakistan Parkinsons Society chairman Dr Haroon Bashir.
Source: Daily Times, 11/8/2008
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FACTS ABOUT P A R K I N S O N DISEASE
C LINICAL FEATURES
OF PARKINSON DISEASE
y PD is the third most common presenting diagnosis in neurology outpatient clinics.
y The incidence of PD is 1.2-1.5 times greater in males than females.
y An impaired sense of smell could be an early indicator of Parkinsons disease.
y Parkinsons disease has been called a family d isor der because caregivers are crucial for the well being of the
Parkinsons patient.
Source: National P arkinson¶s Alliance
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Commonly used medications for the treatment of PD are summarized in Table below:
COMMONLY USED MEDICATIONS FOR THE TREATMENT OF PARKINSON'S
DISEASE
AGENT TYPICAL INITIAL DOSE TOTAL DAILY
DOSEUSEFUL
RANGE
COMMENTS
Carbidopa/levodopa2
5 mg carbidopa + 100 mglevodopa ("25/100" tablet),
twice or three times a day
2001
200 mglevodopa
Carbidopa/levodopa
sustained release
50 mg carbidopa + 200 mg
levodopa ("50/200 sustained
release" tablet) twice a day
2001200 mg
levodopa
Bioavailability 75%
of immediate
release form
Bromocriptine 1.25 mg twice a day 3.7540 mg Titrate slowly
Pergolide 0.05 mg once a day 0.755 mg Titrate slowly
Ropinirole 0.25 mg three times a day 1.524 mg
Pramipexole 0.125 mg three times a day 1.54.5 mg
Entacapone 200 mg with each dose of
levodopa/carbidopa
6002000 mg
Tolcapone 100 mg twice a day or three
times a day
200600 mg May be
hepatotoxic;
requires
monitoring of liver
enzymes
Selegiline 5 mg twice a day 2.510 mg
Amantadine 100 mg twice a day 100200 mg
MEDICATIONS USED IN TREAT MENT
OF PARKINSON DISEASE
Goodman & Gilman's Pharmacology > III. Drugs Acting on the Central Nervous
System > Chapter 20. Treatment of Central Nervous System Degenerative Disorders >
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SITES OF ACTIONS OF COMMON THERAPIES FO
PARKINSON DISEASE
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L E
V
O
D
O
P
A
LEVODOPA
(L-DOPA, L-3,4-dihydroxyphenylalanine) _ the metabolic precursor of dopamine
GENERAL MECHANISM OF ACTION
y Increases dopamine levels in the brain, then stimulates dopaminergic receptors in the basal
ganglia to improve the balance between cholinergic and dopaminergic activity.
HOW L E V O D O P A WORKS
TOXICOLOGICAL DATABASE OF SOME MEDICIN
USED IN PARKINSON DISEAS
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LEVODOPA TOXICITY
y L-DOPA has been found to be toxic for dopaminergic and non-dopaminergic mesencephalic
neurons.
TARGET SYSTEM TOXICITY
y
The principal target organ is C.V.S.y Additional risks are associated with the gastrointestinal tract,
y The peripheral as well as the central nervous system.
MECHANISM OF TOXICITY
y Levodopa augments oxidative stress via the production of quinines, hydrogen peroxide and
oxyradicals.
y Leads to reduction of reduced glutathione, increased level of malondial aldehyde and lipid
hydroperoxides, oxidative DNA and protein damage.
CLINICAL EFFECTS
y Spasm Or Closing Of Eyelids Are Possible Early
Sign Of Overdose. Cardiac Arrhythmias
y Hypotension
y Involuntary Movements Of The Body y Bruxism
y Choreiform y Insomnia
y Haemolytic Anaemia y Psychiatric Disturbances
y Duodenal Ulcer y Tachypnoea
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SYSTEMATIC DESCRIPTION OF CLINICAL EFFECTS OF OVERDOSAGE TOXICITY
Cardiovascular
Hypot ension
y About 30% of patients develop slight orthostatic hypotension early in therapy.
C ar d iac irr egulariti es
y Potentially serious effect of levodopa sinus tachycardia, atrial and ventricular extrasystoles,
atrial flutter and fibrillation, and ventricular tachycardia have been reported.
Neurological
Central nervous syst em (CNS)
y Levodopa result in euphoria, anxiety and insomnia, which may progress to a toxic psychosis or acute
brain syndrome with delusions and hallucinations and paranoia.
Peripheral nervous syst em
y Some patients developed severe oculogyric crises.
Autonomic nervous system
y Abnormal i nvol untary mov ements are variable in type include faciolingual tics, grimacing, head bobbing, and
various oscillatory and rocking movements of the arms, legs or trunk.
Gastrointestinal
y Bleeding and perforation of peptic ulcers have been reported in a few patients.
ANTIDOTE:
y Catechol-O-methyltransferase (COMT) attenuates toxicity.
FIRST AID MEASURES AND MANAGEMENT PRINCIPLES
y For acute overdosage general supportive measures should also be employed.
y Intravenous liquids should be administered as necessary and an adequate airway maintained.
y Emesis (within 30 minutes) may be of value in only very early ingestions; lavage (within 1 hour); activated
charcoal of use
y Supportive therapy: Deanol and pyridoxine of questionable use for dyskinesias, but have been tried;
dantrolene and/or bromocriptine has been used in malignant hyperthermia; choreo-ballistic dyskinesia due
to levodopa can improve with low dose propranolol (30-60 mg/day);
y levodopa-induced psychosis can be treated with remoxipride; amantadine at doses of 200-300 mg/day
can help improve dyskinesia
Parkinson's disease: diagnosis and clinical management
By Stewart A. Factor, William J. Weiner
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S
E
L
E
G
I
L
I
N
E
SELEGILINE (selective irreversible MAO-B inhibitor)
GENERAL MECHANISM OF ACTION
In the brain, a chemical called MAO-B breaks down dopamine, thus preventing its action (a normal
control mechanism). MAO-B inhibitors stop MAO-B from working, and this raises the levels of
dopamine in the brain
HOW S E L E G I L I N E WORKS y
TOXICOLOGICAL DATABASE OF SOME MEDICIN
USED IN PARKINSON DISEAS
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SELEGILINE TOXICITY
1. Asymptomatic (latent)
2
. Neuromuscular excitation and sympathetic hyperactivity3. Central nervous system (CNS) depression with the potential for cardiovascular collapse
4. Secondary complications for survivors of the above
TARGET SYSTEM TOXICITY
y CARDIOVASCULAR SYSTEM.
y CENTRAL NERVOUS SYSTEM
y NEUROMUSCULAR
TOXIC DOSE/RANGE OF TOXICITY
y Ingestion of MAO-B inhibitors in amounts greater than approximately 2 mg/kg should generally be
considered potentially life threatening.
y Fatalities have been reported at serum moclobemide concentrations of 55 mg/L and higher (therapeutic
1.5 to 2.5 mg/L).
MECHANISM OF TOXICITY
y By inhibiting the enzymatic degradation, the cytoplasmic concentrations of these
neurotransmitters are increased, resulting in the tendency for release of these biogenic amines
by a mass action effect.
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CLINICAL EFFECTS
y Headache y Dyskinesia
y
Hallucinations y
Diaphoresis
y Low Blood Pressure On
Standing
y Rhabdomyolysis
y Seizures y Disseminated
Intravascular
Coagulation
y Myoclonus y Mild Agitation
ANTIDOTE & MANAGEMENT
y Benzodiazepines attenuates toxicity.
y The treatment of MAO-B inhibitor overdose is primarily supportive.
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REFERENCES
BOOKS:
y Casarett_And_Doull_s_Toxicology__The_Basic_Science_Of_Poisons
__Seventh_Edition
y Clinical Toxicology Principles and Mechanisms
y Goodman & Gilman's The Pharmacological Basis of Therapeutics
y Hodgson - A Textbook of Modern Toxicology 3e
y Leikin - Poisoning and Toxicology Handbook 4e (Lexi, 2008)
WEBSITES:
y http://www.uspharmacist.com/content/d/senior%20care/c/11699/
y http://www.opfblog.com/3748/1m-in-pakistan-have-parkinsons-disease/
y http://www.pharmacytimes.com/issue/pharmacy/2010/March2010/Featur
eParkinsons031