SAHAR AFFENDY | BP-0550-154

TOXICOLOG
Y
- ANTIPARKINSON DRUGS --
 ANTIPARKINSON DRUGS
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
• Rigidity: 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?

 60’s to 70’s
 10 % of patients before age 40 which termed as
Young Onset PD (YOPD)

What is prevalence of disease in Pakistan?

 There are around one million patients in the country with PD.
 Nearly half or 500,000 people with Parkinson’s Disease are not
taking medication at all in Pakistan.
 Of these patients, around 400,000 to 450,000 are being
treated by family doctors.

According to Pakistan Parkinson’s Society chairman Dr Haroon Bashir.

Source: Daily Times, 11/8/2008

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 CLINICAL FEATURES
OF PARKINSON
DISEASE

FACTS ABOUT P A R K I N S O N DISEASE

 PD is the third most common presenting diagnosis in neurology outpatient clinics.
 The incidence of PD is 1.2-1.5 times greater in males than females.
 An impaired sense of smell could be an early indicator of Parkinson’s disease.
 Parkinson’s disease has been called a family disorder because caregivers are crucial for the well being of the
Parkinson’s patient.
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Source: National Parkinson’s Alliance
 MEDICATIONS USED IN TREATMENT
OF PARKINSON DISEASE
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 COMMENTS
DOSE—USEFUL
RANGE

Carbidopa/levodopa 25 mg carbidopa + 100 mg 200–1200 mg

levodopa ("25/100" tablet), levodopa
twice or three times a day
Carbidopa/levodopa 50 mg carbidopa + 200 mg 200–1200 mg Bioavailability 75%
sustained release levodopa ("50/200 sustained levodopa of immediate
release" tablet) twice a day release form
Bromocriptine 1.25 mg twice a day 3.75–40 mg Titrate slowly
Pergolide 0.05 mg once a day 0.75–5 mg Titrate slowly
Ropinirole 0.25 mg three times a day 1.5–24 mg
Pramipexole 0.125 mg three times a day 1.5–4.5 mg
Entacapone 200 mg with each dose of 600–2000 mg
levodopa/carbidopa
Tolcapone 100 mg twice a day or three 200–600 mg May be
times a day hepatotoxic;
requires
monitoring of liver
enzymes
Selegiline 5 mg twice a day 2.5–10 mg
Amantadine 100 mg twice a day 100–200 mg

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
FOR

PARKINSON DISEASE

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 TOXICOLOGICAL DATABASE OF SOME
MEDICINES
USED IN PARKINSON DISEASE
LEVODOPA
(L-DOPA, L-3,4-dihydroxyphenylalanine) _ the metabolic precursor of dopamine

GENERAL MECHANISM OF ACTION

L E V O D O P A

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  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

LEVODOPA
TOXICITY

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  L-DOPA has been found to be toxic for dopaminergic and non-dopaminergic mesencephalic
neurons.

TARGET SYSTEM TOXICITY

 The principal target organ is C.V.S.
 Additional risks are associated with the gastrointestinal tract,
 The peripheral as well as the central nervous system.

MECHANISM OF TOXICITY
 Levodopa augments oxidative stress via the production of quinines, hydrogen peroxide and
oxyradicals.
 Leads to reduction of reduced glutathione, increased level of malondial aldehyde and lipid
hydroperoxides, oxidative DNA and protein damage.

CLINICAL EFFECTS
 Spasm Or Closing Of Eyelids Are Possible Early  Hypotension
Sign Of Overdose. Cardiac Arrhythmias
 Involuntary Movements Of The Body  Bruxism
 Choreiform  Insomnia

 Haemolytic Anaemia  Psychiatric Disturbances

 Duodenal Ulcer  Tachypnoea
SYSTEMATIC DESCRIPTION OF CLINICAL EFFECTS OF OVERDOSAGE TOXICITY
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 Cardiovascular

Hypotension

 About 30% of patients develop slight orthostatic hypotension early in therapy.

Cardiac irregularities

 Potentially serious effect of levodopa sinus tachycardia, atrial and ventricular extrasystoles,
atrial flutter and fibrillation, and ventricular tachycardia have been reported.

Neurological

Central nervous system (CNS)

 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 system

 Some patients developed severe oculogyric crises.

Autonomic nervous system

 Abnormal involuntary movements are variable in type include faciolingual tics, grimacing, head bobbing, and
various oscillatory and rocking movements of the arms, legs or trunk.

Gastrointestinal

 Bleeding and perforation of peptic ulcers have been reported in a few patients.

ANTIDOTE:
 Catechol-O-methyltransferase (COMT) attenuates toxicity.

FIRST AID MEASURES AND MANAGEMENT PRINCIPLES

 For acute overdosage general supportive measures should also be employed.

 Intravenous liquids should be administered as necessary and an adequate airway maintained.
 Emesis (within 30 minutes) may be of value in only very early ingestions; lavage (within 1 hour); activated
charcoal of use
 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);
 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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 TOXICOLOGICAL DATABASE OF SOME
MEDICINES
USED IN PARKINSON DISEASE
SELEGILINE
(selective irreversible MAO-B inhibitor)

GENERAL MECHANISM OF ACTION

S E L E G I L I N E

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 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


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SELEGILINE TOXICITY

1. Asymptomatic (latent)
2. Neuromuscular excitation and sympathetic hyperactivity
3. Central nervous system (CNS) depression with the potential for cardiovascular collapse
4. Secondary complications for survivors of the above

TARGET SYSTEM TOXICITY

 CARDIOVASCULAR SYSTEM.
 CENTRAL NERVOUS SYSTEM
 NEUROMUSCULAR

TOXIC DOSE/RANGE OF TOXICITY

 Ingestion of MAO-B inhibitors in amounts greater than approximately 2 mg/kg should generally be
considered potentially life threatening.

 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

 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

 Headache  Dyskinesia

 Hallucinations  Diaphoresis

 Low Blood Pressure On  Rhabdomyolysis

Standing
 Seizures  Disseminated
Intravascular
Coagulation
 Myoclonus  Mild Agitation

ANTIDOTE & MANAGEMENT

 Benzodiazepines attenuates toxicity.
 The treatment of MAO-B inhibitor overdose is primarily supportive.

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 REFERENCES

BOOKS:
 Casarett_And_Doull_s_Toxicology__The_Basic_Science_Of_Poisons
__Seventh_Edition

 Clinical Toxicology Principles and Mechanisms

 Goodman & Gilman's The Pharmacological Basis of Therapeutics

 Hodgson - A Textbook of Modern Toxicology 3e

 Leikin - Poisoning and Toxicology Handbook 4e (Lexi, 2008)

WEBSITES:
 http://www.uspharmacist.com/content/d/senior%20care/c/11699/

 http://www.opfblog.com/3748/1m-in-pakistan-have-parkinson’s-disease/

 http://www.pharmacytimes.com/issue/pharmacy/2010/March2010/FeaturePa

rkinsons031

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