Anti Park in Son by Sahar Affendy

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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

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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

Anti Park in Son by Sahar Affendy

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