Parkinson Drug Therapy

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13 April 2012

ANTIPARKINSON’S DRUGS



Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal2

Classification

Drugs affecting brain dopaminergic system Dopamine precursor

Levodopa (l- dopa)

Dopaminergic agonists

Bromocriptine, Lisuride, Pergolide, Piribedil

Peripheral decarboxylase inhibitors Carbidopa, Benserazide

Facilitate dopaminergic transmission Amantadine, Selegiline (Deprenyl)

Drugs affecting brain cholinergic system

Central anticholinergics

Trihexyphenidyl (Benzhexol), Procyclidine, Biperidine

Antihistaminics Orphenadrine, Promethazine







LEVODOPA

95% of an oral dose is decarboxylated in the

peripheral tissues (mainly gut and liver) and

converted into DA

Only about 1-2% of administered levodopa crosses to

the brain




Adverse Effects of Levodopa

Troublesome, dose related, reversible Nausea and vomiting, tolerance develops

Postural hypotension;Tolerance develops

Alteration in taste sensation arrythmia




Dose of levodopa

Start with 0.25 g BD after meals,gradually increase till adequate

response is obtained

Usual dose is 2-3 g/day

LARODOPA®, LEVOPA® 0.5 g tab


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Drug Interactions with Levodopa

Pyridoxine: Abolishes therapeutic effect byenhancing peripheral decarboxylation of levodopa

Phenothiazines, butyrophenones,metoclopramide reverse therapeutic effect by

blocking DA receptors. Reserpine abolishes levodopa action by

preventing entry of DA into synaptic vesicles

Nonselective MAO inhibitors: preventdegradation of synthesis of DA and NA;

hypertensive crisis Antihypertensives: postural hypotension is

accentuated;

Atropine and other anticholinergic drugs haveadditive antiparkinsonian action with low dosesof levodopa, but retard its absorption; efficacymay be reduced



Peripheral decarboxylase inhibitors

Carbidopa and Benserazide Extracerebral dopa-decarboxylase

inhibitors

they do not penetrate blood brain barrierand do not inhibit conversion of levodopato DA in brain

Administered along with levodopa, theyincrease its t1/2



Benefits obtained by Levodopa +Carbidopa

Systemic concentration of DA reduced; nauseaand vomiting are not prominent

Therapeutic doses of levodopa attained quickly

Cardiac complications are minimized

Pyridoxine reversal of levodopa effect not occur

'On-off' effect is minimized since cerebral DAlevels are more sustained

Degree of improvement may be higher; somepatients, not responding adequately to levodopaalone, also improve


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Problems not resolved (or accentuated)by Levodopa + Carbidopa:

1. Involuntary movements

2. Behavioral abnormalitIes

3. Postural hypotension



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Currently levodopa always used with a decarboxylaseinhibitor, except in patients who develop markedinvoluntary movements with the combination

Combination of levodopa with carbidopa has beengiven the name 'Co-careldopa'

Tidomet -LS®,

Sinemet® 10 mg (Carbidopa) +100mg (Levodopa)



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Direct Dopaminergic Agonists

Bromocriptine, Lisuride, Pergolide



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Bromocriptine

Improvement in parkinsoniansymptoms occurs within ½ -1 hr of an

oral dose of bromocriptine; and lasts6-10 hours

High dose required, expensive and

produce intolerable side effects



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Side effects of bromocriptine

vomiting, hallucinations, hypotension,nasal stuffiness, conjunctivalinjunction

Marked fall in BP with the 'first dose'has occurred in some patients withantihypertensives

Used as a supplement to levodopa atend stages: serves to improve controland smoothen 'end of dose' and 'on-off' fluctuations



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e ec ve - n orSelegiline (Deprenyl)

Intracerebral degradation of DA is retarded

Mild antiparkinsonian action in early cases

Administered with levodopa; prolongs levodopaaction, attenuates motor fluctuations and decreases'wearing off' effect

Adjuvant to levodopa, beneficial in 50-70% patientsand permits 20-30% reduction in levodopa dose

Clinical benefits are short lived (6-26 months)




Adverse effects of selegiline

Postural hypotension, nausea,confusion

Contraindicated in convulsive

disorders Interacts with pethidine

Excitement, hyperthermia, respiratorydepression

SELMAX®, SELGIN® 5 mg tab;



Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

AMANTADINE(dopamine releasing drug)

Fascilates the release of dopaminefrom dopaminergic neurons in brain.

Used in mild parkinsonism (less

effective) and is generally given incombination with L-Dopa.

Generally not serious: insomnia,dizziness, confusion, nightmares and

rarely hallucinations

AMANTREL® 100 mg tab

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CATECHOL-O-METHYL TRANSFERASE

E.g Tolcapone and entacapone. Are reversibleCOMT inhibitors.

Used as adjunct toL-Dopa-carbidopa forforadvanced cases of parkinsons disease (PD).

Combined preparation of L-Dopa+carbidopa+entacapone is available .

Adverse effects: dyskinesia,diarrhoea,confusion, hypotension and hallucinations.

Tolcapone is hepatotoxic therefore should beavoided in patients with liver disease.

Entacapone does not cause hepatotoxicity

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ANTICHOLINERGIC DRUGS:

E.g benzhexol, benztropine Are treatment of choice in drug

induced parkinsonism.

Act by reducing increased cholinergicactivity in striatum and have mainlyperipheral action.

Adverse effects:dry mouth confusion,blurring of vision,constipation.

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Dept of Pharmacology Manipal College of Pharmaceutical Sciences Manipal

THANK YOU

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Parkinson Drug Therapy