ANTIPARKINSONS DRUGS

13 April 2012

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
Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

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

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

Adverse Effects of Levodopa

Troublesome, dose related, reversible Nausea and vomiting, tolerance develops Postural hypotension;Tolerance develops Alteration in taste sensation

arrythmia

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

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

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

Drug Interactions with Levodopa

Pyridoxine: Abolishes therapeutic effect by enhancing 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: prevent degradation of synthesis of DA and NA; hypertensive crisis Antihypertensives: postural hypotension is accentuated; Atropine and other anticholinergic drugs have additive antiparkinsonian action with low doses of levodopa, but retard its absorption; efficacy may be reduced Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

Peripheral decarboxylase inhibitors

Carbidopa and Benserazide
Extracerebral dopa-decarboxylase inhibitors they do not penetrate blood brain barrier and do not inhibit conversion of levodopa to DA in brain

Administered along with levodopa, they increase its t1/2

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

Benefits obtained by Levodopa + Carbidopa

Systemic concentration of DA reduced; nausea and 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 DA levels are more sustained

Degree of improvement may be higher; some patients, not responding adequately to levodopa alone, also improve
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Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

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

1. Involuntary movements

2. Behavioral abnormalitIes
3. Postural hypotension

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

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 Currently levodopa always used with a decarboxylase inhibitor, except in patients who develop marked involuntary movements with the combination Combination of levodopa with carbidopa has been given the name 'Co-careldopa'

Tidomet -LS, Sinemet 10 mg (Carbidopa) +100mg (Levodopa)

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

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Direct Dopaminergic Agonists

Bromocriptine, Lisuride, Pergolide

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

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Bromocriptine
Improvement in parkinsonian symptoms occurs within -1 hr of an oral dose of bromocriptine; and lasts 6-10 hours
High dose required, expensive and produce intolerable side effects

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

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Side effects of bromocriptine

vomiting, hallucinations, hypotension, nasal stuffiness, conjunctival injunction Marked fall in BP with the 'first dose' has occurred in some patients with antihypertensives Used as a supplement to levodopa at end stages: serves to improve control and smoothen 'end of dose' and 'onoff' fluctuations
Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

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Selective MAO-B inhibitor Selegiline (Deprenyl)

Intracerebral degradation of DA is retarded Mild antiparkinsonian action in early cases Administered with levodopa; prolongs levodopa action, attenuates motor fluctuations and decreases 'wearing off' effect Adjuvant to levodopa, beneficial in 50-70% patients and permits 20-30% reduction in levodopa dose Clinical benefits are short lived (6-26 months)

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

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Adverse effects of selegiline

Postural hypotension, nausea, confusion Contraindicated in convulsive disorders Interacts with pethidine
Excitement, hyperthermia, respiratory depression

SELMAX, SELGIN 5 mg tab;

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

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AMANTADINE(dopamine releasing drug)

Fascilates the release of dopamine from dopaminergic neurons in brain. Used in mild parkinsonism (less effective) and is generally given in combination with L-Dopa.

Generally not serious: insomnia, dizziness, confusion, nightmares and rarely hallucinations AMANTREL 100 mg tab
Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

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CATECHOL-O-METHYL TRANSFERASE
E.g Tolcapone and entacapone. Are reversible COMT inhibitors. Used as adjunct toL-Dopa-carbidopa forfor advanced cases of parkinsons disease (PD). Combined preparation of LDopa+carbidopa+entacapone is available . Adverse effects: dyskinesia,diarrhoea, confusion, hypotension and hallucinations. Tolcapone is hepatotoxic therefore should be avoided in patients with liver disease. Entacapone does not cause hepatotoxicity

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

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ANTICHOLINERGIC DRUGS:
E.g benzhexol, benztropine Are treatment of choice in drug induced parkinsonism. Act by reducing increased cholinergic activity in striatum and have mainly peripheral action. Adverse effects:dry mouth confusion, blurring of vision,constipation.

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

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THANK YOU

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences Manipal

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