Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSORDEPT. OF PHARMACOLOGYSSIMS & RC.

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It is a chronic, progressive, motor disordercharacterized by

Tremor, resting Rigidity, cogwheel Akinesia, bradykinesia Postural InstabilityETIOLOGY-genetic, environmental toxins, andendogenous toxins, from cellular oxidative reactions.Two major pathogenetic hypotheses:Misfolding of proteinsMitochondrial dysfunction and oxidative stress

Pope John PaulII

Behavioral – depression, anxiety, decreasedmotivation, personality changes,

Sensory – non-specific pains,, restless legs and othersleep problems

Autonomic – constipation, bladder dysfunction,impotence, low blood pressure

MuhammadAli

DRUGS THAT INCREASE DOPAMINE LEVELSDA PRECURSOR-LEVODOPADRUGS THAT RELEASE DOPAMINE-AMANTIDINEDOPAMINERGIC AGONISTS-BROMOCRIPTINEPERGOLIDE, LISURIDE, ROPINIROLE

INHIBIT DOPAMINE METABOLISM-MAO INHIBITORS-SELEGILINE, RASGILINECOMT INHIBITORS-TOLCAPONE, ENTACAPONE

DRUGS INFLUENCING CHOLINERGIC SYSTEM CENTRAL ANTICHLINERGICS-BENZTROPINE,

BENZHEXOL, BIPERIDINE ANTIHISTAMINES-DIPHENHYDRAMINE,

ORPHENADRINE, PROMETHAZINE

Bradykinesia, rigidity, mild tremor, rabbit syndromeCaused by exposure to a dopamine-receptorblocking agent within 6 months of the onset ofsymptoms

Offending drugs include: antipsychotics, anti-emetics,metoclopramide1. Mild cases can frequently remit after cessation of the

offending drug2. Usually unresponsive to dopaminergic therapy3. Elderly patients are most susceptible4. Treatment may include: tetrabenazine, reserpine,

vitamin E, benzodiazepines

still the best, especially short term long term use – motor fluctuations, dyskinesias inversely proportional to age but – nearly all patients eventually require it extends half-life of levodopa, early use for early symptomatic treatment and for rapid

response, i.e. to aid patient to continue working –especially for rigidity & bradykinesia

Helps bradykinesia and rigidity (not really tremor) Small dose increments every few days 6-18 months to see improvementADR- Nausea/flushing/sweating/neuropathyDEMERITS-On-off effect

End of dose deterioration

Ropinorole, Pramipexole, Pergolide Bromocriptine/Cabergoline now avoided due to

cardiac valvulopathy and pleural, pericardial andretroperitoneal fibrosis

Dose -incremental increases Similar S/E profile, less motor complications but less

improvement

DEMERITS-impulse control disorders and excessivedaytime somnolence Hypotension particularly in first few days of

treatment Good evidence in advanced PD to improve off time-

transdermal Rotigotine Amantadine-weak dopamine agonist Increasing Dopamine Agonists often worsens

hallucinations

Antiviral properties. Weak DA, NMDA-receptor antagonist properties-

interferes with excessive glutamate, Glutamateantagonist.

Only for moderate to severe dyskinesia. 100 mg. BD or TDS for dyskinesias -SE-livedo reticularis, ankle edema, hallucinations

Similar to levodopa Nausea. Vomiting. Postural hypotension. Confusion. Hallucinations. Somnolence.

Delays or reduces breakdown of dopamine by MAO-B.Used as monotherapy or in conjunction with L-DOPA, itcan reduce the dosage of L-DOPA by 15%.

MAO-B is an enzyme that metabolizes dopamine.From the breakdown of dopamine, hydrogen peroxide isproduced, which the oxidative stress can damagedopaminergic neurons in the substantia nigra. (Possiblyneuroprotective)Side effects of L-DOPA may be enhanced by selegeline. Nausea and dizziness.

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Inactivates and degrades neurotransmitters,such as dopamine. Mainly used in combination with L-DOPA, it

increases the half-life of L-DOPA. Delays “wearing-off” effect of L-DOPA and

other motor complications such as dyskinesia

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COMT catalyzes methylation of L-DOPA. Addition of COMT inhibitor along with L-DOPA

and carbidopa prolongs the half-life of L-DOPAand increases the amount in the CNS.This increases “on” time for L-DOPA.

Diarrhea and sleep disturbances

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Before commerciality of levodopa, surgicaltreatment were preferred.

Early surgeries were successful with tremors, butfailed to relieve other symptoms.

“Means of last resort” due to high risk of potentialcomplications.

Recent advances in neurosurgical procedures allowfor better treatment.

Deep Brain Stimulation-Brain pacemaker, sendselectrical impulses to brain to stimulate thesubthalamic nucleus.

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MAO-B inhibitors Buccal selegiline or rasagiline can help motor

complications (less commonly used) Severe PD-can admit for subcutaneous

Apomorphine infusion New treatments-dopamine pump if others fail

- Benzatropine, Procyclidine, Orphenadrine- Limited use.- Cognitive impairment in elderly.- Useful in drug induced Parkinsonism.- can be used for excessive salivation.

Orphenadrine-helps drooling Often drooling is more unpleasant for family & they

are delighted if you can improve this Procyclidine-Best in drug-induced Parkinsonism s/e

control SE-confusion, hallucinations, dry mouth, blurred

vision, constipation, nausea, u. retention, glaucoma