Parkinson's Disease: A Comprehensive Overview PDF

Parkinson’s therapy  Parkinson’s disease  Clinical Signs  Classic motor abnormalities  Four Cardinal Signs  Bradykinesia  Muscular Rigidity  Resting Tremors  Abnormalities in Posture and Gait  As well as: impaired speech, sialorrhea(drooling), dysphagia(tro...

Parkinson’s therapy  Parkinson’s disease  Clinical Signs  Classic motor abnormalities  Four Cardinal Signs  Bradykinesia  Muscular Rigidity  Resting Tremors  Abnormalities in Posture and Gait  As well as: impaired speech, sialorrhea(drooling), dysphagia(trouble eating).  Cognitive, perceptual and memory deficits  Global dementia depression, psychosis  Parkinson’s disease  Chemically induced Parkinson’s Disease  Gave researchers the ability to induce the disease in animals  The Frozen Addict  Parkinson’s disease  MPTP was produce from a batch of Designer Opioid that was not prepared correctly  MPPP is a meperidine reverse analog  If the conditions are too acidic then you get MPTP  Parkinson’s disease  Treatment centers on  Replacing Dopamine, either directly (L-DOPA) or indirectly(Dopamine Agonist)  Keeping the Dopamine around longer, MAO inhibitors and COMT Inhibitors  Suppressing Acetylcholine activity  Parkinson’s disease L-DOPA  Rapid,active transport amino acid carrier system in GI  Peak: 0.5-2hrs T1/2 1-3hrs  Rate of absorption is dependent on  Rate of gastric emptying  Meals: delay absorption and reduce peak by 30%  Anticholinergic drugs decrease gastric motility  pH of gastric juice  Length of time the drug is exposed to the degradation enzymes of the gastric and intestinal mucosa  Competition for the active transport system by other Amino Acids.  Parkinson’s disease L-DOPA  Decarboxylation occurs in the intestinal mucosa, which is rich in decarboxylase, as well as other peripheral sites; < 1% penetrates the CNS  Inhibition of decarboxylation markedly increases the fraction available to cross into the brain.  Transport into the brain is via an active mechanism by a neutral amino acid transporter.  Parkinson’s disease L-DOPA  Early in Tx.  Nausea and vomiting reduced by taking with food, may be related to dopamine's interaction with medullary emetic center.  Phenothiazine should not be used: dopamine antagonist  Cardiac arrhythmia: Dopamine is a  agonist  Parkinson’s disease L-DOPA  Long term Tx.  Abnormal involuntary movements related to dopamine conc. in brain  Psychiatric disturbances significant(related to the amine theory of psychosis) hallucination, paranoia, mania, insomnia, anxiety, nightmares, emotional depression.  Orthostatic hypotension, dizziness or fainting on rising to quickly  Parkinson’s disease  Carbidopa  Related to - methyldopa, which is a partial inhibitor/ partial substrate.  The hydrazine functionality makes it a practically irreversible inhibitor of L-Aromatic Amino Acid Decarboxylase  This enzyme is pyridoxal phosphate dependent, the hydrazine reacts with the aldehyde of the pyridoxal  Parkinson’s disease  Before the introduction of carbidopa, individuals had to limit their intake of pyridoxine, which would enhance the peripheral metabolism of L-DOPA.  The inhibitor shows no pharmacological activity on own.  The inhibitor does not cross the blood brain barrier(BBB) therefore the inhibition of decarboxylation only occurs in the periphery Parkinson’s disease  Parkinson’s disease  Apomorphine, Apokyn®  Prototype of dopaminergic Agonist  Used by injection as a emetic in the management of oral ingestion of certain poisons and oral drug overdose. Interacts with the medullary emetic center(chemoreceptor trigger zone)  First dopamine agonist reported beneficial in Parkinsonism.  Use to treat the off and on/off episodes in advanced PD  Parkinson’s disease  Bromocriptine, ergot alkaloid derivative  Agonist at D2 and partial agonist at D1  Less specific than newer agents  Side effects  Dizziness and nausea, Orthostatic hypotension, Mental Disturbances confusion, vivid dreams, hallucinations, paranoid delusions, Dyskinesia Choreiform movements  Recently approved for use in type 2 diabetes to control morning hyperglycemia ( Cycloset®, 0.8 mg)  Parkinson’s disease  Pergolide more potent than bromocriptine  Full agonist at D2 and D1  Side effects  dyskinesia  hallucination  nausea  dry mouth  light headedness  Parkinson’s disease  Ropinirole Requip®  Specific D2 agonist  Less overall side effects than ergot derivatives  Nausea and vomiting can still occur  Can also cause an irresistible urge to sleep  Used increasingly as initial therapy  Less on/off and dyskinesia than L-DOPA  L-DOPA may contribute to oxidative stress accelerating the progression of disease  Parkinson’s disease  Also approved for Restless Leg syndrome.  55% bioavailable  First pass metabolism by 1A2  Half-life 6hr  Parkinson’s disease  Pramipexole Mirapex®  Selective for D2 receptors  Also used as first line in place of L-DOPA  Same side effect profile  90% bioavailable  No metabolism  8-12 hr half-life  Also approved for RLS  Parkinson’s disease  Rotigotine Neupro®  Dopamine agonist  Due to the rigid structure it is locked into a conformation that mimics one of the conformations of Dopamine  The large groups on the nitrogen gives some selective for the D2 receptor as seem before. It is an agonist at D2/D3/D1  Parkinson’s disease  Dopamine and rotigotine overlayed  Parkinson’s disease  Rotigotine cont  Transdermal delivery  45% of the content of patch released over 24 h  Lag time ~ 3 hours after application of patch  Metabolized by conjugation, sulfate(1°) and glucuronidation and N-dealkyation  Warning  As with the previous D2 agonist falling asleep during normal activities sometime without warning  ADR  N+V, Drowiness, Insomnia, hallucination 1° in combination with l-dopa. Application site reactions  Parkinson’s disease  Selegiline Eldepryl® Zelapar®(ODT)  Derivative of L-Methamphetamine  Irreversible inhibitor of MAO-B  Relatively specific for MAO-B at normal doses(