Anti-Parkinson's Drugs

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Parkinson's Disease is

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A progressive, chronic degenerative disorder involving brain regions that control all aspects of movement; results in degeneration of dopamine (DA) neurons in the SUBSTANTIA NIGRA

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Motor Symptoms of Parkinson's Disease

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1. Resting Tremor
2. Muscular Rigidity
3. Bradykinesia/akinesia- most disabling
4. Postural Instability
5. Gait and Posture- shuffling, decreased arm swing, neck and trunk rigid turning, Camtocormia
7. Dystonia
8. Speech and Swallowing Disturbances- hypophonia, festinating speech, drooling, decreased verbal fluency, dysphagia
9. Fatigue
10. Hypomimia
11. Impaired fine motor dexterity/coordination
12. Impaired gross motor coordination
13. Difficulty rolling in bed or rising frmo seat

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Non-motor Symptoms of Parkinson's Disease

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1. Mood disturbances
2. Cognitive disturbances- slow reaction times, dementia, memory loss
3. Sleep disturbances- insomnia, somnolence (drowsiness)
4. Sensation disturbances- visual contrast, double vision, dizziness, pain, spatial reasoning
5. Autonomic disturbances- fainting due to OH, oily skin, urinary incontinence, constipation

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Genetic Factors for Early Onset of Parkinson's Disease

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Defective genes mostly regulating alpha-synuclein and parkin

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Genetic Factors for Late Onset of Parkinson's Disease

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1. T-protein defect
2. Iron metabolism- have more iron deposits in the brain

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Environmental Factors of Parkinson's Disease

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1. Toxins- excess production of free radicals damaging nerve cells
2. Infection- immune factors suggest a viral presence in Lewy bodies
3. Pesticides- high association of parkinsonism with rural areas

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L-dopa (levodopa)

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1. Most reliable and effective oral treatment drug
2. Rapid onset of action, peak plasma levels 1-2 hours post dosing
3. Crosses the BBB via amino acid transporters
4. 90% peripheral metabolism
5. Metabolized by L-aromatic aa decarboxylase into DA in the presynaptic terminals of DA neurons in striatum
6. Must be combined with a peripherally acting dopadecarboxylase inhibitor that can't cross the BBB to prevent premature metabolism

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Problems with L-dopa

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1. End-of-dose failure
2. On-off effect
3. Secondary L-dopa failure
4. Dyskinesias

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L-dopa Peripheral Side Effects

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1. Nausea
2. Vomiting
3. Tachycardia
4. Orthostatic Hypotension
5. Cardiac arrhythmias
6. Anorexia

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L-dopa Central Side Effects

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1. Hallucinations
2. Delusions
3. Motor fluctuations
4. Dyskinesias
5. Vivid dreams
6. Sleep disturbance

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Dangerous Drug Combinations

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1. MAO inhibitors and L-dopa- results in life threatening hypertensive crisis and/or stroke
2. Adrenomimetic amines and L-dopa- used in asthma/emphysema treatment can lead to cardiac arrhythmias

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Dopamine Receptor Agonists

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1. Bromocriptine (Parlodel)
2. Pergolide (Permax)
3. Pramipexole (Mirapex)
4. Ropinirol (Requip)

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Dopamine Receptor Agonist Effects

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1. Stimulate the DA receptor sites directly
2. Long duration of activity, less effective than L-dopa
3. Used to delay initiation of L-dopa therapy
4. Side Effects: same as those for L-dopa with addition of somnolence, insomnia, and fatigue
5. Initially given at low dose that is increased as patient tolerance rises, therapeutic levels reached within a week

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Amantadine

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1. Antiviral compound
2. Mech. of Action: unknown, thought to block uptake and enhance DA release
3. Works in early PD or in combination with L-dopa
4. Not effective in advanced PD when DA stores low
5. Side Effects: confusion, sedation, vivid dreams, hallucinations, OH, nausea/vomiting

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COMT (Catechol-O-methyltransferase) Inhibitors

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1. Entacapone (Comtan)- short half life, taken with each dose of L-dopa/Carbidopa, ONLY inhibits peripheral COMT
2. Tolcapone (Tasmar)- longer duration of action, taken 3 times a day, inhibits BOTH peripheral and central COMT

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COMT Inhibitors Effects

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1. Prevent metabolization of DA and L-dopa to inactive 3-O-methyl dopa
2. Prolongs effects of L-dopa, inhibits peripheral COMT increasing plasma half-life of L-dopa and fraction of L-dopa transported into the CNS
3. Helps with L-dopa "wearing off effect"- prolongs effectiveness of L-dopa
4. Side Effects: POSSIBLE FATAL HEPATOTOXICTY (tolcapone), confusion/ hallucinations, athoptosis

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MAO-B (monoamine oxidase-B) Inhibitors: Selegiline

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1. Irreversible MAO-B Inhibitor
2. Inhibits DA metabolism (enhances endogenous DA levels)
3. Can delay L-dopa therapy/ reduce L-dopa doses
4. DONT administer with tricyclic antidepressants or selective serotonin uptake inhibitors--can be FATAL

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The Anticholinergic Agents

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1. Benztropine
2. Procyclidine
3. Trihexyphenidyl
4. Diphenhydramine (Benadryl)

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Anticholinergic Agent Effects

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1. Replaced belladona alkaloids (ex: atropine)
2. Inhibit Ach activity (trihexyphenidyl)
3. Block muscarinic receptors in striatum (benzotropine)
4. Effective for RELIEVING RIGIDITY and salivation (procyclidine)
5. Side Effects: constipation, urinary retention, confusion, hallucinations, etc
6. Benadryl (antihistamine diphenhydramine) has anticholinergic properties, APPEARS TO BLOCK DA REUPTAKE