Neurological Disease affecting over
four million patients worldwide, over 1.5 Million People in the U.S..
While it can affect individuals at any age, it is most common in the elderly.
The average age of onset is 55 years, although approximately 10 percent of cases
affect those under age 40.
Disease Described in 1817 by James Parkinson, a London Physician Who Described it as a Shaking Palsy Type of Disease Due to less Dopaminergic Cells
Appears Later in Life
Continuous Progressive Neurological Disease, Thereby Causing Increasing Disability of Movement; No Cure
In Terms of Etiology and Clinical Picture, Major Symptoms Involve:
 | Bradykinesia- Slowness in Initiation and Execution of Voluntary Movements |
| Rigidity - Increase Muscle Tone and Increase Resistance to Movement (Arms and Legs Stiff) |
| Tremor - Usually Tremor at Rest, When Person Sits, Arm Shakes, Tremor Stops When Person Attempts to Grab Something |
| Postural Instability - abnormal fixation of posture (stoop when standing), equilibrium, and righting reflex |
| Gait Disturbance - Shuffling Feet |
Usually Other Accompanied Autonomic Deficits Seen Later in Disease Process:
| Orthostatic Hypotension |
| Dementia |
| Dystonia |
| Ophthalmoplegia |
| Affective Disorders |
Loss of Dopaminergic (DA) Cells Located in Basal Ganglia; most symptoms do not appear until striata DA levels decline by at least 70-80%.
Imbalance Between the Excitatory Neurotransmitter Acetylcholine and Inhibitory Neurotransmitters GABA and Dopamine in the Basal Ganglia
The Dopaminergic Neurons in the Basal Ganglia Are mainly affected
Acetylcholine within Striatum Is a tonically activated neuron
it impinges on GABA Neuron by an Excitatory Action
GABA Neuron Has an Inhibitory Action on the Substantia Nigra from Substantia Nigra, Has a Dopaminergic Feed Back Loop Back to Striatum Which Gets Loss Giving Signs and Symptoms of Parkinson Disease
Unknown Reasons for Loss of the Dopamine in the Substantia Nigra
Basal Ganglia
the Basal Ganglia Consists of Five Large Subcortical Nuclei That Participate in Control of Movement:
Caudate Nucleus
Putamen
Globus Pallidus
Subthalamic Nucleus
Substantia Nigra
The Balance of the Five Large Subcortical Nuclei Are Responsible for Smooth Motor Movements
The Primary Input Is from the Cerebral Cortex, and the Output Is Directed Through the Thalamus Back to the Prefrontal, Premotor, and Motor Cortex
The Motor Function of the Basal Ganglia Are therefore mediated by the Frontal Cortex
Neurotransmitters in Basal Ganglia Include Serotonin, Acetylcholine, GABA, Enkephalin, Substance P, Glutamate, and Dopamine
Dopamine from Substantia Nigra Decreases release of Acetylcholine from Striatum.
Drug Therapy
L Dopa Therapy for Parkinson Disease
in Terms of Principle Drugs, L Dopa Is Used for Parkinson Disease
Dopamine Decarboxylase Converts L Dopa to Dopamine That Gets Stored into Secretory Vesicles and Gets Released from Basal Ganglia
Drug Therapy Against Parkinson Disease Is Aimed at Bringing the Basal Ganglia Back to Balance
Want to Decrease Cholinergic Activity Within Basal Ganglia and this Can Be Done Two Ways:
1. Activating Dopamine Receptor in Substantia Nigra Feeding Back to Cholinergic Cells in the Striatum
If Turn off the Cholinergic Cells, Then Things Are Brought Back to Balance
2. Antagonize Acetylcholine
L Dopa Pharmacokinetics
L Dopa Is Readily Absorbed from GI Tract
Usually large doses must be given since ~1% actually enters CNS
Start off with Grams and at the End Get Large Doses of 4 to 5 Grams of L Dopa
L Dopa Metabolized by Dopa Decarboxylase in liver and periphery to Dopamine
Secreted in urine unchanged or conjugated with glucoronyl sulfate
Large Amount of L Dopa Has to Be Given Due to First Pass Effect
Most of L Dopa converted in periphery to NE and EPI
Only about 1% of L Dopa will cross Blood Brain Barrier
Dopamine and Tyrosine Are Not Used for Parkinson Disease Therapy
Dopamine Doesn't Cross the Blood Brain Barrier
Huge Amount of Tyrosine Shuts off Rate Limiting Enzyme Tyrosine Hydroxylase That Normally Converts Tyrosine to Dopamine by Overwhelming Enzyme Tyrosine Hydroxylase, Have a Feedback Loop That Will Turn off Tyrosine Hydroxylase
L Dopa Mechanism of Action for Parkinson Disease Therapy
So Give L Dopa where 1% of the L Dopa Crosses Blood Brain Barrier Where it Gets Converted to Dopamine
L Dopa Replenishes the Dopamine Storage in the Striatum
Had 80 to 90% Destruction of Dopaminergic Neurons, So the Remaining 10% of Dopaminergic Neurons Will Take up the Dopamine That comes from L Dopa
Adverse Effects with L Dopa
Major Problem with L Dopa Is Denervation Supersensitivity of Receptors
If Start out with Certain Number of Receptors in Basal Ganglia and If Destruction of Dopaminergic Neurons, Then Get Increase in Dopamine Receptors
L Dopa Therapy Will Then Increase Dopamine at Synaptic Cleft, but Would Now Have Too Many Receptors Leading to Denervation Supersensitivity
Denervation Supersensitivity
Effect Is Increased Postsynaptic Transmission
Initial Disappearance of Parkinson Syndrome
Onset of Tardive Dyskinesia
Postsynaptic Dopamine Receptor Block by Antipsychotic Drug
Effect Is Reduced Postsynaptic Transmission
Antipsychotic Effects (Mesolimbic)
Extrapyramidal Reactions (Niagrostriatal)
Effects of L Dopa on the Symptoms of Parkinson Disease
L Dopa Fairly Effective in Eliminating Most of the Symptoms of Parkinson Disease
Bradykinesia and Rigidity Quickly Respond to L Dopa
Reduction in Tremor Effect with Continued Therapy
L Dopa less Effective in Eliminating Postural Instability and Shuffling Gait Meaning Other Neurotransmitters Are Involved in Parkinson Disease
Effects of L Dopa on Behavior
In Terms of Behavior, L Dopa Partially Changes Mood by Elevating Mood, and L Dopa Increases Patient Sense of Well Being
Significant Number of Patients Get Behavior Side Effects
Effects of L Dopa on Cardiovascular System
The Cardiovascular Effects Are Cardiac Stimulation Due to Beta Adrenergic Effect on Heart
Tolerance to this effect in Several Weeks
Treat with Propranolol to Block Cardiac Stimulation Effects
Must be careful in treatment of elderly, most will have underlying cardiovascular problems, can transient tachycardia, cardiac arrhythmias and hypertension
in Some Individuals, L Dopa produces Orthostatic Hypotension
Tolerance Will Develop Within Few Weeks
Effects of L Dopa on Gastrointestinal System
Very Common Gastrointestinal Effects of L Dopa Include Nausea, Vomiting, and Anorexia
Probably Due to Stimulation of Chemoreceptor Trigger Zone (CTZ) in Medulla
Tolerance Develops in a Few Weeks to this Effect
Other GI Disturbances Are Abdominal Pain
Some Patients Have Diarrhea and Some Patients Have Constipation
May cause activation of Peptic Ulcer
Control Abdominal Effect by Giving Drug in Low Doses and gradually increase dose.
Give Drug with some food so as to have smething in Stomach
Effects of L Dopa on Endocrine System
L Dopa Conversion to Dopamine
Causes decrease in Prolactin from Stimulation of Dopamine Receptors in Tubularinfundibular System
Side Effects of L Dopa
Some are Irreversible and Dose Dependent
However, Long Term Therapy with L Dopa Not Associated with Renal or Liver Effects
Early in Therapy, 80% of Patients Have Nausea and Vomiting Due to Chemoreceptor Trigger Zone Stimulation
30% of Patients have Orthostatic Hypotension; So must Carefully Regulate Dose
See Cardiac Arrhythmia from Stimulation of Adrenergic Receptors in Heart (Autonomic lecture). Adjust Dose for People with Cardiac Problems
50% of Patients Have Abnormal Involuntary Movements; ie. grimacing of face and tongue movements; slow writhing type of movements (Not Jerky Movements) in Arm and Face
This Is Due to High Dose of Dopa and Occurs Early in Therapy at 2 to 4 Weeks
Best Way to Handle Is by Reducing Dose
Long Term Therapy, Behavioral Disturbances in 20 to 25% of Population
Trouble in Thinking (Cognitive Effects)
L Dopa Can Induce:
| Psychosis |
| Confusion |
| Hallucination |
| Anxiety |
| Delusion |
Treatment Is to reduce Dose and Put Person on Drug Holiday Where Stop All Medication for 3-21 Days and Then Slowly Reinitiate Therapy to Gradually increase dose.
Some Individuals develop Hypomania Which Is Inappropriate Sexual Behavior; "Dirty Old Man", "Flashers"
"On/off" Effect
"On/off" Effect Is like a Light Switch
Without Warning, All of a Sudden, Person Goes from Full Control to Complete Reversion Back to Bradykinesia, Tremor, Etc. Lasting from 30 Minutes to Several Hours and Then Get Control Again
"On/off" Effect Occurs after usually after 2or more years on L Dopa
Treat by Giving Small Dose Regiments from 16 to 20 Hours
Related to Denervation Hypersensitivity
So Multiple Small Doses and Other Antiparkinson Drugs after 2 Years Will Be Needed
"On/off" Effect Has an association with Low Protein Diet
"On/off" Effect May Be Due to Composite of Amino Acids That Use Same Dopamine Transportor across Gastric Mucosa causing extremely low levels of L Dopa in CNS thereby causing symptoms of Parkinson Disease to reappear.
Changing diet (to low protein), may cause large conc of L Dopa in CNS Giving thus producing an 'off' Effect of Symptoms of Parkinson Disease
Drug Interactions with L Dopa
Vitamin B6 - Vitamin B6 Is a Cofactor for Decarboxylation of L Dopa; Vitamin B6 Enhances Conversion of L Dopa to Dopamine in Periphery Making it less Readily for Use in the CNS
So L Dopa Is co-administered with Carbidopa
Carbidopa Is Antagonistic to Peripheral L Dopa Decarboxylation Meaning That it Will Inhibit Peripheral Dopamine Decarboxylase; Carbidopa Doesn't Cross Blood Brain Barrier Meaning it Doesn't Have a Central Effect, but will Block Enzyme Peripherally
By co-administering Carbidopa, will decrease metabolism of L Dopa in GI Tract and Peripheral Tissues thereby increasing L Dopa conc into CNS; meaning we can decrease L Dopa dose and also control the dose of L Dopa much better.
Antipsychotic Drugs - Antipsychotic Drugs Block Dopamine Receptor
Reserpine -Reserpine Depletes Dopamine Storage
Nonspecific MAO Inhibitors - Nonspecific MAO Inhibitors Interfere with L Dopa Breakdown and Exaggerate the CNS (Central) Effects the Nonspecific Mao Inhibitors Can Precipitate Hypertensive Crisis by the tyramine-cheese effect (Tyramine - Tyramine Is Found in Cheese, Coffee, Beer, Pickles, Chocolate, and Herring, when Given to a person Who is taking a MAO Inhibitor Tyramine Is Not broken down therefore producing a tremendous release of Norepinephrine)
Anticholinergics - Anticholinergics Are Used Synergistically with L Dopa as an Antiparkinson Agent, but Anticholinergics Act to Decrease L Dopa Absorption since Anticholinergics Have an Effect on Gastric Emptying Time Which Delays Crossing of Gi Membrane by L Dopa
L Dopa Dosage
L Dopa by Itself Will Have Initial Dosage o f 0.5 Gram to 1 Gram per Day
Usually 2 to 4 Divided Dose ;after Starting with 0.5 Gram, Increment 0.5 Gram Every Four to Five Days in Order to Build up Higher Doses
First Therapeutic Effects Seen When Get to about 2.5 Grams of L Dopa per Day
Sustaining Dose of Drug Is about 5 Grams/day and it Can Go up to 8 Grams per Day
for Reasons of Cardiac Stimulating Effects, Started Using Carbidopa advantage Is Have 50 to 75% Decrease in Optimal Dose of L Dopa So We Can Cut the 5 Grams of L Dopa by 50 to 75%
So there is a decrease in frequency of Nausea and Vomiting
Also Control "On/off" Effect
Involuntary Motion Is Still a Problem with Carbidopa
it Is Usually Initiated by Having about 400 Milligrams of L Dopa to 40 Milligrams of Carbidopa
Tradename of this Combination Is Sinemet Which Comes in Two Forms:
10 Carbidopa/100 L Dopa
25 Carbidopa/250 L Dopa
Other Drugs for Treating Parkinson Disease
Before We Use Other Drugs, We First Use L Dopa until Dosage of L Dopa Starts Becoming High for the Patient Bringing into Play L Dopa's Therapeutic and Toxicity Index Figures
Bromocriptine for Treating Parkinson Disease
Bromocriptine, an Ergotamine Derivative, Acts as a Dopamine Receptor Agonist the Drug Produces Little Response in Patients That Do Not React to Levodopa
Amantadine for Treating Parkinson Disease
Amantadine Effective in the Treatment of Influenza, Has Antiparkinson Action; it appears to Enhance Synthesis, Release, or Reuptake of Dopamine from the Surviving Nigral Neurons
Deprenyl ( Selegiline) for Treating Parkinson Disease
Deprenyl Selectively Inhibits Monoamine Oxidase B Which Metabolizes Dopamine, but Does Not Inhibit Monoamine Oxidase a Which Metabolizes Norepinephrine and Serotonin
The Protective Effects of Selegiline
Although the factors responsible for the loss of nigrostriatal dopaminergic neurons in Parkinson's disease are not understood, the findings from neurochemical studies have suggested that the surviving striatal dopamine neurons accelerate the synthesis of dopamine, thus enhancing the formation of H202 according to the following scheme.
Monoamine oxidase B
Dopamine + 02 + H20 -----------------------> H202 + NH3 +
3,4 dihydroxyphenylacetaldehyde
Glutathione peroxidase
H202 + 2 G S H ----------------------> G S S G + 2 H20
The evidence suggesting that oxidative reactions may contribute to the pathogenesis of Parkinson's disease includes the following. In patients with Parkinson's disease, the iron content is increased in the substantia nigra, the ferritin level is decreased in the brain, and the glutathione concentration is decreased in the substantia nigra. Furthermore, although 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) is not in itself toxic, when oxidized by monoamine oxidase B to the methylphenylpyridium ion, it becomes a select nigral toxin that interferes with mitochondrial respiratory mechanisms. The toxicity of MPTP may be prevented by pretreatment with a monoamine oxidase B inhibitor such as selegiline.
Amphetamine for Treating Parkinson Disease
Amphetamine Has Been Used Adjunctively in the Treatment of Some Parkinsonian Patients it Is Thought That, by Releasing Dopamine and Norepinephrine from Storage Granules, Amphetamine Makes Patients More Mobile and More Motivated
Catechol-O-methyltransferase (COMT) inhibitors - Tolcapone (Tasmar) and Entacapone (Comtan) are two well-studied COMT inhibitors.
| Increases the duration of effect of levodopa dose |
| Can increase peak levels of levodopa |
| Should be taken with carbidopa/levodopa (not effective used alone) |
| Can be most beneficial in treating "wearing off" responses |
| Can reduce carbidopa/levodopa dose by 20-30% |
Antimuscarinic Agents for Treating Parkinson Disease
the Antimuscarinic Agents Are Much less Efficacious than Levodopa, and These Drugs Play Only an Adjuvant Role in Antiparkinson Therapy the Actions of Atropine, Scopolamine, Benztropine, Trihexyphenidyl, and Biperiden Are Similar
Other Links:
Parkinson's Treatment (pdf file)