DRUG THERAPY OF PARKINSON'S DISEASE

Dr. V. John Massari ©

I. Clinical overview of the disease originally called "Paralysis Agitans" by James Parkinson in 1817. Parkinsons's disease is a chronic progressive, nonhereditary neurodegenerative disorder of the extrapyramidal motor system characterized by a deficiency of dopamine in the neostriatum.

A. Signs and symptoms

1. Resting tremor

2. Plastic "cogwheel" rigidity

3. Bradykinesia

a. Difficulty in initiating movements

b. Difficulty in modifying ongoing movements

c. Decrease in spontaneous movements

d. Loss of associated movements

4. Disturbances of Postural reflexes and impaired gait

5. Changes in mood esp. depression can occur in 40% of patients

6. Mild cognitive defects in areas of memory, language, problem-solving skills

B. Types and causes of Parkinsonism

1. Idiopathic

2. Postencephalitic (outbreak in 1918-1927)

3. Drug induced

a. Antipsychotic drugs that block DA receptors (Haloperidol, Thorazine)

b. MPTP

4. Miscellaneous

a. Arteriosclerosis

b. Manganese (miners) and Carbon Monoxide (suicide) poisoning.

II Neuroanatomical Considerations

A. Pyramidal vs extrapyramidal

1. The output of the striatum includes polysynaptic pathways which project back to the cortex, where they MODIFY the firing of the pyramidal motor system. Extrapyramidal disorders are characterized by abnormal involuntary movements and changes in muscle tone (rigidity).

2. Pyramidal disorders are characterized by loss of voluntary movements and weakness.

B. Nigro-striatal DA system

1. Meso-lymbic

2. Tubero-infundibular

III. Neurochemical responses in parkinsonism

A. DA neurons in the SN degenerate, depleting the striatum of DA by more than 80%.

B. Surviving DA nerve terminals increase their turnover of DA

C. DA receptors deprived of DA become supersensitive

D. DA is inhibitory to ACh interneurons in the striatum. A balance between DA and ACh is required to permit smooth control of voluntary movement. This balance can be restored by inhibiting ACh, or by increasing DA, or both. Multiple pathways interconnect the various subnuclei of the basal ganglia which utilize a variety of neuropeptides, GABA, or Glutamate, however the role of these neurotransmitters in the control of motor function is unclear. At present no clinicallly relevant drugs impact neurotransmitters other than DA or ACh.

IV. Drug therapy of Early Stages of Parkinsons disease

A. In the early stages of the disease, asymmetrical tremor and bradykinesia predominate, and medication is often not required.

1. There are two isoenzymes of MAO, ie MAO-A and MAO-B. In the striatum, mainly MAO-B is found. Selegiline, is a selective and irreversible MAO-B inhibitor. It has some benefit in treating the symptoms of the disease. It was speculated that it might little slow the progression of the disease by preventing the formation of toxic intermediates in the DA neurons which are destroyed, because Selegiline and other specific MAO-B inhibitors prevent MPTP-induced parkinsonism in animals. However recent clinical data do not support this hypothesis, because there is no good evidence to support the idea that the progression of the disease is slowed by treatment with Selegiline. Selegiline should not be combined with meperidine or other opioids. This may lead to severe hyperthermia, agitation, and stupor.

2. If treatment is elected, an anticholinergic drug may be useful in younger patients or those in whom tremor is the major complaint. Treatment with these anticholinergic drugs is hazardous in older patients in whom they produce significant CNS side effects such as confusion,agitation, disorientation, delirium, paranoia, & hallucinations.

a. Trihexyphenidyl, Benztropine, Biperiden

1. The duration of action of these drugs differ, and patients may tolerate one drug better than another. Otherwise, none has any advantages over the others.

2. Adverse reactions are due to peripheral and CNS cholinergic blockade. These include dry mouth, mydriasis, tachycardia, constipation, urinary retention, and psychiatric disturbances. (as noted above)

V. Drug therapy after the Onset of Significant Disability

A. Selegiline

B. L-Dopa + Carbidopa (or Benserazide) are almost always administered together

1. Explain why L-Dopa, not DA; and role of peripheral decarboxylase inhibitor in reducing peripheral side effects (esp. CV) and enhancing CNS effects.

2. L-Dopa is well absorbed by the amino acid transport system of the small bowel. 95% is decarboxylated in the liver. It's half life is 1-2 hours in blood. Because of the high doses which are necessary to get a CNS effect, GI distress, nausea, and vomiting are common side effects. This diminishes with time. A similar saturable amino-acid transport system is found in the brain. Dietary amino-acids can compete with L-Dopa for transport and diminish access of the drug to the CNS. For this reason, the drug is most commonly given on an empty stomach.

3. This regimen gives substantial relief to approximately 75% of patients, but with continued use for about 5 years you begin to see the onset of severe fluctuations in motor function and dyskinesias (abnormal involuntary movements) caused by L-Dopa. Also see "on-off" phenomena, "freezing", end of dose deterioration too. Psychiatric disturbances due to L-Dopa are also common, and perhaps not surprising considering the role of DA in the lymbic system. They are more common in the elderly, and include euphoria, anxiety, irritability, hyperactivity, hallucinations, delirium etc. L-Dopa can also cause a variety of CV side effects including disturbances of cardiac rate and rhythm. L-Dopa is not recommended during pregnancy, since it is a potential teratogenic agent. L-Dopa effects are antagonized by antipsychotic drugs such as phenothiazines as well as by reserpine and phenytoin. A hypertensive crisis may occur if L-Dopa is given with a NON-Specific MAO inhibitor, therefore, these drugs must be discontinued 2 weeks prior to giving L-Dopa.

C. As an alternative to the use of L-Dopa, Dopamine Agonists have been investigated. It was anticipated that these drugs might prove superior to L-Dopa, because they do not rely on enzymatic transformation in DA terminals. This would especially be true in late stages of PD, when few terminals survive to permit decarboxylation to DA.

1. Bromocriptine ( D-2 receptor agonist and D-1 partial agonist)

a. Bromocriptine is more effective than the anticholinergic drugs and less effective than levodopa in the symptomatic treatment of parkinsons disease. Its primary use is as an adjunct to l-dopa+carbidopa therapy in patients experiencing fluctuations in therapeutic response, end of dose akinesia, and painful dystonias. There is considerable interindividual variation in response to bromocriptine, therefore careful titration of dose is required. Orthostatic hypotension is a common side effect. Mental disturbances such as those seen with L-Dopa ( confusion, paranoia, and hallucinations) can also occur at low doses.

2. Pergolide

a. It is a more potent Dopamine receptor agonis than bromocriptine, and has a longer half life. It is used for the same purposes as bromocriptine, and has similar toxic effects, except that it is more likely to cause cardiac arrhythmias. Little pharmacokinetic data is available

3. Amantadine

a. A weak DA agonist

b. Enhances release of DA

c. Blocks reuptake of DA

d. Slightly anticholinergic too

e. Amantadine is a much less effective drug than l-dopa, although a small proportion of patients may have a striking initial response. Clinical improvement is usually not sustained beyond 3-6 months when the drug is given alone. More commonly the drug is combined with l-dopa or anticholinergic drugs. The drug has relatively few side effects. Effects noted are those expected for an anticholinergic drug. The drug is probably also teratogenic and embryotoxic. It is also excreted in mothers milk. Caution should be used in combined therapy with other anticholinergic drugs to avoid excessive anticholinergic actions.

VI Drug Therapy in Advanced Parkinsonism

A. Not uncommonly patients alternate between periods of good mobility (on time) often accompanied by dyskinesias, and periods of immobility with painful dystonias (off times). The dyskinesias may occur primarily at the time of greatest improvement in mobility (peak dose effect), or they may be diphasic, emerging immediately before l-dopas therapeutic response and reappearing prior to loss of therapeutic benefit. Rarely, one-half of the body may be "on" and dyskinetic, while the other half is immobile. L-Dopa therapy also begins to diminish in effectiveness, probably secondary to progression of the disease process. Although complete lack of responsiveness rarely occurs even after 20 years of therapy with l-dopa, the quality of motor response deteriorates and symptoms appear that do not respond to L-Dopa such as speech dysfunctions, severe postural instability, and "freezing". Dyskinesias occuring in response to dopaminergic drugs may further impair function and CNS side effects my prevent administration of higher drug doses. Formerly some authorities recommended discontinuation of drugs temporarily, in an effort to reduce adverse drug effects and restore the effects of l-Dopa. However many patients become essentially paralyzed when l-Dopa is withdrawn and are at severe risk of pneumonia and pulmonary emboli. Further since the benefits gained by this maneuver last no more than a few months, drug withdrawal has limited usefulness.

B. Long term therapy at the moment is a combination of L-Dopa and dopamine agonists. Selegeline may accentuate the adverse motor effects caused by L-Dopa and therefore is not used in advanced PD.

VII Experimental Therapy

A. Implants of embryonic dopamine rich ventral mesencephalic tissue reverse motor and behavioral deficits in rodents and monkeys with experimental Parkinsons disease.