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Rinfocan- Prescription Drug Information for Canadians

PARKINSON'S DISEASE- updated Jan 3, 1999

A REVIEW OF THE ETIOLOGY AND DRUG THERAPY

Compiled by: Eric Brandt, B.Sc. Pharm.

Parkinson's disease is a progressive degenerative disease of the nervous system affecting primarily the basal ganglia. Drug therapy improves the quality of the patient's life but has not affected the underlying disease.

The normal balance of catecholamines, dopamine and acetylcholine is upset. There is a deficiency of dopamine in Parkinson's disease. A decline in dopamine results in degeneration and/or denervation of the neuronal tracts within the basal ganglia and degeneration of the tracts running to the cerebral cortex.

The loss of these nigro-striatal dopaminergic neurons causes the striatal cholinergic neurons to become hyperactive.

This imbalance can be partially corrected by increasing dopaminergic transmission or by decreasing cholinergic transmission.

ETIOLOGY:

Prevention may be possible if a cause is found. Factors which have been considered or are now being investigated as possible factors in the development of Parkinson's disease:

a) genetic

b) the process of aging - symptoms may arise when normal, age related loss of neurons is superimposed on pre-existing cell loss due to some previous insult

c) viral infection- epidemic of encephalitis lethargica earlier in this century

d) environmental - some agents may trigger cell damage and death

toxic free radicals may accumulate

i ) lead

ii) mercury

iii) manganese

iv) carbon monoxide

v ) MPTP

- 1-methyl-4-phenyl-1,2,3,6 - tetrahydropyridine

- clinical and pathological evidence that this is a specific neurotoxin

- it is now known that MPTP is not the direct toxin but is a pro-toxin that is taken up by the astrocytes which surround the neurons and then metabolized by monoamine oxidase and produce 1-methyl-4-phenylpyridinium (MPP+)

vi) some industrial chemicals - e.g. the herbicide PARAQUAT

SYMPTOMS

The first three are classical signs of Parkinson's disease:

l. Tremor - present when the involved part of the body is at rest

- diminished with maintenance of posture or performance of volitional acts

- worse with stress

2. Rigidity - stiffness often accompanied by tremor

- passive movements are more difficult

- cogwheeling motion

3. Bradykinesia - difficulty and slowness of voluntary muscle movement

- mask-like face - expressions don't seem to change

- eye-blinking may decrease (reptilian stare)

- akinesia, freezing of motion, is often present

4. Gait disturbance - lack of postural control

- slowing of vcluntary muscles of arms and leg

- propulsion and retropulsion

5. Autonomic symptoms - bowel and bladder dysfunction

- sweating, salivation

6. "Others"

- fatigue

- insomnia

- depression

- dementia

- speech problems

STAGES:

1. Mild unilateral tremor - typically begins in hands and feet

- mild symptoms are noticed but do not cause social disability

2. Moderate bilateral tremor and rigidity

- symptoms progress to mild physical and social disability

3. Significant tremor and rigidity

- disability impairs physical independence or activities of daily living

4. Severely disabled but mobile

- many falls

5. Maximum disability

- psychological changes

- bed-ridden, often in fetal position

DIAGNOSIS:

Effective and appropriate therapy is possible only if there is a specific diagnosis and plan of therapy

a) clinical observations - early symptoms may be very mild

b) diagnostic scanning - positron emission tomography

Problems are often misinterpreted because of subtleties of the clinical presentation.

-inappropriate therapy

- development of drug tolerance

- poor response

- progressive course of disease

- increasing age of patient

- unwanted side effects

- dementia may make interpretation of problems even more difficult

SUPPORTIVE CARE:

a) reduction of stress

b) activity

c) physiotherapy '

d) avoidance of iatrogenic problems

e) diet -> low protein, small meals

DRUG THERAPY:

- examples are listed for each class of drug

- generic formulations of some of these drugs are now available

- patients with mild symptoms may not need medication

- use lowest dose possible to produce reduction in disability without attempting to abolish all signs of the disease

- drug holidays have been implemented after long-term treatment if patients have developed receptor blockade in association with denervation hypersensitivity. The patient should be hospitalized, and medications withdrawn for at least one week to allow renewal of the receptor response. There are risks involved in this procedure, thus many researchers feel that a careful reduction of dose is a wiser procedure.

1. Anticholinergic Drugs

benztropine (Cogentin)

procyclidine (Kemadrin)

trihexyphenidyl (Artane)

biperiden (Akineton)

ethopropazine (Parsitan)

- used to return the balance between cholinergic and dopaminergic mechanisms

- anticholinergics lower the excitatory cholinergic transmission in the basal ganglia

- useful early in the disease when the patient has only slight disability

- may be used if levodopa is contraindicated - e.g. schizophrenic patient

- relieve tremor and rigidity

- because of their side effects they are more useful in the younger patient

- side effects often limit their use:

blurred vision, dry mouth, constipation, urinary retention, tachycardia, confusion, hallucinations

2. Antihistamines

diphenhydramine (Benadryl)

orphenadrine ( Disipal )

- less potent than other drugs used for Parkinson's disease

- most effective in tremor and rigidity with little or no effect on bradykinesia

- side effects of drowsiness may be helpful; while anticholinergic side effects are troublesome

3. Dopnminergic drugs

levodopa ( Larodopa )

levodopa/carbidopa (Sinemet)

controlled release formulations (Sinemet CR) levodopa/benserazide (Prolopa)

- dopamine itself cannot be given because it does not cross the blood-brain barrier

- levodopa is the immediate precursor to dopamine and will cross the blood-brain barrier where it is converted to dopamine and reestablishes the neurotransmitter balance

- rigidity and bradykinesia are decreased with levodopa therapy

- a considerable portion of the levodopa dose is broken down in the peripheral area by the enzyme decarboxylase

- the addition of a decarboxylase inhibitor (carbidopa or benserazide) reduces the side effects which are due to the formation of dopamine in the peripheral areas

- the decarboxylase inhibitor allows more levodopa to cross the blood-brain barrier therefore lower total daily doses of levodopa may be given to achieve the maximum therapeutic effect

- a ratio of 1 to 4 ( 1 decarboxylase inhibitor to 4 parts levodopa) seems to be most beneficial .

- effects of levodopa may be decreased after 2-5 years of therapy,a fluctuating response may be seen

- eating slows or prevents some absorption of levodopa but it is necessary to give this drug with a small amount of food to alleviate gastric upset - larger doses of the drug are given to account for this loss of absorption

- proteins with large neutral amino acids interfere with the transport of levodopa across the blood-brain barrier

Side Effects - nausea and vomiting, constipation, hypotension, dyskinesia, confusion, hallucinations

- there are two theories regarding the initiation of levodopa therapy

a) the progression of the disease and the development of complications associated with levodopa are correlated more closely with the duration of levodopa therapy than with the duration of the disease

b) opposing theory - the complications of levodopa therapy correlate more closely with the disease than with the duration of therapy, therefore levodopa should be used when symptoms are beginning to affect employment or social life so that the patient can have maximum benefit from the drug

4. Indirect dopamine agonist:

amantadine (Symmetrel)

- crosses the blood-brain barrier

- acts by blocking the re-uptake of dopamine so that more active

neurotransmitter remains in the synaptic cleft

- enhances the release of dopamine from the endogenous sites in the nigrostriatal neurons

- is useful in earlier stages of disease before levodopa becomes necessary

- is useful for akinesia

- may be used in conjunction with other anti-Parkinson drugs

- may lose its therapeutic effect in 6-8 wks

- is cleared by the kidneys so should be used with caution in the elderly who may have renal failure

Side effects - nausea, dizziness, insomnia, hallucinations,1ivedo reticularis

5. Direct dopnmine agonists:

bromocriptine (Parlodel) directly stimulates post-synaptic D2 receptor sites

pergolide (Permax) directly stimulates post-synaptic D1 and D2 receptor sites

ten times more potent than bromocriptine

- ergoline derivatives

- bypass presynaptic dopaminergic system and directly stimulate the postsynaptic receptor

- no conversion to dopamine is required

- for akinesia, tremor and rigidity

- cross the blood-brain barrier best when given with levodopa

- cause fewer abnormal involuntary movements than levodopa

- have longer duration of action than levodopa

Side Effects - dyskinesia, nausea and vomiting, orthostatic hypotension, nightmares, hallucinations, paranoid delusions

Note: Domperidone (Motilium) is an extracerebral D2 antagonist

it blocks dopamine receptors outside the C.N.S. and may be given with bromocriptine to reduce the adverse effects of nausea and vomiting. It should be given one-half hour before the bromocriptine or pergolide dose

6. Monoamine oxidase Inhibitor - Type B:

selegiline/deprenyl (Eldepryl, Jumex)

- blocks the normal process of destruction of dopamine

- blocks the re-uptake of dopamine

- allows increased release of dopamine from presynaptic terminals

- has virtually no adverse pressor effects if given at a dose of 10mg/day

- may delay the onse of disability associated with early, otherwise untreated P.D.

- increases the extent and duration of action of levodopa, thus levodopa dose may be reduced by 10-30% when deprenyl is added to treatment regime in more advanced P.D.

- fewer fluctuations in levodopa response occur when deprenyl is added thus it is useful to "wearing off" reactions

- has not been shown to help "freezing"

Side Effects: insomnia - dose should not be given after 1 p.m.

confusion, vivid dreams, anxiety

DRUG INTERACTIONS:

l. Anticholinergics and levodopa or bromocriptine

- delayed gastric emptying decreases levodopa's effect but these drugs are used together

2. Anticholinergics and psychotherapeutic agents

- additive anticholinergic action

3. Diazepam and levodopa

- aggravates ataxia, falling

- short-acting benzodiazepines are used for Parkinsonian patients

4. Clonidine and levodopa or bromocriptine

- may inhibit the anti-Parkinson action of levodopa by stimulating central alpha adrenergic receptors

5. Guanethidine and levodopa or bromocriptine

- enhances hypotensive effect

- monitor blood pressure

6. Reserpine and levodopa or bromocriptine

- as above

7. M.A.0.I. (type A drugs) and levodopa, bromocriptine or deprenyl

- avoid use - these will lower dopamine degradation and may cause hypertension

8. Antipsychotics and levodopa or bromocriptine

- inhibit response to levodopa

9. Phenytoin and levodopa

- lowers therapeutic effect of levodopa but phenytoin alleviates l-dopa induced dyskinesia because of this lowering

- 10. Pyridoxine (Vitamin B6) and levodopa

- B6 enhances metabolism of levodopa so there will be a reduced amount available at sites of action in the brain

- this interaction does not occur if the patient is receiving a peripheral decarboxylase inhibitor

11. Alcohol and bromocriptine

- worsens bromocriptine side effects

12. Selegiline and levodopa - potentiation

AVOID:

l. alpha-methyldopa - may exacerbate parkinsonism

2. Papaverine - may exacerbate parkinsonism

3. Tetrabenazine - depletes catecholamines from the brain

4. Selegiline and M.A.O.I. - type A drugs

although 10 mg per day is the recommended dose for P. D. it is important to know that at doses above 20 mg/day it loses selectivity for MAO-B and inhibits MAO-A as well. Dietary restrictions and avoidance of drugs interacting with MAOI are necessary if higher doses are used.

5. Selegiline and meperidine

New Drugs

Ropinirole ( ReQuip)

What is Requip?

* ReQuip is a drug used for the symptomatic treatment of Parkinson's disease. Its chemical name is ropinirole hydrochloride.

* ReQuip belongs to a class of Parkinson's drugs called the dopamine agonists. However, unlike the existing dopamine agonists, ReQuip has a novel nonergoline chemical structure.

How does ReQuip work?

* Parkinson's results from the death of nerve cells generating dopamine. ReQuip replaces dopamine by mimicking the natural dopamine in the brain, and binding specifically to dopamine receptors, in order to generate anti-Parkinsonian activity.

* ReQuip is effective as symptomatic treatment of early Parkinson's (without concomitant L-dopa).

* ReQuip is also effective as adjunct therapy to L-dopa in the later stages of the disease.

What is the official indication for ReQuip?

* ReQuip is indicated in the symptomatic treatment of the signs and symptoms of idiopathic Parkinson's disease.

* ReQuip can be used both as early therapy, without concomitant levodopa, and as an adjunct to levodopa.

What clinical trials have been done with ReQuip?

* In placebo controlled studies, ReQuip has shown efficacy in both early therapy and adjunct therapy.

The 6-month interim results of an on-going 5-year study comparing ReQuip to levodopa in early therapy showed no difference between the two drugs in Clinical Global Improvement (CGI) in patients at Hoehn & Yahr stages I-II.

* In adjunct therapy with levodopa, ReQuip can decrease the dose of levodopa by 20% and increase the time spent "on" by 1.6 to 3.3 hours.

Were clinical trials conducted in Canada?

* Canada was involved in some of the clinical trials. Trial sites included: Halifax, Quebec City, Toronto, Winnipeg, and Edmonton.

* ReQuip has also been tested extensively in clinical trials internationally, particularly in the US and in Europe.

How do you take ReQuip?

* Patients should consult with their physician when initiating any drug therapy, and ReQuip is no exception.

* Physicians prescribe ReQuip as needed by each individual patient. The dose of ReQuip required will vary according to each patient and the severity of disease.

* Typically, the dose of ReQuip is gradually increased over the course of one month, so as to allow the patients to "wean-on" to the drug.

* Physicians requiring further dosing and administration information should consult with the official product monograph.

How well is ReQuip tolerated?

* ReQuip has a good safety profile, similar to that of a dopamine agonist, with similar tolerability as L-dopa and bromocriptine.

* ReQuip's non-ergoline structure eliminates the risk of serious ergoline-related side effects.

* In early therapy, nausea, dizziness and somnolence were the most frequently reported adverse events. Dyskinesias were not reported with ReQuip in early therapy.

* In adjunct therapy with levodopa, the most common adverse events were nausea, dizziness and dyskinesias.

* If it occurs, nausea appears early in therapy and is transient. It may be counteracted by the prophylactic use of an anti-nauseant called domperidone.

References:

1 Rascol 0, Brooks DJ, Brunt ER et al. Ropinirole in the treatment of early Parkinson's disease: A 6-month interim report of a 5-year L-dopa controlled study. Movement Disorders. In press.

2 Data on file, SB 1001

3 Data on file, SB 1002

4 Data on file, SB 1024

Tolcapone- Tasmar

The inhibition of COMT by Tolcapone increases levodopa bioavailability by limiting its metabolosm, helping achieve a more steady and continuous dopaminergic stimulation in the brain.

The efficacy of tolcapone has been demnstrated in randomized placebo-controlled trials, in patients receiving levodopa therapy with carbidopa or benserazide who experienced end of dose wearing off phenomena and in patients who did not experience such phenomena. In these clinical trials, patients who were experiencing wearing off had a 30% to 50% reduction in OFF time and an improvement in motor functions. In patients who did not experience OFF phenomena there was a 20% improvement in the activities of daily living and an improvement in motor performance. Tolcapone (Tasmar) is indicated as an adjunct to both levodopa/benserazide and levodopa/carbidopa. Available as 100 mg and 200 mg tablets. On November 20, 1998 the sale of Tasmar was suspended by Health Canada

Pramipexole dihydrochloride- Mirapex

In early disease MIrapex has been proven effective in reducing Parkinson's symptoms without the need for concomitant levodopa therapy.

Common adverse reactions in early disease include: nausea, dizziness, somnolence, insomnia, asthenia, and constipation. There was a strong association between hallucinations and discontinuation of treatment in the elderly.

In advanced disease Mirapex clinical trials have shown it to be effective in reducing the symptoms and number of "off" hours when given in conjunction with levodopa.

Common adverse reactions in advanced disease include those seen in early disease trials with the addition of: postural (orthostatic) hypotension, dyskinesia, hallucinations, accidental injury, dream abnormalities and confusion.

Dosage and administration: Pramipexole dihydrochloride should be taken three times daily. Dosage should be increased gradually from a starting dose of 0.375 mg /day given in three divided doses and should not be increased more frequently than every 5-7 days. Mirapex is not recommended at the 6 mg per day dose since the incidence of some adverse effects is higher. For more detailed prescribing information refer to product monograph.