Pharmacologic treatment of Parkinson disease:

Dr behnaz ansari

• The array of pharmacologic and surgical treatments available for the treatment of idiopathic Parkinson disease (PD) is broader than for any other degenerative disease of the central nervous system.

• Management of individual patients requires careful consideration of a number of factors, including the patient's symptoms and signs, age, stage of disease, degree of functional disability, and level of physical activity and productivity. Treatment can be divided into pharmacologic, nonpharmacologic, and surgical therapy.

• nearly all of the available treatments are symptomatic in nature and do not appear to slow or reverse the natural course of the disease. However, several potential neuroprotective agents for PD have shown some promise in animals and/or humans and are undergoing further investigation.

SYMPTOMATIC THERAPY :

• The decision to initiate symptomatic medical therapy in patients with PD is determined by the degree to which the patient is functionally impaired. The timing of this decision varies greatly among patients but is influenced by a number of factors, including :

●The effect of disease on the dominant hand●The degree to which the disease interferes with work, activities of daily living, or social and leisure function●The presence of significant bradykinesia or gait disturbance●Patient values and preferences regarding the use of medications

• The major drugs available for the treatment of PD motor symptoms include:

●Levodopa●Dopamine agonists●Monoamine oxidase (MAO) B inhibitors●Anticholinergic agents●Amantadine●Catechol-O-methyl transferase (COMT) inhibitors

Drug Mechanism Adverse effect

Levodopa-carbidopa Dopamine replacement

DOC for older patients

1. Motor fluctuations: dopamine agonist or amantadine

2. Wearing off: inc dose or frequency

Ropinirole, Pramipexole Dopamine receptor agonist

DOC for <65yo Impulse control disorders-hypersexual and gambling

Amantadine NMDA receptor antagonist

Mild symptoms, tremor

AMS and psychosis

Selegiline, Rasagiline MAO-B inhibitor May delay need for L-dopa

Seratonin syndrome if with SSRIs or tricyclics

**Acutely discontinuing dopa therapy may cause NMS. Treat with a dopamine agonist: bromocriptine, amantadine or dantrolene

Parkinson’s DiseaseSymptoms: (the 4 R’s) initially unilateral disease

1. Resting tremor and cogwheeling2. Rigidity and flexed posture3. Retarded movement (brady and hypokinesia)4. Loss of postural Reflexes

The following general principles can be used to guide the choice of therapy in symptomatic PD:

• Levodopa is the most effective drug for the symptomatic treatment of PD and is the drug of first choice if symptoms, particularly those related to bradykinesia, become intrusive or troublesome. In addition, levodopa should be introduced when akinetic symptoms become disabling for patients receiving other antiparkinsonian drugs.

• The dopamine agonists may be employed either as monotherapy in early PD or in combination with other antiparkinsonian drugs for treatment of more advanced disease. They are ineffective in patients who show no response to levodopa. While dopamine agonists possibly delay the need to initiate levodopa therapy, their use is associated with an increased risk of impulse control disorders.

• Either levodopa or a dopamine agonist can be used initially for patients who require symptomatic therapy for PD . Given the potential that dopamine agonists may be associated with fewer motor fluctuations than levodopa, and the evidence that there is a higher incidence of levodopa-related dyskinesia in young-onset PD, it is reasonable to start therapy with a dopamine agonist in younger patients (age <65 years), and with levodopa in older patients (age ≥65 years). In practice, while symptoms can be controlled initially with dopamine agonists, few patients with progressive disease can be satisfactorily maintained on dopamine agonist monotherapy for more than a few years before levodopa is needed.

• The MAO B inhibitors selegiline and rasagiline may be useful in patients with early PD but have only modest symptomatic benefit as monotherapy.

• Anticholinergic drugs are most useful as monotherapy in patients under 70 years of age with disturbing tremor who do not have significant bradykinesia or gait disturbance. They also may be useful in patients with more advanced disease who have persistent tremor despite treatment with levodopa or dopamine agonists. Their use in older or demented individuals and those without tremor is strongly discouraged.

• Amantadine is a relatively weak antiparkinsonian drug with low toxicity that is most useful in treating younger patients with early or mild PD and perhaps later when dyskinesia becomes problematic. However, toxic side effects are more likely in older patients.

• Low-dose estrogen may be helpful as adjunctive therapy in postmenopausal women

Swallowing restrictions in Parkinson disease:

• Most patients with PD can go without antiparkinson medications for a brief period (ie, <24 hours) when oral intake is temporarily restricted (eg, when perioperative or periprocedural), or when seriously ill.

• In patients who are critically ill and bedbound, the parkinsonian symptoms are typically overshadowed by the burden of other medical problems, and antiparkinson medications may not provide any clear benefit.

• However, sudden withdrawal or dose reduction of antiparkinson medications can rarely precipitate the parkinsonism-hyperpyrexia syndrome.

• When treatment is still desired for patients who are restricted to take nothing by mouth (nil per os; NPO), options include: transdermal rotigotine and apomorphine by injection or continuous infusion. The use of apomorphine requires a test dose prior to ongoing treatment

• For patients with a nasogastric feeding tube, levodopa tablets can be crushed and given through the tube . For patients with dysphagia, orally disintegrating carbidopa-levodopa (Parcopa) is a potential treatment option.

Parkinsonism-hyperpyrexia syndrome :

• There have been reports of patients with PD who developed neuroleptic malignant syndrome in the context of sudden withdrawal or dose reductions of levodopa or dopamine agonists, and rarely amantadine, as well as with switching from one agent to another. In this context, the condition has been termed the parkinsonism-hyperpyrexia syndrome .Prompt recognition and treatment are important, as severe cases and even fatalities have been reported .

• Management of parkinsonism-hyperpyrexia syndrome involves replacing antiparkinson medications at the dose that was used prior to the onset of the syndrome . Levodopa and dopamine agonists can be given orally or via nasogastric tube. Levodopa can also be given intravenously (50 to 100 mg infused over three hours, repeated four times daily) if both oral and nasogastric feeding are contraindicated; options for dopamine agonists include transdermal rotigotine and apomorphine by injection or continuous infusion. The use of apomorphine requires a test dose prior to ongoing treatment.

• In addition to replacing antiparkinson medications, patients with significant hyperthermia and rigidity should be admitted to an intensive care unit setting and undergo aggressive supportive care as well as monitoring for potential dysautonomia and other complications .

• For patients with severe symptoms who do not respond to restarting antiparkinson medications and supportive care within the first day or two, additional though unproven measures to consider include the use of dantrolene, bromocriptine, and/or amantadine.

LEVODOPA:

• Levodopa (L-dopa) is well-established as the most effective drug for the symptomatic treatment of idiopathic or Lewy body PD . It is particularly effective for the management of bradykinetic symptoms and should be introduced when these become intrusive or troublesome or are uncontrolled by other antiparkinsonian drugs. Tremor and rigidity can also respond to levodopa therapy, but postural instability is less likely to do so.

• As noted previously ,either levodopa or a dopamine agonist can be used initially for patients who require symptomatic therapy for PD. It is reasonable to initiate therapy with a dopamine agonist in younger patients (age <65 years), and with levodopa in older patients (age >65 years).

• However, there are exceptions to these general rules, and all treatments should be individualized. Levodopa is the drug of choice if symptoms, particularly those related to bradykinesia, seriously threaten the patient's lifestyle.

• Levodopa is combined with a peripheral decarboxylase inhibitor to block its conversion to dopamine in the systemic circulation and liver (before it crosses the blood-brain barrier) in order to prevent nausea, vomiting, and orthostatic hypotension. In the United States, the decarboxylase inhibitor is carbidopa. The combination drug carbidopa-levodopa (immediate-release Sinemet) is available in tablets of 10/100, 25/100, and 25/250 mg, with the numerator referring to carbidopa and the denominator referring to the levodopa dose.

• An immediate-release formulation of carbidopa-levodopa (Parcopa) is available that dissolves on the tongue and can be taken without water ; its time of onset of action is not different from Sinemet.

Sinemet:

• In some countries, benserazide is the peripheral decarboxylase inhibitor. The combination drug benserazide-levodopa (Madopar or Prolopa) is available in 25/100 and 50/200 mg tablets. In many countries, both carbidopa-levodopa (eg, Sinemet) and benserazide-levodopa (eg, Prolopa) are marketed.

• Controlled-release formulations of carbidopa-levodopa and benserazide-levodopa are available as Sinemet CR and Madopar HBS, respectively. Compared with regular levodopa, the absorption of the controlled-release formulations is approximately 70 percent.

Madopar:

• Treatment should begin with small doses, such as carbidopa-levodopa (Sinemet) 25/100 mg, one-half tablet two to three times daily with meals. Tolerance for the appropriate starting dose must be assessed individually. Once initiated without side effects, the total daily dose of carbidopa-levodopa can be titrated carefully upward over several weeks to a full tablet of 25/100 mg three times daily as tolerated.

• Older adults or those with dementia should begin with smaller doses and slower titration because of their increased susceptibility to psychiatric side effects.

• The vast majority of patients with idiopathic PD will enjoy a significant therapeutic response to moderate doses of levodopa (300 to 600 mg daily).

• Complete absence of response to a levodopa dose of 1000 to 1500 mg/day suggests that the original diagnosis of PD may be incorrect and that one of the other parkinsonian syndromes, such as multiple system atrophy, progressive supranuclear palsy, or vascular parkinsonism should be considered.

• Levodopa should not be stopped abruptly because sudden withdrawal has been associated (rarely) with a syndrome resembling neuroleptic malignant syndrome or akinetic crisis.

• Patients taking levodopa for the first time should take each dose with a meal or snack to avoid nausea, a common early side effect. Patients with more advanced disease, especially those with motor fluctuations, often notice that a dose of levodopa is more effective if taken on an empty stomach 30 minutes before or one hour after meals due to reduced competition with other amino acids for gastrointestinal absorption.

• Small starting doses of levodopa of less than 25/100 mg three times daily combined with a decarboxylase inhibitor (eg, Sinemet, Madopar, or Prolopa) are more likely to cause nausea because of inadequate amounts of carbidopa.

• this can be managed by administering supplemental doses of carbidopa or by use of antiemetics such as trimethobenzamide or domperidone (not available in the United States) taken prior to Sinemet. Phenothiazine antiemetics such as prochlorperazine andmetoclopramide should be avoided because they are dopamine receptor blockers that can aggravate parkinsonian symptoms.

Adverse effects :• Nausea, somnolence, dizziness, and headache are among the more

common early side effects that may accompany treatment with levodopa, but they are not likely to be serious in most patients. More serious adverse reactions to levodopa (mainly in older patients) may include confusion, hallucinations, delusions, agitation, psychosis, and orthostatic hypotension.

• Levodopa may also induce a mild to moderate elevation in serum homocysteine levels , which in turn may be associated with an increased risk of hip fractures in older adults.

• In addition, there is some preliminary evidence suggesting that levodopa exposure in patients with idiopathic PD is associated with elevated methylmalonic acid levels and possibly a higher than expected incidence of sensorimotor peripheral neuropathy

Motor fluctuations :

• These include motor fluctuations (the wearing-off phenomenon), involuntary movements known as dyskinesia, abnormal cramps and postures of the extremities and trunk known as dystonia, and a variety of complex fluctuations in motor function.

• It is estimated that such motor complications occur in at least 50 percent of patients after 5 to 10 years of treatment .

• The risk of motor complications increases with a younger age at PD onset and with higher levodopa doses

• The increase in motor fluctuations over time is most likely due to progressive degeneration of nigrostriatal dopamine terminals, which increasingly limits the normal physiologic uptake and release of dopamine, thereby leading to reduced buffering of the natural fluctuations in plasma levodopa levels that occur due to its 90-minute pharmacologic half-life.

Wearing "off" phenomenon:

• Examine the effect of diet, and avoid taking levodopa with high protein meals.• A sustained-release levodopa formulation may be beneficial, but only in the early stages of

wearing "off" in patients with less advanced PD. • In patients with more advanced PD, reduce the levodopa dose interval by 30 to 60 minutes.

This may require the addition of an extra levodopa dose at the end of the day. • Consider adding the COMT inhibitors entacapone (Comtan) or tolcapone (Tasmar).

Entacapone should be given first because of the small risk that tolcapone can cause an elevation of liver enzymes.

• Consider adding an oral dopamine agonist such as pramipexole or ropinirole. Watch for dopaminergic toxicity such as visual hallucinations and confusion, and be prepared to lower the levodopa dose.

• Consider parenteral apomorphine in patients with sudden and severe wearing "off" effects. This rescue therapy is very effective.

• Consider the MAO B inhibitors rasagiline and selegiline .Be aware that selegiline exerts only a mild effect on the wearing "off" phenomenon, while rasagiline has an effect comparable to entacapone. Rasagiline is now approved in the United States and in the European Union.

Dyskinesia and dystonia:

• Lower the levodopa dose when possible• Replace a portion of the levodopa dose with a dopamine

agonist, if necessary• Replace sustained-release levodopa with regular levodopa, if

dyskinesia is occurring in the late afternoon and evening• Add amantadine to counteract dyskinesia• Manage diphasic dyskinesia with more frequent levodopa

dosing• Use middle-of-the-night levodopa or a dopamine agonist to

treat early morning "off" period dystonia• Reduce the levodopa dose intervals or add a dopamine agonist

to treat "off" period dystonia during the day

DOPAMINE AGONISTS :

• The dopamine agonists (DAs) are a group of synthetic agents that directly stimulate dopamine receptors. The drugs currently approved by the United States Food and Drug Administration (FDA) include bromocriptine, pramipexole, ropinirole, rotigotine, and injectableapomorphine.

• Pergolide has been voluntarily withdrawn from the United States market and is best avoided because it is associated with a risk of cardiac valve problems.

• Apomorphine and lisuride are additional DAs that can be administered parenterally for "rescue therapy" in patients experiencing sudden akinetic episodes.

• Lisuride is not currently approved in the United States, but is available in Europe.

• Injectable apomorphine has been approved by the United States FDA for treatment of motor fluctuations in PD . Apomorphine infusion pumps may also be useful, but are not available in the United States.

• Dopamine agonists (DAs) were initially introduced as adjunctive treatment for advanced PD complicated by reduced levodopa response, motor fluctuations, dyskinesia, and other adverse effects of levodopa.

• DAs are associated with fewer motor fluctuations and the evidence that there is a higher incidence of levodopa-related dyskinesia in young-onset PD, some experts suggest using DAs as initial treatment for PD in patients younger than age 60, and using the more effective agent levodopa in patients 60 and older

• Bromocriptine is usually started at 1.25 mg twice a day; the dose is increased at two to four week intervals by 2.5 mg a day. Most patients can be managed on 20 to 40 mg daily in three to four divided doses, although total daily doses as high as 90 mg can be used.

• Pramipexole is usually started at 0.125 mg three times a day. The dose should be increased gradually by 0.125 mg per dose every five to seven days. Most patients can be managed on total daily doses of 1.5 to 4.5 mg.

Pramipexole:

• Ropinirole is usually started at 0.25 mg three times a day. The dose should be increased gradually by 0.25 mg per dose each week for four weeks to a total daily dose of 3 mg. Most patients can be managed on this dose. After week four, the ropinirole dose may be increased weekly by 1.5 mg a day up to a maximum total daily dose of 24 mg. Benefit most commonly occurs in the dosage range of 12 to 16 mg per day.

Ropirinole:

• Transdermal rotigotine is a once-daily patch that is usually started at 2 mg/24 hours and titrated weekly by increasing the patch size in 2 mg/24 hour increments to a dose of 6 mg/24 hours.

• Apomorphine may be administered either as intermittent rescue injections or as continuous infusions to treat "off" episodes or levodopa-induced motor fluctuations.

• A challenge test dose must precede routine use. This is usually done with a 2 mg subcutaneous injection under medical supervision and monitoring of standing and supine blood pressure before the injection, and repeated at 20, 40, and 60 minutes after.

• Antiemetic therapy (eg, with trimethobenzamide) is initiated three days prior to starting apomorphine and is usually continued for two months before reassessing need.

• However, the use of apomorphine is contraindicated with ondansetron and other serotonin receptor agonists commonly used to treat nausea and vomiting, as the combination may cause severe hypotension and loss of consciousness .

• In addition, dopamine antagonists used to treat nausea and vomiting such as prochlorperazine and metoclopramideshould be avoided, as they may reduce the effectiveness of apomorphine.

• The usual starting dose for intermittent apomorphine use, if the patient tolerates and responds to the test dose, is 2 mg. The dose may be increased by 1 mg per dose every two to four days to a maximum of 6 mg per dose. The average dosing frequency is three times daily and should not exceed five times a day dosing or a total daily dose of 20 mg.

Adverse effects of dopamine agonists :

• Adverse effects caused by dopamine agonists (DAs) are similar to those of levodopa, including nausea, vomiting, sleepiness, orthostatic hypotension, confusion, and hallucinations. Peripheral edema is common with the chronic use of DAs but is rare in patients using levodopa alone.

• These adverse effects of DAs can usually be avoided by initiating treatment with very small doses and titrating to therapeutic levels slowly over several weeks. Patients intolerant of one DA may tolerate another.

• Accumulating evidence suggests that the use of DAs as a class may lead to compulsive use of dopaminergic drugs and/or impulse control disorders in up to 15 percent of patients taking these drugs.

• Ergot-related side effects such as Raynaud phenomenon, erythromelalgia, and retroperitoneal or pulmonary fibrosis are uncommon with bromocriptine and pergolide, and they do not occur at all with the nonergot agonists ropinirole, pramipexole, and rotigotine.

• Dopamine receptor agonists decrease prolactin concentration . Thus, there is a potential for decreased milk production in postpartum women taking these agents, which are contraindicated in women who are breast feeding.

• The manufacturer of pramipexole has issued a warning regarding somnolence that can occur abruptly and without premonition, particularly at a dose above 1.5 mg/day. Patients with PD who drive are at particular risk of developing these "sleep attacks" .

Dopaminergic dysregulation syndrome :

• DDS typically involves male patients with early onset PD who take increasing quantities of dopaminergic drugs despite increasingly severe drug-induced dyskinesia .

• DDS can be associated with a cyclical mood disorder characterized by hypomania or manic psychosis. Tolerance (or frank dysphoria) to the mood elevating effects of dopaminergic therapy develops, and a withdrawal state occurs with dose reduction or withdrawal. Impulse control disorders including hypersexuality and pathologic gambling may accompany DDS.

• Management of DDS is not well studied. Practitioners should limit dopaminergic dose increases when possible, particularly in patients who may have increased susceptibility to DDS. Continuous subcutaneous apomorphine infusions may be useful to suppress off-period dysphoria, and low doses ofclozapine or quetiapine may be helpful for some patients.

Impulse control disorders :

• Dopamine (DA) agonist therapy is associated with an increased risk of impulse control disorders including pathologic gambling, compulsive sexual behavior, or compulsive buying

• A randomized crossover trial of 17 patients found that amantadine (target dose 100 mg twice daily), administered as add-on to baseline antiparkinsonian medications, was effective for reducing or abolishing pathologic gambling in all treated patients.

MAO B INHIBITORS :

• Selegiline, a selective monoamine oxidase (MAO) type B inhibitor , is modestly effective as symptomatic treatment for PD and may have neuroprotective properties.

• In many individuals, selegiline monotherapy does not produce a functionally significant benefit. However, the use of selegiline in early PD is a reasonable option as long as the patient understands its limitations.

• The selective MAO B inhibitor rasagiline has neuroprotective properties in animal models and appears modestly effective as symptomatic treatment for PD in human clinical trials.

• The dose of selegiline used was 5 mg twice daily, with the second dose given at noon to avoid insomnia. However, lower doses are sufficient to induce MAO B inhibition, and 5 mg once daily in the morning is currently recommended. Doses higher than 10 mg daily are of no additional benefit and may result in nonselective MAO inhibition, thereby placing the patient at risk of hypertensive crisis due to dietary interactions with tyramine-containing foods.

Selegiline:

• Rasagiline as monotherapy for PD is usually started at 1 mg daily. When used as adjunctive therapy with levodopa, rasagiline is started at 0.5 mg once daily and can be increased to 1 mg daily based upon response and tolerability

Rasagiline:

Adverse effects :• Selegiline often causes confusion in older adults, thereby limiting

its use in patients with late-onset disease. As previously mentioned, selegiline enhances the effect of levodopa by slowing its oxidative metabolism. Thus, it may increase levodopa-induced side effects such as dyskinesia and psychiatric toxicity.

• Serious adverse reactions have rarely occurred following the concomitant use of selegiline with tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs). In practice, the vast majority of patients on these combinations are able to tolerate them for years without problems. However, the Physicians' Desk Reference (PDR) warns not to use selegiline with either tricyclics or SSRIs.

ANTICHOLINERGICS:

• Dopamine and acetylcholine are normally in a state of electrochemical balance in the basal ganglia. In PD, dopamine depletion produces a state of cholinergic sensitivity so that cholinergic drugs exacerbate and anticholinergic drugs improve parkinsonian symptoms .

• Centrally acting anticholinergic drugs such as trihexyphenidyl and benztropine have been used for many years in PD and continue to have a useful role . Other anticholinergic agents such as biperiden,orphenadrine, and procyclidine produce similar effects and are more commonly used in Europe than the United States.

• Anticholinergic drugs are most useful as monotherapy for patients with PD who are <70 years of age and have disturbing tremor but do not have significant bradykinesia or gait disturbance. They also may be useful in patients with more advanced disease who have persistent tremor despite treatment with levodopa or dopamine agonists.

Adverse effects :

• Older adults and cognitively impaired patients are particularly susceptible to memory impairment, confusion, and hallucinations and should not receive these drugs.

• Peripheral antimuscarinic side effects include dry mouth, blurred vision, constipation, nausea, urinary retention, impaired sweating, and tachycardia. Caution is advised in patients with known prostatic hypertrophy or closed-angle glaucoma.

AMANTADINE :

• Amantadine is an antiviral agent that has mild antiparkinsonian activity . Its mechanism of action is uncertain; it is known to increase dopamine release, inhibit dopamine reuptake, stimulate dopamine receptors, and it may possibly exert central anticholinergic effects . Amantadine has N-methyl-D-aspartate (NMDA) receptor antagonist.

• Amantadine in divided doses of 200 to 400 mg a day may reduce the intensity of levodopa-induced dyskinesia and motor fluctuations in patients with PD.

Amantadine:

Dosing:

• The dose of amantadine in early PD is 200 to 300 mg daily; there is no evidence that larger doses are of additional benefit. The main advantage of this agent is a low incidence of side effects. It is excreted unchanged in the urine and should be used with caution in the presence of renal failure.

Adverse effects :

• Peripheral side effects include livedo reticularis and ankle edema, which are rarely severe enough to limit treatment.

• Confusion, hallucinations, and nightmares occur infrequently, but unpredictably, even after long periods of use without side effects. These effects are more likely when amantadine is used together with other antiparkinsonian drugs in older patients.

COMT INHIBITORS :

• The catechol-O-methyl transferase (COMT) inhibitors tolcapone andentacapone are ineffective when given alone, but they may prolong and potentiate the levodopa effect when given with a dose of levodopa, and thus are useful as levodopa extenders.

• Inhibition of COMT reduces the peripheral (entacapone) and central (tolcapone) methylation of levodopa and dopamine, which in turn increases the plasma half-life of levodopa, produces more stable plasma levodopa concentrations, and prolongs the therapeutic effect of each dose.

• These medications are mainly used to treat patients with motor fluctuations who are experiencing end-of-dose wearing "off" periods, as discussed separately.

Entacapone(200 mg):

Stalevo(50,100,150):

Dosing :

• The starting dose of tolcapone is 100 mg three times daily; the clinical effect is evident immediately. The dose of entacapone is one 200 mg tablet with each dose of levodopa, up to a maximum of eight doses per day.

Adverse effects :

• The most common side effects of tolcapone are due to increased dopaminergic stimulation and include dyskinesia, hallucinations, confusion, nausea, and orthostatic hypotension.

• The adverse effects are managed by lowering the dose of levodopa either before or after the addition of tolcapone. Diarrhea that is poorly responsive to antidiarrheal medications appears in approximately 5 percent of patients. An orange discoloration of the urine is a common but benign adverse event. Elevations in liver enzymes may rarely occur.

• Side effects of entacapone are similar to tolcapone, although entacapone has thus far not been associated with hepatotoxicity.

ESTROGEN:

• Low-dose estrogen may be helpful as adjunctive therapy in postmenopausal women with motor fluctuations on antiparkinsonian medication .

• Furthermore, concerns about adverse effects associated with long-term estrogen/progestin therapy may limit its use in PD.