Parkinson’s Disease

Parkinson’s disease is a progressive neurodegenerative disorder caused by a loss of dopamine (DA) neurons in the substantia nigra and the presence of Lewy bodies (eosinophilic cytoplasmic inclusions) in surviving DA neurons. The disease is characterized by resting tremor, bradykinesia (slowness), rigidity, and postural instability (impaired balance), the latter appearing late in the course of the disease. Long-term disability is typically related to worsening motor fluctuations and dyskinesias, dementia, or imbalance, and death results from the complications of immobility, including pulmonary embolism or aspiration pneumonia.

Although evidence implicates environmental and genetic factors in Parkinson’s disease, its etiology remains unknown. While the term Parkinson’s disease refers to the idiopathic disease, parkinsonism refers to disorders that resemble Parkinson’s disease but have a known cause and variable rates of progression and responses to drug therapy. These include encephalitis lethargica, multiple small strokes, and traumatic brain injury (pugilistic parkinsonism). In addition, parkinsonism can be induced by the long-term use of typical antipsychotic drugs and results from poisoning by manganese, carbon monoxide, or cyanide.

Parkinson’s disease is one of the few neurodegenerative diseases whose symptoms can be improved with drugs. In the late 1960s it was discovered that orally ingested 3,4-dihydroxy-phenylalanine (l-DOPA) improved symptoms dramatically. Primary treatments for Parkinson’s disease now include drugs that increase DA synthesis, decrease DA catabolism, and stimulate DA receptors; secondary compounds antagonize muscarinic cholinergic receptors, enhance DA release, and may antagonize N-methyl-d-aspartate (NMDA) glutamate receptors.

Alzheimer’s Disease

Alzheimer’s disease is a progressive dementing disorder resulting from widespread degeneration of synapses and neurons in the cerebral cortex and hippocampus as well as some subcortical structures. Its defining pathological characteristics are the presence of extracellular senile plaques and intracellular neurofibrillary tangles. The plaques in Alzheimer’s brain consist of an amyloid core surrounded by dystrophic (swollen, distorted) neurites and activated glia secreting a number of inflammatory mediators. The amyloid core consists of aggregates of a polymerized 40- to 42-amino acid peptide (Aβ) that is an alternate processing product of the transmembrane amyloid precursor protein and several accessory proteins. The neurofibrillary tangles are intracellular filaments composed of the microtubule associated protein tau, which is highly phosphorylated at unusual amino acid residues.

Both plaques and tangles are present in brain regions with the greatest degree of neuron and synapse loss and are largely absent from regions that are spared (e.g., cerebellum). Although the best correlate of the severity of dementia is synapse loss, the amount of neurofibrillary tangles appears more closely related to neuron loss than the amount of plaque pathology. The loss of these largely glutamatergic neurons intrinsic to the cortices is responsible for most clinical manifestations of Alzheimer’s disease.

While several neurotransmitter systems deteriorate in Alzheimer’s disease, one of the first and most pronounced reductions occurs within the acetylcholine (ACh) containing projections from the nucleus basalis in the basal forebrain to the cerebral cortex. The septo-hippocampal cholinergic pathway is similarly affected, whereas the

intrinsic striatal cholinergic system remains largely intact. Muscarinic cholinergic receptors in the cerebral cortex and hippocampus remain more or less intact, but nicotinic cholinergic receptors decline.

Current drug treatments for Alzheimer’s disease increase cholinergic transmission by the use of acetylcholinesterase (AChE) inhibitors and blocking the excitotoxic effects of glutamate at NMDA receptors with the antagonist memantine.

Patients with both Parkinson’s and Alzheimer’s diseases may manifest neuropsychiatric disturbances as a result of their primary disease, including psychoses, depression, anxiety, and agitation. These can be treated with the atypical antipsychotics, antidepressants, and anxiolytic compounds discussed in Chapters 29 to Chapters 31. A summary of the treatment of Parkinson’s and Alzheimer’s diseases is provided in the Therapeutic Overview Box.

Parkinson’s Disease Drugs

Current strategies for the treatment of Parkinson’s disease are directed at increasing dopaminergic activity in the striatum to compensate for the loss of nigrostriatal DA neurons (see Fig. 27-8). The major drugs used include compounds that increase the synthesis and decrease the catabolism of DA or directly stimulate DA receptors; secondary compounds block muscarinic cholinergic receptors, enhance DA release, and perhaps antagonize NMDA receptors.

Increased Dopamine Synthesis

l-DOPA was introduced for the treatment of Parkinson’s disease in 1970. It is the precursor of DA and crosses the BBB, whereas DA does not. l-DOPA increases DA synthesis but does not stop progression of the disease. When given alone, only 1% to 3% of an administered dose of l-DOPA reaches the brain; the rest is metabolized peripherally as shown in Figure 28-1. To prevent its peripheral metabolism and increase its availability to the brain, l-DOPA is administered with carbidopa, an aromatic l-amino acid decarboxylase inhibitor that does not cross the BBB. Carbidopa does not have any therapeutic benefit when used alone but increases the amount of l-DOPA available to the brain. However, as a consequence of peripheral inhibition of aromatic l-amino acid decarboxylase, more precursor is metabolized by plasma catechol-O-methyltransferase (COMT) producing 3-o-methyldopa. To overcome this, the COMT inhibitors tolcapone or entacapone are used in combination with l-DOPA/carbidopa. These compounds prolong the plasma t_1/2 of l-DOPA, increasing the time the drug is available to cross the BBB. They also prevent the buildup of 3-o-methyldopa, which competitively inhibits l-DOPA transport across the BBB. Entacapone does not cross the BBB, and its actions are limited to the periphery. However, tolcapone does cross the BBB and also prevents the formation of 3-o-methyldopa in brain and the catabolism of DA (Fig. 28-1).

FIGURE 28–1 Peripheral and central metabolism of l-DOPA and DA depicting the sites of action of enzyme inhibitors. AAAD, Aromatic l-amino acid decarboxylase; AD, aldehyde dehydrogenase; COMT, catechol-O-methyltransferase; MAO, monoamine oxidase.

Alzheimer’s Disease Drugs

Current strategies for the treatment of Alzheimer’s disease are directed primarily at increasing cholinergic activity to compensate for the loss of basal forebrain cholinergic neurons (see Fig. 27-9). Most available compounds are AChE inhibitors, including donepezil, galantamine, and rivastigmine. All of these drugs cross the BBB and are reversible AChE inhibitors. Donepezil and galantamine are specific for AChE, whereas rivastigmine inhibits both AChE and butyrylcholinesterase (ChE). As a consequence of AChE inhibition, ACh released from remaining cholinergic terminals is not rapidly hydrolyzed, leading to prolonged cholinergic receptor activation. In addition, galantamine stimulates presynaptic nicotinic cholinergic receptors in the brain through an allosteric mechanism, enhancing ACh release.

Because the AChE inhibitors indirectly enhance the effects of ACh released from nerve terminals by preventing its catabolism, their effects are more pronounced on active than on quiescent cholinergic neurons. This helps retain the spatial and temporal patterning of cholinergic activity in the brain, unlike directly acting agonists, which would tonically activate all receptors.

Memantine is the first low-affinity NMDA receptor channel blocker approved to treat Alzheimer’s disease. Memantine is a derivative of amantadine (see above) and binds to the open state of the glutamate NMDA receptor to block ion flux through this channel (see Chapter 1). NMDA receptors are critical to learning and memory and neural plasticity in the brain and serve an integrating function by remaining closed until a sufficient dendritic depolarization occurs to overcome blockade of the channel by Mg⁺⁺. Once open, Na⁺ and Ca⁺⁺ enter the cell, with Ca⁺⁺ activating multiple signaling cascades. Excessive opening of the channel can be associated with excitotoxicity in neurons. Although this may contribute to neurodegeneration in Alzheimer’s disease, there is no evidence yet that memantine protects neurons or modifies the course of the disease. It is hypothesized that the low-affinity antagonism of NMDA receptors prevents tonic activation while still permitting opening of the channel during periods of elevated activity critical for memory formation.

Parkinson’s Disease Drugs

l-DOPA is always administered with carbidopa to increase plasma levels and the t_1/2 of l-DOPA and to ensure sufficient l-DOPA is available to cross the BBB. l-DOPA/carbidopa is rapidly absorbed by the gastrointestinal tract but competes with dietary protein for both intestinal absorption and transport across the BBB. l-DOPA/carbidopa is available in an immediate-release form, which has a t_1/2 of only 60 to 90 minutes. Controlled-release formulations are available to minimize the number of daily doses required and prolong therapeutic plasma concentrations. A rapidly dissolving formulation of l-DOPA/carbidopa that dissolves on the tongue is available for Parkinson’s patients who have difficulty swallowing. This preparation dissolves immediately and releases the active drugs within 30 minutes, with other pharmacokinetic parameters similar to the oral preparations.

The COMT inhibitors entacapone and tolcapone are rapidly absorbed, highly bound to plasma proteins, and almost completely inactivated before excretion. Like carbidopa, the COMT inhibitors also prolong the t_1/2 of l-DOPA approximately twofold; entacapone is available in combination with l-DOPA/carbidopa.

Selegiline is rapidly absorbed and metabolized to N-desmethylselegiline, amphetamine, and methamphetamine with half-lives of 2, 18, and 20 hours, respectively. Rasagiline is also rapidly absorbed, but if taken with a meal containing high fat, absorption decreases substantially. Although both selegiline and rasagiline have short to intermediate half-lives, because they are irreversible MAO inhibitors, their effects will be manifest until new enzyme is synthesized.

Bromocriptine, ropinirole and pramipexole differ markedly in their plasma protein binding but have similar half-lives and must be taken orally several times per day. Of particular interest is the newly developed rotigotine preparation. This transdermal patch releases rotigotine continuously over 24 hours, and in contrast to the other DA agonists, appears to maintain fairly constant plasma levels throughout the day.

Ropinirole is metabolized by CYP1A2, which is stimulated by smoking and the proton pump inhibitor omeprazole. Omeprazole is used to treat gastrointestinal problems and is often used by the elderly; thus a potential for drug interactions exists.

Selected pharmacokinetic parameters for drugs used for Parkinson’s disease are listed in Table 28-1.

Alzheimer’s Disease Drugs

All drugs used to treat Alzheimer’s disease have good oral bioavailability but differ widely in their pharmacokinetic profiles (Table 28-1). Donepezil, which has a very long t_1/2, is highly bound to plasma proteins and is metabolized in the liver by CYP2D6 and CYP3A4. Its primary metabolite is equally effective as the parent compound in blocking AChE activity. Galantamine, which is available in immediate-release and extended-release formulations, is also metabolized by CYP2D6 and CYP3A4, but its metabolites are inactive. More than 50% of a dose of donepezil is excreted unchanged, and its hepatic metabolism does not appear to lead to drug interactions or limitations in special populations. In contrast, galantamine is metabolized by CYP2D6 and CYP3A4, and inhibitors of both of these metabolic pathways increase its bioavailability. In addition, poor metabolizers (7% of the population with a genetic variation with decreased CYP2D6 activity) exhibit a significant reduction in clearance of galantamine.

The absorption of rivastigmine is delayed by food, and unlike the other AChE inhibitors, rivastigmine is metabolized by plasma ChE.

Memantine has a long t_1/2, with approximately 75% of an administered dose excreted unchanged in the urine. The renal clearance of memantine involves active tubular secretion that may be altered by pH-dependent reabsorption. Thus memantine clearance can be decreased by alkalinization of urine; that is, use of carbonic anhydrase inhibitors or bicarbonate increases the concentration of memantine and elevates the risk of adverse responses.

Parkinson’s Disease Drugs

The combination of l-DOPA/carbidopa remains the most effective symptomatic treatment for Parkinson’s disease to date, and both immediate- and controlled-release formulations are available, the latter of benefit for patients exhibiting wearing-off effects. The COMT inhibitors do not provide any therapeutic benefit when used alone but may increase a patient’s responses to l-DOPA, especially by reducing motor fluctuations in patients with advanced disease. However, there may be an increased incidence of dyskinesia requiring decreased doses of l-DOPA.

Selegiline and rasagiline enhance clinical responses to l-DOPA and are approved as adjuncts in patients experiencing clinical deterioration during l-DOPA therapy. There is little evidence that these agents have more than modest benefit when used alone.

The DA receptor agonists are effective as monotherapy early in the disease or as an adjunct to l-DOPA in later stages. These compounds are not as efficacious as l-DOPA and have a lower propensity to cause dyskinesias or motor fluctuations. As monotherapy, these compounds are effective for 3 to 5 years, at which time l-DOPA/carbidopa must be initiated. As adjunctive therapy in advanced disease, DA receptor agonists contribute to clinical improvement and allow a reduction in the dose of l-DOPA required. Although the ergot derivatives bromocriptine and pergolide were used for many years, the use of bromocriptine has declined in favor of the non-ergot compounds, and pergolide was withdrawn from the united States market because of its association with cardiac-valve regurgitation.

Apomorphine is effective to treat episodes of immobility (“off” times) in patients with advanced disease. However, apomorphine has strong emetic effects, and an antiemetic must be administered prophylactically before its use.

Antimuscarinics are useful in some patients for controlling tremor and drooling and may have additive therapeutic effects at any stage in the disease. They may be used for short-term monotherapy in tremor-predominant disease but have little value for akinesia or impaired postural reflexes. In contrast, amantadine helps alleviate mild akinesia and rigidity but does not alter tremor. Like the antimuscarinics, it may be useful for short-term monotherapy in patients with mild to moderate disease before initiation of l-DOPA.

It is still unclear whether any of the currently available treatments for Parkinson’s disease alter disease progression.

Alzheimer’s Disease Drugs

The cognitive benefits of the AChE inhibitors in Alzheimer’s disease, although statistically significant, are very modest and fairly controversial. Only a fraction of patients respond, and those who do typically show only a slight improvement in functional ability (daily activities), disturbed behaviors, and cognitive function (6- to 12-month reversal of cognitive impairments). This initial improvement is followed by subsequent decline, albeit from this elevated level of performance. Some degree of benefit has been reported to be retained for several years. Perhaps most importantly, reports claim these drugs can delay institutionalization, a considerable benefit from both a pharmacoeconomic and quality-of life-perspective. They may also benefit dementias resulting from other causes, such as vascular dementias.

Memantine has been used since the beginning of 2004 in the United States but for several years previously in Europe. Memantine improves daily activities and cognitive function scores in moderate to severe cases of Alzheimer’s disease, but these effects are also modest. After a period of initial improvement, patients continue to deteriorate. Importantly, patients on donepezil benefit significantly from memantine, suggesting that these two drugs acting through different mechanisms are additive in improving cognitive function.

Parkinson’s Disease Drugs

The peripheral side effects of l-DOPA include actions on the gastrointestinal and cardiovascular systems. Vomiting may be caused by stimulation of DA neurons in the area postrema, which is outside the BBB. The peripheral decarboxylation of l-DOPA to DA in plasma can activate vascular DA receptors and produce orthostatic hypotension, while the stimulation of both α and β adrenergic receptors by DA can lead to cardiac arrhythmias, especially in patients with preexisting conditions.

Central nervous system effects include depression, anxiety, agitation, insomnia, hallucinations, and confusion, particularly in the elderly, and may be attributed to enhanced mesolimbic and mesocortical dopaminergic activity (see Fig. 27-8). The tricyclic antidepressants or selective serotonin reuptake inhibitors (see Chapter 30) may be used for depression, but the latter may cause worsening of motor symptoms. The atypical antipsychotics clozapine and quetiapine are beneficial for psychotic reactions and do not exacerbate the motor symptoms like the typical antipsychotics (see Chapter 29).

Although l-DOPA/carbidopa remains the most effective treatment for Parkinson’s disease to date, for most patients it is effective for only 3 to 5 years. As the disease progresses, even with continued treatment, the duration of therapeutic activity from each dose decreases. This is known as the “wearing off” effect, and many patients fluctuate in their response between mobility and immobility, known as the “on-off” effect. In addition, after 5 years of continued drug treatment, as many as 75% of patients experience dose-related dyskinesias, characterized by chorea and dystonia, inadequate therapeutic responses, and toxicity at subtherapeutic doses. These effects may represent an adaptive process to alterations in plasma and brain levels of l-DOPA and involve alterations in expression of DA and NMDA receptors.

Tolcapone induced fatal hepatitis in 3 out of 60,000 patients and has been taken off the market in Canada but not the United States. Because of the risk of potentially fatal, acute fulminant liver failure, tolcapone should be used only in patients who have failed to respond to other drugs and who are experiencing motor fluctuations. Baseline liver function tests should be performed before starting tolcapone and should be repeated for the duration of therapy. If patients do not demonstrate a clinical response within 3 weeks, the drug should be withdrawn. Tolcapone is contraindicated in patients with compromised liver function.

Selegiline and rasagiline can cause nausea and orthostatic hypotension. At doses recommended for Parkinson’s disease, which inhibit MAO-B but not MAO-A, selegiline is unlikely to induce a tyramine interaction (see Chapters 11 and Chapters 30); similar data for rasagiline are unavailable. Selegiline may cause rare toxic interactions with fluoxetine and meperidine and can increase the adverse effects of l-DOPA, particularly dyskinesias and psychoses in the elderly. Rasagiline has been reported to increase the incidence of melanoma, and because rasagiline is metabolized by CYP1A2, plasma concentrations may increase in the presence of CYP1A2 inhibitors such as ciprofloxacin and fluvoxamine. MAO inhibitors must be used with caution in patients taking any drug enhancing serotonergic activity, including the antidepressants, dextromethorphan, and tryptophan (see Chapter 30). Combinations of these compounds could induce “serotonin syndrome,” a serious condition characterized by confusion, agitation, rigidity, shivering, autonomic instability, myoclonus, coma, nausea, diarrhea, diaphoresis, flushing, and even death.

DA receptor agonists cause side effects similar to those with l-DOPA, including nausea and postural hypotension. These compounds cause more central nervous system-related effects than l-DOPA, including hallucinations, confusion, cognitive dysfunction, and sleepiness.

Several studies have reported that patients maintained on DA receptor agonists develop increased impulsivity and exhibit pathological gambling, perhaps reflecting stimulation of the midbrain dopaminergic ventral tegmental-nucleus accumbens pathway thought to mediate addictive behaviors (see Chapter 27).

The muscarinic receptor antagonists all cause typical anticholinergic effects as discussed extensively in Chapter 10. Because Parkinson’s disease is predominantly an age-related disorder, and older individuals show increased vulnerability to other dysfunctions including dementia and glaucoma, anticholinergics must be used with caution in the elderly, because these drugs impair memory, exacerbate glaucoma, and may cause urinary retention.

Amantadine may produce hallucinations and confusion, nausea, dizziness, dry mouth, and an erythematous rash of the lower extremities. Symptoms may worsen dramatically if it is discontinued, and amantadine should be used with caution in patients with congestive heart disease or acute angle-closure glaucoma.

Alzheimer’s Disease Drugs

All AChE inhibitors currently available are relatively free of serious side effects. As expected, these compounds have a high incidence of peripheral cholinergic effects such as nausea, vomiting, anorexia, and diarrhea. Rivastigmine is associated with a greater incidence of these effects than the other drugs; it is uncertain if inhibition of ChE activity is responsible. Fortunately, many of these effects demonstrate tolerance, and gradual dosage escalation permits many patients to tolerate their full therapeutic doses. Adverse events with memantine were low in clinical trials, with none exceeding twice the placebo values in 5% or more of patients. High doses can produce dissociative anesthetic type effects similar to ketamine, including confusion, hallucination, hypnosis, and stupor (see Chapter 35).

Common side effects associated with drugs used for Parkinson’s and Alzheimer’s diseases are listed in the Clinical Problems Box.