Drugs for Neurodegenerative Diseases



Drugs for Neurodegenerative Diseases



Classification of Drugs for Neurodegenerative Diseases








aAlso interferon beta-1a (AVONEX), natalizumab (TYSABRI), mitoxantrone (NOVANTRONE), and glatiramer acetate (COPAXONE).


bNote that not all these agents are used uniquely for the treatment of spasticity in neurodegenerative diseases.




Overview


Parkinson disease (PD), Huntington disease (HD), Alzheimer disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS, or Lou Gehrig disease) are neurodegenerative diseases characterized by the progressive loss of neuronal function in a particular part of the central nervous system (CNS). The signs and symptoms of neurodegenerative diseases do not reflect a normal age-related loss of brain neurons. Instead, these progressive disease states are the result of an underlying pathologic process.


Although the cause of these diseases is unknown, evidence suggests the involvement of heredity, autoimmunity, and environmental factors. Substantial progress has been made in the development of drugs to treat PD, and somewhat for AD; however, drug therapy for the other neurodegenerative diseases is limited. New research findings elucidating the pathogenesis of neurodegenerative diseases will enable the development of more successful drugs in the near future.



Parkinson Disease


PD, or paralysis agitans, is characterized by a resting tremor (involuntary trembling when a limb is at rest), rigidity (inability to initiate movements), and bradykinesia (slowness of movement). The disease results from the degeneration of dopaminergic neurons that arise in the substantia nigra and project to other structures in the basal ganglia.



Etiology and Pathogenesis


The causes of neuron degeneration in PD remain largely unknown. In most cases, heredity appears to have a limited role. Scientists, however, have identified a defective gene responsible for a rare condition called autosomal recessive juvenile parkinsonism, which usually affects people in their teens and 20s.


One of the better-known theories for the cause of PD is called the oxidative stress theory. According to this theory, metabolic oxidation of dopamine in the basal ganglia yields highly reactive free radicals that are toxic to dopaminergic neurons and lead to their degeneration. Free radicals are molecules that lack an electron in their outer orbits and are capable of extracting an electron from other molecules and thereby causing cell damage. It is not understood, however, why some individuals would be more susceptible to oxidative stress than others.


The basal ganglia are a group of interconnected subcortical nuclei that include the striatum (caudate and putamen), substantia nigra, globus pallidus, and subthalamus. In healthy individuals, the basal ganglia receive input from the cerebral cortex, process this information, and send feedback to the motor area of the cortex in a way that leads to the smooth coordination of body movements. Even simple movements, such as walking, involve a complex sequence of motor acts whose smooth execution requires the continuous interplay of the cortex and basal ganglia. In patients with PD, neuronal degeneration interrupts this interplay. Because the basal ganglia also participate in procedural memory and other cognitive functions, patients with PD may have difficulty remembering how to perform learned motor skills, such as driving a car.


The basal ganglia function via a series of reciprocal innervations among themselves and the cortex (Fig. 24-1). The striatum receives input from the cerebral cortex and substantia nigra and then sends output to the thalamus via the globus pallidus. The thalamus then feeds information back to the motor area of the cortex. Two pathways connect the striatum and the thalamus: a direct pathway, which is excitatory, and an indirect pathway, which is inhibitory. In patients with PD, the degeneration of dopaminergic neurons results in decreased activity in the direct pathway and increased activity in the indirect pathway. As a result, thalamic feedback to the cortex is reduced, and patients exhibit bradykinesia and rigidity.


image
FIGURE 24-1 Pathophysiology of Parkinson disease. The striatum receives input from the entire cerebral cortex and the substantia nigra and sends projections to the thalamus via direct and indirect pathways through the globus pallidus, substantia nigra, and subthalamus. Striatal dopamine D1 receptors excite the direct pathway, whereas D2 receptors inhibit the indirect pathway. In Parkinson disease, the degeneration of dopaminergic neurons leads to decreased activity in the direct pathway and increased activity in the indirect pathway. As a result of these changes, thalamic input to the motor area of the cortex is reduced, and the patient exhibits rigidity and bradykinesia. GABA, γ-Aminobutyric acid; Glu, glutamate; VA/VL, ventral anterior and ventral lateral nuclei; (+), excitatory; (−), inhibitory.

Excitatory cholinergic neurons also participate in the interconnections between structures in the basal ganglia. In PD, the degeneration of inhibitory dopaminergic neurons leads to a relative excess of cholinergic activity in these pathways. For this reason, patients with PD can be treated effectively with drugs that inhibit cholinergic activity or with drugs that increase dopamine levels in the basal ganglia.



Drugs That Increase Dopamine Levels


Dopamine levels in the basal ganglia can be increased by various drugs in different ways. Levodopa increases dopamine levels by increasing dopamine synthesis; selegiline by inhibiting dopamine breakdown; and amantadine by increasing dopamine release from neurons. Carbidopa and entacapone increase the amount of levodopa that enters the brain and thereby enhance dopamine synthesis. The sites of action of these drugs are illustrated in Figure 24-2.


image
FIGURE 24-2 Mechanisms of dopaminergic drugs used in the treatment of Parkinson disease. Levodopa is transported across the gut wall and the blood-brain barrier and is converted to dopamine in striatal neurons. Carbidopa inhibits the peripheral decarboxylation of levodopa and thereby increases the amount of levodopa that enters the brain. Carbidopa does not cross the blood-brain barrier and does not inhibit dopamine synthesis in the brain. Tolcapone and entacapone inhibit the methylation of levodopa in both peripheral tissues and the brain. Tolcapone and entacapone increase levodopa bioavailability and increase brain uptake of levodopa. Selegiline inhibits the degradation of dopamine to dihydroxyphenylacetic acid (DOPAC) and hydrogen peroxide (H2O2). By this action, selegiline increases dopamine levels in the striatum, and it may reduce the formation of free radicals that are derived from H2O2. Amantadine increases the release of dopamine from striatal neurons. Bromocriptine and other dopamine-receptor agonists activate dopamine receptors in the striatum. Numbered structures and enzymes are as follows: 1, pump that transports large neutral amino acids; 2, aromatic L-amino acid decarboxylase (AADC); 3, catechol-O-methyltransferase (COMT); 4, monoamine oxidase type B (MAO-B).


Levodopa



Pharmacokinetics

Levodopa, also called L-dopa or dihydroxyphenylalanine, is the biosynthetic precursor of dopamine. Levodopa increases the concentration of dopamine in the brain and is the main treatment used to alleviate motor dysfunction in patients with PD. Dopamine itself is not effective in the treatment of PD when administered systemically, because it does not cross the blood-brain barrier to a significant extent.


Levodopa is absorbed from the proximal duodenum by the same process that absorbs large neutral amino acids (see Fig. 24-2). Dietary amino acids compete with levodopa for transport into the circulation, and amino acids can also reduce the transport of levodopa into the brain. For these reasons, the ingestion of high-protein foods can decrease the effectiveness of levodopa, and a protein-restricted diet may improve the response to levodopa in some patients.


Levodopa is metabolized by two pathways in peripheral tissues. It is converted to dopamine by aromatic L-amino acid decarboxylase (AADC), and it is metabolized to 3-O-methyldopa (3OMD) by catechol-O-methyltransferase (COMT). A drug that inhibits LAAD (e.g., carbidopa) or inhibits COMT (e.g., entacapone) is used in combination with levodopa to increase the amount of levodopa that enters brain tissue. LAAD requires vitamin B6 (pyridoxine) as a cofactor. For this reason, vitamin B6 supplements may enhance the peripheral decarboxylation of levodopa and should not be coadministered with levodopa.


Levodopa exhibits a large first-pass effect, and about 95% of an administered dose is metabolized in the gut wall and liver before it reaches the systemic circulation. Additional amounts of levodopa are converted to dopamine and 3OMD before the drug enters the CNS. Therefore only about 1% of the administered dose of levodopa reaches brain tissue.



Mechanisms and Pharmacologic Effects

In the brain, levodopa is taken up by dopaminergic neurons in the striatum and is converted to dopamine by LAAD. Levodopa thereby increases the amount of dopamine released by these neurons in patients with PD, and it serves as a form of replacement therapy. Levodopa can counteract all of the signs of parkinsonism, although the degree and duration of its effectiveness usually are not optimal. As the disease progresses and more dopaminergic neurons are lost, the conversion of levodopa to dopamine declines.


About 60% to 70% of nigrostriatal dopaminergic neurons are lost before the clinical symptoms of PD are first observed, and the degeneration of these neurons continues throughout the course of the disease. Over time, patients begin to experience two types of fluctuation in the effectiveness of levodopa, both of which are probably related to a reduced concentration of dopamine in the striatum. The first type, a wearing off effect, occurs toward the end of a dosage interval. The second type, the on-off phenomenon, is characterized by severe motor fluctuations that occur randomly.



Adverse Effects

When levodopa is used alone, nausea and vomiting occur in about 80% of patients, orthostatic hypotension is reported in 25%, and cardiac dysrhythmias occur in 10%. These effects, which are caused by the action of dopamine on β-adrenoceptors in the case of cardiac arrhythmias, are substantially reduced when carbidopa (see later) is administered with levodopa to block the peripheral formation of dopamine.


About 30% of patients who are treated with levodopa on a long-term basis eventually develop involuntary movements, or dyskinesias, as a result of excessive dopamine concentrations in the striatum. Dyskinesias most often occur when levodopa concentrations are highest, in which case they are called peak-dose dyskinesias. The dyskinesias often involve the oral and facial musculature, and patients can appear as if they are chewing on large pieces of food while protruding their lips. Other common dyskinesias involve writhing and flinging movements of the arms and legs. Less commonly, levodopa causes psychotic effects, including hallucinations and distorted thinking, which are probably caused by excessive dopamine concentrations in mesolimbic and mesocortical pathways. Although dyskinesias and psychotic effects could be managed by reducing the levodopa dosage, the therapeutic efficacy of the drug would be reduced as well.


Some patients treated with levodopa report sedative effects, agitation, delirium, vivid dreams, or nightmares. Others, however, report a pleasant euphoria after taking the drug.



Interactions

Levodopa has important interactions with a number of medications. Drugs that delay gastric emptying, such as anticholinergic drugs, can slow levodopa absorption and reduce its peak serum concentration. Drugs that promote gastric emptying (e.g., antacids) can increase levodopa bioavailability. Nonselective monoamine oxidase inhibitors (MAOIs), for example, the antidepressant phenelzine, inhibit the breakdown of dopamine and sometimes cause a hypertensive crisis in patients receiving levodopa. Antipsychotic drugs block dopamine receptors and can reduce the effectiveness of levodopa and exacerbate motor dysfunction. Because clozapine is much less likely to do this than other antipsychotic drugs, it is often used to manage psychotic reactions in patients receiving levodopa (see Chapter 22).




Carbidopa


Carbidopa, a structural analogue of levodopa, inhibits LAAD thereby reducing the conversion of levodopa to dopamine in peripheral tissues and so increasing the amount of levodopa that enters the brain (see Fig. 24-2). Carbidopa is highly ionized at physiologic pH, and it does not cross the blood-brain barrier. For this reason, it does not inhibit the formation of dopamine in the CNS.


Carbidopa substantially reduces the gastrointestinal and cardiovascular side effects of levodopa and enables about a 75% reduction in the dosage of levodopa. A levodopa-carbidopa combination is available in immediate-release and sustained-release formulations that contain different ratios of the two drugs. The sustained-release formulations are designed to reduce the “wearing off” effect described earlier.



Amantadine


Amantadine is an antiviral drug that is used in the prevention and treatment of influenza but also has a beneficial effect on PD. Amantadine appears to work by increasing the release of dopamine from nigrostriatal neurons, but it may also inhibit the reuptake of dopamine by these neurons. Amantadine is generally better tolerated than levodopa or dopamine agonists, but it is also less effective.


Amantadine is used to treat early or mild cases of PD and as an adjunct to levodopa. Its adverse effects include sedation, restlessness, vivid dreams, nausea, dry mouth, and hypotension. It can also cause livedo reticularis, which is a reddish-blue mottling of the skin with edema. CNS side effects are more likely to occur in the elderly because of their reduced capacity to excrete the drug via the kidneys.



Selegiline




Mechanisms and Pharmacologic Effects

Selegiline inhibits monoamine oxidase type B (MAO-B) and thereby prevents the oxidation of dopamine to dihydroxyphenylacetic acid and hydrogen peroxide, as shown in Figure 24-2. By this action, selegiline increases dopamine levels in the basal ganglia and decreases the formation of hydrogen peroxide. In the presence of iron, hydrogen peroxide is converted to hydroxyl and hydroxide free radicals that may participate in the degeneration of nigrostriatal neurons in patients with PD.


There is evidence that selegiline inhibits the progression of PD either by inhibiting the formation of free radicals or by inhibiting the formation of an active metabolite of an environmental toxin. However, the ability of selegiline to inhibit disease progression is controversial. It was initially suggested by studies showing that selegiline could prevent a form of parkinsonism that is induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP is a toxic by-product of the synthesis of designer street drugs; in the 1980s, people who took what they thought was a meperidine analogue ingested drugs contaminated with MPTP and developed classic signs of parkinsonism. MPTP must be converted to 1-methyl-4-phenylpyridinium by MAO-B before it can damage dopaminergic neurons, and studies have demonstrated that selegiline blocked this reaction. The results of these studies have led some investigators to postulate that idiopathic PD is caused by an environmental toxin whose action resembles that of MPTP. Although unfortunate for the drug abusers who were exposed to MPTP, it did lead to an important animal model for parkinsonism and the development of new agents.



Adverse Effects and Interactions

Adverse effects are listed in Table 24-1. Unlike the nonselective MAOIs used in treating mood disorders, selegiline does not inhibit monoamine oxidase type A (MAO-A), an enzyme that catalyzes the degradation of catecholamines. For this reason, selegiline is much less likely to cause hypertension when it is administered in combination with sympathomimetic amines or when it is taken with foods that contain tyramine. The drug’s selectivity for MAO-B, however, is lost when it is given in higher doses, so the potential for food interaction still exists. Selegiline can cause adverse effects if it is administered with meperidine or with selective serotonin reuptake inhibitors (SSRIs; e.g., fluoxetine), as noted in Chapter 22.



TABLE 24-1


Major Adverse Effects and Major Interactions of Selected Drugs for Neurodegenerative Diseases





























































































































DRUG MAJOR ADVERSE EFFECTS MAJOR DRUG INTERACTIONS
Drugs for Parkinson Disease  
Drugs That Increase Dopamine Levels
Amantadine Dry mouth, hypotension, livedo reticularis, nausea, restlessness, sedation, and vivid dreams Benztropine and trihexyphenidyl potentiate CNS side effects.
Levodopa-carbidopa Agitation; arrhythmias; delirium; distorted thinking, hallucinations, and other psychotic effects; dyskinesias; hypotension; nausea and vomiting; nightmares or vivid dreams; and sedation Antacids may increase bioavailability. Anticholinergic drugs may reduce peak serum level. Antipsychotic drugs, such as haloperidol, may decrease effects. Nonselective MAOIs, such as phenelzine, may cause a hypertensive crisis.
Selegiline Confusion; dyskinesias; hallucinations; hypotension; insomnia; and nausea Severe reactions may result if taken with meperidine or with fluoxetine or other SSRIs.
Rasagiline Same as selegiline Same as selegiline.
Tolcapone Diarrhea and nausea Unknown.
Entacapone Diarrhea and nausea Unknown.
Dopamine Receptor Agonists  
Bromocriptine Confusion, decreased prolactin levels, dry mouth, dyskinesias, hallucinations, nausea, orthostatic hypotension, sedation, and vivid dreams Dopamine antagonists may reduce effects.
Pramipexole Dizziness, hallucinations, insomnia, nausea and vomiting, and sedation Cimetidine inhibits renal excretion and increases serum levels.
Ropinirole Same as pramipexole Ciprofloxacin increases serum levels.
Rotigotine Somnolence, slight BP and HR increase, site irritation Sulfite sensitivity; no major drug interactions.
Acetylcholine Receptor Antagonists
Benztropine Agitation, confusion, constipation, delirium, dry mouth, memory loss, urinary retention, and tachycardia Additive anticholinergic effect with antihistamines and phenothiazines.
Trihexyphenidyl Same as benztropine Same as benztropine.
Drugs for Huntington Disease
Diazepam Arrhythmias, CNS depression, drug dependence, hypotension, and mild respiratory depression Alcohol and other CNS depressants potentiate effects. Cimetidine increases and rifampin decreases serum levels.
Haloperidol Extrapyramidal side effects and increased prolactin levels Barbiturates and carbamazepine decrease and quinidine increases serum levels.
Drugs for Alzheimer Disease  
Donepezil Bradycardia, diarrhea, gastrointestinal bleeding, and nausea and vomiting Anticholinergic drugs inhibit effects.
Rivastigmine Risk of bradycardia and AV block; nausea and vomiting, anorexia, weight loss Anticholinergic drugs inhibit effects. Nicotine use increases oral clearance.
Galantamine Risk of bradycardia and AV block; nausea and vomiting Anticholinergic drugs inhibit effects. Inhibitors of CYP2D6 increase serum levels.
Memantine Confusion, dizziness, drowsiness, headache, insomnia Carbonic anhydrase inhibitors reduce renal elimination of memantine.
Drugs for Multiple Sclerosis  
Baclofen Dizziness, fatigue, and weakness Unknown.
Interferon beta-1b Chills, diarrhea, fever, headache, hypertension, myalgia, pain, and vomiting Increases serum levels of zidovudine.
Prednisone Aggravation of diabetes mellitus, gastrointestinal bleeding, mood changes, pancreatitis, and seizures Barbiturates, carbamazepine, phenytoin, and rifampin decrease serum levels.
Drugs for Amyotrophic Lateral Sclerosis
Baclofen Dizziness, fatigue, and weakness Unknown.
Gabapentin Ataxia, dizziness, drowsiness, nystagmus, and tremor Antacids decrease serum levels.
Riluzole Asthenia, diarrhea, dizziness, drowsiness, increased hepatic enzyme levels, nausea and vomiting, paresthesias, and vertigo Quinolones and theophylline can increase serum levels. Omeprazole, rifampin, and smoking can decrease serum levels.
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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Drugs for Neurodegenerative Diseases

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