NCLEX: Drugs for Neurodegenerative Diseases

Most drugs that affect the central nervous system (CNS) act by altering some step in the neurotransmission process. Drugs affecting the CNS may act presynaptically by influencing the production, storage, release, or termination of action of neurotransmitters. Other agents may activate or block postsynaptic receptors. This chapter provides an overview of the CNS, with a focus on those neurotransmitters that are involved in the actions of the clinically useful CNS drugs. These concepts are useful in understanding the etiology and treatment strategies for the neurodegenerative disorders that respond to drug therapy: Parkinson’s disease, Alzheimer’s disease, multiple sclerosis (MS), and amyotrophic lateral sclerosis.

Drugs for Neurodegenerative Diseases

Drugs for Neurodegenerative Diseases: NEUROTRANSMISSION IN THE CNS

Focus topic: Drugs for Neurodegenerative Diseases

In many ways, the basic functioning of neurons in the CNS is similar to that of the autonomic nervous system (ANS) described in Chapter 3. For example, transmission of information in both the CNS and in the periphery involves the release of neurotransmitters that diffuse across the synaptic space to bind to specific receptors on the postsynaptic neuron. In both systems, the recognition of the neurotransmitter by the membrane receptor of the postsynaptic neuron triggers intracellular changes. However, several major differences exist between neurons in the peripheral ANS and those in the CNS. The circuitry of the CNS is much more complex than that of the ANS, and the number of synapses in the CNS is far greater. The CNS, unlike the peripheral ANS, contains powerful networks of inhibitory neurons that are constantly active in modulating the rate of neuronal transmission. In addition, the CNS communicates through the use of multiple neurotransmitters, whereas the ANS uses only two primary neurotransmitters, acetylcholine and norepinephrine.

Drugs for Neurodegenerative Diseases

Drugs for Neurodegenerative Diseases: SYNAPTIC POTENTIALS

Focus topic: Drugs for Neurodegenerative Diseases

In the CNS, receptors at most synapses are coupled to ion channels. Binding of the neurotransmitter to the postsynaptic membrane receptors results in a rapid but transient opening of ion channels. Open channels allow specific ions inside and outside the cell membrane to flow down their concentration gradients. The resulting change in the ionic composition across the membrane of the neuron alters the postsynaptic potential, producing either depolarization or hyperpolarization of the postsynaptic membrane, depending on the specific ions and the direction of their movement.

A. Excitatory pathways

Focus topic: Drugs for Neurodegenerative Diseases

Neurotransmitters can be classified as either excitatory or inhibitory, depending on the nature of the action they elicit. Stimulation of excitatory neurons causes a movement of ions that results in a depolarization of the postsynaptic membrane. These excitatory postsynaptic potentials (EPSP) are generated by the following: 1) Stimulation of an excitatory neuron causes the release of neurotransmitter molecules, such as glutamate or acetylcholine, which bind to receptors on the postsynaptic cell membrane. This causes a transient increase in the permeability of sodium (Na+) ions. 2) The influx of Na+ causes a weak depolarization, or EPSP, that moves the postsynaptic potential toward its firing threshold. 3) If the number of stimulated excitatory neurons increases, more excitatory neurotransmitter is released. This ultimately causes the EPSP depolarization of the postsynaptic cell to pass a threshold, thereby generating an all-or-none action potential. [Note: The generation of a nerve impulse typically reflects the activation of synaptic receptors by thousands of excitatory neurotransmitter molecules released from many nerve fibers.]

B. Inhibitory pathways

Focus topic: Drugs for Neurodegenerative Diseases

Stimulation of inhibitory neurons causes movement of ions that results in a hyperpolarization of the postsynaptic membrane. These inhibitory postsynaptic potentials (IPSP) are generated by the following: 1) Stimulation of inhibitory neurons releases neurotransmitter molecules, such as γ-aminobutyric acid (GABA) or glycine, which bind to receptors on the postsynaptic cell membrane. This causes a transient increase in the permeability of specific ions, such as potassium (K+) and chloride (Cl−). 2) The influx of Cl− and efflux of K+ cause a weak hyperpolarization, or IPSP, that moves the postsynaptic potential away from its firing threshold. This diminishes the generation of action potentials.

C. Combined effects of the EPSP and IPSP

Focus topic: Drugs for Neurodegenerative Diseases

Most neurons in the CNS receive both EPSP and IPSP input. Thus, several different types of neurotransmitters may act on the same neuron, but each binds to its own specific receptor. The overall action is the summation of the individual actions of the various neurotransmitters on the neuron. The neurotransmitters are not uniformly distributed in the CNS but are localized in specific clusters of neurons, the axons of which may synapse with specific regions of the brain. Many neuronal tracts, thus, seem to be chemically coded, and this may offer greater opportunity for selective modulation of certain neuronal pathways.

Drugs for Neurodegenerative Diseases

Drugs for Neurodegenerative Diseases

Drugs for Neurodegenerative Diseases: NEURODEGENERATIVE DISEASES

Focus topic: Drugs for Neurodegenerative Diseases

Neurodegenerative diseases of the CNS include Parkinson’s disease, Alzheimer’s disease, MS, and ALS. These devastating illnesses are characterized by the progressive loss of selected neurons in discrete brain areas, resulting in characteristic disorders of movement, cognition, or both.

Drugs for Neurodegenerative Diseases: OVERVIEW OF PARKINSON’S DISEASE

Focus topic: Drugs for Neurodegenerative Diseases

Parkinsonism is a progressive neurological disorder of muscle movement, characterized by tremors, muscular rigidity, bradykinesia (slowness in initiating and carrying out voluntary movements), and postural and gait abnormalities. Most cases involve people over the age of 65, among whom the incidence is about 1 in 100 individuals.

A. Etiology

Focus topic: Drugs for Neurodegenerative Diseases

The cause of Parkinson’s disease is unknown for most patients. The disease is correlated with destruction of dopaminergic neurons in the substantia nigra with a consequent reduction of dopamine actions in the corpus striatum, parts of the basal ganglia system that are involved in motor control.

  • Substantia nigra: The substantia nigra, part of the extrapyramidal system, is the source of dopaminergic neurons that terminate in the neostriatum. Each dopaminergic neuron makes thousands of synaptic contacts within the neostriatum and, therefore, modulates the activity of a large number of cells. These dopaminergic projections from the substantia nigra fire tonically rather than in response to specific muscular movements or sensory input. Thus, the dopaminergic system appears to serve as a tonic, sustaining influence on motor activity, rather than participating in specific movements.
  • Neostriatum: Normally, the neostriatum is connected to the substantia nigra by neurons that secrete the inhibitory transmitter GABA at their termini. In turn, cells of the substantia nigra send neurons back to the neostriatum, secreting the inhibitory transmitter dopamine at their termini. This mutual inhibitory pathway normally maintains a degree of inhibition of both areas. In Parkinson’s disease, destruction of cells in the substantia nigra results in the degeneration of the nerve terminals that secrete dopamine in the neostriatum. Thus, the normal inhibitory influence of dopamine on cholinergic neurons in the neostriatum is significantly diminished, resulting in overproduction or a relative overactivity of acetylcholine by the stimulatory neurons. This triggers a chain of abnormal signaling, resulting in loss of the control of muscle movements.
  • Secondary parkinsonism: Drugs such as the phenothiazines and haloperidol, whose major pharmacologic action is blockade of dopamine receptors in the brain, may produce parkinsonian symptoms (also called pseudoparkinsonism). These drugs should be used with caution in patients with Parkinson’s disease.

B. Strategy of treatment

Focus topic: Drugs for Neurodegenerative Diseases

In addition to an abundance of inhibitory dopaminergic neurons, the neostriatum is also rich in excitatory cholinergic neurons that oppose the action of dopamine. Many of the symptoms of parkinsonism reflect an imbalance between the excitatory cholinergic neurons and the greatly diminished number of inhibitory dopaminergic neurons. Therapy is aimed at restoring dopamine in the basal ganglia and antagonizing the excitatory effect of cholinergic neurons, thus reestablishing the correct dopamine/acetylcholine balance.

Drugs for Neurodegenerative Diseases

Drugs for Neurodegenerative Diseases: DRUGS USED IN PARKINSON’S DISEASE

Focus topic: Drugs for Neurodegenerative Diseases

Many currently available drugs aim to maintain CNS dopamine levels as constant as possible. These agents offer temporary relief from the symptoms of the disorder, but they do not arrest or reverse the neuronal degeneration caused by the disease.

A. Levodopa and carbidopa

Focus topic: Drugs for Neurodegenerative Diseases

Levodopa [lee-voe-DOE-pa] is a metabolic precursor of dopamine. It restores dopaminergic neurotransmission in the neostriatum by enhancing the synthesis of dopamine in the surviving neurons of the substantia nigra. In early disease, the number of residual dopaminergic neurons in the substantia nigra (typically about 20% of normal) is adequate for conversion of levodopa to dopamine. Thus, in new patients, the therapeutic response to levodopa is consistent, and the patient rarely complains that the drug effects “wear off.” Unfortunately, with time, the number of neurons decreases, and fewer cells are capable of converting exogenously administered levodopa to dopamine. Consequently, motor control fluctuation develops. Relief provided by levodopa is only symptomatic, and it lasts only while the drug is present in the body. The effects of levodopa on the CNS can be greatly enhanced by coadministering carbidopa [kar-bi-DOE-pa], a dopamine decarboxylase inhibitor that does not cross the blood–brain barrier.

1. Mechanism of action:

  • Levodopa: Dopamine does not cross the blood–brain barrier, but its immediate precursor, levodopa, is actively transported into the CNS and converted to dopamine. Levodopa must be administered with carbidopa. Without carbidopa, much of the drug is decarboxylated to dopamine in the periphery, resulting in nausea, vomiting, cardiac arrhythmias, and hypotension.
  • Carbidopa: Carbidopa, a dopamine decarboxylase inhibitor, diminishes the metabolism of levodopa in the periphery, thereby increasing the availability of levodopa to the CNS. The addition of carbidopa lowers the dose of levodopa needed by four- to five fold and, consequently, decreases the severity of the side effects arising from peripherally formed dopamine.

2. Therapeutic uses: Levodopa in combination with carbidopa is an efficacious drug regimen for the treatment of Parkinson’s disease. It decreases rigidity, tremors, and other symptoms of parkinsonism. In approximately two-thirds of patients with Parkinson’s disease, levodopa–carbidopa substantially reduces the severity of symptoms for the first few years of treatment. Patients typically experience a decline in response during the 3rd to 5th year of therapy. Withdrawal from the drug must be gradual.

3. Absorption and metabolism: The drug is absorbed rapidly from the small intestine (when empty of food). Levodopa has an extremely short half-life (1 to 2 hours), which causes fluctuations in plasma concentration. This may produce fluctuations in motor response, which generally correlate with the plasma concentration of levodopa, or perhaps give rise to the more troublesome “on–off” phenomenon, in which the motor fluctuations are not related to plasma levels in a simple way. Motor fluctuations may cause the patient to suddenly lose normal mobility and experience tremors, cramps, and immobility. Ingestion of meals, particularly if high in protein, interferes with the transport of levodopa into the CNS. Thus, levodopa should be taken on an empty stomach, typically 30 minutes before a meal.

Drugs for Neurodegenerative Diseases

4. Adverse effects:

  • Peripheral effects: Anorexia, nausea, and vomiting occur because of stimulation of the chemoreceptor trigger zone. Tachycardia and ventricular extrasystoles result from dopaminergic action on the heart. Hypotension may also develop. Adrenergic action on the iris causes mydriasis. In some individuals, blood dyscrasias and a positive reaction to the Coombs test are seen. Saliva and urine are a brownish color because of the melanin pigment produced from catecholamine oxidation.
  • CNS effects: Visual and auditory hallucinations and abnormal involuntary movements (dyskinesias) may occur. These effects are the opposite of parkinsonian symptoms and reflect over activity of dopamine in the basal ganglia. Levodopa can also cause mood changes, depression, psychosis, and anxiety.

5. Interactions: The vitamin pyridoxine (B6) increases the peripheral breakdown of levodopa and diminishes its effectiveness. Concomitant administration of levodopa and non-selective monoamine oxidase inhibitors (MAOIs), such as phenelzine, can produce a hypertensive crisis caused by enhanced catecholamine production. Therefore, concomitant administration of these agents is contraindicated. In many psychotic patients, levodopa exacerbates symptoms, possibly through the buildup of central catecholamines. Cardiac patients should be carefully monitored for the possible development of arrhythmias. Antipsychotic drugs are generally contraindicated in Parkinson’s disease, because they potently block dopamine receptors and may augment parkinsonian symptoms. However, low doses of atypical antipsychotics are sometimes used to treat levodopa-induced psychotic symptoms.

Drugs for Neurodegenerative Diseases

Drugs for Neurodegenerative Diseases

B. Selegiline and rasagiline

Focus topic: Drugs for Neurodegenerative Diseases

Selegiline [seh-LEDGE-ah-leen], also called deprenyl [DE-pre-nill], selectively inhibits monoamine oxidase (MAO) type B (metabolizes dopamine) at low to moderate doses. It does not inhibit MAO type A (metabolizes norepinephrine and serotonin) unless given above recommended doses, where it loses its selectivity. By decreasing the metabolism of dopamine, selegiline increases dopamine levels in the brain. When selegiline is administered with levodopa, it enhances the actions of levodopa and substantially reduces the required dose. Unlike nonselective MAOIs, selegiline at recommended doses has little potential for causing hypertensive crises. However, the drug loses selectivity at high doses, and there is a risk for severe hypertension. Selegiline is metabolized to methamphetamine and amphetamine, whose stimulating properties may produce insomnia if the drug is administered later than mid-afternoon. Rasagiline [ra-SAgi- leen], an irreversible and selective inhibitor of brain MAO type B,has five times the potency of selegiline. Unlike selegiline, rasagiline is not metabolized to an amphetamine-like substance.

Drugs for Neurodegenerative Diseases

C. Catechol-O-methyltransferase inhibitors

Focus topic: Drugs for Neurodegenerative Diseases

Normally, the methylation of levodopa by catechol-O-methyltransferase (COMT) to 3-O-methyldopa is a minor pathway for levodopa metabolism. However, when peripheral dopamine decarboxylase activity is inhibited by carbidopa, a significant concentration of 3-O-methyldopa is formed that competes with levodopa for active transport into the CNS. Entacapone [en-TAK-a-pone] and tolcapone [TOLE-ka-pone] selectively and reversibly inhibit COMT. Inhibition of COMT by these agents leads to decreased plasma concentrations of 3-O-methyldopa, increased central uptake of levodopa, and greater concentrations of brain dopamine. Both of these agents reduce the symptoms of “wearing-off” phenomena seen in patients on levodopa−carbidopa. The two drugs differ primarily in their pharmacokinetic and adverse effect profiles.

  • Pharmacokinetics: Oral absorption of both drugs occurs readily and is not influenced by food. They are extensively bound to plasma albumin, with a limited volume of distribution. Tolcapone has a relatively long duration of action (probably due to its affinity for the enzyme) compared to entacapone, which requires more frequent dosing. Both drugs are extensively metabolized and eliminated in feces and urine. The dosage may need to be adjusted in patients with moderate or severe cirrhosis.
  • Adverse effects: Both drugs exhibit adverse effects that are observed in patients taking levodopa–carbidopa, including diarrhea, postural hypotension, nausea, anorexia, dyskinesias, hallucinations, and sleep disorders. Most seriously, fulminating hepatic necrosis is associated with tolcapone use. Therefore, it should be used, along with appropriate hepatic function monitoring, only in patients in whom other modalities have failed. Entacapone does not exhibit this toxicity and has largely replaced tolcapone.

Drugs for Neurodegenerative Diseases

Drugs for Neurodegenerative Diseases

D. Dopamine receptor agonists

Focus topic: Drugs for Neurodegenerative Diseases

This group of antiparkinsonian compounds includes bromocriptine, an ergot derivative, the nonergot drugs, ropinirole [roe-PIN-i-role], pramipexole [pra-mi-PEX-ole], rotigotine [ro-TIG-oh-teen], and the newer agent, apomorphine [A-poe-more-feen]. These agents have a longer duration of action than that of levodopa and are effective in patients exhibiting fluctuations in response to levodopa. Initial therapy with these drugs is associated with less risk of developing dyskinesias and motor fluctuations as compared to patients started on levodopa. Bromocriptine, pramipexole, and ropinirole are effective in patients with Parkinson’s disease complicated by motor fluctuations and dyskinesias. However, these drugs are ineffective in patients who have not responded to levodopa. Apomorphine is an injectable dopamine agonist that is used in severe and advanced stages of the disease to supplement oral medications. Side effects severely limit the utility of the dopamine agonists.

  • Bromocriptine: The actions of the ergot derivative bromocriptine [broe-moe-KRIP-teen] are similar to those of levodopa, except that hallucinations, confusion, delirium, nausea, and orthostatic hypotension are more common, whereas dyskinesia is less prominent. In psychiatric illness, bromocriptine may cause the mental condition to worsen. It should be used with caution in patients with a history of myocardial infarction or peripheral vascular disease. Because bromocriptine is an ergot derivative, it has the potential to cause pulmonary and retroperitoneal fibrosis.
  • Apomorphine, pramipexole, ropinirole, and rotigotine: These are nonergot dopamine agonists that are approved for the treatment of Parkinson’s disease. Pramipexole and ropinirole are orally active agents. Apomorphine and rotigotine are available in injectable and transdermal delivery systems, respectively. Apomorphine is used for acute management of the hypomobility “off” phenomenon in advanced Parkinson’s disease. Rotigotine is administered as a once-daily transdermal patch that provides even drug levels over 24 hours. These agents alleviate the motor deficits in patients who have never taken levodopa and also in patients with advanced Parkinson’s disease who are treated with levodopa. Dopamine agonists may delay the need to use levodopa in early Parkinson’s disease and may decrease the dose of levodopa in advanced Parkinson’s disease. Unlike the ergotamine derivatives, these agents do not exacerbate peripheral vascular disorders or cause fibrosis. Nausea, hallucinations, insomnia, dizziness, constipation, and orthostatic hypotension are among the more distressing side effects of these drugs, but dyskinesias are less frequent than with levodopa. Pramipexole is mainly excreted unchanged in the urine, and dosage adjustments are needed in renal dysfunction. Cimetidine inhibits renal tubular secretion of organic bases and may significantly increase the half-life of pramipexole. The fluoroquinolone antibiotics and other inhibitors of the cytochrome P450 (CYP450) 1A2 isoenzyme (for example, fluoxetine) may inhibit the metabolism of ropinirole, requiring an adjustment in ropinirole dosage.

Drugs for Neurodegenerative Diseases

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E. Amantadine

Focus topic: Drugs for Neurodegenerative Diseases

It was accidentally discovered that the antiviral drug amantadine [a-MAN-ta-deen], used to treat influenza, has an antiparkinsonian action. Amantadine has several effects on a number of neurotransmitters implicated in parkinsonism, including increasing the release of dopamine, blocking cholinergic receptors, and inhibiting the N-methyld- aspartate (NMDA) type of glutamate receptors. Current evidence supports action at NMDA receptors as the primary action at therapeutic concentrations. [Note: If dopamine release is already at a maximum, amantadine has no effect.] The drug may cause restlessness, agitation, confusion, and hallucinations, and, at high doses, it may induce acute toxic psychosis. Orthostatic hypotension, urinary retention, peripheral edema, and dry mouth also may occur. Amantadine is less efficacious than levodopa, and tolerance develops more readily. However, amantadine has fewer side effects.

F. Antimuscarinic agents

Focus topic: Drugs for Neurodegenerative Diseases

The antimuscarinic agents are much less efficacious than levodopa and play only an adjuvant role in antiparkinsonism therapy. The actions of benztropine [BENZ-troe-peen], trihexyphenidyl [tri-hex-ee-FENi- dill], procyclidine [pro-SYE-kli-deen], and biperiden [bi-PER-i-den] are similar, although individual patients may respond more favorably to one drug. Blockage of cholinergic transmission produces effects similar to augmentation of dopaminergic transmission, since it helps to correct the imbalance in the dopamine/acetylcholine ratio. These agents can induce mood changes and produce xerostomia (dryness of the mouth), constipation, and visual problems typical of muscarinic blockers. They interfere with gastrointestinal peristalsis and are contraindicated in patients with glaucoma, prostatic hyperplasia, or pyloric stenosis.

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