Therapy of Parkinsonism
Since there is no cure for parkinsonism, the aim of phar-macological therapy is to provide symptomatic relief. This is obtained through the use of drugs that either in-crease dopaminergic actions or diminish neuronal out-flow from the striatum. These drugs include levodopa, which increases brain dopamine levels; dopamine ago-nists, which directly stimulate dopamine receptors; monoamine oxidase (MAO) inhibitors, which prevent dopamine metabolism; and anticholinergic agents, which reduce the excitatory activity within the striatum (Fig 31.3).
Levodopa (L-DOPA), the most reliable and effective drug used in the treatment of parkinsonism, can be con-sidered a form of replacement therapy. Levodopa is the biochemical precursor of dopamine (Fig. 31.2). It is used to elevate dopamine levels in the neostriatum of parkin-sonian patients. Dopamine itself does not cross the blood-brain barrier and therefore has no CNS effects. However, levodopa, as an amino acid, is transported into the brain by amino acid transport systems, where it is converted to dopamine by the enzyme L-aromatic amino acid decarboxylase.
If levodopa is administered alone, it is extensively metabolized by L-aromatic amino acid decarboxylase in the liver, kidney, and gastrointestinal tract. To prevent this peripheral metabolism, levodopa is coadministered with carbidopa (Sinemet), a peripheral decarboxylase inhibitor. The combination of levodopa with carbidopa lowers the necessary dose of levodopa and reduces pe-ripheral side effects associated with its administration.
Levodopa is widely used for treatment of all types of parkinsonism except those associated with antipsy-chotic drug therapy. However, as parkinsonism pro-gresses, the duration of benefit from each dose of levo-dopa may shorten (wearing-off effect). Patients can also develop sudden, unpredictable fluctuations between mobility and immobility (on-off effect). In a matter of minutes, a patient enjoying normal or nearly normal mobility may suddenly develop a severe degree of parkinsonism. These symptoms are likely due to the progression of the disease and the loss of striatal dopamine nerve terminals.
Other disturbing behaviors that can be produced by levodopa therapy are the dyskinesias. These are exces-sive and abnormal choreiform movements of the limbs, hands, trunk, and tongue. These dyskinesias eventually occur in 40 to 90% of patients receiving long-term high-dosage levodopa therapy. The mechanism underlying these abnormal movements is unclear, but it may be re-lated to fluctuating plasma levels of levodopa and the presence of hypersensitive dopamine receptors. The dyskinesias can be reduced by lowering the dosage; however, the symptoms of parkinsonism may then reap-pear. Most patients prefer to tolerate a certain degree of dyskinesia if their mobility can be improved by levo-dopa therapy.
The most common peripheral side effects are anorexia, nausea, and vomiting (likely due to dopamine’s stimulation of the chemoreceptor trigger zone of the area postrema in the medulla oblongata).
Orthostatic hypotension may occur as a result of the pe-ripheral decarboxylation of levodopa and release of dopamine into the circulation. Cardiac arrhythmias oc-cur in some patients and are attributed to the stimula-tion of cardiac α- and β-adrenoceptors by dopamine.
Centrally mediated adverse effects of levodopa ther-apy include vivid dreams, delusions, hallucinations, con-fusion, and sleep disturbances, especially in the elderly. Certain drugs can interfere with the clinical effectiveness or exacerbate the adverse reactions of levodopa therapy. For instance, nonselective MAO inhibitors (phenelzine, tranylcypromine) should not be administered with lev-odopa, since the combination can precipitate a life-threatening hypertensive crisis and hyperpyrexia.The ad-ditive effects of levodopa and adrenomimetic amines demonstrate that extreme care should be exercised in treating the symptoms of asthma or emphysema in pa-tients with Parkinson’s disease. Also, levodopa should not be given to patients with narrow-angle glaucoma, since it can produce severe mydriasis that would markedly aggravate the glaucoma. Patients with a history of cardiac arrhythmias or recent cardiac infarction should receive levodopa only when absolutely necessary. Also, proteins ingested with meals may produce suffi-cient amounts of amino acids to compete effectively with levodopa transport both in the gastrointestinal tract and in the brain. Levodopa therefore should be administered at least 30 minutes before meals.
Dopamine receptor agonists are considered by many clinicians as the first approach to therapy. They have a long duration of action and are less likely to cause dys-kinesias than levodopa. The rationale for the use of dopamine agonists is that they provide a means of di-rectly stimulating dopamine receptors and do not de-pend on the formation of dopamine from levodopa. As monotherapy, the dopamine agonists are less effective than levodopa but are often used early in the disease to delay initiation of levodopa therapy. When used as an adjunct to levodopa in advanced stages, the dopamine receptor agonists may contribute to clinical improve-ment and reduce levodopa dosage needs.
The four dopamine agonists used in the United States are bromocriptine (Parlodel), pergolide (Permax), pramipexole (Mirapex), and ropinirole (Requip). Bromocriptine, an ergot derivative, is an agonist at the D2-receptors and a partial D1-antagonist. Pergolide, also an ergot derivative, is an agonist at both D1- and D2-receptor subtypes. The more recently introduced noner-got drugs, ropinirole and pramipexole, are selective ago-nists at D2-receptor sites.
All four exert similar therapeutic effects and can produce the same adverse effects seen with levodopa. The differences between the ergot derivatives and the newer agents reside primarily in their adverse effects and tolerability. Postural hypotension, nausea, somno-lence, and fatigue are common adverse effects of bromocriptine and pergolide therapy and can limit the use of these drugs.
Because of these adverse effects, the drugs are gen-erally first administered at low doses and then the dose is gradually increased over weeks or months as toler-ance to the adverse effects develops. These symptoms are generally less frequent and less severe with pramipexole and ropinirole, which allows for a more rapid achievement of therapeutic response. Also, be-cause pramipexole and ropinirole are better tolerated, they are increasingly used as monotherapy.
Another drug used in the treatment of Parkinson’s dis-ease is selegiline (also known as deprenyl, or Eldepryl). It is an irreversible inhibitor of MAO-B, an important enzyme in the metabolism of dopamine (Fig. 33.2). Blockade of dopamine metabolism makes more dopamine available for stimulation of its receptors. Selegiline, as monotherapy, may be effective in the newly diagnosed patient with parkinsonism because its pharmacological effect enhances the actions of endoge-nous dopamine.
Selegiline is also used in conjunction with levodopa– carbidopa in later-stage parkinsonism to reduce lev-odopa dosage requirements and to minimize or delay the onset of dyskinesias and motor fluctuations that usually accompany long-term treatment with levodopa. It has also been proposed that selegiline may slow the progression of the disease by reducing the formation of toxic free radicals produced during the metabolism of dopamine (Fig.31.2). However, any neuroprotective ef-fect of selegiline in parkinsonian patients remains to be established.
Most of the adverse reactions to selegiline are re-lated to actions of increased levels of dopamine, as dis-cussed earlier. At recommended doses, and unlike the nonselective MAO inhibitors used in the treatment of depression, selegiline has little effect on MAO-A and therefore generally does not cause the hypertension as-sociated with the ingestion of tyramine-enriched foods . However, at doses higher than those usually recommended, MAO-A may be inhibited, which increases the risk of a tyramine reaction.
Selegiline should not be coadministered with tricyclic antidepressants or selective serotonin uptake inhibitors because of the possibility of a severe adverse drug reac-tion (e.g., hyperpyrexia, agitation, delirium, coma).
Before the introduction of levodopa, the belladonna alkaloids (e.g., atropine and scopolamine) were the primary agents used in the treatment of parkinsonism. The belladonna alkaloids have been replaced by anti-cholinergic agents with more selective central nervous system (CNS) effects. Trihexyphenidyl (Artane), ben-ztropine mesylate (Cogentin), biperiden (Akineton), and procyclidine (Kemadrin) are useful in most types of parkinsonism.
The efficacy of anticholinergic drugs in parkinsonism is likely due to the ability to block muscarinic receptors in the striatum. In the absence of the inhibitory action of dopamine, the actions of the intrastriatal cholinergic in-terneurons are unopposed, yielding enhanced stimula-tion of muscarinic receptors. Blockade of these recep-tors reduces striatal activity. The muscarinic antagonists exert only modest antiparkinsonian actions and thus are most commonly used during the early stages of the dis-ease or as an adjunct to levodopa therapy.
Of the drugs used for treating parkinsonism, the an-ticholinergics are the only class that can provide benefit in the treatment of the drug-induced parkinsonism seen with antipsychotic therapy. This is because the blockade of dopamine receptors by the antipsychotics leads to in-creased activity of the striatal neurons. Blockade of the muscarinic receptors reduces this excitatory activity.
The adverse effects of the anticholinergic drugs are due to their antimuscarinic effects in other systems (e.g., cycloplegia, dry mouth, urinary retention, and con-stipation). Confusion, delirium, and hallucinations may occur at higher doses.
The antihistamine diphenhydramine (Benadryl), be-cause it has anticholinergic properties, is used for mild parkinsonism and with the elderly, who may not be able to tolerate the more potent anticholinergics, levodopa, or the dopamine agonists.
Amantadine was originally introduced as an antiviral compound , but it is modestly effective in treating symptoms of parkinsonism. It is useful in the early stages of parkinsonism or as an adjunct to levo-dopa therapy. Its mechanism of action in parkinsonism is not clear, but amantadine may affect dopamine release and reuptake. Additional sites of action may include antagonism at muscarinic and N-methyl-D-aspartate (NMDA) receptors. Adverse effects include nausea, dizziness, insomnia, confusion, hallucinations, ankle edema, and livedo reticularis. Amantadine and the anticholinergics may exert additive effects on men-tal functioning.
A recently introduced class of drugs for the treatment of parkinsonism is the catechol-O-methyl transferase (COMT) inhibitors. COMT metabolizes catechol com-pounds, including dopamine and levodopa, producing the inactive compound 3-O-methyl DOPA. The rationale for the use of COMT inhibitors is analogous to that for carbidopa; that is, since COMT is present in the periphery as well as in the CNS, inhibition of peripheral COMT results in an increase in the plasma half-life of levodopa, thereby making more drug available for transfer to the brain. Additionally, com-pounds that block COMT in the CNS also prolong the brain concentration of levodopa.
The two COMT inhibitors in clinical use are tol-capone (Tasmar) and entacapone (Comtan). They are used in combination with levodopa–carbidopa. In pa-tients with motor fluctuations, they increase the “on” time. Adverse effects are similar to those observed with levodopa–carbidopa alone. Tolcapone therapy can cause fatal hepatotoxicity and so should be used only in patients who do not respond to other therapies. Patients taking tolcapone require close monitoring of liver en-zymes for signs of hepatic changes.
Additional approaches to the treatment of Parkinson’s disease include surgical procedures, brain stimulation, and transplantation of dopaminergic cells. In general, surgical procedures are reserved for patients who are refractive to levodopa or who have profound dyskine-sias or fluctuations in response to levodopa. Tremor can be abolished by ablation of the ventral intermediate nu-cleus of the thalamus. Dyskinesias can be effectively controlled by ablation of the posteroventral portion of the globus pallidus. Brain stimulation appears to be a promising technique. High-frequency electrical stimula-tion of the thalamus, subthalamic nucleus, or globus pal-lidus can improve various symptoms of parkinsonism and reduce levodopa dosage.
A potentially promising, although very controver-sial, approach to the treatment of Parkinson’s disease is replacement of dopaminergic neurons. The grafting of fetal substantia nigra tissue, which contains the dop-amine neurons, into the striatum of parkinsonian pa-tients has been modestly successful. The procedure will remain experimental, however, until the many practical problems and ethical issues associated with the use of fetal tissue are resolved. The discovery of pluripotent stem cells is also being viewed as a possible way of de-veloping dopamine neurons for transplant purposes.