Category:Antiparkinsonism agents

The antiparkinsonism agents are the medicines used to treat Parkinson's disease, and the wider group of conditions known as parkinsonism. Parkinson's disease holds a particular place in the history of medicine: it was among the first disorders of the brain to be traced to the loss of a specific population of nerve cells, the dopamine-producing neurons of the midbrain, and the first to be treated by supplying the missing neurotransmitter. That treatment, levodopa, remains one of the most dramatic in medicine; people held nearly motionless for years have stood and walked within days of receiving it. Yet its history, and the history of every medicine built around it since, carries one persistent shadow: these medicines restore the movement the disease takes away, but not one of them has been shown to slow the loss of neurons that causes it. They treat the symptom, and the disease goes on beneath.

The disease was named for the London physician and apothecary James Parkinson, who in 1817 published "An Essay on the Shaking Palsy," the first clear medical description of it.^[1] Parkinson drew his account from only six people, three of them his own patients and three observed on the streets of London, and yet he caught the condition with precision: the resting tremor, the stooped posture and shuffling gait, the gathering weakness, and the slow worsening over years. He called it paralysis agitans, the shaking palsy. The essay was little read for the forty years that followed.

It was Jean-Martin Charcot, working in Paris in the 1860s and 1870s, who recovered the description, corrected and widened it, distinguished the disease from the other disorders that produce a tremor, and gave it the name it now carries, Parkinson's disease.^[2] For a century after Parkinson's essay, however, naming the disease was close to all that medicine could do about it.

The first treatment to do measurable good came, like much in this story, by chance. In 1867 Leopold Ordenstein, a pupil of Charcot's, reported that the alkaloids of belladonna eased the tremor and rigidity of the disease. The discovery was accidental: tinctures of deadly nightshade and henbane had been given to patients to control the heavy drooling that troubles the condition, and the movement symptoms were seen to improve as well.^[2] Charcot took the finding up, prescribing small daily doses of hyoscyamine; later physicians added scopolamine and other anticholinergic preparations, and some tried Indian hemp. These plant alkaloids, and the synthetic anticholinergics later modeled on them, were the mainstay of treatment for the better part of a hundred years. They softened the tremor in some patients; they did little for the slowness and the immobility that disable most.

The modern treatment of Parkinson's disease rests on a chain of discovery made across the 1950s and 1960s. The Swedish pharmacologist Arvid Carlsson established, in the late 1950s, that dopamine was not merely a way station in the making of other neurotransmitters but a transmitter in its own right, concentrated in the parts of the brain that govern movement; he showed that reserpine, which produced a state of parkinsonism-like immobility in animals, did so by depleting dopamine, and that levodopa, the amino acid from which the body builds dopamine, reversed it. Carlsson's work was later recognized with a share of the 2000 Nobel Prize.^[3]

In 1960 the Austrian biochemist Oleh Hornykiewicz, examining the brains of people who had died with Parkinson's disease, found the dopamine of the striatum almost entirely gone. The disease now had a chemical signature. In 1961, with the neurologist Walther Birkmayer, Hornykiewicz gave levodopa by injection to a group of patients and saw what was later described as a miracle: people who had been unable to rise from bed sat, stood, and walked. The effect lasted only hours, however, and through the 1960s attempts to turn it into a usable treatment gave inconsistent results.^[3]

The breakthrough was made by George Cotzias in New York. Rather than give levodopa in the modest doses others had tried, Cotzias built the dose up slowly to very high levels, and found that the benefit could then be sustained. His reports, in 1967 and 1969, showed that ordinary levodopa taken by mouth in this way could return people with advanced Parkinson's disease to something near normal movement.^[4] It was among the most celebrated advances in the medicine of its era.

One refinement made levodopa practical. Taken by mouth, most of a levodopa dose is turned into dopamine in the body before it ever reaches the brain, which both wastes the dose and causes severe nausea. Giving levodopa together with a second medicine that blocks this conversion in the body, but cannot itself enter the brain, answers both problems at once. That second medicine is carbidopa (or, in much of the world, benserazide), and the fixed combination Carbidopa/levodopa has been the standard form of the treatment since the 1970s.^[3]

Levodopa transformed the disease without curing it, and within a few years of its arrival a second problem became plain. As the years pass, the smooth response to each dose gives way to fluctuation: the benefit begins to fade before the next dose is due, the effect known as "wearing-off," and many patients develop dyskinesia, the involuntary writhing movements that appear when a dose is at its height. These motor complications are understood to arise from the advancing disease together with the pulsed, uneven way oral levodopa reaches the brain.^[5] Much of the antiparkinsonism pharmacy built since the 1970s has been an effort to manage them.

One approach stimulates the dopamine receptors directly, with medicines that do not depend on the dwindling neurons to convert them. The first dopamine agonist used in the disease was apomorphine, tried from about 1970 but held back by its side effects and the need to inject it. Bromocriptine came into wide use from 1974. It and the other early agonists, cabergoline among them, were derived from ergot, and were later found to carry a risk of fibrosis of the heart valves and the lungs, so that they are now little used. The non-ergot agonists that followed, pramipexole, ropinirole, and the skin-patch medicine rotigotine, are the agonists in common use today.^[5]

A second approach slows the breakdown of dopamine, and of levodopa, so that each dose lasts longer. The enzyme monoamine oxidase B breaks down dopamine within the brain; the medicine that blocks it, selegiline, was developed in Hungary by the pharmacologist József Knoll and colleagues, who had studied it, in its earlier form deprenyl, from the 1960s.^[6] Rasagiline and safinamide followed as later inhibitors of the same enzyme. The enzyme catechol-O-methyltransferase breaks levodopa down in the body; from the 1980s the Finnish company Orion Pharma developed inhibitors of it, and entacapone and the later opicapone are given alongside levodopa to steady its effect. A third such inhibitor, tolcapone, is effective but used sparingly, because it can, rarely, injure the liver.^[7]

Amantadine reached the disease by the purest accident. It had been introduced as an antiviral medicine when, in 1969, a woman taking it for influenza reported that her Parkinson's tremor and rigidity had eased. The observation held up, and amantadine, whose action is still not fully understood, is now valued in particular for its capacity to reduce levodopa-induced dyskinesia, the one antiparkinsonism medicine in common use that does so.^[8] The oldest medicines, the anticholinergics, have not vanished either: benztropine, trihexyphenidyl, biperiden, and orphenadrine are still used, chiefly in younger patients in whom tremor is the dominant complaint.

From the first, levodopa carried a worry alongside its triumph. Because the brain's handling of dopamine generates reactive byproducts, some researchers feared that levodopa, by flooding the system with dopamine, might itself hasten the death of the neurons it was meant to help. The fear was real enough that some clinicians delayed the medicine, accepting disability in the hope of sparing the brain. The question was put to a formal test in the ELLDOPA trial, reported in 2004, which found no clinical sign that levodopa worsened the disease; if anything, the patients who had taken it fared better.^[9] Levodopa is no longer withheld for fear of toxicity.

The larger hope has been for a medicine that does what none yet does: slow the disease itself. The search has returned, more than once, to the MAO-B inhibitors. A large trial of selegiline in the 1980s, and a trial of rasagiline of unusual design reported in 2009, in which the medicine was begun at different times in different groups so that a disease-slowing effect might in principle be told apart from a simple symptomatic one, each produced results that pointed encouragingly but did not convince.^[10] The honest summary, after sixty years, is the one set at the head of this page: the antiparkinsonism medicines treat the symptoms of the disease, and the search for one that changes its course goes on.

The antiparkinsonism medicines are, with a single exception, attempts to restore the action of dopamine in a brain that is losing the capacity to make it. Levodopa supplies the raw material from which surviving cells build dopamine. The dopamine agonists bypass that step and stimulate the dopamine receptors directly. The MAO-B inhibitors and the COMT inhibitors block two of the enzymes that break dopamine and levodopa down, so that what dopamine there is lasts longer. The anticholinergics act differently, not on dopamine at all, but by damping the activity of acetylcholine, on the long-held understanding that the movement circuits depend on a balance between the two transmitters and that, when dopamine falls, lowering acetylcholine restores part of that balance. Amantadine is the exception, and the least understood; its usefulness against dyskinesia is thought to involve an action on the glutamate system rather than on dopamine.

That these medicines have these actions is well established. The fuller relationship between any one of them and the whole pattern of benefit and of side effect it produces in a given patient is more complex, and remains a subject of research.

Because the antiparkinsonism medicines span several classes, their risks differ, and the safety information for each is best read on its own page. Some patterns run across the class. Levodopa's own long-term difficulty, the wearing-off and the dyskinesia, is described above. The dopamine agonists carry a particular and sometimes serious hazard: in a minority of people they provoke disorders of impulse control, compulsive gambling, shopping, eating, or sexual behavior, which can do considerable harm before the cause is recognized and which generally ease when the medicine is reduced. The agonists can also bring on sudden, overwhelming sleepiness. Across the dopaminergic medicines, hallucinations and confusion may appear, more often in the later stages of the disease, and a fall in blood pressure on standing is common. The anticholinergics can cloud memory and thinking, particularly in older patients. Figures for these risks are population estimates that vary between studies, and individual response varies considerably from person to person.

This category collects the wiki's antiparkinsonism medicine pages, which fall into several groups by their mode of action.

• The dopamine precursors, the core of treatment: Levodopa and the standard fixed combination Carbidopa/levodopa. These carry the Dopamine Precursors subcategory.
• The dopamine agonists, which stimulate the dopamine receptors directly: Apomorphine, Bromocriptine, Cabergoline, Pramipexole, Ropinirole, and Rotigotine. These carry the Dopamine Agonists subcategory.
• The MAO-B inhibitors, which slow the breakdown of dopamine in the brain: Rasagiline, Safinamide, and Selegiline.
• The COMT inhibitors, which prolong the effect of levodopa: Entacapone, Opicapone, and Tolcapone. These carry the COMT Inhibitors subcategory.
• The anticholinergics, the oldest group, used mainly against tremor: Benztropine, Biperiden, Orphenadrine, and Trihexyphenidyl. These carry the Anticholinergics (anti-muscarinic) subcategory.
• Amantadine stands apart, used in particular to reduce levodopa-induced dyskinesia.

This category indexes the medicines whose defining use is the treatment of Parkinson's disease and of parkinsonism, the broader group of conditions that share its slowness, stiffness, and tremor. Most members are used chiefly in Parkinson's disease itself. The boundary is that use, not a single mechanism: the category gathers dopamine precursors, dopamine agonists, two kinds of enzyme inhibitor, the anticholinergics, and amantadine, which have little in common but their purpose.

Several members are used well beyond Parkinson's disease, and are cross-indexed accordingly. The anticholinergics are widely used to treat the parkinsonism and the other movement effects caused by the neuroleptics, which is now a common reason for prescribing them. Some dopamine agonists, bromocriptine and cabergoline in particular, are also used to lower the hormone prolactin and in other endocrine conditions, and ropinirole and pramipexole are used for restless legs syndrome. Following the wiki's multi-membership convention, a medicine is indexed wherever its pharmacology and its uses warrant.

Each antiparkinsonism medicine indexed here has, or in time will have, its own page, built on the wiki's standard structure for a medicine: a history-first account, then pharmacology, indications, adverse effects, and interactions.

This is one of the wiki's MedCategory class-overview pages. It carries the MedCategory and MedCategoryFull marker tags; the second suppresses the member list that MediaWiki would otherwise generate automatically, leaving the curated index above as the one the reader sees. The category sits beneath Medicines and within the Pharmaceutical origin root, the antiparkinsonism medicines being products of scientific discovery rather than of traditional practice, even where, as with the belladonna alkaloids, the story began with a plant.