Introduction to Parkinson's Science/Q Page 50
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Current therapies for Parkinson's
What are the drugs I take meant to do and what symptoms do they address? edit
The major Parkinson's web sites give excellent accounts of drugs and treatments and should be consulted:
The most commonly used drugs for Parkinson's attempt to replace or substitute for the dopamine lost through the death of neurons or to prolong the existence of dopamine in the brain. Thus these drugs are targeted at the main motor symptoms of Parkinson's: tremor, stiffness, slowness of movement, posture and balance. In the early stages they can be very effective.
Dopamine replacement therapy edit
There is simply no practical way of getting the chemical dopamine itself to where it is needed in the brain. On the other hand, a closely related substance, levodopa (or l-dopa) is very effective and is the most important drug for Parkinson's.
Levodopa is actually the precursor of dopamine and is part of a chain of reactions that lead to the synthesis of dopamine.
In the dopamine-producing neurons, tyrosine is first converted to levodopa by the enzyme tyrosine hydroxylase then the levodopa is converted to dopamine by the action of Aromatic L-amino-acid decarboxylase (AAADC)(also known as DOPA decarboxylase, DDC).
Fortunately, when some neurons have died in the substantia nigra of a person with Parkinson's, simply providing levodopa enables the remaining neurons to produce more dopamine by the action of AAADC at the nerve terminals in the striatum (which is where the neurons deliver their dopamine).
Levodopa can be taken by mouth and, unlike dopamine, crosses the the blood brain barrier. But as it is easily denatured, it is usually taken in conjunction with carbidopa or benserazide which inhibit its decarboxylation (loss of the carboxly group, COOH, to produce dopamine) while it is still in the bloodstream. The proprietary preparation Sinemet is comprised of levodopa and carbidopa while Madopar is levodopa with benserazide. These adjuncts are known as DOPA decarboxylase inhibitors.
Over time patients treated with levodopa are prone to develop involuntary movements known as dyskinesia. For this reason patients are often prescribed a dopamine agonist instead of levodopa in the early stages. (See below)
Levodopa can also be administered as a gel by a portable pump directly into the duodenum or upper jejunum by a permanent tube via percutaneous endoscopic gastrostomy (PEG). The proprietary product is called Duodopa.
COMT inhibitors - extending the life of levodopa edit
Levodopa is also degraded in the bloodstream by an enzyme called Catechol-O-methyl transferase. But this degradation can be significantly reduced by drugs such as entacapone and tolcapone (Tasmar) which are Catechol-O-methyl_transferase inhibitors so that a greater proportion of levodopa successfully gets to the brain.
Levodopa, carbidopa and entacapone are the active ingredients in Stalevo.
MAOB inhibitors - extending the life of dopamine edit
When dopamine is released into the synapses of the nerve terminals in the striatum, some of it reaches its receptors on dendrites of the target neurons, some of it is captured by dopamine transporters and taken up again by the source neurons and the rest is quite rapidly metabolised (broken down) largely by an enzyme called monoamine oxidase type B. (See Dopamine production and storage subpage for details.) Normally if free dopamine persisted it would have harmful effects but, in Parkinson's, where insufficient dopamine is being produced, the introduction of a drug to inhibit its breakdown can be beneficial.
Two such MAO-B inhibitors are commonly used for Parkinson's, selegiline (Eldepryl) and rasagiline (Azilect). Sometimes they are used as a monotherapy in the early stages of Parkinson's but are also used later on in conjunction with levodopa and dopamine agonists (see below) to conserve dopamine.
Dopamine agonists edit
For Parkinson's, agonist drugs are used for stimulating the dopamine receptors on the neurons in the putamen. This can partly make up for the failure to receive dopamine from the degenerated neurons in the substantia nigra.
Dopamine agonists are commonly used in early Parkinson's instead of commencing treatment with levodopa straight away. They are far less prone to cause dyskinesia. They are not as potent as levodopa in reducing Parkinson's motor symptoms but can be very effective in the early stages.
Some dopamine agonists when they bind to the dopamine receptors stimulate them for much longer than levodopa. Some formulations extend their persistence in the system so that only one tablet a day needs to be taken. This 'smoothing out' of the receptor stimulation helps counter the 'pulsatile' effect of taking levodopa several times a day which has been thought to increase the risk of dyskinesia induction. Thus dopamine agonists are often taken in conjunction with levodopa. This has the additional advantage of reducing motor fluctuations.
There are quite a number of dopamine agonists. The most commonly prescribed are:
- Ropinirole (Requip).
- Pramipexole (Mirapexin/Sifrol).
- Apomorphine (Apokyn). Almost as potent as levodopa but has a very short half-life. Usually administered as an injection and, for continuous dosing, via a pump.
- Rotigotine (Neupro). This is usually in the form of a transdermal patch.
A more complete list of dopamine agonists is given on the Wikipedia page for dopamine agonists.
Amantadine is a weak antagonist of the NMDA type glutamate receptor. The lack of dopamine causes an increase in the level of glutamate in parts of the basal ganglia circuitry and therefore blocking the glutamate receptors ameliorates some of the Parkinsonian symptoms that this overproduction causes. (See diagram.) Amantadine also increases dopamine release, and blocks dopamine reuptake.
What is deep brain stimulation and how does this surgery work? edit
There are numerous places on the internet where you can get excellent and detailed descriptions of this treatment. 
Basically it involves the implantation of electrodes into the brain. Usually they are positioned in the subthalamic nucleus but sometimes other targets can be used including the internal segment of the globus pallidus and the thalamus. Small electrical pulses are applied through these electrodes by means of a controller implanted under the skin of the chest or abdomen.
DBS works by suppressing the abnormal electrical oscillations in the basal ganglia which arise when the normal dopamine signalling from the substantia nigra is disrupted in Parkinson's. The abnormal electrical oscillations alter the production of certain neurotransmitters, boosting some and suppressing others, and this gives rise to the movement difficulties. The electrical pulses applied through the electrodes reduce the abnormal electrical oscillations which in turn bring the neurotransmitter levels back towards normal.
DBS is an expensive procedure and not without risks and is therefore only usually prescribed when other forms of Parkinson's treatment have lost their effectiveness or are accompanied by severe side effects. Patients are carefully assessed for whether they are likely to benefit from it. Lack of response to levodopa is one counter indication because DBS and dopamine replacement therapy basically target the same cause of motor symptoms, the disruption of the circuitry of the basal ganglia.
Some of the advantages of DBS are:
- In contrast with older surgical techniques such a thalomotomy and pallidotomy it is reversible; if it does not work it can be switched off.
- It is adjustable. Following the operations to insert the electrodes and hook up the controller, various parameters can be adjusted so that the best pattern of stimulation is applied to give the best reduction of Parkinsonian symptoms. Further adjustment is performed as time goes on to keep the treatment optimised.
- The stimulation is continuous so that motor fluctuations, such as those experienced with a drug regime, are kept to a minimum.
- Often the level of medication can be substantially reduced so that effects, such as dyskinesia that occurs after long periods of levodopa use, are reduced or eliminated.
There is also an adverse side to DBS.
- It involves invasive brain surgery which entails risk.
- A surgical procedure is required to replace the batteries of the control unit every five to seven years.
- For some people there may be some worsening of certain symptoms such a speech problems.
- A number of Parkinsonian symptoms, especially non-motor ones, are not alleviated
A good source for studies on DBS can be found on the DBS-STN.org web site: http://www.dbs-stn.org/research_archive.php .
What treatments are there for the other symptoms? edit
Generally the symptoms that do not directly arise from the dysfunction of the substantia nigra and the consequent lack of dopamine production have no Parkinson's-specific treatment (unless, of course, they arise from the Parkinson medication when there might be scope for adjusting dosage).
The non-motor symptoms of Parkinson's arise from the affect of the disease on other parts of both the central and peripheral nervous systems. See Other PD symptoms. As dopamine is not the neurotransmitter utilised in these places, dopamine replacement therapy has negligible effect.
For neuropsychiatric disorders such as psychosis, depression, cognitive impairment and dementia a number of drugs are in common use but with variable and sometimes limited effect. Care has to be taken in their prescription because of possible side effects and, for some, the exacerbation of motor symptoms. There is a need for more research in this field, especially for randomised control trials. As late-stage Parkinson's almost always involves the appearance of Lewy bodies in the cerebral cortex, effective treatment of the cognitive decline accompanying this is unlikely to be possible until the relentless progress of the disease can be controlled.
Sometimes dopamine replacement therapy, notably with dopamine agonists, can trigger impulsive and compulsive behaviours. Often a change or adjustment in Parkinson's medication can control this, maybe in conjunction with psychotherapy.
- REM behaviour disorder (RBD) which may precede the appearance of Parkinson's motor symptoms by many years
- Restless Legs Syndrome
- insomnia and excessive daytime sleepiness
- sleep-disordered breathing such as sleep apnoea.
- non-REM parasomnias e.g., confusional arousals, somnambulism, somniloquy (sleep talking), sleep eating, and sexsomnia.
Any therapeutic interventions should be preceded by a proper assessment of sleep patterns and abnormal behaviour by, for instance, overnight polysomnography. Many of these sleep disorders appear to be related to the deposition of alpha-synuclein in various parts of the brain in and around the brain stem and there is no direct treatment for this. On the other hand a carefully worked out menu of medication adjustment involving both dosage and timing changes, use of melatonin and other drugs (such as short-acting hypnotics which can carry some risk) and diet and lifestyle changes can lead to an improvement in symptoms. Continuous positive airway pressure (CPAP) apparatus is commonly used to treat obstructive sleep apnoea.
Autonomic symptoms include
- Orthostatic hypotension (drop of blood pressure when standing up)
- Gastrointestinal dysfunction (eg swallowing, delayed stomach emptying and constipation)
- Sialorrhoea (drooling)
- Urinary dysfunction (eg urinary incontinence and urine retention)
- Sexual dysfunction
Because they arise from degeneration in parts of autonomic nervous system and, secondarily, from changes in the relative levels of various neurotransmitters, symptomatic treatment can usually only go so far. Referral to clinics which deal with the specific symptoms that are most troublesome is a common approach when a variety of pharmacological therapies might be prescribed along with physical, dietary and lifestyle measures. The latter might include use of materials, devices or appliances, exercises for improving general physical condition, control of fluid intake, avoidance of or increase in certain dietary components and deliberate behavioural changes. This group of symptoms tend to be the most distressing and embarrassing to the patient and help with avoiding withdrawal and social isolation can be important.
Sensory deficits include
- loss of sense of smell and taste,
- pain and
- paraesthesia (sensations of tickling, tingling, burning, pricking, or numbness in the skin).
The loss of the sense of smell is due to degeneration of the olfactory bulb and often precedes the onset of motor symptoms and it appears that treatment is rarely if ever offered.
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- The striatum has two parts, the putamen and the cuadate nucleus. The terminals from the neurons in the substantia nigra are located in the putamen and that is why both terms are used when describing the location where there is a dopmaine deficit in Parkinson's.
- While there is a lot of evidence that Amantadine has anti-Parkinsonian properties, a Cochrane review that assessed the randomised controlled trials that have been carried out to compare it with placebo concluded that they all had shortcomings which resulted in the review stating that "there is not enough evidence from trials about the effects of amantadine for people with Parkinson's disease." http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003468/abstract
- Articles on Deep Brain Stimulation: National Institutes for Neurological Diseases and Stroke, Parkinson's UK, Wikipedia , Mayo Clinic
- Smith, Yoland, Thomas Wichmann, Stewart A Factor, and Mahlon R DeLong. “Parkinson’s Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa.” Neuropsychopharmacology 37, no. 1 (January 2012): 213–246. doi:10.1038/npp.2011.212. Section THERAPEUTICS FOR NONMOTOR SYMPTOMS OF PD: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3238085/#__sec16title.
- Wishart, Steven, and Graeme J. A. Macphee. “Evaluation and Management of the Non-Motor Features of Parkinson’s Disease.” Therapeutic Advances in Chronic Disease 2, no. 2 (March 2011): 69–85. doi:10.1177/2040622310387847.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3513877/.
- Müller, Thomas. “Drug Therapy in Patients with Parkinson’s Disease.” Translational Neurodegeneration 1 (May 24, 2012): 10. doi:10.1186/2047-9158-1-10.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514092/
- Hindle, John V. “The Practical Management of Cognitive Impairment and Psychosis in the Older Parkinson’s Disease Patient.” Journal of Neural Transmission (Vienna, Austria: 1996) (February 22, 2013). doi:10.1007/s00702-013-0994-0. http://www.ncbi.nlm.nih.gov/pubmed/23430276.
- Parkinson's UK, Parkinson's drugs and impulsive and compulsive behaviour. http://www.parkinsons.org.uk/about-parkinsons/treating-parkinsons/drugs/compulsive-behaviours.aspx
- Parkinson's UK information sheet on Impulsive and compulsive behaviour in Parkinson's http://www.parkinsons.org.uk/pdf/fs77_impulsivecompulsivebehaviour.pdf
- Swick, Todd J. “Parkinson’s Disease and Sleep/Wake Disturbances.” Parkinson’s Disease 2012 (2012): 1–14. doi:10.1155/2012/205471.http://www.hindawi.com/journals/pd/2012/205471/.
- Truini, A., M. Frontoni, and G. Cruccu. “Parkinson’s Disease Related Pain: a Review of Recent Findings.” Journal of Neurology 260, no. 1 (January 2013): 330–334. doi:10.1007/s00415-012-6754-5. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535357/.
- Wasner, Gunnar, and Günther Deuschl. “Pains in Parkinson Disease--many Syndromes Under One Umbrella.” Nature Reviews. Neurology 8, no. 5 (May 2012): 284–294. doi:10.1038/nrneurol.2012.54. http://www.ncbi.nlm.nih.gov/pubmed/22508236.
- Parkinson's UK information leaflet on Pain in Parkinson's http://www.parkinsons.org.uk/PDF/FS37_PaininParkinsons.pdf