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Parkinson's Disease Management

From Mediwikis

Principles

There are two main objectives to the management of Parkinson's Disease (PD):

  1. Try and replace dopamine effects
  2. Deal with non motor symptoms effectively

To understand the management of PD it is important that you understand the pathophysiology, see also Parkinson's Disease

Basic Pathophysiology

There is a loss of the dopaminergic pathway especially in the Substantia Nigra (found in the Midbrain) which normally plays a critical role in motor control. There is also a build up of alpha synuclein in the form of Lewy Bodies which leads to neuronal loss.

There is no curative treatment for PD yet but replacing the dopamine or modifying other aspects of neurotransmission help to relieve symptoms as much and for as long as possible without causing to many side effects.

Medication

There are two broad classes of medication:

  1. Those that enhance dopaminergic transmission
  2. Anticholinergics

Enhancing the Transmission of Dopamine

There are several different medications in this class:

  1. Levodopa aka L-dopa
  2. Monoamine Oxidase Inhibitors aka MAOIs
  3. Catechol-O-Methyl Transferase Inhibitors aka COMTIs
  4. Dopamine Agonists

L-dopa

  • L-dopa is the precursor for dopamine
  • Can be given orally as good absorption in the upper small intestine
  • Given with a decarboxylase inhibitor to prevent the breakdown of L-dopa in the periphery to dopamine. e.g. carbidopa, benserazide
  • Increasing peripheral dopamine leads to a number of side effects including nausea, cardiac arrhythmias and posthural hypotension, this is why it is important to prescribe L-dopa in combination with a decarboxylase inhibitor
  • Levodopa and a decarboxylase inhibitor are often given as one preparation, e.g. co-careldopa (trade name = sinemet), co-beneldopa (trade name = madopar)
  • Rapid acting 'rescue' preparations available that are soluble and given e.g. in the morning to relieve freezing after waking

There are several important complications in the form of Motor problems, these are present in 50% of patients after 5 years of treatment and are almost universal after 10 years:

  • on-off fluctuations - where the patient swings from very akinetic to very dyskinetic
  • Wearing off phenomena - where the patient becomes more symptomatic as the drug effects start to wear off but before the next dose is due
  • Dyskinesias - dose related involuntary movements worse at either peak dose or biphasically (just after dose and just before next dose)

To try and reduce these:

  • The dose should be fractionated (smaller doses more often)
  • The smallest dose that relieves symptoms should be used
  • Avoid taking the dose with meals as this leads to irregular absorption from the small intestine (L-dopa uses the same transporters as amino acids and has to compete for them when the patient is digesting a meal)
  • If these symptoms are severe then there are surgical options which provide a continuous enteric infusion into the duodenum

Side effects of levodopa include:

  • Nausea
  • Posthural hypotension
  • Agitation, confusion and visual hallucinations

Because of the issues above, it is important to prescribe levodopa in appropriate patients. It is used as first line therapy in the over 70s as the other forms of medication tend to cause problems with confusion. It is not used as first line therapy in the under 70s as it has a limited 'life-span' as medication until the motor complications become too severe. In this group the first line treatment would be selected from the list below and tailored towards limiting symptoms.

MAOIs and COMTIs

Both of these classes of drugs inhibit the breakdown of the neurotransmitter dopamine in the synapse. This prolongs the action of the patient's endogenous dopamine, but can also be used as an adjunct treatment with L-dopa to reduce prescribed doses.

  • MAOIs = selegiline, rasagiline
  • COMTIs = entacopone, tolcapone

Entacapone can increase dyskinesias and cause diarrhea. Tolcapone rarely causes liver failure and so patients should have fortnightly LFTs.

Dopamine Agonists

These are first line treatment in younger patients and stimulate the D1 and D2 receptors that are normally activated by dopamine. They don't cause motor fluctuations or dyskinesias but there use is limited in the elderly where they tend to cause confusion and psychosis.

The first generation dopamine agonists are no longer used in the treatment of PD, this is because they caused serious fibrosis of internal organs, including the heart, lungs, liver and kidneys e.g. bromocriptine, cabergoline, pergolide. (Bromocriptine is still seen in the treatment of prolactinomas)

The dopamine agonists used now include:

  • Ropinerole and Pramipexole

Side effects include:

  • Posthural Hypotension
  • Ankle Oedema
  • Somnolence (= excessive tiredness, take care in drivers as can cause narcoleptic type sleep attacks)
  • Impulse Control Disorders (seen in 15% of patients taking the form of sudden gambling and shopping addictions and hypersexuality)

Apomorphine

This has a similar structure to dopamine and acts as an agonist to D1 and D2 receptors. It is used in severe PD in young patients when L-dopa is no longer of real benefit. It is given as a subcutaneous injection/infusion. There are several side effects:

  • Severe nausea (give domperidone - antiemetic concurrently)
  • In overdose causes respiratory depression (as it is a morphine derivative can reverse with naloxone)
  • Confusion, psychosis
  • Rarely autoimmune haemolytic anaemia (do FBCs)

Anti-muscarinics aka Anti-cholinergics

  • Given orally
  • Improve tremor, rigidity, muscle cramps and stiffness
  • Have no impact on bradykinesia
  • Share side effects with other anti-cholinergics:
    • Dry mouth, blurred vision, confusion, hallucinations, constipation, urinary retention
  • e.g. benzhexol, orphenadrine

Amantadine

This drug both increases dopamine synthesis and release and decreases neuronal uptake, it also acts as a minor antimuscarinic. It can reduce L-dopa induced dyskinesias. There are several side effects:

  • Ankle oedema
  • Posthural hypotension
  • Confusion - moreso in the elderly

NB: In PD patients or those patients in which PD is suspected it is imperative not to prescribe dopamine antagonists, the main ones being the antiemetic prochlorperazine and first generation antipsychotics including haloperidol. These inhibit the action of dopamine and lead to a profound worsening of symptoms.

Management of Non-Motor Symptoms

There are many symptoms seen in PD that are non-motor, it is important to treat these effectively too to maximise the patient's quality of life, for example:

  • antidepressents
  • laxatives
  • Pain killers, especially NSAIDs - patients often get frozen shoulder

PD patients should be encouraged to be as mobile as possible and engage in regular exercise, many other branches of medicine will be involved in their care for a more holistic approach, e.g. physio, speech therapy and occupational therapy.