Parkinson’s Disease

Parkinson’s Disease (PD) is a neurodegenerative disorder whereby loss of dopaminergic neurons from the basal ganglia (specifically the substantia nigra) results in motor symptoms which are the hallmark of the disease. This disorder is characterised by bradykinesia, muscle rigidity, resting tremor and impairment of postural balance.

The exact mechanisms that result in the loss of these neurons is not clear, environmental factors and genetics have been implicated.

According to available figures, it is estimated to affect approximately 6.3 million people worldwide. It is the second most common neurodegenerative disorder –an Australian report (2011) estimates that 1 in 350 Australians now have the condition, and more than 30 people are diagnosed daily.

Increasing age is a risk factor for the development of PD.  Incidence is reported as 1:1000 for people over 65 and 1:100 over 75. It is important to note that whilst increasing age is a risk factor for development, it is not a normal part of the ageing process.

The average age of diagnosis is 55 -65 years. The term ‘young onset’ is attributed to those diagnosed between 21 -40 and prior to this the term ‘juvenile onset’ is used. Parkinson’s is slightly more common in males than females (ratio 5:4). (Parkinson’s Australia, ‘Description, Incidence and Theories of Causation’)

PD can be classified as either:

Primary PD – also termed idiopathic (no demonstrable cause) 

Secondary PD – also termed acquired PD, which can be caused by factors such as:

1.      Trauma (head injuries, boxing)
2.      Infection
3.      Drugs or chemicals

Strategies to treat PD

The primary goal of treatment is to redress the imbalance of dopamine and to a lesser extent acetylcholine

There are two primary ways to do this:

• Increase the amount or action of dopamine or inhibitacetylcholine

Increasing the amount of dopamine is the primary mechanism utilised in the modern treatment of PD. Methods include:

• Replace Dopamine
• Inhibit the breakdown of dopamine both centrally and peripherally
• Mimic the action of dopamine
• Increase the release of dopamine

Each of the classes of drugs used to treat Parkinson’s disease will be considered in turn, starting with levodopa (L-dopa)

Watch the following lecture on Parkinson’s Disease Introduction including the therapeutic strategies (12 minutes)

Pharmacology of Drugs for Parkinson’s Disease

• Levodopa (l-dopa) – the precursor for dopamine. Dopamine is not used because it is hydrophilic and, therefore not able to cross the BBB.  Levodopa is converted to dopamine by enzyme dopa decarboxylase (which requires cofactor vitamin B6 – supplementation of this vitamin in PD is controversial).  As most of the conversion (>95%) occurs outside the CNS, this agent is normally co-administered with a peripheral dopa decarboxylase inhibitor carbidopa or benserazide.  The advantages of this combination include less peripheral adverse effects due to less peripheral conversion (hypotension, nausea and vomiting…); and less peripheral conversion also increases the availability of administered and unmetabolised levodopa to cross the BBB, thus reducing the dosage required for treatment (by 10 folds).
• Entacapone (a COMT inhibitor) or selegiline (a selective MAO-B inhibitor). These enzyme inhibitors prevent the metabolism of dopamine, thus prolonging the neurotransmission.  Entacopone also inhibits the metabolism of l-dopa, increasing the amount crossing BBB into CNS.  These agents are used as adjuncts whilst selegiline alone can also be used in early PD.

L-dopa/carbidopa/entacapone combination is available for those with motor fluctuation (after long-term use of levodopa/carbidopa combination).

• Pramipexole, bromocriptine, cabergoline and some other D2 receptor agonists (non-ergot derivatives preferred).
• Benztropine (antimuscarinic) plus others. It is used as adjunct, with predictable adverse effects (S1 lectures).  Benefits tremor in PD.
• Amantadine. The mechanism of action is not clear and an increase in dopamine release is mainly responsible for its clinical efficacy (it is an antiviral agent!).

Adverse effects produced with the use of these agents (except benztropine) are mainly due to overstimulation of D2 receptors, including nausea (D2 receptors in CTZ), schizophrenic-like psychoses (D2 receptors in mesolimbic pathway) and postural hypotension (peripheral vasodilation).  Long-term (2-5 years) use of levodopa can also produce some undesirable motor complications, such as dyskinesias and ‘on-off’ effect.  These may be related to the progression of neurodegeneration, absorption of levodopa and the D2 receptor regulation.

Watch the following lecture on pharmacology of Drugs for Parkinson’s Disease (18 minutes)

 Lecture Notes