Let’s decipher those meds- drugs for Parkinson’s

This is one of many short articles to help people with health conditions needing more information on their prescribed therapy.

In parkinsons death of lewy bodies to damage of the nigrostriatal pathway. The neurones necessary for the production of (Dopamine)DA acting on the corpus stratum ( caudate +putaman) in the basal ganglia are damaged. This leads to problems with movement such as resting tremor, rigidity, akathisia ( difficulty initiating movement), bradykinesia( slowness of movement), micrographia etc.

Basal Ganglia is essential for the control of fine movement.

With the reduction in DA the brain the acetylcholine (Ach) tries to compensate for lack of stimulation leading to the tremors.

Fig1. ( I do not claim any credit for the diagram above).

Administering Dopamine (DA) may seem to be a logical treatment, but its an protein ( from aminoacid tyrosine) which would be metabolised in the stomach by peptidase enzymes. For this reason, L-Dopa precursor is administered as pro-drug but even that carries its challenges. L-dopa may convert into DA and act with the receptors in the periphery, meaning that not only would side-effects  ( nausea, vomiting)arise but less would reach the brain ( the desired target of therapeutic action) and therefore a higher dose would be required.

Noting this, the treatment is actually a combination of both DA and decarboxylase inhibitor. Examples are co-beneldopa and co-carbidopa.

Sometimes, as the condition progresses, physicians might like to consider stepping up the treatment by also including a COMT inhibitor. This reduces the peripheral and central break down of L-dopa ( Entacapone). A formulation consisting of levadopa, carbidopa and entacopone has been branded Stalevo. However, similarly MAO_B inhibitor can be used in combinational therapy. They differ by acting only in the brain  and preventing breakdown of DA rather than levadopa.

Other useful treatments that should not be disregarded are anti-muscarincs. These work on reversing the brains compensatory effect, by preventing Ach production and thereby reduce symptoms such as resting tremor.  This is known as counterbalancing the cholinergic excess and examples of such drugs are procyclidine, orphenadrine,trihexyphenadyl, amantadine.

Factors that should not be neglected are some major causes of parkinsonism. Many antiemetics work on the principle that by blocking DA receptors in the CTZ (chemoreceptor trigger zone in the medulla oblongata) symptoms of vomiting and nausea can be managed. However, this means that antiemetics such as metoclopramide, and prochloperazine can actually trigger symptoms of parkinsonism. A major side-effect of levadopa and DA- agonists are nausea and vomiting therefore an alternative drug to manage this side-effect would have to have a different method of action. A acceptable antiemetic would be domperidone, which does not cross the blood brain barrier. However, this also carries a risk of cardiovascular events, therefore should be used for relief of serious symptoms and for the shortest duration.

With the progression of parkinsons, end of dose deterioration or nocturnal immobility/rigidity  where “on” periods (duration of benefit) are progressively shorter and  “off” periods ( duration with restricted movements) are longer, modified or slow release may be an option .Motor complications ( fluctuations/dyskinesias/muscle spasms). Co –administration of MAO_B and COMT  would also delay the need for a high dose of levadopa which would delay the progression of the condition.

Side-effects of levadopa can also include constipation ( overactive autonomic)and increased frequency of urination ( overactive parasympathetic). Constipation can be treated with lactulose, Glycerol suppositories and macrogol. Increase frequency of urination can be treated with tamsulosin ( vasicare) (a blocker) and sudafenasine.

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