Personalising treatment of Parkinson's disease

With the prevalence of Parkinson's disease set to increase by 4% every year, pharmacogenomics is helping to improve the quality of life for patients.

 
 Illustration by Sarah Nagorcka

Illustration by Sarah Nagorcka

 

Gene Dosage is a monthly column by Janan Arslan that finds out what genome science is uncovering about each individual's unique response to drugs and pharmaceuticals. Janan is a graduate student and pharmacogenomics researcher with a keen interest in personalised medicine.

Parkinson’s disease is a chronic neurodegenerative disorder, most classically characterised by tremor (trembling in arms, legs and other body parts), slowed movement, muscle rigidity and stiffness, and impaired gait and balance. It affected an estimated 69,208 Australians in 2014, with 53% being male and 47% female. About 1 in 340 people currently live with Parkinson’s, and its prevalence is expected to increase to 123,781 patients by 2034.

Most people usually hear about Parkinson's disease in connection with high-profile sufferers, particularly actor Michael J. Fox and former heavyweight boxer Muhammad Ali (who, I am sad to say, passed away only a few days ago).

  Muhammad Ali, here receiving the Presidential Medal of Freedom in 2005, lived publicly with Parkinson’s disease for decades.   Paul Morse/Wikimedia Commons  (public domain)

Muhammad Ali, here receiving the Presidential Medal of Freedom in 2005, lived publicly with Parkinson’s disease for decades. Paul Morse/Wikimedia Commons (public domain)

For some people, like myself, the disease may hit a little closer to home ‒ my cousin has suffered and struggled with Parkinson's for several years now. Watching a loved one lose control over their own body and senses can be painful, to say the least. It probably doesn’t help that he is considerably younger than most patients ‒ some naïve part of you thinks that the youth are impervious to such crippling diseases.

Several treatment options are available, including medications or deep brain simulations, where electrodes are surgically implanted onto the brain to modulate or disrupt abnormal patterns of neural signalling. For my cousin, medication has become an integral part of his life ‒ probably the most important part, actually. As he nears his next dose, you can slowly see the struggle creep in, and he increasingly becomes uncomfortable in his own skin.

Typically, Parkinson's disease is treated with dopaminergic drugs. The disease's symptoms are due to dopamine depletion or deficiency, so these drugs replace or prevent the degradation of dopamine. As there is a plethora of antiparkinsonian drugs, I will select only a handful for this column, specifically those dispensed in Australia in 2014, and those with metabolic/pharmacogenomics information currently available.

To treat his Parkinson's symptoms, my cousin currently uses Madopar, one of Australia’s most commonly prescribed antiparkinsonian medications. It is a combination of the drugs levodopa and benserazide. Levodopa is an orally administered prodrug that is used to replace the dopamine lost due to Parkinson’s. Like other prodrugs, it is inactive in its original state and requires absorption and conversion to be therapeutically beneficial to a patient.

  A 19th century illustration of a patient with Parkinson’s disease.   William Richard Gowers, after Paul de Saint-Leger/Wikimedia Commons  (public domain)

A 19th century illustration of a patient with Parkinson’s disease. William Richard Gowers, after Paul de Saint-Leger/Wikimedia Commons (public domain)

The enzyme catechol-o-methyltransferase (COMT) metabolises 5% of levodopa to form 3-O-methyldopa (3-OMD), while over 90% is decarboxylated ‒ has a carboxyl group removed ‒ to form dopamine. To minimise the formation of dopamine outside the brain, levodopa must be combined with a decarboxylase (DC) inhibitor like benserazide, which reduces side effects such as nausea and postural hypotension. Benserazide is absorbed in the gastrointestinal tract and metabolised to its main metabolite, trihydroxybenzylhydrazine, which acts as a DC inhibitor.

Another commonly used combination is levodopa and carbidopa. Similar to benserazide, carbidopa reduces the decarboxylation of levodopa to dopamine, thus reducing side effects.

When levodopa is combined with a DC inhibitor such as benserazide or carbidopa, its metabolism is shifted to the formation of 3-OMD by the COMT enzyme. Studies have shown that genetic variants in the COMT gene relate to altered enzyme activity. These variants may cause differences in response amongst patients, as they affect the enzyme's ability to metabolise the medication.

The anticholinergic drug benztropine, which blocks the neurotransmitter acetylcholine in the brain, can alleviate some Parkinson's symptoms such as tremor.  CYP2C19 and CYP2D6 enzymes are responsible for the metabolism of benztropine. Common side effects of the medication include a dry mouth, nose and throat; confusion; and cognitive disturbances, just to name a few.     

Another class of drugs used in the treatment of Parkinson’s disease are the dopamine receptor agonists. Dopamine agonists can improve the motor function of patients, and are used especially for treating impaired involuntary movement, or dyskinesia.

  A diagram of the COMT enzyme, which metabolises the drug levodopa.   Fvasconcellos/Wikimedia Commons  (public domain)

A diagram of the COMT enzyme, which metabolises the drug levodopa. Fvasconcellos/Wikimedia Commons (public domain)

Alternatively, dopamine agonists can delay the introduction of levodopa to minimise the long-term complications associated with the drug. Unlike levodopa, which is converted to dopamine, dopamine agonists act directly on dopamine receptors to mimic the effects of dopamine.

Dopamine agonists can be further categorised into two subclasses: ergot-derived and non-ergot-derived. Ergot-derived dopamine agonists include bromocriptine, lisuride, pergolide, and cabergoline. This group is called 'ergot-derived' because they were first produced from ergot, a type of fungus that contaminates rye grain. Bromocriptine is metabolised by CYP3A4/3A5, while lisuride, pergolide, and cabergoline are simply metabolised by CYP3A4. They all have similar side effects: nausea, vomiting, orthostatic hypotension, confusion, hallucinations, insomnia and dizziness, just to name a few from a very long list of concerning possibilities.

Non-ergot-derived dopamine agonists include ropinirole, pramipexole, rotigotine, and apomorphine. It is suggested that ropinirole is mainly metabolised by CYP1A2, and to a lesser extent by CYP3A4. The metabolism of the other three drugs is not well understood. The side effects associated with both the ergot-derived and non-ergot-derived dopamine agonists are near identical.

Parkinson's disease is quite genuinely a debilitating condition. Anything we can do to help patients lead quality lives is a worthwhile venture. Whether we achieve this using personalised medicine, precision medicine, or whichever other fields of medicine prove useful, any little bit of extra help will certainly go a long way.

Edited by Andrew Katsis and Ellie Michaelides.