Parkinson’s disease is a neurodegenerative disorder, currently affecting over 1 million people in the United States. Men are 1.5 times more likely to develop the condition than women. The cause of the condition is currently unknown (idiopathic), but certain environmental and genetic factors are known to play a role. Drugs used in Parkinson’s disease seek to achieve two things: to enhance dopaminergic activity, and to inhibit cholinergic activity – effects which are believed to help attenuate progression of the disease. Below, we’re going to briefly summarize the pharmacology of Parkinson’s disease. Though there is no cure for the condition, it is treatable – and these drugs go some way toward achieving that goal.
Pharmacology of Parkinson’s Disease
There are several classes of drug used in the pharmacology of Parkinson’s disease, including:
- Dopamine receptor agonists
- Selective MAO type B inhibitors
- Catechol-O-methyltransferase (COMT) inhibitors
- Antimuscarinic drugs
Other treatment options, aside from medicines, are also available – including surgery, rehabilitation, and palliative care. Patients are also advised on their diet, something which becomes particularly important as the disease progresses. Life expectancy in patients with Parkinson’s disease is significantly reduced. Average life expectancy without treatment is between 8-10 years, but with levodopa treatment this rises to 15 years. However, it would be wrong to assume that all patients follow the same patterns of prognosis.
Dopamine cannot cross the blood-brain barrier – it needs to be shuttled there. That shuttling compound is levodopa, a compound which – when taken up in dopaminergic neurons – is converted into dopamine (a conversion carried out by L-aromatic amino acid decarboxylase). In this way, dopamine deficiencies can be treated and symptoms of Parkinson’s disease can be attenuated.
Levodopa, also known as L-DOPA, is biosynthesised from the amino acid L-tyrosine and acts as a precursor to the neurotransmitter dopamine, but also norepinephrine and epinephrine, too. When administered orally, the drug is absorbed by the small intestine. However, if L-DOPA is administered to the patient alone, with no other drug, it is rapidly converted into dopamine in the gut wall, liver, and kidney.
In order to avert this loss of dopamine for the brain, levodopa is taken with a dopa decarboxylase inhibitor – such as carbidopa or benserazide. The dopa decarboxylase inhibitor, unlike L-DOPA, cannot cross the blood brain barrier and, as a result, it does not prevent the conversion of L-DOPA to dopamine in the central nervous system.
Levodopa has a relatively short half-life, of around 1 hour. Unwanted effects with levodopa include nausea (which can be reduced if the drug is taken with food, but protein interferes with absorption), vomiting, red discolouration of urine, sedation, postural hypotension, vivid dreams, and visual hallucinations. Some patients experience confusion, arrhythmias, dyskinesia, disturbed respiration, and hair loss.
Dopamine Receptor Agonists
The dopaminergic theme continues with the dopamine receptor agonists – drugs which directly agonise – or promote – central dopaminergic receptors. Members of this drug class include:
These drugs have a longer duration of action than levodopa, and are selective agonists at D1, D2, and D3 receptors to varying degrees. Let’s take a look at some of these drugs:
- Apomorphine is an agonist at D1 and D2 As apomorphine is a powerful emetic agent (induces vomiting), it should be taken with an antiemetic. It has a half-life of around 45 minutes, and is administered by both oral and subcutaneous routes. Due to rapid hepatic metabolism, apomorphine has a short duration of action.
- Bromocriptine is a potent agonist at D2 It can be administered by oral and intravenous means, and is extensively metabolised by the liver. It has a half-life of around 12 hours. Bromocriptine is primarily excreted in the bile. Unwanted effects include nausea, hypotension, headache, and vomiting.
- Ropinirole and pramipexole, though they act at D2 receptors for their clinical agonist activity, also act at D3 receptors. Unwanted effects with D3 agonists include hypersexuality, punding, and compulsive gambling – even in patients who haven’t had a history of these conditions (known as dopamine dysregulation syndrome). Other general unwanted effects with the aforementioned drugs include nausea, dizziness, hallucinations, and night terrors.
- Cabergoline is a potent agonist at D2 receptors, a drug which is administered orally. It is moderately protein bound, and has a long half-life of around 60 hours. It is excreted in the urine (23%) and faeces (60%). Unwanted effects with cabergoline include nausea, constipation, dry mouth, depression, sleep disturbances, hypotension, and peripheral oedema.
The next drug in our pharmacology of Parkinson’s disease is amantadine; a drug with antiviral as well as antiparkinsonian effects. One of the great limitations of amantadine is the rapid onset of tolerance, which renders fruitless its clinical capacity. It is well absorbed from the gut and has quite a long half-life – of around 12 hours. Amantadine is excreted unchanged by the kidney.
Amantadine is used in Parkinson’s disease because it increases dopamine release and blocks dopamine reuptake. The drug stimulates the release of dopamine from nerve terminals, an effect which has proved beneficial in patients with levodopa-induced dyskinesias. Unwanted effects with amantadine include anorexia, nausea, peripheral oedema, anxiety, insomnia, and seizures (when taken in high doses).
Selective MAO type B Inhibitors
Examples of selective MAO-B inhibitors include rasagiline and selegiline.
Both rasagiline and selegiline are irreversible inhibitors of the type B version of the MAO enzyme – an enzyme responsible for the breakdown of dopamine. At low doses, rasagiline and selegiline are relatively selective for MAO-B. By blocking the breakdown of dopamine, they increase dopamine’s presence in the CNS. Both drugs are well absorbed from the gut and are extensively metabolised by hepatic means (short half-lives of 2 hours).
Unwanted effects with selective MAO type B inhibitors are widespread, and include:
- Nausea, dry mouth
- Constipation, diarrhoea
- Fatigue and dizziness
- Insomnia, agitation, confusion
- Muscle and bone pain
We now turn our attention to the COMT inhibitors, examples of which include entacapone and tolcapone.
The enzyme COMT is responsible for breaking down levodopa – both peripherally and in the CNS – to a large degree. By inhibiting COMT, levodopa availability increases. Studies show that, by inhibiting COMT, these drugs double the half-life of levodopa (when administered with a dopa decarboxylase inhibitor, such as carbidopa/benserazide). Entacapone does not cross the blood-brain barrier, but tolcapone does –inhibiting COMT in the CNS.
Both entacapone and tolcapone have variable pharmacokinetic profiles. For example, tolcapone is well absorbed by the gut, whereas entacapone is moderately absorbed from the gut. Both tolcapone and entacapone have short half-lives, in the region of 2 hours. Unwanted effects are similar to other antiparkinsonian drugs and include nausea, vomiting, dry mouth, anorexia, dyskinesias, urine discolouration, confusion, insomnia, and abdominal pain.
The final class in our pharmacology of Parkinson’s disease is antimuscarinic drugs – medicines which block central muscarinic receptors.
Examples of relevant antimuscarinic drugs include benzatropine, procyclidine, and orphenadrine. Antimuscarinic drugs are deployed in Parkinson’s disease to strike a balance between cholinergic activity and dopaminergic activity. They are generally well absorbed from the gut and are extensively metabolised in the liver. Half-lives range between 5-17 hours. Unwanted effects include dry mouth, constipation, urinary retention, and dizziness.
That’s about it for the pharmacology of Parkinson’s disease. This section is only meant as an overview to what is a complex topic. If you’re feeling up for it though, why not test your knowledge of everything in this article with our quick-fire ten question quiz.