20.2.2.3 Treatment to Enhance the Dopaminergic System

Probably, the most obvious way to enhance the dopaminergic system is to give dopamine. However, dopamine is not active after oral administration as it is metabolised by monamine oxidase and catechol-O-methyl transferase, which are found in the gut. To avoid intestinal metabolism, dopamine can be administered intravenously. But, after intravenous administration, dopamine does not cross the blood brain barrier to have central effects. Thus, we cannot use dopamine in Parkinson’s disease.

A very important way to enhance the dopaminergic system is to increase the synthesis of dopamine. L-DOPA is the precursor of dopamine. It is absorbed from the gut on the transport system for the aromatic amino acids. L-DOPA also gains entry into CNS, with transport across the blood brain barrier also being mediated by the transporter for the aromatic amino acids. Once in dopaminergic neurones, L-DOPA is converted to dopamine in the presence of the enzyme L-aromatic acid decarboxylase.

There are dopaminergic nerves in the central nervous system and in the peripheral nervous system, which means that after the administration of L-dopa, the levels of dopamine are boosted in both the central and peripheral nervous system (Figure 20.7).

In the central nervous system, this achieves are required goal, increased levels of dopamine, enhancing the dopaminergic system to overcome the Parkinson’s disease. However, in the peripheral nervous system, the increased levels of dopamine lead to side effects including nausea.

Figure 20.7 Effect of L-DOPA and Carbidopa (Copyright QUT, Sheila Doggrell

To overcome this problem, L-DOPA is used with an inhibitor of L-aromatic amino decarboxylase that does not cross the blood brain barrier e.g. carbidopa. Thus, carbidopa inhibits the conversion of L-DOPA to dopamine but only in the peripheral nervous system (Figure 20.7). This removes the detrimental effects associated with a build-up of dopamine in the peripheral nervous system. It also means that there are higher levels of L-DOPA in the circulation that can be transported to the central nervous system. In the central nervous system, the L-DOPA can still be converted to dopamine to enhance the dopaminergic system to overcome Parkinson’s disease. Thus, with this combination of L-DOPA and carbidopa, we get the benefits of L-DOPA in the central nervous system without the peripheral side effects.

L-DOPA and carbidopa are formulated together into one tablet, which makes it easier for the subject to remember to take. To be effective on an ongoing basis, three or more combination tablets are needed a day. Initially L-DOPA has a dramatic effect in improving or removing the signs and symptoms of Parkinson’s disease. It is like a miracle, the subject has apparent full recovery. Unfortunately, this does not last.

Parkinson’s disease is a progressive disease, which means there is a progressive loss of dopaminergic neurones. The dopaminergic neurons are needed to convert the L-DOPA to dopamine. Thus, with a decreasing number of dopaminergic neurones present, there is decreasing ability of dopaminergic neurones to convert L-DOPA to dopamine. Thus, the miracle does not last. This progressive loss of dopaminergic neurones contributes to the loss of effectiveness of L-DOPA with long term use.

With long term use of combination of L-DOPA and carbidopa, there is the “wearing off” phenomenon. In the “wearing off” stage, L-DOPA is only effective for 1 to 2 hours, and then rigidity and akinesia (slowness/loss of movement) returns. This is partly due to the progressive nature of Parkinson’s disease, but there may be other factors involved. Increasing the dose frequency with the L-DOPA can reduced the rigidity and akinesia, but often leads to dyskinesia (excessive and involuntary movements). In addition to nausea, L-DOPA may induce hallucinations and confusion in the elderly.

A second approach to enhancing dopaminergic neurotransmission in Parkinson’s disease, is to promote the release of endogenous dopamine. Amantadine increases the release of dopamine from the dopaminergic nerves in the striatum (Figure 20.8).

Figure 20.8 Mechanism of action of amantadine (Copyright QUT, Sheila Doggrell)

Amantadine also has antimuscarinic activity and blocks glutamate NMDA receptors (figure 20.8) and these effects may contribute to its benefit in Parkinson’s disease. The benefit of antimuscarinic activity in Parkinson’s disease is discussed in the next section. Blockade of glutamate NMDA receptors has been shown to be useful in Alzheimer’s disease.

Amantadine is not very effective alone. It is only used alone in the early stages of Parkinson’s disease where there are still sufficient stores of endogenous dopamine to allow amantadine to release dopamine.

In late-stage Parkinson’s disease, the disease cannot be controlled by L-DOPA/carbidopa, and amantadine can be useful in combination with L-DOPA. It is especially effective where there is dyskinesia with the L-DOPA/carbidopa combination.

A third approach to enhance dopaminergic transmission is to use drugs that are agonists at dopamine D receptor receptors. Dopamine D₁- and D₂- receptors are abundant in the striatum, and the ones to target in Parkinson’s disease. Stimulation of these receptors will mimic the effect of the missing endogenous dopamine. There are a number of dopamine receptor agonists available including older non-selective agonists: e.g. bromocriptine, and some agents that select for one receptor. Cabergoline is a selective agonist for dopamine D₂ receptors.

Bromocriptine stimulates vascular D₁ receptors to induce vasodilation causing hypotension, which is an adverse effect in Parkinson’s disease. This suggests that agents that are selective for dopamine D₂-receptor may be better than bromocriptine. Bromocriptine also causes nausea and fatigue.

Cabergoline is selective for the dopamine D₂ receptors, and is generally well tolerated. It has a long elimination half-life, which means that cabergoline can be used once a day.

Cabergoline can be used alone in early Parkinson’s disease. Unfortunately, none of the presently available dopamine receptor agonists are effective for long when used alone in Parkinson’s disease. Cabergoline can be used in late-stage Parkinson’s disease in combination with L-DOPA and carbidopa to overcome the fluctuations with L-DOPA.

A final approach to enhancing dopaminergic transmission is to reduce the inactivation of the endogenous dopamine. Dopamine is inactivated by either monoamine oxidase or catechol-O-methyl-transferase (Figure 20.5). Inhibition of either of these enzymes will lead to increased levels of dopamine (Figure 20.5).

Selegilene is a selective inhibitor of monamine oxidase-B, which is the form of monoamine oxidase that breaks down dopamine. Preventing the metabolism of dopamine, by inhibiting monoamine oxidase-B, leads to increased levels of dopamine.

Unfortunately, the benefit observed with selegilene is modest effect and, consequently, it is used primarily in early or mild Parkinson’s disease. The metabolites of selegilene include amphetamine and methamphetamine, which may cause anxiety and insomnia.

Catechol-O-methyl-transferase (COMT) is involved in the metabolism of dopamine. In the periphery, catechol-O-methyl-transferase also metabolises L-DOPA, and this metabolism leads to inactivation of the L-DOPA.

Entacapone is an inhibitor of catechol-O-methyl-transferase. In the periphery, the ability of entacapone to inhibit the inactivation of L-DOPA leads to more L-DOPA being available to be transported into the central nervous system. In the central nervous system, entacapone lead to increased levels of dopamine by preventing its metabolism by entacapone.

The duration of action of entacapone is short; about 2 hours. Entacapone is not used alone; it is usually administered at same time as the L-DOPA/carbidopa combination. When L-DOPA is given alone, up to 99% of it is metabolised in periphery. The effect of entacapone is mainly in the periphery, where inhibiting the metabolism of L-DOPA by catechol-O-methyltransferase increases the amount of L-DOPA that reaches the central nervous system to be converted into dopamine. Combination tablets of L-DOPA, carbidopa and entacapone are available for when the treatment of Parkinson’s disease with the combination of L-DOPA and carbidopa is no longer fully effective.