The Whitworths of Arizona, bringing science to you in everyday language.

Friday, July 31, 2015

How PD Drugs Interact with Cognition

Many people with LBD start out with Parkinson’s. They may have been using PD drugs successfully to improve mobility for a long time. Then as the disorder progresses into LBD, these drugs can begin to cause more problems than they solve.

To understand why, it helps to know how dopamine (DO) and acetylcholine (ACh) interact. These chemicals are both neurotransmitters (NTs) that pass messages from one nerve cell to another. Different NTs in different parts of the brain pass different messages. For instance, dopamine in the midbrain controls small motor function. ACh is in several parts of the brain, but in the cerebral cortex, it controls cognition. These two NTs operate on a ratio system. Think of a teeter-totter. When dopamine levels go up, ACh levels appear to go down even when they haven’t really changed. Conversely, when ACh levels go down, dopamine levels appear to go up, even when they haven’t really changed. It’s the ratio that counts, not the actual amount. We call this the DO/ACh balance. (See the 8/23/13 blog for some photos and another discussion of this same subject.)

Parkinson’s occurs when Lewy bodies invade the midbrain and decrease dopamine. However, no neurotransmitter can cross the blood brain barrier (BBB), and so doctors can’t just add more dopamine. Instead, PD drugs work around this problem in several ways: by using: a precursor to replace dopamine, enzyme inhibitors to preserve dopamine, dopamine agonist to mimic the NT, or an anticholinergic to maintain the DO/ACh balance. The drugs named below are not necessarily the only ones in that class, but are examples of those most commonly used.

1. Replace. These drugs end up replacing or adding dopamine.

Sinemet: (carbadopa/levadopa) Levadopa,is a precursor to dopamine. Unlike dopamine, it can cross the BBB. Once in the brain, levadopa is converted to dopamine. However, in practice, the large doses required can cause unwanted side effects. Adding carbadopa, which inhibits the enzymes that break down levadopa, allows the use of smaller doses. Sinemet is drug most commonly used to manage PD. It tends to become less effective with long use, and its effect on physical symptoms can become erratic.

Symmetral: (amantadine) is an anti-viral drug thought to increase dopamine levels while inhibiting its breakdown. Tolerance to the drug develops quickly, making it less effective. It is seldom useful for very long.

Cognitive issues. As Lewy bodies migrate into cognitive areas where acetylcholine is the active neurotransmitter, Sinemet can tip the DO/ACh balance so that cognitive dysfunctions may occur. Research has shown that early hallucinations and confusion in PD patients are most often drug-related. A reduction in Sinemet dosages frequently decreases or stops these symptoms. However, PD is progressive. The symptoms will probably reappear at a later date, at which time dementia drugs should be considered.

2. Preserve. These drugs work by inhibiting the enzymes that break down levadopa or those that break down dopamine.

Drugs like Comtess (entacapone) inhibit the enzyme, catechol O-methyltransferase (COMT). They act much like carbadopa to reduce the breakdown of levodopa before it becomes dopamine. This allows more dopamine to be manufactured and released into the system. This drug might be used to assist the action of carbadopa.

Drugs like Azilect (rasagiline) inhibit the enzyme Monoamine-oxidase B (MOAB). This decreases the breakdown of dopamine after it is manufactured. They are often used as an adjunct to Sinemet. They can greatly improve and smooth out the functioning of Sinemet.

Cognitive issues. As with Sinemet, these drugs will tip the DO/ACh balance and appear to decrease the level of ACh. They often work well until the disorder progresses into the cognitive areas of the brain, at which time cognitive symptoms can appear or increase. The MOAB inhibitors tend to cause fewer problems than the COMT inhibitors.

3. Mimic. These drugs are dopamine agonists (chemicals that act like another chemical.)

Drugs like Requip (ropinrole) mimic the action of dopamine and allows better control of PD symptoms. This drug can be used alone in early PD or as an adjunct to Sinemet as it begins to show fluctuations in effectiveness.

Cognitive issues. As the disorder progresses in the cognitive areas of the brain, these drugs tend to increase dementia symptoms but the effect is seldom permanent. Symptoms disappear when the drig is stopped.

4. Balance. These drugs change DO/ACh balance ratio by decreasing acetycholine. They are called anticholinergics. LBD caregivers learn early on to avoid all anticholinergics because they trigger LBD drug sensitivity symptoms, where a drug acts adversely or as an overdose.

Artane (disipal) has been used with PD to increase the ratio of dopamine to ACh. These drugs are not used much anymore because they cause too many side effects.

Cognitive issues. The direct reduction of ACh by these drugs is the most likely of all to cause cognitive problems and to cause them earlier than other PD drugs do.

The bottom line is that for any PD drug to work, it must in some fashion change the DO/ACh balance ratio so that there is, or there appears to be, more dopamine in the system—and thus, less ACh. This process usually works work well until there is cognitive involvement. Then the lack of (or apparent lack of) ACh causes an increased loss of cognitive functioning. The good news is that this drug related loss lasts only as long as the drugs are in the body. At this point, doctors work to help their patients balance mobility with cognition. For instance, benign hallucinations might be tolerated for better mobility, but scary ones might justify fewer PD drugs even though mobility will be greatly decreased.

Family Caregiver Alliance Fact Sheet: Parkinson’s Drug Therapy & Drug Research.

Klein JC, et al. (2010) Neurotransmitter changes in dementia with Lewy bodies and Parkinson disease dementia in vivo. Neurology. 2010 Mar 16;74(11):885-92.

For information about Lewy body disorders, read our books:

A Caregivers’ Guide to Lewy Body Dementia

Managing Cognitive Issues in Parkinson’s & Lewy Body Dementia

Helen and James Whitworth are not doctors. As informed caregivers, they share the information here for educational purposes only. It should never be used instead of a physician's advice.

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