Pharmacology Drug Therapy Of Parkinson's Disease Ve-Vi

Front 1

What does COMT do?

Back 1

When decarboxylation of levodopa is inhibited (using carbidopa to block AAAD), the predominant pathway of levodopa metabolism in the periphery is by COMT to yield 3-OMD

Front 2

How do COMT inhibitors work?

Back 2

COMT inhibitors block this conversion of levodopa to 3-OMD and thus prevent this “metabolic loss” of the drug, allowing more to cross the BBB. Entacapone is only peripherally active, whereas tolcapone acts on both peripheral and central COMT. These drugs are selective and reversible inhibitors of COMT.

Front 3

How are COMT inhibitors used in PD treatment?

Back 3

These drugs are not used in the initial treatment of PD. Rather, they are used in the management of the motor complications that develop after prolonged levodopa therapy, “wearing off” and levodopa-induced dyskinesias

Front 4

Why is entacapone used more than tolcapone?

Back 4

Because tolcapone has been associated with rare but serious hepatotocity

Front 5

Describe the absorption, half-life, and metabolism of entacapone.

Back 5

Entacapone is rapidly absorbed, and has a half-life in plasma of ~ 2 hrs. It is essentially 100% protein bound, and is metabolized by the liver.

Front 6

Describe the use of levodopa and entacapone together

Back 6

Because of its short half-life, it is typically administered together with each dose of levodopa when it is used for the complication of wearing off.

When entacapone is given together with levodopa, the plasma half-life of levodopa is increased, and the bioavailability of levodopa is approximately doubled. Inhibition of COMT leads to an increase in the area under the levodopa plasma concentration x time curve, but without significantly altering Cmax or Tmax. Clinically, this increases the duration of action of a dose of levodopa, without markedly increasing side effects associated with peak dose effects of levodopa, although these can occur.

Front 7

What are the side effects of COMT inhibitors?

Back 7

a. Diarrhea–typically begins after being on the medication for weeks.
b. Discoloration of urine – harmless.
c. Increase in levodopa-related side effects such as dyskinesia, hallucinations and nausea, because of increased levodopa bioavailability. T his is easily treated by decreasing the dosage of levodopa.

Front 8

Describe the use of antimuscarinic drugs in PD

Back 8

Antimuscarinic drugs were used in the treatment of PD prior to the discovery of dopamine and the advent of dopaminergic drugs. However, they are primarily effective only on parkinsonian rest tremor, and do not typically improve rigidity and bradykinesia to a significant degree.

Front 9

How are antimuscarinic drugs currently used in PD treatment

Back 9

Thus, in current clinical practice they are not commonly used for the treatment of PD except for the occasional patient with isolated rest tremor.

Front 10

What is the mechanism of antimuscarinic drugs in the treatment of PD?

Back 10

The mechanism by which these medications improve PD tremor is not known, although they are believed to act on the cholinergic interneurons present in the striatum.

Front 11

What antimuscarinic drugs are used in PD treatment? What are the side effects?

Back 11

Typically used agents include benztropine and trihexyphenidyl. Side effects of antimuscarinic drugs include urinary retention, dry mouth, constipation and confusion.

Front 12

What is the long duration effect of levodopa? What causes it?

Back 12

When PD patients are initially treated with levodopa, the clinical benefits of the drug do not correspond to plasma concentrations of levodopa; a stable clinical benefit is maintained despite fluctuations in the plasma concentrations of levodopa, and if levodopa is discontinued, it takes many days for the motor improvement to dissipate. Thus although the plasma half-life of levodopa is ~2 hrs, patient derive stable motor improvement taking medication at 8 hour intervals. This effect is called the long duration effect of levodopa, and is believed to result because of a storage compartment for the drug in the brain, presumably the DA nerve terminals. However, the response of post-synaptic receptors may also be important in this response.

Front 13

What is the course of levodopa therapy?

Back 13

Typically 2-4 years

Front 14

Describe "wearing off"

Back 14

The patient will notice a decrement of motor function in between doses of levodopa. In these patients, the motor response now roughly parallels the plasma levels of levodopa; they have lost the long duration effect and now manifest the short duration response. The cause of wearing off is not precisely known, although it is believed to result from the progressive loss of the storage capacity of DA nerve terminals as they degenerate.

Front 15

What is levodopa-induced dyskinesias?

Back 15

These are abnormal involuntary movements that are provoked by levodopa. These abnormal movements often occur as a “peak dose” effect of DA, at a point after a dose of levodopa when the concentration of DA is maximal (i.e., the patient derives improvement in normal motor function in the first hour, but then has a period of abnormal movement as DA concentrations peak, followed by resolution of these abnormal movements as the concentration of DA falls). However, these abnormal responses to levodopa can become far less predictable, and some patients may completely lose the ability to respond normally to levodopa, and instead only show abnormal involuntary movement to the drug.

Front 16

What causes levodopa-induced dyskinesias?

Back 16

These complications appear to result from alterations in the response of post-synaptic DA receptors, although other alterations in the motor circuit are likely also involved. One (unproven) theory holds that the non-physiologic peaks and troughs produced by levodopa administration are themselves involved in the pathogenesis of these motor complications, and this is part of the basis for a “levodopa-sparing” treatment strategy.

Front 17

What is the "levodopa-sparing" treatment strategy?

Back 17

A treatment strategy in which patients are initially treated with DA agonists and levodopa therapy is delayed until absolutely necessary.

Front 18

What strategies are available to treat wearing off effects?

Back 18

This can be treated either by taking smaller doses of levodopa more frequently, or by preventing the degree of DA receptor stimulation to fall below a critical level. The second strategy can be accomplished either by extending the clinical effectiveness of an individual dose of levodopa, for example by using Sinemet-CR, or co-administering a COMT inhibitor or selegeline, or by adding a DA agonist. Because the duration of action for DA agonists is significantly longer than levodopa, they help to maintain the level of DA receptor stimulation above the level required to clinical efficacy, even as plasma levodopa concentrations fall.

Front 19

In practice, what strategy is used to treat wearing off? Why?

Back 19

Preventing the degree of DA receptor stimulation to fall below a critical level.
This is typically used, since:
a) it is practically difficult to take medications more frequently,
b) lower dosages of medication mean that the peak plasma concentration of each dose will be closer to the minimal effective concentration needed for clinical benefit, and small changes in absorption or distribution may lead to failures of individual doses and
c) there is concern that this type of levodopa regimen may further promote the development of the abnormal movements.

Front 20

How do you treat levodopa-induced dyskinesias?

Back 20

This is treated by decreasing the fluctuations in DA concentration that occur with levodopa administration, and decreasing peak concentrations of DA. This may be accomplished by using sinemet-CR, or by using lower doses of levodopa together with DA agonists or COMT inhibitors, to prevent patient from losing clinical efficacy during troughs of levodopa (termed “going off”; patients deriving clinical benefit are said to be “on”). Amantadine is also used to decrease levodopa-induced dyskinesias; the anti-glutamatergic action of amantadine is thought to mediate this effect.