Pharmacology Drug Therapy Of Parkinson's Disease Va-D

Front 1

Describe the mechanism of action for levodopa

Back 1

Levodopa is the precursor to DA. Decarboxylation of levodopa by aromatic amino acid decarboxylatse (AAAD) yields DA. Levodopa that reaches the brain is converted to DA in dopamine terminals (and likely other cell types), thus correcting the deficiency in striatal dopamine and restoring movement.

Front 2

What is the primary site for levodopa absorption?

Back 2

The proximal small bowel

Front 3

Describe the role of the stomach in levodopa absorption

Back 3

Very little drug is absorbed by the stomach. However, the stomach may play a significant role in levodopa pharmacokinetics.

Front 4

Describe transport of levodopa into cells

Back 4

Levodopa crosses membranes through the large neutral amino acid (LNAA) carrier system. Entry of levodopa from the gut into the plasma, and entry into the brain across the BBB are both mediated by LNAA transport. This carrier system is saturable at concentrations of LNAAs normally found in plasma. Therefore the entry of levodopa into both the plasma and the brain may be significantly inhibited by ingested protein, and in clinical practice the relationship of mealtime to medication may significantly influence the effectiveness of a given dose of drug.

Front 5

Despite the fact that levodopa is well absorbed by the gut, and can easily cross the blood-brain barrier, less than 5% of an oral dose of levodopa is delivered to the brain. Why?

Back 5

The reason for this is that high levels of both AAAD and COMT in the gut wall act as an enzymatic barrier to levodopa; much of the drug is converted in the periphery to DA (which cannot cross the BBB) or the inactive 3-O-methyldopa (3-OMD). Furthermore, the conversion of levodopa to DA in the periphery produces nausea which limits the dosage of the drug that can be taken. This likely occurs from the action of DA at the area postrema, where there is a weak BBB.

Front 6

What is the role of AAAD inhibitors in the treatment of Parkinson's disease?

Back 6

The coadministration of an AAAD inhibitor that does not cross the BBB prevents the conversion of levodopa to dopamine in the periphery. This greatly increases the concentration of prodrug that enters the brain, and the degree of dopamine replacement in hte striatum. The use of AAAD inhibitors permits an approximate four fold reduction of levodopa requires for optimal symptom control. This is the major benefit of AAAD inhibitors; plasma half-life is only modestly prolonged.

Front 7

In the US what AAAD is used with levodopa? In Europe?

Back 7

US: Carbidopa
Europe: Benzserazide

Front 8

What is Sinemet?

Back 8

The combination of levodopa and an carbidopa.

Front 9

What is Sinemet CR?

Back 9

Sinemet is a slow release preparation. The drug is embedded in a matrix that greatly slows release of the drug. This has the effect of smoothing out the pharmacokinetic profile of plasma levodopa and most relevant clinically, increasing the duration of action. This allows the patient to potentially take fewer doses per day and is beneficial in treating the "wearing off" phenomenon.

Front 10

What is the Cmax of levodopa? What is the half-life?

Back 10

The Cmax typically occurs 15-45 min after an oral dose, and this roughly correlates with onset of clinical effect. The plasma half-life is 1-2 hours, but cause of a long duration effect of the dopaminergic drugs, the drug is initially given T.I.D. without any apparent fluctuation in motor response of the patient.

Front 11

To what protein does levodopa bind?

Back 11

Levodopa is not appreciably bound to protein.

Front 12

Describe the side effects of levodopa

Back 12

a) Confusion and somnolence - often in older patients; may be "peak dose" effect that can be controlled
b) Nausea - if troublesome, may treat with supplemental carbidopa or domperidone.
c) Hypotension
d) Hallucinations - treated with an atypical antipsychotic such as clozaril, that does not block D2 receptors and, therefore, does not worsen parkinsonism as do classical neuroleptics.

Front 13

What is domperidone?

Back 13

A dopaminergic antagonist that does not cross the BBB. Thus can act at the area postrema, but does not exacerbate parkinsonism.

Front 14

What receptors bind apomorphine?

Back 14

D1: ++
D2: ++
D3: ++

Front 15

What receptors bind Bromocriptine (Parlodel)?

Back 15

D1: 0
D2: ++
D3: ++

Front 16

What receptors bind cabergoline (Dostinex)?

Back 16

D1: 0
D2: +++
D3: +++

Front 17

What receptors bind pergolide (Permax)?

Back 17

D1: +
D2: ++
D3: +++

Front 18

What receptors bind pramipexole (Mirapex)?

Back 18

D1: 0
D2: ++
D3: ++++

Front 19

What receptors bind ropinirole (Requip)?

Back 19

D1: 0
D2: ++
D3: ++++

Front 20

What are the theoretical advantages of DA agonist therapy over levodopa therapy?

Back 20

First, because the plasma half-life of these agents tends to be significantly longer that levodopa, and is not complicated by issues of metabolic convesion, they should offer a smoother more prolonged pharmacodynamic effect.

Second, directly stimulating DA receptors should eliminate the complications imposed by a (presumably) degenerating population of DA neurons (and pool of AAAD).

Third, some in vitro data esists to suggest that DA agonist might have neuroprotective effects, although this has not been demonstrated in patients.

Front 21

Describe how DA therapy is used clinically

Back 21

Many clinicians use agonist treatment early in disease, when symptoms are milder. However, monotherapy with dopamine agonists is rarely successful for more than three years; after that time patients generally need either the addition or substitution of levodopa, the most efficacious drug for the treatment of the motor symptoms of PD. The other important clinical role for dopamine agonists is in the management of levodopa induced dyskinesias and wearing off.

Front 22

What is the most important site of agonsm for Parkinsons treatment? What drugs bind here?

Back 22

It is generally accepted that the D2 receptor is the most important site of agonism for the observed anti-parkinson effect. All of the DA agonists have significant activity at the D2 receptor.

Front 23

What is used to decide with DA agonist should be used for a patient?

Back 23

This decision is usually based on the side effect profile of the individual patient.

Front 24

What DA agonists are ergot derivatives?

Back 24

Bromocriptine
Cabergoline
Pergolide

Front 25

What DA agonists are non-ergot derivatives?

Back 25

Apomorphine
Pramipexole
Ropinirole

Front 26

What side effects are unique to ergot-derivatives?

Back 26

Ergot-derivatives may produce unique side effect of “St Anthony’s Fire” which is red inflamed skin, particularly in the extremities. This resolves upon discontinuation of the drug. Ergot-derivatives may also very rarely cause retroperitoneal, pericardial or pleuropulmonary fibrosis.

Front 27

What is the typical half-life of DA agonists?

Back 27

They typically have plasma half-lives of 6-8 hours. important a role for the administration of agonists as they do for levodopa. The notable exception is cabergoline, which has an elimination half-life = 65 hours.

Front 28

What role do pharmacokinetic considerations play in administration of DA agonists?

Back 28

In general, pharmacokinetic considerations do not play nearly as important a role for the administration of agonists as they do for levodopa. The notable exception is cabergoline, which has an elimination half-life = 65 hours, allowing single daily dosing.

Front 29

What are the side effects of dopamine agonists?

Back 29

a. Orthostatic Hypotension – tends to occur at onset of therapy. Medications are started slowly and at night (when patient is typically supine).
b. Ankle edema – all DA agonists.
c. Hallucinations – all DA agonists.
d. St. Anthony’s Fire (Ergot derivatives).
e. Nausea.

Front 30

How was amantadine originally used?

Back 30

It was originally used as an antiviral agent, and during that use it was found to improve the symptoms of PD.

Front 31

What is the mechanism of amantadine?

Back 31

Amantadine’s mechanism of action is not well studied. The anti-PD effect of amantadine appears to result from its ability to cause release of DA in an amphetamine-like manner. Amantadine is also a NMDA receptor blocker, and this action is thought to mediate its effectiveness at controlling levodopa-induced dyskinesias. Although amantadine does not appear to be a direct anticholinergic, it may induce anticholinergic-like side effects.

Front 32

Describe the role of amantadine in PD treatment?

Back 32

Amantadine is typically used either early in the course of PD, when symptoms are mild, or as during advanced PD in control of levodopa-induced side effects. During early disease, it may be particularly useful in the control of PD tremor.

Front 33

What is the Cmax of amantadine? What is its half-life?

Back 33

Cmax: 1-4 hours
Plasma t1/2=15-24hr

Front 34

How is amantadine excreted?

Back 34

Excreted almost entirely unchanged in the urine. Dosage must be altered accordingly in renal failure.

Front 35

What is the typical dose of amantadine?

Back 35

100 mg BID or TID

Front 36

What are the side effects of amantadine?

Back 36

The drug is typically well tolerated. Ankle edema and livedo reticularis occur most commonly. Anticholinergic effects (dry mouth, urinary retention, confusion/hallucination) may also occur.

Front 37

Why might MAOIs be important in the treatment of PD?

Back 37

A large body of evidence suggests that excess oxidative stress is a key factor in the pathogenesis of PD. The metabolism of DA normally generates free radicals, and this may be the basis of selective vulnerability of DA neurons observed in PD. Therefore, there has been a great deal of interest in using anitioxidant therapies as neuroprotectants for PD, and MAOI’s have received the greatest attention in this regard.

Front 38

What have studies about selegiline shown?

Back 38

A number of clinical studies have explored whether selegiline, a selective MAOB inhibitor, slows the actual progression of DA neurodegeneration in PD, but these studies have either been inconclusive or not demonstrated any neuroprotective benefit. This may relate to the fact that in the rain, selegiline probably only inhibits MAOB by ~20%.

Front 39

What is selgiline?

Back 39

A selective MAOB inhibitor.

Front 40

What is wrong with MAOA inhibitors?

Back 40

The inhibition of MAOA exposes patients to the potentially fatal side effect known as the "cheese effect", caused by tyramine.

Front 41

What is the cheese effect?

Back 41

Tyramine, an amino acid found in a number of foods and metabolized by MAOA in the gut, is an indirect sympathomimetic that produces release of norepinephrine from sympathetic nerve terminals and epinephrine from the adrenal medulla. Tyramine acts by being taken up into nerve terminals and synaptic vesicles, displacing active neurotransmitters. Patients on non-selective MAO inhibitors that ingest tyramine-containing foods may develop severe hypertension leading to cardiac failure or intracerebral hemorrhage. Therefore, patients on non-selective MAO inhibitors must adhere to strict dietary restriction of tyramine-containing foods, including (but not limited to) alcohol (esp. chianti wine), banana peels, broad beans (i.e., fava), cheese, fish (esp. if smoked, fermented or pickled), sausage, pepperoni, salami, sauerkraut, shrimp paste and brewers yeast.

Front 42

What drug-drug interactions must be avoided with MAOA inhibitors?

Back 42

Patients on MAOA inhibitors must also avoid levodopa, meperidine (Demerol), and tricyclic and SSRI antidepressants.

Front 43

What are non-selective MAO inhibitors used for?

Back 43

The non-selective MAO inhibitors are sometimes used by neurologists specializing in the treatment of PD, and are also sometimes used as antidepressants. Non-selective agents used nclude phenelzine (Nardil) and tranylcypromine (Parnate).

Front 44

How does selegeline inhibit MAOB?

Back 44

Selegeline inhibits MAOB irreversibly by acting as a suicide substrate for the enzyme

Front 45

What effect does selegeline have on PD?

Back 45

Selegeline produces a mild symptomatic benefit of the motor symptoms of PD.

Front 46

Where is MAOB predominantly localized?

Back 46

In glia

Front 47

What is responsible for the clinical efficacy of selegeline?

Back 47

The metabolism of eldepryl to methamphetamine

Front 48

Where is selegeline absorbed?

Back 48

In the GI tract

Front 49

Does selegeline cross the BBB?

Back 49

Yes. it is highly lipophilic, so it rapidly entes the brain.

Front 50

How is selegiline metabolized? How is it excreted?

Back 50

Selegiline is metabolized to L-amphetamine and L-methamphetamine, predominantly in the liver, and these metabolites also enter the brain. All metabolites are excreted via urine.

Front 51

What is the typical dosage of selegiline?

Back 51

5-10 mg/day. Higher doses should not be used as they will lead to concentrations that produce non-selective inhibition of MAO.

Front 52

What are the side effects of selegiline?

Back 52

a. Nightmares and insomnia. Generally by limiting the dosage to a single dose given in the morning.
b. Impotence.
c. Worsening of levodopa-induced dyskinesias.