Tolcapone

♦ Another predominantly peripherally acting COMT inhibitor, indicated for wearing off symptoms of PD.

♦ Available in two doses: 100 mg and 200 mg (USA only).

♦ It has a longer half-life than entacapone and is recommended to be taken no more than three times daily.

♦ May also cause diarrhoea generally after 1 month often requiring discontinuation of the drug. There have been three reported cases of acute liver failure potentially associated with tolcapone use. Therefore, frequent monitoring of liver function tests for 6 months and regularly thereafter is needed. This liver function monitoring is a requirement of the medicine regulators.

62 Dopamine agonists. Several oral and one subcutaneous agent are available, with different properties; apomorphine, for example, has the shortest half-life and cabergoline has the longest. Most involve hepatic metabolism.

Dopamine agonists

Dopamine agonists (DAs) can be used as monotherapy in early disease or as an adjunct in later disease.

DAs have a direct action on postsynaptic dopamine receptors. There are several different postsynaptic dopamine receptors (see 16). D1, D2, and D3 are the principal subtypes. Further details of dopamine receptor types and affinities are described in Chapter 1. As DAs vary in their receptor affinity, switching between agents may be clinically advantageous. Several DAs are available with varying properties (summarized in 62). However, the US Food and Daig Administration (FDA) has withdrawn pergolide because of its potential to cause fibrosis of the heart valves.

62 Dopamine agonists. Several oral and one subcutaneous agent are available, with different properties; apomorphine, for example, has the shortest half-life and cabergoline has the longest. Most involve hepatic metabolism.

Pharmacokinetic properties of dopamine agonists

PREPARATION

ABSORPTION

TIME TO MAXIMUM PLASMA

CONCENTRATION

BIOAVAILABILITY

ELIMINATION HALF-LIFE

CLEARANCE

Apomorphine (subcutaneous)

Very rapid

4-12 min

100%

33 mins

Extra-hepatic

Bromocriptine

Rapid

1-3 hr

6%

15 hr*

Hepatic

Cabergoline (Europe)

Rapid

0.5-4 hr

50-80%

63-68 hr#

Hepatic

Lisuride (Europe)

Rapid

0.2-1.2 hr

10-20%

1.3-2.5 hr

Hepatic

Pergolide (Europe)

55% absorbed

1-3 hr

20-60%

27 hr

Hepatic

Pramipexole

Rapid

1-3 hr

90%

8-12 hr+

Renal

Ropinirole

Rapid

1.5 hr

50%

6 hr

Hepatic

* Bromocriptine plasma elimination half-life is 3-4 hr for the parent drug and 50 hr for the inactive metabolites. The elimination of parent drug from plasma occurs biphasically with a terminal half-life of about 15 hr.

# In healthy volunteers.

+ 8 hr in the young to 12 hr in the elderly.

Note: Pergolide is withdrawn in USA; pergolide and cabergoline second-line in Europe.

When changing from one DA to another, overnight switching is usually effective if equivalent doses are used (63). Although less potent and subject to more side-effects than levodopa (see 13), DAs have been proven in several trials to reduce and delay motor fluctuations, and delay the need to start levodopa. They are commonly used early as monotherapy, particularly in younger patients who are at higher risk of developing motor fluctuations. DAs can be broadly divided according to the presence of an ergot ring: ergot-based agonists (bromocriptine, pergolide, cabergoline, and lisuride) and non-ergot compounds (apomor-phine, pramipexole, and ropinirole). Adverse effects occur as a class effect, the most common being nausea, dizziness, ankle swelling, confusion, hallucinations, and psychosis. O Adverse effects can be minimized by low initial doses and slow titration. Ropinirole has a starter pack which eases this process. O Idiosyncratic side-effects are reported more commonly with DAs then other PD medications and may include weight gain, compulsive behaviour, hypersexuality, and compulsive gambling. They have also been associated with excessive or sudden-onset sleepiness.

63 Dopamine agonist conversion chart.

O Domperidone 10-20 mg three times daily helps to lessen nausea, dizziness, and postural hypotension (Europe). O Ergot adverse effects (64) include pulmonary, pericardial, and retroperitoneal fibrosis and are reported for the ergot-based agonists. However, the site of action may be the 5-hydroxytryptamine 2B (5-HT2B) serotonin receptor rather than simply the presence of an ergot ring, as the ergot-derived DA lisuride does not cause fibrotic reactions and has a very low affinity for this receptor (65). O Fibrotic heart valve changes detected on echocardiography (particularly the tricuspid valve) are reported in patients treated with pergolide and cabergoline. Monitoring of symptoms (in particular breathlessness), blood tests (erythrocyte sedimentation rate (ESR) and creatinine), chest X-ray, pulmonary function tests, and echocardiogram are recommended for patients taking these preparations long term. Pergolide has been withdrawn in the USA, and cabergoline and other ergot-derived DAs are considered second-line agents because of the issues over fibrotic complications.

♦ The transdermal agent rotigotine and CR ropini-role prolonged release are newer options. Both may reduce fluctuations by long duration of action.

Dopamine agonists: approximate dose equivalents

BROMOCRIPTINE

CABERGOLINE

SALT BASE

ROPINIROLE

1 mg tid

0.5 mg od

0.125 mg tid

0.125 mg tid 0.088 mg tid

Starter pack then 1 mg tid

2.5 mg tid

1 mg od

0.25 mg tid

0.25 mg tid 0.18 mg tid

1 mg tid

5 mg tid

2 mg od

0.5 mg tid

0.5 mg tid 0.36 mg tid

2 mg tid

7.5 mg tid

3 mg od*

0.75 mg tid

0.75 mg tid 0.54 mg tid

3 mg tid

10 mg tid

4 mg od

1 mg tid

1 mg tid 0.7 mg tid

4 mg tid

12.5 mg tid

5 mg od

1.25mg tid

1.25mg tid 0.88 mg tid

6mg tid

15 mg tid

6 mg od

1.5 mg tid

1.5 mg tid 1.05 mg tid**

8mg tid

*Cabergoline maximum dose is now 3mg per day **or 1.06mg if using 0.7 mg tablet + 2 x 0.18 mg tablets

Note: Pergolide is withdrawn in the USA; pergolide and cabergoline second-line in Europe.

Longest half-life (36 hours) — The 'original' DA - from 1974 — Strong link to fibrotic reactions — Used less commonly —

DOPAMINE AGONISTS Ergot Non-ergot

Cabergoline Pramipexole Bromocriptine Ropinirole Pergolide Apomorphine Lisuride Rotigotine

— D3 activity may give antidepressant effect

— Prolonged-release once-daily available —Administered subcutaneously

— Transdermal patch

64 Dopamine agonists: ergot and non-ergot.The broad division of DAs into ergot and non-ergot drugs and some key clinical features are shown.

65 The 5-HT2B receptor and fibrotic complications.

Activity of several ergot-based DAs at the 5-HT2B serotonin receptor is considered important in the development of cardiac valve abnormalities and other fibrotic complications. Although lisuride is an ergot-derived DA, it does not have agonist activity at the 5-HT2B receptor and this is likely to be the reason that it has not been associated with such complications.

Bromocriptine

Partial agonist

Pergolide, cabergoline

Potent full agonists

Lisuride

Antagonist; not linked to valvulopathy

Pergolide, cabergoline

Potent full agonists

Lisuride

Antagonist; not linked to valvulopathy

Myofibroblast mitogenesis

Excess activity

Excess activity

Apomorphine is a DA which undergoes extensive first-pass metabolism and has to be administered parenterally. It can be given as a continuous waking day subcutaneous infusion (available in this form in Europe) or by bolus subcutaneous injections as needed as a 'rescue' therapy for wearing off. Currently, it is reserved for patients with advanced disease and significant motor fluctuations. Tire continuous delivery system smooths out off periods and dyskinesias, but may take a few weeks to reach a new 'steady state'. Oral DAs can usually be discontinued (sometimes a pre-bedtime single oral dose is given, as the infusion is usually discontinued overnight). A few patients have moved on to 24-hr infusions, and tolerance is not problematic. Oral drugs can often be reduced (gradually) and some patients successfully convert to apomorphine monotherapy in the daytime (but with overnight levodopa). For intermittent injections, efficacy is often felt within 10-20 minutes but lasts usually only for 1-1.5 hr. An extended outpatient/day case titration visit is often required to determine the optimal tolerated dose (see Chapter 8). Premedication with domperidone (available in Europe) for 3 days or trimethobenzamide 3-7 days prior to initiation is required to minimize GI side-effects.

Rotigotine is a non-ergot D3/D2/D1 DA delivered transdermally over a 24-hr period. O It is approved for the symptomatic treatment of early idiopathic PD (Europe and USA) and as an adjunct in later disease (Europe only). O It is supplied as 2, 4, and 8 mg patches. The recommended starting dose is 2 mg/24 hr. This may be increased by 2 mg/24 hr every week until therapeutic response in achieved. The recommended top dose is 16 mg/24 hr. O Aside from skin reactions, its side-effects are similar to those of other DAs: nausea, somnolence, and lower extremity oedema.

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