Apomorphine

The Food and Drug Administration (FDA) approved apomorphine, a nonergoline dopamine agonist, as a subcutaneously injected treatment for severe off episodes in 2004. It was first used in the 1930s as an emetic and was found to have benefit for PD over 50 years ago. Although the mechanism of action is unclear, it is thought that apomorphine ameliorates symptoms of PD by stimulating D2 receptors within the caudate nucleus and putamen. It has a high affinity for D4 receptors; moderate affinity for D2, D3, and D5; moderate affinity for adrenergic receptors; and low affinity for D1 and 5-hydroxytryptamine (5-HT) receptors (Table 1). In addition to the FDA-approved formulation administered subcutaneously, it has also been administered as an intravenous infusion, intranasal spray, sublingual tablet, and as a rectal suppository (8). Although intravenous administration of apomorphine results in consistent motor control, allowing for a reduction in oral medications, unanticipated intravascular thrombotic complications, secondary to apomorphine crystal accumulation, have led to termination of this route of administration (9). Subcutaneously administered apomorphine has a rapid onset of 7.3 to 14 minutes after administration and a short half-life of 45 to 90 minutes. The rate of uptake after apomorphine injection is influenced by factors such as location, temperature, depth of injection, and body fat. Plasma protein binding of apomorphine is approximately 30%, and its metabolism is unclear (Table 2) (10).

Apomorphine may be given subcutaneously every two hours. A test dose of 2 mg is administered to determine the initial dosing, and may be titrated to an effective dosage by 1 mg increments up to a maximum single exposure of 6 mg (11). There are limited data for dosing over five times per day, and at this dosing frequency, continuous subcutaneous infusion should be considered. Side effects of apomorphine include nausea, vomiting, QT-interval prolongation on EKG, and hypotension. Because of the powerful emetic action of apomorphine, treatment is initiated three

TABLE 2 Dopamine Agonists in Parkinson's Disease

Dopamine agonist

t1/2

Metabolism

N

S

H

OH

RPF

Bromocriptine

3-8 hr

Hepatic

37

8

12

44

2-5%

Pergolide

27 hr

Hepatic

24

6

14

2

2-5%

Pramipexole

8-12 hr

Renal

18

13

19

16

0

Ropinirole

4-6 hr

Hepatic

20

12

15

17

0

Apomorphine

40 min

Unclear

30

35

10

20

0

Abbreviations: H, hallucinations;N, nausea; OH, orthostatic hypotension; RPF, retroperitoneal or pulmonary fibrosis; S, somnolence.

Source: From Ref. 1. Additional data are collected from published package inserts.

Abbreviations: H, hallucinations;N, nausea; OH, orthostatic hypotension; RPF, retroperitoneal or pulmonary fibrosis; S, somnolence.

Source: From Ref. 1. Additional data are collected from published package inserts.

days after beginning antiemetic agents—domperidone or trimethobenzamide (12). Apomorphine should not be administered with antiemetic serotonin type 3 receptor (5HT3) antagonists, such as ondansetron, granisetron, dolasetron, and palonosetron, because of the risks of severe hypotension and syncope. QT-interval prolongation has been found to be insignificant with doses less than 6 mg.

Dewey et al. (13) demonstrated a 62% improvement in off-state UPDRS scores in subjects with advanced PD, 20 minutes after administering apomorphine in a 2:1 randomized, placebo-controlled trial. Subcutaneously administered apomorphine was also shown to be effective in 30 patients for up to five years of therapy (14).

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