Dopamine agonists Apomorphine

Rescue with a dopamine agonist (apomorphine) given with domperidone or trimethobenzamide... 

Cory-Slechta DA, McKoy L, Richfield EK. 1997c. Time course and regional basis of Pb-induced changes in MK-801 binding Reversal by chronic treatment with the dopamine agonist apomorphine but not the D1 agonist SKF-82958. J Neurochem 68 2012-2023. 

Apomorphine is a nonergot dopamine agonist given as a subcutaneous rescue injection. For patients with advanced PD with intermittent off episodes despite optimized therapy, subcutaneous apomorphine triggers an on response within 20 minutes, and duration of effect is up to 100 minutes. Most patients require 0.06 mg/kg. Prior to injection, patients should be premedicated with the antiemetic trimethobenzamide. It is contraindicated with the serotonin-3-receptor blockers (e.g., ondansetron). 

Apomorphine hydrochloride (44 Apokyn Bertek, 2004), is a semisynthetic derivative of opium alkaloid morphine (43) isolated from poppy (Papaver somniferum), and it has long been known for its erectile activity at the effective dose of 2-6 mg physicians discovered the effect over 100 years ago, but found the drug, at a much higher dose (ca. 200 mg), to be more suitable for poison victims as an emetic because it also causes serious nausea and vomiting. Apomorphine exerts its erectile effect at the central nervous system the drug has been found to be a non-selective dopamine agonist which activates both Di-like and D2-like... 

Pharmacokinetics Non-ergot dopamine agonists are rapidly absorbed. The absolute bioavailability is more than 90%. Steady-state concentrations are achieved within 2 days of dosing. Terminal half-life is about 8 hours (about 40 minutes for apomorphine) in young healthy volunteers and about 12 hours in elderly volunteers. Urinary excretion is the major route of elimination. 

There are also other non-monoaminergic alkaloids in some sacred plants which enhance catecholaminergic function. The white and blue water lilies, Nymphaea ampla and caerulea were employed as hallucinogens in both the Old and New worlds. These species contain apomorphine (an opiate with dopamine agonist activity), together with nuciferine and nornuciferine. 

Repeated ECS enhances apomorphine and other dopamine agonist-induced hyperactivity and stereotypy [Grahame-Smith et al. 1978 A. R. Green 1984 Modigh 1989]. Although apomorphine-stimulated behavior is not a face valid model for depression, ECS sensitizes apomorphine-stimulated behavior very... 

There is no evidence that one agonist is superior to another individual patients, however, may respond to one but not another of these agents. Apomorphine is a potent dopamine agonist but is discussed separately in a later section in this chapter because it is used primarily as a rescue drug for patients with disabling response fluctuations to levodopa. 

Subcutaneous injection of apomorphine hydrochloride (Apokyn), a potent dopamine agonist, is effective for the temporary relief ("rescue") of off-periods of akinesia in patients on optimized dopaminergic therapy. It is rapidly taken up in the blood and then the brain, leading to clinical benefit that begins within about 10 minutes of injection and persists for up to 2 hours. The optimal dose is identified by administering increasing test doses until adequate benefit is achieved or a maximum of 10 mg is reached. Most patients require a dose of 3-6 mg, and this should be given no more than about three times daily. 

Dopamine - low doses of the dopamine agonist apomorphine increase slow-wave sleep and, like other dopaminometics, cause somnolence in patients with Parkinson s disease. Conversely, dopamine autoreceptor antagonists, which enhance dopamine release, reduce both REM and non-REM sleep. Stimulants such as cocaine cause arousal by activating D2 postsynaptic receptors, effects which are blocked by most neuroleptics. 

Smokers who have been abstinent for several weeks, or those who smoke for the first time, often experience nausea even at low blood nicotine concentrations. This aversive effect is due to the action of the drug on the chemoreceptor trigger zone whereby it indirectly activates the release of dopamine. Apomorphine and related dopamine agonists also cause nausea by activating the dopaminergic system in this brain region. 

Other applications for dopamine agonists. The traditional use of apomorphine as an emetic stems from its dopaminomimetic actions in the brainstem. This mechanism of action has been identified retrospectively, since apomorphine was employed to induce vomiting long before it was known to be a DA agonist. 

More recently, we initiated a series of experiments to test the activity of new derivatives of apomorphine, some of which had been classified as dopamine agonists or antagonists (40-45). Pretreatment of rats with 50 or 100 ug/100 g body weight of (-)N-n-propylnorapomorphine (NPA) or the prodrug (-)... 

The synthesis of a number of radiolabelled apomorphine derivatives has been described.59-62 A full paper has appeared on the preparation of (—)-2,10,11-trihydroxy-/V-(n-propyl)noraporphine, a dopaminergic compound with anticonvulsant activity.63 The potential dopamine-inhibiting properties of (—)-N-(2-chloroethyl)norapomorphine and related compounds have been assessed. A-Chloroethylation in the aporphine series can abolish dopamine agonist action, and can confer a long-lasting dopamine antagonist potential.64... 

Dopamine agonists include bromocriptine, cabergoline, lysuride, pergolide, apomorphine, pramipexole and ropinirole. These drugs are not converted into dopamine but have a direct effect on dopamine receptors in the brain. Dopamine agonists are used both as adjuncts to co-careldopa and co-beneldopa therapy and also initially in early Parkinson s disease, especially in younger adults. 

Dopamine agonists are used in newly diagnosed patients but also have a place in the treatment of more advanced disease. Apomorphine is only used in advanced disease. 

Apomorphine is a potent dopamine agonist, which is sometimes useful in advanced Parkinson s disease for patients with severe unpredictable off periods on treatment. It is only available as a subcutaneous injection or infusion and thus requires significant patient and/or carer involvement in treatment. It is highly emetogenic so patients must receive domperidone, starting at least 2 days before apomorphine treatment. 

These marked changes in sensitivity of the system not only define the asymptotic level of recovery but may also contribute to some of the marked side effects of treatment associated with advanced denervation in animals or advanced disease in man. In PD patients, as the disease (and the level of underlying degeneration) advances, so also the window of effective response to l-DOPA narrows between doses where the drug has no effect, and doses at which it induces abnormal dyskinesia but then wears off rapidly (Marsden and Parkes, 1977). Similarly in experimental animals with extensive bilateral dopamine denervation, treatment with the dopamine agonist apomorphine can substantially alleviate the profound impairment in drinking in the few days after the... 

Fray PJ, Sahakian BJ, Robbins TW, Koob GF, Iversen SD (1980) An observational method for quantifying the behavioural effects of dopamine agonists contrasting effects of d-amphetamine and apomorphine. 

---