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Apomorphine, sold under the brand name Apokyn among others, is a type of aporphine having activity as a non-selective dopamine agonist which activates both D2-like and, to a much lesser extent, D1-like receptors. It also acts as an antagonist of 5-HT2 and α-adrenergic receptors with high affinity. The compound is an alkaloid belonging to nymphaea caerulea, or blue lotus, but is also historically known as a morphine decomposition product made by boiling morphine with concentrated acid, hence the -morphine suffix. Contrary to its name, apomorphine does not actually contain morphine or its skeleton, nor does it bind to . The apo- prefix relates to it being a morphine derivative ("comes from morphine").
Historically, apomorphine has been tried for a variety of uses, including as a way to relieve anxiety and craving in alcoholics, an emetic (to induce vomiting), for treating stereotypies (repeated behaviour) in farmyard animals, and more recently in treating erectile dysfunction. Currently, apomorphine is used in the treatment of Parkinson's disease. It is a potent emetic and should not be administered without an antiemetic such as domperidone. The emetic properties of apomorphine are exploited in veterinary medicine to induce therapeutic emesis in canines that have recently ingested toxic or foreign substances.
Apomorphine was also used as a private treatment of heroin addiction, a purpose for which it was championed by the author William S. Burroughs. Burroughs and others claimed that it was a "metabolic regulator" with a restorative dimension to a damaged or dysfunctional dopaminergic system. Despite anecdotal evidence that this offers a plausible route to an abstinence-based mode, no clinical trials have ever tested this hypothesis. A recent study indicates that apomorphine might be a suitable marker for assessing central dopamine system alterations associated with chronic heroin consumption. There is, however, no clinical evidence that apomorphine is an effective and safe treatment regimen for opiate addiction.
IV administration of apomorphine is highly discouraged, as it can crystallize in the veins and create a blood clot (thrombus) and block a pulmonary artery (pulmonary embolism).
Other side effects include orthostatic hypotension and resultant fainting, sleepiness, dizziness, runny nose, sweating, paleness, and flushing. More serious side effects include dyskinesias (especially when taking L-DOPA), fluid accumulation in the limbs (edema), suddenly falling asleep, confusion and hallucinations, increased heart rate and heart palpitations, and persistent erections (priapism). The priapism is caused by apomorphine increasing arterial blood supply to the penis. This side effect has been exploited in studies attempting to treat erectile dysfunction.
Apomorphine improves motor function by activating dopamine receptors in the nigrostriatal pathway, the limbic system, the hypothalamus, and the pituitary gland. It also increases blood flow to the supplementary motor area and to the dorsolateral prefrontal cortex (stimulation of which has been found to reduce the tardive dyskinesia effects of L-DOPA). Parkinson's has also been found to have excess iron at the sites of neurodegeneration; both the ( R)- and ( S)-enantiomers of apomorphine are potent iron Chelation and radical scavengers.
Apomorphine also decreases the breakdown of dopamine in the brain (though it inhibits its synthesis as well). It is an upregulator of certain neural growth factors, in particular NGF but not BDNF, epigenetic downregulation of which has been associated with addictive behaviour in rats.
Apomorphine causes vomiting by acting on dopamine receptors in the chemoreceptor trigger zone of the medulla; this activates the nearby vomiting center.
Apomorphine possesses affinity for the following receptors (note that a higher Ki indicates a lower affinity): Note: Values for humans are used. If there is more than one value listed for humans, their average is used.
| + Serotonin ! Receptor !! Ki (nM) !Action | ||
| 2,523 | partial agonist | |
| 2,951 | no action | |
| 5-HT1D | 1,230 | no action |
| 5-HT2A | 120 | antagonist |
| 5-HT2B | 132 | antagonist |
| 5-HT2C | 102 | antagonist |
| + Norepinephrine/Epinephrine ! Receptor !! Ki (nM) !Action | ||
| 1,995 | antagonist | |
| 676 | antagonist | |
| α1D-adrenergic | 64.6 | antagonist |
| α2A-adrenergic | 141 | antagonist |
| α2B-adrenergic | 66.1 | antagonist |
| α2C-adrenergic | 36.3 | antagonist |
It has a Ki of over 10,000 nM (and thus negligible affinity) for β-adrenergic, H1, and mACh.
Apomorphine has a high clearance rate (3–5 L/kg/hr) and is mainly metabolized and excreted by the liver. It is likely that while the cytochrome P450 system plays a minor role, most of apomorphine's metabolism happens via auto-oxidation, Glucuronidation, Methylation, N-demethylation, and sulfation. Only 3–4% of the apomorphine is excreted unchanged and into the urine. The half-life is 30–60 minutes, and the effects of the injection last for up to 90 minutes.
Toxicity depends on the route of administration; the LD50s in mice were 300 mg/kg for the oral route, 160 mg/kg for intraperitoneal, and 56 mg/kg intravenous. (2025). 9780471476627, Wiley, John & Sons, Incorporated. ISBN 9780471476627
The modern medical history of apomorphine begins with its synthesis by Arppe in 1845 from morphine and sulfuric acid, although it was named sulphomorphide at first. Matthiesen and Wright (1869) used hydrochloric acid instead of sulfuric acid in the process, naming the resulting compound apomorphine. Initial interest in the compound was as an emetic, tested and confirmed safe by London doctor Samuel Gee, and for the treatment of stereotypies in farmyard animals. Key to the use of apomorphine as a behavioural modifier was the research of Erich Harnack, whose experiments in rabbits (which do not vomit) demonstrated that apomorphine had powerful effects on the activity of rabbits, inducing licking, gnawing and in very high doses convulsions and death.
In the 1950s the neurotransmitter dopamine was discovered in the brain by Katharine Montagu, and characterised as a neurotransmitter a year later by Arvid Carlsson, for which he would be awarded the Nobel Prize. A. N. Ernst then discovered in 1965 that apomorphine was a powerful stimulant of dopamine receptors. This, along with the use of sublingual apomorphine tablets, led to a renewed interest in the use of apomorphine as a treatment for alcoholism. A series of studies of non-emetic apomorphine in the treatment of alcoholism were published, with mostly positive results. However, there was little clinical consequence.
In the UK, however, the publication of J. Y. Dent's (who later went on to treat Burroughs) 1934 paper "Apomorphine in the treatment of Anxiety States" laid out the main method by which apomorphine would be used to treat alcoholism in Britain. His method in that paper is clearly influenced by the then-novel idea of aversion:However, even in 1934 he was suspicious of the idea that the treatment was pure conditioned reflex – "though vomiting is one of the ways that apomorphine relives the patient, I do not believe it to be its main therapeutic effect." – and by 1948 he wrote:This led to his development of lower-dose and non-aversive methods, which would inspire a positive trial of his method in Switzerland by Dr Harry Feldmann.
Despite his claims throughout his life, Burroughs never really cured his addiction and was back to using opiates within years of his apomorphine "cure", nonetheless insisting on apomorphine's effectiveness in several works and interviews.
There is renewed interest in the use of apomorphine to treat addiction, in both smoking cessation and alcoholism. As the drug is known to be reasonably safe for use in humans, it is a viable target for repurposing.
Apomorphine has been researched as a possible treatment for erectile dysfunction and female hypoactive sexual desire disorder, though its efficacy has been limited.
One of the reasons apomorphine is a preferred drug is its reversibility: in cases of prolonged vomiting, the apomorphine can be reversed with dopamine antagonists like the phenothiazines (for example, acepromazine). Giving apomorphine after giving acepromazine, however, will no longer stimulate vomiting, because apomorphine's target receptors are already occupied.
Apomorphine does not work in cats, who have too few dopamine receptors.
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