Apomorphine

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 opioid receptors. The apo- prefix relates to it being a morphine derivative.
Historically, apomorphine has been tried for a variety of uses, including as a way to relieve anxiety and craving in alcoholics, an emetic, for treating stereotypies 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.

Medical uses

Parkinson's disease

The use of apomorphine to treat "the shakes" was first suggested by Weil in France in 1884, although seemingly not pursued until 1951. Its clinical use was first reported in 1970 by Cotzias et al., although its emetic properties and short half-life made oral use impractical. A later study found that combining the drug with the antiemetic domperidone improved results significantly. The commercialization of apomorphine for Parkinson's disease followed its successful use in patients with refractory motor fluctuations using intermittent rescue injections and continuous infusions.
Apomorphine is used in advanced Parkinson's disease intermittent hypomobility, where a decreased response to an anti-Parkinson drug such as L-DOPA causes muscle stiffness and loss of muscle control. While apomorphine can be used in combination with L-DOPA, the intention is usually to reduce the L-DOPA dosing, as by this stage the patient often has many of dyskinesias caused by L-DOPA and hypermobility periods. When an episode sets in, the apomorphine is injected subcutaneously or applied sublingually, and signs subside. It is used an average of three times a day. Some people use portable mini-pumps that continuously infuse them with apomorphine, allowing them to stay in the "on" state and using apomorphine as an effective monotherapy.

Contraindications

The main and absolute contraindication to using apomorphine is the concurrent use of adrenergic receptor antagonists; combined, they cause a severe drop in blood pressure and fainting. Alcohol causes an increased frequency of orthostatic hypotension, and can also increase the chances of pneumonia and heart attacks. Dopamine antagonists, by their nature of competing for sites at dopamine receptors, reduce the effectiveness of the agonistic apomorphine.
IV administration of apomorphine is highly discouraged, as it can crystallize in the veins and create a blood clot and block a pulmonary artery.

Side effects

Nausea and vomiting are common side effects when first beginning therapy with apomorphine; antiemetics such as trimethobenzamide or domperidone, dopamine antagonists, are often used while first starting apomorphine. Around 50% of people grow tolerant enough to apomorphine's emetic effects that they can discontinue the antiemetic.
Other side effects include orthostatic hypotension and resultant fainting, sleepiness, dizziness, runny nose, sweating, paleness, and flushing. More serious side effects include dyskinesias, fluid accumulation in the limbs, suddenly falling asleep, confusion and hallucinations, increased heart rate and heart palpitations, and persistent erections. 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.

Pharmacology

Mechanism of action

Apomorphine's R-enantiomer is an agonist of both D₁ and D₂ dopamine receptors, with higher activity at D₂. The members of the D₂ subfamily, consisting of D₂, D₃, and D₄ receptors, are inhibitory G protein–coupled receptors. The D₄ receptor in particular is an important target in the signaling pathway, and is connected to several neurological disorders. Shortage or excess of dopamine can prevent proper function and signaling of these receptors leading to disease states.
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. Parkinson's has also been found to have excess iron at the sites of neurodegeneration; both the - and -enantiomers of apomorphine are potent iron chelators and radical scavengers.
Apomorphine also decreases the breakdown of dopamine in the brain. 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 :

Receptor	K_i	Action
5-HT_1A	2,523	partial agonist
5-HT_1B	2,951	no action
5-HT_1D	1,230	no action
5-HT_2A	120	antagonist
5-HT_2B	132	antagonist
5-HT_2C	102	antagonist

Receptor	K_i	Action
α_1A-adrenergic	1,995	antagonist
α_1B-adrenergic	676	antagonist
α_1D-adrenergic	64.6	antagonist
α_2A-adrenergic	141	antagonist
α_2B-adrenergic	66.1	antagonist
α_2C-adrenergic	36.3	antagonist

It has a K_i of over 10,000 nM for β-adrenergic, H₁, and mACh.
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.

Pharmacokinetics

While apomorphine has lower bioavailability when taken orally, due to not being absorbed well in the GI tract and undergoing heavy first-pass metabolism, it has a bioavailability of 100% when given subcutaneously. It reaches peak plasma concentration in 10–60 minutes. Ten to twenty minutes after that, it reaches its peak concentration in the cerebrospinal fluid. Its lipophilic structure allows it to cross the blood–brain barrier.
Apomorphine has a high clearance rate 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, O-glucuronidation, O-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.

Chemistry

Properties

Apomorphine has a catechol structure similar to that of dopamine.

Synthesis

Several techniques exist for the creation of apomorphine from morphine. In the past, morphine had been combined with hydrochloric acid at high temperatures to achieve a low yield of apomorphine, ranging anywhere from 0.6% to 46%.
More recent techniques create the apomorphine in a similar fashion, by heating it in the presence of any acid that will promote the essential dehydration rearrangement of morphine-type alkaloids, such as phosphoric acid. The method then deviates by including a water scavenger, which is essential to remove the water produced by the reaction that can react with the product and lead to decreased yield. The scavenger can be any reagent that will irreversibly react with water such as phthalic anhydride or titanium chloride. The temperature required for the reaction varies based upon choice of acid and water scavenger. The yield of this reaction is much higher: at least 55%.

Historical medical uses

The pharmacological effects of the naturally occurring analog aporphine in the blue lotus were known to the ancient Egyptians and Mayans, with the plant featuring in tomb frescoes and associated with entheogenic rites. It is also observed in Egyptian erotic cartoons, suggesting that they were aware of its erectogenic properties.
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 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 demonstrated that apomorphine had powerful effects on the activity of rabbits, inducing licking, gnawing and in very high doses convulsions and death.