apomorphine 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 historically 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 (" from morphine"). not to be confused with aporphine or morphine. apomorphineclinical datatrade namesapokyn, kynmobiahfs/drugs.commonographmedlineplusa604020license data us dailymed: apomorphine pregnancycategory au: b3 routes ofadministrationsubcutaneous injection (sq), sublingualatc codeg04be07 (who) n04bc07 (who) qv03ab95 (who)legal statuslegal status au: s4 (prescription only) ca: ℞-only uk: pom (prescription only) us: ℞-only in general: ℞ (prescription only) pharmacokinetic databioavailability100% following injectionprotein binding~50%metabolismliver, phase iionset of action10–20 minelimination half-life40 minutesduration of action60–90 minexcretionliveridentifiers iupac name (6ar)-6-methyl-5,6,6a,7-tetrahydro-4h-dibenzoquinoline-10,11-diol cas number58-00-4 yhcl: 41372-20-7 ypubchem cid6005iuphar/bps33drugbankdb00714 ychemspider5783 yuniin21far7b4shcl: f39049y068 ykeggd07460 ychebichebi:48538 ychemblchembl53 ncomptox dashboard (epa)dtxsid8022614 echa infocard100.000.327 chemical and physical dataformulac17h17no2molar mass267.328 g·mol−13d model (jsmol)interactive image smiles oc1=c(o)c(c2=cc=cc3=c2(c4)n(c)cc3)=c4c=c1 inchi inchi=1s/c17h17no2/c1-18-8-7-10-3-2-4-12-15(10)13(18)9-11-5-6-14(19)17(20)16(11)12/h2-6,13,19-20h,7-9h2,1h3/t13-/m1/s1 ykey:vmwnqduvqkeioc-cybmujfwsa-n y data pageapomorphine (data page) ny (what is this?) (verify) 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. medical uses apomorphine is used in advanced parkinson's disease intermittent hypomobility ("off" episodes), 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 (a sudden drop in blood pressure when getting up), 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 (thrombus) and block a pulmonary artery (pulmonary embolism). 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 (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. 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 (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 chelators 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. 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 possesses affinity for the following receptors (note that a higher ki indicates a lower affinity): dopamine receptorki (nm) action d1484 (partial) agonista d252 partial agonist (ia = 79% at d2s; 53% at d2l) d3 26 partial agonist (ia = 82%) d4 4.37 partial agonist (ia = 45%) d5 188.9 (partial) agonista athough its efficacies at d1 and d5 are unclear, it is known to act as an agonist at these sites. serotonin receptorki (nm) action 5-ht1a2,523 partial agonist 5-ht1b2,951 no action 5-ht1d 1,230 no action 5-ht2a 120 antagonist 5-ht2b 132 antagonist 5-ht2c 102 antagonist norepinephrine/epinephrine receptorki (nm) action α1a-adrenergic1,995 antagonist α1b-adrenergic676 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, 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. 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. 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 (around 150 °c) 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%.conversion of morphine (i) to apomorphine (ii) in the presence of acid following the example of the morphine skeleton dehydration rearrangement, outlined by bentley. history the pharmacological effects of the naturally-occurring analog aporphine in the blue lotus (nymphaea caerulea) 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 (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. treatment of alcoholism apomorphine was one of the earliest used pharmacotherapies for alcoholism. the keeley cure (1870s to 1900) contained apomorphine, among other ingredients, but the first medical reports of its use for more than pure emesis come from james tompkins and charles douglas. tompkins reported, after injection of 6.5 mg ("one tenth of a grain"):in four minutes free emesis followed, rigidity gave way to relaxation, excitement to somnolence, and without further medication the patient, who before had been wild and delirious, went off into a quiet sleep.douglas saw two purposes for apomorphine: a paroxysm of dipsomania ... in minute doses it is much more rapidly efficient in stilling the dipsomaniac craving than strychnine or atropine… four or even 3m of the solution usually checks for some hours the incessant demands of the patient… when he awakes from the apomorphine sleep he may still be demanding alcohol, though he is never then so insistent as before. accordingly it may be necessary to repeat the dose, and even to continue to give it twice or three times a day. such repeated doses, however, do not require to be so large: 4 or even 3m is usually sufficient.this use of small, continuous doses (1/30th of a grain, or 2.16 mg by douglas) of apomorphine to reduce alcoholic craving comes some time before pavlov's discovery and publication of the idea of the "conditioned reflex" in 1903. this method was not limited to douglas; the irish doctor francis hare, who worked in a sanatorium outside london from 1905 onward, also used low-dose apomorphine as a treatment, describing it as "the most useful single drug in the therapeutics of inebriety". he wrote:in (the) sanatorium it is used in three different sets of circumstances: (1) in maniacal or hysterical drunkenness: (2) during the paroxysm of dipsomania, in order to still the craving for alcohol; and (3) in essential insomnia of a special variety... the patient's mental condition is entirely altered. he may be sober: he is free from the time being from any craving from alcohol. the craving may return, however, and then it is necessary to repeat the injection, it may be several times at intervals of a few hours. these succeeding injections should be quite small, 3 to 6 min. being sufficient. doses of this size are rarely emetic. there is little facial pallor, a sensation as of the commencement of sea-sickness, perhaps a slight malaise with a sudden subsidence of the craving for alcohol, followed by a light and short doze.he also noted there appeared to be a significant prejudice against