| 词条 | Naloxone | ||||||||||||||||||||||||||||
| 释义 |
| Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 440816974 | IUPAC_name = (4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-prop-2-enyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one | image = Naloxone.svg | width = 225px | image2 = Naloxone-3D-balls.png | width2 = 250px | tradename = Narcan, Evzio, others | Drugs.com = {{drugs.com|monograph|naloxone-hydrochloride}} | licence_EU = yes | pregnancy_AU = B1 | pregnancy_US = C | pregnancy_US_comment = [1] | pregnancy_category = | legal_AU = S3 | legal_AU_comment = [1] | legal_DE = Anlage 1 | legal_UK = POM | legal_US = Rx only | legal_status = | routes_of_administration = Endotracheal, intranasal, IV, IM | bioavailability = 2% (by mouth, 90% absorption but high first-pass metabolism) 50% (intranasally) | protein_bound = | metabolism = Liver | onset = 2 min ({{abbrlink|IV|intravenous injection}}), 5 min ({{abbrlink|IM|intramuscular injection}})[1] | elimination_half-life = 1–1.5 h | duration_of_action= 30–60 min[1] | excretion = Urine, bile | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 465-65-6 | ATC_prefix = A06 | ATC_suffix = AH04 | ATC_supplemental = {{ATC|V03|AB15}} | PubChem = 5284596 | IUPHAR_ligand = 1638 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB01183 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 4447644 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 36B82AMQ7N | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D08249 | ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI = 7459 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 80 | synonyms = EN-1530; N-Allylnoroxymorphone; 17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one | C=19 | H=21 | N=1 | O=4 | SMILES = O=C1[C@@H]2OC3=C(O)C=CC4=C3[C@@]2([C@]5(CC1)O)CCN(CC=C)[C@@H]5C4 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C19H21NO4/c1-2-8-20-9-7-18-15-11-3-4-12(21)16(15)24-17(18)13(22)5-6-19(18,23)14(20)10-11/h2-4,14,17,21,23H,1,5-10H2/t14-,17+,18+,19-/m1/s1 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = UZHSEJADLWPNLE-GRGSLBFTSA-N }}Naloxone, sold under the brandname Narcan among others, is a medication used to block the effects of opioids, especially in overdose.[1] Naloxone may be combined with an opioid (in the same pill) to decrease the risk of opioid misuse.[1] When given intravenously, naloxone works within two minutes, and when injected into a muscle, it works within five minutes;[1] it may also be sprayed into the nose.[2] The effects of naloxone last about half an hour to an hour.[3] Multiple doses may be required, as the duration of action of most opioids is greater than that of naloxone.[1] Administration to opioid-dependent individuals may cause symptoms of opioid withdrawal, including restlessness, agitation, nausea, vomiting, a fast heart rate, and sweating.[1] To prevent this, small doses every few minutes can be given until the desired effect is reached.[1] In those with previous heart disease or taking medications that negatively affect the heart, further heart problems have occurred.[4] It appears to be safe in pregnancy, after having been given to a limited number of women.[5] Naloxone is a non-selective and competitive opioid receptor antagonist.[15][16] It works by reversing the depression of the central nervous system and respiratory system caused by opioids.[4] Naloxone was patented in 1961 and approved for opioid overdose in the United States in 1971.[6] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[7] Naloxone is available as a generic medication.[4] Its wholesale price in the developing world is between $0.50 and $5.30 per dose.[8] Vials of naloxone are not very expensive (less than $25) in the United States.[9] The price for a package of two auto-injectors in the US, however, has increased from $690 in 2014 to $4,500 in 2016.[10] The 2018 price for the NHS in the United Kingdom is about £5 per dose.[11] {{TOC limit|3}}Medical usesOpioid overdoseNaloxone is useful both in acute opioid overdose and in reducing respiratory or mental depression due to opioids.[4] Whether it is useful in those in cardiac arrest due to an opioid overdose is unclear.[12] It is included as a part of emergency overdose response kits distributed to heroin and other opioid drug users and emergency responders. This has been shown to reduce rates of deaths due to overdose.[13] A prescription for naloxone is recommended if a person is on a high dose of opioid (>100 mg of morphine equivalence/day), is prescribed any dose of opioid accompanied by a benzodiazepine, or is suspected or known to use opioids nonmedically.[14] Prescribing naloxone should be accompanied by standard education that includes preventing, identifying, and responding to an overdose; rescue breathing; and calling emergency services.[15] Preventing opioid abuseNaloxone is poorly absorbed when taken by mouth, so it is commonly combined with a number of oral opioid preparations, including buprenorphine and pentazocine, so that when taken orally, just the opioid has an effect, but if misused by injecting, the naloxone blocks the effect of the opioid.[4][16] This combination is used in an effort to prevent abuse.[16] In Germany, tilidine is sold in a fixed combination with naloxone. Other usesNaloxone can be used on infants who were exposed to intrauterine opiates administered to mothers during delivery. However, there is insufficient evidence for the use of naloxone to lower cardiorespiratory and neurological depression in these infants.[17] Infants exposed to high concentrations of opiates during pregnancy may have CNS damage in the setting of perinatal asphyxia. Naloxone has been studied to improve outcomes in this population, however the evidence is currently weak.[18][19] In people with shock, including septic, cardiogenic, hemorrhagic, or spinal shock, those who received naloxone had improved blood flow. The importance of this is unclear.[20] Naloxone is also experimentally used in the treatment for congenital insensitivity to pain with anhidrosis, an extremely rare disorder (one in 125 million) that renders one unable to feel pain or differentiate temperatures.{{citation needed|date=January 2015}} Naloxone can also be used as an antidote in overdose of clonidine, a medication that lowers blood pressure.[21] Naloxone can also be used to treat itchiness brought on by opioid use.[22] Routes of administrationNaloxone is most commonly injected intravenously for fastest action, which usually causes the drug to act within a minute, and lasts up to 45 minutes. It can also be administered via intramuscular, subcutaneous injection, or nasal spray.[23] There is a prepackaged nasal spray that does not require assembly and delivers a consistent dose.[24] It can be repeated if necessary.[25] A non-FDA approved wedge device (nasal atomizer) attached to a syringe may be used to create a mist that delivers the drug to the nasal mucosa.[26] This is useful near facilities where many overdoses occur that already stock injectors.[27] If minimal or no response is observed within 2–3 minutes, dosing may be repeated every 2 minutes until the maximum dose of 10 mg has been reached. If no response occurs at this time, alternative diagnosis and treatment should be pursued. The effects of naloxone may wear off before those of the opioids, and they may require repeat dosing at a later time. Patients experiencing effects should be monitored for respiratory rate, heart rate, blood pressure, temperature, ABGs and level of consciousness. Those with a greater risk for respiratory depression should be identified prior to administration and watched closely.[28] In April 2014, the US Food and Drug Administration (FDA) approved a hand-held automatic injector naloxone product that is pocket-sized and can be used in nonmedical settings such as in the home.[12] It is designed for use by laypersons, including family members and caregivers of opioid users at-risk for an opioid emergency, such as an overdose.[29] A nasal spray was developed in a partnership between LightLake Therapeutics and the National Institute on Drug Abuse.[30] The approval process was fast-tracked as one initiative to reduce the death toll caused by opiate overdoses. At the time of approval, an estimated 16,000 annual deaths were attributed to prescription opioid overdoses in the US.[31] Naloxone can be used along with oxycodone controlled release and may help reduce constipation associated with opioids. Naloxone has low systemic bioavailability when taken by mouth due to hepatic first pass metabolism, but it does block opioid receptors that are located in the intestine.[32] Special populationsPregnancy and breastfeedingNaloxone is pregnancy category B or C in the United States.[4] Studies in rodents given a daily maximum dose of 10 mg naloxone showed no harmful effects to the fetus, although human studies are lacking and the drug does cross the placenta, which may lead to the precipitation of withdrawal in the fetus. In this setting, further research is needed before safety can be assured, so naloxone should be used during pregnancy only if it is a medical necessity.[33] Whether naloxone is excreted in breast milk is unknown, however, it is not orally bioavailable and therefore is unlikely to affect a breastfeeding infant.[34] Kidney and liver dysfunctionCurrently, no established clinical trials have been conducted in person with insufficient kidney function or liver disease, and as such, these people should be monitored closely if naloxone is clinically indicated. Cardiovascular diseaseNaloxone should be used with caution in people with cardiovascular disease as well as those that are currently taking medications that could have adverse effects on the cardiovascular system such as causing low blood pressure, fluid accumulation in the lungs (pulmonary edema), and abnormal heart rhythms. There have been reports of abrupt reversals with opioid antagonists leading to pulmonary edema and ventricular fibrillation.[35] Side effectsNaloxone has little to no effect if opioids are not present. In people with opioids in their system, it may cause increased sweating, nausea, restlessness, trembling, vomiting, flushing, and headache, and has in rare cases been associated with heart rhythm changes, seizures, and pulmonary edema.[36][37] Besides the side effects listed above, naloxone also has other adverse events, such as other cardiovascular effects (hypertension, hypotension, tachycardia, ventricular fibrillation, ventricular tachycardia) and central nervous system effects, such as agitation, body pain, brain disease, and coma. In addition to these adverse effects, naloxone is also contraindicated in people with hypersensitivity to naloxone or any of its formulation components.[38] Naloxone has been shown to block the action of pain-lowering endorphins which the body produces naturally. These endorphins likely operate on the same opioid receptors that naloxone blocks. It is capable of blocking a placebo pain-lowering response, if the placebo is administered together with a hidden or blind injection of naloxone.[39] Other studies have found that placebo alone can activate the body's μ-opioid endorphin system, delivering pain relief by the same receptor mechanism as morphine.[40][41] PharmacologyPharmacodynamics
Naloxone is a lipophilic compound that acts as a non-selective and competitive opioid receptor antagonist.[45][46] The pharmacologically active isomer of naloxone is (−)-naloxone.[43][47] Naloxone's binding affinity is highest for the μ-opioid receptor, then the δ-opioid receptor, and lowest for the κ-opioid receptor;[45] naloxone has negligible affinity for the nociceptin receptor.[48] If naloxone is administered in the absence of concomitant opioid use, no functional pharmacological activity occurs, except the inability for the body to combat pain naturally. In contrast to direct opiate agonists, which elicit opiate withdrawal symptoms when discontinued in opiate-tolerant people, no evidence indicates the development of tolerance or dependence on naloxone. The mechanism of action is not completely understood, but studies suggest it functions to produce withdrawal symptoms by competing for opiate receptor sites within the CNS (a competitive antagonist, not a direct agonist), thereby preventing the action of both endogenous and xenobiotic opiates on these receptors without directly producing any effects itself.[49] PharmacokineticsWhen administered parenterally (nonorally or nonrectally, e.g. intravenously or by injection), as is most common, naloxone has a rapid distribution throughout the body. The mean serum half life has been shown to range from 30 to 81 minutes, shorter than the average half life of some opiates, necessitating repeat dosing if opioid receptors must be stopped from triggering for an extended period. Naloxone is primarily metabolized by the liver. Its major metabolite is naloxone-3-glucuronide, which is excreted in the urine.[49] ChemistryNaloxone, also known as N-allylnoroxymorphone or as 17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one, is a synthetic morphinan derivative and was derived from oxymorphone (14-hydroxydihydromorphinone), an opioid analgesic.[50][51][52] Oxymorphone, in turn, was derived from morphine, an opioid analgesic and naturally occurring constituent of the opium poppy.[53] Naloxone is a racemic mixture of two enantiomers, (–)-naloxone (levonaloxone) and (+)-naloxone (dextronaloxone), only the former of which is active at opioid receptors.[54][55] The drug is a highly lipophilic, allowing it to rapidly penetrate the brain and to achieve a far greater brain to serum ratio than that of morphine.[50] Opioid antagonists related to naloxone include cyprodime, nalmefene, nalodeine, naloxol, and naltrexone.[56] The chemical half-life of naloxone is such that injection and nasal forms have been marketed with 24-month and 18-month shelf-lives, respectively.[57] A 2018 study noted that the nasal and injection forms presented as chemically stable to 36- and 28-months, respectively, which prompted an as yet incomplete five year stability study to be initiated.[57] This suggests that expired caches of material in community and healthcare settings may still be efficacious substantially beyond their labeled expiration dates.[57] HistoryNaloxone was patented in 1961 by Mozes J. Lewenstein, Jack Fishman, and the company Sankyo.[6] It was approved for opioid abuse treatment in 1971 by the FDA with opioid abuse kits being distributed by many states to medically untrained people beginning in 1996. From the period of 1996 to 2014, the CDC estimates over 26,000 cases of opioid overdose have been reversed using the kits.[58] Society and cultureNamesNaloxone is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|BAN|British Approved Name}}, {{abbrlink|DCF|Dénomination Commune Française}}, {{abbrlink|DCIT|Denominazione Comune Italiana}}, and {{abbrlink|JAN|Japanese Accepted Name}}, while naloxone hydrochloride is its {{abbrlink|USAN|United States Adopted Name}} and {{abbrlink|BANM|British Approved Name}}.[59][60][61][62]The patent for naloxone has expired; consequently, it is available in generic medication. Brand names of naloxone include Narcan, Nalone, Evzio, Prenoxad Injection, Narcanti, Narcotan, and others. Legal statusIn the United States, naloxone is available without a prescription in every state with the exception of Hawaii.[63][64] However, depending on the pharmacy, a pharmacist may have to write a prescription or not be able to give naloxone to comply with accounting rules regarding prescription medications, as naloxone is still considered a prescription only medication under FDA rules. While paramedics have carried naloxone for decades, law enforcement officers in many states throughout the country carry naloxone to reverse the effects of heroin overdoses when reaching the location prior to paramedics. As of July 12, 2015, law enforcement departments in 28 states are allowed to or required to carry naloxone to quickly respond to opioid overdoses.[65] In Australia, as of February 1, 2016, naloxone is now available "over the counter" in pharmacies without a prescription.[66] It comes in single-use filled syringe similar to law enforcement kits. In Canada, naloxone single-use syringe kits are distributed and available at various clinics and emergency rooms. Alberta Health Services is increasing the distribution points for naloxone kits at all emergency rooms, and various pharmacies and clinics province-wide. Also in Alberta, take-home naloxone kits are available and commonly distributed in most drug treatment or rehabilitation centres, as well as in pharmacies where pharmacists can distribute single-use take-home naloxone kits or prescribe the drug to addicts. All Edmonton Police Service and Calgary Police Service patrol cars carry an emergency single-use naloxone syringe kit. Some Royal Canadian Mounted Police patrol vehicles also carry the drug, occasionally in excess to help distribute naloxone among users and concerned family/friends. Nurses, paramedics, medical technicians, and emergency medical responders can also prescribe and distribute the drug. Following Alberta Health Services, Health Canada reviewed the prescription-only status of naloxone, resulting in plans to remove it in 2016, allowing naloxone to be more accessible.[67][68] Due to the rising number of drug deaths across the country, Health Canada proposed a change to make naloxone more widely available to Canadians in support of efforts to address the growing number of opioid overdoses.[69] In March 2016, Health Canada did change the prescription status of naloxone, as "pharmacies are now able to proactively give out naloxone to those who might experience or witness an opioid overdose."[70] Prehospital accessLaws in many jurisdictions have been changed in recent years to allow wider distribution of naloxone.[71][72] Several states have also moved to permit pharmacies to dispense the medication without the person first seeing a physician or other non-pharmacist professional.[73] Over 200 naloxone distribution programs utilize licensed prescribers to distribute the drug, often through the use of standing medication orders [101][74] whereby the medication is distributed under the medical authority of a physician or other prescriber (such as a pharmacist under California's AB1535). Following the use of the nasal spray device by police officers on Staten Island in New York, an additional 20,000 police officers will begin carrying naloxone in mid-2014. The state's Office of the Attorney General will provide US$1.2 million to supply nearly 20,000 kits. Police Commissioner William Bratton said: "Naloxone gives individuals a second chance to get help".[75] Emergency Medical Service Providers (EMS) routinely administer naloxone, except where basic Emergency Medical Technicians are prohibited by policy or by state law.[76] A survey of US naloxone prescription programs in 2010 revealed that 21 out of 48 programs reported challenges in obtaining naloxone in the months leading up to the survey, due mainly to either cost increases that outstripped allocated funding or the suppliers' inability to fill orders.[105] The approximate cost of a 1 ml ampoule of naloxone in the US is estimated to be significantly higher than in most Western countries.[101] Projects of this type are under way in many North American cities.[77][78] CDC estimates that the US programs for drug users and their caregivers prescribing take-home doses of naloxone and training on its use have prevented 10,000 opioid overdose deaths.[77] Healthcare institution-based naloxone prescription programs have also helped reduce rates of opioid overdose in North Carolina, and have been replicated in the US military.[79][80] Programs training police and fire personnel in opioid overdose response using naloxone have also shown promise in the US, and effort is increasing to integrate opioid fatality prevention in the overall response to the overdose crisis.[81][82][83][84] Pilot projects were also started in Scotland in 2006. Also in the UK, in December 2008, the Welsh Assembly government announced its intention to establish demonstration sites for take-home naloxone.[85] As of February 2016, Pharmacies across Alberta and some other Canadian jurisdictions are allowed to distribute take-home naloxone kits. Additionally, the Minister of Health issued an order to change basic life support provider's medical scope, within EMS, to administer naloxone in the event of a suspected narcotic overdose. These are part of the government's plan to tackle a growing fentanyl drug crisis.[86] IdentificationThe CAS number of naloxone is 465-65-6; the anhydrous hydrochloride salt has CAS 357-08-4 and the hydrochloride salt with 2 molecules of water, hydrochloride dihydrate, has CAS 51481-60-8. MediaThe 2013 documentary film Reach for Me: Fighting to End the American Drug Overdose Epidemic interviews people involved in naloxone programs aiming to make naloxone available to opioid users and people with chronic pain.[87] See also
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2012|url=http://www.huffingtonpost.com/2012/04/26/naloxone-drug-overdose-antidote_n_1456531.html|deadurl=no|archiveurl=https://web.archive.org/web/20120518161613/http://www.huffingtonpost.com/2012/04/26/naloxone-drug-overdose-antidote_n_1456531.html|archivedate=2012-05-18|df=}} 83. ^{{cite journal |vauthors=Davis CS, Beletsky L | title = Bundling occupational safety with harm reduction information as a feasible method for improving police receptiveness to syringe access programs: evidence from three U.S. cities | journal = Harm Reduct J | volume = 6 | issue = 1| pages = 16 | year = 2009 | pmid = 19602236 | pmc = 2716314 | doi = 10.1186/1477-7517-6-16 }} 84. ^{{cite web|title=2013 National drug control strategy|year=2013|url=http://www.whitehouse.gov//sites/default/files/ondcp/policy-and-research/ndcs_2013.pdf|archiveurl=https://web.archive.org/web/20130506222525/http://www.whitehouse.gov/sites/default/files/ondcp/policy-and-research/ndcs_2013.pdf|archive-date=6 May 2013|deadurl=no|df=}} 85. ^{{cite web|url=http://www.ihra.net/files/2010/08/26/Danny_Morris.pdf|title=IHRA 21st International Conference Liverpool, 26th April 2010 - Introducing 'take home' Naloxone in Wales|accessdate=9 March 2011|deadurl=no|archiveurl=https://web.archive.org/web/20110720062721/http://www.ihra.net/files/2010/08/26/Danny_Morris.pdf|archivedate=20 July 2011|df=}} 86. ^Naloxone kits now available at drug stores as province battles fentanyl crisis - Injection drug can temporarily reverse overdoses {{webarchive|url=https://web.archive.org/web/20160304141621/http://www.cbc.ca/news/canada/calgary/naloxone-kits-fentanyl-overdose-province-1.3451860 |date=2016-03-04 }}. Retrieved 29 February 2016. 87. ^Reach for Me: Fighting to End the American Drug Overdose Epidemic {{webarchive|url=https://web.archive.org/web/20141217004049/http://reach4me.org/ |date=2014-12-17 }} External links
13 : Alcohols|Allyl compounds|Antidotes|Chemical substances for emergency medicine|GABAA receptor negative allosteric modulators|Kappa antagonists|Ketones|Morphinans|Opioid antagonists|Phenol ethers|Sigma antagonists|World Health Organization essential medicines|RTT |
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