ميثادون

الميثادون


Methadone.svg
1 : 1 Mixture (racemate)
الاسم النظامي (أيوپاك)
الاسم النظامي (أيوپاك)
(RS)-6-(Dimethylamino)-4,4-diphenylheptan-3-one
المعينات Identifiers
رقم CAS 76-99-3
كود ATC N02AC52 N07BC02, R05DA06
PubChem 4095
بنك العقاقير DB00333
بيانات كيميائية
الصيغة C21H27NO 
كتلة جزيئية 309.445 g/mol
SMILES search in eMolecules, PubChem
بيانات الحركية الدوائية Pharmacokinetic
التوافر الحيوي 40-90% (oral)
الأيض Hepatic
عمر النصف 24-36 h
اخراج Urine, Test by specific gravity and bilirubin
اعتبارات علاجية
فئة السلامة أثناء الحمل

Reduction of oxygen to unborn child due to depression of breathing

الوضع القانوني

Schedule II(الولايات المتحدة) Class A (UK)

Dependence Liability Moderate
المسارات oral, intravenous, insufflation, sublingual, rectal

Methadone (also known as Symoron, Dolophine, Amidone, Methadose, Physeptone, Heptadon, Phy and many other names) is a synthetic opioid, used medically as an analgesic, antitussive and a maintenance anti-addictive for use in patients on opioids. It was developed in Germany in 1937. Although chemically unlike morphine or heroin, methadone also acts on the opioid receptors and thus produces many of the same effects. Methadone is also used in managing chronic pain owing to its long duration of action and very low cost. Methadone was introduced into the United States in 1947 by Eli Lilly and Company.

Methadone is useful in the treatment of opioid dependence. It has cross-tolerance with other opioids including heroin and morphine and a long duration of effect. Oral doses of methadone can stabilise patients by mitigating opioid withdrawal syndrome. Higher doses of methadone can block the euphoric effects of heroin, morphine, and similar drugs. As a result, properly dosed methadone patients can reduce or stop altogether their use of these substances.

Methadone is approved for different indications in different countries. Common is approval as an analgesic and approval for the treatment of opioid dependence. It is not intended to reduce the use of non-narcotic drugs such as cocaine, methamphetamine, or alcohol.

Today, a number of pharmaceutical companies produce and distribute methadone. The racemic hydrochloride is the only form available in most countries, such as هولندا, Belgium, فرنسا and in the United States, as of March 2008. The tartrate and other salts of the laevorotary form (levomethadone, with trade names including Polamidone and Heptadon) are available in Europe and elsewhere. These are possibly more potent and lack the cardiac effects such as lengthened QT interval caused by the dextrorotary form. The major producer remains Mallinckrodt, who sells bulk methadone to most of the producers of generic preparations and also distributes its own brand name product in the form of tablets, dispersible tablets and oral concentrate under the name Methadose in the United States.[1]

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التركيب

ثنائي ميتيل امينو -6نائي فينيل -4.4هيبتانون -3. يحوي الميثادون في بنيته على كربون غير متناظر فيوجد له مصاوغان ضوئيان(-) و(+) والمركب الطبي هو المركب الراسمي الذي يستعمل بشكل ملح هيدروكلوريد

الصفات:

مسحوق ابيض مر الطعم قليل الانحلال في الماء وينحل في الكلورفورم ان المجموعة الكربونية(-CO2-) في بنية الميتادون هي مجموعة ضعيفة النشاط الكيميائي نتيجة لتوضعها

الاستعمال

يتمتع الميثادون بتاثير مسكن للالم وبتاثير مضاد لتشنج العضلات وتاثيره المسكن اقوى من تاثير المورفين يستعمل الميثادون على نحو واسع في معالجة الادمان على الافيونات ويعطى بمقدار 10-40 ملغ فمويا كل 24ساعة ولتثبيط اعراض الانسحاب.

الجرعة

يعطى بمقدار 2.5-10ملغ باليوم عن طريق الفم او حقنا بالعضل او بشكل تحاميل يستعمل الميثادون على نحو واسع في معالجة الادمان على الافيونات ويعطى بمقدار 10-40 ملغ فمويا كل 24ساعة

الاثار الجانبية

تاثيره المسكن اقوى من تاثير المورفين ولكنه اكثر سمية ويسبب الاعراض الثانوية نفسها (غثيان- قيئا-اعتيادا)

Adverse effects of methadone include:[2][3][4][5][6]


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ألية التاثير

Methadone is a full µ-opioid agonist. Methadone also binds to the glutamatergic NMDA (N-methyl-D-aspartate) receptor, and thus acts as a receptor antagonist against glutamate. Glutamate is the primary excitatory neurotransmitter in the CNS. NMDA receptors have a very important role in modulating long term excitation and memory formation. NMDA antagonists such as dextromethorphan (DXM), ketamine (a dissociative anaesthetic, also M.O.A+.), tiletamine (a veterinary anaesthetic) and ibogaine (from the African tree Tabernanthe iboga, also M.O.A+.) are being studied for their role in decreasing the development of tolerance to opioids and as possible for eliminating addiction/tolerance/withdrawal, possibly by disrupting memory circuitry. Acting as an NMDA antagonist may be one mechanism by which methadone decreases craving for opioids and tolerance, and has been proposed as a possible mechanism for its distinguished efficacy regarding the treatment of neuropathic pain. Methadone also acted as a potent, noncompetitive α3β4 neuronal nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines.[7]

الاستقلاب(الايض)

Methadone has a slow metabolism and very high fat solubility, making it longer lasting than morphine-based drugs. Methadone has a typical elimination half-life of 15 to 60 hours with a mean of around 22. However, metabolism rates vary greatly between individuals, up to a factor of 100,[8][9] ranging from as few as 4 hours to as many as 130 hours,[10] or even 190 hours.[11] This variability is apparently due to genetic variability in the production of the associated enzymes CYP3A4, CYP2B6 and CYP2D6. Many substances can also induce, inhibit or compete with these enzymes further affecting (sometimes dangerously) methadone half-life. A longer half life frequently allows for administration only once a day in Opioid detoxification and maintenance programs. Patients who metabolize methadone rapidly, on the other hand, may require twice daily dosing to obtain sufficient symptom alleviation while avoiding excessive peaks and troughs in their blood concentrations and associated effects.[10] This can also allow lower total doses in some such patients. The analgesic activity is shorter than the pharmacological half-life; dosing for pain control usually requires multiple doses per day.[بحاجة لمصدر]

The toxic effects of an overdose can be treated with naloxone.[2] Naloxone is preferred to the newer, longer acting antagonist naltrexone. Despite Methadone's much longer duration of action compared to either heroin and other shorter-acting agonists, and the need for repeat doses of the antagonist naloxone, it is still used for overdose therapy. As naltrexone has a longer half life, it is more difficult to titrate. If too large a dose of opioid antagonist is given to a dependent patient, it will result in withdrawal symptoms (possibly severe). When using naloxone, the naloxone will be quickly eliminated and the withdrawal will be short lived. Doses of naltrexone take longer to be eliminated from the patient's system.


ادوية مشابهة

There are two methadone isomers. The racemic mixture is more common as it is cheaper to produce. The laevorotary isomer, which is isolated by several recrystalisations from racemic methadone, is more expensive to produce. It is stronger than the racemic mixture and is marketed especially in continental Europe as an analgesic under the trade names Levo-Polamidone, Polamidone, Heptanone, Heptadone, Heptadon and others. It is used as the hydrochloride salt almost exclusively with some uncommon pharmaceuticals and research subjects consisting of the tartrate.

The closest chemical relative of methadone in clinical use is levo-α-acetylmethadol or LAAM. It has a longer duration of action (from 48 to 72 hours), permitting a reduction in frequency of use. In 1994, it was approved as a narcotic addiction treatment. In the Netherlands, like methadone and all other strong opioids, LAAM is a List I drug of the Opium Law, and in Schedule II of the United States Controlled Substances Act. LAAM has since been removed from the US and European markets due to reports of rare cardiac side effects.

Other drugs which are not structurally related to methadone are also used in maintenance treatment, particularly Subutex (buprenorphine) and Suboxone (buprenorphine combined with naloxone). In the NL, Switzerland, the UK and a few other European countries, however, not only buprenorphine and oral methadone but also injectable methadone and pharmaceutical diamorphine (heroin) or other opioids may be used for outpatient maintenance treatment of opiate addiction, and treatment is generally provided in much less heavily regulated environments than in the United States. In the United Kingdom, diamorhpine is used extremely selectively and is not available on prescription to addicts; except in specialist trials which involved no more than 300 participants. A study from Austria indicated that oral morphine (in the form of MS-Contin) provides better results than oral methadone, and studies of heroin maintenance have indicated that a low background dose of methadone combined with heroin maintenance may significantly improve outcomes for less-responsive patients.[12] Other opiates such as dihydrocodeine in both extended-release and immediate-release form are also sometimes used for maintenance treatment as an alternative to methadone or buprenorphine in some European countries.[13]

Another close relative of methadone is dextropropoxyphene, first marketed in 1957 under the trade name of Darvon. Oral analgesic potency is one-half to one-third that of codeine, with 65 mg approximately equivalent to about 600 mg of aspirin. Dextropropoxyphene is prescribed for relief of mild to moderate pain. Bulk dextropropoxyphene is in Schedule II of the United States Controlled Substances Act, while preparations containing it are in Schedule IV. More than 100 tons of dextropropoxyphene are produced in the United States annually, and more than 25 million prescriptions are written for the products. Since dextropropoxyphene produces relatively modest pain relief compared to other opioids but still produces severe respiratory depression at high doses, it is particularly dangerous when abused, as drug users may take dangerously high doses in an attempt to achieve narcotic effects. This narcotic is among the top 10 drugs reported by medical examiners in recreational drug use deaths. However, dextropropoxyphene is still prescribed for the short term relief of opiate withdrawal symptoms, particularly when the aim of treatment is to smooth detoxification to a drug free state rather than a switch to maintenance treatment.

Other analogues of methadone which are still in clinical use are dipipanone (Diconal) and dextromoramide (Palfium) which are shorter-lasting but considerably more effective as analgesics. In the 1980s and beginning of the 1990s, before pharmaceutical grade IV heroin treatment became available to heroin addicts, as either single drug replacement for street heroin, or to be used alongside prescribed methadone, oral dextromoramide was prescribed to heroin addicts instead, because even when taken orally it still produces a strong, so called "rush", without the need of IV administration and any of the risks involved with it. These drugs have a high potential for abuse and dependence and were notorious for being widely abused and sought after by drug addicts in the 1970s. They are still rarely used for the relief of severe pain in the treatment of terminal cancer or other serious medical conditions


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مصادر

  1. ^ Pharmaceuticals.Mallinckrodt.com
  2. ^ أ ب Public Health Issue: Methadone Maintenance Therapy RICHARD SADOVSKY, M.D. - Anderson IB, Kearney TE. Use of methadone. West J Med January 2000;172:43-6.
  3. ^ "Dolophine Drug Description". RxList.
  4. ^ "Methadone". MedlinePlus. Archived from the original on 2008-02-27.
  5. ^ "Methadone". Drugs.com.
  6. ^ "Methadone". MedicineNet.
  7. ^ "Blockade of Rat α3β4 Nicotinic Receptor Function by Methadone, Its Metabolites, and Structural Analogs — JPET".
  8. ^ Kell MJ (1994). "Utilization of plasma and urine methadone concentrations to optimize treatment in maintenance clinics: I. Measurement techniques for a clinical setting". Journal of addictive diseases: the official journal of the ASAM, American Society of Addiction Medicine. 13 (1): 5–26. PMID 8018740.
  9. ^ Eap CB, DeglonJ-J, Boumann P. (1999). "Pharmacokinetics and pharmacogenetics of methadone: Clinical relevance". Heroin Addiction and Related Clinical Problems: the official journal of EUROPAD, European Opiate Addiction Treatment Association. 1 (1): 19–34.CS1 maint: Multiple names: authors list (link)
  10. ^ أ ب Eap CB, Buclin T, Baumann P (2002). "Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence". Clinical pharmacokinetics. 41 (14): 1153–93. PMID 12405865.CS1 maint: Multiple names: authors list (link)
  11. ^ Manfredonia, John (2005-03-18). "Prescribing Methadone for Pain Management in End-of-Life Care". JAOA The Journal of the American Osteopathic Association. Retrieved 2007-01-29.
  12. ^ Michels II, Stover H, Gerlach R. Substitution treatment for opioid addicts in Germany. Harm Reduction Journal. 2007 February 2;4:5.
  13. ^ Robertson JR, Raab GM, Bruce M, McKenzie JS, Storkey HR, Salter A. Addressing the efficacy of dihydrocodeine versus methadone as an alternative maintenance treatment for opiate dependence: A randomized controlled trial. Addiction. 2006 December;101(12):1752-9.

روابط اضافية

قالب:Drugs used in addictive disorders