Pregabalin
| Structural formula | ||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
||||||||||||||||||||||
| General | ||||||||||||||||||||||
| Non-proprietary name | Pregabalin | |||||||||||||||||||||
| other names |
( S ) -3- (Aminomethyl) -5-methylhexanoic acid ( IUPAC ) |
|||||||||||||||||||||
| Molecular formula | C 8 H 17 NO 2 | |||||||||||||||||||||
| External identifiers / databases | ||||||||||||||||||||||
|
||||||||||||||||||||||
| Drug information | ||||||||||||||||||||||
| ATC code | ||||||||||||||||||||||
| Drug class | ||||||||||||||||||||||
| properties | ||||||||||||||||||||||
| Molar mass | 159.23 g mol −1 | |||||||||||||||||||||
| Physical state |
firmly |
|||||||||||||||||||||
| Melting point |
186-188 ° C |
|||||||||||||||||||||
| safety instructions | ||||||||||||||||||||||
|
||||||||||||||||||||||
| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | ||||||||||||||||||||||
Pregabalin is a drug from the group of anticonvulsants . It has been approved throughout the EU since 2004 for the treatment of neuropathic pain , epilepsy and generalized anxiety disorder (GAS). The best known brand is Lyrica . Generics have been available in Germany since December 1, 2014 .
In 2009, Pregabalin was ranked 12th among the top-selling patent-protected pharmaceuticals in Germany, with sales of around 220 million euros.
chemistry
Pregabalin is a derivative of γ-aminobutyric acid ( GABA ). It can also be viewed as structurally related to L- leucine . Both structural similarities are discussed in connection with its pharmacological effect. The pregabalin molecule is a zwitterion with an isoelectric point at 7.4:
It is easily soluble in aqueous media at pH values below 3.7.
synthesis
In the enantioselective synthesis of pregabalin is first starting from isobutyraldehyde and acrylonitrile the salt in multiple stages from the tert -Butylammonium- cation and the anion of 3-cyano-5-methyl-3-hexenoate prepared, whose C = C double bond then an enantioselective hydrogenation subjected and ( S ) -3-cyano-5-methylhexanoic acid gives. The reduction of the nitrile group then provides pregabalin. There are also alternative syntheses in which resolution is the key step.
pharmacology
The mechanism of action of pregabalin was only discovered a few years ago. It differs from that of γ-aminobutyric acid (GABA), because pregabalin does not act on the GABA receptors, but the GABA-like effect is caused by other mechanisms.
In the central nervous system ( CNS ), pregabalin binds to a subunit of voltage-dependent calcium channels of the P / Q type, which means voltage-controlled calcium channels (abbreviation VGCCs ) in the “Purkinje cells” of the cerebellum and as R-type “r” emaining VGCCs for voltage-gated Ca 2+ channels ). The flow of calcium into the nerve endings is throttled so that an increased release of the neurotransmitters glutamic acid , noradrenaline and substance P is normalized. This active approach as a calcium channel blocker combines the very different areas of application, neuropathic pain, generalized anxiety disorder and epilepsy.
Pregabalin is rapidly absorbed and has an estimated bioavailability of over 90 percent. It is hardly metabolized and is excreted unchanged via the kidneys. The plasma half-life is 6.3 hours.
Medical use
application areas
Pregabalin is used in adults to treat epilepsy (with and without secondary generalization), peripheral and central neuropathic pain (for example, diabetes mellitus , shingles , fibromyalgia, or spinal cord injuries ), and generalized anxiety disorder . It is effective in daily doses of 150 to 300 mg, an increase of up to 600 mg per day is possible. The dosage is set individually.
Pregabalin is able to reduce withdrawal symptoms in opiate addiction and is obtained and used by opiate addicts due to its relatively easy accessibility (often also on the black market ).
Some studies have shown that pregabalin can also be used successfully (as an off-label therapy ) in the treatment of social phobia .
Clinical efficacy and safety
Neuropathic pain
The effectiveness has been shown in studies in diabetic neuropathy , post-therapeutic neuralgia and after spinal cord injury. Efficacy has not been studied in other models of neuropathic pain . Pregabalin has been studied in 10 controlled clinical studies, up to 13 weeks when given twice a day and up to 8 weeks when given three times a day. Overall, the safety and efficacy profiles were similar when given twice and three times. In clinical studies lasting up to 12 weeks, both peripheral and central neuropathic pain experienced a reduction in pain within the 1st week and persisted throughout the treatment period.
In controlled clinical trials in peripheral neuropathic pain, 35% of pregabalin-treated patients and 18% of placebo-treated patients experienced a 50% improvement in pain score. Among the patients who did not experience sleepiness, 33% of the pregabalin-treated patients experienced such improvement and 18% of the placebo-treated patients. In the drowsy patients, the responder rates were 48% for pregabalin and 16% for placebo.
In the controlled clinical trial in central neuropathic pain, 22% of pregabalin-treated patients and 7% of placebo-treated patients experienced a 50% improvement in pain scores.
epilepsy
Additional therapy
Pregabalin has been studied in three controlled clinical studies given twice daily and three times daily for 12 weeks each. Overall, the tolerability and efficacy profile were similar for twice and three times daily dosing. A reduction in seizure frequency was observed within the first week.
Children and young people
The efficacy and safety of pregabalin as add-on therapy for epilepsy have not been established in pediatric patients below 12 years of age and adolescents. The side effects seen in a pharmacokinetic and safety study involving patients 3 months to 16 years of age (n = 65) were similar to those seen in adults. The results of a one-year open-label safety study involving 54 pediatric epilepsy patients aged 3 months to 16 years show that side effects fever and upper respiratory tract infections were seen more frequently than in studies in adults. Monotherapy (newly diagnosed patients): In a controlled clinical study lasting 56 weeks, pregabalin was investigated when administered twice daily. In terms of the six-month seizure-free endpoint, pregabalin was not non-inferior to lamotrigine . Pregabalin and lamotrigine were both safe and well tolerated.
Generalized anxiety disorders
Pregabalin has been studied in 6 controlled studies over a period of 4 to 6 weeks as well as in an 8-week study in elderly patients and in a long-term relapse prevention study with a double-blind relapse prevention phase of 6 months. An improvement in symptoms of generalized anxiety disorder according to the Hamilton Anxiety Scale (HAM-A) was observed within the 1st week. In controlled clinical trials lasting 4 to 8 weeks, 52% of pregabalin-treated patients and 38% of placebo-treated patients showed at least 50% improvement in overall HAM-A score from baseline.
Side effects and restrictions on use
The most common side effects include dizziness , tiredness, drowsiness , decreased alertness , feeling drunk, especially when starting treatment. In addition, blurred vision, double vision, balance disorders , erectile dysfunction , edema , nausea and vomiting can occur. Weight gain is common. Uncommon side effects include muscle twitching, muscle spasms, irregular heartbeat , weakness, and falls. Rarely occurring side effects are swallowing difficulties, high blood sugar, muscle damage, kidney failure, chest pain and changes in vision (depth perception, flashes of light, optical brightness). Other side effects that have been reported after marketing and the frequency of which cannot be determined include heart failure ( heart failure ), changes in the recording of electrical changes ( ECG ) to the heart associated with irregular heartbeat, fluid in the lungs , loss of consciousness, seizures as well Hypersensitivity and allergic reactions.
After discontinuing pregabalin therapy, withdrawal symptoms were sometimes severe in some patients. Pregabalin should therefore not be discontinued suddenly, but rather gradually dosed, as otherwise there may be an accumulation of epileptic seizures. Drowsiness and sleepiness can lead to falls, especially in the elderly.
There are indications of a potential for dependence on pregabalin; there are corresponding reports from Germany and Sweden. The technical information has been expanded to include the following note: “Cases of improper use, abuse and addiction have been reported. Caution should be exercised in patients with a history of drug abuse and the patient should be monitored for symptoms of improper use, abuse or dependence on pregabalin (...). "
The active ingredient pregabalin can increase the effects of CNS-depressing substances such as lorazepam and alcohol , up to and including weak breathing (respiratory failure) and coma. It is believed to also exacerbate cognitive and gross motor impairments after taking oxycodone .
Simultaneous use of pregabalin and oral hormonal contraceptives ("birth control pills") is possible.
In the case of renal insufficiency, the dosage must be reduced.
Use in children and adolescents
There are no studies on its use in children and adolescents under 18 years of age. It cannot therefore be recommended that these groups of people use pregabalin.
Use in pregnant women and while breastfeeding
There are no controlled clinical studies of pregabalin in pregnant women. However, animal studies suggest that there may be a risk to the fetus. Pregabalin should therefore only be used during pregnancy if absolutely necessary. According to the manufacturer Pfizer, the use during pregnancy is excluded, it is explicitly stated that women of childbearing potential must use an "effective method of contraception".
Effects on ability to drive
Taking pregabalin may make you feel drowsy or sleepy. Patients are therefore advised not to drive a car, use complex machines, or perform other potentially dangerous activities until it is known whether their ability to perform such activities is impaired.
See also
Web links
- Instructions for use ( Red List Patient Information Service)
- Entry on pregabalin in Pharmawiki
- Lyrica on the European Medicines Agency website
- rating
Individual evidence
- ^ The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals. 14th edition, 2006, pp. 1327-1328, ISBN 978-0-911910-00-1 .
- ↑ a b Data sheet Pregabalin from Sigma-Aldrich , accessed on April 22, 2011 ( PDF ).
- ^ Association of Statutory Health Insurance Physicians Westphalia-Lippe (last publication: December 19, 2014).
- ↑ U. Schwabe, D. Paffrath (editor): Drug Ordinance Report 2010 (Springer Medizin Verlag, Heidelberg).
- ^ J. Cook, W. Addicks, Yi H. Wu: Application of the Biopharmaceutical Classification System in Clinical Drug Development — An Industrial View , I .: AAPS J. 2008 Jun; 10 (2): 306-310. doi : 10.1208 / s12248-008-9036-5 , PMC 2751386 (free full text).
- ^ A b Axel Kleemann , Jürgen Engel, Bernd Kutscher and Dieter Reichert: Pharmaceutical Substances , Thieme-Verlag Stuttgart, 5th edition (2009), pp. 1135–1138, ISBN 978-3-13-558405-8 ; also online with biannual additions and updates.
- ^ Pharmaceutical newspaper online, accessed on January 23, 2015 .
- ↑ N. Kämmerer, T. Lemenager, M. Grosshans, F. Kiefer, D. Hermann: [Pregabalin for the reduction of opiate withdrawal symptoms]. In: Psychiatric Practice. Volume 39, Number 7, October 2012, pp. 351-352, doi : 10.1055 / s-0032-1305042 . PMID 22689280 .
- ↑ P. Kawalec, A. Cierniak, A. Pilc, G. Nowak: Pregabalin for the treatment of social anxiety disorder. In: Expert opinion on investigational drugs. Volume 24, number 4, April 2015, pp. 585-594, doi : 10.1517 / 13543784.2014.979283 , PMID 25361817 (review).
- ↑ Information for professionals (summary of the product characteristics / SPC) "Lyrica" (Pfizer), March 2015, Satz-Rechen-Zentrum Berlin, Fachinformationsdienst.
- ↑ Information for professionals (summary of the product characteristics / SPC) "Lyrica" (Pfizer), March 2015, Satz-Rechen-Zentrum Berlin, Fachinformationsdienst.
- ↑ Information for professionals (summary of the product characteristics / SPC) "Lyrica" (Pfizer), March 2015, Satz-Rechen-Zentrum Berlin, Fachinformationsdienst.
- ↑ Information for professionals (summary of the product characteristics / SPC) "Lyrica" (Pfizer), March 2015, Satz-Rechen-Zentrum Berlin, Fachinformationsdienst.
- ↑ Communication from the Drugs Commission of the German Medical Association on the potential for dependence on pregabalin , June 5, 2011.
- ↑ Baden-Württemberg State Medical Association: Lyrica® (Pregabalin) - The new addictive substance , October 25, 2012.
- ↑ M. Grosshans, J. Mutschler, D. Hermann et al .: Pregabalin abuse, dependence, and withdrawal: a case report . American Journal of Psychiatry 167 (2010), p. 869.
- ^ S. Schwan, A. Sundstrom, E. Stjernberg et al .: A signal for an abuse liability for pregabalin results from the Swedish spontaneous adverse drug reaction reporting system , European Journal of Clinical Pharmacology 66 (2010), pp. 947-953 .
- ↑ Specialist information on Lyrica hard capsules ( Memento of the original from August 7, 2015 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. , Pfizer, February 2013.
- ↑ a b c Specialist information from the Swiss Medicines Compendium: Lyrica®; Status: July 2007.
- ↑ "Lyrica" leaflet (Pfizer), January 2012.
