Chemistry:Lofepramine

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Short description: Chemical compound
Lofepramine
Lofepramin.svg
Lofepramine-from-xtal-1987-ball-and-stick.png
Clinical data
Trade namesGamanil, Lomont, Tymelyt, others
Other namesLopramine; DB-2182; Leo-460; WHR-2908A[1][2][3][4]
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability7%[5]
Protein binding99%[6]
MetabolismHepatic (via cytochrome P450, including CYP2D6)[7]
MetabolitesDesipramine (major)
Elimination half-lifeUp to 5 hours;[1] 12–24 hours (active metabolites)
ExcretionUrine, feces (mostly as metabolites)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC26H27ClN2O
Molar mass418.97 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Lofepramine, sold under the brand names Gamanil, Lomont, and Tymelyt among others, is a tricyclic antidepressant (TCA) which is used to treat depression.[7][3][8] The TCAs are so named as they share the common property of having three rings in their chemical structure. Like most TCAs lofepramine is believed to work in relieving depression by increasing concentrations of the neurotransmitters norepinephrine and serotonin in the synapse, by inhibiting their reuptake.[7] It is usually considered a third-generation TCA, as unlike the first- and second-generation TCAs it is relatively safe in overdose and has milder and less frequent side effects.[9]

Lofepramine is not available in the United States , Canada , Australia or New Zealand, although it is available in Ireland, Japan , South Africa and the United Kingdom , among other countries.[1]

Depression

In the United Kingdom, lofepramine is licensed for the treatment of depression which is its primary use in medicine.[6][10]

Lofepramine is an efficacious antidepressant with about 64% patients responding to it.[11]

Contraindications

To be used with caution, or not at all, for people with the following conditions:[7]

And in those being treated with amiodarone or terfenadine.[7]

Pregnancy and lactation

Lofepramine use during pregnancy is advised against unless the benefits clearly outweigh the risks.[7] This is because its safety during pregnancy has not been established and animal studies have shown some potential for harm if used during pregnancy.[7] If used during the third trimester of pregnancy it can cause insufficient breathing to meet oxygen requirements, agitation and withdrawal symptoms in the infant.[7] Likewise its use by breastfeeding women is advised against, except when the benefits clearly outweigh the risks, due to the fact it is excreted in the breast milk and may therefore adversely affect the infant.[7] Although the amount secreted in breast milk is likely too small to be harmful.[13]

Side effects

The most common adverse effects (occurring in at least 1% of those taking the drug) include agitation, anxiety, confusion, dizziness, irritability, abnormal sensations, like pins and needles, without a physical cause, sleep disturbances (e.g. sleeplessness) and a drop in blood pressure upon standing up.[13] Less frequent side effects include movement disorders (like tremors), precipitation of angle closure glaucoma and the potentially fatal side effects paralytic ileus and neuroleptic malignant syndrome.[13]

Dropout incidence due to side effects is about 20%.[11]

Side effects with unknown frequency include (but are not limited to):[13]

Withdrawal

If abruptly stopped after regular use it can cause withdrawal effects such as sleeplessness, irritability and excessive sweating.[7]

Overdose

Main page: Medicine:Tricyclic antidepressant overdose

Compared to other TCAs, lofepramine is considered to be less toxic in overdose.[13] Its treatment is mostly a matter of trying to reduce absorption of the drug, if possible, using gastric lavage and monitoring for adverse effects on the heart.[7]

Interactions

Lofepramine is known to interact with:[13][7]

  • Alcohol. Increased sedative effect.
  • Altretamine. Risk of severe drop in blood pressure upon standing.
  • Analgesics (painkillers). Increased risk of ventricular arrhythmias.
  • Anticoagulants (blood thinners). Lofepramine may inhibit the metabolism of certain anticoagulants leading to a potentially increased risk of bleeding.
  • Anticonvulsants. Possibly reduce the anticonvulsant effect of antiepileptics by lowering the seizure threshold.
  • Antihistamines. Possible increase of antimuscarinic (potentially increasing risk of paralytic ileus, among other effects) and sedative effects.
  • Antimuscarinics. Possible increase of antimuscarinic side-effects.
  • Anxiolytics and hypnotics. Increased sedative effect.
  • Apraclonidine. Avoidance advised by manufacturer of apraclonidine.
  • Brimonidine. Avoidance advised by manufacturer of brimonidine.
  • Clonidine. Lofepramine may reduce the antihypertensive effects of clonidine.
  • Diazoxide. Enhanced hypotensive (blood pressure-lowering) effect.
  • Digoxin. May increase risk of irregular heart rate.
  • Disulfiram. May require a reduction of lofepramine dose.
  • Diuretics. Increased risk of reduced blood pressure on standing.
  • Cimetidine, diltiazem, verapamil. May increase concentration of lofepramine in the blood plasma.
  • Hydralazine. Enhanced hypotensive effect.
  • Monoamine oxidase inhibitors (MAOIs). Advised not to be started until at least 2 weeks after stopping MAOIs. MAOIs are advised not to be started until at least 1–2 weeks after stopping TCAs like lofepramine.
  • Moclobemide. Moclobemide is advised not to be started until at least one week after treatment with TCAs is discontinued.
  • Nitrates. Could possibly reduce the effects of sublingual tablets of nitrates (failure to dissolve under tongue owing to dry mouth).
  • Rifampicin. May accelerate lofepramine metabolism thereby decreasing plasma concentrations of lofepramine.
  • Ritonavir. May increase lofepramine concentration in the blood plasma.
  • Sodium nitroprusside. Enhanced hypotensive effect.
  • Thyroid hormones. Effects on the heart of lofepramine may be exacerbated.

Pharmacology

Pharmacodynamics

Site LPA DSI Species Ref
NET 5.4 0.63–3.5 Human [14][15]
DAT >10,000 3,190 Human [14]
5-HT1A 4,600 ≥6,400 Human [16][17]
5-HT2A 200 115–350 Human [16][17]
5-HT2C ND 244–748 Rat [18][19]
5-HT3 ND 4,402 Mouse [19]
5-HT7 ND >1,000 Rat [20]
α1 100 23–130 Human [16][21][15]
α2 2,700 ≥1,379 Human [16][21][15]
β >10,000 ≥1,700 Rat [22][23]
D1 500 5,460 Human/rat [24]
D2 2,000 3,400 Human [16][21]
H1 245–360 60–110 Human [25]

[16][21]

H2 4,270 1,550 Human [25]
H3 79,400 >100,000 Human [25]
H4 36,300 9,550 Human [25]
mACh 67 66–198 Human [16][21]
  M1 67 110 Human [26]
  M2 330 540 Human [26]
  M3 130 210 Human [26]
  M4 340 160 Human [26]
  M5 460 143 Human [26]
σ1 2,520 4,000 Rodent [27][28]
σ2 ND 1,611 Rat [28]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Lofepramine is a strong inhibitor of norepinephrine reuptake and a moderate inhibitor of serotonin reuptake.[28] It is a weak-intermediate level antagonist of the muscarinic acetylcholine receptors.[28]

Lofepramine has been said to be a prodrug of desipramine,[29] although there is also evidence against this notion.[8]

Pharmacokinetics

Lofepramine is extensively metabolized, via cleavage of the p-chlorophenacyl group, to the TCA, desipramine, in humans.[7][8][1] However, it is unlikely this property plays a substantial role in its overall effects as lofepramine exhibits lower toxicity and anticholinergic side effects relative to desipramine while retaining equivalent antidepressant efficacy.[8] The p-chlorophenacyl group is metabolized to p-chlorobenzoic acid which is then conjugated with glycine and excreted in the urine.[7] The desipramine metabolite is partly secreted in the faeces.[7] Other routes of metabolism include hydroxylation, glucuronidation, N-dealkylation and N-oxidation.[7][1]

Chemistry

Lofepramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure.[30] Other dibenzazepine TCAs include imipramine, desipramine, clomipramine, and trimipramine.[30][31] Lofepramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine.[32][29] Unlike other tertiary amine TCAs, lofepramine has a bulky 4-chlorobenzoylmethyl substituent on its amine instead of a methyl group.[31] Although lofepramine is technically a tertiary amine, it acts in large part as a prodrug of desipramine, and is more similar to secondary amine TCAs in its effects.[33] Other secondary amine TCAs besides desipramine include nortriptyline and protriptyline.[34][33] The chemical name of lofepramine is N-(4-chlorobenzoylmethyl)-3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine and its free base form has a chemical formula of C26H27ClN2O with a molecular weight of 418.958 g/mol.[2] The drug is used commercially mostly as the hydrochloride salt; the free base form is not used.[2][3] The CAS Registry Number of the free base is 23047-25-8 and of the hydrochloride is 26786-32-3.[2][3]

History

Lofepramine was developed by Leo Läkemedel AB.[35] It first appeared in the literature in 1969 and was patented in 1970.[35] The drug was first introduced for the treatment of depression in either 1980 or 1983.[35][36]

Society and culture

Generic names

Lofepramine is the generic name of the drug and its INN and BAN, while lofepramine hydrochloride is its USAN, BANM, and JAN.[2][3][37][4] Its generic name in French and its DCF are lofépramine, in Spanish and Italian and its DCIT are lofepramina, in German is lofepramin, and in Latin is lofepraminum.[3][4]

Brand names

Brand names of lofepramine include Amplit, Deftan, Deprimil, Emdalen, Gamanil, Gamonil, Lomont, Tymelet, and Tymelyt.[1][2][3][4]

Availability

In the United Kingdom , lofepramine is marketed (as the hydrochloride salt) in the form of 70 mg tablets [12] and 70 mg/5 mL oral suspension.[38]

Research

Fatigue

A formulation containing lofepramine and the amino acid phenylalanine is under investigation as a treatment for fatigue as of 2015.[39]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Lofepramine Hydrochloride" (in en). Martindale: The Complete Drug Reference. The Pharmaceutical Press. https://www.medicinescomplete.com/mc/martindale/current/2522-w.htm. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 738–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA738. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 614–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA614. 
  4. ↑ 4.0 4.1 4.2 4.3 "Lofepramine". Drugs.com. https://www.drugs.com/international/lofepramine.html. 
  5. ↑ "Lofepramine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness". Drugs 37 (2): 123–140. February 1989. doi:10.2165/00003495-198937020-00003. PMID 2649353. 
  6. ↑ 6.0 6.1 "Lofepramine 70mg tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Merck Serono. 18 November 2010. http://www.medicines.org.uk/emc/medicine/20961/SPC/Lofepramine+70mg+tablets/. 
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 7.14 7.15 "Lofepramine 70 mg Film-coated Tablets - Summary of Product Characteristics (SPC) - (eMC)". Datapharm. April 2016. http://www.medicines.org.uk/emc/medicine/33411. 
  8. ↑ 8.0 8.1 8.2 8.3 "A comparison of the pharmacological properties of the novel tricyclic antidepressant lofepramine with its major metabolite, desipramine: a review". International Clinical Psychopharmacology 2 (4): 281–297. October 1987. doi:10.1097/00004850-198710000-00001. PMID 2891742. 
  9. ↑ "SAFC Commercial Life Science Products & Services | Sigma-Aldrich". Safcglobal.com. 2015-05-12. http://www.safcglobal.com/safc-pharma/en-us/home/small-molecule-api/services-overview/generic-products/lofepramine-hydrochloride.html. 
  10. ↑ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8. https://archive.org/details/bnf65britishnati0000unse. 
  11. ↑ 11.0 11.1 "Meta-analyses of the efficacy and tolerability of the tricyclic antidepressant lofepramine". The Journal of International Medical Research (SAGE Publications) 19 (3): 183–201. 1991. doi:10.1177/030006059101900304. PMID 1834491. 
  12. ↑ 12.0 12.1 "Lofepramine 70mg Tablets". http://www.medicines.org.uk/emc/medicine/27917/spc. 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 Joint Formulary Committee (2017). BNF 73 (British National Formulary) March 2017. London, UK: Pharmaceutical Press. pp. 354–355. ISBN 978-0-85711-276-7. 
  14. ↑ 14.0 14.1 Cite error: Invalid <ref> tag; no text was provided for refs named pmid9537821
  15. ↑ 15.0 15.1 15.2 Cite error: Invalid <ref> tag; no text was provided for refs named pmid9400006
  16. ↑ 16.0 16.1 16.2 16.3 16.4 16.5 16.6 "Binding of antidepressants to human brain receptors: focus on newer generation compounds". Psychopharmacology 114 (4): 559–565. May 1994. doi:10.1007/bf02244985. PMID 7855217. 
  17. ↑ 17.0 17.1 "Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro". European Journal of Pharmacology 132 (2–3): 115–121. December 1986. doi:10.1016/0014-2999(86)90596-0. PMID 3816971. 
  18. ↑ "Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor". Psychopharmacology 126 (3): 234–240. August 1996. doi:10.1007/bf02246453. PMID 8876023. 
  19. ↑ 19.0 19.1 "Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications". NIDA Research Monograph 178: 440–466. March 1998. PMID 9686407. 
  20. ↑ "Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtype". The Journal of Biological Chemistry 268 (24): 18200–18204. August 1993. doi:10.1016/S0021-9258(17)46830-X. PMID 8394362. 
  21. ↑ 21.0 21.1 21.2 21.3 21.4 "Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro". The Journal of Pharmacology and Experimental Therapeutics 230 (1): 94–102. July 1984. PMID 6086881. 
  22. ↑ "Antidepressant biochemical profile of the novel bicyclic compound Wy-45,030, an ethyl cyclohexanol derivative". Biochemical Pharmacology 35 (24): 4493–4497. December 1986. doi:10.1016/0006-2952(86)90769-0. PMID 3790168. 
  23. ↑ "Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding". Cellular and Molecular Neurobiology 19 (4): 467–489. August 1999. doi:10.1023/A:1006986824213. PMID 10379421. 
  24. ↑ "Pharmacological properties of the active metabolites of the antidepressants desipramine and citalopram". European Journal of Pharmacology 576 (1–3): 55–60. December 2007. doi:10.1016/j.ejphar.2007.08.017. PMID 17850785. 
  25. ↑ 25.0 25.1 25.2 25.3 "Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics". Naunyn-Schmiedeberg's Archives of Pharmacology 385 (2): 145–170. February 2012. doi:10.1007/s00210-011-0704-0. PMID 22033803. 
  26. ↑ 26.0 26.1 26.2 26.3 26.4 "Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics". Biochemical Pharmacology 45 (11): 2352–2354. June 1993. doi:10.1016/0006-2952(93)90211-e. PMID 8100134. 
  27. ↑ "1,3-Di(2-[5-3Htolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs"]. Proceedings of the National Academy of Sciences of the United States of America 83 (22): 8784–8788. November 1986. doi:10.1073/pnas.83.22.8784. PMID 2877462. Bibcode: 1986PNAS...83.8784W. 
  28. ↑ 28.0 28.1 28.2 28.3 Cite error: Invalid <ref> tag; no text was provided for refs named PDSP
  29. ↑ 29.0 29.1 Metabolism of Drugs and Other Xenobiotics. John Wiley & Sons. 23 February 2012. pp. 302–. ISBN 978-3-527-64632-6. https://books.google.com/books?id=f-XHh17NfwgC&pg=PA302. 
  30. ↑ 30.0 30.1 Polypharmacy in Psychiatry Practice, Volume I: Multiple Medication Use Strategies. Springer Science & Business Media. 15 February 2013. pp. 270–271. ISBN 978-94-007-5805-6. https://books.google.com/books?id=jy-LMZU7338C&pg=PA270. 
  31. ↑ 31.0 31.1 Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. 2008. pp. 580, 607. ISBN 978-0-7817-6879-5. https://books.google.com/books?id=R0W1ErpsQpkC&pg=PA580. 
  32. ↑ Pharmacodynamics and Drug Development: Perspectives in Clinical Pharmacology. John Wiley & Sons. 20 September 1994. pp. 160–. ISBN 978-0-471-95052-3. https://books.google.com/books?id=ncRXa8Dq88QC&pg=PA160. 
  33. ↑ 33.0 33.1 Shorter Oxford Textbook of Psychiatry. OUP Oxford. 9 August 2012. pp. 532–. ISBN 978-0-19-162675-3. https://books.google.com/books?id=Y1DtSGq-LnoC&pg=PA532. 
  34. ↑ Pharmacology Secrets. Elsevier Health Sciences. 2002. pp. 39–. ISBN 978-1-56053-470-9. https://books.google.com/books?id=_QQsj3PAUrEC&pg=PA39. 
  35. ↑ 35.0 35.1 35.2 "Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters". Chemical Communications (25): 3677–3692. July 2009. doi:10.1039/b903035m. PMID 19557250. 
  36. ↑ Medical Toxicology. Lippincott Williams & Wilkins. 2004. pp. 836–. ISBN 978-0-7817-2845-4. https://books.google.com/books?id=BfdighlyGiwC&pg=PA836. 
  37. ↑ Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 6 December 2012. pp. 168–. ISBN 978-94-011-4439-1. https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA168. 
  38. ↑ "Lofepramine Rosemont 70mg/5ml Oral Suspension - Summary of Product Characteristics (SPC) - (eMC)". 26 January 2016. http://www.medicines.org.uk/emc/medicine/10656. 
  39. ↑ "Lofepramine/phenylalanine - MultiCell Technologies" (in en). AdisInsight. Springer International Publishing AG. http://adisinsight.springer.com/drugs/800022855. 



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