Lofepramine

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Lofepramine
Lofepramin.svg
Lofepramine-from-xtal-1987-ball-and-stick.png
Clinical data
Trade names Gamanil, Lomont, Tymelyt, others
Synonyms Lopramine; DB-2182; Leo-460; WHR-2908A[1][2][3][4]
AHFS/Drugs.com International Drug Names
Routes of
administration
Oral
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability 7%[6]
Protein binding 99%[7]
Metabolism Hepatic (via cytochrome P450, including CYP2D6)[5]
Metabolites Desipramine (major)
Biological half-life Up to 5 hours;[1] 12–24 hours (active metabolites)
Excretion Urine, feces (mostly as metabolites)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.041.254
Chemical and physical data
Formula C26H27ClN2O
Molar mass 418.958 g/mol
3D model (JSmol)
 NYesY (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.[5][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.[5] 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]

Medical uses[edit]

In the United Kingdom, lofepramine is licensed for the treatment of depression which is its primary use in medicine.[7][10]

Contraindications[edit]

To be used with caution, or not at all, for people with the following conditions:[5]

And in those being treated with amiodarone or terfenadine.[5]

Pregnancy and lactation[edit]

Lofepramine use during pregnancy is advised against unless the benefits clearly outweigh the risks.[5] This is because its safety during pregnancy has not been established and animal studies have shown some potential for harm if used during pregnancy.[5] If used during the third trimester of pregnancy it can cause insufficient breathing to meet oxygen requirements, agitation and withdrawal symptoms in the infant.[5] 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.[5] Although the amount secreted in breast milk is likely too small to be harmful.[12]

Side effects[edit]

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.[12] 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.[12]

Side effects with unknown frequency include (but are not limited to):[12]

Withdrawal[edit]

If abruptly stopped after regular use it can cause withdrawal effects such as sleeplessness, irritability and excessive sweating.[5]

Overdose[edit]

Compared to other TCAs, lofepramine is considered to be less toxic in overdose.[12] 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.[5]

Interactions[edit]

Lofepramine is known to interact with:[12][5]

Pharmacology[edit]

Pharmacodynamics[edit]

Lofepramine (and metabolite)[13]
Site LPA DSI Species Ref
SERT 70 17.6–163 Human [14][15]
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][13]
σ2 ND 1,611 Rat [13]
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.[13] It is a weak-intermediate level antagonist of the muscarinic acetylcholine receptors.[13]

Lofepramine has been said to be a prodrug of desipramine,[28] although there is also evidence against this notion.[8]

Pharmacokinetics[edit]

Lofepramine is extensively metabolized, via cleavage of the p-chlorophenacyl group, to the TCA, desipramine, in humans.[5][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.[5] The desipramine metabolite is partly secreted in the faeces.[5] Other routes of metabolism include hydroxylation, glucuronidation, N-dealkylation and N-oxidation.[5][1]

Chemistry[edit]

Lofepramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure.[29] Other dibenzazepine TCAs include imipramine, desipramine, clomipramine, and trimipramine.[29][30] Lofepramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine.[31][28] Unlike other tertiary amine TCAs, lofepramine has a bulky 4-chlorobenzoylmethyl substituent on its amine instead of a methyl group.[30] 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.[32] Other secondary amine TCAs besides desipramine include nortriptyline and protriptyline.[33][32] 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[edit]

Lofepramine was developed by Leo Läkemedel AB.[34] It first appeared in the literature in 1969 and was patented in 1970.[34] The drug was first introduced for the treatment of depression in either 1980 or 1983.[34][35]

Society and culture[edit]

Generic names[edit]

Lofepramine is the generic name of the drug and its INN and BAN, while lofepramine hydrochloride is its USAN, BANM, and JAN.[2][3][36][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[edit]

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

Availability[edit]

In the United Kingdom, lofepramine is marketed (as the hydrochloride salt) in the form of 70 mg tablets [11] and 70 mg/5 mL oral suspension.[37]

Research[edit]

Fatigue[edit]

A formulation containing lofepramine and the amino acid phenylalanine is under investigation as a treatment for fatigue as of 2015.[38]

References[edit]

  1. ^ a b c d e f "Lofepramine Hydrochloride: Martindale: The Complete Drug Reference". MedicinesComplete. The Pharmaceutical Press. Retrieved 3 August 2017. 
  2. ^ a b c d e f J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 738–. ISBN 978-1-4757-2085-3. 
  3. ^ a b c d e f g Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 614–. ISBN 978-3-88763-075-1. 
  4. ^ a b c d https://www.drugs.com/international/lofepramine.html
  5. ^ a b c d e f g h i j k l m n o p "Lofepramine 70 mg Film-coated Tablets - Summary of Product Characteristics (SPC) - (eMC)". electronic Medicines Compendium (eMC). Datapharm. April 2016. Retrieved 3 August 2017. 
  6. ^ Lancaster, SG; Gonzalez, JP (February 1989). "Lofepramine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness". Drugs. 37 (2): 123–140. PMID 2649353. doi:10.2165/00003495-198937020-00003. 
  7. ^ a b "Lofepramine 70mg tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Merck Serono. 18 November 2010. Retrieved 21 November 2013. 
  8. ^ a b c d Leonard BE (October 1987). "A comparison of the pharmacological properties of the novel tricyclic antidepressant lofepramine with its major metabolite, desipramine: a review". International Clinical Psychopharmacology. 2 (4): 281–97. PMID 2891742. doi:10.1097/00004850-198710000-00001. 
  9. ^ "SAFC Commercial Life Science Products & Services | Sigma-Aldrich". Safcglobal.com. 2015-05-12. Retrieved 2016-02-24. 
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  11. ^ a b "Lofepramine 70mg Tablets". 
  12. ^ a b c d e f Joint Formulary Committee, ed. (2017). BNF 73 (British National Formulary) March 2017. London, UK: Pharmaceutical Press. pp. 354–355. ISBN 978-0857112767. 
  13. ^ a b c d e Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017. 
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  19. ^ a b Toll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, Schwartz RW, Haggart D, O'Brien A, White A, Kennedy JM, Craymer K, Farrington L, Auh JS (1998). "Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications". NIDA Res. Monogr. 178: 440–66. PMID 9686407. 
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  25. ^ a b c d Appl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R (2012). "Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics". Naunyn Schmiedebergs Arch. Pharmacol. 385 (2): 145–70. PMID 22033803. doi:10.1007/s00210-011-0704-0. 
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  27. ^ Weber E, Sonders M, Quarum M, McLean S, Pou S, Keana JF (1986). "1,3-Di(2-[5-3H]tolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs". Proc. Natl. Acad. Sci. U.S.A. 83 (22): 8784–8. PMC 387016Freely accessible. PMID 2877462. 
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  37. ^ "Lofepramine Rosemont 70mg/5ml Oral Suspension - Summary of Product Characteristics (SPC) - (eMC)". 26 January 2016. Retrieved 3 August 2017. 
  38. ^ "Lofepramine/phenylalanine - MultiCell Technologies - AdisInsight". AdisInsight. Springer International Publishing AG. Retrieved 3 August 2017.