Lofepramine

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Lofepramine
Lofepramin.svg
Lofepramine3Dan2.gif
Systematic (IUPAC) name
N-(4-chlorobenzoylmethyl)-3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine
Clinical data
Trade names Lomont, Emdalen, Gamanil
AHFS/Drugs.com International Drug Names
Legal status
  • UK: POM (Prescription only)
Routes of
administration		 Oral
Pharmacokinetic data
Bioavailability 7%[1]
Protein binding 99%[2]
Metabolism Hepatic (via P450 cytochromes)
Biological half-life 1.7-2.5 hours (dose-dependent; parent drug); 12-24 hours (active metabolites)
Excretion Urine (mostly as metabolites)
Identifiers
CAS Number 23047-25-8 N
ATC code N06AA07 (WHO)
PubChem CID: 3947
IUPHAR/BPS 7551
ChemSpider 3810 YesY
UNII OCA4JT7PAW YesY
KEGG D08140 YesY
ChEBI CHEBI:47782 YesY
ChEMBL CHEMBL87708 YesY
Chemical data
Formula C26H27ClN2O
Molecular mass 418.958 g/mol
  • Clc1ccc(cc1)C(=O)CN(C)CCCN4c2ccccc2CCc3c4cccc3
  • InChI=1S/C26H27ClN2O/c1-28(19-26(30)22-13-15-23(27)16-14-22)17-6-18-29-24-9-4-2-7-20(24)11-12-21-8-3-5-10-25(21)29/h2-5,7-10,13-16H,6,11-12,17-19H2,1H3 YesY
  • Key:SAPNXPWPAUFAJU-UHFFFAOYSA-N YesY
 NYesY (what is this?)  (verify)

Lofepramine (brand name: Lomont (UK) Emdalen (ZA), Gamanil (IE, UK (discontinued)) & Tymelyt (discontinued)) is a third generation[3] tricyclic antidepressant which was introduced in 1983 for the treatment of depressive disorders.[4] Lofepramine is less sedating than, for instance, amitriptyline, and is safer in overdose than older tricyclics.[2]

Indications

In the United Kingdom, Lofepramine is licensed for the treatment of depression which is its primary use in medicine.[2][5]

Side effects[6]

  • Common
    • Constipation
    • Dry Mouth
    • Blurred Vision
    • Sleepiness
  • Uncommon
    • Central nervous system side-effects, particularly in the elderly, anxiety, dizziness, agitation, confusion, sleep disturbances, irritability, and paraesthesia
    • Headache
    • Nausea
    • Palpitations
    • Urinary Retention
    • Sexual Dysfunction
  • Rare
    • Constipation (leading to paralytic ileus, particularly in the elderly)
    • Skin Rashes
  • Very Rare
    • Blurred Vision (precipitation of angle-closure glaucoma)

Other side effects

Delusions, nightmares, facial oedema, general feeling of being unwell, bleeding from skin, inflammation of mucous membranes, loss of taste, psychiatric problems such as self-harm, pins and needles, sweating, dizziness. Can cause behavioural disturbance in the young. May produce weight gain or cause changes in the levels of blood sugar. Some patients report muscular discomfort, particularly in the shoulders.

Interactions[7]

Lofepramine is known to interact with

Contraindications

Mechanism of action

Lofepramine is a strong inhibitor of norepinephrine reuptake (Ki=5.4 nM) and a moderate inhibitor of serotonin reuptake (Ki=70 nM).[10] It is a weak-intermediate level antagonist of the muscarinic acetylcholine receptors (Ki values of 67 nM, 330 nM, 130 nM, 340 nM, 460 nM for M1, M2, M3, M4 & M5 respectively).[10]

The measured affinity [Kd (nM)] of Lofepramine at different receptor or transporter binding sites are listed below:

Compound SERT NET M1
Lofepramine 70 5.4 67

Pharmacokinetics

It is partially converted to its active metabolite desipramine in vivo.[4] 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.[4]

Warnings

To be used with caution for epileptic patients or those with glaucoma or psychosis. Lofepramine should not be given to people who have suffered liver failure or heart disease. Not advisable for use in pregnant women.

Availability

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

Synthesis

Lofepramine synthesis: E. Eriksoo et al., GB 1177525 ; eidem, U.S. Patent 3,637,660 (1970, 1972 both to Leo AB).

References

  1. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ 2.0 2.1 2.2 Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ 4.0 4.1 4.2 Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ 10.0 10.1 Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lomont , SPC from the eMC
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