Lofepramine

Lofepramine

Lofepramine
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
Legal status
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 Registry Number  N
ATC code N06
PubChem CID:
IUPHAR/BPS
ChemSpider  Y
UNII  Y
KEGG  Y
ChEBI  Y
ChEMBL  Y
Chemical data
Formula C26H27ClN2O
Molecular mass 418.958 g/mol
 N   

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]

Contents

  • Indications 1
  • Side effects 2
    • Other side effects 2.1
  • Interactions 3
  • Contraindications 4
  • Mechanism of action 5
  • Pharmacokinetics 6
  • Warnings 7
  • Availability 8
  • Synthesis 9
  • References 10

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. ^ 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.  
  2. ^ a b c "Lofepramine 70mg tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Merck Serono. 18 November 2010. Retrieved 21 November 2013. 
  3. ^ http://www.safcglobal.com/safc-pharma/en-us/home/small-molecule-api/services-overview/generic-products/lofepramine-hydrochloride.html
  4. ^ a b c 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.  
  5. ^ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press.  
  6. ^ https://www.medicinescomplete.com/mc/bnf/current/PHP2352-tricyclic-and-related-antidepressant-drugs.htm#PHP2353. 
  7. ^ https://www.medicinescomplete.com/mc/bnf/current/bnf_int252-antidepressants-tricyclic-related.htm. 
  8. ^ "Tricyclic and related antidepressant drugs / Contraindications". 
  9. ^ "Lofepramine 70mg Tablets". 
  10. ^ a b Roth, BL; Driscol, J (12 January 2011). Database"i"PDSP K. Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 21 November 2013. 
  11. ^ Lomont , SPC from the eMC