Lofepramine

Lofepramine

Clinical data
Trade names	Lomont, Emdalen, Gamanil
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral
ATC code	N06AA07 (WHO)
Legal status
Legal status	UK: POM (Prescription only)
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
IUPAC name N-(4-chlorobenzoylmethyl)-3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine
CAS Number	23047-25-8 N
PubChem (CID)	3947
IUPHAR/BPS	7551
ChemSpider	3810 Y
UNII	OCA4JT7PAW Y
KEGG	D08140 Y
ChEBI	CHEBI:47782 Y
ChEMBL	CHEMBL87708 Y
ECHA InfoCard	100.041.254
Chemical and physical data
Formula	C26H27ClN2O
Molar mass	418.958 g/mol
3D model (Jmol)	Interactive image
SMILES Clc1ccc(cc1)C(=O)CN(C)CCCN4c2ccccc2CCc3c4cccc3
InChI 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 Y Key:SAPNXPWPAUFAJU-UHFFFAOYSA-N Y
NY (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

• Alcohol. Increased sedative effect
• Antiepileptics. Possibly antagonise the anticonvulsant effect of antiepileptics by lowering the convulsive threshold
• Antihistamines. Possible increase of antimuscarinic 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
• Diazoxide. Enhanced hypotensive effect
• Hydralazine. Enhanced hypotensive effect
• Monoamine oxidase inhibitors (MAOIs). Do not start until 2 weeks after stopping MAOIs, also MAOIs should not be started until at least 1–2 weeks after stopping tricyclic-related antidepressants
• Moclobemide. do not start moclobemide for at least 1 week after stopping tricyclic-related antidepressants
• Nitrates. Possibly reduce effects of sublingual tablets of nitrates (failure to dissolve under tongue owing to dry mouth)
• Sodium Nitroprusside. Enhanced hypotensive effect

Contraindications

• In the immediate recovery period after myocardial infarction
• In arrhythmias (particularly heart block)
• In the manic phase of bipolar disorder
• In acute porphyria^[8]
• With Amiodarone
• With Terfenadine
• In severe liver and/or severe renal impairment^[9]

Mechanism of action

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

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

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]

This has assertion however has been contradicted in many papers and texts (Seminars in General Adult Psychiatry - Page 84), that claim the bioavailability of lofepramines metabolite, desipramine, is ultimately higher than that of the parent compound.

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 ^[9] and 70mg/5ml oral suspension.^[11]

Synthesis

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

References