Lofepramine
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| Clinical data | |
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| Trade names | Lomont, Emdalen, Gamanil |
| AHFS/Drugs.com | International Drug Names |
| Routes of administration |
Oral |
| ATC code | N06AA07 (WHO) |
| Legal status | |
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| 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 | |
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| CAS Number | 23047-25-8  |
| PubChem (CID) | 3947 |
| IUPHAR/BPS | 7551 |
| ChemSpider | 3810  |
| UNII | OCA4JT7PAW |
| KEGG | D08140 |
| ChEBI | CHEBI:47782 |
| ChEMBL | CHEMBL87708 |
| ECHA InfoCard | 100.041.254 |
| Chemical and physical data | |
| Formula | C26H27ClN2O |
| Molar mass | 418.958 g/mol |
| 3D model (Jmol) | Interactive image |
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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[edit]
In the United Kingdom, Lofepramine is licensed for the treatment of depression which is its primary use in medicine.[2][5]
Side effects[6][edit]
- 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[edit]
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][edit]
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[edit]
- 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[edit]
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[edit]
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, that claim the bioavailability of lofepramines metabolite, desipramine, is ultimately higher than that of the parent compound,[11] and that it's reduced cardio toxicity, is due to lofepramines antagonism on the cardiac effects of desipramine.[12]
Warnings[edit]
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[edit]
In the United Kingdom, lofepramine is marketed (as the hydrochloride salt) in the form of 70 mg tablets [9] and 70 mg/5ml oral suspension.[13]
Synthesis[edit]
References[edit]
- ^ 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. doi:10.2165/00003495-198937020-00003. PMID 2649353.
- ^ a b c "Lofepramine 70mg tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Merck Serono. 18 November 2010. Retrieved 21 November 2013.
- ^ "SAFC Commercial Life Science Products & Services | Sigma-Aldrich". Safcglobal.com. 2015-05-12. Retrieved 2016-02-24.
- ^ 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. doi:10.1097/00004850-198710000-00001. PMID 2891742.
- ^ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.
- ^ https://www.medicinescomplete.com/mc/bnf/current/PHP2352-tricyclic-and-related-antidepressant-drugs.htm#PHP2353. Missing or empty
|title=(help) - ^ https://www.medicinescomplete.com/mc/bnf/current/bnf_int252-antidepressants-tricyclic-related.htm. Missing or empty
|title=(help) - ^ "Tricyclic and related antidepressant drugs / Contraindications".
- ^ a b "Lofepramine 70mg Tablets".
- ^ a b Roth, BL; Driscol, J (12 January 2011). "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 21 November 2013.
- ^ Seminars In General Adult Psychiatry - Page 84 - https://books.google.ie/books?id=6PGzHFuS1xkC&pg=PA84&lpg=PA84&dq=Seminars+in+General+Adult+Psychiatry+-+lofepramine&source=bl&ots=EkAcTEAsEW&sig=qdv6nyt3hlF-Hq0yvhQ1zL4Jspg&hl=en&sa=X&ved=0ahUKEwiC-Pftz_jRAhVsK8AKHQu7BQsQ6AEIGTAA#v=onepage&q=Seminars%20in%20General%20Adult%20Psychiatry%20-%20lofepramine&f=false
- ^ Clinical Pharmacy and Therapeutics - Page 470 - https://books.google.ie/books?id=CcDRAQAAQBAJ&pg=PA470&lpg=PA470&dq=Clinical+pharmacy+and+therapeutics+lofepramine&source=bl&ots=9kMFDW8-4H&sig=x5j1PSIGAlviRZpfZPuH6GZjAU8&hl=en&sa=X&ved=0ahUKEwiynd-J0PjRAhVpLMAKHVt-AnwQ6AEIGTAA#v=onepage&q=Clinical%20pharmacy%20and%20therapeutics%20lofepramine&f=false
- ^ Lofepramine Rosemont, SPC from the eMC
