Biperiden

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Biperiden Stereoisomers.png
Biperiden-3D-sticks.png
Systematic (IUPAC) name
(1RS,2SR,4RS)-1-(bicyclo[2.2.1]hept-5-en-2-yl)-1-phenyl-3-(piperidin- 1-yl)propan-1-ol
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a699058
Pregnancy cat.
Legal status
Routes Oral, IM, IV
Pharmacokinetic data
Bioavailability 33 ± 5% (oral)
Protein binding 60%
Metabolism Hepatic hydroxylation
Half-life 18 to 24 hours
Excretion Renal
Identifiers
CAS number 514-65-8 YesY
ATC code N04AA02
PubChem CID 2381
DrugBank DB00810
ChemSpider 2289 YesY
UNII 0FRP6G56LD YesY
KEGG D00779 YesY
ChEBI CHEBI:3112 YesY
ChEMBL CHEMBL1101 YesY
Chemical data
Formula C21H29NO 
Mol. mass 311.461 g/mol
 YesY (what is this?)  (verify)

Biperiden is an antiparkinsonian agent[1] of the anticholinergic type.[2] The original brand name, which still exists and is manufactured by BASF/Knoll Pharma, is Akineton. Generics are available worldwide.

Pharmacokinetics[edit]

The oral bioavailability is only 33 +/- 5% due to extensive first-pass metabolism. In young, healthy volunteers, peak plasma concentrations following a single oral 4 mg immediate-release dose are reached after 1.5 hours. The elimination half-life has been determined as 18.4 hours, and may be prolonged in geriatric patients. After a 4 mg intravenous dose, the elimination half-life is approximately 24 hours.

Pharmacology[edit]

Biperiden has an atropine-like blocking effect on all peripheral structures which are parasympathetic-innervated (e.g. cardiovascular and visceral organs). It also has a prominent central blocking effect on M1 receptors. Biperiden does also act as FIASMA (functional inhibitor of acid sphingomyelinase).[3]

Uses[edit]

Biperiden is used for the adjunctive treatment of all forms of Parkinson's disease and for reduced sweating in methadone users (postencephalitic, idiopathic, and arteriosclerotic). It seems to exert better effects in the postencephalitic and idiopathic than in the arteriosclerotic type.

Biperiden is also commonly used to improve parkinsonian signs and symptoms related to antipsychotic drug therapy.

It relieves muscle rigidity, reduces abnormal sweating related with Clozapine and Methadone use[4][5] and salivation, improves abnormal gait, and to lesser extent, tremor.

Contraindications and cautions[edit]

  • Hypersensitivity to biperiden
  • Narrow angle glaucoma
  • Ileus
  • Caution : Patients with obstructive diseases of the urogenital tract, patients with a known history of seizures and those with potentially dangerous tachycardia

Special patient groups[edit]

Pregnancy and lactation[edit]

  • Pregnancy : In animal studies biperiden had no embryo- or fetotoxic effects. There is no sufficient clinical data on pregnant women. The drug should therefore be used cautiously during pregnancy.
  • Lactation : Biperiden is found in the milk of lactating women. No sufficient clinical data exists regarding effects for the newborns. Additionally, biperiden may decrease maternal milk production. It is therefore recommended that biperiden is not used during lactation.

Pediatric patients[edit]

Children and adolescents aged 1 year and older may be treated. The clinical experience is mainly on the shortterm treatment of acute drug induced dystonic reactions. Doses should be reduced according to the weight of the patients.

Side effects[edit]

Dose-dependent side effects are frequent. Particularly geriatric patients may react with confusional states or develop delirium.

  • CNS : Drowsiness, vertigo, headache, and dizziness are frequent. With high doses nervousness, agitation, anxiety, delirium, and confusion are noted. Biperiden may be abused due to a short acting mood-elevating and euphoriant effect. The normal sleep architecture may be altered (REM sleep depression). Biperiden may lower the seizure-threshold. Some instances of dementia have been noted to correlate with chronic administration of anticholinergic medications such as Biperiden for Parkinson's disease.[6]
  • Peripheral side effects : Blurred vision, dry mouth, impaired sweating, abdominal discomfort, and obstipation are frequent. Tachycardia may be noted. Allergic skin reactions may occur. Parenteral use may cause orthostatic hypotension.
  • Eyes : Biperiden causes mydriasis with or without photophobia. It may precipitate narrow angle glaucoma.

Interactions[edit]

  • Other anticholinergic drugs (e.g. spasmolytics, antihistamines, TCAs) : Side effects of biperiden may be increased.
  • Quinidine : Increased anticholinergic action (particular on AV conduction).
  • Antipsychotics : Long term use of biperiden may mask or increase the risk of tardive dyskinesia.
  • Pethidine (meperidine) : Central effects and side effects of pethidine may be increased.
  • Metoclopramide : Action of metoclopramide is decreased.
  • Alcohol : Risk of serious intoxication.

Dosage[edit]

Strictly individual. Oral, and in some countries, IV and IM use is possible. The usual oral daily doses are between 2 and 16 mg. If possible, patients should be started with a low initial dose which is increased slowly.

Overdose[edit]

Biperiden mimics an atropine intoxication with mydriasis, dryness of mucous membranes, red face, atonic states of bowels and bladder, and hyperthermia in high doses. Central consequences are agitation, confusion, and hallucinations. An untreated overdose may be fatal, particular in children. Premortal signs are respiratory depression and cardiac arrest. A specific antagonist is physostigmine which combines a peripheral and a central action. Carbachol can be used to treat atonic bowels and bladder. The vital functions should be monitored and stabilized. It may be necessary to treat hyperthermia with cooling blankets.

History[edit]

Biperiden was synthesized by the German chemist W. Klavehn from Knoll AG, Germany. In March 1953 a patent was applied for in Germany and subsequently in many other countries.

Synthesis[edit]

Biperidinsynthesis

The drug can be synthesised from the nucleophilic reaction of acetylnorbornene with a suitable grignard reagent.[7] Water is then added as the workup to form the final product.

References[edit]

  1. ^ Jackisch R, Kruchen A, Sauermann W, Hertting G, Feuerstein TJ (October 1994). "The antiparkinsonian drugs budipine and biperiden are use-dependent (uncompetitive) NMDA receptor antagonists". Eur. J. Pharmacol. 264 (2): 207–11. doi:10.1016/0014-2999(94)00528-1. PMID 7851484. 
  2. ^ Pehl C, Wendl B, Kaess H, Pfeiffer A (October 1998). "Effects of two anticholinergic drugs, trospium chloride and biperiden, on motility and evoked potentials of the oesophagus". Aliment. Pharmacol. Ther. 12 (10): 979–84. doi:10.1046/j.1365-2036.1998.00398.x. PMID 9798802. 
  3. ^ Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P (2011). "Identification of novel functional inhibitors of acid sphingomyelinase". PLoS ONE 6 (8): e23852. doi:10.1371/journal.pone.0023852. PMC 3166082. PMID 21909365. 
  4. ^ Richardson C, Kelly DL, Conley RR (August 2001). "Biperiden for excessive sweating from clozapine". Am J Psychiatry 158 (8): 1329–30. doi:10.1176/appi.ajp.158.8.1329-a. PMID 11481174. 
  5. ^ Caflisch C, Figner B, Eich D (February 2003). "Biperiden for excessive sweating from methadone". Am J Psychiatry 160 (2): 386–7. doi:10.1176/appi.ajp.160.2.386. PMID 12562595. 
  6. ^ Nishiyama K, Mizuno T, Sakuta M, Kurisaki H (1993). "Chronic dementia in Parkinson's disease treated by anticholinergic agents. Neuropsychological and neuroradiological examination.". Adv Neurol 60: 479–83. PMID 8420174. 
  7. ^ http://www.sumobrain.com/patents/wipo/Process-producing-acetylnorbornene-intermediate-in/WO2008065672.html