Meprobamate

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Meprobamate
Meprobamate2DCSD.svg
Meprobamate3DanJ.gif
Systematic (IUPAC) name
[2-(carbamoyloxymethyl)-2-methyl-pentyl] carbamate
Clinical data
Trade names Miltown
AHFS/Drugs.com monograph
MedlinePlus a682077
Pregnancy cat. C (AU) D (US)
Legal status Prescription Only (S4) (AU) Schedule IV (US)
Routes Oral
Pharmacokinetic data
Bioavailability ?
Metabolism Hepatic
Half-life 10 hours
Excretion Renal
Identifiers
CAS number 57-53-4 YesY
ATC code N05BC01
PubChem CID 4064
DrugBank DB00371
ChemSpider 3924 YesY
UNII 9I7LNY769Q YesY
KEGG D00376 YesY
ChEMBL CHEMBL979 YesY
Chemical data
Formula C9H18N2O4 
Mol. mass 218.250 g/mol
Physical data
Density 1.229 g/cm³
Melt. point 105–106 °C (221–223 °F)
Boiling point 200 °C (392 °F) to 210 °C (410 °F)
 YesY (what is this?)  (verify)

Meprobamate (marketed under the brand names Miltown by Wallace Laboratories, Equanil by Wyeth, and Meprospan) is a carbamate derivative which is used as an anxiolytic drug. It was the best-selling minor tranquilizer for a time, but has largely been replaced by the benzodiazepines, due to their wider therapeutic index (lower toxicity) and lower incidence of serious side effects.

History[edit]

Meprobamate was first synthesized by Bernard John Ludwig, PhD, and Frank Milan Berger, MD, at Carter Products in May 1950. Wallace Laboratories, a subsidiary of Carter Products, bought the license and named it Miltown after the borough of Milltown in New Jersey. Launched in 1955, it rapidly became the first blockbuster psychotropic drug in American history, becoming popular in Hollywood and gaining notoriety for its seemingly miraculous effects.[1]

In the mid-1940s, Dr. Berger was working in a laboratory of a British drug company, looking for a preservative for penicillin, when he noticed that a compound called mephenesin had a sedative effect in small laboratory animals (rodents). Dr. Berger subsequently referred to this sedating or “tranquilizing” effect in a now-historic article, published by The British Journal of Pharmacology in 1946. However, there were three major drawbacks to the use of mephenesin as a tranquilizer: a very short duration of action, greater effect on the spinal cord than on the brain, and a weak activity.[2] After moving to Wallace Laboratories in New Jersey, Dr. Berger and a chemist, Dr. Bernard Ludwig, synthesized a chemically-related tranquilizing compound, meprobamate, that was able to overcome these three drawbacks.[3] It was soon prescribed under the trade name Miltown. It has been marketed under over 100 trade names, from "Amepromat" through "Quivet" to "Zirpon".[4]

A December 1955 study of 101 patients at the Mississippi State Hospital in Whitfield, Mississippi, found meprobamate useful in the alleviation of "mental symptoms." Three percent of the patients made a complete recovery, 29% were greatly improved, and 50% were somewhat better. Eighteen percent realized little change. Self-destructive patients became cooperative and calmer, and experienced a resumption of logical thinking. In 50% of the cases relaxation brought about more favorable sleep habits. Hydrotherapy and all types of shock treatment were halted.[5] Meprobamate was found to help in the treatment of alcoholics by 1956.[6] By 1957, over 36 million prescriptions had been filled for meprobamate in the US alone, a billion pills had been manufactured, and it accounted for fully a third of all prescriptions written.[7] Dr. Berger, clinical director of Wallace Laboratories (who died on March 16, 2008, aged 94[8]), described it as a relaxant of the central nervous system, whereas other tranquilizers suppressed it. A University of Michigan study found that meprobamate affected driving skills. Though patients reported being able to relax more easily, meprobamate did not completely alleviate their tense feelings. The disclosures came at a special scientific meeting at the Barbizon Plaza Hotel in New York City, at which Aldous Huxley addressed an evening session. He predicted the development of many chemicals "capable of changing the quality of human consciousness", in the next few years.[9]

In January 1960, Carter Products, Inc., makers of Miltown and American Home Products Corporation, which marketed Equanil, were charged with having conspired to monopolize the market in mild tranquilizers. It was revealed that the sale of meprobamate earned $40,000,000 for the defendants. Of this amount American Home Products accounted for approximately 2/3 and Carter about 1/3. The U.S. government sought an order mandating that Carter make its meprobamate patent available at no charge to any company desiring to use it.[10]

In April 1965, meprobamate was removed from the list of tranquilizers when experts ruled that the drug was a sedative instead. The U.S. Pharmacopoeia published the ruling. At the same time the Medical Letter disclosed that meprobamate could be addictive at dosage levels not much above recommended.[11] In December 1967, meprobamate was placed under abuse control amendments to the Food, Drug and Cosmetic Act. Records on production and distribution were required to be kept. Limits were placed on prescription duration and refills.[12]

Production continued throughout the 1960s, but by 1970 it was listed as a controlled substance after it was discovered to cause physical and psychological dependence.

On January 19, 2012, the European Medicines Agency recommended suspension throughout the European Union of all medicines containing meprobamate, "due to serious side effects seen with the medicine." The Agency’s Committee for Medicinal Products for Human Use (CHMP) "concluded that the benefits of meprobamate do not outweigh its risks."[13]

Usage and legal status[edit]

European Union[edit]

Suspension recommended for human use in 2012, see above under History.

United States[edit]

Controlled substance. See above under History.

Canada[edit]

Schedule IV substance (federal). For British Columbia only: Schedule I Prescription drug tagged TS - Targeted Substance (along with the benzodiazepines)[14] Provincial regulations may vary, e.g. for BC see library.bcpharmacists.org/D-Legislation_Standards. It is no longer readily available.[15]

Pharmacology[edit]

Although it was marketed as being safer, meprobamate has most of the pharmacological effects and dangers of the barbiturates (though it is less sedating at effective doses). It is reported to have some anticonvulsant properties against absence seizures, but can exacerbate generalized tonic-clonic seizures.

Meprobamate's mechanism of action is not completely known. It has been shown in animal studies to have effects at multiple sites in the central nervous system, including the thalamus and limbic system. Meprobamate binds to GABAA receptors[16] which interrupts neuronal communication in the reticular formation and spinal cord, causing sedation and altered perception of pain. It has been shown that meprobamate has the ability to activate currents even in the absence of GABA.[17] This relatively unique property makes meprobamate exceptionally dangerous when used in combination with other GABA-mediated drugs (including alcohol). It is also a potent adenosine reuptake inhibitor (AdoRI),[18][19] which is most likely responsible for its lower degree of sedation compared to barbiturates. Related drugs include carisoprodol and tybamate (prodrugs of meprobamate) and mebutamate.

Indications[edit]

Meprobamate is licensed for the short-term relief of anxiety, although it is not known whether the purported anti-anxiety effects of meprobamate are separable from its sedative effects. Its effectiveness as a selective agent for the treatment of anxiety has not been proven in humans,[20] and is not used as often as the benzodiazepines for this purpose. As of 2012, meprobamate is no longer used in any developed nation.

Meprobamate is available in 200 mg and 400 mg tablets for oral administration. Meprobamate is also a component of the combination drug Equagesic (discontinued in the UK in 2002) acting as a muscle relaxant.

Meprobamate, like barbiturates, possesses an analgesic/anesthetic potential. It is also found as a component of the combination analgesic "Stopayne" capsules (along with acetaminophen, caffeine, and codeine phosphate).

Meprobamate DOJ.jpg

Overdose[edit]

Symptoms of meprobamate overdose include: drowsiness, sluggishness, unresponsiveness, or coma; loss of muscle control; severe impairment or cessation of breathing; or shock. Death has been reported with ingestion of as little as 12g of meprobamate and survival with as much as 40g. In an overdose, meprobamate tablets may form a gastric bezoar, requiring physical removal of the undissolved mass of tablets through an endoscope; therefore, administration of activated charcoal should be considered even after 4 or more hours or if levels are rising.

Preparations which contain paracetamol may also induce severe liver toxicity resulting from paracetamol poisoning. The exact form of the preparation used should be identified immediately if possible, as patients who have also overdosed on paracetamol can reduce/avoid permanent liver damage with the administration of acetylcysteine.

Health issues[edit]

Meprobamate is a Schedule IV drug (US) (S5 in South Africa) under the Convention on Psychotropic Substances. With protracted use it can cause physical dependence and a potentially life-threatening abstinence syndrome similar to that of barbiturates and alcohol (delerium tremens). For this reason, discontinuation is often achieved through an extended regimen of slowly decreasing doses over a period of weeks, or even months. Alternatively, the patient may be switched to a longer-acting gabaminergic agent such as diazepam (in a manner similar to the use of methadone therapy for opiate addiction) before attempting de-titration.

An acute cerebral edema caused by a reaction to Equagesic, a combination of aspirin and meprobamate, is believed to have caused the death of Bruce Lee.

European Medicines Agency recommended suspension of marketing authorisations for meprobamate-containing medicines in the European Union in January 2012.

Synthesis[edit]

Meprobamate synthesis:[21][22][23]

Meprobamate, 2-methyl-2-propyl-1,3-propandiol dicarbamate is synthesized by the reaction of 2-methylvaleraldehyde with two molecules of formaldehyde and the subsequent transformation of the resulting 2-methyl-2-propylpropan-1,3-diol into the dicarbamate via successive reactions with phosgene and ammonia.

See also[edit]

References[edit]

  1. ^ Tone, Andrea (2009). "The Fashionable Pill". The Age of Anxiety: A History of America's Turbulent Affair with Tranquilizers. New York: Basic Books. ISBN 978-0-465-08658-0. 
  2. ^ Berger FM. (1947). "Mode of Action of Myanesin". Br J Pharmacol. 2 (4): 241–250. 
  3. ^ Ludwig BJ, Piech E. (1951). "Some anticonvulsant agents derived from 1, 3-propanediol". J Am Chem Soc. 73 (12): 5779–5781. doi:10.1021/ja01156a086. 
  4. ^ http://webbook.nist.gov/cgi/cbook.cgi?ID=57-53-4
  5. ^ "New Hope Arises On Cancer Serum", The New York Times, December 28, 1955, Page 21.
  6. ^ Author unknown (1956-04-01). "ALCOHOLIC PERIL FOUND IN DRUGS; Some Tranquilizing Therapy May Be Habit-Forming, Physicians Tell Parley". The New York Times. p. 28. Retrieved 2009-01-23. 
  7. ^ Dokoupil, Tony (2009-01-22). "How Mother Found Her Helper". Newsweek. Retrieved 2009-01-23. 
  8. ^ Carey, Benedict (2008-03-21). "Frank Berger, 94, Miltown Creator, Dies". The New York Times. Retrieved 2009-02-01. 
  9. ^ "'BEHAVIOR' DRUGS NOW ENVISIONED; Aldous Huxley Predicts They Will Bring Re-Examining of Ethics and Religion". The New York Times. 1956-10-19. Retrieved 2009-02-01. 
  10. ^ Ranzal, Edward (1960-01-28). "TRUST SUIT NAMES 2 DRUG CONCERNS; Makers of Tranquilizers Are Accused". The New York Times. Retrieved 2009-02-01. 
  11. ^ "MILTOWN OFF LIST OF TRANQUILIZERS; But It Will Continue to Be Used as a Sedative". The New York Times. 1965-04-22. Retrieved 2009-02-01. 
  12. ^ "Tranquilizer Is Put Under U.S. Curbs; Side-Effects Noted". The New York Times. 1967-12-06. Retrieved 2009-02-01. 
  13. ^ "Questions and answers on the suspension of the marketing authorisations for oral meprobamate-containing medicines". 2012-01-19. Retrieved 2012-01-20. 
  14. ^ "NAPRA - Search National Drug Schedule" (ASP). National Association of Pharmacy Regulatory Authorities. 2009. Retrieved 2014-01-07. 
  15. ^ Personal communication from a pharmacist
  16. ^ Rho JM, Donevan SD, Rogawski MA (March 1997). "Barbiturate-like actions of the propanediol dicarbamates felbamate and meprobamate". J. Pharmacol. Exp. Ther. 280 (3): 1383–91. PMID 9067327. 
  17. ^ Rho JM, Donevan SD, Rogawski MA (March 1997). "Barbiturate-like actions of the propanediol dicarbamates felbamate and meprobamate". J. Pharmacol. Exp. Ther. 280 (3): 1383–91. PMID 9067327. 
  18. ^ Phillis JW, Delong RE. (1984). "A purinergic component in the central actions of meprobamate". Eur J Pharmacol. 101 (3–4): 295–297. doi:10.1016/0014-2999(84)90174-2. PMID 6468504. 
  19. ^ DeLong RE, Phillis JW, Barraco RA. (1985). "A possible role of endogenous adenosine in the sedative action of meprobamate". Eur J Pharmacol. 118 (3): 359–362. doi:10.1016/0014-2999(85)90149-9. PMID 4085561. 
  20. ^ Brunton, Laurence; John Lazo; Keith Parker (2005-10-28). Goodman And Gilman's The Pharmacological Basis of Therapeutics (11 ed.). McGraw-Hill Professional. ISBN 0-07-142280-3. 
  21. ^ F.M. Berger, B.J. Ludwig, U.S. Patent 2,724,720 (1955).
  22. ^ F.A. Fries, K. Moenkemeyer, CH 373026  (1963).
  23. ^ Ludwig, B. J.; Piech, E. C. (1951). "Some Anticonvulsant Agents Derived from 1,3-Propanediols". Journal of the American Chemical Society 73: 5779. doi:10.1021/ja01156a086.  edit

External links[edit]