Meperidine Hydrochloride (Demerol) Meperidine hydrochloride is a schedule II opioid analgesic pain reliever also known by the trade name “Demerol.” It is a narcotic analgesic used for moderate to severe pain relief and is qualitatively similar to morphine. Meperidine was initially synthesized as an anticholingeric drug, but was found to have analgesic properties. Though meperidine was initially portrayed as having clinical advantages, studies have proven that it is vastly inferior to other analgesics for reasons including poor efficacy, normeperidine toxicity, and negative drug interactions (Latta, Ginsberg, & Barkin, 2002). Major uses & efficacy Meperidine hydrochloride is used for moderate to severe pain relief, preoperative medication, obstetrical analgesia, or to support anesthesia. It can be used to relieve migraines. There are not consistent conclusions about meperidine's efficacy, with studies reporting conflicting reports on the sedative abilities of meperidine compared to morphine (McEvoy, 1998), though a 10mg morphine dose is equal to a 75-100mg dose of meperidine, and meperidine’s duration is around 50% compared to morphine’s (Westring & Fribourg, 1974). There have been suggestions to remove meperidine from the health system (Beckwith, Fox, Chandramouli, 2002). Pharmacokinetics Meperidine hydrochloride is an injection administered through intramuscular, subcutaneous, or intravenous routes, with intramuscular the typical route for repeated administrations. Demerol is administered orally in tablets that contain 50 or 100mg of the Demerol brand of meperidine hydrochloride. Meperidine’s primary therapeutic function is relieving pain by stimulating theμ-opioid receptors in the nervous system. Taken orally, about 50% of the dose reaches systemic circulation and peak plasma levels occur in 1-2 hours. It appears in the cerebrospinal fluid and also will cross the placenta (Apgar, Burns, Brodie, & Papper, 1952). It has a larger volume of distribution and a longer halflife than heroin or morphine (Karch & Drummer, 2008). Through oral administration its half-life is 3-4 hours (Hershey, 1983); through IV injection its half-life is 8 hours. Normeperidine has a longer half-life, averaging between 15-30 hours (Hershey, 1983). Meperidine is primarily eliminated through the liver, and normeperidine through the liver and kidney. Major contraindications Therapeutic doses of meperidine have occasionally resulted in severe and sometimes fatal reactions in individuals who have taken monoamine oxidase (MAO) inhibitors within the last fourteen days (McEvoy, 1998). Symptoms have included coma, respiratory depression, cyanosis, and hypotension, as well as serotonin syndrome including agitation, hyperthemia, tachycardia, tremors, and impaired consciousness. Before administering a narcotic to a patient, sensitivity tests are conducted with small, incremental doses first administered while the patient's condition is closely monitored. In addition to those who use MAO inhibitors, meperidine is also not to be used in those with respiratory insufficiency, such as patients with asthma, due to its respiratory depressant effects (Osol & Hoover, 1975). Meperidine may cause hypotension in those who have had blood loss due to trauma (Young & Koda-Kimble, 1995). Additionally those who have renal failure also should not use meperidine (Szeto et al., 1977). Side effects Side effects of meperidine include increased heart rate, respiratory depression, elevated cerebrospinal fluid pressure, dizziness, sedation, coma, dysphoria, weakness, and agitation (Gilman, Goodman, & Gilman, 1985; McEvoy, 1998), typical of opiate agonists. Meperidine is only used for acute pain relief. Prolonged use of meperidine results in the build up of meperidine metabolites, normeperidine, which increases the risk of toxicity, which can include seizures (Szeto et al., 1977). Prolonged intramuscular administration can result in fibrosis of muscle tissue (Ellenhorn & Barceloux, 1988). Meperidine also has the same addictive potential as morphine, and Demerol can be abused by crushing, snorting, or injecting the medication. Such abuse can result in overdose and commonly exhibit symptoms of CNS depression. Those with severe overdose can experience circulatory collapse, cardiac arrest, or death (McEvoy, 1998). References: Apgar V., Burns J.J., Brodie B.B., Papper E.M. (1952). The transmission of meperidine across the human placenta. American Journal of Obstetrics and Gynecology, 64(6):1368-70. Beckwith M., Fox E., Chandramouli J. (2002). Removing meperidine from the health-system formulary— frequently asked questions. Journal of Pain & Palliative Care Pharmacotherapy, 16(3)45-69. Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 723 Gilman, A.G., L.S.Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 7th ed. New York: Macmillan Publishing Co., Inc., 1985., p. 514 Hershey L.A. (1983) Meperidine and central neurotoxcitiy. Annals of Internal Medicine, 98(4):548-549. Karch S.B., Drummer O. (2008). Karch's Pathology of Drug Abuse, Fourth Edition. Boca Raton, FL: CRC Press. Latta K.S., Ginsberg B., Barkin R.L. (2002). Meperidine: a critical review. Am J Ther, 9(1):53-68. McEvoy G.K. (1998). American Hospital Formulary Service-Drug Information 1998. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 1674 Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 1045 Szeto H.H., Inturrisi C.E., Houde R., Saal S., Cheigh J., Reidenberg M.M. (1977). Accumulation of normeperidine, an active metabolite of meperidine, in patients with renal failure of cancer. Ann Intern Med; 86:738–741 Westring D.W., Fribourg E. (1974). Meperidine vs morphine. JAMA, 230(11):1512. Young, L.Y., M.A. Koda-Kimble (eds.). Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver, WA., Applied Therapeutics, Inc. 1995., p. 7-10 Alyssa Moore Benzatropine (Cogentin) • Used adjunctively to treat parkinsonism and most of the extrapyramidal side effects of neuroleptics (dystonia, akathisia, rigidity, bradykinesia and tremor, but not tardive dyskinesia) Mechanisms of action: • Selective M1 muscarinic ACh receptor antagonist • Also blocks DA reuptake o The combination of blocking DA reuptake and antagonizing ACh release reduces the imbalance of DA and ACh, which is thought to improve early Parkinson’s symptoms → • Functional inhibitor of acid sphingomyelinase (FIASMA): sphingomyelinase metabolites are associated with the balance between neural apoptosis and proliferation Dosing: • Parkinsonism (oral): 1-4 mg twice daily o Start at .5 mg and titrate up by .5 mg every 5-6 days • Extrapyramidal (injection): 1-4 mg once or twice daily o Can be used to treat acute dystonic reactions and transient or chronic extrapyramidal symptoms Pharmacokinetics: • Half-life: variable and around 36 hours, but greatest effect at 6-8 hours • Selective for M1 ACh receptor subtype • ~95% binds to serum proteins • Poor bioavailability • Clinical activity observed after 1-2 hours after oral administration and a few minutes after intramuscular administration, and effects last ~24 hours Receptor Selectivity: Receptor KI M1 .231 M2 1.4 M3 1.1 M4 1.1 M5 2.8 Metabolism & Excretion: • Metabolism is hepatic but not well understood • Mainly excreted through urine Side Effects: • Dry mouth, blurred vision, confusion, drowsiness, constipation, urinary retention, tachycardia*, anorexia, delirium, depression, nervousness, heat stroke* Interactions & Contraindication: • Has additive effects with cannabinoids, barbiturates, opioids, and alcohol • Should not be used with other anticholinergics in patients particularly sensitive to their effects (i.e., patients with known tachycardia) • Should not be used by patients with glaucoma • Use in hot weather increases susceptibility to heat stroke; concomitant use of tricyclic antidepressants and/or phenothiazines • Can reduce gastric motility and efficacy of levodopa (via increased gastric deactivation) • Can lower concentration of phenothiazines (i.e., haloperidol), worsening schizophrenia symptoms • Should not be used in patients under 3 years References: Bolden C, Cusack B, Richelson E (1992). "Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells". J. Pharmacol. Exp. Ther. 260 (2): 576–80. Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL: Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter. Drug Alcohol Depend. 2015 Feb 1;147:1-19. doi: 10.1016/j.drugalcdep.2014.12.005. Epub 2014 Dec 18. Reith, M. E. A., Berfield, J. L., Wang, L. C., Ferrer, J. V, & Javitch, J. A. (2001). The Uptake Inhibitors Cocaine and Benztropine Differentially Alter the Conformation of the Human Dopamine Transporter. Journal of Biological Chemistry, 276(31), 29012–29018. https://doi.org/10.1074/jbc.M011785200 https://www.drugbank.ca/drugs/DB00245 https://www.rxlist.com/cogentin-drug.htm#description
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