Meperidines reversed

Fig. 11.14 Structures of the phenylpiperidine, meperidine reverse meperidine (MPPP), MPTP, and MPP+.

Meperidine reversibly blocks voltage-gated Na currents with a half-maximum inhibiting concentration (ICjg) of 112 pM. Clinically, meperidine shows a dose-dependent blockade of both the sensory and motor fibers of the ulnar nerve after infiltration. Two percent meperidine blocks both sensory and motor activity at the hypothenar muscle. Intrathecal doses of meperidine 50 mg can provide short-duration spinal anesthesia. 

Exploratory research on structure activity relationships in the meperidine series revealed the interesting fact that the oxygen atom and carbonyl group of this molecule could often be interchanged. That is, the so-called "reversed meperidine" (C) still exhibits analgesic activity in experimental animals. (Note that, except for the interchange, the rest of the molecule is unchanged.)... 

Further chemical modification of the phenylpiperidine moiety has proven unusually fruitful in producing medicinal agents that affect the central nervous system. First, a series of compounds loosely related to the reversed meperidines produced several drugs with important antipsychotic activity. Further discussion of this pharmacologic activity, often referred to as major tranquilizer activity, will be found in the section on phenothiazines. The group led by Janssen took advantage of the chemistry of the... 

Patients who are acutely intoxicated with an opioid usually present with miosis, euphoria, slow breathing and slow heart rate, low blood pressure, and constipation. Seizures may occur with certain agents such as meperidine (Demerol ). It is critically important to monitor patients carefully to avoid cardiac/ respiratory depression and death from an excessive dose of opioids. One strategy is to reverse the intoxication by utilizing naloxone (Narcan ) 0.4 to 2 mg IV every 2 to 3 minutes up to 10 mg. Alternatively, the IM/SC route may be used if IV access is not available. Because naloxone is shorter-acting than most abused opioids, it may need to be readministered at periodic intervals otherwise the patient could lapse into cardiopulmonary arrest after a symptom-free interval of reversed... 

Fever, rigors, chills, malaise headaches, myalgia Nausea, emesis Neutropenia Hepatic enzyme elevation Cutaneous—alopecia, transient, mild rashlike reaction Acetaminophen (APAP). NSAID if APAP is not effective. Meperidine for severe chills and rigors. Bedtime administration. 5-HT3 antagonist, prochlorperazine, metoclopramide, fluids Weekly complete blood count reduce dose by 30-50% Liver function tests (LFTs) weekly withhold treatment until LFTs normalize restart at 30-50% dose reduction reversible on dose reduction or cessation. Interferon is contraindicated in patients with psoriasis because exacerbation of psoriasis has been noted during IFN therapy. 

Derivatives of 4-phenyl-4-hydroxypiperidine, which may be formally regarded as reversed meperidines, have yielded a series of potent antipsychotic drugs such as haloperidol (83) and bromoperidol (84). Retention of carbon at the 4-position interestingly leads to a molecule with quite different activity. 

Meperidine, 299, 300, 303, 306 reversed, 303 Mephenesin, 118 Mephenesin carbamate, 118 Mephenhydramine, 44 Mephenoxolone, 119 Mephentermine, 72 Mephenytoin, 246 Mephobarbital, 273 Mepivacaine, 17 Meprobamate, 218 Mequoqualone, 354 Meralluride, 224 Mercaptomerine, 224 Mesoridazine, 389 Mesterolone, 174... 

Meperidine (Demerol) [C-ll] [Narcotic Analgesic] Uses Moderate/ severe pain Action Narcotic analgesic Dose Adults. 25-50 mg IV, 50-100 mg IM Peds. 1 mg/kg IV/IM (onset w/in 5 min IV and 10 min IM duration about 2 h) Caution [C, ] Contra Convulsive disorders and acute abdomen Disp Prefilled 1 mL syringes 25, 50, 75, 100 mg/mL various amps and vials oral syrup and tabs SE N/V (may be severe), dizziness, weakness, sedation, miosis, resp d ession, xerostomia (dry mouth) Interactions t CNS depression W/ opiates, sedatives/ hypnotics TCNS stimulation W/amphetamines t risk of tox W7 phenytoin EMS Pt should be receiving O2 prior to administration have resuscitation equipment and naloxone available naloxone can be used as an antidote to reverse resp depression aspirate prior to IM administration inadv tent IV admin of IM doses may cause tach and syncope mix w/ NS to make a 10 mg/mL soln and inj very slowly N/V may be sev e may premedicate w/ an antiemetic... 

Symptoms of overdose with meperidine are qualitatively different from those of morphine in that seizures rather than sedation are common. Respiratory depression and miosis are present. While naloxone reverses overdose-associated toxicity, its use in patients who have received large, frequent doses of meperidine may precipitate seizures. 

L B. The most commonly used treatment and the most effective is to stabilize the patient with methadone and gradually reduce the maintenance dose until the patient is drug free. The administration of meperidine would reverse the abstinence syndrome but it is unlikely to help the patient terminate his opioid habit. The use of naltrexone would likely further precipitate the abstinence syndrome and without additional counseling, would not likely offer long-term beneht. 

Naloxone (Narcan) and naltrexone hydrochloride (Trexan) reverse the respiratory depressant action of narcotics related to morphine, meperidine, and methadone. They differ from other narcotic analgesics in several respects. Naloxone does not cause respiratory depression, pupillary constriction, sedation, or analgesia. However, it does antagonize the actions of pentazocine. Naloxone neither antagonizes the respiratory depressant effects of barbiturates and other hypnotics nor aggravates their depressant effects on respiration. Similar to nalorphine, naloxone precipitates an abstinence syndrome when administered to patients addicted to opiate-like drugs. 

As a Schedule II opioid narcotic, meperidine is highly addictive. Treatment for opioid overdose usually involves administration of an opioid antagonist such as Narcan (naloxone), which reverses or blocks the effects of the drug. However, in some cases, those who overdose on meperidine do not respond well to opioid antagonists. 

Lieberman AN, Goldstein M. Reversible parkinsonism related to meperidine. N Engl J Med 1985 312(8) 509. 

Arylpiperidines with an Oxygen Substituent at Q Reversal of the ester in meperidine gives MPPP (iV-methyl-4-phenyl-4-... 

A variety of C3 alkylated derivatives of the reversed esters of meperidine were examined (see Ref 405). Incorporation of a methyl group at C3 yields a- and jS-prodine (101 and 102, Fig. 7.23) (437). The J3 isomer (102) has five times the potency of the a isomer. X-ray crystallography and NMR indicate that the preferred conformation of the prodines is the chair form, with the phenyl ring equatorial (see Refs. 283, 438). Computational studies also indicate a preference for this conformer in the case of the reversed esters the energy differences between the equatorial and axial conformers (1.9-3.4 kcal/mol) are much greater than the differences between the two conformers of meperidine f/jand ketobemi-done(105) (410). 

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