What are the pharmacodynamics of demerol?

Answer 1

normeperidine

Answer 2

2.0 Pharmacokinetics

Onset and Duration

Drug Concentration Levels

ADME 2.1 Onset and Duration

A) Onset 1) Initial Response a) Analgesia, subcutaneous: 10 minutes (Gilman et al, 1985). 1) Analgesia, intramuscular: 10 minutes (Gilman et al, 1985).

2) Analgesia, epidural: 5 to 30 minutes (Glynn et al, 1981). 2) Peak Response a) Analgesia, intramuscular: 30 to 50 (AMA Department of Drugs, 1986b). B) Duration 1) Single Dose a) Analgesia, subcutaneous: 2 to 4 hours (Gilman et al, 1985; AMA Department of Drugs, 1986b). 1) Analgesia, intramuscular: 2 to 4 hours (Gilman et al, 1985; AMA Department of Drugs, 1986b).

2) Anesthesia, intrathecal: 77 minutes (sensory block); 47 minutes (motor block) (Naguib et al, 1986).

3) Analgesia, epidural: 6 to 8 hours (Glynn et al, 1981).

2.2 Drug Concentration Levels

A) Therapeutic Drug Concentration 1) Analgesia, not well established a) The apparent minimally effective level for analgesia in most patients has been reported to be 0.2 mcg/mL one hour following an INTRAMUSCULAR dose of 1 mg/kg (Shih et al, 1976).

b) Blood concentrations of 0.7 mcg/mL maintained by an INTRAVENOUS infusion provided relief from severe pain in 95% of the cases studied (Austin et al, 1980).

c) Mean minimally effective plasma levels were lower with patient controlled analgesia (296 ng/mL) than with 100 mg intramuscular injections given every 3 to 4 hours (551 ng/mL) when studied in a small series of 10 post-surgical patients (Baumann et al, 1991).

d) Lower mean plasma levels of meperidine were found in patients using patient-controlled epidural analgesia than in patients using PCA delivered intravenously (Paech et al, 1994a). In a double-blind, crossover study of post-Cesarian patients, plasma levels during EPIDURAL administration were about one-half that of the period during which patients received INTRAVENOUS patient controlled analgesia meperidine. B) Time to Peak Concentration 1) Intramuscular, 25 minutes (Boreus et al, 1983). a) Mean maximal plasma levels of 200 to 230 ng/mL were reached within 25 minutes after 100 mg meperidine intramuscular, persisting for 120 minutes (Boreus et al, 1983). From Micromedex 2.3 ADME

Absorption Distribution Metabolism Excretion Elimination Half-life

2.3.1 Absorption

A) Bioavailability 1) Absorption following ORAL administration varies (Mather et al, 1975a; Stambaugh, 1976; Burn, 1955). a) Well absorbed following PARENTERAL administration (Mather et al, 1975a; Stambaugh, 1976; Burn, 1955).

b) Entry of normeperidine into systemic circulation is rapid and depends on the rate of absorption and first-pass metabolism of meperidine rather than the rate of elimination of drug or metabolite. Oral doses of meperidine generate greater amounts of normeperidine than equianalgesic intravenous doses (Pond & Kretschzmar, 1981b). 2) Intramuscular, injection: 57% (Jacobsen et al, 1988). a) Within 240 minutes following doses of 1 mg/kg in children (Jacobsen et al, 1988). 3) Intranasal: 78% (Striebel et al, 1993).

2.3.2 Distribution

A) Distribution Sites 1) Protein Binding a) 65% to 80% (Bennett et al, 1987). 1) Alpha-1 acid glycoprotein (AAG) and albumin are the major binding proteins of meperidine. In vitro, percent binding to albumin is relatively independent of either meperidine or albumin concentrations, ranging from approximately 16% to 21%. However, binding to AAG is AAG-concentration dependent. At normal AAG levels (50 to 100 mg/dL), percent of meperidine binding was 32% to 46%. When AAG levels increase (as in stress) to 200 to 300 mg/dL, meperidine binding also increases to 55% to 66%. In vivo, this increased meperidine binding may be interpreted as apparent tolerance (Julius et al, 1989). a) In the elderly, MEPERIDINE is less protein bound; however, the clearance rate is unchanged. This suggests that the volume of distribution may be greater with more available free drug (Wallace & Watanabe, 1977). 2) OTHER DISTRIBUTION SITES a) CEREBROSPINAL FLUID (CSF) (Boreus et al, 1983). 1) Following 100 mg intramuscular meperidine (equivalent to 87 mg base), parent compound was detected in CSF within 18 minutes (25 ng/mL), reaching a plateau within 90 minutes. The normeperidine metabolite was not detectable before 90 minutes. Serum/CSF concentration ratios for both the parent and metabolite were 0.46 and 0.42, respectively, at 240 minutes (Boreus et al, 1983). Following 1 mg/kg intrathecal dosing, CSF:plasma ratio was found to be 0.38 at 16 hours (Maurette et al, 1989). 3) PLACENTA (Rayburn et al, 1989a; Savona-Ventura et al, 1991) a) Feto-maternal plasma concentrations ratios have been reported to range from 0.35 to 3.5 (Tomson et al, 1982; Husemeyer et al, 1982a) with mean ratios of 0.63 to 0.65 (Rayburn et al, 1989a; Savona-Ventura et al, 1991) which reached maximums of 0.95 at 3 to 4 hours after maternal dosing. B) Distribution Kinetics 1) Distribution Half-Life a) 4.2 minutes (Klotz et al, 1974). 1) Distribution (alpha) half-life was reported to be 0.19 hours in both normal and cirrhotic patients (Klotz et al, 1974). a) In pregnant patients, intramuscular, intravenous, or epidural doses were associated with distribution half-lives between 7.3 and 8.3 minutes (Husemeyer et al, 1982a). 2) Volume of Distribution a) 3.1 to 5 L/kg (Bennett et al, 1987; Persson et al, 1988).

2.3.3 Metabolism

A) Metabolism Sites and Kinetics 1) LIVER (AMA, 1986). a) Meperidine, when given orally, is 50% metabolized in the first pass through the liver (AMA Department of Drugs, 1986b). 1) Any enhancement of meperidine metabolism to normeperidine may be associated with reduced analgesic efficacy and greater potential for normeperidine toxicity (Pond & Kretschzmar, 1981b). B) Metabolites 1) Normeperidine (active) (Anderson et al, 1976).

2) Normeperidinic acid (active) (Anderson et al, 1976).

3) Meperidinic acid (active) (Anderson et al, 1976). a) Meperidine is demethylated to form normeperidine, which is then hydrolyzed along with meperidine to normeperidinic acid and meperidinic acid. The acid metabolites are less active than meperidine and are further metabolized through conjugation (Anderson et al, 1976).

b) Meperidine use in newborns was studied, and normeperidine formation was reported to be slower in this age group (Pokela et al, 1992a).

2.3.4 Excretion

A) Kidney 1) Renal Excretion (%) a) 0.5% to 5.2% (average 2.2%) unchanged (Klotz et al, 1974). 2) The active metabolite, normeperidine, is reported to be excreted 0.6% to 21% (average 6.2%) unchanged in the urine (Klotz et al, 1974).

3) Fifty-three percent of the total metabolites are excreted in the urine in the 24-hour period following administration (Anderson et al, 1976).

4) The cumulative urinary excretion of normeperidine over 24 hours was significantly lower in geriatric patients than in young patients (Odar-Cederlof et al, 1985). In geriatric patients only 2.7% was excreted compared to 7.1% in young patients.

5) A study of Caucasian, Nepalese, and Chinese surgical patients failed to show differences in the proportional excretion of metabolites (Houghton et al, 1993). B) Other 1) OTHER EXCRETION a) Higher concentrations in the saliva than in the blood have been reported after intramuscular administration. Levels vary two- to seven-fold (Freeborn et al, 1980).

2.3.5 Elimination Half-life

A) Parent Compound 1) ELIMINATION HALF-LIFE a) 3.2 to 3.7 hours (Klotz et al, 1974; McHorse et al, 1975; Mather et al, 1975a). 1) Acute viral hepatitis is reported to prolong half-life (McHorse et al, 1975). In cirrhosis, beta half-life increased to 7.0 hours (Klotz et al, 1974).

2) In the elderly, meperidine has a greater half-life (Wallace & Watanabe, 1977).

3) In the neonate, the half-life of MEPERIDINE has been variously reported as 7 to 40 hours (Kuhnert et al, 1985a), or 4.9 to 16.8 hrs (Poleka et al, 1992), in term infants less than one week of age.

4) In pregnant patients terminal half-lives were shorter for either intravenous or epidural dosing (157 to 188 minutes) compared to intramuscular (227 minutes) with data collected over 2 hours only. Following epidural dosing in non-pregnant volunteers, the terminal half-life was 286 minutes (Husemeyer et al, 1982a). B) Metabolites 1) normeperidine, 24 to 48 hours, (Szeto et al, 1977; Verbeeck et al, 1980). a) Active metabolites accumulate in patients with ESRD to cause seizures (Bennett et al, 1994a).

b) Normeperidine may accumulate to high concentrations in patients receiving frequent doses of meperidine. Seizures have been attributed to such a process (Szeto et al, 1977; Verbeeck et al, 1980). From Micromedex