Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The polymorphic cytochrome P-450 DB1 (P-450 IID6) is responsible for the O-demethylation of codeine to morphine by human liver microsomes. The influence of P-450 DB1 variable activity on the bioactivation of codeine in vivo to morphine and on its analgesic effect was investigated in phenotyped healthy volunteers--7 extensive [EM] and 1 poor [PM] metabolizer of debrisoquine. After pretreatment with oral placebo or quinidine sulphate 50 mg, codeine phosphate 100 mg or placebo were administered orally according to a double-blind randomized crossover design. In EM subjects the plasma morphine Cmax was 17.9 nmol/l, whereas virtually no morphine was detectable after quinidine pretreatment (1.5 nmol/l), and in the PM subject (0.60 nmol/l). In EM codeine significantly increased subjective (VAS) and objective (R-III reflex) pain thresholds in response to selective transcutaneous nerve stimulation, whereas no significant analgesia was detected after placebo, or after codeine with quinidine pretreatment, or in the PM. In PM of genetic origin, or due to environmental alteration of the phenotypic expression (i.e. drug interaction), codeine is not activated into morphine and is an inefficient analgesic.
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PMID:Impact of environmental and genetic factors on codeine analgesia. 178 73

The influence of rifampicin on the toxicity, analgesic effect and pharmacokinetics of acetaminophen was studied in male albino mice. Repeated administration of rifampicin (50 mg/kg i.p. daily for 6 days) shortened hexobarbital sleeping time and increased liver weight, microsomal cytochrome P-450 and heme contents, NADPH-cytochrome c reductase and ethylmorphine-N-demethylase activities. Aniline hydroxylase activity was decreased and glucuronidation of p-nitrophenol was unaffected. Rifampicin pretreatment changed neither the LD50 of acetaminophen nor the hepatic glutathione level nor the glutathione depletion provoked by the toxic dose of acetaminophen (737 mg/kg p.o.). This suggests that rifampicin has no influence on the amount of acetaminophen toxic metabolites formed in the liver. Rifampicin decreased the acetaminophen analgesic effect in mice. Rifampicin decreased the Cmax, the half-time, the MRT and the AUC of acetaminophen and accelerated its clearance. The plasma concentration of acetaminophen glucuronide and acetaminophen sulfate was increased. It is assumed that the most probable mechanism by which rifampicin decreases acetaminophen analgesia is the accelerated acetaminophen elimination.
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PMID:Influence of rifampicin on the toxicity and the analgesic effect of acetaminophen. 773 32

A 1-year-old Standardbred gelding had received xylazine hydrochloride (0.75 to 1.00 mg/kg [0.34 to 0.45 mg/lb] of body weight, IV) during 2 surgeries for debridement of a wound. The horse was given chloramphenicol (55 mg/kg [25 mg/lb], PO, q 6 h) for 5 days, and was anesthetized a third time with xylazine (0.75 mg/kg, IM). Five hours after administration of xylazine, the horse remained markedly sedated and had clinical signs of gaseous distention of the large bowel (bloat) requiring trocharization. Administration of yohimbine (0.03 mg/kg [0.01 mg/lb], i.v.) eliminated signs of sedation within 5 minutes. Moderate flatulence developed, and gastrointestinal sounds could be heard within all 4 abdominal quadrants within 15 minutes of yohimbine administration. The remainder of recovery was unremarkable. Xylazine induces bradycardia and decreases gastrointestinal motility in addition to causing sedation, muscle relaxation, and analgesia. Chloramphenicol can inhibit oxidase activity of cytochrome P-450 and inhibit metabolism and elimination of drugs such as xylazine.
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PMID:Use of yohimbine to reverse prolonged effects of xylazine hydrochloride in a horse being treated with chloramphenicol. 918 28

The analgesic effect and adverse events of the weak opioid codeine is assumed to be mediated by its metabolite morphine. The cytochrome P-450 enzyme CYP2D6 catalysing the formation of morphine exhibits a genetic polymorphism. Two distinct phenotypes, the extensive (EMs) and poor metabolisers (PMs), are present in the population. The prevalence of PMs in the Caucasian population is 7% to 10%. Since PMs do not express functional CYP2D6, they have a severely impaired capacity to metabolise drugs which are substrates of this enzyme. Provided the analgesic effect and the adverse events of codeine are mediated by its metabolite morphine, large phenotype-related differences are to be expected and PMs, as they form only trace amounts of morphine, can serve as a model to test the hypothesis whether the analgesia and adverse events of codeine are mediated by the parent drug or its metabolite morphine. Therefore we have studied in a randomised placebo-controlled double-blind trial the analgesic effect of 170 mg codeine (p.o.) compared to 20 mg morphine (p.o.) and placebo in 9 EMs and 9 PMs using the cold pressor test. The duration and intensity of the side effects were assessed using visual analogue scales (VAS). Codeine and morphine concentrations were measured in serum and urine. Compared to placebo, 20 mg morphine caused a significant increase in pain tolerance in both phenotypes, EMs and PMs (16.2+/-27.4 vs. -0.66+/-27.4 s x h, n=18). However, following administration of codeine, analgesia was only observed in EMs but not in PMs (EMs: 54.9+/-42.2 vs. 1.7+/-4.2 s x h, P < 0.01; PMs: 9.6+/-10.9 vs. 3.3+/-23.7 s x h, not significant). Adverse events were significantly more pronounced after morphine and codeine compared to placebo in both EMs and PMs. In contrast to the phenotype-related differences in the analgesic effect of codeine, however, no difference in adverse events between the phenotypes could be observed. In the pharmacokinetic studies, significant differences between the two phenotypes in the formation of morphine after codeine administration could be observed. Whereas morphine plasma concentrations were similar in PMs (Cmax: 44+/-13 nmol/l: AUC: 199+/-45 nmol x h/l) and EMs (Cmax: 48+/-17 nmol/l); AUC: 210+/-65 nmol x h/l) after morphine administration, following 170 mg codeine, morphine plasma concentrations comparable to those after morphine application were only observed in EMs (Cmax: 38+/-16 nmol/l; AUC: 173+/-90 nmol x h/l). In PMs only traces of morphine could be detected in plasma (Cmax: 2+/-1 nmol/l; AUC: 10+/-7 nmol x h/l). The percentage of the codeine dose converted to morphine and its metabolites was 3.9% in EMs and 0.17% in PMs. The interindividual variability in analgesia of codeine which is related to genetically determined differences in the formation of morphine clearly indicate that this metabolite is responsible for the analgesic effect of codeine. In contrast to the analgesic effect, frequency and intensity of the adverse events did not present significant differences between the two phenotypes. These findings have implications for the clinical use of codeine. Since side effects occurred in both EM and PM subjects, the use of codeine as an analgesic will expose 7% to 10% of patients who are PMs to the side effects of the drug without providing any beneficial analgesic effects.
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PMID:Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. 969 56