Tramadol metabolism

Isolated seizures that are not epilepsy can be caused by stroke, central nervous system trauma, central nervous system infections, metabolic disturbances (e.g., hyponatremia and hypoglycemia), and hypoxia. If these underlying causes of seizures are not corrected, they may lead to the development of recurrent seizures I or epilepsy. Medications can also cause seizures. Some drugs that are commonly associated with seizures include tramadol, bupropion, theophylline, some antidepressants, some antipsy-chotics, amphetamines, cocaine, imipenem, lithium, excessive doses of penicillins or cephalosporins, and sympathomimetics or stimulants. 

Fluoxetine and paroxetine inhibit cytochrome CYP P-450 2D6 and thus may affect metabolism of some opioids, e.g. codeine, 0) codone and tramadol, that are partly metabolised by CYP2D6, many antipsychotic drugs and tricyclic antidepressants. 

Pharmacokinetic properties Tramadol is extensively metabolized by O- and N-demethylation yielding the active metabolite O-desmethyl-tramadol (Ml) and several... 

Tramadol is available as drops, capsules, and sustained-release formulations for oral use, suppositories for rectal use, and solution for intramuscular, intravenous, and subcutaneous injection. After oral administration, tramadol is rapidly and almost completely absorbed. Sustained-release tablets release the active ingredient over a period of 12 h, reach peak concentrations after 4.9 h, and have a bioavailability of 87 to 95% compared with capsules. One 100-mg dose given to healthy volunteers resulted in plasma levels of 375 ng/ml at 1.5 h.55 Tramadol is 20% bound to plasma protein and it is rapidly distributed in the body it is mainly metabolized by O- and A-demethylation forming glucuronides and sulfates that are excreted by the kidney. 

Impaired metabolic capacity may decrease the conversion of drugs to active metabolites, e.g. codeine, tramadol. 

Tramadol 70% following single dose, 90% at steady state [48] 20 6 30 Not significant [49] N- and O-demethylation via CYP3A4 and CYP2D6 followed by glucuronidation or sulphation First-pass metabolism of 20-30% [49] Yes. CYP2D6 O-demethylation produces active metabolite... 

Most opioids are metabolised in the liver and many (exceptions include tramadol) undergo a high first-pass effect [50], Because of this, clearance is highly dependent on liver blood flow, rather than the capability of hep-atocyte enzymes. If liver blood flow is reduced, as in hepatic cirrhosis with portal hypertension for example, the metabolism of most opioids would be expected to decrease, with a subsequent increase in oral bioavailability and risk of accumulation. 

FLECAINIDE OPIOIDS Methadone and tramadol may t flecainide levels Methadone and tramadol inhibit CYP2D6-mediated metabolism of flecainide Monitor PR and BP closely... 

MAOIs PETHIDINE, MORPHINE, PHENOPERIDINE, DEXTROMETHORPHAN Two types of reaction are reported 1. Risk of serotonin syndrome with dextromethorphan, pethidine or tramadol and MAOIs 2. Depressive - respiratory depression, hypotension, coma Type 1 reactions are attributed to inhibition of reuptake of serotonin -more common with pethidine, phenoperidine, dextromethorphan. Type II reactions are attributed to MAOI inhibition of metabolism of opioids - more common with morphine Avoid co-administration do not give dextromethorphan, pethidine or tramadol for at least 2 weeks after cessation of MAOI... 

SSRIs OPIOIDS 1. Possible 1 analgesic effect of oxycodone and tramadol 2. T serotonin effects, including possible cases of serotonin syndrome, when opioids (oxycodone, pethidine, pentazocine, tramadol) are co-administered with SSRIs (fluoxetine and sertraline) 3. SSRIs may t codeine, fentanyl, methadone, pethidine and tramadol levels 1. Uncertain. Paroxetine inhibits CYP2D6, which is required to produce the active form of tramadol. 2. Uncertain 3. SSRIs inhibit CYP2D6-mediated metabolism of these opioids 1. Consider using an alternative opioid 2. Look for signs of T serotonin activity, particularly on initiating therapy 3. Watch for excessive narcotization... 

TCAs OPIOIDS 1. Risk of t respiratory depression and sedation 2. t levels of morphine 3. Case reports of seizures when tramadol was co-administered with TCAs 4. TCAs may t codeine, fentanyl, pethidine and tramadol levels 1. Additive effect 2. Uncertain likely t bioavailability of morphine 3. Unknown 4. TCAs inhibit CYP2D6-mediated metabolism of these opioids 1. Warn patients of this effect. Titrate doses carefully 2. Warn patients of this effect. Titrate doses carefully 3. Consider an alternative opioid 4. Watch for excessive narcotization... 

CARBAMAZEPINE ANALGESICS - OPIOIDS 1.1 efficacy of fentanyl and methadone 2.1 tramadol levels 1. t hepatic metabolism of fentanyl and methadone, and possibly an effect at the opioid receptor 2. t metabolism of tramadol 1. Be aware that the dose of fentanyl and methadone may need to be t 2. Watch for poor effect of tramadol. Consider using an alternative opioid... 

IMATINIB ANALGESICS-OPIOIDS May cause t plasma concentrations, with a risk of toxic effects of codeine, dextromethorphan, hydroxycodone, methadone, morphine, oxycodone, pethidine and tramadol Inhibition of CYP2D6-mediated metabolism of these opioids Monitor for clinical efficacy and toxicity. Warn patients to report t drowsiness, malaise or anorexia. Measure amylase and lipase levels if toxicity is suspected. Tramadol causes less respiratory depression than other opiates, but need to monitor BP and blood counts, and advise patients to report wheezing, loss of appetite and fainting attacks. Need to consider 1 dose. Methadone may cause Q-T prolongation the CHM has recommended that patients with heart and liver disease who are on methadone should be carefully monitored for heart conduction abnormalities such as Q-T prolongation on ECG as they may lead to sudden death. Also need to monitor patients on more than 100 mg methadone daily and thus an t in plasma concentrations necessitates close monitoring of cardiac and respiratory function... 

ALFENTANIL, FENTANYL, PETHIDINE, TRAMADOL CIMETIDINE Cimetidine may t fentanyl, pethidine and tramadol levels Cimetidine inhibits CYP2D6-medi-ated metabolism of these opioids. Ranitidine weakly inhibits CYP2D6 Watch for excessive narcotization... 

Tramadol is an opioid with additional actions the basis of its analgesic effects appears to derive from a combination of (relatively weak) agonist action on p-receptors, inhibition of neuronal noradrenaline uptake and enhanced serotonin release. It is rapidly absorbed from the gastrointestinal tract, 20% of an oral dose undergoes first-pass metabolism and less than 30% dose is excreted unchanged in the urine (W2 6 h). Tramadol is approximately as effective as pethidine for postoperative pain and as morphine for moderate chronic pain. 

The metabolism of tramadol by CYP2D6 is important for its analgesic effect tramadol may therefore be a poor analgesic in poor metabolizers by CYP2D6, while extensive metabolizers may have better analgesia and more adverse effects (SEDA-21, 90). 

Inhibition of the hepatic metabolism of tramadol to morphine by quinidine may reduce its opioid effects (SEDA-21, 90). 

Fig. 5. Schematic of the microdialysis/CL flow sensor chip system for in vivo and real time monitoring the metabolism of tramadol in rabbit blood.

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