Propoxyphene metabolism

Elderly- Propoxyphene metabolism rate may be reduced in some patients. Consider increased dosing interval. 

Propoxyphene interacts with several drugs. The use of sedatives in combination with propoxyphene can be fatal. In addition, the metabolism of the drug is increased in smokers due to induction of liver enzymes. Thus, smokers may require a higher dose of the drug for pain relief. Propoxyphene enhances the effects of both warfarin and carbamazepine and may increase the toxicity associated with both drugs, such as bleeding and sedation, respectively. 

Cimetidine, propoxyphene, and isoniazid also have been reported to inhibit metabolism of carbamazepine. It is essential to monitor blood levels and adjust the dose if necessary whenever additional drugs are given to patients taking carbamazepine. 

It is dextro isomer of propoxyphene which is an analgesic and possesses antitussive property. It has low analgesic activity even half of codeine. It is metabolized in Uver. Side effects include vomiting, epigastric distress and sedation. The demethylated metabolite of propoxyphene is cardiotoxic. It is used in the treatment of mild type of pain. 

Drugs that may inhibit cytochrome P450 metabolism of other drugs include amiodarone, androgens, atazanavir, chloramphenicol, cimetidine, ciprofloxacin, clarithromycin, cyclosporine, delavirdine, diltiazem, diphenhydramine, disulfiram, enoxacin, erythromycin, fluconazole, fluoxetine, fluvoxamine, furanocoumarins (substances in grapefruit juice), indinavir, isoniazid, itraconazole, ketoconazole, metronidazole, mexile-tine, miconazole, nefazodone, omeprazole, paroxetine, propoxyphene, quinidine, ritonavir, sulfamethizole, verapamil, voriconazole, zafirlukast, and zileuton. 

Lopinavir/Ritonavir (Kaletra) [Anrirelroviral/Protease Inhibitor] Uses HIV Infxn Action Protease inhibitor Dose Adults. Tx naive 2 tab PO daily or 1 tab PO bid Tx experiencedpt 1 tab PO bid (T dose if w/ amprenavir, efavirenz, fosamprenavir, nelfinavir, nevirapine) Peds. 7-15 kg 12/3 mg/kg PO bid 15-40 kg 10/2.5 mg/kg PO bid >40 kg Adult dose w/ food Caution [C, /-] Numerous interactions Contra w/drugs dependent on CYP3A/CYP2D6 (Table VI-8) Disp Tab, soln SE Avoid disulfiram (soln has EtOH), metronidazole GI upset, asthenia, T cholesterol/triglycerides, pancreatitis protease metabolic synd Interactions T Effects Wl clarithromycin, erythromycin T effects OF amiodarone, amprenavir, azole andfungals, bepridil, cisapride, cyclosporine, CCBs, ergot alkaloids, flecainide, flurazepam, HMG-CoA reductase inhibitors, indinavir, lidocaine, meperidine, midazolam, pimozide, propafenone, propoxyphene, quinidine, rifabutin, saquinavir, sildenafil, tacrolimus, terfenadine, triazolam, zolpidem 1 effects Wl barbiturates, carbamazepine, dexamethasone, didanosine, efavirenz, nevirapine, phenytoin, rifabutin, rifampin, St. John s wort 1 effects OF OCPs, warfarin EMS Use andarrhythmics and benzodiazepines... 

Carbamazepine + phenytoin, tricyclic antidepressants, typical neuroleptics, valproate, clonazepam, warfarin, nefazodone and propoxyphene —> reduced plasma concentration of carbamazepine due to increased metabolism. 

BETA-BLOCKERS OPIOIDS 1. Risk of t plasma concentrations and effects of labetalol, metoprolol and propranolol t systemic effects of timolol eye drops 2. t plasma concentrations of esmolol when morphine is added 3. t plasma concentrations of metoprolol and propranolol when dextro-propoxyphene is added 1. Methadone inhibits CYP2D6, which metabolizes these beta-blockers 2. Unknown 3. i hepatic clearance of metoprolol and propanolol 1. Monitor BP at least weekly until stable 2. Monitor BP closely 3. Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (lightheadedness, dizziness on standing, etc.)... 

AMPHETAMINES ANALGESICS-OPIOIDS-alfentanil, fentanyl, propoxyphene t plasma concentrations of amphetamine, with risk of toxic effects Due to inhibition of CYP2D6-mediated metabolism of amphetamine Avoid concurrent use... 

Cigarette smoke contains minute amounts of polycyclic aromatic hydrocarbons, such as benzol nr pyrene. which are potent inducers of microsomal cytochrome P-4S0 enzymes. This induction increases the oxidation of some drugs in nnokets. For example, theophylline is metabolized more rapidly in smokers than in nonsmokers. This difference is reflected in the marked difference in the plasma half-life of theophylline between smokers (r /2 4.1 hours) and non-smokers u A 7.2 hours). Other drugs, such as phenacetin. pentazocine. and propoxyphene, also reportedly undergo more rapid metabolism in smokers than in nonsmokers. " ... 

Opioids cause a release of endorphins producing a feeling of pleasure. Examples of abuse include heroin, a highly addictive opioid that metabolizes to morphine and readily passes into the brain producing an immediate euphoria. Pharmaceutical or medicinal abused opioids include oxycontin, hydrocodone, codeine, methadone, and propoxyphene. 

Methadone undergoes significant hepatic metabolism by N-demethylation and cycliza-tion to form pyrrolidines and pyrroline (23). Propoxyphene is also hepatically metabolized predominantly by N-demethylation and renally eliminated. The metabolite norpropoxy-phene is cardiotoxic and produces arrhythmias and pulmonary edema that have led to reports of cardiac arrest and death (59). This is especially problematic because of the long half-life of norpropoxyphenethat accumulates with repeated doses of the parent drug. Methadone is excreted in the urine but also in the bile (23). 

Propoxyphene is rapidly absorbed and undergoes extensive hepatic first-pass metabolism to norpropoxyphene (Figure 34-42). The elimination ty2 for propoxyphene is about 15 hours (8 to 24), and that for norpropoxyphene is 27 hours (24 to 34). Norpropoxyphene may contribute to the analgesic and cardiotoxic effects of propoxyphene. ... 

At present only one metabolite of propoxyphene hydrochloride has been discovered. This metabolite, des-N-methyl propoxyphene, is produced by enzymatic N-demethylation in the liver. To study this metabolic process, propoxyphene hydrochloride labelled with C14 in the N-methyl position was utilized14. Laboratory rats and human beings were dosed with the labelled analgesic15. C1402 was detected in incubates of rat liver and in the expired air of rats. The dinitrophenyl derivative of des-N-methyl propoxyphene was isolated from human urine. 

Simultaneous measurements of plasma levels of deuterated and unlabeled d- and 1-propoxyphene revealed that the plasma levels of the more analge-sically active d-isomer were higher and the half-life was longer. On the other hand, simultaneous measurements of (+)- and (-)-propranolol indicated no differences in the rate of elimination of the isomers in dogs. Finally, the metabolism of carbon-13 labeled R- and S-a -methyldopa has revealed a high degree of stereoselectivity favoring the S-enantiomer for both transport across the blood-brain barrier and brain decarboxylase activity 7... 

Carbamazepine is metabolized to an active 10,11-epoxide metabolite, thus medications that inhibit 3A4 isoenzymes may result in carbamazepine toxicity (e.g., cimetidine, dUtiazem, erythromycin, fluoxetine, fluvoxamine, isoniazid, itraconazole, ketoconazole, nefa-zodone, propoxyphene, and verapamil). " When carbamazepine is combined with valproate, the carbamazepine dose should be reduced because valproate displaces carbamazepine from protein binding sites, thus increasing free levels." Combining clozapine and carbamazepine is not recommended because of the possibdity of bone marrow suppression with both agents. ... 

Many other synthetic compounds such as dextropropoxyphene (D-propoxyphene) and methadone, for example, are potent narcotic analgesics (opioid agonists) and their use is controlled in most countries. Dextropropoxyphene is extensively metabolized by N-demethylation and by other routes. Methadone is metabolized largely by N-demethy-lation and hydroxylation. Dextropropoxyphene is thermally labile but may be measured together with nordextro-propoxyphene by HPLC with electrochemical oxidation detection methadone and some metabolites may also be measured using this same system. 

Barbiturates and heavy smoking induce nortriptyline metabolism and decrease therapeutic efficacy phenothiazines and haloperidol decrease its metabolism, decreasing therapeutic efficacy methylphenidate, cimetidine, oral contraceptives, propoxyphene, and beta-blockers may inhibit nortriptyline metabolism, increasing plasma levels and toxicity (see Tables 5 through 7). 

A combined respiratory-metabolic acidosis occurs due to hypercapnia and lactic acid formation. Death may occur. Naloxone (0.4 to 2 mg IV) reverses the propoxyphene-induced respiratory depression. 

Phenobarbital, phenytoin, and valproic acid may increase the metabolism of carbamazepine by inducing CYP3A4 carbamazepine may enhance the biotransformation of phenytoin. Concurrent administration of carbamazepine may lower concentrations of valproic acid, lamotrigine, tiagabine, and topiramate. Carbamazepine reduces both the plasma concentration and therapeutic effect of haloperidol. The metabolism of carbamazepine may be inhibited by propoxyphene, erythromycin, cimetidine, fluoxetine, and isoniazid. 

After oral administration, concentrations of propoxyphene peak at 1-2 hours. There is great variability between subjects in the rate of clearance average t ofpropoxyphene in plasma after a single dose is 6-12 hours, which is longer than that of codeine. In humans, the major route of metabolism is H-demethylation to yield norpropoxyphene, which has a t of 30 hours and may accumulate to toxic levels with repeated doses. 

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