Propoxyphene
Discover related
2 sources
Mechanism of action
Propoxyphene acts as a weak agonist at OP1, OP2, and OP3 opiate receptors within the central nervous system (CNS). Propoxyphene primarily affects OP3 receptors, which are coupled with G-protein receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine, and noradrenaline is inhibited. Opioids such as propoxyphene also inhibit the release of vasopressin, somatostatin, insulin, and glucagon. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.
... Propoxyphene binds primarily to mu-opioid receptors & produces analgesia & other CNS effects that are similar to those seen with morphine-like opioids.
Pharmacodynamics
Propoxyphene, a synthetic opiate agonist, is structurally similar to methadone. Its general pharmacologic properties are those of the opiates as a group. The analgesic effect of propoxyphene is due to the d-isomer, dextropropoxyphene. It binds to the opiate receptors and leads to a decrease of the perception of pain stimuli. Propoxyphene possesses little to no antitussive activity and no antipyretic action.
Pharmacokinetics
Half-life
6-12 hours
Propoxyphene has an elimination half-life of 6-12 hours.
The half life of elimination of the parent compound is 6 to 12 hours. The half life of elimination of norpropoxyphene is 30 to 36 hours.
... Norpropoxyphene has a longer plasma half-life in the dog than propoxyphene. /Propoxyphene hydrochloride/
In geriatric patients 70-78 years of age, elimination half-lives of propoxyphene and norpropoxyphene reportedly were 13-35 and 22-41 hours, respectively.
Absorption
The major route of metabolism is cytochrome CYP3A4 mediated N-demethylation to norpropoxyphene, which is excreted by the kidneys. In 48 hours, approximately 20% to 25% of the administered dose of propoxyphene is excreted via the urine, most of which is free or conjugated norpropoxyphene.
16 L/kg
2.6 L/min
Following oral administration, propoxyphene hydrochloride and napsylate are absorbed principally in the upper small intestine. The napsylate salt appears to be absorbed more gradually than the hydrochloride salt. Equimolar doses of propoxyphene hydrochloride or napsylate provide similar plasma concentrations. The bioavailability of oral propoxyphene hydrochloride doses of 65, 130, or 195 mg is equivalent to that of oral propoxyphene napsylate doses of 100, 200, or 300 mg, respectively.
Peak plasma propoxyphene concentrations are usually achieved within 2-2.5 hours following oral administration of propoxyphene hydrochloride capsules or propoxyphene napsylate suspension (no longer commercially available in the US) and within 3 hours following oral administration of propoxyphene napsylate tablets. The analgesic effect occurs within 15 minutes to 1 hour and persists for 4-6 hours. Therapeutic plasma propoxyphene concentrations are 50 ng/mL or greater. Peak plasma concentrations achieved with the recommended 65-mg dose of propoxyphene hydrochloride may range from 50-120 ng/mL, while concentrations of the norpropoxyphene metabolite range from 100-200 ng/mL.
Only a small fraction of the absorbed dose (30%-70%) enters the general circulation in unmetabolized form. The rest is metabolized by intestinal and hepatic enzymes during absorption. Single dose kinetics indicate complete oral absorption. Peak plasma levels of propoxyphene after an oral 65 mg dose are 84-94 ng/ml (0.084-0.094 ug/ml) and are reached in 1.1-1.5 hr.
Metabolism
Hepatic
Propoxyphene undergoes extensive first-pass metabolism by intestinal and hepatic enzymes. Propoxyphene is metabolized mainly via N-demethylation (mediated by cytochrome P-450 (CYP) isoenzyme 3A4) to form norpropoxyphene. Ring hydroxylation and glucuronide formation appear to be minor metabolic pathways for the drug. Norpropoxyphene has an elimination half-life of 30-36 hours. Norpropoxyphene and unchanged propoxyphene are excreted mainly in urine. Approximately 20-25% of an orally administered 65-mg dose of propoxyphene hydrochloride may be recovered in urine as unchanged drug (trace amount) and free or conjugated norpropoxyphene within 48 hours.It appears that the unchanged drug is excreted mainly within 6 hours and the metabolite is excreted in the 6- to 48-hour period following administration. Renal clearance of propoxyphene is about 2.6 L/minute.
Formation of cytochrome p450 metabolic intermediate complexes in vivo occurred with propoxyphene in native & phenobarbital-induced rats. In vivo formation correlated with relative ability for it to form metabolic intermediate complexes & inhibit mixed function oxidation reactions in vitro.
Yields 3-dimethylamino-1,2-diphenyl-2-butyl propionate-n-oxide iN pig & 3-methylamino-1,2-diphenyl-2-butyl propionate iN rat. From table/
Presystemic metabolism is believed to occur mainly in the liver with some minor intestinal participation. The aim of this study was to investigate the respective part of each of these two organs in the metabolism of the analgesic d-propoxyphene. Pharmacological doses of d-propoxyphene were given in the duodenum (ID), the portal vein (IP), and the femoral vein (IV) of male Wistar rats. A tracer dose of (14)C-d-propoxyphene was also administered either in IV, IP, or ID as well as in hepatectomized rats or rats with bile duct diversion. In vitro demethylation occurring in liver and intestinal microsomes was also studied. Absolute DP bioavailability obtained after oral administration was two times higher than that observed after portal administration (48.9% vs. 23.2%, respectively), an result opposite (i.e. a lower bioavailability) of that expected on the basis of the existence of a liver enzyme saturation phenomenon. The (14)C-d-propoxyphene cumulative excretion after (14)C-d-propoxyphene administration was significantly lower after IV or ID administration than after injection in the portal vein as a bolus or within 20 min. The biliary excretion of the labeled compound varied in the opposite direction, being greater after IV or ID than after IP administration, suggesting that the metabolism of d-propoxyphene in the liver is influenced by an extrahepatic transformation. This most likely occurs in the gut since the production of (14)C-d-propoxyphene after IV administration was similar to that after ID administration. This transformation did not prohibit d-propoxyphene detection in the systemic blood but was sufficient to increase the part eliminated with bile and to decrease the part demethylated NP. Demethylation mainly occurs in the liver since the production of (14)C-d-propoxyphene was nearly abolished in hepatectomized rats. Furthermore, microsomes of hepatic but not of intestinal origin were able to demethylate d-propoxyphene. Our data suggest that the transformation of d-propoxyphene occurring in gut after oral administration is responsible for changes in the hepatic metabolism of the drug.
Dextropropoxyphene has known human metabolites that include Nordextropropoxyphene.
External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.