Chemical formula: C₁₇H₁₉NO₃ Molecular mass: 285.338 g/mol PubChem compound: 5284570
Like morphine, hydromorphone is an agonist of mu receptors. The pharmacological actions of hydromorphone and morphine do not differ significantly. The oral analgesic potency ratio of hydromorphone to morphine is approximately 5-10:1. Hydromorphone and related opioids produce their major effects on the central nervous system and bowel. The effects are diverse and include analgesia, drowsiness, changes in mood, respiratory depression, decreased gastrointestinal motility, nausea, vomiting and alteration of the endocrine and autonomic nervous system.
Preclinical studies indicate various effects of opioids on components of the immune system. The clinical significance of these findings is unknown.
In vitro and preclinical studies indicate various effects of natural opioids, such as morphine, on components of the immune system: the clinical significance of these findings is unknown. Whether hydromorphone, a semisynthetic opioid, has immunological effects similar to morphine is unknown.
Hydromorphone is absorbed from the gastrointestinal tract and undergoes pre-systemic elimination resulting in an oral bioavailability of about 32%.
The onset of action after intravenous and subcutaneous injection is usually within 5 minutes and 5-10 minutes, respectively. The duration of action is 3-4 hours after intravenous or subcutaneous injection. After epidural administration of 1 mg hydromorphone hydrochloride, a latency of 22.5 ± 6 minutes was observed until full analgesia was achieved. The effect was maintained for 9.8 ± 5.5 hours (n=84 patients aged 22-84).
Hydromorphone hydrochloride crosses the placenta barrier. According to published data, hydromorphone is excreted into breast milk at low amounts.
Plasma protein binding of hydromorphone is low (<10%). This percentage of 2.46 ng/ml remains constant up to very high plasma levels of 81.99 ng/ml, which are only very rarely achieved with very high hydromorphone doses.
Hydromorphone hydrochloride has a relatively high distribution volume of 1.22 ± 0.23 l/kg (C.I.: 90%: 0.97–1.60 l/kg) (n=6 male subjects), which suggests a pronounced tissue uptake.
The course of the plasma concentration time curves after single administration of hydromorphone hydrochloride 2 mg i.v. or 4 mg oral to 6 healthy volunteers in a randomised cross-over study revealed a relatively short elimination half-life of 2.64 ± 0.88 hours (1.68-3.87 hours).
Hydromorphone is metabolised by direct conjugation or reduction of the keto group with subsequent conjugation. After absorption, hydromorphone is primarily metabolised to hydromorphone-3-glucuronide, hydromorphone-3-glucoside and dihydroisomorphine-6-glucuronide. Smaller portions of the metabolites dihydroisomorphine-6-glucoside, dihydromorphine and dihydroisomorphine have also been found. Hydromorphone is metabolised via the liver; a smaller portion is excreted unchanged via the kidneys.
Hydromorphone metabolites were found in plasma, urine and human hepatocyte test systems. There are no indications of hydromorphone being metabolised in vivo via the cytochrome P 450 enzyme system. In vitro, hydromorphone has a minor inhibition effect (IC50 >50 µM) on recombinant CYP isoforms, including CYP1A2, 2A6, 2C8, 2D6 und 3A4. Hydromorphone is therefore not expected to inhibit the metabolism of other active substances which metabolise via these CYP isoforms.
Hydromorphone was non-genotoxic in a bacterial mutation test, in the in vitro human lymphocyte chromosome aberration assay and the in vivo mouse micronucleus assay but positive in the mouse lymphoma assay with metabolic activation. Similar findings have been reported with other opioid analgesics. Long term carcinogenicity studies have not been performed.
No effects on male or female fertility or sperm parameters were observed in rats at oral hydromorphone doses of 5 mg/kg/day (30 mg/m²/day, which is 1.4 times higher than the expected human dose on a body surface area basis).
In a rat pre- and post-natal study, there was an increase in pup mortality and reduced body weight gain in the early postnatal period, associated with maternal toxicity. No effects on continued pup development or reproductive performance were observed.
Hydromorphone was not teratogenic in pregnant rats nor rabbits given oral doses during the major period of organ development. Evidence of a teratogenic effect in mice and hamsters has been reported in the literature.
Hydromorphone was not teratogenic in rats and rabbits at doses that caused maternal toxicity. Reduced foetal development was found in rabbits at doses of 50 mg/kg (developmental no-effect level was established at a dose of 25 mg/kg or 380 mg/m² at an active substance exposure (AUC) almost four times above the one expected in humans). No evidence of foetal toxicity was observed in rats treated with oral hydromorphone doses as high as 10 mg/kg (308 mg/m² with an AUC about 1.8 times above the one expected in humans).
Perinatum and postpartum rat pup (F1) mortality was increased at doses of 2 and 5 mg/kg/day and bodyweights were reduced during lactation period.
Long-term carcinogenicity studies have not been performed.
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