Hydromorphone
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Mechanism of action
Hydromorphone is an opioid agonist that can bind to different types of opioid receptors. Its analgesic effect is suggested to be related to the effect on the mu-opioid receptors. It has been reported to also have a minor affinity for the delta and kappa receptor. On the other hand, it is known to act at the level of the medulla which allows it to depress the respiratory drive and suppress cough. The onset of action of the immediate release form of hydromorphone is achieved in 15-20 minutes and having a lasting effect for 3-4 hours while the extended-release form onset of action is of 6 hours lasting for about 13 hours.
/Accumulation of the active morphine-3-glucuronide (M3G) and hydromorphone-3-glucuronide (H3G) metabolites is one proposed mechanism for the development of neuroexcitatory effects including allodynia and opioid-induced hyperalgesia (OIH).
Pharmacodynamics
In clinical trials, hydromorphone has been shown to be suitable for pain relief in patients that do not tolerate the side effects of [morphine] or that suffer from renal failure or asthma. It has been shown to be 5-7 times more potent than morphine with a shorter duration of analgesia. Some of the observed effects of the consumption of hydromorphone for acute pain are complete and longlasting pain relief when compared to other pain relief agents such as [meperidine], [morphine], [diamorphine], [bupivacaine], [indomethacin], and [fentanyl]. On the same trials, hydromorphone was shown to produce respiratory depression, lower cognitive function, miosis, mydriasis, constipation, hypotension, and vertigo but to present a reduced incidence of pruritus (which indicates a lower release of histamine) and nausea. The respiratory depression is known to be caused by the effect on the brain stem respiratory centers as well as to a reduction in the responsiveness of this brain stems to increase carbon dioxide tension.
Pharmacokinetics
Half-life
The half-life of hydromorphone immediate-release is of 2-3 hour while the extended release can range from 8-15 hours.
The parent drug has a half-life of elimination of 2.5 hours.
The terminal elimination half-life of hydromorphone after IV administration is about 2.3 hours. /Hydromorphone hydrochloride/
/In beagle dogs/, the serum half-life after SC hydromorphone at 0.1 mg kg(-1) and 0.5 mg kg(-1) was 0.66 hours and 1.11 hours, respectively. Hydromorphone has a short half-life, suggesting that frequent dosing intervals are needed. Based on pharmacokinetic parameters calculated in this study, 0.1 mg kg(-1) IV or SC q 2 hours or a constant rate infusion of hydromorphone at 0.03 mg kg(-1) hour(-1) are suggested for future studies to assess the analgesic effect of hydromorphone.
The purpose of this study was to determine the pharmacokinetics of hydrocodone and its active metabolite hydromorphone in six healthy Greyhound dogs. Hydrocodone bitartrate was administered at a targeted dose of 0.5 mg/kg PO. ... The mean hydromorphone CMAX was 5.2 ng/mL at 1.37 hr with a terminal half-life of 3.07 hr. ...
For more Biological Half-Life (Complete) data for HYDROMORPHONE (6 total), please visit the HSDB record page.
Absorption
The immediate release version of hydromorphone reaches its peak concentration after 30-60 minutes while the extended-release version reaches the peak concentration after 9 hours. When administered orally, hydromorphone is absorbed mainly in the upper small intestine with a bioavailability of 60% due to intensive first-pass metabolism. In the controlled-release version of hydromorphone, the absorption follows a biphasic pharmacokinetic profile. However, even though there are clear distinctions in the absorption pathway of hydromorphone, the AUC of both versions is reported to be of 34 ng.h/ml which indicates an equivalence. The parenteral administration of hydromorphone, which is the most common pathway, presents an almost immediate absorption as observed by the presence of peak plasma concentration almost immediately. This peak plasma concentration declines rapidly due to fast redistribution into liver, spleen, kidney and skeletal muscle. In the parenteral route, the pharmacokinetic profile is log-linear and dose-dependent and to present a higher bioavailability of 78%. Other administration routes such as rectal, nasal, intraspinal and transdermal present lower bioavailability and changes in their pharmacokinetic profile.
The main elimination route of hydromorphone is through the urine in the form of the main metabolite hydromorphone-3-glucuronide. The elimination of the parent compound represents 7% of the urine elimination and 1% of the fecal elimination.
The volume of distribution of hydromorphone is reported to be of 4 L/kg.
The mean plasma clearance of hydromorphone is reported to be of 105.7 ml/min. The systemic clearance is reported to be of 1.96 L/min.
Hydromorphone hydrochloride is rapidly but incompletely absorbed from the gastrointestinal tract after oral doses; peak plasma concentrations occur within 0.5 to 1 hour. Oral bioavailability is about 50% as it undergoes extensive first-pass metabolism. Hydromorphone is about 8 to 19% bound to plasma proteins. A plasma elimination half-life of about 2.5 hours has been reported after oral or intravenous doses. Hydromorphone appears to be widely distributed in the tissues; it crosses the placenta and is distributed into breast milk. It is extensively metabolized by glucuronidation in the liver and excreted in the urine mainly as conjugated hydromorphone, dihydroisomorphine, and dihydromorphine. /Hydromorphone hydrochloride/
Hydromorphone hydrochloride is well absorbed following oral, rectal, or parenteral administration. Hydromorphone has a more rapid onset and may have a shorter duration of action than does morphine. The onset of action of hydromorphone with conventional (immediate-release) preparations is usually 15-30 minutes and analgesia is maintained for 4-5 hours, depending on the route of administration. /Hydromorphone hydrochloride/
Metabolism
The metabolism of hydromorphone is mainly hepatic and it is represented by the generation of hydromorphone-3-glucuronide through glucuronidation reactions. This primary metabolic pathway is done by the activity of the UDP-glucuronosyltransferase-2B7. The first-pass hepatic metabolism is so large that it represents 62% of the initial administered dose. On the other hand, hydromorphone is also characterized by the presence of minor metabolic pathways such as the CYP3A4- and CYP2C9-driven generation of norhydromorphone.
Metabolism is primarily via the liver, with metabolites and unchanged drug excreted in the urine.
Hydromorphone is metabolized primarily in the liver where it undergoes conjugation with glucuronic acid and is excreted principally in the urine as the glucuronide conjugate. /Hydromorphone hydrochloride/
Pain is one the most common symptoms experienced by palliative care patients. The treatment of pain involves the use of strong opioids such as hydromorphone, morphine, methadone, fentanyl, oxycodone, oxymorphone, or levorphanol for moderate to severe pain. Hydromorphone is metabolized by the liver to hydromorphone-3-glucuronide (H3G), a compound that can potentially cause neuroexcitatory phenomena with accumulation. Pharmacokinetic studies have shown that H3G levels in patients with renal insufficiency are 4 times as high as those with normal renal function; however, reports have been conflicting as to whether or not it is safe to use hydromorphone in renal insufficiency.
Morphine is one of several opioids used to treat chronic pain. Because of its high abuse potential, urine drug tests can confirm "consistency with prescribed medications." Hydromorphone is a recently described minor metabolite of morphine, but few data exist on the characteristics of this metabolic pathway or the relationship of morphine and hydromorphone between and within subjects. Part I of this retrospective study shows that formation of hydromorphone from morphine is concentration-dependent and possibly saturated at high concentrations of morphine. In addition, the percentage of ultra-rapid metabolizers and poor metabolizers can be determined using the lower asymptote of a sigmoidal mathematical fit and are estimated to be 0.63 and 4.0%, respectively. Expected limits of morphine and hydromorphone (as a result of morphine metabolism) concentrations in the urine were established. Part II of this study used the metabolic ratio (hydromorphone-morphine) to determine the inter-patient and intra-patient variability in morphine metabolism to hydromorphone. Metabolic ratio values varied over a large range; 25-fold and 7-fold, respectively. The expected limits established in this study can assist in assessing the cause for possible variances in metabolism, such as drug interactions. The wide variability between and within subjects may explain unpredictable, adverse effects.
For more Metabolism/Metabolites (Complete) data for HYDROMORPHONE (8 total), please visit the HSDB record page.
Protein binding
The protein-bound form of hydromorphone corresponds to about 8-19% of the administered dose.
External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.