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nalbuphine hydrochloride injection Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism of Action

Nalbuphine is an agonist at kappa opioid receptors and an antagonist at mµ opioid receptors.

Pharmacodynamics

Nalbuphine Hydrochloride Injection is a potent analgesic. Its analgesic potency is essentially equivalent to that of morphine on a milligram basis up to a dosage of approximately 30 mg.

The opioid antagonist activity of nalbuphine hydrochloride is one-fourth as potent as nalorphine and 10 times that of pentazocine.

Nalbuphine hydrochloride may produce the same degree of respiratory depression as equianalgesic doses of morphine. However, Nalbuphine Hydrochloride Injection exhibits a ceiling effect such that increases in dose greater than 30 mg do not produce further respiratory depression in the absence of other CNS active medications affecting respiration.

Nalbuphine hydrochloride by itself has potent opioid antagonist activity at doses equal to or lower than its analgesic dose. When administered following or concurrent with mµ agonist opioid analgesics (e.g., morphine, oxymorphone, fentanyl), nalbuphine hydrochloride may partially reverse or block opioid-induced respiratory depression from the mµ agonist analgesic. Nalbuphine Hydrochloride Injection may precipitate withdrawal in patients dependent on opioid drugs. Nalbuphine Hydrochloride Injection should be used with caution in patients who have been receiving mµ opioid analgesics on a regular basis.

Effects on the Central Nervous System

Nalbuphine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. However, there may be a ceiling effect for the respiratory depression caused by nalbuphine. Although a mixed agonist/antagonist, the respiratory depressant effects of nalbuphine can be reversed by naloxone.

Nalbuphine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Nalbuphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

During use of nalbuphine during anesthesia, a higher incidence of bradycardia has been reported in patients who did not receive atropine pre-operatively.

Opioids produce peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see ADVERSE REACTIONS]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see ADVERSE REACTIONS].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of nalbuphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see DOSAGE AND ADMINISTRATION].

Pharmacokinetics

The onset of action of Nalbuphine Hydrochloride Injection occurs within 2 to 3 minutes after intravenous administration, and in less than 15 minutes following subcutaneous or intramuscular injection. The plasma half-life of nalbuphine is 5 hours, and in clinical studies the duration of analgesic activity has been reported to range from 3 to 6 hours.

The metabolic pathway for nalbuphine has not been defined, but is likely hepatic.

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