Morphine-induced respiratory

The existence of further alternative transcripts of MOP was postulated by the observation that in knockout mice with disrupted exon 1, heroin but not morphine was still analgesically active. Based on earlier observations that the antagonist naloxazone blocked morphine-induced antinociception but not morphine-induced respiratory depression, a subdivision of the MOP in pi and p2 was proposed. However, no discrete mRNA for each of these MOP subtypes has been found. It is, however, possible that subtypes of MOPs result from heterodimerization with other opioid receptors or by interaction with other proteins. 

Morphine can cause constipation, spasms of the sphincter of Oddi, urinary retention, and pruritus (secondary to histamine release) (see Table 54-4). In head trauma patients who are not ventilated, morphine-induced respiratory depression can increase intracranial pressure and cloud the neurologic examination results. 

Gairola RL, Gupta PK, Pandley K. Antagonists of morphine-induced respiratory depression. A study in postoperative patients. Anaesthesia 1980 35(1) 17-21. 

A patient who was receiving modified-release morphine for mahgnant pain had a respiratory arrest after intrathecal bupivacaine 12.5 mg. She recovered after treatment with naloxone. Another patient who was taking modified-release morphine was given intrathecal morphine 10 mg and bupivacaine 7.5 mg. He had respiratory distress and became comatose. Morphine-induced respiratory depression was not diagnosed and the patient subsequently died. In both cases, respiratory distress and sedation was probably due to opioid action in the absence of the stimulating effect of pain on respiration, due to the intrathecal bupivacaine (198). 

Konieczko KM, Jones JG, Barrowcliffe MP, Jordan C, Altman DG. Antagonism of morphine-induced respiratory depression with nalmefene. Br J Anaesth 1988 61(3) 318-23. 

The membrane separating fetal blood from maternal blood in the intervillous space, the placental barrier, resembles other membranes, in that hpid-soluble substances diffuse readily but water-soluble substances either do not or diffuse poorly. Thus, for instance, morphine-induced respiratory depression and miosis may occur in both the mother and her newborn infant. The children of narcotic-addicted mothers will be bom with an addiction to narcotics. 

Morphine antagonists and partial agonists. The effects of opioids can be abolished by the antagonists naloxone or naltrexone (A), irrespective of the receptor type involved. Given by itself, neither has any effect in normal subjects however, in opioid-dependent subjects, both precipitate acute withdrawal signs. Because of its rapid presystemic elimination, naloxone is only suitable for parenteral use. Naltrexone is metabolically more stable and is given orally. Naloxone is effective as antidote in the treatment of opioid-induced respiratory paralysis. Since it is more rapidly eliminated than most opioids, repeated doses may be needed. Naltrexone may be used as an adjunct in withdrawal therapy. 

Nalbuphine hydrochloride is structurally related to oxymorphone and naloxone. It is approximately equipotent with morphine. Nalbuphine is metabolised in the liver to inactive metabolites. The plasma terminal half-life is approximately 5 h. The onset of analgesia is within 2-3 min of intravenous administration and 15 min after intramuscular injection, and lasts 3-6 h with an adult dose of 10 mg. With equi-analgesic doses, similar degrees of respiratory depression to that of morphine occur up to a dose of approximately 0.45 mg-kg-1. With higher doses a ceiling effect occurs. Sedation, possibly mediated by K-receptor activation, occasionally occurs. The incidence of psychotomimetic side effects is lower than with pentazocine. The abuse potential is low, but is can cause withdrawal symptoms in opioid-dependent subjects. It has occasionally been used to reverse opioid-induced respiratory depression. 

Buprenorphine is a semi-synthetic derivative of thebaine, one of the opium alkaloids. It is approximately 30 times as potent as morphine. A dose of 0.3 mg intramuscularly has a duration of analgesic action of 6-18 h. Buprenorphine is also effective sublingually. The average bio-availability by this route is about 55%, but absorption is slow and the time to achieve peak plasma concentrations is variable, with a range of 90-360 min. The onset of action is rather slow (5-15 min) after both intramuscular and intravenous administration, possibly due to slow receptor association. Buprenorphine binds to and dissociates from the p receptor very slowly, which may account for its low potential for physical abuse. It also means that buprenorphine-induced respiratory depression is difficult to reverse with naloxone, even with very high doses. Doxapram may in these circumstances be useful. Drowsiness and dizziness are the most common side effects, although they rarely... 

Side-effects Morphine induces a variety of centrally- and peripherally-mediated side-effects. The most important of which is respiratory depression following parenteral administration, especially in the postoperative situation. Chronic oral application induces constipation and chronic treatment with oral morphine must be supplemented with laxatives. Other frequent side-effects are nausea, vomiting, dizziness and sedation. 

Tolerance develops to the narcotic and analgesic actions of morphine, so that increasingly larger doses are needed to render patients pain free. Tolerance develops to many effects of morphine such as analgesia, euphoria, narcosis, respiratory depression, hypotension, and antidiuresis. Morphine-induced bradycardia may be experienced. However, no tolerance develops to morphine-induced miosis or constipation. If the administration of morphine is discontinued, the tolerance is lost and the preaddiction analgesic doses of morphine become effective once more. 

Cerebral circulation is not affected directly by therapeutic doses of morphine. However, opioid-induced respiratory depression and CO2 retention can result in cerebral vasodilation and an increase in cerebrospinal fluid pressure the pressure increase does not occur when PCO2 is maintained at normal levels by artificial ventilation. 

Quinidine sulfate 600 mg, given one hour before intravenous morphine sulfate 150 mierograms/kg, did not alter morphine-induced miosis in healthy subjects. However, the same dose of quinidine given before oral morphine sulfate 30 mg (with ondansetron as an antiemetic) increased morphine-induced miosis by 56%. This increase was considered proportionate to the increase in morphine AUC (60%) and maximum level (88%). There was no change in the elimination half-life of morphine. Similarly, in another study in healthy subjects, quinidine 800 mg, given one hour before intravenous morphine 7.5 mg did not alter the respiratory depressant nor mitotic effects of morphine, and there was no change in plasma morphine or morphine glucuronide levels. ... 

Morphine, C17H19NO3, is a complex phenolic compound whose pentacyclic structure is derived from tyrosine. It is analgesic, narcotic and a powerful respiratory depressant which was previously used iu cough elixirs. Morphine induces euphoria and dependency in some people, anxiety and nausea in others. The central nervous system effects occur through stimulation of specific receptors. Opiate receptors are widely distributed in animals they respond to both endogenous transmitters (peptides) and ingested plant alkaloids. The main receptor types are 8 emotional X. sedative x analgesic a psychotomimetic (Robinson 1986). 

In 1907 Windaus and Vogt completed the first chemical synthesis of histamine and soon after Sir Henry Dale and coworkers began investigations that showed that histamine was a powerful vasodepressant, it stimulated smooth muscle from the gut and respiratory tract and caused shock when injected into laboratory animals mimicking the systemic effects of anaphylaxis. These early results were followed by demonstration of the involvement of histamine in vascular reactions of the skin and the observation that morphine caused the so-called triple response in human skin, that is, the event sequence of an initial red spot followed by a red irregular flare and a fluid-filled wheal. Over 30 years later antihistamines were shown to reduce morphine-induced skin wheals, and histamine itself was detected in effluents of isolated perfused cat gastrocnemius muscle after arterial injection of opium alkaloids. Released histamine was also detected in cat skin, and raised levels were found in plasma after intravenous injection of morphine. 

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