Morphine respiration

Male or female Beagle or Labrador-Harrier dogs weighing 15-25 kg are used for the test. The dog is anesthetized by intravenous injection of 35M0 mg/kg pentobarbital sodium followed by subcutaneous injection of 2 mg/kg morphine. Respiration is maintained through a tracheal tube with N2O/O2 (3 1) using a positive pressure respirator. 

Morphine and its salts are very valuable analgesic drugs but are highly addictive. In addition to suppression of pain, morphine causes constipation, decreases pupillary size and depresses respiration. Only the (-l-)-stereoisoraer is biologically active. They appear to produce their effects on the brain by activating neuronal mechanisms normally activated by... 

The synthesis of dextromethorphan is an outgrowth of early efforts to synthesize the morphine skeleton. /V-Methy1morphinan(40) was synthesized in 1946 (58,59). The 3-hydroxyl and the 3-methoxy analogues were prepared by the same method. Whereas the natural alkaloids of opium are optically active, ie, only one optical isomer can be isolated, synthetic routes to the morphine skeleton provide racemic mixtures, ie, both optical isomers, which can be separated, tested, and compared pharmacologically. In the case of 3-methoxy-/V-methylmorphinan, the levorotatory isomer levorphanol [77-07-6] (levorphan) was found to possess both analgesic and antitussive activity whereas the dextrorotatory isomer, dextromethorphan (39), possessed only antitussive activity. Dextromethorphan, unlike most narcotics, does not depress ciUary activity, secretion of respiratory tract fluid, or respiration. 

Morphine. This alkaloid exerts both a depressing and a stimulating action on the central nervous system, the depression affecting the brain especially the sensation of pain and the respiration the cerebral motoi functions are less affected. The stimulant action in the cord is best seen in the cold-blooded animals, when it may develop into tonic convulsions. In higher animals, but rarely in man, there may be some indication of this stimulant action. In cats it may also involve the motor areas, and they... 

These general results have entailed much detailed chemical and pharmacological work on the influence of structural changes on particular items in the pharmacological action of morphine, e.g., its effect on respiration. ... 

Codeine (morphine methyl ether) resembles morphine in its general effect, but is less toxic and its depressant action less marked and less prolonged, whilst its stimulating action involves not only the spinal cord, but also the lower parts of the brain. In small doses in man it induces sleep, which is not so deep as that caused by morphine, and in large doses it causes restlessness and increased reflex excitability rather than sleep. The respiration is slowed less than by morphine (cf. table, p. 261). Cases of addiction for codeine can occur but according to Wolff they are rare. The best known ethers of morphine are ethylmorphine and benzyl-morphine [cf., table, p. 261), both used to replace morphine or codeine for special purposes. 

In a study of chronic morphine poisoning in dogs, wide variability was noted not only with respect to the direct effects of the alkaloid but also the effects observed when it was withdrawn after a period of months.24 The variability in the initial response of dogs to morphine is illustrated in another study25 in which one dog (No. 15) showed pupillary contraction (8 to 5 mm), a slight decrease in pulse rate (130 to 108), and a marked decrease in respiration rate (150 to 40). Another dog (No. 20) showed no contraction of the pupil (6 to 6 mm), a marked decrease in pulse rate (120 to 50), and a marked increase in respiration rate (42 to 96). Still another dog (No. 45) showed slight pupillary expansion (7 to 8 mm ), decrease in pulse rate (138 to 96), and over a 4-fold increase in respiration rate (43 to 180). 

Respiratory g and 5 ligands participate in the regulation of respiration (Su et al. 1998). Respiratory suppression is a regular feature of morphine, which suppresses all phases of respiration. Respiratory arrest is the most frequent cause of death from morphine or heroin overdose. In... 

In 1976 Martin proposed the theory that there are three subtypes of opioid receptor on the basis of behavioural studies using a chronic spinal dog model which revealed that the opioids morphine (mu) (1), ketazocine (kappa) (2) and A-allylnormetazocine (SKF 10047) (4) (sigma) had different effects on respiration, heart rate and locomotor activity [13]. Furthermore, these ligands were unable to replace each other to prevent withdrawal symptoms in dogs that had been chronically treated with one of the compounds. 

Morphine may suppress respiration in the elderly, those taking other CNS depressants, the very ill, and those patients with respiratory problems therefore, lower doses may be required. 

Respiratory depression At the usual adult dose of 10 mg/70 kg, nalbuphine causes respiratory depression approximately equal to that produced by equal doses of morphine. However, nalbuphine exhibits a ceiling effect increases in dosage beyond 30 mg produce no further respiratory depression. Respiratory depression induced by nalbuphine can be reversed by naloxone. Administer nalbuphine with caution at low doses to patients with impaired respiration (eg, from other medication, uremia, bronchial asthma, severe infection, cyanosis, or respiratory obstructions). 

Action on respiration Morphine depresses the medullary respiratory centre in medulla oblongata and by reducing the sensitivity of the medullary respiratory centre to increased plasma CO. The rise in arterial... 

Pre-anaesthetic medication These agents reduce the salivary and respiratory secretion and are administered half an hour before general anaesthesia. They also prevent laryngospasm. Atropine is given in combination with morphine as a preanaesthetic medication to antagonize the central depressant action of morphine on respiration. 

When given intravenously to a morphine-treated subject, the antagonist completely and dramatically reverses the opioid effects within 1-3 minutes. In individuals who are acutely depressed by an overdose of an opioid, the antagonist effectively normalizes respiration, level of consciousness, pupil size, bowel activity, and awareness of pain. In dependent subjects who appear normal while taking opioids, naloxone or naltrexone almost instantaneously precipitates an abstinence syndrome. 

Selected orally active compounds (Graudums et al. (Grunenthal GmbH), 1997 Sundermann et al. (Grunenthal GmbH), 2000) exhibited a wide range of p-opioid affinity (Ki 0.1 to 0.0001 pM) but affinities to the PAA and/or BTZ site were always quite constant (Ki 1 to 0.1 pM). Compounds with very pronounced p-affinities are at least 10 times more potent than morphine in vivo, have an excellent safety index and a relatively mild effect on respiration in comparison to other very strong opioids, e.g. fentanyl. 

The mechanisms underlying (he development of tolerance are not fully understood. Biochemically, it may he attractive to explain tolerance by decreased absorption, altered distribution, increased biotransfomiatiun, and/or increased excretion of the drug However, these processes have been shown to he unrelated to (he development of tolerance. Thus, cellular adaptation offers the greatest likelihood for clarifying the phenomenon. Evidence for cellular adaptation is the finding that (he respiration of chemically stimulated cortical slices of brain front normal rats is markedly deptessed by morphine, whereas the respiration of those from rats chronically dosed with morphine is unaffected... 

The effects of morphine, codeine, and heroin in the brain are dose-related. Small doses produce drowsiness, decreased anxiety and inhibition, reduced concentration, muscle relaxation, pain relief, depressed respiration, constricted pupils, nausea, and a decreased cough reflex, which is why codeine found its way into cough suppressants. At slightly higher doses, morphine and heroin can produce a state of intense elation or euphoria. 

Certain forms of dyspnea yield only to opiates. Especially in this category is the dyspnea of acute left ventricular failure and pulmonary edema. Most authorities agree that morphine is contraindicated in patients with pulmonary edema caused by chemical respiratory irritants. If needed in such cases for severe pain, its use should be combined with oxygen inhalation and positive-pressure therapy. In bronchial asthma, morphine is usually contraindicated because there is danger of addiction, the drug tends to depress respiration and to constrict bronchioles, and patients with asthma may be allergic to the drug. Deaths have occurred from the use of morphine in asthma. 

Morphine depresses respiration by decreasing the responsiveness of the respiratory center to C02... 

Morphine depresses all phases of respiration (respiratory rate, tidal volume, and minute volume) when given in subhypnotic and subanalgesic doses (Figure 47.6). In humans, a morphine overdose causes respiratory arrest and death. Therefore, morphine and other narcotic analgesics should be used with extreme caution in patients with asthma, emphysema, and cor pulmonale, and in disorders that may involve hypoxia, such as chest wound, pneumothorax, or bulbar poliomyelitis. 

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